CN106243003B - Methanesulfonylbenzamide derivative, its preparation method and the purposes pharmaceutically of cyclic hydrocarbon radical substitution - Google Patents

Abstract

The present invention relates to the methanesulfonylbenzamide derivative of cyclic hydrocarbon radical substitution, its preparation method and purposes pharmaceutically.Specifically, the invention discloses formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or prodrug, and its preparation method and application, in formula the definition of each group refer to specification.

Description

The methanesulfonylbenzamide derivative of cyclic hydrocarbon radical substitution, its preparation method with pharmaceutically Purposes

Technical field

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

Background technology

Recently, Cox of Britain etc. reports the SCN9A genes of coded voltage gate Nav1.7 passages first on Nature Mutation causes the unexpected result of study of the individual indifference to pain of heredity.The individual of the genetic mutation congenital loses the pain sensation, but body Other functions it is completely normal, in addition it has recently been demonstrated that expression DRG neurons valtage-gated Nav1.7 passages participate in The generation of pain signal simultaneously plays the incoming function gate of control pain sensation signal.Research prompting Nav1.7 passages may turn into choosing Selecting property treats pain and the drug target having no side effect.

Blockings of Nav1.7 (PN1, the SCN9A) VGSC to tetraodotoxin is sensitive, and it is mainly expressed in tip sympathetic neuron And sensory neuron.SCN9A genes are replicated by a variety of species (including the mankind, rat and rabbit), and show people and rat base Therefore the amino acid between has about 90% uniformity.

Increasing physical evidence shows Nav1.7 in a variety of pain statuses (including acute, chronic, inflammatory and/or god Through property pain) in play the part of important role, in the mankind, Nav1.7 protein accumulations particularly cause pain in neuroma Neuroma.The increased mutation (whether heredity or sporadic) of Nav1.7 functions has been considered as being related to primary erythromelalgia (a kind of disease for the cusalgia and inflammation for being characterized as four limbs), and sudden extreme pain disease.Relevant non-selective sodium channel blocks Agent lidocaine and mexiletine can relax the symptom of heredity erythromelalgia, and carbamazepine can effectively lower PEPD's The number of invasion and attack and the report result of severity are consistent with above-mentioned observation.Other cards of Nav1.7 roles in pain The phenotype for the mutation lost according to the function of being found in SCN9A genes.Follow-up research has shown the function that can cause SCN9A genes Lose many different mutation from CIP phenotypes.

Because Nav1.7 is specifically expressed without other in cardiac muscle cell and central nervous system etc. in DRG sensory neurons Tissue expression, therefore research and develop its specific blockage agent and be used to treat chronic pain, it is not only possible to curative effect is improved, and side effect also can be significantly Reduce, and the selective depressant of Nav1.7 ion channels may be used with nearly the treatment of various pain.

In addition, the Nav1.5 and Nav1.2 of one of member of the protein family are also important a kind of ionic passage, NaV1.5 mainly expresses (Raymond, C.K. etc., op.cit.) in cardiac muscle cell, including atrium, ventricle, sinoatrial 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 NaV1.5 unlatching.The exception of NaV1.5 functions can cause the formation of a variety of arrhythmia cordis.Human body NaV1.5 mutation causes more Kind of cardiac arrhythmia syndrome, including, for example, long QT3 (LQT3), Brugada syndromes (BS), heredity cardiac conduction defect, Sudden sudden death syndrome (SUNDS) and SIDS (SIDS) (Liu, H. etc., Am.J.Pharmacogenomics (2003),3(3):173-9).Sodium channel blockers treatment is widely used in treatment arrhythmia cordis.Therefore Nav1.5 is suppressed Passage can produce cardiac toxic.In addition altimeter reaches (Raymond, C.K. etc., J.Biol.Chem. to NaV1.2 in the brain (2004),279(44):It is 46234-41) and to normal cerebral function important.Therefore suppressing Nav1.2 passages can be to big Brain, which produces, suppresses toxicity.

Therefore, in view of the limited effect of currently available medicament and unacceptable side effect, there is an urgent need to develop more to pacify Complete effective antalgesic, makes it have compared with high effect and less side effect.And Nav1.7 ion channels are developed without additive town The important target of pain medicine, develop with Nav1.7 ion channels high selectivity and with the suppression of good Pharmacokinetic Characteristics Preparation is very necessary.

The content of the invention

Apply it is an object of the invention to provide a kind of Nav1.7 ion channels selective depressant and its in medicine.

First aspect present invention, there is provided 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_1-20Alkoxy, halo C_1-20Alcoxyl Base.

In another preference, R₁For fluorine；R₂For cyclopropyl.

In another preference, Z CR₇, R₇It is defined as described above.

In another preference, n 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 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 is hydrogen.

In another preference, Z 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 are hydrogen.

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

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

In another preference, Z N.

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

Second aspect of the present invention provides a kind of pharmaceutical composition, and the composition is included 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 its is pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug, or second aspect of the present invention described pharmaceutical composition are preparing treatment disease or disease Application in the medicine of disease.

In another preference, the disease or illness be selected from pain, depression, angiocardiopathy, respiratory disease, Mental illness or its combination.

In another preference, the disease or illness are selected from the pain related to HIV, the neuropathy of HIV therapy induction Change, trigeminal neuralgia, PHN, Acute Pain, thermo-responsive, sarcoidosis, IBS, sieve's g grace disease, with 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 fever, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, Bipolar Depression Disease, anxiety disorder, schizophrenia, sodium channel toxin associated conditions, familial erythromelalgia, primary erythromelalgia Disease, familial rectal pain, cancer, locally and systemically epilepsy, tonic seizures, restless leg syndrome, arrhythmia cordis, fiber flesh Bitterly, the neuroprotection under the ischemic disease state as caused by apoplexy or neurotrosis, tachyarrhythmia, auricular fibrillation And ventricular fibrillation.

In another preference, the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy Pain, trauma pain, surgical pain, postoperative pain, production pain, labor pains, toothache, chronic ache, rest pain, Pain, pain, chronic cephalalgia, antimigraine, sinus headache, tension headache, phantom limb pain, the surrounding of maincenter mediation of periphery mediation Neurotrosis, trigeminal neuralgia, PHN, Acute Pain, familial erythromelalgia, primary are erythematous Acrodynia, familial rectal pain or fibromyalgia or its combination.

Fourth aspect present invention provides a kind of method for treating mammalian diseases or illness, and methods described needs including giving The object (such as mammal) wanted applies the compound as described in the first aspect present invention of therapeutically effective amount, or it can pharmaceutically connect Salt, solvate, stereoisomer or the prodrug received, or the pharmaceutical composition described in second aspect of the present invention.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical scheme.As space is limited, exist This no longer tires out one by one states.

Brief description of the drawings

Fig. 1 is that rat cryalgesia tests baseline chart.

Fig. 2 is compound Z-2 using the additional Dunnett multiple comparative test result figures of one-way analysis of variance.

Embodiment

The present inventor is by in-depth study extensively, it has unexpectedly been found that cyclic hydrocarbon radical substitution (the particularly ring of the present invention Propyl group substitutes) methanesulfonylbenzamide derivative not only there is higher inhibitory activity to Nav1.7, while to Nav1.5 It is obvious weaker with Nav1.2 inhibitory activity, there is obvious selection inhibitory activity.Also shown in pain model test simultaneously Go out obvious analgesic effect, there is obvious medicine in pharmacokinetic for assimilation effect and good bioavilability, 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 " refers to the aliphatic hydrocarbyl of the saturation of the straight chain comprising 1 to 20 carbon atom and side chain, It is defined as below similar；More preferably C_1-10Alkyl, nonrestrictive example include：Methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyls, 1, 1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methylpents Base, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methyl oneself Base, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- Ethyl pentyl group, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- Dimethylhexanyl, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- Methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its various branched chain isomers etc.；It is more excellent Elect C as_1-6Alkyl, most preferably C_1-3Alkyl.

As used herein, " part is unsaturated " refers to the π containing one or more unsaturated bonds but without total conjugated Electronic system.

As used herein, " C_1-20Alkoxy " refers to-O- (C_1-20Alkyl), wherein alkyl is as defined above.It is preferred that C_1-10 Alkoxy, more preferably C_1-6Alkoxy, most preferably C_1-3Alkoxy.Non-limiting example includes 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 one or more (such as 1,2,3,4 or 5) hydrogen in group and substituted by halogen.

For example, " halo C_1-20Alkyl " refers to alkyl and substituted by one or more (such as 1,2,3,4 or 5) halogens, wherein alkane Base is as defined above.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- Dichloroethyls, a bromoethyl, a fluorine Ethyl, a methyl fluoride, difluoromethyl, trifluoromethyl etc..

In another example " halo C_1-20Alkoxy " refers to alkoxy and substituted by one or more (such as 1,2,3,4 or 5) halogens, Wherein alkoxy is as defined above.Preferably halo C_1-10Alkoxy, more preferably halo C_1-6Alkoxy, it is most preferably Halo C_1-3Alkoxy.Including but not limited to trifluoromethoxy, trifluoro ethoxy, a fluorine methoxyl group, a fluorine ethyoxyl, difluoro Methoxyl group, difluoroethoxy etc..

As used herein, " substituted " refers to one or more of group hydrogen atom, preferably 1~5 hydrogen atom each other Independently substituted by the substituent of respective number, more preferably 1~3 hydrogen atom is independently of one another by the substituent of respective number Substitution.Self-evident, substituent is only in their possible chemical position, and those skilled in the art can not pay excessively Possible or impossible substitution (by experiment or theoretical) is determined in the case of effort.For example, amino or hydroxyl with free hydrogen Base is probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.

Preparation method

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

Formula (I) compound of the present invention is referred to following synthetic routes and prepared, in specific operation process, Ke Yigen According to needing that the step in method is extended or merged.

Route 1

Step 1：In the presence of alkali systems, pass through the reactive group of possessed nucleophilic property in formula (I-b) compound With formula (I-a) compound substitution reaction (such as nucleophilic substitution reaction etc.) production (I-c) compound occurs for (such as OH), properly Alkali systems include being present in DMSO potassium tert-butoxide, the sodium hydride being present in DMF, the potassium carbonate etc. for being present in DMF, formula (I-a) Lev in is leaving group, including but not limited to triflate；Chlorine, bromine, iodine；Sulfonate group, such as methanesulfonic acid Ester, tosylate, brosylate, p-methyl benzenesulfonic acid ester etc.；Acyloxy, such as acetoxyl group, trifluoroacetyl epoxide.X For chlorine, bromine or iodine.

Step 2：Formula (I-c) compound at a certain temperature, uses conjunction by group X and cyclic hydrocarbon radical borate or boric acid Suitable catalyst and appropriate solvent are reacted, generation compound I.Using Suzuki methods, palladium catalyst used can be with 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 react to obtain formula (I-d) compound by Suzuki, then be sent out with formula (I-b) compound Raw substitution reaction generation compound of formula I, the reaction condition and group definition of each step are the same as 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 methods,

Method 1

Using formula (I-a-1-1) compound as initiation material, substitution, condensation, bromo, substitution, hydrolysis and acylation are passed sequentially through Reaction obtains formula (I-a-1) compound, wherein the popular response that each step is well known to the skilled person.

Method 2

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

The reaction in each step is popular response well known by persons skilled in the art above.Unless otherwise specified, synthesize Reagent and starting compound used in route are commercially available to be obtained, or those skilled in the art do not assimilate according to designed Compound structural reference known method is prepared.

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

Series compound of the present invention is high to Nav1.7 inhibitory activity, at the same to Nav1.5 and Nav1.2 inhibitory activity compared with It is weak, selection inhibitory activity is respectively provided with to Nav1.5 and Nav1.2.Series compound of the present invention is the suppression for having statistical significance The effect of cold stimulation allodynia.Series compound of the present invention not only has obvious medicine for assimilation effect and good biology profit Expenditure, and there is obvious metabolic stability.

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method 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 and number are calculated by weight.Unless separately Definition, term used herein are identical with meaning known to one skilled in the art.It is in addition, any similar to described content Or equal method and material all can be applied in the present invention.

As used herein, DMB 2,4- dimethoxy-benzyls, THF are tetrahydrofuran, 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)Cl₂For double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, TFA is trifluoroacetic acid, and TBSCl is fert-butyidimethylsilyl Chlorosilane, NCS are N- chlorosuccinimides, and DHP is dihydropyran, LiAlH₄For lithium aluminium hydride reduction, PMB is to methoxybenzyl Base, LiHMDS are two (trimethyl silicon substrate) lithium amides, Pd₂(dba)₃For three (dibenzalacetone) two palladium, RuPhos is the rings of 2- bis- Hexyl phosphorus -2', 6'- diisopropoxy -1,1'- biphenyl, DMAP are DMAP, and THP is oxinane, and n-BuLi is N-BuLi, TMsOTf are Trimethylsilyl trifluoromethanesulfonate, and TEBAC is triethyl benzyl ammonia chloride, and HATU is 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters, DMF is dimethylformamide, and DMSO is dimethyl sulfoxide (DMSO), DIEA is DIPEA, and BINAP is double diphenyl phosphine -1, the 1'- dinaphthalenes of (2R, 3S) -2,2'-.

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

Compound 1-a preparation method：

Step a:It is partly dissolved in compound 1-a-1 (41.7g, 0.271mol) in dichloromethane (500ml) solution Bromine (103.8g, 0.65mol) is added, adds iron powder (46.2g, 0.82mol) in batches under nitrogen guard mode, is heated To 40 DEG C, stir 24 hours, be cooled to room temperature, 10% insurance amidin (200ml*3) washing, liquid separation, aqueous phase EA (100ml*3) is extracted, and saturated aqueous common salt (50ml) washing, sodium sulphate is dried, and filtering, filtrate is spin-dried for obtaining a black solid (45g), add ethyl acetate and be beaten to obtain compound 1-a-2 (45g, yield：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), dichloromethane (270ml), N are added in DMAP (21g, 0.172mol) reaction bulb₂Protection, room temperature Overnight, water (100ml) is quenched, and HCl (1M) adjusts pH=1~2, DCM (3*150ml), saturated aqueous common salt (100ml) washing, sulfuric acid Sodium is dried, and filtering, filtrate is spin-dried for obtaining compound as white solid 1-a-3 (22.5g, yield 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, reaction solution is gradually clarified, will dissolving AIBN (238mg, 1.45*10^-3Mmol dichloroethane solution) is added drop-wise in above-mentioned reaction solution, reaction overnight.Room temperature is cooled to, sodium hydrosulfite is water-soluble Liquid (10%, 100ml) is quenched, liquid separation, aqueous phase ethyl acetate (3*150ml) extraction, middle ammoniacal liquor (150ml) and methanol (100ml) Mixed solution in add above-mentioned reaction solution, it is allowed to reaction solution is warmed to room temperature, stir 10 minutes, ethyl acetate (100ml*3) extraction Take, merge organic phase, saturated aqueous common salt (50ml) washing, sodium sulphate is dried, and filtering and concentrating obtains 27g crude products, and ethyl acetate is beaten Slurry obtains compound 1-a-4 (5.2g, yield：18%).ESI-MS：389.9(M+H)⁺。

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

Step e:In 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), 3~4 points of stir about Clock, then tricyclohexyl phosphine borofluoride (3.68g, 10mmol) and palladium (225mg, 1mmol) sequentially add above-mentioned reaction In liquid, 110 DEG C are heated to, is stirred overnight, be down to room temperature, reaction solution, ethyl acetate (100ml) dilution, silicon is quenched in water (50ml) Diatomaceous earth is filtered, liquid separation, and hydrochloric acid (1mol/L) is acidified to pH=2, ethyl acetate (4*50ml) extraction, and saturated aqueous common salt (20ml) is washed Wash, sodium sulphate is dried, and filtering and concentrating obtains grease, is prepared HPLC and is purified to obtain 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)。

Compound 2-a preparation method：

Step a:Under nitrogen protection, 0~5 DEG C, tetrahydrochysene is added into the reaction bulb equipped with NaH (6.4g, 0.167mol) Furans (165ml) solution；At 0~5 DEG C, isopropanol (12.8ml, 0.167mol) is added dropwise into above-mentioned turbid solution, time for adding is about 1 hour, after finishing, reaction solution allowed to be warming up to room temperature, stirs 1 hour.The four of compound 2-a-1 (15.57g, 0.105mol) Hydrogen furans (50ml) solution is added in above-mentioned turbid solution, is heated to 60 DEG C, is stirred overnight, at 30 DEG C, saturated ammonium chloride (50ml) It is quenched with water (60ml), liquid separation, ethyl acetate (3x50ml) extraction, saturated aqueous common salt (20ml) washing, sodium sulphate is dried, concentration Obtain black liquor compound 2-a-2 (20.0g, yield 71%)；ESI-MS:172.0(M+H)⁺。

Step b:Sodium acetate is added into compound 2-a-2 (6g, 0.035mol) ethyl acetate (30ml) solution (3.2g, 0.039mol), under stirring, less than 7 DEG C, bromine (10.6g, 0.042mol) is added dropwise into above-mentioned turbid solution, Allow a liter room temperature, be stirred overnight.Below 5 DEG C, by sodium hydroxide (4.6g) and the aqueous solution (20ml) of sodium thiosulfate (2g) (pH is less than 8 during dropwise addition) is added dropwise in reaction solution, and liquid separation, aqueous phase is extracted with ethyl acetate (2x40ml), merges organic phase, saturation Saline solution (30ml) is washed, and sodium sulphate is dried, and filtering, is concentrated to give grease, column chromatography (silica gel：300-400 mesh, eluant, eluent：Stone Oily ether) purifying obtain compound 2-a-3 (5.1g, yield：58%), it is 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, reaction solution nitrogen displacement 3 times, is heated to 65 DEG C, is stirred overnight, ethyl acetate dilution (400ml), washing (6x30ml), saturated aqueous common salt (50ml) washing, sodium sulphate dry, filtering, 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, water (19ml), acetic acid are added into compound 2-a-4 (6.0g, 0.02mol) reaction bulb (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 Spun off with oil pump, residue is diluted with ethyl acetate (250ml), and water (2x30ml) is washed, saturated aqueous common salt (20ml) washing, mistake Filter, sodium sulphate are dried, and are concentrated to give a dark oil thing, column chromatography (silica gel：200-300 mesh；Eluant, eluent-petroleum ether：Ethyl acetate =15：1) purifying obtains compound 2-a (5.1g, yield：58%), it is a liquid.ESI-MS:188.0(M+H)⁺。

Compound 3-a preparation method：

Compound 4-a preparation method：

Step a:Compound 4-a-1 (23.4g, 0.148mol) is added into the cold concentrated sulfuric acid (120ml), treats that substrate is molten Xie Hou, less than 5 DEG C are maintained the temperature at, N- N-iodosuccinimides (33g, 0.148mol) are added portionwise, the temperature is maintained after finishing Degree, stir 5 hours.Reaction solution is poured into the frozen water (20ml) being stirred vigorously, and filtering, filter cake uses ethanol：Water (1：1) it is beaten, Filtering, obtains compound 4-a-2 (8.0g, yield：20%), it is a pink solid.ESI-MS:285.0(M+H)⁺。

Step b:Di-tert-butyl dicarbonate (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, 60 DEG C are heated to, It is stirred overnight.Ethyl acetate dilutes (300ml), and watery hydrochloric acid is washed (1M, 30ml), saturated sodium bicarbonate aqueous solution (30ml), saturation Saline solution (20ml) is washed, and sodium sulphate is dried, and filtering, is concentrated to give to obtain compound 4-a-3 (8.0g, yield：93%), it 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 Sour potassium (5.0g, 3.64x10^-2Mol dimethyl sulfoxide (30ml) is added in), is stirred overnight at room temperature under nitrogen protection, ethyl acetate is dilute Release (300ml), water (3x30ml) washing, saturated aqueous common salt (20ml) washing, sodium sulphate is dried, and filtering and concentrating obtains compound 4- A-4 (8.91g, yield：89.8%), it 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 displacement three times, are heated to 150 DEG C, microwave reaction 45 minutes.LCMS shows part accessory substance as in product Chlorine also substituted by ring third class.Ethyl acetate is diluted, and diatomite filtering, is concentrated to give 1.7g yellow oils, and Pre-HPLC is purified, It is concentrated to give compound 4-a-5 (0.06g, yield：50%), it 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, stirred 24 hours under condition of nitrogen gas.Concentration of reaction solution obtains white solid, molten It is purified to obtain compound 4-a (0.32g, yield in ethyl acetate：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).

Compound 5-a preparation method：

For compound 5-a using compound 4-a-1 as initiation material, prepared by reference compound 4-a method, unlike Change compound 2-a in step c into compound 3-a.

The 4- of embodiment 1 ((3- chloro- 4- (trifluoromethyl) phenoxy group) methyl) fluoro- N- (sulfonyloxy methyls of -5- cyclopropyl -2- Base) benzamide (Z-1) preparation

Step 1：To compound 1-a (150mg, 0.522mmol) and the 5ml dichloros of triethylamine (106mg, 1.044mmol) Methylsufonyl chloride (60mg, 0.522mmol) is added in zero degrees celsius in dichloromethane, is stirred at room temperature 2 hours.Reaction terminates, instead Liquid is answered to pour into frozen water, dichloromethane extraction, organic phase is washed with saturated common salt, anhydrous sodium sulfate drying, filtering, filtrate decompression It is concentrated to give pale yellowish oil crude Compound 1-b (147mg).It is directly used in and reacts in next step.

Step 2：Compound 1-b (117mg, 0.32mmol), 3- chloro- 4- (trifluoromethyl) phenol (68mg, 0.32mmol), Potassium carbonate (89mg, 0.64mmol) is added in 5ml acetonitrile solutions, and 60 degrees Celsius are stirred 2 hours.Reaction terminates, and is cooled to room temperature, Reaction solution is concentrated under reduced pressure, and adds 10ml water, and regulation pH is 7, dichloromethane extraction (2 × 10ml), organic phase saturated aqueous common salt Wash, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated to give crude product.White solid chemical combination is obtained after purification through preparing liquid phase separation Thing Z-1 (60.3mg), yield：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 prepared using compound 1-a as initiation material with reference to the method for embodiment 1, different It is to change 3- chloro- 4- (trifluoromethyl) phenol in step 2 into 3,4- chlorophenesic acids, 3,5- chlorophenesic acids respectively.

The 4- of embodiment 4 (the chloro- 6- isopropyl pyridines -3- bases epoxides of 5-) -5- cyclopropyl -2- fluoro- N- (methyl sulphonyl) benzene The preparation of formamide (Z-4)

Compound 4-a (100mg, 0.273mmol), compound 6-a (52mg, 0.546mmol), HATU (2- (7- azobenzenes And triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester) (104mg, 0.273mmol), DIPEA (N, N- diisopropyl second Amine) (71mg, 0.546mmol), DMAP (DMAP) (4mg, 0.027mmol) add 5ml dichloromethane solutions in, It is stirred at room temperature 3 hours.Reaction terminates, reaction solution washing, saturated common salt washing, anhydrous sodium sulfate drying, filtering, and filtrate decompression is dense Contract to obtain crude product.Yellow solid compound Z-4 (21mg), MS m/z (ESI) are obtained after purification through TLC:443.1[M+H]⁺。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 prepared using compound 6-a as initiation material with reference to the method for embodiment 4, the difference is that will step Compound 4-a in rapid changes compound 5-a into.

5- cyclohexenyl groups-the 4- of embodiment 6 ((3,4- dichlorophenoxies) ethyl) -2- fluoro- N- (methyl sulphonyl) benzoyl The preparation of amine (Z-7)

With the synthetic method that compound 6-b (471mg) is the step 2 of raw material reference implementation example 6, unlike by 4- in step (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester changes 2- rings into The ring of hexyl -4,4,5,5- tetramethyl -1,3,2- dioxies boron penta.Obtain yellow compound z-7 (36.8mg), yield 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)。

The 4- of embodiment 7 ((the chloro- 6- isopropyl pyridines -3- bases epoxides of 5-) methyl) -5- cyclopropyl -2- fluoro- N- (methyl sulphurs Acyl group) benzamide (Z-8) preparation

Step 1：Added into compound 2-a (86mg, 0.46mmol) 8ml acetonitrile solutions 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, filtering, filter cake Hydrochloric acid (3N, 5ml), ethyl acetate extraction are added, organic phase is concentrated under reduced pressure to obtain yellow solid compound 8-b (130mg).MS m/z (ESI):495.0[M+H]⁺.It is directly used in and reacts in next step.

Step 2：Into compound 8-b (117mg, 0.32mmol) toluene and water add cyclopropylboronic acid (68mg, 0.32mmol), tricyclohexyl phosphine (89mg, 0.64mmol), potassium carbonate (89mg, 0.64mmol), palladium (89mg, 0.64mmol), argon gas is protected, and 100 DEG C are stirred 1 hour.Reaction terminates, and is cooled to room temperature, ethyl acetate extraction, organic phase is used full Wash, anhydrous sodium sulfate drying, filter with sodium acid carbonate, filtrate decompression is concentrated to give crude product.Through prepare liquid phase separation after purification in vain Color solid chemical compound Z-8 (18mg), yield：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).

The 4- of embodiment 8 ((3- chloro- 4- (trifluoromethyl) phenoxy group) methyl) fluoro- N- (sulfonyloxy methyls of -5- cyclopropyl -2- Base) benzamide (Z-9) preparation

Step 1：Compound 3-chlorin -4- (trifluoromethyl) phenol (200mg, 1.017mmol), compound 1-a-4 (395mg, 1.017mmol), potassium carbonate (218mg, 2.035mmol) is added in 10ml acetonitrile solutions, and 80 degrees Celsius are stirred overnight.Reaction knot Beam, room temperature is cooled to, be poured into water, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, filtering, filtrate concentration Obtain yellow solid compound 9-b (0.647g).MS m/z(ESI):503.9[M-H]^-.It is directly used in and reacts in next step.

Step 2：Compound 9-b (300mg, 0.594mmol), cyclopropylboronic acid (103mg, 1.189mmol), Pd (dppf) Cl₂(44mg, 0.059mmol), cesium carbonate (388mg, 1.189mmol) are added in 10ml dioxane solutions, argon gas protection, and 80 DEG C it is stirred overnight.Reaction terminates, and is cooled to room temperature, diatomite filtering, filtrate decompression concentrates, pure through Combi-flash column chromatographies Change obtains crude product, adds proper amount of methanol ultrasound to wash, filters to obtain compound as white solid z-9 (37mg).Yield：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 using compound 1-a-4 as initiation material, with reference to the method system of embodiment 9 It is standby, the difference is that changing 3- chloro- 4- (trifluoromethyl) phenol in step 1 into 4- chlorophenols, the chloro- 4- fluorophenols of 3-, 2- respectively Chloro- 4- (trifluoromethyl) phenol.

The 4- of embodiment 12 ((the chloro- 4- cumenes epoxides of 3-) methyl) -5- cyclopropyl -2- fluoro- N- (methyl sulphonyl) benzene The preparation of formamide (Z-13)

Step 1：To hydroquinones (2g, 0.018mol) and the 20ml of compound 2- iodopropanes (3.072g, 0.018mol) The 10ml aqueous solution of potassium hydroxide (1.070g, 0.019mol) is added in alcohol reflux solution, return stirring is overnight.Reaction knot Beam, room temperature is cooled to, be concentrated under reduced pressure, add 2N hydrochloric acid, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, mistake Filter, filtrate are concentrated to give crude product, purify to obtain yellow oily compound 13-b (1.031g) through Combi-flash column chromatographies.Purity： 89.84%, yield：37%, it is directly used in and reacts in next step.

Step 2：Chloroacetic chloride is added dropwise into compound 13-b (330mg, 2.168mmol) 5ml chloroform solns (189mg, 2.602mmol), it is stirred at room temperature 6 hours.Reaction terminates, and appropriate sodium bicarbonate solution is added dropwise, and separates organic phase, Anhydrous sodium sulfate drying, filtering, filtrate are concentrated to give yellow oily crude Compound 13-c (400mg).Yield：95%, directly use Reacted in next step.

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

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

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

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 gas protection, 90 DEG C are stirred overnight.Reaction terminates, and is cooled to room temperature, diatomite filtering, filtrate Be concentrated under reduced pressure to obtain crude product, purifies to obtain crude product through Combi-flash column chromatographies, then through prepare liquid phase separation after purification it is white solid Body compound Z-13 (33.54mg), yield：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).

Compound Z-0 preparation

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) are 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) is washed.Anhydrous sodium sulfate drying, filter.Filtrate is spin-dried for Rotary Evaporators, residue column chromatography (PE:EA=3:1) Light yellow solid Z-0-2 (15.2g, yield are obtained after purification: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：In N₂Under protection, Z-0-2 (8.0g, 0.04mol) is dissolved in anhydrous THF (80ml), mixture is cold But -78 DEG C are arrived, LiHMDS (1M, 48ml, 0.048mol) THF solution is added dropwise.After being added dropwise to complete, mixture is at -78 DEG C, stirring 0.5h.Reaction solution is slowly ramped to room temperature, 1h is stirred, -78 DEG C is then cooled to, by 5- chloro- 2,4- difluoro chlorides THF (50ml) solution of (11.11g, 0.048mol) is added drop-wise to above-mentioned reaction solution.Mixture rises to room at -78 DEG C after stirring 1h Temperature, and 16h is stirred at room temperature.Added into reaction solution in saturated aqueous ammonium chloride (250ml), with ethyl acetate (3x 100ml) extract, merge organic phase, washed with saturated aqueous common salt (200ml), dry, 40 DEG C are spin-dried for.Crude product crosses post (100-200 mesh Silica gel), leacheate is petroleum ether：Ethyl acetate=(4:1) Z-0-3 (5.11g, yield, are obtained：31.8%) it 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), 0 is cooled in ice bath DEG C stirring, lithium aluminium hydride (8.4g, 220mmol) is added portionwise.Mixture adds water quenching to go out reaction, adds hydrochloric acid after 0 DEG C is stirred 2h (6N) adjusts PH=3, separates aqueous phase, organic phase anhydrous sodium sulfate drying, filters.Filtrate is spin-dried for Rotary Evaporators, is obtained 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), then adds chlorine Change sulfoxide (50mL).Mixture under nitrogen protection, is heated to return stirring 3h.Mixture is down to room temperature, adds water (200mL) to quench Go out reaction, separate organic phase, aqueous phase is extracted (200x 2mL) with dichloromethane.Merge organic phase brine It, anhydrous sulphur Sour sodium is dried, and is filtered.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 Cymag (29g, 606mmol).Mixture under nitrogen protection, is heated to 80 DEG C of stirring 3h.Reactant mixture is cooled to room temperature, adds moisture to dissipate, and 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, adds water quenching to go out instead Should, ethyl acetate extraction (400x 2mL), merge organic phase washing (200x 2mL), anhydrous sodium sulfate drying, filter.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：Compound Z-0-8 (10.5g, 50.2mmol) is dissolved in ethanol (150mL), 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 Yellow solid (15g) is evaporated to obtain, 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), it is cold in ice bath But to 0 DEG C, TFAA (30.5g, 145.2mmol), triethylamine (14.7g, 145.2mmol) are added.Mixture is in nitrogen Under protection, stirring 4h is warmed to room temperature.Reactant mixture adds sodium carbonate and reaction is quenched to neutrality, separates aqueous phase, organic phase is used full With brine It (100x 2mL), anhydrous sodium sulfate drying, filter.Evaporated under reduced pressure obtains brown solid Z-0-10 and (12.0g, received 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 0 DEG C is cooled to, adds Boron tribromide (36.7g, 146.6mmol).Mixture under nitrogen protection, is warmed to room temperature stirring 4h.Instead Answer mixture to be slowly added into frozen water (100mL), separate aqueous phase, organic phase saturated common salt water washing (100x 2mL), anhydrous sulphur Sour sodium is dried, and is filtered.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：Compound Z-0-11 (25.0g, 69mmol) is dissolved in methanol (100mL), 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 Residue (100mL) is added to, 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, are obtained:38%).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) it is 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 phase and (100mL x 2), saturated common salt water washing is washed with water (100x 2mL), anhydrous sodium sulfate drying, filter.Evaporated under reduced pressure obtains red solid Z-0-13 (15.1g, yield:>100%). ESI-MS(M+H)+:600.1, purity=28% (UV254)

Step 12：Compound Z-0-13 (12.0g, 20mmol) is dissolved in dichloromethane (40mL), adds trifluoro second Sour (20mL).Mixture under nitrogen protection, stirs 24h at room temperature.It is yellow solid that evaporated under reduced pressure, which obtains crude product, through HPLC systems It is standby to obtain white solid 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 determines

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

Diaphragm voltage clamp electrophysiology can be with direct measurement and the current blocking of fixed rate voltage gated sodium channel (various Nav) And time and the voltage dependence of blocking can be determined, it has been interpreted the knot of the tranquillization to sodium channel, opening and inactivated state Difference is closed to reflect the suppression of compound or activation effect (Hille, B., Journal of General Physiology (1977),69:497-515)。

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

Manual patch clamp experiments scheme is as follows：

(1) preparation of solution and compound：HNav1.7 and hNav1.5 electric currents are recorded using whole-cell patch-clamp recording technique. In experiment, the constituent (mM) of extracellular fluid：HEPES：5,NaCl：40,KCl：3,CaCl₂：1,MgCl₂：1,CdCl₂：0.1, TEA-Cl：20.PH value is adjusted to 7.3 with NaOH, while is depressed into 310-320mOsm with sucrose regulation infiltration, 4 DEG C of guarantors after filtering Deposit.The constituent (mM) of intracellular fluid：HEPES：10,NaCl：10,CsOH：5,CsF：140,EGTA：1.PH is adjusted with CsOH Value is depressed into 280-290mOsm to 7.3, while with sucrose regulation infiltration, -20 DEG C of preservations after filtering.

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).Above-mentioned stock solution is serially diluted with DMSO before experiment, then used again Further dilution obtains the test solution of required concentration to extracellular fluid.DMSO ultimate densities are no more than 0.30% in extracellular fluid.

(2) manual patch clamp experiments：Take cell suspension to be added in 35mm culture dish, be placed in inverted microscope objective table On.After cell attachment, with extracellular fluid perfusion, flow velocity is 1-2mL/min.Glass microelectrode draws the step of instrument two by microelectrode and drawn System, it is 2-5M Ω that it, which enters water power resistance,.Pass through Digidata 1440 (Molecular Devices) and pCLAMP softwares (10.2 Version, Molecular Devices) A/D-D/A digital-to-analogue conversions, carry out stimulating granting and signal acquisition；Patch clamp amplifier (Multiclamp 700B, Molecular Devices) amplified signal, is filtered into 4KHz.

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

One kind is inactivation stimulation programs, and command potential is arranged on the V of corresponding passage_1/2, i.e., about 50% passage is in Inactivated state.Then voltage is given to -120mV, continues 50ms.Then depolarising extremely -10mV, continue 20ms and draw sodium current, Eventually pass back to command potential.This stimulation programs can also be referred to as the voltage stimulation programs of channel status dependence.

Another kind is non-inactivation stimulation programs, keeps command potential in -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 passages all do not have Inactivated state is lived through, but directly enters line activating from quiescent condition.

The time interval of above two voltage stimulation programs is 10s.Before and after the depression effect of compound is by dosing Curent change is calculated, and IC₅₀Numerical value is fitted gained by Hill equations.If compound is different in above two Voltage shows the difference for having certain multiple to channelling effect under stimulating, then the compound is with State-dependence to the passage Property.

Data analysis

Electric current and blank control current standard (compound peaks tail currents/right after each drug concentration is acted on According to thing peak tail currents), then calculate (1- (the compound peaks tail currents/tester of inhibiting rate corresponding to each drug concentration Peak tail currents)).Average and standard error are calculated each concentration, and every kind of compound is calculated with following equation 503nhibiting concentration：

Inhibiting rate=1/ (1+ (IC₅₀/c)^h)

Nonlinear fitting is carried out to dose-dependent effect with above equation, wherein c represents drug concentration, IC₅₀For half suppression Concentration processed, h represent hill coefficient.Curve matching and IC₅₀Calculating utilize IGOR softwares complete.As a result 1 and table are shown in Table respectively 2。

1 representative compound of the present invention of table is under two kinds of concentration to Nav1.7 inhibiting rate

IC of 2 representative compound of the present invention of table 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 informations：People's voltage-gated sodium channel hypotype 1.2 is stably expressed by recombinant HEK 293 cell system (hNaV1.2) .cDNA follows strictly GenBank sequence numbers:NM_001040142.1.

The HEK293 cell lines of stable expression Nav1.2 passages are containing 10% hyclone and 1.2mg/ml G418 Cultivated in DMEM culture mediums, cultivation temperature is 37 DEG C, gas concentration lwevel 5%.

Passage：Remove old culture medium and washed once with PBS, then add 1ml TrypLE^TMExpress solution, 37 DEG C be incubated 1 minute.When cell departs from from ware bottom, the complete mediums of 37 DEG C of 5ml preheating are added.Cell suspension suction pipe is light Featheriness, which is beaten, separates the cell of aggregation.Cell suspension is transferred in sterile centrifuge tube, 1000rmp is centrifuged 5 minutes and collected carefully Born of the same parents.Amplification maintains culture, cell is inoculated in into 10 cm cell culture dishes, each Tissue Culture Dish, inoculating cell amount is 3.5*10⁵(final volume：10ml).

To maintain the electrophysiologic activity of cell, cell density must be no more than 80%.

Patch-clamp detects, cell TrypLE before experiment^TMExpress is separated, and 3*103 cells are taped against on cover glass, (final volume is cultivated in 24 orifice plates：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 manipulated in inverted microscope (IX71, Olympus) lower-pilot microelectrode (MP285, Sutter Instruments) touches recording electrode on cell, gives negative-pressure ward, forms G Ω sealing-ins.Shape Flying capacitance compensation is carried out after into G Ω sealing-ins, then proceedes to give negative pressure, inhales broken cell film, form whole-cell recording technique pattern.So The compensation of electric capacity at a slow speed is carried out afterwards and records membrane capacitance and series resistance, and gives series resistance compensation, does not give electric leakage compensation. The start recording after electric current of whole-cell recording technique is stable.Experimental data is acquired and is stored in by EPC-10 amplifiers (HEKA) In PatchMaster (HEKA) software.

Start to be administered after the electric current of whole-cell recording technique is stable, each drug concentration acts on that (or electric current was to steady to 5 minutes It is fixed), each test compound detection 1000nM concentration values.By the cover glass for being covered with cell be placed in be inverted it is micro- in record bathe In groove, test compound and the outer liquid without compound are flowed through successively using the method for gravity perfusion from low concentration to high concentration Cell is recorded so as to act on cell, fluid exchange is carried out using vavuum pump in record.Each cell is without compound Outer liquid in the electric current that detects as the control group of oneself.It is independent to repeat to detect 3 cells.All electro physiology experiments are in room temperature Lower progress.

Liquid used in sodium-ion channel record：

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

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

The stimulation protocol of sodium-ion channel:

The film potential of cell is maintained into -90mV first, then with 5mv step interval, by cell membrane potential step to - 120mV to 100mV.

Inhibiting rate result is calculated as shown in table a by above-mentioned formula.

Nav1.7 and Nav1.2 inhibiting rate compares under table a concentration of the same race

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

Can be seen that representative compound of the present invention from table 1, table 2 and table a has higher inhibitory activity to Nav1.7, It is obvious to Nav1.5 and Nav1.2 inhibitory activity weaker, therefore representative compound of the present invention is not only to Nav1.5 but also right Nav1.2 is respectively provided with selectivity.

The cold stimulation allodynia method of test case 2

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

Detection compound and packet：

Solvent control thing (Vehicle)：5% dimethyl acetamide (traditional Chinese medicines science and technology), the hydroxy stearate of 5% polyethylene glycol -15 Acid esters (solutol) (Sigma) and 90% physiological 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 acetamide, and the hydroxyl of 5% polyethylene glycol -15 is hard Resin acid ester and 90% physiological saline.

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

The compound of table 3 efficacy testing in spinal nerve ligated rats is grouped

Experimental method：

1.1. Spinal Nerve Ligation Model

Surgical procedure performs sterile working.

Operating theater instruments (scissors, tweezers, scalpel, cotton of performing the operation, suture, dilator) has sterilized before surgery.

Use that (50mg/kg, intraperitoneal injection) anesthetized animal of amobarbital.Animal toe is extruded to confirm animal surgery Preceding holonarcosis.Ophthalmic ointment is smeared in animal eye to prevent animal corneal from drying.

Animal lower part of the body operative region hair is shaved off, using Iodophor and 70% ethanol to operation area skin sterilization three Time.Start to perform the operation after dry skin.

A longitudinal cut is opened at animal waist sacrum rear portion using scalpel, exposure left side paraspinal muscle, uses dilator Separating muscle tissue is to expose vertebrae.

Separation left side spinal nerve L5 and L6, are ligatured using 6-0 silk threads.

Sew up a wound.

Sterile surgery apparatus, sterilized using hot pearl sterilizer.

Animal is placed on electric blanket by Post operation, and 5mL physiological saline is subcutaneously injected to prevent anti-avulsion water.It is complete Deng animal (can be freely movable) puts back to animal in cage after revival.

1.2. the super quick baseline test of cryalgesia and packet

Administration a few days ago, the super quick baseline of cryalgesia is carried out to rat and is tested, 100 μ l acetone are coated in into animal using pipettor Art side back foot part skin.Record animal was patted in one minute, contracting pin, foot-up, licked the time for licking art parapodum portion.Acetone test is altogether Carry out twice, two minor ticks 10 minutes.Time sum is recorded as the rat cryalgesia hypersensitivity time twice.It is previous according to being administered Animal is grouped by it cryalgesia hypersensitivity test result at random.

1.3. the super quick test of cryalgesia

After administration two hours, 100 μ l acetone are coated in toe section skin behind animal art side using pipettor.Record animal exists Patted in one minute, contracting pin, foot-up, lick the time for licking impacted foot.Acetone test is carried out twice altogether, and two minor ticks 10 divide Clock.Time sum is recorded as the rat cryalgesia hypersensitivity time twice.

1.4. administration

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

The administration of table 4 record and the weight of animals

The super quick test result of the rat cryalgesia of table 5

1.5. data collection and analysis

Data are collected using Excel softwares.Use Prism software analysis datas.

Experimental result is as depicted in figs. 1 and 2, the results showed that example compound Z-2 of the present invention is in spinal nerve ligated rats mould Have in type and suppress cold stimulation allodynia effect, be statistically significant suppression effect in rat nerves within the body pain model Fruit.

In Fig. 2, compared with solvent control thing, Dunnett multiple comparative tests, * * * p are added using one-way analysis of variance <0.001, oral administration of compound Z-2 and compound Z-0 (100mg/kg and 75mg/kg) suppress Rat Spinal Nerve Tissue respectively after two hours The cryalgesia for ligaturing induction is super quick.

Test case 3：Rat in vivo studies

Determining rat using LC/MS/MS methods, gavage and intravenous give after embodiment compound blood plasma at different moments respectively In drug concentration, pharmacokinetics behavior of the research the compounds of this invention in rat body, evaluate its characteristics of pharmacokinetics.

Experimental program：

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

Administering mode and dosage：Give SD rats dorsalis pedis vein administration (1mg/kg, 1mL/kg, 5%DMAC (dimethyl second Acid amides), 5%Solutol HS 15 (hydroxy stearic acid ester of polyethylene glycol -15) and 90% salt solution and gastric infusion (2mg/kg, 2mL/kg, the 0.5%CMC-Na aqueous solution)

Blood specimen collection：Meet being selected before administration the animal of requirement of experiment first, mark of weighing.Before gathering blood sample, binding Rat, the rat of each administration is in predetermined blood sampling time point (intravenously administrable：Before administration, after administration 0.083, 0.25th, 0.5,1,2,4,8,24h blood samplings, totally 9 time points；Gastric infusion：Before administration, after administration 0.083, 0.25th, 0.5,1,2,4,8,24h blood samplings, 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, which is transferred to, is previously added K₂EDTA's In 1.5mL test tubes.The blood sample adopted be placed on it is wet on ice, centrifugation 5min (2000g, 4 DEG C), take out blood plasma, whole process taking a blood sample Completed afterwards in 15min.All samples are required for depositing in -70 DEG C of refrigerators until sample analysis.

Drug concentration is determined using LC/MS/MS methods, section Example compound of the present invention is in same dose and administering mode Under, the pharmacokinetic property parameter in rat body is as shown in table 6：

The compound of table 6 is in Pharmacokinetics in Rat parameter

As can be seen from Table 6, the medicine of example compound of the present invention is for good absorbing, has obvious medicine for assimilation effect, together When show good bioavilability.

Test case 4：Metabolic stability is tested

1. the preparation of buffer solution

Buffer A：Prepare 1L and contain 1mM EDTA (Sigma, V900157-100G), 100mM potassium dihydrogen phosphate.

Buffer B：Prepare 1L and contain 1mM EDTA, 100mM dipotassium hydrogen phosphate solution.

Buffer solution C：700mL buffer Bs are taken, are titrated with buffer A, are adjusted to PH as 7.4.

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

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

2.2 take 20uL (20mg/mL) hepatomicrosome (Corning Lot.452161) and rat liver microsomes (Corning Lot.452501) storing liquid is added separately to 513.4uL buffer solution C, is operated on ice wet.Preparation obtains 0.75mg/mL livers Particulate liquid solution.

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

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

2.5 weigh 5mg reduced Coenzyme IIs (Roche, 10621706001), are dissolved in 1mL buffer solutions C.It is configured to 6mM Reduced Coenzyme II solution.Reduced Coenzyme II solution is dispensed into reaction plate.

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

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

Reaction plate is put into 37 degree of constant temperature water box and preheats 5min by 2.8.In reaction plate, add 15uL reduced forms auxiliary per hole The solution of enzyme II starts reaction and timing.5,15,30,45,60min time points, 135uL is added per hole and contains interior target ice acetonitrile Terminating reaction.

2.9 reaction plate is sealed with aluminium film, it is placed on shaking mixer, 500rpm, 5min.Reaction plate is placed on centrifugation again Centrifuged in machine, 15min, 3750rpm.

2.10 take sample and pure water according to 1:1 dilution proportion, LC/MS detections.By obtained numerical value according to below equation meter Calculation obtains half-life period as shown in table 7 and clearance rate.

Half-life period：0.693/K (slope that brooding time maps out with log concentration value)

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

Wherein K values and scale factor are those skilled in the art according to existing method and hepatomicrosome description of product secretary What the method for load was calculated.

The rat of table 7 and people's hepatomicrosome metabolic stability experimental result

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

All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (4)

1. the compound shown in a kind of formula (I), or its pharmaceutically acceptable salt：

In formula,

R₁For fluorine；R₂For cyclopropyl；N is 1；Z is CR₇；

R₃、R₄、R₅、R₇It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, trifluoro Methoxyl group, trifluoro ethoxy, trifluoromethyl, R₆For hydrogen；

And R₃、R₄、R₅、R₇In two be hydrogen.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that the compound is selected from The following group：

3. a kind of pharmaceutical composition, the composition includes compound described in claim 1 or 2 or its is pharmaceutically acceptable Salt；And pharmaceutically acceptable carrier.

4. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, or medicine group as claimed in claim 3 Application of the compound in the medicine for the treatment of disease or illness is prepared, the disease or illness are selected from pain, depression, cardiovascular disease Disease, respiratory disease, mental illness or its combination.