CN109912514A - (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof - Google Patents

(2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof Download PDF

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CN109912514A
CN109912514A CN201711328866.5A CN201711328866A CN109912514A CN 109912514 A CN109912514 A CN 109912514A CN 201711328866 A CN201711328866 A CN 201711328866A CN 109912514 A CN109912514 A CN 109912514A
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alkyl
compound
base
phenyl
alkoxy
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CN109912514B (en
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金传飞
张英俊
薛亚萍
郭正江
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Guangdong HEC Pharmaceutical
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Abstract

The invention discloses (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof, and the pharmaceutical composition comprising such compound, they can be used for inhibiting serotonin reuptake transporter.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 especially disturbance of emotion in the treatment.

Description

(2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives and application thereof
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for treating central nervous system dysfunction, especially feelings The compound and pharmaceutical composition and its application method and purposes of sense obstacle.Particularly, of the present invention is that can be used as 5- (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives of serotonin reuptake inhibitor.
Background technique
Serotonin (5-HT, serotonin), a kind of neurotransmitter for transmitting signal 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 mind 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, include tricyclic antidepressant (TCAs) and Monoamine oxidase inhibitors (MAOIs), these drugs are mainly by neurotransmitter (dopamine, norepinephrine and 5- hydroxyl color 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 the 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 transporter, It can effectively inhibit central nervous system presynaptic membrane to absorb 5-HT from synaptic cleft and in conjunction with 5-HT transporter, increase For the 5-HT actually utilized in gap, to achieve the purpose that treatment.
In all indications relevant to serotonin dysfunction, depression is most important, because defending according to the world Raw Organization, depression have become the fourth-largest burden property disease of the mankind.The year two thousand twenty is expected, the disability of depression adjusts the service life 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 clinical research in relation to depression shows that the phenomenon that 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 related diseases.
The present invention provides a kind of noval chemical compounds with serotonin reuptake transporter inhibitory activity, before having preferable clinical application Scape.Compared with existing similar compound, the compound of the present invention has better drug effect, and medicine is for property and/or toxicological profile.
Summary of the invention
Only summarize some aspects of the 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 When variant with citation, it is subject to the disclosure of the specification.
The present invention relates to a kind of novel (2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives, with 5-HT transporter (SERT) there is stronger binding affinity, 5-HT reuptake can be inhibited, so as to be used to prepare treatment central nervous system (CNS) drug of dysfunction, is especially 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, hydrate, solvate, metabolite, can pharmaceutically connect geometric isomer The salt or its prodrug received,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8, X and Y there is meaning as described in the present invention.
In one embodiment, X can be CRxOr N.
In one embodiment,For singly-bound or double bond.
In one embodiment, whenWhen for singly-bound, Y is N or CH.
In one embodiment, whenWhen for double bond, Y C.
In one embodiment, R1、R2、R3And RxIt is each independently 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-C6 Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6The C that alkylamino or hydroxyl replace1-C6Alkyl.
In one embodiment, R4、R5、R6And R7It is each independently 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-C6 Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy or C1-C6Halogenated alkoxy.
In one embodiment, R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R1、R2、R3And RxIt is each independently 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-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or hydroxyl Substituted C1-C4Alkyl.
In one embodiment, R4、R5、R6And R7It 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, R1、R2、R3And RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、 -SH、-COOH、-CONH2,-C (=O) CH3,-C (=O) OCH3, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, first Oxygroup, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R4、R5、R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、 - COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
In another embodiment, compound of the present invention is compound or tool with one of following structure There are stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, the solvent of the compound of one of following structure Compound, 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 any combination.
In another embodiment, pharmaceutical composition of the present invention, further comprising treatment central nervous system The drug of the drug of dysfunction, the treatment central nervous system dysfunction is antidepressant, anxiolytic drugs, conduct The salts drugs of mood stabilizers, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, as choosing Drug, nervous stimulants, nicotinic antagonists or their any combination of selecting property serotonin reuptake inhibitor.
In yet another embodiment, it is amitriptyline that the present invention, which treats the drug of central nervous system dysfunction, (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 any combination.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, treating or mitigating central nervous system dysfunction.For example, in one embodiment, the drug For preventing, treating or mitigating mammalian central nervous system dysfunction, in another embodiment, the drug is used for Prevent, treat or mitigate the central nervous system dysfunction of 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 disturbance, 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 disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, treating 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 disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for inhibiting 5- hydroxytryptamine reuptake.
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 source of people 5-HT transporter (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 present 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 in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention 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 range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention 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 where (including 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 invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the 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 Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, the 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 that one component is taken into account in the embodiment.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, conformer (rotational isomer), geometry (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 achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced " 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, Br, I, N3,-CN ,-NO2,-NH2,-OH ,-SH ,-COOH ,-CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-alkyl ,-C (=O)-alkoxy, alkyl, alkoxy, alkylthio group, alkylamino, alkenyl, alkynyl, Halogenated alkyl, halogenated alkoxy, the alkyl that hydroxyl replaces, naphthenic base, heterocycle, aryl, heteroaryl etc..
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention 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 the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
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 ", indicate contain 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 Replace.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 not It is limited to, 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), tert-butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be optionally by one or more institutes of the present invention Replaced the substituent group of description comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.
Term " alkoxy " indicates 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 Replaced the substituent group that the present invention describes.
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 " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), second Sulfenyl (EtS ,-SCH2CH3), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH2CH2CH3), 2- rosickyite base (i-PrS, i- rosickyite Base ,-SCH (CH3)2), etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets It invents replaced described substituent group.
Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..
Term " halogenated alkyl " or " halogenated alkoxy " indicate alkyl or alkoxy base by one or more halogen atoms Replaced, wherein alkyl and alkoxy base have meaning as described in the present invention, and such example includes, but is not limited to, Trifluoromethyl, trifluoromethoxy etc..In one embodiment, C1-C6Halogenated alkyl includes fluorine-substituted C1-C6Alkyl；Another In embodiment, C1-C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl；In yet another embodiment, C1-C2Halogenated alkyl packet Containing fluorine-substituted C1-C2Alkyl.
As described in the invention, substituent R is keyed to the ring system formed on the ring at center (following institute by one Show) it represents substituent R and can may replace or any reasonable position replaced place is any on ring.For example, formula a Substituent R any possible substituted position on piperazine ring is represented, such as formula a1-a5It is shown:
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used 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, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of 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 into 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, 1977,66:1-19. documented.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 acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur 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 alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.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-C8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In some embodiments, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In other embodiments, a compounds of this invention point Son can be combined with more than one hydrone, such as dihydrate, in further embodiments, a compounds of this invention Molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remains with The biological effectiveness of the compound of nonhydrated form.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
Term " therapeutically effective amount " refers to that when delivering medicine to main body to treat disease, the component of compound is enough to this disease The treatment of disease works." therapeutically effective amount " can be with the item of compound, disease and severity and main body to be treated Part, the age, weight, gender etc. and change.
(2- heteroaryl aminocarbonyl phenyl) azepine ring derivatives of the present invention, pharmaceutically acceptable salt, drug system Agent and combinations thereof may be used as selective serotonin reuptake inhibitor, special to mankind's central nervous system dysfunction It is not that the treatment of the disturbance of emotion has potential purposes, the disturbance of emotion includes but is not limited to depression, anxiety disorder, social activity Neurosis, obsessive-compulsive disorder, panic attack, 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 be included in the invention as disclosed compound of present 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 is with regard to this clear and definition.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to and can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use 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 and be used to prepare and/or purify compound shown in formula (I) and/or for separating compound shown in this formula (I) Enantiomer intermediate.
Any structural formula that the present invention provides, which is also intended to, indicates 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 Isotope including 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 of compound shown in preparation 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 includes 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 are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al., Ansel’s PharmaceuticalDosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins, Philadelphia；Gennaro A.R.et al., Remington:The Science and Practiceof Pharmacy (2000) Lippincott, Williams & Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In PharmaceuticalPress, Chicago.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate 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 is administered can directly 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.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, disintegrating agent, 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 of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make 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 those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains 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 capsule, 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 injection, infusion or implantation parenteral administration, for part or entirely Body administration.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, mixed 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 be prepared according to conventional method known to the technical staff in pharmaceutical science field (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.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition 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 pharmaceutical composition
Compound provided by the invention and pharmaceutical composition can be used for preparing for preventing, treating or mitigating 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 in pharmaceutical composition of the invention The reuptake of serotonin, the compound of the present invention can be used as treatment mankind's central nervous system (CNS) dysfunction, especially The drug of the disturbance of emotion, 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.
The compound of the present invention can be applied to, but be not limited to, and use the compound of the present invention or pharmaceutical composition Effective quantity administers to a patient to prevent, treat or mitigate central nervous system dysfunction disease.It is described in response to 5- hydroxyl Tryptamines regulation central nervous system dysfunction, further comprise but be not limited to, depression, anxiety disorder, social phobia, Obsessive-compulsive disorder, panic attack, specific phobias, agoraphobia, mania, panic disorder, posttraumatic stress disorder, schizophrenia Disease, sleep disturbance, bipolar disorders, besetment and behavior disorder, dyskinesia, sex dysfunction, musculoskeletal pain obstacle, Cognitive disorder, memory disorders, Parkinson's disease, Huntington's disease, phobia, substance abuse or habituation, drug addiction withdrawal disease Shape 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, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with 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 be administered simultaneously, or before it or later with one or more other therapeutic agents.The compounds of this invention can To be administered respectively with other therapeutic agents by identical or different administration route, or therewith with the administration of same 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 Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing 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 purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemical reagent Factory, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform 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 flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、 DMSO-d6、 CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0 ppm) or chloroform (7.26 ppm) as ginseng Sighting target is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened Singlet, wide is unimodal), dd (doublet of doublets, double doublet), dt (doublet of triplets, it is double Triplet).Coupling constant J is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1 x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses 1260 pre-HPLC or Calesep pump of Agilent, 250 pre-HPLC (pillar type Number: 50/80 mm DAC of NOVASEP), detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention:
BOC, Boc tert-butoxycarbonyl min minutes mmol, mM mM
CH2Cl2, h hours μM micromoles of DCM methylene chloride
CDC1310% palladium carbon nM nanomole of deuterated chloroform 10%Pd/C
DMSO dimethyl sulfoxide t-BuONa sodium tert-butoxide μ g microgram
DMSO-d6Deuterated dimethyl sulfoxide Na2CO3Mg milligrams of sodium carbonate, sodium acetate
EtOAc, EA ethyl acetate NaHCO3G grams of sodium bicarbonate
CH3OH, MeOH methanol K2CO3Kg kilograms of potassium carbonate
N-BuOH n-butanol Na2SO4Sodium sulphate PE petroleum ether (60-90 DEG C)
DMF N,N-dimethylformamide NaCl sodium chloride RT, rt, r.t. room temperature
CF3COOH, TFA trifluoroacetic acid KCl potassium chloride Rt retention time
Et3N triethylamine HCl hydrochloric acid Saline physiological saline
(Boc)2O di-tert-butyl dicarbonate N2Nitrogen BSA bovine serum albumin
Toluene toluene H2ML, ml milliliters of hydrogen
Tri- (hydroxyl first of Tris (dibenzylideneacetone) dipalladium (0) tris(dibenzylideneacetone) dipalladium Tris-HCl Base) aminomethane-hydrochloric acid
Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R1、R2、 R3、R4、R5、 R6、R7、R8, X and Y there is definition of the present invention.
Synthetic schemes 1
Formula (4) compound represented can be prepared by synthetic schemes 1: the 2- bromaniline containing different substituents (1) by coupling reaction obtain compound (2), compound (2) obtained with the pyrilamine containing different substituents or pyridine amine coupling To compound (3), compound (3) slough in acid condition Boc protect to obtain target compound (4)。
Synthetic schemes 2
Wherein, L is leaving group: F, Br.
Formula (4) compound represented can be prepared by synthetic schemes 2: aniline containing different substituents (5) logical Cross coupling reaction obtain compound (6), compound (6) be coupled to obtain with the 2- chlorine pyrimidine containing different substituents or 2- chloropyridine Compound (3), compound (3) slough in acid condition Boc protect to obtain target compound (4)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
The synthesis of 1 4,6- dimethyl-N-of embodiment (2- (piperazine -1- base) phenyl) pyrimidine -2- amine
The synthesis of step 1) 1- (2- bromophenyl) piperazine
Successively by 2- bromaniline (10g, 58.13mmol), bis- (2- chloroethyl) amine hydrochlorates (10.37g, 58.13mmol) It is added in n-butanol (50mL) with potassium carbonate (16.05g, 116.2mmol), reaction is warming up to 130 DEG C of reactions under nitrogen atmosphere 50 hours.Stop reaction, be cooled to room temperature, reaction solution adds water (150mL) to dilute, and methylene chloride (50mL × 3) extraction is associated with Machine phase, anhydrous sodium sulfate is dry, and vacuum distillation removes solvent, and gained crude product chromatographs (methylene chloride: methanol (V:V) by column =20:1) it isolates and purifies to obtain title compound (brown oil, 7.01g, 50%).
MS(ESI,pos.ion)m/z:241.05[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.62 (dd, J=7.9,1.3Hz, 1H), 7.29~7.21 (m, 1H), 7.08 (d, J=7.2Hz, 1H), 6.97~6.95 (m, 1H), 3.48 (t, 4H), 3.15~3.05 (m, 4H)
The synthesis of step 2) 4- (2- bromophenyl) piperazine -1- t-butyl formate
1- (2- bromophenyl) piperazine (12g, 50mmol) and triethylamine (21mL, 150mmol) are successively added to dichloromethane In alkane (50mL), it is then slowly added to di-tert-butyl dicarbonate (21.8g, 100mmol), after addition, room temperature reaction 2 is small When.Stop reaction, reaction solution successively uses water (50mL), saturated salt solution (50mL) to wash, and anhydrous sodium sulfate is dry, vacuum distillation Solvent is removed, gained crude product isolates and purifies to obtain titled by column chromatography (petroleum ether: ethyl acetate (V:V)=50:1) It closes object (colorless and transparent oily object, 6.82g, 40%).
MS(ESI,pos.ion)m/z:341.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.59 (dd, J=7.9,1.3Hz, 1H), 7.33~7.23 (m, 1H), 7.05 (d, J=7.2Hz, 1H), 6.97~6.93 (m, 1H), 3.63 (t, 4H), 3.00 (t, 4H), 1.50 (s, 9H)
The synthesis of step 3) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate
Successively by 4- (2- bromophenyl) piperazine -1- t-butyl formate (280mg, 0.82mmol), 4,6- dimethyl pyrimidine -2- Amine (151mg, 1.23 mmol), sodium tert-butoxide (0.16g, 1.16mmol), tris(dibenzylideneacetone) dipalladium (75mg, 0.082mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (102mg, 0.164mmol) is added to dry toluene In (20mL), reaction is warming up to 120 DEG C and reacts 12 hours under nitrogen atmosphere.Stop reaction, is cooled to room temperature, reaction solution pours into In water (100mL), ethyl acetate (40mL × 3) extraction merges organic phase, successively passes through water (50mL), saturated salt solution (50mL) is washed, and anhydrous sodium sulfate is dry, and vacuum distillation removes solvent, and gained crude product chromatographs (methylene chloride: methanol by column (V:V)=50:1) it isolates and purifies to obtain title compound (white solid, 274mg, 87%).
MS(ESI,pos.ion)m/z:384.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.61 (d, J=8.2Hz, 1H), 8.17 (s, 1H), 7.18 (t, J= 7.8Hz, 1H), 7.12 (d, J=7.8Hz, 1H), 6.97 (t, J=7.6Hz, 1H), 6.50 (s, 1H), 3.67 (t, 4H), 2.87 (t,4H),2.40(s,6H),1.51(s,9H).
The synthesis of step 4) 4,6- dimethyl-N-(2- (piperazine -1- base) phenyl) pyrimidine -2- amine
By 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, It 0.52mmol) is added in methylene chloride (6 mL), trifluoroacetic acid (3mL) then is added, it is small that 1 is reacted at room temperature after addition When.Stop reaction, saturated sodium bicarbonate solution quenching reaction, organic phase, anhydrous sodium sulfate are collected in methylene chloride (6mL) extraction Dry, vacuum distillation removes solvent, and gained crude product is isolated and purified by column chromatography (methylene chloride: methanol (V:V)=15:1) Obtain title compound (yellow solid, 119mg, 81%).
MS(ESI,pos.ion)m/z:284.10[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 9.83 (s, 1H), 9.36 (s, 2H), 8.31 (d, J=8.0Hz, 1H), 7.28 (d, J=7.7Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 7.17 (t, J=7.3Hz, 1H), 7.03 (s, 1H), 3.48~3.45 (m, 4H), 3.13~3.03 (m, 4H), 2.51 (s, 6H)；
13C NMR(151MHz,DMSO-d6)δ(ppm):153.6,142.3,132.7,125.8,125.1,121.6, 120.9,112.5,49.2,43.3,40.2；HPLC:99.8%.
The synthesis of embodiment 24,6- dimethoxy-N- (2- (piperazine -1- base) phenyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- ((4,6- dimethoxypyridin -2- base) amino) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- bromophenyl) piperazine Piperazine -1- t-butyl formate (280mg, 0.82mmol), 4,6- dimethoxypyridin -2- amine (191mg, 1.23mmol), the tert-butyl alcohol Sodium (0.16g, 1.16mmol), tris(dibenzylideneacetone) dipalladium (75mg, 0.082mmol) and (±) -2,2'- pairs-(diphenyl phosphine Base) -1,1'- dinaphthalene (102mg, 0.164mmol) 120 DEG C of nitrogen protection reactions preparation in 12 hours in dry toluene (20mL). Gained crude product by column chromatography (methylene chloride: methanol (V:V)=50:1) isolates and purifies to obtain title compound, and (white is solid Body, 238mg, 70%).
MS(ESI,pos.ion)m/z:416.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.52 (d, J=8.2Hz, 1H), 8.15 (s, 1H), 7.18 (t, J= 7.8Hz, 1H), 7.13 (d, J=7.8Hz, 1H), 6.99 (t, J=7.6Hz, 1H), 5.61 (s, 1H), 3.97 (s, 6H), 3.67 (t, 4H), 2.88 (t, J=4.6Hz, 4H), 1.52 (s, 9H)
The synthesis of step 2) 4,6- dimethoxy-N- (2- (piperazine -1- base) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methoxy pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.48mmol) and trifluoroacetic acid (3mL) exist It prepares within room temperature reaction 1 hour in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=15: 1) it isolates and purifies to obtain title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:316.10[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.26 (dd, J=8.0,1.0Hz, 1H), 8.18 (s, 1H), 7.22 ~7.11 (m, 2H), 7.03 (t, J=12,1H), 5.68 (s, 1H), 3.87 (s, 6H), 3.32~3.22 (m, 4H), 3.06~ 2.98(m,4H)；
13C NMR(151MHz,DMSO-d6)δ(ppm):172.1,159.1,141.5,134.4,125.4,123.0, 120.7,120.5,81.0,54.3,48.8, 43.6；
HPLC:99.1%.
The synthesis of 3 4- of embodiment (piperazine-1- base)-3- (pyrimidine -2 --amino) cyanophenyl
The synthesis of step 1) 3- amino -4- (piperazine -1- base) cyanophenyl
3- amino -4- fluorobenzonitrile (3.0g, 22mmol) and Piperazine anhydrous (7.6g, 88.2mmol) are successively added to diformazan In base sulfoxide (50mL), under nitrogen atmosphere, reaction is warming up to 130 DEG C and reacts 48 hours.Stop reaction, is cooled to room temperature.Reaction Liquid is poured into water, and methylene chloride extraction merges organic phase, and successively by washing, saturated common salt washing, anhydrous sodium sulfate is dry, Vacuum distillation removes solvent, and gained crude product is isolated and purified and marked by column chromatography (methylene chloride: methanol (V:V)=10:1) It inscribes compound (brown oil, 1.56g, 35%).
MS(ESI,pos.ion)m/z:203.10[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.59~7.51 (m, 1H), 7.28~7.21 (m, 1H), 6.97~ 6.95 (m, 1H), 6.28 (s, 2H), 3.47 (t, 4H), 3.15~3.07 (m, 4H)
The synthesis of step 2) 4- (2- amino -4- cyano-phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 3- amino -4- (piperazine Piperazine -1- base) cyanophenyl (1.3g, 6.4 mmol), di-tert-butyl dicarbonate (2.2g, 10mmol) and triethylamine (2.7mL, 19.2mmol) prepare within room temperature reaction 2 hours in methylene chloride (20mL).Gained crude product chromatographs (petroleum ether: second by column Acetoacetic ester (V:V)=10:1) it isolates and purifies to obtain title compound (white solid, 1.64g, 85%).
MS(ESI,pos.ion)m/z:247.20[M+H-56]+；
1HNMR(600MHz,CDCl3) δ (ppm): 7.00 (dd, J=8.1,1.8Hz, 1H), 6.94 (d, J=1.8Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 3.55~3.50 (m, 4H), 2.86~2.83 (m, 4H), 1.46 (s, 9H)
The synthesis of step 3) 4- (4- cyano-2- (pyrimidine -2 --amino) phenyl) piperazine-1- t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), 2- chlorine pyrimidine (113mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs-(diphenyl phosphine Base) -1,1'- dinaphthalene (82mg, 0.132mmol) is in dry toluene (20 mL), lower 120 DEG C of reactions, the 12 hours systems of nitrogen atmosphere It is standby.Gained crude product isolates and purifies to obtain title compound (white by column chromatography (methylene chloride: methanol (V:V)=50:1) Solid, 131mg, 52%).
MS(ESI,pos.ion)m/z:381.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.94 (s, 1H), 8.50 (d, J=4.8Hz, 2H), 8.16 (s, 1H), 7.29 (s, 1H), 7.15 (d, J=8.2Hz, 1H), 6.84 (t, J=4.8Hz, 1H), 3.77~3.61 (m, 4H), 3.02~ 2.82(m,4H),1.50(s,9H).
The synthesis of step 4) 4- (piperazine-1- base)-3- (pyrimidine -2 --amino) cyanophenyl
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- (pyrimidine -2 --amino) phenyl) piperazine-1- t-butyl formate (200mg, 0.53mmol) and trifluoroacetic acid (3mL) be in dichloromethane It prepares within room temperature reaction 2 hours in alkane (6mL).Gained crude product passes through column chromatography (methylene chloride: methanol (V:V)=15:1) separation Purifying obtains title compound (white solid, 119mg, 80%).
MS(ESI,pos.ion)m/z:281.20[M+H]+；
1HNMR(400MHz,CDCl3) δ (ppm): 8.91 (d, J=1.2Hz, 1H), 8.48 (d, J=4.8Hz, 2H), 8.15 (s, 1H), 7.27~7.25 (m, 1H), 7.16 (d, J=8.2Hz, 1H), 6.80 (t, J=4.8Hz, 1H), 3.10~3.05 (m, 4H), 2.92~2.88 (m, 4H), 2.34 (s, 1H)；
13C NMR(100MHz,CDCl3)δ(ppm):159.5,158.0,145.2,135.1,125.9,121.3,120.7, 119.5,113.4,108.1,52.7, 46.4；
HPLC:98.8%.
The synthesis of 4 3- of embodiment ((4,6- dimethyl pyrimidine -2- base) amino) -4- (piperazine -1- base) cyanophenyl
Step 1) 4- (4- cyano -2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate Synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), the chloro- 4,6- dimethyl pyrimidine (141mg, 0.99mmol) of 2-, Sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs - (diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132mmol) is in dry toluene (20mL), the lower 120 DEG C of reactions 12 of nitrogen atmosphere Hour preparation.Gained crude product isolates and purifies to obtain title compound by column chromatography (methylene chloride: methanol (V:V)=50:1) Object (white solid, 183mg, 68%).
MS(ESI,pos.ion)m/z:409.30[M+H]+；
1HNMR(600MHz,CDCl3) δ (ppm): 8.95 (s, 1H), 7.28 (d, J=5.6Hz, 1H), 7.13 (d, J= 8.1Hz,1H),6.60(s,1H), 3.70(s,4H),2.90(s,4H),2.44(s,6H),1.50(s,9H).
The synthesis of step 2) 3- ((4,6- dimethyl pyrimidine -2- base) amino) -4- (piperazine -1- base) cyanophenyl
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.49mmol) and trifluoroacetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: methanol by column (V:V)=15:1) it isolates and purifies to obtain title compound (white solid, 139mg, 90%).
MS(ESI,pos.ion)m/z:309.25[M+H]+；
1HNMR(600MHz,DMSO-d6)δ(ppm):9.73(s,1H),9.58(s,2H),8.58(s,1H),7.61(d,J =8.1Hz, 1H), 7.38 (d, J=8.2Hz, 1H), 7.08 (s, 1H), 3.44~3.40 (m, 4H), 3.17~3.15 (m, 4H),2.52(s,6H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):154.4,146.8,133.0,129.1,124.3,122.3, 119.3,113.2,107.1,48.2,42.9, 40.0；
HPLC:99.5%.
The synthesis of 5 3- of embodiment ((4,6- dimethoxypyridin -2- base) amino) -4- (piperazine -1- base) cyanophenyl
Step 1) 4- (4- cyano -2- ((4,6- dimethoxypyridin -2- base) amino) phenyl) piperazine -1- t-butyl formate Synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), the chloro- 4,6- dimethoxypyridin of 2- (173mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132mmol) in dry toluene (20mL), nitrogen atmosphere It prepares within lower 120 DEG C of reactions 12 hours.Gained crude product is isolated and purified by column chromatography (methylene chloride: methanol (V:V)=50:1) Obtain title compound (white solid, 145mg, 50%).
MS(ESI,pos.ion)m/z:441.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.87 (d, J=1.5Hz, 1H), 7.91 (s, 1H), 7.27 (dd, J= 8.1,1.6Hz, 1H), 7.13 (d, J=8.2Hz, 1H), 5.65 (s, 1H), 3.96 (s, 6H), 3.67~3.63 (m, 4H), 2.90~2.87 (m, 4H), 1.50 (s, 9H)；
13C NMR(150MHz,CDCl3)δ(ppm):172.0,158.1,154.7,144.5,135.2,125.7,121.8, 120.6,119.4,108.3,82.0, 80.2,54.1,51.5,28.4.
The synthesis of step 2) 3- ((4,6- dimethoxypyridin -2- base) amino) -4- (piperazine -1- base) cyanophenyl
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4,6- dimethoxypyridin -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.45mmol) and trifluoro second Sour (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: methanol by column (V:V)=15:1) it isolates and purifies to obtain title compound (white solid, 141mg, 92%).
MS(ESI,pos.ion)m/z:341.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.88 (d, J=1.8Hz, 1H), 7.93 (s, 1H), 7.29~7.26 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 5.66 (s, 1H), 3.97 (s, 6H), 3.16~3.12 (m, 4H), 2.96~2.93 (m,4H)；
13C NMR(100MHz,CDCl3)δ(ppm):172.1,158.3,145.0,135.3,125.7,121.7,120.6, 119.5,108.1,81.9,54.1, 52.4,46.2；
HPLC:98.5%.
The synthesis of embodiment 64- (piperazine -1- base) -3- ((4- (trifluoromethyl) pyrimidine -2-base) amino) cyanophenyl
Step 1) 4- (4- cyano -2- ((4- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) piperazine -1- t-butyl formate Synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (181mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132mmol) in dry toluene (20mL), nitrogen atmosphere It prepares within lower 120 DEG C of reactions 12 hours.Gained crude product is isolated and purified by column chromatography (methylene chloride: methanol (V:V)=50:1) Obtain title compound (white solid, 175mg, 59%).
MS(ESI,pos.ion)m/z:449.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.84 (d, J=1.7Hz, 1H), 8.72 (d, J=4.9Hz, 1H), 8.37 (s, 1H), 7.34 (dd, J=8.2,1.8Hz, 1H), 7.18 (d, J=8.2Hz, 1H), 7.12 (d, J=4.9Hz, 1H), 3.68~3.65 (m, 4H), 2.90~2.85 (m, 4H), 1.49 (s, 9H)
The synthesis of step 2) 4- (piperazine -1- base) -3- ((4- (trifluoromethyl) pyrimidine -2-base) amino) cyanophenyl
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- ((4- (trifluoromethyl) pyrimidine -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.45mmol) and trifluoro second Sour (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: methanol by column (V:V)=15:1) it isolates and purifies to obtain title compound (white solid, 141mg, 90%).
MS(ESI,pos.ion)m/z:349.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.85 (d, J=1.5Hz, 1H), 8.73 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.36 (dd, J=8.2,1.7Hz, 1H), 7.22 (d, J=8.2Hz, 1H), 7.12 (d, J=4.9Hz, 1H), 3.14~3.10 (m, 4H), 3.00~2.84 (m, 4H)；
13C NMR(100MHz,CDCl3)δ(ppm):160.6,159.6,156.7,145.57,134.4,126.8, 121.6,120.9,119.2,118.9,114.0, 108.4,52.9,46.3；
HPLC:98.8%.
The synthesis of 7 4- of embodiment (piperazine -1- base) -3- (pyridine -2- base amino) cyanophenyl
The synthesis of step 1) 4- (4- cyano -2- (pyridine -2- base amino) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), 2- chloropyridine (112mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs-(diphenyl phosphine Base) -1,1'- dinaphthalene (82mg, 0.132mmol) is in dry toluene (20 mL), lower 120 DEG C of reactions, the 12 hours systems of nitrogen atmosphere It is standby.Gained crude product isolates and purifies to obtain title compound (white by column chromatography (methylene chloride: methanol (V:V)=50:1) Solid, 198mg, 79%).
MS(ESI,pos.ion)m/z:380.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.55 (s, 1H), 8.27 (d, J=4.7Hz, 1H), 7.57 (t, J= 7.8Hz, 1H), 7.40 (s, 1H), 7.21 (d, J=8.1Hz, 1H), 7.08 (d, J=8.1Hz, 1H), 6.84~6.80 (m, 1H), 6.79 (d, J=8.3Hz, 1H), 3.60~3.52 (m, 4H), 2.88~2.83 (m, 4H), 1.47 (s, 9H)
The synthesis of step 2) 4- (piperazine -1- base) -3- (pyridine -2- base amino) cyanophenyl
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- (pyridine -2- base amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.53mmol) and trifluoroacetic acid (3mL) be in dichloromethane It prepares within room temperature reaction 2 hours in alkane (6mL).Gained crude product passes through column chromatography (methylene chloride: methanol (V:V)=15:1) separation Purifying obtains title compound (white solid, 120mg, 81%).
MS(ESI,pos.ion)m/z:280.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.61 (s, 1H), 8.30 (d, J=3.7Hz, 1H), 7.58 (dd, J= 11.0,4.3Hz, 1H), 7.44 (s, 1H), 7.26~7.19 (m, 1H), 7.13 (d, J=8.1Hz, 1H), 6.86~6.82 (t, J=11.9Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 3.08~3.02 (m, 4H), 2.92~2.87 (m, 4H), 2.30 (s, 1H)；
13C NMR(151MHz,CDCl3)δ(ppm):154.5,148.2,145.2,137.8,136.2,125.2,120.5, 120.2,119.6,116.0,110.8, 107.8,52.4,46.5；
HPLC 99.4%.
The synthesis of 8 2- of embodiment ((5- cyano -2- (piperazine -1- base) phenyl) amino) nicotinic acid nitrile
The synthesis of step 1) 4- (4- cyano -2- ((nicotinonitrile -2- base) amino) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- cyanogen Base phenyl) piperazine -1- t-butyl formate (200mg, 0.66mmol), 2- chlorine nicotinic acid nitrile (137mg, 0.99mmol), sodium tert-butoxide (127mg, 1.32mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs-(diphenyl phosphine Base) -1,1'- dinaphthalene (82mg, 0.132mmol) is in dry toluene (20 mL), lower 120 DEG C of reactions, the 12 hours systems of nitrogen atmosphere It is standby.Gained crude product isolates and purifies to obtain title compound (yellow by column chromatography (methylene chloride: methanol (V:V)=50:1) Solid, 187mg, 70%).
MS(ESI,pos.ion)m/z:349.15[M+H-56]+；
1H NMR(600MHz,CDCl3) δ (ppm): 9.12 (d, J=1.1Hz, 1H), 8.86 (s, 1H), 8.52 (dd, J= 4.9,1.8Hz, 1H), 7.87 (dd, J=7.7,1.9Hz, 1H), 7.35 (dd, J=8.1,1.8Hz, 1H), 7.24 (d, J= 8.2Hz, 1H), 6.93 (dd, J=7.7,5.0Hz, 1H), 3.74~3.68 (m, 4H), 2.90~2.81 (m, 4H), 1.50 (s, 9H).
The synthesis of step 2) 2- ((5- cyano -2- (piperazine -1- base) phenyl) amino) nicotinic acid nitrile
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- cyano -2- ((nicotinonitrile -2- base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.49mmol) and trifluoroacetic acid (3mL) It prepares within room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)= It 15:1) isolates and purifies to obtain title compound (white solid, 104 mg, 70%).
MS(ESI,pos.ion)m/z:305.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 9.10 (d, J=1.6Hz, 1H), 8.87 (s, 1H), 8.51 (dd, J= 4.9,1.7Hz, 1H), 7.86 (dd, J=7.6,1.8Hz, 1H), 7.34 (d, J=1.8Hz, 1H), 7.31~7.24 (m, 1H), 6.91 (dd, J=7.6,5.0Hz, 1H), 3.24~3.09 (m, 4H), 3.06~2.74 (m, 4H), 1.96 (s, 1H)；
13C NMR(151MHz,CDCl3)δ(ppm):155.2,152.2,145.5,141.6,135.2,126.5,121.4, 121.3,119.4,116.3,114.7, 108.6,94.5,52.9,46.5；
HPLC:96.6%.
The synthesis of 9 N- of embodiment (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
The synthesis of step 1) 2- (piperazine -1- base) -5- (trifluoromethyl) aniline
This step title compound method referring to described in 3 step 1 of embodiment is prepared, i.e. the fluoro- 5- (fluoroform of 2- Base) aniline (4.0g, 22.4 mmol) and Piperazine anhydrous (9.0g, 100mmol) the nitrogen guarantor in anhydrous dimethyl sulphoxide (50mL) It protects lower 135 DEG C of reactions 48 hours and prepares.Gained crude product is separated pure by column chromatography (methylene chloride: methanol (V:V)=15:1) Change obtains title compound (brown oil, 1.65g, 30%).
MS(ESI,pos.ion)m/z:246.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.01~6.97 (m, 2H), 6.95 (s, 1H), 3.58 (brs, 4H), 2.78(brs,4H).
The synthesis of step 2) 4- (2- amino -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. 2- (piperazine -1- base) - 5- (trifluoromethyl) aniline (1.6 g, 6.5mmol), di-tert-butyl dicarbonate (1.7g, 7.8mmol) and triethylamine (1.4mL, 10mmol) prepare within room temperature reaction 2 hours in methylene chloride (20mL).Gained crude product chromatographs (petroleum ether: acetic acid second by column Ester (V:V)=10:1) it isolates and purifies to obtain title compound (yellow solid, 1.35g, 60%).
MS(ESI,pos.ion)m/z:290.20[M+H-56]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.01~6.97 (m, 2H), 6.95 (s, 1H), 3.58 (brs, 4H), 2.88(brs,4H),1.48(s, 9H).
Step 3) 4- (2- (pyrimidine) -2- base amino) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.58mmol), 2- chlorine pyrimidine (100mg, 0.87mmol), uncle Sodium butoxide (127mg, 0.87mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- double-(two Phosphenyl) for -1,1'- dinaphthalene (82mg, 0.132mmol) in dry toluene (20mL), the lower 120 DEG C of reactions 12 of nitrogen atmosphere are small When prepare.Gained crude product isolates and purifies to obtain title compound by column chromatography (methylene chloride: methanol (V:V)=50:1) (yellow oil, 184mg, 75%).
MS(ESI,pos.ion)m/z:424.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.90 (s, 1H), 8.49 (d, J=4.8Hz, 2H), 8.29 (s, 1H), 7.24 (d, J=8.1Hz, 1H), 7.18 (d, J=8.2Hz, 1H), 6.79 (t, J=4.8Hz, 1H), 3.67 (brs, 4H), 2.89(brs,4H),1.50(s,9H).
The synthesis of step 4) N- (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- (pyrimidine) -2- Base amino) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.47mmol) and trifluoroacetic acid (3mL) exist It prepares within room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=15: 1) it isolates and purifies to obtain title compound (yellow solid, 137mg, 90%).
MS(ESI,pos.ion)m/z:324.20[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 9.54 (s, 2H), 9.28 (s, 1H), 8.70 (d, J=4.9Hz, 1H), 8.54 (d, J=1.4Hz, 1H), 7.47~7.42 (m, 1H), 7.38 (d, J=8.3Hz, 1H), 7.09 (t, J= 4.9Hz, 1H), 3.33~3.21 (m, 4H), 3.21~3.06 (m, 4H)；13C NMR(151MHz,DMSO-d6)δ(ppm): 158.5,157.7,145.6,133.8,125.3,124.7,121.7,120.8,117.5,113.7, 48.3,43.2；
HPLC:98.7%.
The synthesis of 10 4,6- dimethyl-N-of embodiment (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
Step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid uncle The synthesis of butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.58mmol), the chloro- 4,6- dimethyl pyrimidine of 2- (124mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132 mmol) in dry toluene (20mL), nitrogen atmosphere It prepares within lower 120 DEG C of reactions 12 hours.Gained crude product is isolated and purified by column chromatography (methylene chloride: methanol (V:V)=50:1) Obtain title compound (faint yellow solid, 222mg, 85%).
MS(ESI,pos.ion)m/z:452.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 9.01 (s, 1H), 8.15 (s, 1H), 7.23 (dd, J=8.3,1.5Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 6.57 (s, 1H), 3.70~3.59 (m, 4H), 2.90~2.85 (m, 4H), 2.43 (s, 6H),1.51(s,9H).
The synthesis of step 2) 4,6- dimethyl-N-(2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.44mmol) and trifluoro Acetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: first by column Alcohol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 139mg, 90%).
MS(ESI,pos.ion)m/z:352.20[M+H]+；
1H NMR (400MHz, MeOD) δ (ppm): 8.80 (s, 1H), 7.57 (d, J=1.6Hz, 2H), 7.13 (s, 1H), 3.71~3.63 (m, 4H), 3.29~3.21 (m, 4H), 2.66 (s, 6H)；
13C NMR(100MHz,MeOD)δ(ppm):152.4,145.1,132.5,127.5,124.0,122.0,121.9, 118.0,112.6,48.8,43.3；HPLC:99.4%.
The conjunction of 11 4,6- dimethoxy-N- of embodiment (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine At
Step 1) 4- (2- ((4,6- dimethoxypyridin -2- base) amino) -4- (trifluoromethyl) phenyl) piperazine -1- formic acid The synthesis of the tert-butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.58mmol), the chloro- 4,6- dimethoxypyridin of 2- (152mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132 mmol) is in dry toluene In (20mL), prepare within nitrogen atmosphere lower 120 DEG C of reactions 12 hours.Gained crude product by column chromatograph (methylene chloride: methanol (V: V)=50:1) it isolates and purifies to obtain title compound (yellow solid, 210mg, 75%).
MS(ESI,pos.ion)m/z:484.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 9.00 (d, J=1.7Hz, 1H), 8.07 (s, 1H), 7.25 (dd, J= 8.3,1.5Hz, 1H), 7.18 (d, J=8.2Hz, 1H), 5.65 (s, 1H), 3.98 (s, 6H), 3.69~3.61 (m, 4H), 2.90~2.82 (m, 4H), 1.52 (s, 9H)
The synthesis of step 2) 4,6- dimethoxy-N- (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.41mmol) and trifluoro Acetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: first by column Alcohol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 141mg, 90%).
MS(ESI,pos.ion)m/z:384.15[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 9.62 (s, 2H), 8.67 (s, 2H), 7.39 (dd, J=8.4, 1.6Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 5.83 (s, 1H), 3.90 (s, 6H), 3.34~3.26 (m, 4H), 3.18~ 3.05(m,4H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):171.8,158.0,145.0,134.4,125.3,124.8, 121.5,120.0,117.5,81.6,54.7, 48.3,43.2；
HPLC:99.6%.
The conjunction of 12 N- of embodiment (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine At
Step 1) 4- (4- (trifluoromethyl) -2- ((4- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) piperazine -1- formic acid The synthesis of the tert-butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) piperazine -1- t-butyl formate (200mg, 0.58mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (159mg, 0.87mmol), sodium tert-butoxide (127mg, 0.87 mmol), tris(dibenzylideneacetone) dipalladium (60mg, 0.066mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (82mg, 0.132 mmol) is in dry toluene In (20mL), prepare within nitrogen atmosphere lower 120 DEG C of reactions 12 hours.Gained crude product by column chromatograph (methylene chloride: methanol (V: V)=50:1) it isolates and purifies to obtain title compound (yellow solid, 131mg, 46%).
MS(ESI,pos.ion)m/z:492.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.89 (s, 1H), 8.71 (d, J=4.8Hz, 1H), 8.52 (s, 1H), 7.31 (d, J=8.0Hz, 1H), 7.23 (d, J=8.2Hz, 1H), 7.10 (d, J=4.9Hz, 1H), 3.69 (brs, 4H), 2.91(brs,4H),1.51(s,9H).
The synthesis of step 2) N- (2- (piperazine -1- base) -5- (trifluoromethyl) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (4- (fluoroform Base) -2- ((4- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) piperazine -1- t-butyl formate (200mg, 0.41mmol) and Trifluoroacetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (dichloromethane by column Alkane: methanol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 144mg, 90%).
MS(ESI,pos.ion)m/z:392.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.89 (s, 1H), 8.72 (d, J=4.9Hz, 1H), 8.58 (s, 1H), 7.35~7.30 (m, 1H), 7.27 (d, J=8.2Hz, 1H), 7.10 (d, J=4.9Hz, 1H), 3.16~3.11 (m, 4H), 2.95~2.89 (m, 4H)；
13C NMR(151MHz,CDCl3)δ(ppm):160.6,159.7,156.5,144.3,134.2,127.2,124.2, 120.6,120.4,119.5,115.4, 108.1,53.1,46.5；
HPLC:99.8%.
The synthesis of 13 N- of embodiment (2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- aminophenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate
Successively by 2- bromaniline (2.0g, 11.6mmol), 4- (connection frequency ester -2- base) -5,6- dihydropyridine -1 (2H)-formic acid The tert-butyl ester (4.33g, 14.0 mmol), sodium acetate (1.7g, 17.4mmol) and [bis- (diphenylphosphino) ferrocene of 1,1'-] two Palladium chloride (490mg, 0.6mmol) is added to the in the mixed solvent of n,N-Dimethylformamide (30mL) and water (3mL), nitrogen The lower reaction of protection is warming up to 95 DEG C and reacts 12 hours.Stopping reaction, reaction solution pours into water (100mL), methylene chloride (30mL × 3) it extracts, merges organic phase, successively washed by water, saturated common salt, anhydrous sodium sulfate is dry, and vacuum distillation removes solvent, institute Crude product by column chromatograph (methylene chloride: methanol (V:V)=50:1) isolate and purify to obtain title compound (yellow solid, 2.39g, 75%).
MS(ESI,pos.ion)m/z:175.20[M+H-100]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.14~7.04 (m, 1H), 7.00 (d, J=7.5Hz, 1H), 6.76 (t, J=7.4Hz, 1H), 6.72 (d, J=8.0Hz, 1H), 5.78 (s, 1H), 4.06 (d, 2H), 3.65 (t, J=5.3Hz, 2H),2.42(t,2H),1.52(s,9H).
Step 2) 4- (2- (pyrimidine -2 --amino) phenyl)-5,6- dihydropyridine-1 (2H)-t-butyl formate synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- aminobenzene Base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (130mg, 0.40mmol), 2- chlorine pyrimidine (100mg, 0.64mmol), Sodium tert-butoxide (62mg, 0.64mmol), tris(dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (±) -2,2'- double-(two Phosphenyl) in dry toluene (20mL), lower 120 DEG C of nitrogen atmosphere are reacted 12 hours -1,1'- dinaphthalene (50mg, 0.08mmol) Preparation.Gained crude product isolates and purifies to obtain title compound (Huang by column chromatography (methylene chloride: methanol (V:V)=50:1) Color grease, 116mg, 82%).
MS(ESI,pos.ion)m/z:353.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.95 (s, 1H), 8.45 (d, J=4.7Hz, 2H), 7.11~7.05 (m, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.75 (t, J=7.4Hz, 1H), 6.73 (d, J=8.0Hz, 1H), 5.76 (s, 1H), 4.05 (d, 2H), 3.65 (t, J=5.3Hz, 2H), 2.43 (t, 2H), 1.50 (s, 9H)
The synthesis of step 3) N- (2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- (pyrimidine -2- Base amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.57mmol) and trifluoroacetic acid (3mL) be two It prepares within room temperature reaction 2 hours in chloromethanes (6mL).Gained crude product chromatographs (methylene chloride: methanol (V:V)=15:1) by column It isolates and purifies to obtain title compound (yellow oil, 137 mg, 95%).
MS(ESI,pos.ion)m/z:253.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.40 (d, J=4.8Hz, 1H), 8.27 (d, J=8.2Hz, 1H), 7.44 (s, 1H), 7.33~7.29 (m, 1H), 7.14 (dd, J=7.5,1.2Hz, 1H), 7.05 (dd, J=10.7,4.1Hz, 1H), 6.70 (t, J=4.8Hz, 1H), 5.84 (s, 1H), 3.53 (d, J=2.5Hz, 2H), 3.11 (t, J=5.6Hz, 2H), 2.33 (d, J=1.8Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.2,158.0,135.8,135.1,133.7,128.4,127.6, 127.3,122.8,120.5,112.5, 45.0,43.2,30.0；
HPLC:96.2%.
The synthesis of 14 4,6- dimethyl-N-of embodiment (2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine
Step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-formic acid uncle The synthesis of butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- aminobenzene Base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (130mg, 0.40mmol), the chloro- 4,6- dimethyl pyrimidine of 2- (91mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64mmol), tris(dibenzylideneacetone) dipalladium (37mg, 0.04mmol) and (±)- 2,2'- bis--(diphenyl phosphine) -1,1'- dinaphthalenes (50mg, 0.08mmol) are in dry toluene (20mL), and lower 120 DEG C of nitrogen atmosphere It reacts 12 hours and prepares.Gained crude product is isolated and purified and is marked by column chromatography (methylene chloride: methanol (V:V)=50:1) It inscribes compound (yellow oil, 126mg, 83%).
MS(ESI,pos.ion)m/z:381.25[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.34 (d, J=8.2Hz, 1H), 7.35~7.25 (m, 1H), 7.20 (s, 1H), 7.12 (dd, J=7.6,1.6Hz, 1H), 7.03 (td, J=7.5,1.0Hz, 1H), 6.50 (s, 1H), 5.80 (s, 1H), 4.09 (d, J=2.3Hz, 2H), 3.66 (t, J=5.6Hz, 2H), 2.41 (t, 2H), 2.38 (s, 6H), 1.52 (s, 9H).
The synthesis of step 2) 4,6- dimethyl-N-(2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.53mmol) and trifluoro Acetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: first by column Alcohol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 134mg, 90%).
MS(ESI,pos.ion)m/z:281.25[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm): 9.68 (s, 1H), 9.51 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.45~7.34 (m, 1H), 7.29~7.17 (m, 1H), 7.02 (s, 1H), 5.75 (s, 1H), 3.70 (d, 2H), 3.35 ~3.28 (m, 2H), 2.57~2.49 (m, 2H), 2.46 (s, 6H)；13C NMR(100MHz,DMSO-d6)δ(ppm):154.0, 135.3,133.9,133.8,128.9,128.6,125.9,124.1,122.3,112.4, 41.7,40.7,39.6,26.2；
HPLC:95.1%.
The conjunction of 15 4,6- dimethoxy-N- of embodiment (2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine At
Step 1) 4- (2- ((4,6- dimethoxy-pyridine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-formic acid The synthesis of the tert-butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- aminobenzene Base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (130mg, 0.40mmol), the chloro- 4,6- dimethoxypyridin of 2- (112mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64 mmol), tris(dibenzylideneacetone) dipalladium (37mg, 0.04mmol) (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (50mg, 0.08mmol) in dry toluene (20mL), nitrogen atmosphere It encloses lower 120 DEG C of reactions 12 hours and prepares.Gained crude product is separated pure by column chromatography (methylene chloride: methanol (V:V)=50:1) Change obtains title compound (white solid, 155mg, 94%).
MS(ESI,pos.ion)m/z:413.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.35 (d, J=8.2Hz, 1H), 7.36~7.24 (m, 2H), 7.13 (dd, J=7.6,1.6Hz, 1H), 7.05 (dd, J=7.4,1.0Hz, 1H), 5.82 (s, 1H), 5.60 (s, 1H), 4.12 (d, J =2.4Hz, 2H), 3.93 (s, 6H), 3.68 (t, J=5.5Hz, 2H), 2.41 (s, 2H), 1.53 (s, 9H)
The synthesis of step 2) 4,6- dimethoxy-N- (2- (1,2,3,6- tetrahydropyridine -4- base) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methoxy pyrimidine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.64mmol) and three Fluoroacetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: Methanol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 190mg, 95%).
MS(ESI,pos.ion)m/z:313.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.33 (d, J=8.3Hz, 1H), 7.33~7.29 (m, 1H), 7.18 (s, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.4Hz, 1H), 5.85 (s, 1H), 5.59 (s, 1H), 3.92 (s, 6H), 3.70 (d, J=34.1Hz, 2H), 3.30~3.22 (m, 2H), 2.51~2.45 (m, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):172.1,159.1,136.2,135.5,132.4,128.2,127.8, 124.1,122.5,121.1,80.8, 54.0,43.6,42.2,29.7；
HPLC:96.7%.
The conjunction of 16 N- of embodiment (2- (1,2,3,6,-tetrahydropyridine -4- base) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine At
Step 1) 4- (2- ((4- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-formic acid The synthesis of the tert-butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- aminobenzene Base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (130mg, 0.40mmol), 2- chloro- 4- (trifluoromethyl) pyrimidine (117mg, 0.64mmol), sodium tert-butoxide (62mg, 0.64 mmol), tris(dibenzylideneacetone) dipalladium (37mg, 0.04mmol) (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (50mg, 0.08mmol) in dry toluene (20mL), nitrogen atmosphere It encloses lower 120 DEG C of reactions 12 hours and prepares.Gained crude product is separated pure by column chromatography (methylene chloride: methanol (V:V)=50:1) Change obtains title compound (yellow oil, 80mg, 44%).
MS(ESI,pos.ion)m/z:365.20[M+H-56]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.63 (d, J=4.8Hz, 1H), 8.22 (d, J=8.2Hz, 1H), 7.42 (s, 1H), 7.38~7.32 (m, 1H), 7.21~7.15 (m, 1H), 7.13 (t, J=7.4Hz, 1H), 7.03 (d, J= 4.9Hz, 1H), 5.82 (s, 1H), 4.10 (s, 2H), 3.66 (t, J=5.2Hz, 2H), 2.41 (t, 2H), 1.53 (s, 9H)
The synthesis of step 2) N- (2- (1,2,3,6,-tetrahydropyridine -4- base) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4- (trifluoro Methyl) pyrimidine -2-base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.48mmol) and three Fluoroacetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: Methanol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow solid, 138mg, 90%).
MS(ESI,pos.ion)m/z:321.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.61 (d, J=4.8Hz, 1H), 8.26 (d, J=8.2Hz, 1H), 7.73 (s, 1H), 7.36~7.29 (m, 1H), 7.17 (dd, J=7.6,1.3Hz, 1H), 7.10~7.03 (m, 1H), 7.00 (d, J=4.9Hz, 1H), 5.86 (s, 1H), 3.57 (d, J=2.6 Hz, 2H), 3.13 (t, J=5.6Hz, 3H), 2.36 (d, J =1.9Hz, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.5,160.2,156.4,135.0,134.9,133.9,128.5, 127.8,127.4,123.5,120.7, 120.4,107.5,44.9,43.1,29.9；
HPLC:96.7%.
The synthesis of 17 4,6- dimethyl-N-of embodiment (2- (piperidin-4-yl) phenyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) piperidines -1- t-butyl formate
Successively by 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-formic acid uncle Butyl ester (500mg, 1.31mmol) and 10% palladium carbon (100mg) are added in anhydrous methanol (10mL), and system is placed in atmosphere of hydrogen Lower room temperature reaction 16 hours.Stop reaction, filter, collect filtrate, vacuum distillation removes solvent, and gained crude product is chromatographed by column (methylene chloride: methanol (V:V)=50:1) isolates and purifies to obtain title compound (yellow oil, 401mg, 80%).
MS(ESI,pos.ion)m/z:383.30[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.71 (d, J=7.9Hz, 1H), 7.21~7.16 (m, 3H), 7.13 (t, J=7.1Hz, 1H), 6.42 (s, 1H), 4.33~3.98 (m, 2H), 2.89~2.83 (m, 1H), 2.72~2.65 (m, 2H), 2.27 (s, 6H), 1.79~1.72 (m, 2H), 1.57~1.49 (m, 2H), 1.46 (s, 9H)
The synthesis of step 2) 4,6- dimethyl-N-(2- (piperidin-4-yl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) phenyl) piperidines -1- t-butyl formate (200mg, 0.52mmol) and trifluoroacetic acid (3mL) be two It prepares within room temperature reaction 2 hours in chloromethanes (6mL).Gained crude product chromatographs (methylene chloride: methanol (V:V)=15:1) by column It isolates and purifies to obtain title compound (yellow solid, 103mg, 70%).
MS(ESI,pos.ion)m/z:283.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.80 (d, J=7.9Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.22 (t, J=7.4Hz, 1H), 7.14 (t, J=7.5Hz, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 3.19 (t, J= 12.0Hz, 2H), 2.90~2.86 (m, 1H), 2.73 (t, J=11.7 Hz, 2H), 2.31 (s, 6H), 1.84~1.78 (m, 2H), 1.71~1.65 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):167.7,160.9,138.6,136.3,126.6,126.4,124.8, 124.1,111.4,47.0,37.0, 33.3,23.9；
HPLC:98.6%.
The synthesis of 18 4,6- dimethoxy-N- of embodiment (2- (piperidin-4-yl) phenyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- ((4,6- dimethoxypyridin -2- base) amino) phenyl) piperidines -1- t-butyl formate
This step title compound method referring to described in 17 step 1 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methoxy pyrimidine -2- base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (500mg, 1.21mmol) and 10% palladium carbon (100mg) is reacted at room temperature 16 hours in anhydrous methanol (10mL), under atmosphere of hydrogen and is prepared.Gained crude product is logical Cross column chromatography (methylene chloride: methanol (V:V)=50:1) isolate and purify to obtain title compound (white solid, 451mg, 90%).
MS(ESI,pos.ion)m/z:415.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.79 (d, J=7.8Hz, 1H), 7.20~7.15 (m, 2H), 7.11 (dd, J=10.9,4.0Hz, 1H), 6.79 (s, 1H), 5.52 (s, 1H), 4.22 (d, J=5.1Hz, 2H), 3.82 (s, 6H), 2.90~2.86 (m, 1H), 2.79~2.72 (m, 2H), 1.77~1.70 (m, 2H), 1.61~1.53 (m, 2H), 1.46 (s, 9H).
The synthesis of step 2) 4,6- dimethoxy-N- (2- (piperidin-4-yl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methoxy pyrimidine -2- base) amino) phenyl) piperidines -1- t-butyl formate (200mg, 0.48mmol) and trifluoroacetic acid (3mL) exist It prepares within room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=15: 1) it isolates and purifies to obtain title compound (yellow oil, 136 mg, 90%).
MS(ESI,pos.ion)m/z:315.20[M+H]+；
1H NMR(600MHz,DMSO-d6) δ (ppm): 8.77 (s, 1H), 7.44~7.36 (m, 1H), 7.25 (dd, J= 6.6,2.5Hz, 1H), 7.18 (dd, J=6.4,2.9Hz, 2H), 5.52 (s, 1H), 3.74 (s, 7H), 3.23 (d, J= 11.7Hz, 2H), 3.15~3.04 (m, 1H), 2.80 (t, J=11.8Hz, 2H), 1.79 (d, J=12.4Hz, 2H), 1.74~ 1.64(m,2H)；
13C NMR(150MHz,DMSO-d6)δ(ppm):172.1,161.3,140.8,137.0,127.6,126.5, 126.4,125.8,79.6,53.9,45.3, 34.9,31.0；
HPLC:96.8%.
The synthesis of 19 N- of embodiment (2- (piperidin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- ((4- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) piperidines -1- t-butyl formate
This step title compound method referring to described in 17 step 1 of embodiment is prepared, i.e. 4- (2- ((4- (three Methyl fluoride) pyrimidine -2-base) amino) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (500mg, 1.19mmol) and 10% palladium carbon (100mg) is reacted at room temperature 16 hours in anhydrous methanol (10mL), under atmosphere of hydrogen and is prepared.Gained crude product is logical Cross column chromatography (methylene chloride: methanol (V:V)=50:1) isolate and purify to obtain title compound (yellow oil, 402mg, 80%).
MS(ESI,pos.ion)m/z:423.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.59 (d, J=4.7Hz, 1H), 7.67~7.59 (m, 1H), 7.36 (dd, J=6.7,2.5Hz, 1H), 7.25~7.21 (m, 2H), 7.18 (s, 1H), 6.99 (d, J=4.9Hz, 1H), 3.23 (t, 2H), 2.91~2.83 (m, 1H), 2.76 (t, J=11.4Hz, 2H), 1.82~1.75 (m, 2H), 1.73~1.69 (m, 2H), 1.49(s,9H).
The synthesis of step 2) N- (2- (piperidin-4-yl) phenyl) -4- (trifluoromethyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4- (trifluoro Methyl) pyrimidine -2-base) amino) phenyl) piperidines -1- t-butyl formate (200mg, 0.47mmol) and trifluoroacetic acid (3mL) exist It prepares within room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=15: 1) it isolates and purifies to obtain title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:323.15[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.57 (d, J=4.8Hz, 1H), 7.66~7.55 (m, 1H), 7.38 (dd, J=6.6,2.5Hz, 1H), 7.27~7.20 (m, 2H), 7.19 (s, 1H), 6.99 (d, J=4.9Hz, 1H), 3.22 (t, 2H), 2.90~2.82 (m, 1H), 2.75 (t, J=11.4Hz, 2H), 1.82~1.78 (m, 2H), 1.73~1.63 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):161.6,160.7,156.7,140.2,134.8,127.0,126.7, 126.5,125.3,120.4,107.3, 47.0,37.2,33.5；
HPLC:98.6%.
The synthesis of 20 N- of embodiment (2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
Step 1) 4- (2- amino -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate synthesis
Successively by 2- bromo- 5- (trifluoromethyl) aniline (2.0g, 8.3mmol), 4- (pinacol ester -2- base) -5,6- dihydro Pyridine -1 (2H)-t-butyl formate (3.1g, 10mmol), potassium acetate (1.23g, 12.5mmol) and [bis- (diphenylphosphines of 1,1'- Base) ferrocene] palladium chloride (343mg, 0.42mmol) is added to the mixed of N,N-dimethylformamide (30mL) and water (2mL) In bonding solvent, under nitrogen atmosphere, reaction is warming up to 90 DEG C and reacts 16 hours.Stop reaction, is cooled to room temperature, reaction solution pours into In water (100mL), methylene chloride (30mL × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and vacuum distillation removes solvent, Gained crude product isolates and purifies to obtain title compound that (yellow is solid by column chromatography (methylene chloride: methanol (V:V)=50:1) Body, 2.42g, 85%).
MS(ESI,pos.ion)m/z:243.15[M+H-100]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.08 (d, J=7.9Hz, 1H), 6.99 (d, J=7.8Hz, 1H), 6.94 (s, 1H), 5.82 (s, 1H), 4.08 (d, 2H), 3.66 (t, J=5.4Hz, 2H), 2.40 (t, 2H), 1.52 (s, 9H)
Step 2) 4- (2- (pyrimidine -2 --amino)-4- (trifluoromethyl) phenyl)-5,6- dihydropyridine-1 (2H)-formic acid The synthesis of the tert-butyl ester
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (400mg, 1.17mmol), 2- chlorine pyrimidine (148mg, 1.29mmol), sodium tert-butoxide (169mg, 1.76 mmol), tris(dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (149mg, 0.24 mmol) is at dry toluene (20mL) In, it prepares within nitrogen atmosphere lower 120 DEG C of reactions 12 hours.Gained crude product by column chromatograph (methylene chloride: methanol (V:V)= It 50:1) isolates and purifies to obtain title compound (yellow oil, 394mg, 80%).
MS(ESI,pos.ion)m/z:421.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.75 (s, 1H), 8.47 (d, J=4.7Hz, 2H), 7.31 (d, J= 13.5Hz, 1H), 7.23 (d, J=7.9Hz, 1H), 6.81 (t, J=4.8Hz, 1H), 5.86 (s, 1H), 4.12 (d, 2H), 3.68 (t, J=5.0Hz, 2H), 2.41 (t, 2H), 1.53 (s, 9H)
The synthesis of step 3) N- (2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- (pyrimidine -2- Base amino) -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.48mmol) and three Fluoroacetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: Methanol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow oil, 138mg, 90%).
MS(ESI,pos.ion)m/z:321.10[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.78 (s, 1H), 8.46 (d, J=4.6Hz, 2H), 7.54 (s, 1H), 7.28 (d, J=8.7Hz, 1H), 7.23 (d, J=7.8Hz, 1H), 6.79 (t, J=4.6Hz, 1H), 5.91 (s, 1H), 3.59 (d, J=1.6Hz, 2H), 3.16 (t, J=5.4Hz, 2H), 2.35 (s, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):159.7,158.1,150.7,136.6,135.9,134.2,129.9, 128.7,128.2,118.8,116.5, 113.2,44.9,43.0,29.7；
HPLC:92.1%.
21 4,6- dimethyl-N-of embodiment (2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine -2- The synthesis of amine
Step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) -5,6- dihydro pyrrole The synthesis of pyridine -1 (2H)-t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (400mg, 1.17mmol), the chloro- 4,6- diformazan of 2- Yl pyrimidines (184mg, 1.29mmol), sodium tert-butoxide (169mg, 1.76mmol), tris(dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (149 mg, 0.24mmol) is at dry toluene (20mL) In, it prepares within nitrogen atmosphere lower 120 DEG C of reactions 12 hours.Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=50: 1) it isolates and purifies to obtain title compound (yellow solid, 367mg, 70%).
MS(ESI,pos.ion)m/z:449.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.95 (s, 1H), 7.35 (s, 1H), 7.22 (d, J=7.7Hz, 1H), 7.21 (d, J=7.9Hz, 1H), 5.91 (s, 1H), 3.55 (d, 2H), 3.14 (t, J=5.0Hz, 2H), 2.39 (s, 6H), 2.34(t,2H),1.49(s,9H).
Step 2) 4,6- dimethyl-N-(2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.44mmol) prepared within room temperature reaction 2 hours in methylene chloride (6mL) with trifluoroacetic acid (3mL).Gained crude product passes through column layer Analysis (methylene chloride: methanol (V:V)=15:1) isolates and purifies to obtain title compound (yellow solid, 123mg, 80%).
MS(ESI,pos.ion)m/z:349.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.94 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=7.8Hz, 1H), 7.20 (d, J=7.9Hz, 1H), 6.56 (s, 1H), 5.91 (s, 1H), 3.63 (d, 2H), 3.20 (t, J=5.0Hz, 2H), 2.40(s,6H),2.38(t,2H)；
13C NMR(150MHz,CDCl3)δ(ppm):167.8,159.3,137.0,135.3,134.4,129.8,128.6, 127.6,124.3,118.2,116.3, 112.4,44.6,42.8,29.7,23.9；
HPLC:99.4%.
22 4,6- dimethoxy-N- of embodiment (2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine - The synthesis of 2- amine
Step 1) 4- (2- ((4,6- dimethoxypyridin -2- base) amino) -4- (trifluoromethyl) phenyl) -5,6- dihydro pyrrole The synthesis of pyridine -1 (2H)-t-butyl formate
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e. 4- (2- amino -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (400mg, 1.17mmol), the chloro- 4,6- diformazan of 2- Oxygroup pyrimidine (225mg, 1.29mmol), sodium tert-butoxide (169mg, 1.76mmol), tris(dibenzylideneacetone) dipalladium (110mg, 0.12mmol) and (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalene (149 mg, 0.24mmol) is in no water beetle In benzene (20mL), prepare within nitrogen atmosphere lower 120 DEG C of reactions 12 hours.Gained crude product chromatographs (methylene chloride: methanol by column (V:V)=50:1) it isolates and purifies to obtain title compound (yellow solid, 281mg, 50%).
MS(ESI,pos.ion)m/z:481.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.79 (s, 1H), 7.39 (s, 1H), 7.26~7.21 (m, 1H), 7.18 (d, J=7.9Hz, 1H), 5.91 (s, 1H), 5.64 (s, 1H), 3.90 (s, 6H), 3.75 (d, J=1.9Hz, 2H), 3.36 (t, J=5.8Hz, 2H), 2.52~2.38 (m, 2H), 1.50 (s, 9H)
Step 2) 4,6- dimethoxy-N- (2- (1,2,3,6- tetrahydropyridine) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methoxy pyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.42mmol) prepared within room temperature reaction 2 hours in methylene chloride (6mL) with trifluoroacetic acid (3mL).Gained crude product passes through column layer Analysis (methylene chloride: methanol (V:V)=15:1) isolates and purifies to obtain title compound (white solid, 128mg, 80%).
MS(ESI,pos.ion)m/z:381.15[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.91 (s, 1H), 7.38 (s, 1H), 7.28~7.24 (m, 1H), 7.22 (d, J=7.9Hz, 1H), 5.90 (s, 1H), 5.63 (s, 1H), 5.37 (s, 1H), 3.92 (s, 6H), 3.78 (d, J=1.9Hz, 2H), 3.36 (t, J=5.7Hz, 2H), 2.54~2.48 (m, 2H)；
13C NMR(100MHz,CDCl3)δ(ppm):172.0,158.5,136.9,134.5,130.1,128.6,124.6, 124.2,118.5,117.5,81.8, 54.1,53.4,43.2,41.8；
HPLC:99.4%.
The synthesis of 23 N- of embodiment (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
The synthesis of step 1) 4- (2- (pyrimidine -2 --amino)-4- (trifluoromethyl) phenyl) piperidines-1- t-butyl formate
This step title compound method referring to described in 17 step 1 of embodiment is prepared, i.e. 4- (2- (pyrimidine -2- Base amino) -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (500mg, 0.95mmol) and 10% palladium carbon (100mg) is reacted at room temperature 16 hours in anhydrous methanol (10mL), under atmosphere of hydrogen and is prepared.Gained crude product is logical Cross column chromatography (methylene chloride: methanol (V:V)=50:1) isolate and purify to obtain title compound (colorless oil, 301mg, 75%).
MS(ESI,pos.ion)m/z:423.25[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.42 (d, J=4.8Hz, 1H), 8.13 (s, 1H), 7.43 (d, J= 8.1Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 7.05 (s, 1H), 6.78 (t, J=4.8Hz, 1H), 4.27~4.19 (m, 2H), 2.96~2.88 (m, 1H), 2.80~2.72 (m, 2H), 1.91~1.77 (m, 2H), 1.66~1.51 (m, 2H), 1.50 (s,9H).
The synthesis of step 2) N- (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- (pyrimidine -2- Base amino) -4- (trifluoromethyl) phenyl) piperidines -1- t-butyl formate (200mg, 0.47mmol) and trifluoroacetic acid (3mL) exist It prepares within room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product by column chromatograph (methylene chloride: methanol (V:V)=15: 1) it isolates and purifies to obtain title compound (yellow solid, 121mg, 80%).
MS(ESI,pos.ion)m/z:323.20[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.39(d,1H),8.10(s,1H),7.41(d,1H),7.39(d, 1H), 7.16 (s, 1H), 6.74 (t, 1H), 4.26~4.18 (m, 2H), 3.24~3.18 (m, 2H), 2.94~2.86 (m, 2H), 2.74~2.62 (m, 2H), 1.80~1.72 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):160.9,158.3,142.0,136.4,129.0,127.2,124.1, 121.7,121.2,113.0,46.6, 36.9,32.6；
HPLC:91.1%.
The synthesis of 24 4,6- dimethyl-N-of embodiment (2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
Step 1) 4- (2- ((4,6- dimethyl pyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) piperidines -1- formic acid uncle The synthesis of butyl ester
This step title compound method referring to described in 17 step 1 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) -5,6- dihydropyridine -1 (2H)-t-butyl formate (500mg, 1.11mmol) reacts at room temperature 16 hours and prepare in anhydrous methanol (10mL), under atmosphere of hydrogen with 10% palladium carbon (100mg).Institute Crude product is obtained to isolate and purify to obtain title compound (colorless oil by column chromatography (methylene chloride: methanol (V:V)=50:1) Object, 400mg, 80%).
MS(ESI,pos.ion)m/z:451.20[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.32 (s, 1H), 7.37~7.29 (m, 2H), 7.08 (s, 1H), 6.54 (s, 1H), 4.25 (s, 2H), 2.94~2.88 (m, 1H), 2.83~2.72 (m, 2H), 2.36 (s, 6H), 1.83~1.76 (m, 2H), 1.72~1.55 (m, 2H), 1.48 (s, 9H)
The synthesis of step 2) 4,6- dimethyl-N-(2- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidine -2- amine
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e. 4- (2- ((4,6- bis- Methylpyrimidine -2- base) amino) -4- (trifluoromethyl) phenyl) piperidines -1- t-butyl formate (200mg, 0.44mmol) and trifluoro Acetic acid (3mL) is prepared for room temperature reaction 2 hours in methylene chloride (6mL).Gained crude product chromatographs (methylene chloride: first by column Alcohol (V:V)=15:1) it isolates and purifies to obtain title compound (yellow oil, 139mg, 90%).
MS(ESI,pos.ion)m/z:351.20[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.39 (s, 1H), 7.39 (d, J=8.0Hz, 1H), 7.34 (d, J= 7.9Hz, 1H), 7.08 (s, 1H), 6.53 (s, 1H), 3.22 (t, 2H), 2.93~2.84 (m, 1H), 2.79 (t, J= 11.8Hz, 2H), 2.67 (s, 1H), 2.35 (s, 6H), 1.85~1.79 (m, 2H), 1.76~1.63 (m, 2H)；
13C NMR(150MHz,CDCl3)δ(ppm):167.8,160.2,140.5,139.8,136.9,128.6,126.9, 124.3,120.4,119.7,112.2, 46.9,37.0,33.1,23.8；
HPLC:98.7%.
Biologic test
Embodiment A: the affinity of humanization 5-HT transporter of the evaluation 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 (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1%BSA) formed mixed system in, be added or be added without Compound is tested, is incubated for 60 minutes altogether.
And in the mixed system of above-mentioned condition, 10 μM of imipramine are added, for measuring non-specific binding value.
Sample after incubation is with 96 like cell collectors (Unifilter, Packard) under vacuum conditions by pre- dipped The glass fiber filter (GF/B, Packard) of 0.3%PEI quickly filters, and uses ice-cold 50mM Tris-HCl and 150mM NaCl repeated flushing is several times.Dry filter membrane uses scintillation solution in scintillation counter (Topcount, Packard) (Microscint 0, Packard) calculates remaining radioactivity.Experimental result is with special relative to control group radioligand Property combine suppression percentage indicate.
Standard reference compound is imipramine, competition linearity curve is obtained by the experiment test of series of concentrations, to calculate IC out50.As a result referring to Table A, Table A is affinity experimental result of the compounds of this invention to humanization 5-HT transporter (SERT).
Affinity measurement result of the Table A the compounds of this invention to source of people 5-HT transporter (SERT)
Example No. IC50(nM)
Embodiment 1 15.0
Embodiment 2 10.9
Embodiment 3 20.0
Embodiment 4 10.6
Embodiment 5 8.9
Embodiment 6 13.2
Experimental result shows that the compounds of this invention has stronger affinity to source of people 5-HT transporter (SERT).
Embodiment B rat intravenous or stomach-filling quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses the compounds of this invention in the intracorporal pharmacokinetic of rat, and animal information is detailed in Table B.
Table B animal subject information table 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 solution, to animal subject carry out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm Centrifugation 10 minutes is collected plasma solutions, and is saved at -20 DEG C or -70 DEG C.For gastric infusion group, dosage is 2.5mg/kg or 5mg/kg, then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour When venous blood sampling (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, collect plasma solutions, and in -20 DEG C or -70 It is saved at DEG C.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analysis.Analysis the result shows that, in rat body The compounds of this invention measured by way of intravenous injection administration and gastric infusion has exposure magnitude big, 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 better clinic to answer Use prospect.
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 ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description 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 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 not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (10)

1. a kind of compound is stereoisomer, the geometrical isomerism of compound shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
X can be CRxOr N；
For singly-bound or double bond；
WhenWhen for singly-bound, Y is N or CH；
WhenWhen for double bond, Y C；
R1、R2、R3And RxIt is each independently 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 The C that amino or hydroxyl replace1-C6Alkyl；
R4、R5、R6And R7It is each independently 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；With
R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
2. compound according to claim 1, wherein R1、R2、R3And RxBe each independently H, D, F, Cl, Br, I ,-CN ,- NO2、-NH2、-OH、-SH、-COOH、-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkane Base, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4 The C that alkylamino or hydroxyl replace1-C4Alkyl.
3. compound according to claim 1, wherein R4、R5、R6And R7Be 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-C4Alkane Oxygroup or C1-C4Halogenated alkoxy.
4. compound according to claim 1 or 2, wherein R1、R2、R3And RxBe each independently H, D, F, Cl, Br, I ,- CN、-NO2、-NH2、-OH、-SH、-COOH、-CONH2,-C (=O) CH3,-C (=O) OCH3, methyl, ethyl, n-propyl, isopropyl Base ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
5. compound according to claim 1 or 3, wherein R4、R5、R6And R7Be each independently H, D, F, Cl, Br, I ,- CN、-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3Or-CH2CF3。
6. compound according to claim 1 for the compound with one of following structure or has one of following knot The stereoisomer of the compound of structure, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug:
7. a kind of pharmaceutical composition includes compound as claimed in any one of claims 1 to 6；With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.
8. pharmaceutical composition according to claim 7 further includes treatment central nervous system dysfunction Drug, the drug of the treatment central nervous system dysfunction is amitriptyline, desipramine, Mirtazapine, Bupropion, auspicious Bo Xiting, Prozac, Trazodone, Sertraline, Duloxetine, Fluvoxamine, Milnacipran, left-handed Milnacipran, first text is gone to draw Method is pungent, vilazodone, Venlafaxine, Dapoxetine hydrochloride, Nefazodone, femoxetine, chlorimipramine, Citalopram, Escitalopram Pulan, Paxil, lithium carbonate, buspirone, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, piperazine sieve Grand, Clozapine, modafinil, Mecamylamine, Cabergoline, adamantane, imipramine, Pramipexole, thyroxine, right U.S. are husky Sweet smell, quinindium, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, Pipamperone, dimension are for smooth, sharp It sleeps peaceful, perphenazine or their any combination.
9. pharmaceutical composition described in compound as claimed in any one of claims 1 to 6 or claim 7-8 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating central nervous system dysfunction.
10. purposes according to claim 9, the drug is for preventing, treating or mitigating the disturbance of emotion.
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