CN105461635B - Phenylpiperazine derivatives and its application method and purposes - Google Patents

Phenylpiperazine derivatives and its application method and purposes Download PDF

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Publication number
CN105461635B
CN105461635B CN201510796434.1A CN201510796434A CN105461635B CN 105461635 B CN105461635 B CN 105461635B CN 201510796434 A CN201510796434 A CN 201510796434A CN 105461635 B CN105461635 B CN 105461635B
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compound
piperazine
bases
oxygroup
pyrimidine
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CN105461635A (en
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金传飞
梁海平
张英俊
张
亢宁
李勇
刘言萍
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Guangdong HEC Pharmaceutical
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Ruyuan Yao Autonomous County Dazhong Drug Trading Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms

Abstract

The invention discloses Phenylpiperazine derivatives and its application methods and purposes, specifically, pharmaceutical composition the present invention relates to a kind of novel (2 (heteroaryl oxygroup) phenyl) bridged piperazine derivatives and comprising such compound, they can be used for inhibiting 5 hydroxytryptamine reuptakes.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and their purposes in pivot nervous system dysfunction, the particularly disturbance of emotion in the treatment.

Description

Phenylpiperazine derivatives and its application method and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating central nervous system dysfunction, particularly feelings The compound and composition and its application method and purposes of sense obstacle.Particularly, of the present invention is that can be used as 5- hydroxyl colors The Phenylpiperazine derivatives of amine reuptaking inhibitor.
Background technology
Serotonin (5-HT, serotonin), a kind of neurotransmitter that signal is transmitted in brain and nervous system, In central nervous system (CNS) dysfunction, especially in anxiety, depression, invasion and impulsion mood, important angle play 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, it reuptakes serotonin from nerve synapse gap and enters presynaptic god Through member, the concentration of synaptic cleft serotonin is directly affected.
In history, the drug therapy of the disturbance of emotion start from the 1950s, including tricyclic antidepressant (TCAs) and Monoamine oxidase inhibitors (MAOIs), these drugs are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl colors Amine) blocking effect play curative effect.However, the non-selective and undesirable side effect to target limits making for they With.To in the 1980s, 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 It is small, even if excessive use, also smaller (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 generates inhibiting effect to 5-HT transporters, Effectively central nervous system presynaptic membrane can be inhibited to absorb 5-HT from synaptic cleft by being combined with 5-HT transporters, increased For the 5-HT actually utilized in gap, so as to achieve the purpose that treatment.
In all and relevant indication of serotonin dysfunction, depression is most important, because being defended according to the world Raw Organization, depression are had become as the fourth-largest burden property disease of the mankind.Expect the year two thousand twenty, the disability adjustment service life of depression 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)。
However, the phenomenon that clinical research in relation to depression shows not responding to known SSRIs is very prominent, another It usually will appear delay through the therapeutic effect that commonly overlooked factor is SSRIs in anti depressant therapy, symptom is being treated sometimes It is former week in can also deteriorate.In addition, sex dysfunction is common side effect for SSRIs.It is therefore desirable to develop energy Enough compounds for improving treatment depression and other serotonin relevant diseases.
The present invention provides a kind of noval chemical compounds with serotonin reuptake transporter inhibitory activity, and having preferable clinic should Use prospect.Compared with existing similar compound, the compound of the present invention has better drug effect, and medicine is for property and/or toxicity Learn characteristic.
Invention content
Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification With citation it is variant when, be subject to the disclosure of the specification.
The present invention relates to a kind of novel (2- (heteroaryl oxygroup) phenyl) bridged piperazine derivatives, with 5-HT transporters (SERT) there is stronger binding affinity, 5-HT reuptakes can be inhibited, so as to be used to prepare treatment central nervous system (CNS) drug of dysfunction, is particularly used to prepare the drug of the treatment disturbance of emotion, and the disturbance of emotion includes but and unlimited In depression, anxiety disorder, social phobia, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, terrified barrier Hinder and posttraumatic stress disorder.
The compounds of this invention property is stablized, good security, has pharmacodynamics and pharmacokinetic advantage, such as good Brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., thus have compared with Good potential applicability in clinical practice.
Pharmaceutical composition the present invention also provides the method for preparing this kind of compound and containing such compound.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, R1、R2、Ry、R3、R4、R5、R6And R7With meaning as described in the present invention.
In one embodiment, R1For 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-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R2For 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-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, RyFor 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-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, R3、R5And R6Respectively stand alone as H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkane Oxygroup), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, R7For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R1For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, RyFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-CONH2、-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogenated alkoxy.
In one embodiment, R3、R5And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy or C1-C4Halogen For alkoxy.
In one embodiment, R1For 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, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R2For 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, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, RyFor 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, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In one embodiment, R3、R5And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
Each R of the present invention1、R2、Ry、R3、R4、R5、R6And R7Individually optionally by one or more RwReplaced；With
Each RwIt independently is H, D, F, Cl, Br, I ,-NO2、-CN、-N3、-NH2,-OH ,-SH, oxo (=O), C1-C4Alkane Base, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylamino, C1-C4 Alkylthio group, NH2-(C1-C4Alkylidene)-, HO- (C1-C4Alkylidene)-, HS- (C1-C4Alkylidene)-, (C1-C4Alkoxy)-(C1- C4Alkylidene)-, (C1-C4Alkylamino)-(C1-C4Alkylidene)-, (C1-C4Alkylthio group)-(C1-C4Alkylidene)-, C3-C6Cycloalkyl, (C3-C6Cycloalkyl)-(C1-C4Alkylidene)-, the heterocycle of 3-7 annular atom composition, (heterocycle that 3-7 annular atom forms Base)-(C1-C4Alkylidene)-, phenyl, phenyl-(C1-C4Alkylidene)-, the heteroaryl or (5-6 ring of 5-6 annular atom composition Former molecular heteroaryl)-(C1-C4Alkylidene)-.
In one embodiment, compound of the present invention, for one of following structure compound or with The stereoisomer of the compound of one of following 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 includes chemical combination disclosed by the invention Object.
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their arbitrary combination.
In one embodiment, pharmaceutical composition of the present invention, further comprising treatment central nervous system work( The drug of energy obstacle, the drug of the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, as feelings Feel the salts drug of stabilizer, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, alternatively Drug, nervous stimulants, nicotinic antagonists or their the arbitrary combination of property serotonin reuptake inhibitor.
In another embodiment, the drug of present invention treatment central nervous system dysfunction is amitriptyline (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), Prozac (fluoxetine), Trazodone (trazodone), Sertraline (sertraline), Duloxetine (duloxetine), Fluvoxamine (fluvoxamine), Milnacipran (milnacipran), left-handed Milnacipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), Venlafaxine (venlafaxine), Dapoxetine hydrochloride (dapoxetine), Nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), Olanzapine (olanzapine), Quetiapine (quetiapine), Risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), Clozapine (clozapine), modafinil (modafinil), Mecamylamine (mecamylamine), card Ergot woods (cabergoline), adamantane (adamantane), imipramine (imipramine), Pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinindium (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), Pipamperone (pipamperone), dimension for smooth (vestipitant), Librium (chlordiazepoxide), perphenazine (perphenazine) or their arbitrary combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is used to preventing, treat or mitigating central nervous system dysfunction.For example, in one embodiment, the drug is used for Prevention, treatment mitigate mammalian central nervous system dysfunction, and in another embodiment, the drug is for pre- Anti-, treatment or the central nervous system dysfunction for mitigating people.
In one embodiment, the central nervous system dysfunction refers to depression, anxiety disorder, social phobia Disease, obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, spirit point Split disease, sleep-disorder, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain barrier Hinder, cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal Symptom and premenstrualtension syndrome.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is used to preventing, treat or mitigating the disturbance of emotion.
In one embodiment, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, Obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is used to inhibit serotonin reuptake transporter.
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
Biological results show that the compounds of this invention has strong affinity to people source 5-HT transporters (SERT), because This compound provided by the invention can be used as preferable selective serotonin reuptake inhibitor.
In addition, there is some compounds of the invention serotonin reuptake transporter inhibition and norepinephrine reuptake to inhibit Property synergy, other of the invention compounds have serotonin reuptake transporter inhibition and dopamine reuptake inhibition There are serotonin, norepinephrine and the triple reuptakes of dopamine to inhibit to make for synergy, the other compound of the present invention With.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS editions and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March,John Wiley&Sons,New York:Description in 2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are 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.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment for being taken into account in the embodiment in the component of one.
Term " stereoisomer " refers to there is identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.It is different that stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometry Structure body (cis/trans) isomers, atropisomer, etc..
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) including the mutual inversion of phases that is carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to some such compounds, raw material, composition and/or dosage form, they are cured rationally Learn judge in the range of, suitable for patient tissue contacts and without excessive toxicity, irritation, allergy or with rational profit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaces " can exchange use, i.e., with term " unsubstituted or by ... .. replaces " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, cycloalkyl, heterocycle, Aryl, heteroaryl etc..
In each section of this specification, the substituent group that the present invention discloses compound is disclosed according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " halogen " and " halogenated " 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 " represented containing 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein, the substituent group institute that the alkyl group can be described optionally by one or more present invention Substitution.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (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), tertiary butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " represents the linear chain or branch chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one carbon-to-carbon sp2Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substituent group stated is replaced, the positioning of positioning or " E " and " Z " including " cis " and " trans ".
Term " alkynyl " represents the linear chain or branch chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one tri- keys of carbon-to-carbon sp, wherein, the alkynyl group can be retouched optionally by one or more present invention The substituent group stated is replaced.
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In 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.The alkoxy base can be optionally 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 " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " represents alkyl, alkenyl or alkoxy base by one A or multiple halogen atoms are replaced, and wherein alkyl, alkenyl and alkoxy base have meaning as described in the present invention, such Example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..In one embodiment, C1-C6Halogenated alkyl takes comprising fluorine The C in generation1-C6Alkyl；In another embodiment, C1-C4Halogenated alkyl includes the C of fluorine substitution1-C4Alkyl；In another embodiment party In case, C1-C4Halogenated alkyl includes the C of fluorine substitution1-C2Alkyl.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion by pro-drug is hydrolyzed or is influenced in blood or tissue through enzymatic conversion for precursor structure in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.
" metabolite " refers to specific compound or its salt in vivo by the obtained product of metabolism.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound The methods of solution, amidated, deamidation, esterification, degreasing, enzymatic lysis etc., obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. recorded.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 hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of included N is formed.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, 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 one or more solvent molecules are formed with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethanol amine or its mixture.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
Phenylpiperazine derivatives of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof, can be with As selective serotonin reuptake inhibitor, to controlling for mankind's central nervous system dysfunction, the particularly disturbance of emotion Treatment has potential purposes, and the disturbance of emotion includes but is not limited to, and depression, social phobia, obsessive-compulsive disorder, is shied at anxiety disorder Probably breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
Unless otherwise mentioned, all suitable isotope variations 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 indicate, then the structure All stereoisomers all consider within the present invention, and disclose compound as the present invention and be included in the invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body clearly and is defined with regard to this.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refers to that substance or composition must be with other ingredients comprising preparation and/or using it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be used to prepare and/or purify compound shown in formula (I) and/or for detaching compound shown in this formula (I) Enantiomer intermediate.
Any structural formula that the present invention provides, which is also intended to, represents these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to the intermediates for preparing compound shown in formula (I).
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or its individual stereoisomer, isomery The racemic or non-racemic mixture of body or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition further include at least one pharmaceutically acceptable carrier, adjuvant or excipient and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient agent are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
It will also be appreciated that certain compounds of the present invention can exist to treat or if appropriate in a free form Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters or when patient in need be administered can it is direct or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.It in addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.Suitable pharmaceutically acceptable excipient includes following The excipient of type：Diluent, filler, adhesive, disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, Solvent, cosolvent, suspending agent, emulsifier, sweetener, corrigent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, Plasticiser, tackifier, antioxidant, preservative, stabilizer, surfactant and buffer.Technical staff can be appreciated that, certain Pharmaceutically acceptable excipient can provide more than one function, and provide alternative function, this depends in preparation depositing There are which other excipient in how much excipient and preparation.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field 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 the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof, it is each which includes mixing Kind ingredient.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
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 can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard shell capsules, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.
Pharmaceutical composition provided by the invention can be by injecting, being transfused or be implanted into parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mix Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to known to the technical staff in pharmaceutical science field conventional method come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, can the delivering active ingredients from patch agent be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.
The purposes of the compounds of this invention and composition
Compound and pharmaceutical composition provided by the invention can be used for preparing for preventing, treating or mitigate mammal, The drug of central nervous system dysfunction including the mankind can be used for preparing the medicine for inhibiting serotonin reuptake transporter Product.
Specifically, the amount of compound effectively detectably can selectively inhibit 5- hydroxyls in the composition of the present invention The reuptake of tryptamines, the compound of the present invention can be used as treatment mankind's central nervous system (CNS) dysfunction, particularly feelings Feel the drug of obstacle, the disturbance of emotion includes but is not limited to, depression, anxiety disorder, social phobia, obsessive-compulsive disorder, terrified Breaking-out, specific phobias, agoraphobia, mania, panic disorder and posttraumatic stress disorder.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate central nervous system dysfunction disease.It is described in response to serotonin The central nervous system dysfunction of regulation and control further comprises but is not limited to that depression, social phobia, is forced at anxiety disorder Disease, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia, is slept at panic attack Dormancy obstacle, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, cognition Obstacle, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal symptom and Premenstrualtension syndrome etc..
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, the compound of the present invention includes its pharmaceutically acceptable derivates.
In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound Once daily or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.The present invention Open compound can simultaneously or before it or later be administered with one or more other therapeutic agents.The compounds of this invention can To be administered respectively by identical or different administration route with other therapeutic agents or therewith to be administered with pharmaceutical compositions.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice 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 to that this to be further illustrated The content of invention.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.It for example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as appropriate protection interference group, by using other known reagent in addition to described in the invention Or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware 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 spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), marked by the use of TMS (0ppm) or chloroform (7.26ppm) as reference It is accurate.When there is multiplet, following abbreviation will be used：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 is represented with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level four bars HPLC-M (pillar models of Agilent： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (containing the H of 0.1% formic acid2O the ratio in), using electron spray ionisation (ESI), under 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), it is detected in 210nm/254nm with UV.
The use of brief word below is through the present invention：
BOC, Boc tert-butoxycarbonyl
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
EDTA ethylenediamine tetra-acetic acids
Et3N, TEA triethylamines
EtOAc, EA ethyl acetate
MeOH methanol
G grams
H hours
HCl hydrogen chloride
NH3Ammonia
KCl potassium chloride
MgSO4Magnesium sulfate
K2CO3Potassium carbonate
MeCN、CH3CN acetonitriles
ML, ml milliliters
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention times
TFA trifluoroacetic acids
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
BSA bovine serum albumins
Boc2O di-tert-butyl dicarbonates
Following synthetic schemes describes the step of preparation present invention discloses compound, unless otherwise stated, wherein each R1、R2、 RyAnd R4With definition of the present invention.
Synthetic schemes 1
Formula (4) compound represented can be prepared by synthetic schemes 1：Compound (1) and compound (2) with carbonic acid Potassium is alkali, reaction generation compound (3).Compound (3) Boc protecting groups are sloughed in the ethyl acetate solution of hydrogen chloride after, then Alkalization obtain target compound (4)。
Synthetic schemes 2
Formula (10) compound represented can be prepared by synthetic schemes 2：First, compound (5) replaced by piperazine Generation compound (6)；Then, compound (6) protected with tertbutyloxycarbonyl after again catalytic hydrogenation take off benzyl and obtain compound (8)；Compound (8) and compound (2) using potassium carbonate as alkali, reaction generation compound (9)；Finally, compound (9) in hydrogen chloride Ethyl acetate solution in slough Boc protecting groups after, Re-boostering test obtain target compound (10)。
Synthetic schemes 3
Formula (14) compound represented can be prepared by synthetic schemes 3：Compound (11) and compound (2) with carbon Sour potassium be alkali, reaction generation compound (12)；Compound (12) with piperazine -1- t-butyl formates occur substitution reaction obtain chemical combination Object (13)；Compound (13) Boc protecting groups are sloughed in the ethyl acetate solution of hydrogen chloride after, Re-boostering test obtains target compound (14)。
Synthetic schemes 4
Formula (17) compound represented can be prepared by synthetic schemes 4：Compound (8) and compound (15) with carbon Sour potassium be alkali, reaction generation compound (16)；Compound (16) Boc protecting groups are sloughed in the ethyl acetate solution of hydrogen chloride Afterwards, Re-boostering test obtain target compound (17)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
1 4,6- dimethoxys -2- of embodiment (2- (piperazine -1- bases) phenoxy group) pyrimidine
The synthesis of step 1) 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
4- (2- hydroxy phenyls) piperazine -1- t-butyl formates (0.42g, 1.51mmol), the chloro- 4,6- dimethoxys of 2- is phonetic Pyridine (0.28g, 1.60mmol) and potassium carbonate (0.42g, 3.02mmol) are in DMSO (10mL) is added sequentially to, then reaction solution 110 DEG C are warming up to react 20 hours.After reaction, reaction solution is cooled to room temperature, and adds in water (20mL) washing, Ran Houyong Ethyl acetate (20mL × 3) extracts.The organic phase of merging is dried over anhydrous sodium sulfate, filtering, filtrate decompression concentration.Residue passes through Silicagel column purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound for faint yellow solid (0.44g, 70.1%).
MS(ESI,pos.ion)m/z:417.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.20-7.15(m,2H),7.09-7.05(m,2H),5.76(s,1H), 3.77(s,6H),3.29(brs,4H),2.92(brs,4H),1.45(s,9H).
The synthesis of step 2) 4,6- dimethoxys -2- (2- (piperazine -1- bases) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.29g, It 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.17g, 77.3%).
MS(ESI,pos.ion)m/z:317.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):7.27-7.23(m,2H),7.19-7.13(m,2H),6.02(s, 1H),3.75(s,6H),3.16(brs,4H),2.91(brs,4H).
2 4,6- dimethyl -2- of embodiment (2- (piperazine -1- bases) phenoxy group) pyrimidine
The synthesis of step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), the chloro- 4,6- dimethyl pyrimidines (0.23g, 1.60mmol) of 2- Crude product is prepared in reaction in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol), and crude product is through silica gel column purification Title compound is obtained after (petrol ether/ethyl acetate (v/v)=2/1) as faint yellow solid (0.39g, 67.2%).
MS(ESI,pos.ion)m/z:385.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.21-7.17(m,2H),7.12-7.08(m,2H),6.73(s,1H), 3.19-3.17(m,4H),2.90-2.88(m,4H),2.36(s,6H),1.44(s,9H).
The synthesis of step 2) 4,6- dimethyl -2- (2- (piperazine -1- bases) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.27g, It 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.18g, 90.0%).
MS(ESI,pos.ion)m/z:285.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):7.21-7.18(m,1H),7.16-7.13(m,2H),7.11-7.09 (m,1H),7.04(s,1H),3.08-3.05(m,4H),2.77(brs,4H),2.32(s,6H).
3 4,6- of embodiment, bis- chloro- 2- (2- (piperazine -1- bases) phenoxy group) pyrimidines
The synthesis of step 1) 4- (2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
Under nitrogen protection, by 4- (2- hydroxy phenyls) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 4,6- bis- Chloro- 2- (methylsulfonyl) pyrimidine (0.36g, 1.60mmol) and potassium carbonate (0.42g, 3.02mmol) are added to dichloromethane (10mL) In, then reaction solution reacts 12 hours at room temperature.After reaction, reaction solution is washed with water (20mL × 3), merging it is organic It is mutually dried over anhydrous sodium sulfate, filters, filtrate decompression concentration.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v) =2/1) title compound is obtained as faint yellow solid (0.32g, 49.8%).
MS(ESI,pos.ion)m/z:426.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.27-7.23(m,1H),7.20-7.14(m,2H),7.12-7.09 (m,2H),3.23-3.21(m,4H),2.88-2.86(m,4H),1.45(s,9H).
The synthesis of bis- chloro- 2- of step 2) 4,6- (2- (piperazine -1- bases) phenoxy group) pyrimidine
By 4- (2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.30g, It 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.18g, 78.6%).
MS(ESI,pos.ion)m/z:326.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):7.77(s,1H),7.28-7.25(m,2H),7.20-7.16(m, 2H),3.09(brs,4H),2.89(brs,4H).
The fluoro- 2- of 4 5- of embodiment (2- (piperazine -1- bases) phenoxy group) pyrimidine
The synthesis of step 1) 4- (2- ((5-FU -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), the chloro- 5-FUs of 2- (0.21g, 1.59mmol) and carbonic acid Potassium (0.42g, 3.02mmol) reaction in the DMSO (10mL) is prepared crude product, crude product through silica gel column purification (petroleum ether/ Ethyl acetate (v/v)=2/1) after obtain title compound as faint yellow solid (0.45g, 79.6%).
MS(ESI,pos.ion)m/z:275.2[M+H-Boc]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.38(s,2H),7.25-7.19(m,2H),7.17-7.10(m,2H), 3.24-3.21(m,4H),2.95-2.92(m,4H),1.44(s,9H).
The synthesis of the fluoro- 2- of step 2) 5- (2- (piperazine -1- bases) phenoxy group) pyrimidine
4- (2- ((5-FU -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.26g, 0.69mmol) is molten Solution adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride in dichloromethane (5mL), and then reaction solution reacts at room temperature 2 hours.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, and is consolidated with sodium carbonate It is 7 that body, which adjusts pH, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is dried over anhydrous sodium sulfate successively, mistake Filter, filtrate decompression are concentrated to give title compound as faint yellow solid (0.18g, 94.7%).
MS(ESI,pos.ion)m/z:275.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.69(s,2H),7.24-7.19(m,2H),7.14-7.13(m, 2H),3.09(brs,4H),2.83(brs,4H).
5 2- of embodiment (2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formamides
The synthesis of step 1) 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chlorine pyrimidine -4- formamides (0.25g, 1.59mmol) and Crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silica gel column purification (stone Oily ether/ethyl acetate (v/v)=2/1) after obtain title compound as faint yellow solid (0.36g, 59.8%)
MS(ESI,pos.ion)m/z:400.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.74 (d, J=4.8Hz, 1H), 7.82 (d, J=4.8Hz, 1H), 7.46 (d, J=2.6Hz, 1H), 7.28-7.25 (m, 1H), 7.23 (dd, J=7.7,1.7Hz, 1H), 7.18-7.14 (m, 1H), 7.10 (d, J=7.8Hz, 1H), 5.69 (s, 1H), 3.16-3.15 (m, 4H), 2.97-2.83 (m, 4H), 1.43 (s, 9H)
The synthesis of step 2) 2- (2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formamides
By 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates (0.28g, It 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.14g, 66.7%)
MS(ESI,pos.ion)m/z:300.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.76 (d, J=4.5Hz, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.73 (d, J=4.5Hz, 1H), 7.27-7.24 (m, 2H), 7.16-7.15 (m, 2H), 3.09 (brs, 4H), 2.77 (brs,4H).
6 2- of embodiment (2- (piperazine -1- bases) phenoxy group) -4- (trifluoromethyl) pyrimidine
The synthesis of step 1) 4- (2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (0.29g, 1.58mmol) and crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.48g, 75.0%).
MS(ESI,pos.ion)m/z:425.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.74 (d, J=4.8Hz, 1H), 7.35 (d, J=4.9Hz, 1H), 7.27-7.26(m,1H),7.25-7.22(m,1H),7.19-7.14(m,2H),3.17-3.15(m,4H),2.91-2.89(m, 4H),1.43(s,9H).
The synthesis of step 2) 2- (2- (piperazine -1- bases) phenoxy group) -4- (trifluoromethyl) pyrimidine
By 4- (2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates (0.30g, It 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.18g, 84.1%).
MS(ESI,pos.ion)m/z:325.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.97 (d, J=4.8Hz, 1H), 7.79 (d, J=4.9Hz, 1H), 7.29-7.26(m,2H),7.19-7.16(m,2H),3.08-3.06(m,4H),2.76(brs,4H).
7 2- of embodiment (2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formonitrile HCNs
The synthesis of step 1) 4- (2- ((4- cyanopyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base phenyl) piperazine -1- t-butyl formates (0.42g, 1.51mmol), 2- chlorine pyrimidine -4- formonitrile HCNs (0.22g, 1.58mmol) and carbon Crude product is prepared in the reaction in DMSO (10mL) of sour potassium (0.42g, 3.02mmol), and crude product is through silica gel column purification (oil Ether/ethyl acetate (v/v)=2/1) after obtain title compound as faint yellow solid (0.29g, 50.3%).
MS(ESI,pos.ion)m/z:382.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.75 (d, J=4.8Hz, 1H), 7.33 (d, J=4.8Hz, 1H), 7.10-7.07 (m, 2H), 6.99 (d, J=8.5Hz, 2H), 3.61-3.59 (m, 4H), 3.16-3.14 (m, 4H), 1.49 (s, 9H).
The synthesis of step 2) 2- (2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formonitrile HCNs
By 4- (2- ((4- cyanopyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.27g, 0.71mmol) It is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution is anti-at room temperature It answers 2 hours.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, and uses sodium carbonate It is 7 that solid, which adjusts pH, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is dried over anhydrous sodium sulfate successively, mistake Filter, filtrate decompression are concentrated to give title compound as faint yellow solid (0.033g, 16.5%).
MS(ESI,pos.ion)m/z:282.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.40 (d, J=5.2Hz, 1H), 8.34 (s, 1H), 7.31-7.16 (m,4H),3.13-3.10(m,4H),2.88(brs,4H).
8 4,6- dimethoxys -2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
The synthesis of step 1) 1- (2- (benzyloxy) -4- (trifluoromethyl) phenyl) piperazine
Under nitrogen protection, by 2- (benzyloxy) -1- fluoro- 4- (trifluoromethyl) benzene (7.49g, 27.72mmol) and anhydrous piperazine Piperazine (7.16g, 83.15mmol) is added in anhydrous DMSO (50mL), and then reaction solution is warming up to 130 DEG C and reacts 20 hours.Instead After answering, reaction solution is cooled to room temperature, is then poured into water (100mL), extracted with dichloromethane (20mL × 3). Organic phase is dried over anhydrous sodium sulfate, filtering, filtrate decompression concentration.Residue is through silica gel column purification (methylene chloride/methanol (v/ V) title compound=30/1) is obtained as white solid (3.35g, 35.9%).
MS(ESI,pos.ion)m/z:337.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.48-7.47(m,2H),7.43-7.39(m,2H),7.37-7.33 (m, 1H), 7.23 (dd, J=8.3,1.0Hz, 1H), 7.16 (d, J=1.7Hz, 1H), 6.97 (d, J=8.2Hz, 1H), 5.15 (s,2H),3.16-3.14(m,4H),3.05-3.03(m,4H).
The synthesis of step 2) 4- (2- (benzyloxy) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates
1- (2- (benzyloxy) -4- (trifluoromethyl) phenyl) piperazine (2.50g, 7.43mmol) is dissolved in dichloromethane In (50mL), after being cooled to 0 DEG C, triethylamine (1.55mL, 11.15mmol) and Boc are sequentially added thereto2O(1.78g, 8.18mmol), then reaction solution reacts 2 hours at room temperature.After reaction, reaction solution is washed with water (20mL × 3).It is organic It is mutually dried over anhydrous sodium sulfate, filters, filtrate decompression concentration.Residue is through silica gel column purification (petrol ether/ethyl acetate (v/v) =50/1) title compound is obtained as white solid (2.11g, 65.1%).
MS(ESI,pos.ion)m/z:437.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.46-7.45(m,2H),7.43-7.39(m,2H),7.37-7.33 (m, 1H), 7.22 (d, J=8.3Hz, 1H), 7.17 (s, 1H), 6.96 (d, J=8.2Hz, 1H), 5.13 (s, 2H), 3.57- 3.55(m,4H),3.11-3.09(m,4H),1.49(s,9H).
The synthesis of step 3) 4- (2- hydroxyls -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates
4- (2- (benzyloxy) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (2.10g, 4.81mmol) is molten In tetrahydrofuran/dichloromethane (10mL/10mL), 10%Pd/C (0.3g) is then added in thereto.Reaction solution is placed in room temperature It is lower reaction 12 hours, after reaction, filtering, filtrate decompression concentration, be dried to obtain title compound for white solid (1.40g, 83.8%).
MS(ESI,pos.ion)m/z:347.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.21-7.20 (m, 2H), 7.14 (dd, J=8.3,1.4Hz, 1H), 3.63-3.60(m,4H),2.88-2.85(m,4H),1.49(s,9H).
Step 4) 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid The synthesis of the tert-butyl ester
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), the chloro- 4,6- dimethoxypyridins of 2- The reaction in DMSO (10mL) of (0.28g, 1.59mmol) and potassium carbonate (0.41g, 3.00mmol) is prepared to obtain crude product, Crude product obtains title compound as faint yellow solid after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) (0.45g, 61.9%)
MS(ESI,pos.ion)m/z:485.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.43 (d, J=7.7Hz, 2H), 7.03 (d, J=8.2Hz, 1H), 5.79 (s, 1H), 3.77 (s, 6H), 3.32 (t, J=4.8Hz, 4H), 3.01 (brs, 4H), 1.45 (s, 9H)
The synthesis of step 5) 4,6- dimethoxys -2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) the tertiary fourth of piperazine -1- formic acid Ester (0.34g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, so Reaction solution reacts 2 hours at room temperature afterwards.After reaction, the solvent in reaction solution is evaporated off.It is added in into gained residue Water (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively It is dried over anhydrous sodium sulfate, filters, filtrate decompression is concentrated to give title compound as faint yellow solid (0.21g, 77.8%).
MS(ESI,pos.ion)m/z:385.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.59-7.57 (m, 2H), 7.30 (d, J=8.2Hz, 1H), 6.05 (s,1H),3.74(s,6H),3.26(brs,4H),2.96(brs,4H).
9 4- methoxyl group -6- methyl -2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
Step 1) 4- (2- ((4- methoxyl group -6- methylpyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- The synthesis of t-butyl formate
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- chloro-4-methoxy -6- methyl be phonetic Crude product is prepared in pyridine (0.25g, 1.58mmol) and potassium carbonate (0.41g, 3.00mmol) reaction in DMSO (10mL), slightly Product obtains title compound as faint yellow solid after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) (0.43g, 61.1%)
MS(ESI,pos.ion)m/z:469.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.44-7.41 (m, 2H), 7.04 (d, J=8.3Hz, 1H), 6.31 (s, 1H),3.72(s,3H),3.28-3.27(m,4H),3.00-2.99(m,4H),2.35(s,3H),1.45(s,9H).
The synthesis of step 2) 4- methoxyl group -6- methyl -2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- ((4- methoxyl group -6- methylpyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid The tert-butyl ester (0.33g, 0.70mmol) is dissolved in dichloromethane (5mL), and add in hydrogen chloride ethyl acetate solution (2mL, 4M), then reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.To gained residue Middle addition water (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).What is merged is organic Mutually be dried over anhydrous sodium sulfate successively, filter, filtrate decompression be concentrated to give title compound for faint yellow solid (0.17g, 65.4%)
MS(ESI,pos.ion)m/z:369.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):7.43-7.41(m,1H),7.11-7.10(m,1H),7.04(s, 1H),6.30(s,1H),3.72(s,3H),3.08-3.05(m,4H),2.77(brs,4H),2.32(s,3H).
10 2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) -4- (trifluoromethyl) pyrimidine
Step 1) 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- formic acid The synthesis of the tert-butyl ester
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine Crude product is prepared in the reaction in DMSO (10mL) of (0.29g, 1.59mmol) and potassium carbonate (0.41g, 3.00mmol), thick to produce Product obtained after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.44g, 59.5%).
MS(ESI,pos.ion)m/z:493.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.76 (d, J=4.8Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=4.9Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 3.15-3.14 (m, 4H), 2.96-2.94 (m,4H),1.43(s,9H).
The synthesis of step 2) 2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) -4- (trifluoromethyl) pyrimidine
By 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) the tertiary fourth of piperazine -1- formic acid Ester (0.34g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, so Reaction solution reacts 2 hours at room temperature afterwards.After reaction, the solvent in reaction solution is evaporated off.It is added in into gained residue Water (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively It is dried over anhydrous sodium sulfate, filters, filtrate decompression is concentrated to give title compound as faint yellow solid (0.15g, 55.4%).
MS(ESI,pos.ion)m/z:393.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):9.01 (d, J=4.8Hz, 1H), 7.86 (d, J=4.9Hz, 1H), 7.73 (s, 1H), 7.64 (d, J=7.6Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 3.22 (t, J=4.4Hz, 4H), 2.86 (brs,4H).
11 4,6- of embodiment, bis- chloro- 2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidines
Step 1) 4- (2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) tertiary fourth of piperazine -1- formic acid Ester
This step title compound is referred to the described method of 3 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 4,6- bis- chloro- 2- (methylsulfonyl) pyrimidine Crude product is prepared in the reaction in DCM (10mL) of (0.36g, 1.60mmol) and potassium carbonate (0.41g, 3.00mmol), thick to produce Product obtained after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.44g, 59.5%).
MS(ESI,pos.ion)m/z:493.1[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.51 (dd, J=8.3,1.3Hz, 1H), 7.42 (d, J=1.8Hz, 1H), 7.15 (s, 1H), 7.12 (d, J=8.4Hz, 1H), 3.25-3.23 (m, 4H), 2.96-2.94 (m, 4H), 1.45 (s, 9H).
The synthesis of bis- chloro- 2- of step 2) 4,6- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.35g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).Merge organic interdependent time through nothing Aqueous sodium persulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.20g, 71.7%).
MS(ESI,pos.ion)m/z:393.0[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.87 (s, 1H), 7.73 (d, J=1.7Hz, 1H), 7.66-7.64 (m, 1H), 7.38 (d, J=8.5Hz, 1H), 3.26-3.24 (m, 4H), 2.98 (brs, 4H)
12 2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
The synthesis of step 1) 4- (2- (pyrimidine-2-yloxy) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- chlorine pyrimidine (0.18g, 1.58mmol) and crude product is prepared in potassium carbonate (0.41g, 3.0mmol) reaction in DMSO (10mL), and crude product is through silica gel Title compound is obtained after column purification (petrol ether/ethyl acetate (v/v)=2/1) as faint yellow solid (0.38g, 59.6%).
MS(ESI,pos.ion)m/z:425.1[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.54 (d, J=4.8Hz, 2H), 7.48 (d, J=8.4Hz, 1H), 7.45(s,1H),7.09-7.06(m,2H),3.20-3.19(m,4H),3.00-2.98(m,4H),1.43(s,9H).
The synthesis of step 2) 2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- (pyrimidine-2-yloxy) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.30g, It 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.14g, 61.1%).
MS(ESI,pos.ion)m/z:325.0[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.72-8.66(m,2H),7.60-7.18(m,4H),3.24(brs, 4H),2.84(brs,4H).
The fluoro- 2- of 13 5- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
Step 1) 4- (2- ((5-FU -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), the fluoro- 2- chlorine pyrimidines of 5- (0.21g, 1.60mmol) and crude product is prepared in potassium carbonate (0.41g, 3.00mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.53g, 79.8%).
MS(ESI,pos.ion)m/z:443.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.39 (s, 2H), 7.49 (d, J=8.4Hz, 1H), 7.44 (d, J= 1.6Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 3.22-3.21 (m, 4H), 3.00-2.98 (m, 4H), 1.45 (s, 9H)
The synthesis of the fluoro- 2- of step 2) 5- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- ((5-FU -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.31g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.19g, 79.2%).
MS(ESI,pos.ion)m/z:343.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.80-8.70 (m, 2H), 7.62 (s, 1H), 7.59 (d, J= 8.4Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 3.24-3.22 (m, 4H), 2.89 (brs, 4H)
14 2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine -4- formamides
Step 1) 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid uncles The synthesis of butyl ester
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), 2- chlorine pyrimidine -4- formamides Crude product is prepared in the reaction in DMSO (10mL) of (0.25g, 1.60mmol) and potassium carbonate (0.41g, 3.00mmol), thick to produce Product obtained after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.28g, 39.9%).
MS(ESI,pos.ion)m/z:468.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.75 (d, J=4.8Hz, 1H), 7.86 (d, J=4.8Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.11 (d, J=8.4Hz, 1H), 5.72 (s, 1H), 3.17 (brs,4H),2.97(brs,4H),1.43(s,9H).
The synthesis of step 2) 2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine -4- formamides
By 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.33g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.11g, 42.5%).
MS(ESI,pos.ion)m/z:368.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.80 (d, J=4.6Hz, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.79 (d, J=4.6Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=8.1Hz, 1H), 7.34 (d, J=8.3Hz, 1H), 3.24(brs,4H),2.84(brs,4H).
15 4,6- dimethyl -2- of embodiment (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
Step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid uncles The synthesis of butyl ester
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (2- hydroxyls Base -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.52g, 1.50mmol), the chloro- 4,6- dimethyl pyrimidines of 2- Crude product is prepared in the reaction in DMSO (10mL) of (0.22g, 1.58mmol) and potassium carbonate (0.41g, 3.00mmol), thick to produce Product obtained after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.44g, 64.8%).
MS(ESI,pos.ion)m/z:453.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.43 (d, J=8.4Hz, 1H), 7.40 (s, 1H), 7.05 (d, J= 8.3Hz,1H),6.77(s,1H),3.22-3.21(m,4H),2.98-2.97(m,4H),2.37(s,6H),1.44(s,9H).
The synthesis of step 2) 4,6- dimethyl -2- (2- (piperazine -1- bases) -5- (trifluoromethyl) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formates (0.32g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.16g, 60.2%).
MS(ESI,pos.ion)m/z:353.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.58 (d, J=7.6Hz, 1H), 7.54 (s, 1H), 7.32 (d, J= 7.9Hz,1H),7.09(s,1H),3.22(brs,4H),2.85(brs,4H),2.35(s,6H).
16 3- of embodiment ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
The synthesis of step 1) 3- (benzyloxy) -4- (piperazine -1- bases) benzonitrile
This step title compound is referred to the described method of 8 step 1 of embodiment and is prepared, i.e., by 3- (benzyloxies Base) reaction in DMSO (50mL) of -4- fluorobenzonitriles (6.29g, 27.68mmol) and Piperazine anhydrous (7.15g, 83.04mmol) Crude product is prepared, crude product obtains title compound after silica gel column purification (methylene chloride/methanol (v/v)=30/1) and is Brown solid (3.25g, 40.0%).
MS(ESI,pos.ion)m/z:294.2[M+H]+.
The synthesis of step 2) 4- (2- (benzyloxy) -4- cyano-phenyls) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 8 step 2 of embodiment and is prepared, i.e., by 3- (benzyloxies Base) -4- (piperazine -1- bases) benzonitrile (2.18g, 7.43mmol), triethylamine (1.55mL, 11.15mmol) and Boc2O Crude product is prepared in (1.78g, 8.17mmol) reaction in dichloromethane (50mL), and crude product is through silica gel column purification (oil Ether/ethyl acetate (v/v)=50/1) after obtain title compound as bright yellow solid (1.99g, 68.2%).
MS(ESI,pos.ion)m/z:394.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.43-7.39 (m, 4H), 7.37-7.34 (m, 1H), 7.26 (dd, J= 8.2,1.4Hz, 1H), 7.14 (d, J=1.3Hz, 1H), 6.89 (d, J=8.2Hz, 1H), 5.11 (s, 2H), 3.54-3.53 (m, 4H),3.12(brs,4H),1.47(s,9H).
The synthesis of step 3) 4- (4- cyano-2-hydroxys phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 8 step 3 of embodiment and is prepared, i.e., by 4- (2- (benzyls Oxygroup) -4- cyano-phenyls) piperazine -1- t-butyl formates (1.90g, 4.83mmol) and 10%Pd/C (0.3g) tetrahydrofuran/ Title compound is prepared as white solid (1.17g, 80.1%) in reaction in dichloromethane (10mL/10mL).
MS(ESI,pos.ion)m/z:248.1[M+H-56]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.21 (d, J=1.7Hz, 1H), 7.19 (dd, J=8.1,1.8Hz, 1H), 7.13 (d, J=8.1Hz, 1H), 3.63-3.61 (m, 4H), 2.89 (brs, 4H), 1.48 (s, 9H)
Step 4) 4- (4- cyano -2- ((4,6- dimethoxypyridin -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), the chloro- 4,6- dimethoxypyridins of 2- (0.28g, 1.59mmol) and crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.46g, 68.7%).
MS(ESI,pos.ion)m/z:442.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.47 (dd, J=8.4,1.5Hz, 1H), 7.42 (d, J=1.7Hz, 1H), 6.98 (d, J=8.4Hz, 1H), 5.79 (s, 1H), 3.77 (s, 6H), 3.32-3.21 (m, 4H), 3.06 (brs, 4H), 1.44(s,9H).
The synthesis of step 5) 3- ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
By 4- (4- cyano -2- ((4,6- dimethoxypyridin -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.31g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.19g, 79.1%).
MS(ESI,pos.ion)m/z:342.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.60-7.57 (m, 2H), 7.30 (d, J=8.2Hz, 1H), 6.05 (s,1H),3.74(s,6H),3.26(brs,4H),2.96(brs,4H).
17 3- of embodiment ((4,6- dichloro pyrimidine -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
The conjunction of step 1) 4- (4- cyano -2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates Into
This step title compound is referred to the described method of 3 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), 4,6- bis- chloro- 2- (methylsulfonyl) pyrimidine Crude product is prepared in the reaction in DMSO (10mL) of (0.36g, 1.60mmol) and potassium carbonate (0.42g, 3.02mmol), thick to produce Product obtained after silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.33g, 48.3%).
MS(ESI,pos.ion)m/z:451.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.56 (dd, J=8.4,1.9Hz, 1H), 7.45 (d, J=1.9Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=8.4Hz, 1H), 3.35-3.23 (m, 4H), 3.11-2.88 (m, 4H), 1.47 (s, 9H).
The synthesis of step 2) 3- ((4,6- dichloro pyrimidine -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
By 4- (4- cyano -2- ((4,6- dichloro pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.32g, It 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging is successively through anhydrous sulphur Sour sodium drying, filtering, filtrate decompression are concentrated to give title compound as faint yellow solid (0.24g, 96.4%).
MS(ESI,pos.ion)m/z:351.2[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.87 (s, 1H), 7.84 (d, J=1.7Hz, 1H), 7.74 (dd, J =5.6,1.2Hz, 1H), 7.32 (d, J=8.5Hz, 1H), 3.30 (brs, 4H), 3.00 (brs, 4H)
18 3- of embodiment ((5-FU -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
The synthesis of step 1) 4- (4- cyano -2- ((5-FU -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), the fluoro- 2- chlorine pyrimidines (0.21g, 1.59mmol) of 5- Crude product is prepared in reaction in DMSO (10mL) with potassium carbonate (0.42g, 3.02mmol), and crude product is through silica gel column purification Title compound is obtained after (petrol ether/ethyl acetate (v/v)=2/1) as faint yellow solid (0.52g, 85.8%).
MS(ESI,pos.ion)m/z:400.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.41 (s, 2H), 7.54 (dd, J=8.4,1.8Hz, 1H), 7.46 (d, J=1.7Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 3.31-3.21 (m, 4H), 3.15-2.98 (m, 4H), 1.46 (s, 9H)
The synthesis of step 2) 3- ((5-FU -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
By 4- (4- cyano -2- ((5-FU -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.28g, It 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then reaction solution It reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water (15mL) is added in into gained residue, And it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).Merge organic interdependent time through anhydrous slufuric acid Sodium is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.19g, 90.5%).
MS(ESI,pos.ion)m/z:300.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.75 (s, 2H), 7.76 (d, J=1.9Hz, 1H), 7.70 (dd, J =8.4,1.9Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 3.35-3.23 (m, 4H), 2.91 (brs, 4H)
19 4- of embodiment (piperazine -1- bases) -3- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) benzonitrile
Step 1) 4- (4- cyano -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (0.29g, 1.59mmol) and crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.44g, 64.5%).
MS(ESI,pos.ion)m/z:450.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.77 (d, J=4.8Hz, 1H), 7.54 (dd, J=8.3,1.2Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 7.41 (d, J=4.9Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 3.16-3.15 (m, 4H),3.01-2.99(m,4H),1.42(s,9H).
The synthesis of step 2) 4- (piperazine -1- bases) -3- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) benzonitrile
By 4- (4- cyano -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates (0.31g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.18g, 74.5%).
MS(ESI,pos.ion)m/z:350.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):9.01 (d, J=4.8Hz, 1H), 7.86 (d, J=4.9Hz, 1H), 7.73 (s, 1H), 7.64 (d, J=7.6Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 3.22 (brs, 4H), 2.86 (brs, 4H)
20 3- of embodiment ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
Step 1) 4- (4- cyano -2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), the chloro- 4,6- dimethyl pyrimidines of 2- (0.23g, 1.59mmol) and crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.43g, 69.2%).
MS(ESI,pos.ion)m/z:410.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.46 (dd, J=8.3,1.9Hz, 1H), 7.39 (d, J=1.9Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.78 (s, 1H), 3.26-3.23 (m, 4H), 3.05-3.03 (m, 4H), 2.37 (s, 6H),1.43(s,9H).
The synthesis of step 2) 3- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- (piperazine -1- bases) benzonitrile
By 4- (4- cyano -2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) phenyl) piperazine -1- t-butyl formates (0.29g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.15g, 64.5%).
MS(ESI,pos.ion)m/z:310.2[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):7.63-7.62(m,1H),7.59(s,1H),7.36(s,1H), 7.13(s,1H),3.27(brs,4H),2.90(brs,4H),2.39(s,6H).
21 2- of embodiment (5- cyano -2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formamides
Step 1) 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) -4- cyano-phenyls) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 1 step 1 of embodiment and is prepared, i.e., by 4- (4- cyanogen Base -2- hydroxy phenyls) piperazine -1- t-butyl formates (0.46g, 1.52mmol), 2- chlorine pyrimidine -4- formamides (0.25g, 1.59mmol) and crude product is prepared in potassium carbonate (0.42g, 3.02mmol) reaction in DMSO (10mL), and crude product is through silicon Rubber column gel column purifying (petrol ether/ethyl acetate (v/v)=2/1) after obtain title compound for faint yellow solid (0.29g, 45.0%).
MS(ESI,pos.ion)m/z:425.2[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.68 (d, J=4.8Hz, 1H), 7.81 (d, J=4.8Hz, 1H), 7.47 (dd, J=8.4,1.7Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.34 (d, J=2.2Hz, 1H), 6.98 (d, J= 8.4Hz,1H),6.07(s,1H),3.11(brs,4H),2.96(brs,4H),1.35(s,9H).
The synthesis of step 2) 2- (5- cyano -2- (piperazine -1- bases) phenoxy group) pyrimidine -4- formamides
By 4- (2- ((4- carbamyls pyrimidine -2-base) oxygroup) -4- cyano-phenyls) piperazine -1- t-butyl formates (0.30g, 0.71mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.11g, 48.0%).
MS(ESI,pos.ion)m/z:325.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.80 (d, J=4.8Hz, 1H), 7.82 (d, J=4.8Hz, 1H), 7.77 (dd, J=8.4,1.7Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 7.34 (d, J=2.2Hz, 1H), 6.98 (d, J= 8.4Hz,1H),6.12(s,1H),3.11(brs,4H),2.96(brs,4H).
22 4,6- dimethyl -2- of embodiment (5- nitros -2- (piperazine -1- bases) phenoxy group) pyrimidine
The synthesis of step 1) 2- (the fluoro- 5- nitro-phenoxies of 2-) -4,6- methylpyrimidines
Under nitrogen protection, by the fluoro- 5- nitrophenols (0.47g, 2.99mmol) of 2-, chloro- 4, the 6- dimethyl pyrimidines of 2- (0.43g, 3.05mmol) and potassium carbonate (0.83g, 5.98mmol) are added in DMSO (10mL), and then reaction solution is warming up to 110oC reacts 20 hours.After reaction, reaction solution is cooled to room temperature, and adds in water (20mL) washing, then with acetic acid second Ester (30mL × 3) extracts.After the organic phase of merging is dried over anhydrous sodium sulfate, filtering, filtrate decompression concentration.Residue is through silica gel Column purification (petrol ether/ethyl acetate (v/v)=20/1) obtains title compound as white solid (0.55g, 69.8%).
MS(ESI,pos.ion)m/z:264.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.20 (dd, J=6.8,2.8Hz, 1H), 8.17-8.13 (m, 1H), 7.31 (t, J=9.6Hz, 1H), 6.84 (s, 1H), 2.41 (s, 6H)
Step 2) 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- nitrobenzophenones) piperazine -1- t-butyl formates Synthesis
Under nitrogen protection, by 2- (the fluoro- 5- nitro-phenoxies of 2-) -4,6- dimethyl pyrimidines (0.39g, 1.48mmol), piperazine Piperazine -1- t-butyl formates (0.30g, 1.63mmol) and potassium carbonate (0.41g, 2.96mmol) are added in DMSO (10mL), so Reaction solution is warming up to 110 afterwardsoC reacts 20 hours.After reaction, reaction solution is cooled to room temperature, and is washed with water (30mL), Then it is extracted with ethyl acetate (30mL × 3).The organic phase of merging is dried over anhydrous sodium sulfate, filtering, filtrate decompression concentration.It is residual Stay object through silica gel column purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound for red solid (0.23g, 36.2%).
MS(ESI,pos.ion)m/z:430.3[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.20 (dd, J=8.8,2.8Hz, 1H), 8.01 (d, J=2.8Hz, 1H), 6.99 (d, J=8.8Hz, 1H), 6.81 (s, 1H), 3.29-3.27 (m, 4H), 3.16-3.13 (m, 4H), 2.39 (s, 6H),1.44(s,9H).
The synthesis of step 3) 4,6- dimethyl -2- (5- nitros -2- (piperazine -1- bases) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethyl pyrimidine -2- bases) oxygroup) -4- nitrobenzophenones) piperazine -1- t-butyl formates (0.30g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.20g, 87.0%).
MS(ESI,pos.ion)m/z:330.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.08 (dd, J=8.8,2.4Hz, 1H), 7.99 (d, J=1.6Hz, 1H), 7.30 (d, J=8.8Hz, 1H), 7.09 (s, 1H), 3.38-3.37 (m, 4H), 2.88-2.86 (m, 4H), 2.33 (s, 6H).
23 4,6- dimethoxys -2- of embodiment (5- nitros -2- (piperazine -1- bases) phenoxy group) pyrimidine
The synthesis of step 1) 2- (the fluoro- 5- nitro-phenoxies of 2-) -4,6- dimethoxypyridins
This step title compound is referred to the described method of 22 step 1 of embodiment and is prepared, i.e., by the fluoro- 5- of 2- The chloro- 4,6- dimethoxypyridins (0.53g, 3.05mmol) of nitrophenol (0.47g, 2.99mmol), 2- and potassium carbonate (0.83g, 5.96mmol) crude product is prepared in reaction in DMSO (10mL), and crude product purifies (petroleum ether/acetic acid through silica gel column chromatography Ethyl ester (v/v)=20/1) after obtain title compound as white solid (0.48g, 54.3%).
MS(ESI,pos.ion)m/z:296.1[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.24 (dd, J=6.8,2.8Hz, 1H), 8.18-8.15 (m, 1H), 7.33 (t, J=9.6Hz, 1H), 5.85 (s, 1H), 3.83 (s, 6H)
Step 2) 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- nitrobenzophenones) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 22 step 2 of embodiment and is prepared, i.e. (2- is fluoro- by 2- 5- nitro-phenoxies) -4,6- dimethoxypyridins (0.44g, 1.49mmol), piperazine -1- t-butyl formates (0.31g, 1.64mmol) and crude product is prepared in potassium carbonate (0.41g, 3.00mmol) reaction in DMSO (10mL), and crude product is through silicon Obtained after gel column chromatography eluting (petrol ether/ethyl acetate (v/v)=2/1) title compound for faint yellow solid (0.30g, 43.6%).
MS(ESI,pos.ion)m/z:462.3[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.09-8.06 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 5.81 (s, 1H),3.78(s,6H),3.36-3.34(m,4H),3.16-3.14(m,4H),1.45(s,9H).
The synthesis of step 3) 4,6- dimethoxys -2- (5- nitros -2- (piperazine -1- bases) phenoxy group) pyrimidine
By 4- (2- ((4,6- dimethoxypyridin -2- bases) oxygroup) -4- nitrobenzophenones) piperazine -1- t-butyl formates (0.32g, 0.69mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.21g, 89.7%).
MS(ESI,pos.ion)m/z:362.1[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):8.11 (dd, J=8.8,2.4Hz, 1H), 8.07 (d, J=1.6Hz, 1H), 7.31 (d, J=8.8Hz, 1H), 6.06 (s, 1H), 3.75 (s, 6H), 3.44-3.42 (m, 4H), 2.99-2.97 (m, 4H).
24 2- of embodiment (5- nitros -2- (piperazine -1- bases) phenoxy group) -4- (trifluoromethyl) pyrimidine
The synthesis of step 1) 2- (the fluoro- 5- nitro-phenoxies of 2-) -4- (trifluoromethyl) pyrimidine
This step title compound is referred to the described method of 22 step 1 of embodiment and is prepared, i.e., by the fluoro- 5- of 2- Nitrophenol (0.47g, 2.99mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (0.55g, 3.00mmol) and potassium carbonate (0.83g, 5.98mmol) crude product is prepared in reaction in DMSO (10mL), and crude product is through silica gel column purification (petrol ether/ethyl acetate (v/v)=20/1 title compound is obtained after) as white solid (0.66g, 60.2%).
MS(ESI,pos.ion)m/z:304.0[M+H-HCl]+.
Step 2) 4- (4- nitros -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates Synthesis
This step title compound is referred to the described method of 22 step 2 of embodiment and is prepared, i.e., by 2- (2- Fluoro- 5- nitro-phenoxies) -4- (trifluoromethyl) pyrimidine (0.45g, 1.48mmol), piperazine -1- t-butyl formates (0.30g, 1.63mmol) and crude product is made in potassium carbonate (0.41g, 3.00mmol) reaction in DMSO (10mL), and crude product is through silica gel Title compound is obtained after column purification (petrol ether/ethyl acetate (v/v)=2/1) as faint yellow solid (0.32g, 45.9%).
MS(ESI,pos.ion)m/z:414.2[M+H-56]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.78 (d, J=4.8Hz, 1H), 8.16 (dd, J=8.9,2.6Hz, 1H), 8.09 (d, J=2.6Hz, 1H), 7.43 (d, J=4.9Hz, 1H), 7.07 (d, J=8.9Hz, 1H), 3.22-3.20 (m, 4H),3.11-3.09(m,4H),1.44(s,9H).
The synthesis of step 3) 2- (5- nitros -2- (piperazine -1- bases) phenoxy group) -4- (trifluoromethyl) pyrimidine
By 4- (4- nitros -2- ((4- (trifluoromethyl) pyrimidine -2-base) oxygroup) phenyl) piperazine -1- t-butyl formates (0.33g, 0.70mmol) is dissolved in dichloromethane (5mL), and adds in the ethyl acetate solution (2mL, 4M) of hydrogen chloride, then Reaction solution reacts 2 hours at room temperature.After reaction, the solvent in reaction solution is evaporated off.Water is added in into gained residue (15mL), and it is 7 to adjust pH with sodium carbonate solid, is then extracted with dichloromethane (15mL × 3).The organic phase of merging passes through successively Anhydrous sodium sulfate is dried, filtering, and filtrate decompression is concentrated to give title compound as faint yellow solid (0.24g, 92.3%).
MS(ESI,pos.ion)m/z:370.1[M+H]+；
1H NMR(DMSO-d6,600MHz)δ(ppm):8.98 (d, J=4.8Hz, 1H), 7.86 (dd, J=8.9,2.6Hz, 1H), 7.75 (d, J=2.6Hz, 1H), 7.63 (d, J=4.9Hz, 1H), 7.35 (d, J=8.9Hz, 1H), 3.22-3.20 (m, 4H),2.90(brs,4H).
Biologic test
Embodiment A：Evaluate the affinity of humanization 5-HT transporter of the compound to expression in Chinese hamster ovary celI
Experimental method
Under the conditions of 22 DEG C, to cell membrane homogenate albumen (12 μ g), 2nM [3H] imipramine and buffer solution (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1%BSA) formed mixed system in, add in or be added without survey Compound is tried, is incubated 60 minutes altogether.
And in the mixed system of above-mentioned condition, 10 μM of imipramine are added in, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum by pre- dipped Glass fiber filter (GF/B, Packard) fast filtering of 0.3%PEI, and use ice-cold 50mM Tris-HCl and 150mM NaCl is rinsed several times repeatedly.Dry filter membrane, in scintillation counter (Topcount, Packard), uses scintillation solution (Microscint 0, Packard) calculates remaining radioactivity.Experimental result is with special relative to control group radioligand Property combine suppression percentage represent.
Standard reference compound is imipramine, competition linearity curve is obtained by the experiment test of series concentration, so as to calculate Go out IC50.As a result referring to Table A, Table A is the compounds of this invention to the affinity experimental result of humanization 5-HT transporters (SERT).
Table A the compounds of this invention is to the affinity measurement result of people source 5-HT transporters (SERT)
Experimental result shows that the compounds of this invention has stronger affinity to people source 5-HT transporters (SERT).
Embodiment B rats intravenous or gavage quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses pharmacokinetic of the compounds of this invention in rat body, and animal information refers to Table B.
Table B animal subject information tables of the present invention
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, animal subject is carried out to Medicine.For being injected intravenously administration group, dosage is 1mg/kg or 2mg/kg, then time point upon administration for 0.083, 0.25th, 0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and under 3,000 or 4,000rpm from The heart 10 minutes collects plasma solutions, and in -20oC or -70oIt is preserved under C.For gastric infusion group, dosage 2.5mg/kg Or 5mg/kg, venous blood sampling when then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour (0.3mL), and centrifuged 10 minutes under 3,000 or 4,000rpm, plasma solutions are collected, and preserved at -20 DEG C or -70 DEG C.
The plasma solutions obtained are collected to above-mentioned each group and carry out LC/MS/MS analyses.Analysis result shows in rat body The compounds of this invention measured by way of being injected intravenously administration and gastric infusion is big with exposure magnitude, and clearance rate is low, raw The preferable pharmacokinetic properties such as object availability height.Illustrate that the compounds of this invention druggability is more preferable, there is preferably clinical answer Use prospect.Wherein embodiment 23 synthesizes the obtained pharmacokinetic parameter of compound and refers to table C.
Table C embodiment 23 synthesizes pharmacokinetic parameter of the obtained compound in rat body
Grouping It is injected intravenously administration group Gastric infusion group
Dose(mg/kg) 2 5
AUCINF(h*ng/mL) 1156.23 874.74
AUClast(h*ng/mL) 1154.86 869.75
Cl(L/h/kg) 1.77 --
Cmax(ng/mL) 1463.33 434
F (%) -- 30.3
The experimental results showed that the compounds of this invention has preferable pharmacokinetic property in rat body.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " is shown " embodiment " The description of example ", " specific example " or " some examples " etc. means to combine the specific spy that the embodiment, embodiment or example describe Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by the difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (7)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body or pharmaceutically acceptable salt,
Wherein：
R1It independently is F, Cl, Br, I, C1-C4Alkyl or C1-C4Alkoxy；
R2It independently is H or D；
RyIt independently is F, Cl, Br, I, C1-C4Alkyl or C1-C4Alkoxy；
R4It independently is-CN ,-NO2Or C1-C4Halogenated alkyl；
R3、R5And R6It is each independently H or D；With
R7For H or D.
2. compound according to claim 1, wherein R1It independently is F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl Base, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；
R2It independently is H or D；
RyIt independently is F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl Base oxygroup.
3. compound according to claim 1, wherein R4It independently is-CN ,-NO2Or-CF3；
R3、R5And R6It is each independently H or D.
4. compound according to claim 1, for the compound with one of following structure or with one of following knot Stereoisomer, tautomer or the pharmaceutically acceptable salt of the compound of structure：
5. a kind of pharmaceutical composition includes the compound described in claim 1-4 any one；With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is arbitrary Combination.
6. the purposes of compound in medicine preparation described in claim 1-4 any one, the drug is used to prevent, treat Or mitigate central nervous system dysfunction.
7. purposes according to claim 6, the drug is used to preventing, treat or mitigating the disturbance of emotion.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1360583A (en) * 1999-05-21 2002-07-24 比奥维特罗姆股份公司 Novel compounds, their use and preparation
WO2002059108A1 (en) * 2001-01-23 2002-08-01 Eli Lilly And Company Melanocortin receptor agonists
CN1436191A (en) * 2000-05-25 2003-08-13 塔加西普特公司 Heteroaryldiazabicycloalkanes as nicotinic cholinergic receptor ligands
CN1561336A (en) * 2001-10-04 2005-01-05 H·隆德贝克有限公司 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
WO2005094896A2 (en) * 2004-03-26 2005-10-13 Baylor University Targeted serotonin reuptake inhibitors
CN101686983A (en) * 2007-05-10 2010-03-31 Amr科技公司 Aryl and heteroaryl substituted tetrahydrobenzo-1, 4-diazepine and their use for blocking the reuptake of norepinephrine, dopamine and 5-hydroxytryptamine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1360583A (en) * 1999-05-21 2002-07-24 比奥维特罗姆股份公司 Novel compounds, their use and preparation
CN1436191A (en) * 2000-05-25 2003-08-13 塔加西普特公司 Heteroaryldiazabicycloalkanes as nicotinic cholinergic receptor ligands
WO2002059108A1 (en) * 2001-01-23 2002-08-01 Eli Lilly And Company Melanocortin receptor agonists
CN1561336A (en) * 2001-10-04 2005-01-05 H·隆德贝克有限公司 Phenyl-piperazine derivatives as serotonin reuptake inhibitors
WO2005094896A2 (en) * 2004-03-26 2005-10-13 Baylor University Targeted serotonin reuptake inhibitors
CN101686983A (en) * 2007-05-10 2010-03-31 Amr科技公司 Aryl and heteroaryl substituted tetrahydrobenzo-1, 4-diazepine and their use for blocking the reuptake of norepinephrine, dopamine and 5-hydroxytryptamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
抗抑郁新药沃替西汀;范宁等;《中国新药杂志》;20141231;第23卷(第16期);第1847-1850页 *

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