CN106279071A - Phenylpiperazine derivatives and using method thereof and purposes - Google Patents

Phenylpiperazine derivatives and using method thereof and purposes Download PDF

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Publication number
CN106279071A
CN106279071A CN201610652904.1A CN201610652904A CN106279071A CN 106279071 A CN106279071 A CN 106279071A CN 201610652904 A CN201610652904 A CN 201610652904A CN 106279071 A CN106279071 A CN 106279071A
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compound
piperazine
phenyl
sulfenyl
title compound
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CN106279071B (en
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金传飞
易超
张英俊
薛亚萍
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to Phenylpiperazine derivatives and using method thereof and purposes, specifically disclose a class for suppressing Phenylpiperazine derivatives and the pharmaceutical composition thereof of 5 hydroxytryptamine reuptake.The method that the invention still further relates to prepare this compounds and pharmaceutical composition, and they purposes in pivot nervous system dysfunction, particularly affective disorder in the treatment.

Description

Phenylpiperazine derivatives and using method thereof and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, be particularly used for treating central nervous system dysfunction, particularly feelings The sense compound of obstacle and compositions, and using method and purposes.Especially, of the present invention is can be as 5-hydroxyl color The Phenylpiperazine derivatives of amine reuptake inhibitor.
Background technology
5-hydroxy tryptamine (5-HT, serotonin), a kind of neurotransmitter transmitting signal in brain and nervous system, In central nervous system (CNS) dysfunction, especially anxiety, depression, invade and get excited in emotion, play important angle Color.Serotonin Transporter (5-HT transporter, 5-HTT/serotonin transporter, SERT) is a kind of right 5-HT has the transmembrane transporter of high affinity, and it is reuptaked serotonin from nerve synapse gap and enters presynaptic god Through unit, directly affect the concentration of synaptic space serotonin.
In history, the Drug therapy of affective disorder starts from the 1950's, including tricyclic antidepressant (TCAs) and Oxidase inhibitor (MAOIs), these medicines are mainly by neurotransmitter (dopamine, norepinephrine and 5-hydroxyl color Amine) blocking effect play curative effect.But, the non-selective and less desirable side effect to target limits making of they With.To the eighties in 20th century, selective serotonin reuptake inhibitor (selective serotonin reuptake Inhibitors, SSRIs) appearance, change this situation.Compared with TCAs, this kind of curative effect of medication is suitable, but side effect Little, though excessive use, the least (Sarko J.Andidepressant, the old and new.A review of toxicity of generation of their adverse effects and toxicity in overdose.Emerg Med Clin North Am, 2000；18(4):637-54).Selective serotonin reuptake inhibitor mainly produces inhibitory action to 5-HT transporter, Effectively central nervous system's presynaptic membrane can be suppressed to absorb 5-HT from synaptic space by being combined with 5-HT transporter, increase Gap is available for the 5-HT of actual utilization, thus reaches the purpose for the treatment of.
In all indications relevant to 5-hydroxy tryptamine dysfunction, depression is most important, because defending according to the world Raw Organization, depression has become the mankind's the fourth-largest burden disease.Expecting the year two thousand twenty, the disability of depression adjusts the life-span Annual meeting leaps to the second of all diseases.(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMC Med.2011,9:90)。
But, the clinical research about depression shows that the phenomenon not responding to known SSRIs is the most prominent, another Would generally occur postponing through the therapeutical effect that commonly overlooked factor is SSRIs in anti depressant therapy, symptom is in treatment sometimes Former weeks in also can deteriorate.Additionally, sexual dysfunction is common side effect for SSRIs.It is therefore desirable to exploitation energy Enough compounds improving treatment depression and other 5-hydroxy tryptamine relevant diseases.
The invention provides a class and there is the noval chemical compound of serotonin reuptake transporter inhibitory activity, possess the most clinical answering Use prospect.Compared with existing similar compound, the compound of the present invention has more preferable drug effect, medicine for character and/or toxicity Learn characteristic.
Summary of the invention
Hereinafter some aspects of the present invention are only summarized, it is not limited to this.These aspects and other parts are later There is more complete explanation.All lists of references in this specification are incorporated in this by entirety.Work as the disclosure of the specification With quote document variant time, be as the criterion with the disclosure of the specification.
The present invention relates to (2-(heteroaryl epoxide) phenyl) bridged piperazine derivatives that a class is novel, itself and 5-HT transporter (SERT) there is stronger binding affinity, 5-HT reuptake can be suppressed, such that it is able to be used for preparing treatment central nervous system (CNS) handicapped medicine, especially for the medicine of preparation treatment affective disorder, described affective disorder includes but does not limit In, depression, anxiety neurosis, social phobia, obsession, panic attack, specific phobias, agoraphobia, mania, hinder in terror Hinder and posttraumatic stress disorder.
The compounds of this invention stable in properties, safety is good, has pharmacodynamics and pharmacokinetic advantage, the best Brain/blood plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability etc., therefore possess relatively Good potential applicability in clinical practice.
The present invention also provides for preparing the method for this compounds and the pharmaceutical composition containing this compounds.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Q is-O-or-S-；
M is-O-,-S-,-CH2-or-NH-；
R and t is each independently 0 or 1；
N is 0,1,2,3,4 or 5；With
Each R1And R2There is implication of the present invention.
In one embodiment, each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxyl), C1- C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the substituted C of hydroxyl1-C6Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxyl), C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkyl halide Base, C1-C6Alkoxyl or C1-C6Halogenated alkoxy.
In one embodiment, each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxyl), C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1- C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the substituted C of hydroxyl1-C4Alkane Base.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl or C1-C4Halogenated alkoxy.
In one embodiment, each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、- CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2、 Methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-pro-pyl epoxide or isopropyl epoxide.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-pro-pyl, isopropyl ,-CF3Or-CH2CF3。
In one embodiment, compound of the present invention, it is to have the compound of one of following structure or have One of the following stereoisomer of compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises chemical combination disclosed by the invention Thing.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprise further pharmaceutically acceptable excipient, Carrier, adjuvant or their combination in any.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprise treatment central nervous system's merit further Can the medicine of obstacle, the medicine of described treatment central nervous system dysfunction be antidepressant drug, anxiolytic drugs, as feelings The sense salts medicine of stabilizer, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, conduct select The property medicine of serotonin reuptake inhibitor, central nervous stimulant, nicotinic antagonists or their combination in any.
In another embodiment, the present invention treats the medicine of central nervous system dysfunction is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), amfebutamone (bupropion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), Sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), midalcipran (milnacipran), left-handed midalcipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), Clomipramine (clomipramine), citalopram (citalopram), escitalopram (escitalopram), paroxetine (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), olanzapine (olanzapine), Quetiapine (quetiapine), risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl (perospirone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), card Ergota woods (cabergoline), diamantane (obsolete) (adamantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinidine (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), dimension for smooth (vestipitant), Chlordiazepoxide (chlordiazepoxide), perphenazine (perphenazine) or their combination in any.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for preventing, treating or alleviate central nervous system dysfunction.Such as, in one embodiment, described medicine is used for Preventing, treat or alleviate mammalian central nervous system dysfunction, in another embodiment, described medicine is for pre- Prevent, treat or alleviate the central nervous system dysfunction of people.
In one embodiment, described central nervous system dysfunction refers to depression, anxiety neurosis, social phobia Disease, obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, spirit point Split disease, sleep disorder, bipolar disorders, obsessive idea and behavior disorder, the dyskinesia, sexual dysfunction, musculoskeletal pain barrier Hinder, cognitive disorder, dysmnesia, parkinson, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal Symptom and premenstrualtension syndrome.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for preventing, treating or alleviate affective disorder.
In one embodiment, described affective disorder includes, but are not limited to, depression, anxiety neurosis, social phobia, Obsession, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for suppressing serotonin reuptake transporter.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), separation and the method for purification.
Biological results shows, the compounds of this invention has strong affinity to people source 5-HT transporter (SERT), because of The compound that this present invention provides can be as preferable selective serotonin reuptake inhibitor.
Additionally, some compounds of the present invention have serotonin reuptake transporter inhibition and norepinephrine reuptake suppression The synergy of property, other compounds of the present invention have serotonin reuptake transporter inhibition and dopamine reuptake inhibition Synergy, the other compound of the present invention has the suppression of 5-hydroxy tryptamine, norepinephrine and dopamine triple reuptake and makees With.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and Content in terms of him will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the of the present invention or method of equivalent and material can be used in Put into practice the present invention.The present invention is not limited to method of the present invention and material.At the document combined, patent and similar material One or more different from the application or conflicting in the case of (include but not limited to defined term, term application, institute The technology described, etc.), it is as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, it should apply following definition used in the present invention.For purposes of the present invention, chemical element With periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can Reference " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry Description in March, John Wiley&Sons, New York:2007, entire contents is incorporated by reference into the present invention.
Context except as otherwise noted or has significantly conflict, article used in the present invention " ", " (kind) " and " described " be intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have many Use in the component of is taken into account in the embodiment of described embodiment or use.
Term " stereoisomer " refers to have identical chemical constitution, but atom or group spatially arrangement mode is different Compound.Stereoisomer includes that enantiomer, diastereomer, conformer (rotamer), geometry are different Structure body (cis/trans) isomer, atropisomer, etc..
What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to so some compounds, raw material, compositions and/or dosage form, and they are rationally doctor Learn in the range of judging, it is adaptable to patient tissue contacts and without excessive toxicity, zest, allergy or with reasonably profit Other problems that benefit/Hazard ratio is symmetrical and complication, and it is effective to given application.
Term " optionally " or " optionally " refer to the event described subsequently or situation can but not necessarily occur, and this is retouched State and include situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to This key can exist or can not exist, and this description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or the compounds comprised as example special inside embodiment, subclass and the present invention.
Term " optionally by .... replaced ", can with term " unsubstituted or quilt ... .. is replaced " exchange use, i.e. Described structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group bag of the present invention Include, but be not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxyl, alkylthio group, alkylamino, cycloalkyl, heterocyclic radical, Aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
Term " unsaturated " or " undersaturated " represent that part is containing one or more degrees of unsaturation.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C1-C6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1-20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 Individual carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but does not limit In, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen Base ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t- BuO, t-butoxy ,-OC (CH3)3), etc..
Term " haloalkyl " represents that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Implication as described in the present invention, such example comprises, but is not limited to ,-CF3、-CH2CF3、-CHFCH3、-CH2CH2F、 CF2CH3Deng.In one embodiment, C1-C6Haloalkyl comprises the substituted C of fluorine1-C6Alkyl；In another embodiment, C1- C4Haloalkyl comprises the substituted C of fluorine1-C4Alkyl；In yet another embodiment, C1-C4Haloalkyl comprises the substituted C of fluorine1-C2 Alkyl.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for block or protect the functional of hydroxyl, suitable blocking group to include trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxy Ylmethyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro second Base, etc..Document refers to for the description that blocking group is general: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug Discuss and be referred to documents below: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.14, A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document is incorporated herein by this.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2-naphthalene sulfonate, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, special penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By suitable alkali The salt obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any comprised N's The quaternary ammonium salt that the compound of group is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is suitable, nontoxic that pharmaceutically acceptable salt farther includes Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention Molecule can combine with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule Can combine with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention divides Son can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with non- The biological effectiveness of the described compound of hydrated form.
Term " therapeutically effective amount " refers to when delivering medicine to main body to treat disease, and the component of compound is enough to this disease Sick treatment onset." therapeutically effective amount " can be along with compound, disease and the order of severity, and has the bar of main body to be treated Part, the age, body weight, sex etc. and change.
The Phenylpiperazine derivatives that the present invention relates to, its pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof thing, permissible As selective serotonin reuptake inhibitor, to controlling of mankind's central nervous system dysfunction, particularly affective disorder Treating has potential purposes, described affective disorder to include, but are not limited to, depression, anxiety neurosis, social phobia, obsession, frightened Probably outbreak, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
Unless otherwise mentioned, all suitable isotope changes of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicates, then this structure All stereoisomers all consider within the present invention, and be included in the invention as present invention compound of coming into the open.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or time dotted line indicates, then the stereoisomerism of this structure Body clearly and defines with regard to this.
Within the nitrogen oxides of the compounds of this invention is also contained in the scope of the present invention.Can be by often using at an elevated temperature With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, aoxidize corresponding nitrogen-containing basic material, or pass through With acid reaction excessively in applicable solvent, such as, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or Chloroform or dichloromethane react with 3-chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or compositions must be with other compositions comprising preparation and/or use it The mammal for the treatment of is chemically and/or compatible in toxicology.In another embodiment, described salt is not necessarily and pharmaceutically may be used The salt accepted, could be for compound shown in preparation and/or purification formula (I) and/or is used for separating compound shown in this formula (I) The intermediate of enantiomer.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or its single stereoisomer, isomery The raceme of body or non-racemic mixture or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient further, and optionally Ground, other treatment and/or prevention composition.
Suitably carrier, adjuvant and excipient agent be well known to those skilled in the art and be described in detail in such as Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；GennaroA.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, in Chicago.
It will also be appreciated that some compound of the present invention can exist in a free form for treating, if or suitably Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivant Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Compound of the present invention or its metabolite or any other adduct of residue or derivant are provided indirectly.
The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing Split-phase is held, and can be substantially reduced the present invention and come into the open the interaction of effect of compound and causing not during to avoid being administered patient It it is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent, Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and alternative function is provided, this depend on preparation exists which there is in how many these excipient and preparation other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and be used for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to prepare the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Come into the open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof, and this technique includes that mixing is each Plant composition.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as ambient temperature and atmospheric pressure and make Standby.
Compound disclosed by the invention is usually formulated as being adapted to pass through the dosage form that patient is administered by required approach.Example As, dosage form includes that those are suitable for the dosage form of following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, powder, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspensoid and redissolution powder；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) topical, such as ointment, ointment, lotion, molten Liquor, paste, spray, foam and gel.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention is permissible It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. The most in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
The present invention provide pharmaceutical composition can with compressed tablet, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, methyl fibre Prepared by dimension element, starch or calcium alginate.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible Agent, elixir and syrup.
Time suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or dimension Hold the compositions of release, such as by by microparticle material coating or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention provides can also carry with the form of liposome, micelle, microsphere or nanometer system Supply.
The pharmaceutical composition that the present invention provides can provide with non-effervescent or the granule of effervescent and powder, to reconstruct Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent granule or powder and excipient can include dilution Agent, sweeting agent and wetting agent.The pharmaceutically acceptable carrier and the excipient that use in effervescent granule or powder can wrap Include organic acid and carbon dioxide source.
Coloring agent and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.
The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutical effect Preparation, or with supplement the material co-formulation of intended effect.
The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the present invention use parenteral include intravenous, intra-arterial, intraperitoneal, sheath in, in ventricle, in urethra, breast In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid Bodily form formula.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees Remington:The Science and Practice of Pharmacy, ibid).
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspensoid or liquid composite.
The pharmaceutical composition being suitable for transdermal administration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of topical can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.
The compounds of this invention and the purposes of compositions
Compound and pharmaceutical composition that the present invention provides can be used for preparing for preventing, treat or alleviating mammal, Medicine including the central nervous system dysfunction of the mankind, it is also possible to for preparation for suppressing the medicine of serotonin reuptake transporter Product.
Specifically, in the compositions of the present invention, the amount of compound can the most optionally suppress 5-hydroxyl The reuptake of tryptamines, the compound of the present invention can be as treatment mankind central nervous system (CNS) dysfunction, particularly feelings The medicine of sense obstacle, described affective disorder includes, but are not limited to, depression, anxiety neurosis, social phobia, obsession, terrified Outbreak, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compound of the present invention can apply to, but is not limited to, and uses the compound of the present invention or the effective of compositions Patient is administered by amount prevents, treats or alleviates central nervous system dysfunction disease.Described in response to 5-hydroxy tryptamine The central nervous system dysfunction of regulation and control, farther includes but is not limited to, and depression, anxiety neurosis, social phobia, forces Disease, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, sleep Dormancy obstacle, bipolar disorders, obsessive idea and behavior disorder, the dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognition Obstacle, dysmnesia, parkinson, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom and Premenstrualtension syndrome etc..
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), mark as reference with TMS (0ppm) or chloroform (7.26ppm) Accurate.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-M (pillar model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% in flowing The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in, uses electron spray ionisation (ESI), under 210nm/254nm, Detect with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detect at 210nm/254nm UV.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
CH2Cl2, DCM dichloromethane
CDCl3Deuterochloroform
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylenediaminetetraacetic acid
EtOAc, EA ethyl acetate
MeOH methanol
G gram
H hour
ML, ml milliliter
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
BSA bovine serum albumin
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound, unless otherwise indicated, the most each R1、R2 With n, there is definition of the present invention.
Synthetic schemes 1
Synthetic method 1
Compound 3 can be prepared by following process: under [Pd] catalyst, suitable alkali and heating condition, changes Compound 1 reacts with optionally substituted phenylmercaptan. and obtains intermediate 2.Intermediate 2 slough Boc protection after, then with 3-oxetanone At room temperature react with sodium cyanoborohydride and obtain target compound 3.
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment
The synthesis of embodiment 1:1-(2-((4-chlorphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
Step 1) synthesis of 4-(2-((4-chlorphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
Successively by 4-(2-bromophenyl) piperazine-1-t-butyl formate (0.34g, 1.0mmol), to chlorothio-phenol (0.17g, 1.2mmol), double (2-diphenylphosphine) phenylates (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and anhydrous DMSO (10mL) join in 50mL reaction bulb, lower addition three (dibenzalacetone) two palladium (23mg, 0.025mmol) of nitrogen protection. Reaction is warming up to 100 DEG C and reacts 24 hours.Reaction terminate after, be cooled to room temperature, reactant liquor add water (40mL) dilution, ethyl acetate (20mLx 3) extracts, and collects organic facies, and anhydrous sodium sulfate is dried, and decompression is distilled off solvent, and gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=20/1) obtains title compound (white solid, 0.26g, 65.0%).
MS(ESI,pos.ion)m/z:405.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36～7.29 (m, 4H), 7.21～7.19 (m, 1H), 7.12 (d, J =7.9Hz, 1H), 6.95 (m, 1H), 6.88 (d, J=7.9Hz, 1H), 3.17 (s, 4H), 2.53 (s, 4H), 1.38 (s, 9H).
Step 2) synthesis of 1-(2-((4-chlorphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
By 4-(2-((4-chlorphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.24g, 0.6mmol) and dichloromethane Alkane (2mL) is added sequentially in 25mL reaction bulb, is subsequently added trifluoroacetic acid (1mL), room temperature reaction 2 hours.After reaction terminates, Decompression is distilled off solvent and obtains grease.Gained grease is dissolved in absolute methanol (5mL), is sequentially added into 3-oxa-subsequently Cyclobutanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol), after interpolation, room temperature reaction 20 hours. Adding saturated aqueous ammonium chloride (40mL) washing, ethyl acetate (20mL x 3) extracts, collected organic layer, and anhydrous sodium sulfate is done Dry, decompression is distilled off solvent, and gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) Obtain title compound (white solid, 0.15g, 71.0%).
MS(ESI,pos.ion)m/z:361.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.34～7.26 (m, 4H), 7.19～7.16 (m, 1H), 7.10 (d, J =7.9Hz, 1H), 6.96 (m, 1H), 6.89 (d, J=7.8Hz, 1H), 4.67 (m, 4H), 3.55～3.51 (m, 1H), 3.10 (s,4H),2.46(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):150.4,134.3,133.9,133.0,132.8,129.6,129.5, 127.3,124.6,120.4,75.6,59.4,51.4,50.0.
The synthesis of embodiment 2:1-(2-((2,4 dichloro benzene base) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
Step 1) synthesis of 4-(2-((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.34g, 1.0mmol), 2,4 dichloro benzene thiophenol (0.22g, 1.2mmol), double (2-diphenylphosphine) benzene Ether (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=20/1) and obtain title compound (white solid, 0.04g, 10.0%).
MS(ESI,pos.ion)m/z:439.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.46 (d, J=2.1Hz, 1H), 7.27～7.25 (m, 1H), 7.10～ 7.08 (m, 2H), 7.07 (d, J=8.3Hz, 1H), 7.01～6.96 (m, 2H), 3.11 (s, 4H), 2.38 (s, 4H), 1.35 (s, 9H).
Step 2) synthesis of 1-(2-((2,4 dichloro benzene base) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((2,4-bis- Chlorphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.26g, 0.6mmol) and trifluoroacetic acid (1mL) be at dichloromethane (2mL) room temperature reaction in, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction in methanol (5mL).Gained slightly produces Thing carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.18g, 75.0%).
MS(ESI,pos.ion)m/z:395.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45 (d, J=2.1Hz, 1H), 7.27～7.24 (m, 1H), 7.12～ 7.09 (m, 2H), 7.07 (d, J=8.4Hz, 1H), 7.01～6.96 (m, 2H), 4.67 (t, J=6.6Hz, 2H), 4.63 (t, J =6.2Hz, 2H), 3.54～3.51 (m, 1H), 3.10 (s, 4H), 2.39 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):151.6,136.3,133.4,133.2,131.5,129.7,128.6, 127.6,124.6,120.8,75.6,59.3,51.3,50.0.
The synthesis of embodiment 3:1-(oxetanylmethoxy-3-base)-4-(2-(p-methylphenyl sulfenyl) phenyl) piperazine
Step 1) synthesis of 4-(2-(p-methylphenyl sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.40g, 1.18mmol), to methylbenzene phenyl-sulfhydrate (0.175g, 1.41mmol), double (2-diphenylphosphines) Phenylate (0.54g, 0.1mmol), sodium tert-butoxide (0.283g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (light yellow liquid, 0.30g, 66.2%).
MS(ESI,pos.ion)m/z:385.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (d, J=8.1Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 7.10～7.09 (m, 1H), 7.05 (dd, J=7.9,1.5Hz, 1H), 6.92～6.86 (m, 1H), 6.74 (dd, J=7.9, 1.1Hz,1H),3.11(s,4H),2.50(s,4H),2.37(s,3H),1.38(s,9H).
Step 2) synthesis of 1-(oxetanes-3-base)-4-(2-(p-methylphenyl sulfenyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. (2-is (to methylbenzene for 4- Base sulfenyl) phenyl) piperazine-1-t-butyl formate (0.20g, 0.52mmol) and trifluoroacetic acid (4mL) be in dichloromethane (8mL) Room temperature reaction, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.06g, 0.78mmol) With sodium cyanoborohydride (0.065g, 1.04mmol) room temperature reaction preparation in 20 hours in methanol (6mL).Gained crude product is carried out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.15g, 84.7%).
MS(ESI,pos.ion)m/z:341.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (d, J=8.0Hz, 2H), 7.19 (d, J=8.0Hz, 2H), 7.12～7.09 (m, 1H), 7.07 (dd, J=7.9,1.5Hz, 1H), 6.92～6.88 (m, 1H), 6.74 (dd, J=7.9, 1.1Hz, 1H), 4.68 (dt, J=14.8,6.4Hz, 4H), 3.58～3.54 (m, 1H), 3.12 (s, 4H), 2.52 (s, 4H), 2.37(s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.2,138.4,135.0,134.5,130.3,129.3,127.6, 126.0,124.5,119.9,75.6,59.3,51.2,50.0,21.3.
The synthesis of embodiment 4:1-(2-((4-methoxyphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
Step 1) synthesis of 4-(2-((4-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.50g, 1.47mmol), to methoxybenzenethiol (0.303g, 2.20mmol), double (2-diphenyl Phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 140 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (light yellow liquid, 0.45g, 76.6%).
MS(ESI,pos.ion)m/z:401.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43～7.41 (m, 2H), 7.05 (dd, J=5.1,1.4Hz, 2H), 6.94～6.92 (m, 2H), 6.90～6.88 (m, 1H), 6.61 (d, J=7.8Hz, 1H), 3.81 (s, 3H), 3.14 (s, 4H), 2.54(s,4H),1.38(s,9H).
Step 2) synthesis of 1-(2-((4-methoxyphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((4-methoxy Base phenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.45g, 1.12mmol) and trifluoroacetic acid (4mL) be at dichloromethane (8mL) room temperature reaction in, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.121g, 1.68mmol) within 20 hours, prepare with sodium cyanoborohydride (0.14g, 2.24mmol) room temperature reaction in methanol (6mL).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.32g, 80.2%).
MS(ESI,pos.ion)m/z:357.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.46～7.41 (m, 2H), 7.07 (dd, J=5.1,1.4Hz, 2H), 6.95～6.91 (m, 2H), 6.91～6.85 (m, 1H), 6.63 (d, J=7.7Hz, 1H), 4.72～4.64 (m, 4H), 3.83 (s, 3H), 3.61～3.57 (m, 1H), 3.12 (s, 4H), 2.54 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.2,148.6,136.9,136.2,126.4,125.6,124.5, 122.7,119.9,115.2,75.6,59.3,55.4,51.2,50.0.
The synthesis of embodiment 5:1-(oxetanylmethoxy-3-base)-4-(2-(an aminomethyl phenyl sulfenyl) phenyl) piperazine
Step 1) synthesis of 4-(2-(an aminomethyl phenyl sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.80g, 2.35mmol), 3-methylbenzene phenyl-sulfhydrate (0.379g, 3.06mmol), double (2-diphenylphosphines) Phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.562g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (light yellow liquid, 0.42g, 46.4%).
MS(ESI,pos.ion)m/z:385.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.26 (s, 1H), 7.23 (dd, J=4.5,2.5Hz, 2H), 7.15～ 7.11 (m, 2H), 7.06 (dd, J=7.9,1.2Hz, 1H), 6.93～6.91 (m, 1H), 6.82 (dd, J=7.9,1.4Hz, 1H),3.12(s,4H),2.50(s,4H),2.33(s,3H),1.38(s,9H).
Step 2) synthesis of 1-(oxetanes-3-base)-4-(2-(an aminomethyl phenyl sulfenyl) phenyl) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. a 4-(2-(methylbenzene Base sulfenyl) phenyl) piperazine-1-t-butyl formate (0.40g, 1.04mmol) and trifluoroacetic acid (4mL) be in dichloromethane (8mL) Room temperature reaction, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.112g, 1.56mmol) within 20 hours, prepare with sodium cyanoborohydride (0.13g, 1.20mmol) room temperature reaction in methanol (6mL).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.21g, 59.3%).
MS(ESI,pos.ion)m/z:341.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.28 (s, 1H), 7.24 (dd, J=4.6,2.6Hz, 2H), 7.16～ 7.11 (m, 2H), 7.08 (dd, J=7.9,1.2Hz, 1H), 6.94～6.90 (m, 1H), 6.84 (dd, J=7.9,1.4Hz, 1H), 4.70～4.65 (m, 4H), 3.59～3.55 (m, 1H), 3.12 (s, 4H), 2.49 (s, 4H), 2.33 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.7,139.2,134.3,134.1,133.2,130.7,129.2, 128.8,128.6,126.5,124.4,120.0,75.5,59.3,51.2,49.9,21.3.
The synthesis of embodiment 6:1-(2-((3-methoxyphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
Step 1) synthesis of 4-(2-((3-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.50g, 1.47mmol), 3-methoxybenzenethiol (0.308g, 2.20mmol), double (2-diphenyl Phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (light yellow liquid, 0.41g, 64.6%).
MS(ESI,pos.ion)m/z:401.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.25～7.23 (m, 1H), 7.16～7.13 (m, 1H), 7.06 (dd, J =7.9,1.3Hz, 1H), 7.02～6.99 (m, 1H), 6.96 (dd, J=2.4,1.7Hz, 1H), 6.95～6.91 (m, 2H), 6.86～6.85 (m, 1H), 3.75 (s, 3H), 3.12 (s, 4H), 2.48 (s, 4H), 1.37 (s, 9H).
Step 2) synthesis of 1-(2-((3-methoxyphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((3-methoxy Base phenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.41g, 1.02mmol) and trifluoroacetic acid (4mL) be at dichloromethane (8mL) room temperature reaction in, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.11g, 1.53mmol) within 20 hours, prepare with sodium cyanoborohydride (0.128g, 2.04mmol) room temperature reaction in methanol (6mL).Gained Crude product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.30g, 82.6%).
MS(ESI,pos.ion)m/z:357.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.27～7.23 (m, 1H), 7.16～7.14 (m, 1H), 7.08 (dd, J =8.0,1.2Hz, 1H), 7.02～7.00 (m, 1H), 6.97 (dd, J=2.4,1.7Hz, 1H), 6.95～6.90 (m, 2H), 6.86～6.84 (m, 1H), 4.69～4.64 (m, 4H), 3.76 (s, 3H), 3.58～3.53 (m, 1H), 3.11 (s, 4H), 2.48 (s,4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.2,148.6,136.9,136.2,126.4,125.6,124.5, 122.7,119.9,115.2,75.6,59.3,55.4,51.2,50.0.
The synthesis of embodiment 7:1-(2-((4-fluorophenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
Step 1) synthesis of 4-(2-((4-fluorophenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.50g, 1.47mmol), to fluoro thiophenol (0.283g, 2.20mmol), double (2-diphenylphosphine) benzene Ether (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (light yellow liquid, 0.43g, 75.3%).
MS(ESI,pos.ion)m/z:389.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44～7.40 (m, 2H), 7.15～7.12 (m, 1H), 7.08 (d, J =1.4Hz, 1H), 7.08～7.05 (m, 2H), 6.94～6.90 (m, 1H), 6.72 (dd, J=7.9,1.3Hz, 1H), 3.11 (s,4H),2.51(s,4H),1.38(s,9H).
Step 2) synthesis of 1-(2-((4-fluorophenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((4-fluorobenzene Base) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.33g, 0.85mmol) and trifluoroacetic acid (4mL) be at dichloromethane (8mL) Middle room temperature reaction, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.092g, 1.28mmol) within 20 hours, prepare with sodium cyanoborohydride (0.107g, 1.70mmol) room temperature reaction in methanol (6mL).Gained Crude product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound (white solid, 0.157g, 53.8%).
MS(ESI,pos.ion)m/z:345.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45～7.40 (m, 2H), 7.15～7.11 (m, 1H), 7.09 (d, J =1.4Hz, 1H), 7.08～7.05 (m, 2H), 6.94～6.89 (m, 1H), 6.74 (dd, J=7.9,1.3Hz, 1H), 4.70～ 4.66 (m, 4H), 3.60～3.55 (m, 1H), 3.11 (s, 4H), 2.50 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):163.7,162.0,149.4,136.1,134.4,127.9,126.5, 124.6,120.2,116.7,116.5,75.5,59.3,51.2,49.9.
The conjunction of embodiment 8:1-(2-((2,4-3,5-dimethylphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine Become
Step 1) synthesis of 4-(2-((2,4-3,5-dimethylphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromophenyl) piperazine Piperazine-1-t-butyl formate (0.34g, 1.00mmol), 2,4-thiophenol dimethyl benzene (0.17g, 1.20mmol), double (2-diphenyl Phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (light yellow liquid, 0.28g, 70.0%).
MS(ESI,pos.ion)m/z:399.50[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (d, J=7.8Hz, 1H), 7.16 (s, 1H), 7.08～7.04 (m, 2H), 7.03 (d, J=7.6Hz, 1H), 6.89～6.85 (m, 1H), 6.54 (d, J=7.6Hz, 1H), 3.16～3.13 (m, 4H), 2.55～2.53 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H), 1.36 (s, 9H).
Step 2) synthesis of 1-(2-((2,4-3,5-dimethylphenyl) sulfenyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((2,4-bis- Aminomethyl phenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.24g, 0.60mmol) and trifluoroacetic acid (4mL) be at dichloromethane (8mL) room temperature reaction in, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.20mmol) room temperature reaction in methanol (6mL).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.16g, 75.2%).
MS(ESI,pos.ion)m/z:355.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 7.08～7.02 (m, 2H), 7.01 (d, J=7.6Hz, 1H), 6.88～6.85 (m, 1H), 6.51 (d, J=7.6Hz, 1H), 4.71～4.68 (m, 4H), 3.63～3.59 (m, 1H), 3.14～3.11 (m, 4H), 2.56～2.51 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):149.1,142.5,139.4,136.3,134.7,131.8,128.0, 126.3,125.6,124.6,120.0,75.7,59.4,51.3,50.2,21.3,20.7.
Embodiment 9:1-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-aminomethyl phenyl)-4-(oxetanylmethoxy-3-base) piperazine The synthesis of piperazine
Step 1) synthesis of 4-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-methyl Phenyl) piperazine-1-t-butyl formate (0.60g, 1.69mmol), 2,4-thiophenol dimethyl benzene (0.303g, 2.20mmol), double (2-diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.406g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) be 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product is carried out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (light yellow solid, 0.45g, 64.6%).
MS(ESI,pos.ion)m/z:413.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.34 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 7.02 (d, J= 7.7Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 6.89 (dd, J=8.0,1.3Hz, 1H), 6.38 (d, J=1.4Hz, 1H), 3.60(s,4H),2.98(s,4H),2.37(s,3H),2.33(s,3H),2.13(s,3H),1.50(s,9H).
Step 2) 1-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-aminomethyl phenyl)-4-(oxetanylmethoxy-3-base) piperazine Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((2,4-fluorine Phenyl) sulfenyl)-4-aminomethyl phenyl) piperazine-1-t-butyl formate (0.40g, 0.97mmol) and trifluoroacetic acid (4mL) be at dichloro Room temperature reaction in methane (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.14g, 1.45mmol) and sodium cyanoborohydride (0.122g, 1.94mmol) be 20 hours systems of room temperature reaction in methanol (6mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) and obtains title compound (white Solid, 0.152g, 42.6%).
MS(ESI,pos.ion)m/z:369.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.35 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.02 (d, J= 7.7Hz, 1H), 6.99 (d, J=8.0Hz, 1H), 6.89 (dd, J=8.0,1.4Hz, 1H), 6.34 (d, J=1.4Hz, 1H), 4.74～4.63 (m, 4H), 3.61～3.57 (m, 1H), 3.10 (s, 4H), 2.53 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H),2.12(s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):146.8,142.1,139.0,135.8,134.2,131.6,128.2, 127.8,126.9,126.3,119.8,75.6,59.3,51.4,50.1,21.2,21.0,20.6.
The synthesis of embodiment 10:4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(phenylsulfartyl) cyanophenyl
Step 1) synthesis of 4-(4-cyano group-2-(phenylsulfartyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), phenylmercaptan. (0.13g, 1.20mmol), double (2-diphenylphosphines) Phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) and obtain title compound (white solid, 0.29g, 72.6%).
MS(ESI,pos.ion)m/z:396.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44～7.42 (m, 5H), 7.37 (dd, J=8.4,1.8Hz, 1H), 7.07 (d, J=8.3Hz, 1H), 6.98 (d, J=1.7Hz, 1H), 3.19 (s, 4H), 2.50 (s, 4H), 1.38 (s, 9H).
Step 2) synthesis of 4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(phenylsulfartyl) cyanophenyl
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- (phenylsulfartyl) phenyl) piperazine-1-t-butyl formate (0.24g, 0.6mmol) and trifluoroacetic acid (1mL) be at dichloromethane (2mL) Middle room temperature reaction, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction in methanol (5mL).Gained slightly produces Thing carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.18g, 84.1%).
MS(ESI,pos.ion)m/z:352.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.44～7.40 (m, 5H), 7.38 (dd, J=8.3,1.8Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 6.99 (d, J=1.7Hz, 1H), 4.68 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.57～3.55 (m, 1H), 3.18 (s, 4H), 2.50 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):153.2,135.5,134.3,131.5,131.2,130.4,130.0, 129.3,120.0,119.0,107.2,75.5,59.3,50.7,49.6.
Embodiment 11:3-((4-methoxyphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Synthesis
Step 1) synthesis of 4-(4-cyano group-2-((4-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), to methoxybenzenethiol (0.17g, 1.20mmol), double (2-bis- Phenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) obtains title compound (white solid, 0.22g, 52.0%).
MS(ESI,pos.ion)m/z:426.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43～7.41 (m, 2H), 7.33～7.31 (m, 1H), 7.02～ 6.99 (m, 1H), 6.97～6.96 (m, 2H), 6.80 (s, 1H), 3.87 (s, 3H), 3.18 (s, 4H), 2.57 (s, 4H), 1.38 (s,9H).
Step 2) conjunction of 3-((4-methoxyphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Become
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((4-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.26g, 0.60mmol) and trifluoroacetic acid (4mL) be two Room temperature reaction in chloromethanes (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) be 20 hours systems of room temperature reaction in methanol (6mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) and obtains title compound (in vain Color solid, 0.32g, 80.2%).
MS(ESI,pos.ion)m/z:382.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42～7.41 (m, 2H), 7.34～7.32 (m, 1H), 7.03～ 7.01 (m, 1H), 6.97～6.95 (m, 2H), 6.81 (s, 1H), 4.70 (t, J=6.4Hz, 2H), 4.66 (t, J=6.1Hz, 2H), 3.87 (s, 3H), 3.60～3.57 (m, 1H), 3.17 (s, 4H), 2.55 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):161.1,152.3,137.9,137.5,129.6,120.5,119.8, 119.3,116.0,107.4,75.6,59.4,55.6,50.9,49.8.
Embodiment 12:3-((3-methoxyphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Synthesis
Step 1) synthesis of 4-(4-cyano group-2-((3-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), 3-methoxybenzenethiol (0.17g, 1.20mmol), double (2-bis- Phenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) obtains title compound (white solid, 0.20g, 48.0%).
MS(ESI,pos.ion)m/z:426.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38～7.36 (m, 1H), 7.32～7.29 (m, 1H), 7.04～ 7.01 (m, 3H), 6.97～6.94 (m, 2H), 3.82 (s, 3H), 3.17 (s, 4H), 2.51 (s, 4H), 1.38 (s, 9H).
Step 2) conjunction of 3-((3-methoxyphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Become
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((3-methoxyphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.26g, 0.60mmol) and trifluoroacetic acid (4mL) be two Room temperature reaction in chloromethanes (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) be 20 hours systems of room temperature reaction in methanol (6mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) and obtains title compound (in vain Color solid, 0.13g, 57.0%).
MS(ESI,pos.ion)m/z:382.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37～7.35 (m, 1H), 7.32～7.30 (m, 1H), 7.04～ 7.01 (m, 3H), 6.97～6.95 (m, 2H), 4.69 (t, J=6.5Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.80 (s, 3H), 3.58～3.55 (m, 1H), 3.18 (s, 4H), 2.51 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.7,153.3,135.5,132.3,131.7,130.9,130.5, 126.50,120.0,119.6,119.1,115.1,107.3,75.6,59.3,55.6,50.9,49.7.
Embodiment 13:4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-((4-(trifluoromethyl) phenyl) sulfenyl) The synthesis of cyanophenyl
Step 1) conjunction of 4-(4-cyano group-2-((4-(trifluoromethyl) phenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate Become
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), to trifluoromethyl thiophenol (0.21g, 1.20mmol), double (2- Diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product is carried out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (white solid, 0.09g, 20.0%).
MS(ESI,pos.ion)m/z:464.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.60～7.56 (m, 2H), 7.51～7.49 (m, 1H), 7.39～ 7.36 (m, 2H), 7.31～7.28 (m, 1H), 7.10 (d, J=8.3Hz, 1H), 3.18 (s, 4H), 2.41 (s, 4H), 1.38 (s, 9H).
Step 2) 4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-((4-(trifluoromethyl) phenyl) sulfenyl) cyanophenyl Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((4-trifluoromethyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.28g, 0.60mmol) and trifluoroacetic acid (4mL) exist Room temperature reaction in dichloromethane (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) be 20 hours systems of room temperature reaction in methanol (6mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) and obtains title compound (in vain Color solid, 0.18g, 73.0%).
MS(ESI,pos.ion)m/z:420.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.60～7.56 (m, 2H), 7.51～7.48 (m, 1H), 7.39～ 7.36 (m, 2H), 7.31～7.28 (m, 1H), 7.10 (d, J=8.3Hz, 1H), 4.67 (t, J=6.5Hz, 2H), 4.61 (t, J =6.1Hz, 2H), 3.55～3.50 (m, 1H), 3.19 (s, 4H), 2.40 (s, 4H)；
13C NMR(150MHz,CDCl3)δ(ppm):155.1,138.3,135.2,132.3,131.6,131.3,126.6, 126.5,120.6,118.7,107.2,75.5,59.3,50.8,49.6.
The conjunction of embodiment 14:4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(p-methylphenyl sulfenyl) cyanophenyl Become
Step 1) synthesis of 4-(4-cyano group-2-(p-methylphenyl sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), to methylbenzene phenyl-sulfhydrate (0.15g, 1.20mmol), double (2-hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (light yellow liquid, 0.19g, 46.2%).
MS(ESI,pos.ion)m/z:410.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37～7.35 (m, 3H), 7.22 (d, J=7.9Hz, 2H), 7.05 (d, J=8.2Hz, 1H), 6.89 (d, J=1.4Hz, 1H), 3.16 (s, 4H), 2.54 (s, 4H), 2.41 (s, 3H), 1.38 (s, 9H).
Step 2) synthesis of 4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(p-methylphenyl sulfenyl) cyanophenyl
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- (p-methylphenyl sulfenyl) phenyl) piperazine-1-t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) be at dichloromethane (8mL) room temperature reaction in, after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.20mmol) room temperature reaction in methanol (6mL).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtain title compound (white solid, 0.16g, 75.8%).
MS(ESI,pos.ion)m/z:366.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37～7.35 (m, 3H), 7.24 (d, J=7.9Hz, 2H), 7.04 (d, J=8.2Hz, 1H), 6.89 (d, J=1.4Hz, 1H), 4.69 (t, J=6.5Hz, 2H), 4.66 (t, J=6.2Hz, 2H), 3.59～3.56 (m, 1H), 3.17 (s, 4H), 2.54 (s, 4H), 2.41 (s, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.7,140.0,137.0,135.3,131.1,130.4,129.9, 127.0,119.9,119.2,107.3,75.6,59.4,50.9,49.8,21.5.
The conjunction of embodiment 15:4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(an aminomethyl phenyl sulfenyl) cyanophenyl Become
Step 1) synthesis of 4-(4-cyano group-2-(an aminomethyl phenyl sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), 3-methylbenzene phenyl-sulfhydrate (0.15g, 1.20mmol), double (2-hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) obtain title compound (light yellow liquid, 0.36g, 89.0%).
MS(ESI,pos.ion)m/z:410.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (dd, J=8.2,1.8Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.28 (s, 1H), 7.23 (t, J=8.1Hz, 2H), 7.02 (d, J=8.3Hz, 1H), 6.99 (d, J=1.7Hz, 1H), 3.16(s,4H),2.51(s,4H),2.36(s,3H),1.38(s,9H).
Step 2) synthesis of 4-(4-(oxetanylmethoxy-3-base) piperazine-1-base)-3-(an aminomethyl phenyl sulfenyl) cyanophenyl
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- (an aminomethyl phenyl sulfenyl) phenyl) piperazine-1-t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) be at dichloromethane Room temperature reaction in alkane (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.20mmol) room temperature reaction in methanol (6mL).Gained is thick Product carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) obtain title compound (white solid, 0.16g, 75.7%).
MS(ESI,pos.ion)m/z:366.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.37 (dd, J=8.2,1.8Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 7.28 (s, 1H), 7.24 (t, J=8.1Hz, 2H), 7.04 (d, J=8.3Hz, 1H), 6.97 (d, J=1.7Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.58 (m, 1H), 3.18 (s, 4H), 2.52 (s, 4H), 2.37 (s,3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.9,140.0,136.1,135.2,131.7,131.1,130.6, 130.3,130.1,129.9,119.9,119.1,107.2,75.5,59.3,50.8,49.7,21.4.
Embodiment 16:3-((2,4-3,5-dimethylphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) benzene The synthesis of nitrile
Step 1) synthesis of 4-(4-cyano group-2-((2,4-3,5-dimethylphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), 2,4-thiophenol dimethyl benzene (0.17g, 1.20mmol), double (2- Diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) be 130 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product enters Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.33g, 78.2%).
MS(ESI,pos.ion)m/z:424.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.35～7.32 (m, 2H), 7.19 (s, 1H), 7.07～7.03 (m, 2H), 6.66～6.63 (m, 1H), 3.21 (s, 4H), 2.58 (s, 4H), 2.38 (d, J=4.6Hz, 3H), 2.28 (d, J= 4.7Hz,3H),1.38(s,9H).
Step 2) 3-((2,4-3,5-dimethylphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((2,4-3,5-dimethylphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.25g, 0.60mmol) and trifluoroacetic acid (4mL) exist Room temperature reaction in dichloromethane (8mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.90mmol) and sodium cyanoborohydride (0.08g, 1.20mmol) be 20 hours systems of room temperature reaction in methanol (6mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=10/1) and obtains title compound (in vain Color solid, 0.18g, 79.0%).
MS(ESI,pos.ion)m/z:380.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.33～7.31 (m, 2H), 7.19 (s, 1H), 7.07～7.05 (m, 2H), 6.66～6.62 (m, 1H), 4.66～4.72 (m, 4H), 3.62～3.59 (m, 1H), 3.20 (s, 4H), 2.57 (s, 4H), 2.39 (d, J=4.6Hz, 3H), 2.28 (d, J=4.7Hz, 3H)；
13C NMR(150MHz,CDCl3)δ(ppm):152.7,142.8,140.8,136.8,136.4,132.5,129.6, 129.1,128.6,125.8,119.9,119.3,107.4,75.6,59.4,50.8,49.8,21.4,20.7.
The conjunction of embodiment 17:3-((4-fluorophenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Become
Step 1) synthesis of 4-(4-cyano group-2-((4-fluorophenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.00mmol), 4-fluoro thiophenol (0.15g, 1.2mmol), double (2-diphenyl Phosphine) phenylate (0.27g, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) and obtain title compound (white solid, 0.08g, 20.0%).
MS(ESI,pos.ion)m/z:414.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45～7.41 (m, 2H), 7.39 (dd, J=8.2,1.8Hz, 1H), 7.13 (t, J=8.6Hz, 2H), 7.06 (d, J=8.2Hz, 1H), 6.88 (d, J=1.8Hz, 1H), 3.17 (s, 4H), 2.52 (s,4H),1.36(s,9H).
Step 2) synthesis of 3-((4-fluorophenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((4-fluorophenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.25g, 0.6mmol) and trifluoroacetic acid (1mL) be at dichloromethane Room temperature reaction in alkane (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction in methanol (5mL).Gained slightly produces Thing carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) obtain title compound (white solid, 0.13g, 56.7%).
MS(ESI,pos.ion)m/z:370.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.45～7.40 (m, 2H), 7.39 (dd, J=8.2,1.8Hz, 1H), 7.14 (t, J=8.5Hz, 2H), 7.06 (d, J=8.2Hz, 1H), 6.89 (d, J=1.8Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.59～3.55 (m, 1H), 3.17 (s, 4H), 2.53 (s, 4H)；
13C NMR(151MHz,CDCl3) δ (ppm): 164.4,162.8,152.8,137.0 (d, J=7.6Hz), 136.1, 130.6,130.3,126.1 (d, J=4.5Hz), 120.1,118.9,117.5,117.4,107.4,75.5,59.3,50.8, 49.7.
The conjunction of embodiment 18:3-((4-chlorphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Become
Step 1) synthesis of 4-(4-cyano group-2-((4-chlorphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.50g, 1.37mmol), 4-chlorothio-phenol (0.296g, 2.05mmol), double (2-hexichol Base phosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.384g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out column chromatography Isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) obtains title compound (white solid, 0.15g, 27.2%).
MS(ESI,pos.ion)m/z:430.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42 (dd, J=13.0,5.0Hz, 2H), 7.40～7.34 (m, 2H), 7.29～7.24 (m, 1H), 7.08～6.98 (m, 2H), 3.59 (s, 4H), 3.06 (s, 4H), 1.49 (s, 9H).
Step 2) synthesis of 3-((4-chlorphenyl) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((4-chlorphenyl) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.14g, 0.33mmol) and trifluoroacetic acid (1mL) be at dichloromethane Room temperature reaction in alkane (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.036g, 0.5mmol) and sodium cyanoborohydride (0.042g, 0.66mmol) be 20 hours systems of room temperature reaction in methanol (5mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) and obtains title compound (in vain Color solid, 0.105g, 82.7%).
MS(ESI,pos.ion)m/z:386.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.41 (dd, J=8.3,1.9Hz, 1H), 7.40～7.37 (m, 2H), 7.37～7.32 (m, 2H), 7.06 (d, J=8.3Hz, 1H), 7.02 (d, J=1.8Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.67～3.54 (m, 1H), 3.16 (s, 4H), 2.49 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):153.3,135.4,135.2,134.6,131.8,130.7,130.1, 129.9,120.1,118.7,107.3,75.4,59.2,50.7,49.5.
Embodiment 19:3-((2,4 dichloro benzene base) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Synthesis
Step 1) synthesis of 4-(4-cyano group-2-((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(2-bromo-4-cyano group Phenyl) piperazine-1-t-butyl formate (0.37g, 1.0mmol), 2,4 dichloro benzene thiophenol (0.22g, 1.2mmol), double (2-hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=15/1) and obtain title compound (white solid, 0.23g, 49.0%).
MS(ESI,pos.ion)m/z:464.11[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.53 (s, 1H), 7.45 (dd, J=8.3,1.8Hz, 1H), 7.26～ 7.23 (m, 2H), 7.09 (d, J=8.3Hz, 1H), 7.01 (d, J=1.8Hz, 1H), 3.19 (s, 4H), 2.46 (s, 4H), 1.37 (s,9H).
Step 2) conjunction of 3-((2,4 dichloro benzene base) sulfenyl)-4-(4-(oxetanylmethoxy-3-base) piperazine-1-base) cyanophenyl Become
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(4-cyano group-2- ((2,4 dichloro benzene base) sulfenyl) phenyl) piperazine-1-t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) be room temperature reaction preparation in 20 hours in methanol (5mL). Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=20/1) and obtains title compound (white is solid Body, 0.13g, 49.7%).
MS(ESI,pos.ion)m/z:420.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.54 (s, 1H), 7.47 (dd, J=8.3,1.8Hz, 1H), 7.24～ 7.21 (m, 2H), 7.09 (d, J=8.3Hz, 1H), 7.00 (d, J=1.7Hz, 1H), 4.68 (t, J=6.6Hz, 2H), 4.63 (t, J=6.2Hz, 2H), 3.55 (m, 1H), 3.19 (s, 4H), 2.46 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):154.2,138.3,135.7,135.5,132.6,132.1,131.6, 130.6,129.9,128.3,120.5,118.7,107.5,75.5,59.3,50.7,49.7.
Embodiment 20:1-(oxetanylmethoxy-3-base)-4-(2-(phenylsulfartyl)-4-(trifluoromethyl) phenyl) piperazine Synthesis
Step 1) synthesis of 4-(2-(phenylsulfartyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), phenylmercaptan. (0.13g, 1.2mmol), double (2-hexichol Base phosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product carries out post layer Analyse isolated and purified (petrol ether/ethyl acetate (v/v)=30/1) and obtain title compound (white solid, 0.24g, 54.3%).
MS(ESI,pos.ion)m/z:439.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42～7.40 (m, 2H), 7.39～7.35 (m, 4H), 7.10 (d, J =8.3Hz, 1H), 7.08 (d, J=1.5Hz, 1H), 3.16 (s, 4H), 2.49 (s, 4H), 1.38 (s, 9H).
Step 2) synthesis of 1-(oxetanylmethoxy-3-base)-4-(2-(phenylsulfartyl)-4-(trifluoromethyl) phenyl) piperazine
This step title compound prepares, i.e. with reference to the method described by embodiment 1 step 24-(2-(phenyl sulfur Base)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate(0.26g, 0.6mmol) and trifluoroacetic acid (1mL) are at dichloromethane Room temperature reaction in alkane (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) within 20 hours, prepare with sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction in methanol (5mL).Gained slightly produces Thing carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (white solid, 0.16g, 65.6%).
MS(ESI,pos.ion)m/z:395.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.42～7.40 (m, 2H), 7.39～7.36 (m, 4H), 7.11 (d, J =8.3Hz, 1H), 7.07 (d, J=1.5Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.56 ～3.53 (m, 1H), 3.16 (s, 4H), 2.48 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.7,134.5,133.6,132.3,129.7,128.7,126.3, 125.9 (d, J=39.6Hz), 125.0,123.7,123.2,119.9,75.6,59.3,51.0,49.8.
Embodiment 21:1-(oxetanylmethoxy-3-base)-4-(2-(p-methylphenyl sulfenyl)-4-(trifluoromethyl) phenyl) The synthesis of piperazine
Step 1) synthesis of 4-(2-(p-methylphenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), 4-methylbenzene phenyl-sulfhydrate (0.15g, 1.2mmol), double (2-diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product enters Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.32g, 71.2%).
MS(ESI,pos.ion)m/z:453.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (s, 1H), 7.35～7.31 (m, 2H), 7.22 (d, J= 8.0Hz, 2H), 7.11 (d, J=8.3Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 3.18 (s, 4H), 2.54 (s, 4H), 2.40 (s,3H),1.38(s,9H).
Step 2) 1-(oxetanylmethoxy-3-base)-4-(2-(p-methylphenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. (2-is (to methylbenzene for 4- Base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.27g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) be room temperature reaction preparation in 20 hours in methanol (5mL). Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title compound (white is solid Body, 0.21g, 86.6%).
MS(ESI,pos.ion)m/z:409.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (s, 1H), 7.35～7.32 (m, 2H), 7.22 (d, J= 7.9Hz, 2H), 7.10 (d, J=8.3Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.67 (t, J=6.2Hz, 2H), 3.59～3.56 (m, 1H), 3.16 (s, 4H), 2.53 (s, 4H), 2.40 (s, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.0,139.3,136.0,134.6,130.7,127.9,126.4, 126.2,125.1,124.5,123.1,119.7,75.6,59.4,51.0,49.9,21.4.
Embodiment 22:1-(oxetanylmethoxy-3-base)-4-(2-(an aminomethyl phenyl sulfenyl)-4-(trifluoromethyl) phenyl) The synthesis of piperazine
Step 1) synthesis of 4-(2-(an aminomethyl phenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), 3-methylbenzene phenyl-sulfhydrate (0.15g, 1.2mmol), double (2-diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product enters Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.27g, 60.0%).
MS(ESI,pos.ion)m/z:453.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (dd, J=8.4,1.6Hz, 1H), 7.28～7.25 (m, 2H), 7.22 (d, J=7.8Hz, 1H), 7.17 (d, J=7.8Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 7.08 (d, J=1.7Hz, 1H),3.17(s,4H),2.51(s,4H),2.35(s,3H),1.38(s,9H).
Step 2) 1-(oxetanylmethoxy-3-base)-4-(2-(an aminomethyl phenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. a 4-(2-(methylbenzene Base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.27g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) be room temperature reaction preparation in 20 hours in methanol (5mL). Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title compound (white is solid Body, 0.21g, 86.6%).
MS(ESI,pos.ion)m/z:409.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.36 (dd, J=8.3,1.6Hz, 1H), 7.27～7.25 (m, 2H), 7.23 (d, J=7.8Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 7.07 (d, J=1.7Hz, 1H), 4.69 (t, J=6.6Hz, 2H), 4.66 (t, J=6.2Hz, 2H), 3.57～3.54 (m, 1H), 3.16 (s, 4H), 2.50 (s,4H),2.35(s,3H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.6,139.7,135.0,134.3,131.9,130.8,129.6, 126.5,126.3,126.1,125.9,125.6,125.0,123.5,123.2,119.8,75.6,59.4,51.0,49.8, 21.4.
Embodiment 23:1-(2-((3-methoxyphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3- Base) synthesis of piperazine
Step 1) conjunction of 4-(2-(3-methoxyphenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate Become
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), 3-methoxybenzenethiol (0.17g, 1.2mmol), double (2-diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product enters Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.14g, 30.0%).
MS(ESI,pos.ion)m/z:469.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.7Hz, 1H), 7.30 (t, J=8.1Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 7.00 (d, J=7.7Hz, 1H), 6.96～6.97 (m, 1H), 6.90～6.88 (m, 1H), 3.78 (s, 3H), 3.16 (s, 4H), 2.49 (s, 4H), 1.37 (s, 9H).
Step 2) 1-(2-((3-methoxyphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3-base) The synthesis of piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. a 4-(2-(methylbenzene Base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) be room temperature reaction preparation in 20 hours in methanol (5mL). Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title compound (white is solid Body, 0.21g, 47.9%).
MS(ESI,pos.ion)m/z:425.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (dd, J=8.3,1.5Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.15 (d, J=1.6Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 7.01 (d, J=7.7Hz, 1H), 6.96～6.94 (m, 1H), 6.90～6.87 (m, 1H), 4.69 (t, J=6.6Hz, 2H), 4.65 (t, J=6.2Hz, 2H), 3.78 (s, 3H), 3.57 (m,1H),3.16(s,4H),2.49(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):160.5,152.8,134.2,133.6,131.0,130.5,128.9, 126.1,125.6,123.9,119.9,118.4,114.6,75.6,59.4,55.5,51.0,49.8.
Embodiment 24:1-(2-((4-methoxyphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3- Base) synthesis of piperazine
Step 1) conjunction of 4-(2-(4-methoxyphenyl sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate Become
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), 4-methoxybenzenethiol (0.17g, 1.2mmol), double (2-diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetone) two palladium (23mg, 0.025mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product enters Row column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.19g, 40.0%).
MS(ESI,pos.ion)m/z:469.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43～7.41 (m, 2H), 7.31 (dd, J=8.3,1.5Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 6.97～6.96 (m, 1H), 6.95～6.93 (m, 1H), 6.86 (d, J=1.7Hz, 1H), 3.83(s,3H),3.16(s,4H),2.54(s,4H),1.38(s,9H).
Step 2) 1-(2-((4-methoxyphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3-base) The synthesis of piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. (2-is (to methylbenzene for 4- Base sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) be two Room temperature reaction in chloromethanes (2mL).After reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) be room temperature reaction preparation in 20 hours in methanol (5mL). Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title compound (white is solid Body, 0.11g, 44.0%).
MS(ESI,pos.ion)m/z:425.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.43～7.40 (m, 2H), 7.31 (dd, J=8.3,1.5Hz, 1H), 7.10 (d, J=8.2Hz, 1H), 6.97～6.95 (m, 2H), 6.86 (d, J=1.7Hz, 1H), 4.70 (t, J=6.6Hz, 2H), 4.67 (t, J=6.2Hz, 2H), 3.85 (s, 3H), 3.60～3.56 (m, 1H), 3.16 (s, 4H), 2.55 (s, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):160.7,151.5,137.1,126.7,126.4,126.2,125.1, 123.3,122.7,121.4,119.6,115.6,75.6,59.4,55.5,51.0,49.9.
Embodiment 25:1-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy- 3-yl) synthesis of piperazine
Step 1) 4-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.41g, 1.0mmol), 2,4-thiophenol dimethyl benzene (0.17g, 1.2mmol), Double (2-diphenylphosphine) phenylate (27mg, 0.05mmol), sodium tert-butoxide (0.14g, 1.5mmol) and three (dibenzalacetones) two Palladium (23mg, 0.025mmol) is 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product Carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.44g, 95.0%).
MS(ESI,pos.ion)m/z:467.25[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.35 (d, J=7.8Hz, 1H), 7.30 (dd, J=8.2,1.6Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.2Hz, 1H), 7.07 (d, J=7.8Hz, 1H), 6.70 (d, J=2.0Hz, 1H), 3.16(s,4H),2.55(s,4H),2.37(s,3H),2.29(s,3H),1.38(s,9H).
Step 2) 1-(2-((2,4-3,5-dimethylphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3- Base) synthesis of piperazine
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((2,4-bis- Aminomethyl phenyl) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.28g, 0.6mmol) and trifluoroacetic acid (1mL) room temperature reaction in dichloromethane (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxa- Cyclobutanone (0.07g, 0.9mmol) and sodium cyanoborohydride (0.08g, 1.2mmol) room temperature reaction 20 hours in methanol (5mL) Preparation.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title compound (in vain Color solid, 0.13g, 51.5%).
MS(ESI,pos.ion)m/z:423.18[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.36 (d, J=7.8Hz, 1H), 7.31 (dd, J=8.3,1.6Hz, 1H), 7.17 (s, 1H), 7.11 (d, J=8.2Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 6.72 (d, J=1.8Hz, 1H), 4.71 (t, J=6.6Hz, 2H), 4.68 (t, J=6.2Hz, 2H), 3.61～3.58 (m, 1H), 3.18 (s, 4H), 2.56 (s, 4H),2.37(s,3H),2.29(s,3H)；
13C NMR(151MHz,CDCl3)δ(ppm):151.9,142.4,140.1,136.3,135.6,132.1,128.3, 126.6,126.2,125.1,123.0,122.7,119.7,75.6,59.4,51.0,49.9,21.4,20.6.
Embodiment 26:1-(2-((4-chlorphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3-base) The synthesis of piperazine
Step 1) synthesis of 4-(2-((4-chlorphenyl) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate
This step title compound prepares with reference to the method described by embodiment 1 step 1, i.e. 4-(the bromo-4-of 2-(three Methyl fluoride) phenyl) piperazine-1-t-butyl formate (0.60g, 1.47mmol), 4-chlorothio-phenol (0.318g, 2.2mmol), double (2-diphenylphosphine) phenylate (54mg, 0.1mmol), sodium tert-butoxide (0.412g, 2.5mmol) and three (dibenzalacetone) two palladium (46mg, 0.05mmol) be 100 DEG C of reactions reaction preparation in 24 hours under nitrogen protection in DMSO (10mL).Gained crude product is carried out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=30/1) obtain title compound (white solid, 0.29g, 41.7%).
MS(ESI,pos.ion)m/z:474.05[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.6Hz, 1H), 7.36～7.31 (m, 4H), 7.13 (d, J=1.7Hz, 1H), 7.08 (d, J=8.3Hz, 1H), 3.53 (s, 4H), 3.02 (s, 4H), 1.48 (s, 9H).
Step 2) 1-(2-((4-chlorphenyl) sulfenyl)-4-(trifluoromethyl) phenyl)-4-(oxetanylmethoxy-3-base) piperazine Synthesis
This step title compound prepares with reference to the method described by embodiment 1 step 2, i.e. 4-(2-((4-chlorobenzene Base) sulfenyl)-4-(trifluoromethyl) phenyl) piperazine-1-t-butyl formate (0.29g, 0.61mmol) and trifluoroacetic acid (1mL) exist Room temperature reaction in dichloromethane (2mL), after reaction terminates, decompression is distilled off solvent, gained grease and 3-oxetanone (0.066g, 0.92mmol) and sodium cyanoborohydride (0.077g, 1.22mmol) be 20 hours systems of room temperature reaction in methanol (5mL) Standby.Gained crude product carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) and obtains title compound (white Solid, 0.229g, 87.7%).
MS(ESI,pos.ion)m/z:429.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.40 (dd, J=8.3,1.6Hz, 1H), 7.36～7.30 (m, 4H), 7.14～7.10 (m, 2H), 4.68 (t, J=6.6Hz, 2H), 4.64 (t, J=6.2Hz, 2H), 3.57～3.53 (m, 1H), 3.14(s,4H),2.46(s,4H)；
13C NMR(151MHz,CDCl3)δ(ppm):152.9,134.5,134.2,133.44,131.2,129.8, 126.3,126.2,124.1,123.9,120.0,75.4,59.2,50.9,49.6.
Biologic test
Embodiment A: evaluate the affinity of the compound humanization 5-HT transporter to expressing in Chinese hamster ovary celI
Experimental technique
Under the conditions of 22 DEG C, to cell membrane homogenate albumen (12 μ g), 2nM [3H] imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mMNaCl, 5mM KCl and 0.1%BSA) in the mixed system that formed, add or be added without surveying Examination compound, hatches 60 minutes altogether.
And in the mixed system of above-mentioned condition, add 10 μMs of imipramine, be used for recording non-specific binding value.
Sample after hatching passes through pre-dipped under vacuum with 96 like cell catchers (Unifilter, Packard) Glass fiber filter (GF/B, the Packard) fast filtering of 0.3%PEI, and use ice-cold 50mM Tris-HCl and 150mMNaCl rinses several times repeatedly.It is dried filter membrane, in scintillation counter (Topcount, Packard), uses scintillation solution (Microscint 0, Packard) calculates the radioactivity of residual.Experimental result is with special relative to matched group radioligand Property combine suppression percentage ratio represent.
Standard reference compound is imipramine, obtains competitive curve by the experiment test of series concentration, thus calculates Go out IC50.Result sees Table A, and Table A is the compounds of this invention affinity experimental result to humanization 5-HT transporter (SERT).
The Table A the compounds of this invention affinity measurement result to people source 5-HT transporter (SERT)
Experimental result shows, the compounds of this invention has stronger affinity to people source 5-HT transporter (SERT).
Embodiment B: the Pharmacokinetic Evaluation after rat intravenous or the quantitative the compounds of this invention of gavage
The compounds of this invention pharmacokinetic in rat body is assessed by the present invention, and animal information refers to Table B.
Table B animal subject of the present invention information table
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline Aqueous solution or the form of 10%DMSO+10%KolliphorHS 15+80% normal saline solution, animal subject is carried out to Medicine.For intravenous administration group, dosage is 1mg/kg or 2mg/kg, time point the most upon administration is 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 little venous blood sampling constantly (0.3mL), and 3,000 or 4, under 000rpm from The heart 10 minutes, collects plasma solutions, and preserves at-20 DEG C or-70 DEG C.For gastric infusion group, dosage is 2.5mg/ Kg or 5mg/kg, time point the most upon administration is that the little vein constantly in 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 takes Blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm, collect plasma solutions, and protect at-20 DEG C or-70 DEG C Deposit.
Collect, to above-mentioned each group, the plasma solutions obtained and carry out LC/MS/MS analysis.Analysis result shows, in rat body The compounds of this invention measured by the way of intravenous administration and gastric infusion has exposure value greatly, and clearance rate is low, raw The high preferable pharmacokinetic property of thing availability.Illustrate that the compounds of this invention druggability is more preferable, there is the most clinical answering Use prospect.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, revises, replaces and modification.

Claims (10)

1. a compound, it is the stereoisomer of compound, tautomerism shown in the compound shown in formula (I) or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
Q is-O-or-S-；
M is-O-,-S-,-CH2-or-NH-；
R and t is each independently 0 or 1；
N is 0,1,2,3,4 or 5；
Each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-CONH2,-C (=O) NHCH3、- C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxyl), C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6 Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or hydroxyl replace C1-C6Alkyl；With
R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxyl), C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl or C1-C6 Halogenated alkoxy.
Compound the most according to claim 1, the most each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、- OH、-SH、-COOH、-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxyl), C1-C4Alkyl, C2-C4Alkene Base, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or The substituted C of hydroxyl1-C4Alkyl.
Compound the most according to claim 1, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2、C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl or C1-C4Halogen For alkoxyl.
Compound the most according to claim 1 and 2, the most each R1Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、- NH2、-OH、-SH、-COOH、-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, N-pro-pyl epoxide or isopropyl epoxide.
5. according to the compound described in claim 1 or 3, wherein R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2, methyl, ethyl, n-pro-pyl, isopropyl ,-CF3Or-CH2CF3。
Compound the most according to claim 1, it is to have the compound of one of following structure or have one of following knot The stereoisomer of the compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt Or its prodrug:
7. a pharmaceutical composition, comprises the compound described in claim 1-6 any one；With
Described pharmaceutical composition comprises pharmaceutically acceptable excipient, carrier, adjuvant the most further or theirs is any Combination.
Pharmaceutical composition the most according to claim 7, it comprises treatment central nervous system dysfunction further Medicine, the medicine of described treatment central nervous system dysfunction is amitriptyline, desipramine, mirtazapine, amfebutamone, auspicious Bo Xiting, fluoxetine, trazodone, Sertraline, duloxetine, fluvoxamine, midalcipran, left-handed midalcipran, nor-literary composition draw Method is pungent, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, Clomipramine, citalopram, Ai Sixi phthalein Pulan, paroxetine, lithium carbonate, buspirone, olanzapine, Quetiapine, risperidone, Ziprasidone, Aripiprazole, piperazine sieve Grand, clozapine, modafinil, mecamylamine, cabergoline, diamantane (obsolete), imipramine, pramipexole, thyroxine, right U.S. husky Sweet smell, quinidine, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, dimension are for smooth, sharp Sleep peaceful, perphenazine or their combination in any.
9. the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one exist Preparing the purposes in medicine, described medicine is used for preventing, treating or alleviate central nervous system dysfunction.
Purposes the most according to claim 9, described medicine is used for preventing, treating or alleviate affective disorder.
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