CN105175360B - Ether-type aryl bridged piperazine derivatives and its salt, preparation method and purposes - Google Patents

Ether-type aryl bridged piperazine derivatives and its salt, preparation method and purposes Download PDF

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CN105175360B
CN105175360B CN201510561570.2A CN201510561570A CN105175360B CN 105175360 B CN105175360 B CN 105175360B CN 201510561570 A CN201510561570 A CN 201510561570A CN 105175360 B CN105175360 B CN 105175360B
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CN105175360A (en
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陈洪
马录芳
姚景才
冯爱青
孙涛
罗光远
王豹
陈夏雨
俞佳俊
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Luoyang Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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Abstract

The invention discloses ether-type aryl bridged piperazine derivatives（Ⅰ）.Wherein：m、X、Y、Z、R1– R5Be defined in the specification.It is used for anti-tumor application the invention also discloses the preparation method of these ether-type aryl bridged piperazine derivatives and using these new derivatives.Compound of the present invention is studied through Pharmacodynamic, anticancer experiment in vitro, is as a result shown：Some compounds show preferable antitumor activity, can develop as new antineoplastic.

Description

Ether-type aryl bridged piperazine derivatives and its salt, preparation method and purposes
Technical field
The present invention relates to the discovery field of pharmaceutical chemistry, lead compound, and in particular to a kind of new ether-type aryl Bridged piperazine derivatives, its preparation method and the purposes in antineoplastic.
Background technology
Prostate cancer turns into the important diseases for threatening elderly men health.Prostate cancer is western countries' male's incidence of disease Highest, the death rate occupy deputy entity tumor（J. Radiat. Res, 2011, 52, 743-751）.In the U.S., forefront The incidence of disease of gland cancer alreadys exceed lung cancer, turns into first tumour for endangering men's health.Estimate according to American Cancer Society, 2013 The new hair prostate cancer in about 238590, the U.S. of year, has 29720 will die from this disease（CA Cancer J. Clin. 2013, 63, 11-30）.In Europe, new hair cases for prostate cancer about 416700 people that are made a definite diagnosis every year, prostate cancer The 22.8% of whole male cancers is accounted for, accounts for the 9.5% of whole male cancer deaths numbers（Eur. J. Cancer, 2013, 49, 1374-1403）.And also accelerating in the relatively low Asian countries of the past incidence of disease, in recent years number of patients growth（China's experiment is outer Section's magazine.2005,9,1031-1034）.
Clinically, localized disease can be cut off or be destroyed cancer cell by operation or radiotherapy to cure.However, turn Shifting property prostate cancer can not cure and androgen ablation therapy turns into standard treatment.Although various chemotherapeutic drugs are used alone Thing is combined with radiotherapy to treat patients with terminal, but to prostate cancer without any traditional cancer treatment method It is very successful.Other research displays：Once tumour cell turns into Hormone refractory, for Hormone-refractory prostate cancer For, the cytotoxic agent of standard can hardly improve treatment results or survival rate, although they can delay to a certain extent Solve the pain of patient.Therefore, it is urgent to invent and develop more effective, safety antiprostate cancer.
It is an object of the invention to provide a kind of new ether-type aryl bridged piperazine derivatives and its salt.
It is a further object of the present invention to provide the preparation method of above-mentioned new ether-type aryl bridged piperazine derivatives and its salt.
Another object of the present invention is to provide purposes of the new ether-type aryl bridged piperazine derivatives in antineoplastic.
The new ether-type aryl bridged piperazine derivatives of the present invention have following formulas（Ⅰ）Structure：
Wherein：
m = 0、1；
X=C or N;Y=C or N;Z=C or N;
R1 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl, direct-connected or side chain Alkoxy, undersaturated alkoxy, F, Cl, Br, I, CF3、CN、NO2、OH、CHO、SR6, alkyl sulfuryl, substitution or unsubstituted virtue Base sulfuryl, amino, acyl group, ester group；
R2 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl, direct-connected or side chain Alkoxy, undersaturated alkoxy, F, Cl, Br, I, CF3、CN、NO2、OH、CHO、SR6, alkyl sulfuryl, substitution or unsubstituted virtue Base sulfuryl, amino, acyl group, ester group；
R3 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl, direct-connected or side chain Alkoxy, undersaturated alkoxy, F, Cl, Br, I, CF3、CN、NO2、OH、CHO、SR6, alkyl sulfuryl, substitution or unsubstituted virtue Base sulfuryl, amino, acyl group, ester group；
R4 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl, direct-connected or side chain Alkoxy, undersaturated alkoxy, F, Cl, Br, I, CF3、CN、NO2、OH、CHO、SR6, alkyl sulfuryl, substitution or unsubstituted virtue Base sulfuryl, amino, acyl group, ester group；
R5 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl, direct-connected or side chain Alkoxy, undersaturated alkoxy, F, Cl, Br, I, CF3、CN、NO2、OH、CHO、SR6, alkyl sulfuryl, substitution or unsubstituted virtue Base sulfuryl, amino, acyl group, ester group；
R6 =H, direct-connected or branched alkyl, undersaturated alkyl, substitution or unsubstituted phenyl, aralkyl.
Ether-type aryl bridged piperazine derivatives of the present invention are prepared by following methods：Raw material 4- (bromoethane) benzene second first Acid（1）Intermediate 2 is reduced into by borane dimethyl sulphide complex compound (BMS), secondly intermediate 2 under base catalysis with 5,6,7,8- Tetralol reacts to obtain intermediate 3, again intermediate 3 under base catalysis with paratoluensulfonyl chloride（TsCl）Reaction generation The intermediate 4 of hydroxyl protection.With corresponding aryl piperazines class compound or Arylpiperidine class compound nucleophilic occurs for last intermediate 4 Substitution reaction obtains corresponding compound 5-28.
Above-claimed cpd of the present invention is studied through Preliminary pharmacological, anticancer experiment in vitro, is as a result shown：Some compound tables Now good antitumor activity, new antineoplastic can be developed.
Preferred compounds of the invention have following compounds 5,6,7,8,9,10,11,12,13,14,15,16,17,18, 19th, 20,21,22,23,24,25,26,27,28 structure:
The preparation process of intermediate 2 of the present invention is as follows：
The preparation technology of intermediate 2 includes：
4- (bromoethane) phenylacetic acid obtains 2- (4- with borane dimethyl sulphide complex compound (BMS) reaction at normal temperatures (bromomethyl)-
phenyl)ethanol（Intermediate 2）.
The preparation process of intermediate 3 of the present invention is as follows：
The preparation technology of intermediate 3 includes：
2-(4-(bromomethyl)phenyl)ethanol（Intermediate 2）Under potassium carbonate catalysis, with 5,6,7,8- tetra- Hydrogen-beta naphthal reacts to obtain 2- (4- ((5,6,7,8-tetrahydronaphthalen-2-yloxy) methyl) phenyl) ethanol（Intermediate 3）.
The preparation process of intermediate 4 of the present invention is as follows：
The preparation technology of intermediate 4 includes：
2-(4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)phenyl)ethanol（In Mesosome 3）Under triethylamine catalysis, react to obtain 2- (4- ((5,6,7,8- with paratoluensulfonyl chloride tetrahydronaphthalen-2-yloxy)methyl)phenyl)ethyl 4-methylbenzenesulfonate（In Mesosome 4）.
The compounds of this invention 5-28 preparation process is as follows：
Compound 5-28 preparation technology includes：
Intermediate 4 reacts to obtain compound 5-28 with corresponding aryl piperazines class compound or Arylpiperidine class compound
The salt of ether-type aryl bridged piperazine derivatives of the present invention is represented by following II：
Wherein HX is physiologically acceptable acid
The salt of ether-type aryl bridged piperazine derivatives of the present invention mainly includes hydrobromate, hydriodate, hydrochloride, height Chlorate, sulfate, maleate, fumarate, malate, tartrate, citrate, benzoate, mandelate, One kind in mesylate, esilate, benzene sulfonate, oxalates, phosphate, succinate, ruins pool hydrochlorate, lactate
The preparation method of ether-type aryl bridged piperazine derivatives officinal salt of the present invention, it is characterized in that：By ether-type aryl Bridged piperazine derivatives are dissolved in organic solvent, are then added HX acid, are stirred under normal temperature, the solid of precipitation is ether-type aryl piperazine derivatives The inorganic acid salt or acylate of thing.
Ether-type aryl bridged piperazine derivatives involved in the present invention, Preliminary pharmacological research（Anti tumor activity in vitro is tested）, As a result show：Some compounds show good antitumor activity, can further develop as new antineoplastic.
Embodiment：
The present invention is further illustrated below by embodiment.Embodiment gives synthesizing, being related for representative noval chemical compound Structural Identification data and compound activity data.Mandatory declaration, following embodiments are to be used to illustrate rather than to this hair Bright limitation.The scope of protection of present invention is belonged to according to the simple modifications that the essence of the present invention is carried out to the present invention.
Fusing point test is with a Fisher Johns hot-stage analyzers (thermometer does not correct).
All target compounds（Hydrochloride）'s1HNMR,13C NMR are determined with Switzerland Bruker AVANCE AV-400NB, TMS does internal standard.
Low Resolution Mass Spectra（EI）Determined with Thremo DSQ mass spectrographs.
Embodiment 1：The preparation of intermediate 2
5 g (0.021 mol) 4- (bromoethane) phenylacetic acid, 100 mL tetrahydrochysene furans are added in 250 mL round-bottomed flasks Mutter, 21.9 mL borane dimethyl sulphides complex compounds (BMS, 2M in THF) are slowly added at 0 DEG C.Reactant mixture exists After 1 h is reacted at 0 DEG C, then gradually recover normal temperature.Reaction is slowly added to water terminating reaction after terminating, and is extracted with ethyl acetate （100 mL × 3）, merging organic phase, organic phase uses water and saturated common salt water washing respectively, and anhydrous magnesium sulfate is dried, filtering, Concentration.Crude product does not have purifying to be directly used in reaction in next step.
Embodiment 2：The preparation of intermediate 3
4 g are added in 250 mL round-bottomed flasks（18.7 mmol）The g of intermediate 2,2.76（18.7 mmol）5,6,7,8- Tetralol, 10.32 g（74.8 mmol）Potassium carbonate, 150 mL acetonitriles, reacts 16 h at 60 DEG C.TLC displays are former Material reaction is complete.Stop reaction, filter, concentration.Crude on silica gel column chromatography purifies, eluant, eluent：V (ethyl acetate):V (stones Oily ether)=1:15, obtain 4.14 g white solids, yield：70%（Calculated with raw material 4- (bromoethane) phenylacetic acid）.M.p.: 61- 62 oC; 1H NMR (500 MHz, CDCl3) δ in ppm: 7.39 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 8.2, 2.7 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 5.00 (s, 2H), 3.87 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 6.5 Hz, 2H), 2.75 (br s, 2H), 2.71 (br s, 2H), 1.78 (dt, J = 6.6, 3.4 Hz, 4H), 1.48 (s, 1H); MS (EI, m/z): 282 (M+), 251, 182, 147, 135 (100%), 117, 105, 91.
Embodiment 3：The preparation of intermediate 4
4 g are added in 250 mL round-bottomed flasks（14.18 mmol）The g of intermediate 3,5.73（56.72 mmol）Three second Amine, 0.17 g 4-（N, N- dimethyl）Aminopyridine (catalytic amount), 100 mL dichloromethane, 4.04 are slowly added at 0 DEG C g（21.3 mmol）Paratoluensulfonyl chloride（TsCl）Dichloromethane solution.Reactant mixture reacts 16 h at 0 DEG C, and TLC shows Show that raw material reaction is complete.Water terminating reaction is slowly added to, is extracted with dichloromethane（100 mL × 3）, merge organic phase, it is organic Water and saturated common salt water washing are mutually used respectively, and anhydrous magnesium sulfate is dried, and is filtered, concentration.Crude on silica gel column chromatography purifies, and washes De- agent：V (ethyl acetate):V (petroleum ether)=1:20, obtain 5.87 g white solids, yield：95%.M.p.: 92-93oC;1H NMR (500 MHz, CDCl3) δ in ppm: 7.68 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.73 (dd, J = 8.2, 2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 4.98 (s, 2H), 4.21 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 2.74
(br s, 2H), 2.70 (br s, 2H), 2.43 (s, 3H), 1.78 (dt, J = 6.6, 3.4 Hz, 4H); MS (EI, m/z): 436 (M+), 289, 264, 236, 155, 117 (100%), 104, 91.
Embodiment 4：The preparation of compound 5
100 mg are added in 25mL round-bottomed flasks（0.23 mmol）The mg of intermediate 4,44.5（0.27 mmol）N- phenyl Piperazine, 190.4 mg（1.38 mmol）Potassium carbonate, 15 mL acetonitriles react 16 h at 85 DEG C, and TLC shows that raw material has reacted Entirely.Stop reaction, filter, concentration.Crude on silica gel column chromatography purifies, eluant, eluent：V (ethyl acetate):V (petroleum ether)= 1:20, obtain 58.8 mg white solids, yield：60%.M.p.: 140-141oC (HCl salt); MS (ESI, m/z): 427.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.54 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.74 – 6.65 (m, 2H), 5.01 (s, 2H), 3.82 (d, J = 10.7 Hz, 2H), 3.62 (d, J = 10.7 Hz, 2H), 3.45 – 3.01 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.69 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 149.5, 137.5, 136.6, 135.9, 129.6, 129.1, 128.7, 127.9, 120.0, 116.0, 114.5, 112.5, 68.7, 55.9, 50.5, 45.4, 29.0, 28.9, 27.9, 22.9, 22.6.
Embodiment 5：The preparation of compound 6
The reaction of intermediate 4 and 1- (2- pyridine radicals) piperazine, building-up process is the same as embodiment 4.68.7 mg white solids are obtained, Yield：70%.M.p.: 166-167oC (HCl salt); MS (ESI, m/z): 428.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.84 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.96 (br s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 – 7.28 (m, 3H), 6.98 (t, J = 6.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.72 – 6.69 (m, 2H), 5.02 (s, 2H), 4.53 (d, J = 10.7 Hz, 2H), 3.93 – 2.97 (m, 10H), 2.67 (br s, 2H), 2.62 (br s, 2H), 1.69 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 137.5, 136.5, 135.9, 129.6, 128.7, 127.9, 114.5, 113.9, 112.5, 68.7, 55.9, 49.9, 42.9, 29.0, 28.9, 27.9, 22.9, 22.6.
Embodiment 6：The preparation of compound 7
The reaction of intermediate 4 and 1- (2- aminomethyl phenyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 82.9 mg whites Body, yield：82%.M.p.: 183-184oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR (500 MHz, DMSO-d 6) δ in ppm: 10.96 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 – 6.92 (m, 5H), 6.74 – 6.68 (m, 2H), 5.03 (s, 2H), 3.63 (d, J = 10.7 Hz, 2H), 3.44 – 3.34 (m, 2H), 3.30 – 3.06 (m, 8H), 2.67 (br s, 2H), 2.63 (br s, 2H), 2.27 (s, 3H), 1.70 (dt, J = 6.4, 3.4 Hz, 4H).
Embodiment 7：The preparation of compound 8
The reaction of intermediate 4 and 1- (4- aminomethyl phenyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 75.9 mg whites Body, yield：75%.M.p.: 167-168oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.56 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13 – 6.89 (m, 5H), 6.79 – 6.63 (m, 2H), 5.02 (s, 2H), 3.75 (d, J = 10.7 Hz, 2H), 3.62 (d, J = 10.7 Hz, 2H), 3.43 – 3.06 (m, 8H), 2.67 (br s, 2H), 2.62 (br s, 2H), 2.22 (s, 3H), 1.69 (br s, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 147.1, 137.5, 136.6, 135.9, 129.6, 129.5, 129.3, 128.7, 127.9, 116.4, 114.5, 112.5, 68.7, 55.9, 50.4, 46.0, 29.0, 28.9, 27.9, 22.9, 22.6, 20.0.
Embodiment 8：The preparation of compound 9
The reaction of intermediate 4 and 1- (3- aminomethyl phenyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 80.9 mg whites Body, yield：80%.M.p.: 178-179oC (HCl salt); MS (ESI, m/z): 441.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.80 (s, 1H), 7.65 – 7.27 (m, 8H), 6.96 (d, J = 8.3 Hz, 1H), 6.74 – 6.63 (m, 2H), 4.98 (s, 2H), 4.66 (t, J = 12.0 Hz, 2H), 4.30 (br s, 2H), 3.76 – 3.56 (m, 4H), 3.50 – 3.13 (m, 4H), 2.72 (br s, 2H), 2.68 (br s, 2H), 2.40 (s, 3H), 1.76 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.8, 141.9, 141.6, 138.7, 137.5, 134.9, 131.6, 130.9, 130.3, 130.1, 129.3, 128.7, 121.7, 118.3, 115.2, 112.9, 69.8, 58.6, 51.4, 49.4, 30.4, 30.1, 28.9, 23.8, 23.5, 21.9.
Embodiment 9：The preparation of compound 10
The reaction of intermediate 4 and 1- (2- benzonitriles) piperazine, building-up process is the same as embodiment 4.62.2 mg white solids are obtained, Yield：60%.M.p.: 131-132oC (HCl salt); MS (ESI, m/z): 452.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.20 (s, 1H), 7.60 (dd, J = 7.7, 1.2 Hz, 1H), 7.55 (t,J = 7.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.20 – 7.07 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.76 – 6.64 (m, 2H), 4.99 (s, 2H), 3.95 – 2.99 (m, 12H), 2.72 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.5, 153.9, 138.3, 136.8, 135.4, 134.4, 134.1, 130.0, 129.8, 129.0, 128.3, 124.1, 119.8, 117.8, 114.8, 112.6, 107.3, 69.6, 58.8, 52.5, 48.6, 30.0, 29.8, 28.6, 23.5, 23.2.
Embodiment 10：The preparation of compound 11
The reaction of intermediate 4 and 1- (2- anisyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 75.5 mg whites Body,
Yield：72%.M.p.: 154-155oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 12.98 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.12 – 6.85 (m, 5H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H), 3.86 (s, 3H), 3.66 – 3.49 (m, 6H), 3.39 – 3.04 (m, 6H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.2, 151.7, 138.6, 138.0, 136.4, 135.3, 129.7, 129.5, 128.7, 127.9, 124.3, 121.0, 118.8, 114.5, 112.3, 111.1, 69.3, 58.5, 55.2, 52.3, 47.2, 29.6, 29.5, 28.3, 23.1, 22.9.
Embodiment 11：The preparation of compound 12
The reaction of intermediate 4 and 1- (2- ethoxyphenyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 75.6 mg whites Body,
Yield：70%.M.p.: 171-172oC (HCl salt); MS (ESI, m/z): 471.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.97 (s, 1H), 8.17 (d, J = 5.8 Hz, 1H), 7.44- 7.32 (m, 5H), 7.16 – 6.90 (m, 3H), 6.84 – 6.66 (m, 2H), 5.03 (s, 2H), 4.95 (br s, 2H), 4.48 (br s, 2H), 4.36 (q, J = 6.0 Hz, 2H), 3.69 (d, J = 9.5 Hz, 4H), 3.36 (br s, 4H), 2.77 (br s, 2H), 2.73 (br s, 2H), 1.77 (dt, J = 6.4, 3.4 Hz, 4H), 1.67 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.5, 151.9, 138.3, 137.0, 134.9, 131.6, 130.0, 129.8, 129.0, 128.3, 123.8, 121.6, 114.8, 114.1, 112.6, 69.6, 65.4, 58.4, 49.3, 48.7, 29.9, 29.8, 28.6, 23.4, 23.2, 14.9.
Embodiment 12：The preparation of compound 13
The reaction of intermediate 4 and 1- (4- anisyls) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 78.6 mg whites Body, yield：75%.M.p.: 146-147oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.48 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.71 (m, 2H), 5.02 (s, 2H), 3.70 (s, 3H), 3.64 (t, J = 12.0 Hz, 4H), 3.40 – 3.10 (m, 8H), 2.66 (br s, 2H), 2.62 (br s, 2H), 1.69 (t,J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 155.8, 153.9, 147.2, 142.7, 137.3, 136.3, 135.7, 129.4, 128.5, 127.7, 118.1, 114.3, 114.2, 112.3, 68.5, 55.7, 55.0, 50.3, 46.8, 28.8, 28.7, 27.7, 22.7, 22.4.
Embodiment 13：The preparation of compound 14
The reaction of intermediate 4 and 1- (3- anisyls) piperazine, building-up process is the same as embodiment 4.73.4 mg white solids, Yield：70%.M.p.: 181-182oC (HCl salt); MS (ESI, m/z): 457.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.74 – 6.52 (m, 4H), 6.45 (dd, J = 8.1, 1.9 Hz, 1H), 5.01 (s, 2H), 3.83 (d, J = 10.7 Hz, 2H), 3.73 (s, 3H), 3.60 (d, J = 10.7 Hz, 2H), 3.46 – 3.03 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.69 (br s, 4H); 13C NMR (101 MHz, DMSO) δ in ppm: 162.1, 157.9, 152.6, 139.4, 138.4, 137.7, 131.7, 131.5, 130.5, 129.7, 116.3, 114.4, 110.2, 107.1, 104.0, 70.6, 57.8, 56.8, 52.3, 47.1, 30.9, 30.7, 29.7, 24.8, 24.5.
Embodiment 14：The preparation of compound 15
The reaction of intermediate 4 and 1- (the chloro- 2- anisyls of 5-) piperazine, building-up process is the same as embodiment 4.67.6 mg without Color oily liquids, yield：60%.M.p.: 182-183oC (HCl salt); MS (ESI, m/z): 491.1 [M+1]+;1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.40 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.07 – 6.90 (m, 4H), 6.72 – 6.68 (m, 2H), 5.01 (s, 2H), 3.79 (s, 3H), 3.60 (d, J = 10.7 Hz, 2H), 3.54 (d, J = 10.7 Hz, 2H), 3.39 – 3.07 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.68 (t, J = 2.8 Hz, 4H);13C NMR (101 MHz, DMSO-d 6) δ in ppm: 155.6, 150.2, 140.2, 137.1, 136.1, 135.5, 129.2, 128.3, 127.5, 124.0, 122.1, 117.7, 114.1, 112.8, 112.1, 68.3, 55.6, 55.3, 50.4, 46.1, 28.6, 28.5, 27.5, 22.5, 22.2.
Embodiment 15：The preparation of compound 16
The reaction of intermediate 4 and 1- (2- fluorophenyls) piperazine, building-up process is the same as embodiment 4.66.3 mg white solids are obtained, Yield：65%.M.p.: 157-158oC (HCl salt); MS (ESI, m/z): 445.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.41 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 – 7.00 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 10.8 Hz, 2H), 5.02 (s, 2H), 3.64 (d, J = 10.7 Hz, 2H), 3.50 (d, J = 10.7 Hz, 2H), 3.36 – 3.10(m, 8H), 2.66 (br s, 2H), 2.62 (br s, 2H), 1.69 (br s, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.4, 154.0, 138.7, 137.9, 136.9, 136.3, 130.0, 129.1, 128.3, 125.3, 123.7, 120.0, 116.6, 116.4, 114.9, 112.9, 69.1, 56.5, 51.2, 47.3, 29.4, 29.3, 28.3, 23.3, 23.0.
Embodiment 16：The preparation of compound 17
The reaction of intermediate 4 and 1- (4- fluorophenyls) piperazine, building-up process is the same as embodiment 4.71.4 mg white solids are obtained, Yield：70%.M.p.: 159-160oC (HCl salt); MS (ESI, m/z): 445.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.16 – 6.90 (m, 5H), 6.71 (m, 2H), 5.02 (s, 2H), 3.75 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 10.7 Hz, 2H), 3.41 – 3.07 (m, 8H), 2.67 (br s, 2H), 2.62 (br s, 2H), 1.69 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 158.0, 156.2, 155.6, 146.5, 137.8, 136.8, 136.1, 129.9, 128.9, 128.1, 118.1, 118.1, 115.8, 115.6, 114.7, 112.7, 68.9, 56.1, 50.7, 46.4, 29.2, 29.1, 28.1, 23.1, 22.8.
Embodiment 17：The preparation of compound 18
The reaction of intermediate 4 and 1- (2,4- difluorophenyl) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 69.0 mg whites Body, yield：65%.M.p.: 137-138oC (HCl salt); MS (ESI, m/z): 463.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.11 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.27 (d,J = 8.0 Hz, 2H), 7.00 – 6.91 (m, 2H), 6.87 – 6.78 (m, 2H), 6.75 – 6.62 (m, 2H), 4.98 (s, 2H), 3.67 (t, J = 12.0 Hz, 4H), 3.40 – 3.00 (m, 8H), 2.72 (br s, 2H), 2.69 (br s, 2H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 160.2, 157.7, 157.0, 156.58, 154.5, 138.3, 136.8, 135.5, 134.7, 134.6, 130.0, 129.8, 129.0, 128.3, 120.6, 120.5, 114.8, 112.6, 111.4, 111.2, 105.3, 105.0, 104.8, 69.6, 58.7, 52.4, 47.8, 29.9, 29.8, 28.6, 23.5, 23.2.
Embodiment 18：The preparation of compound 19
The reaction of intermediate 4 and 1- (2- chlorphenyls) piperazine, building-up process is the same as embodiment 4.79.3 g white solids are obtained, are received Rate：75%. M.p.: 159-160oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.10 (s, 1H), 7.43 – 7.21 (m, 6H), 7.13 – 7.02 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.77 – 6.64 (m, 2H), 4.99 (s, 2H), 3.88 – 2.96 (m, 12H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.68 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.6, 147.1, 138.3, 136.8, 135.6, 130.7, 130.0, 129.8, 129.0, 128.9, 128.3, 128.1, 125.4, 121.1, 114.8, 112.6, 69.6, 58.8, 52.6, 48.1, 30.0, 29.8, 28.6, 23.5, 23.2.
Embodiment 19：The preparation of compound 20
The reaction of intermediate 4 and 1- (4- chlorphenyls) piperazine, building-up process is the same as embodiment 4.68.7 mg white solids are obtained, Yield：65%.M.p.: 157-158oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.56 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.71 (m, 2H), 5.02 (s, 2H), 3.83 (d, J = 10.7 Hz, 2H), 3.62 (d,J = 10.7 Hz, 2H), 3.40 – 3.07 (m, 8H), 2.67 (br s, 2H), 2.62 (br s, 2H), 1.69 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.2, 148.6, 137.8, 136.8, 136.1, 129.9, 129.0, 128.9, 128.1, 123.7, 117.7, 114.7, 112.7, 68.9, 56.1, 50.5, 45.4, 29.2, 29.1, 28.1, 23.1, 22.8.
Embodiment 20：The preparation of compound 21
The reaction of intermediate 4 and 1- (3- chlorphenyls) piperazine, building-up process is the same as embodiment 4.65.5 mg white solids are obtained, Yield：62%.M.p.: 146-147oC (HCl salt); MS (ESI, m/z): 461.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.21 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.00 – 6.90 (m, 3H), 6.80 (d, J = 6.5 Hz, 1H), 6.74 – 6.64 (m, 2H), 4.98 (s, 2H), 3.84 – 2.95 (m, 12H), 2.72 (br s, 2H), 2.69 (br s, 2H), 1.76 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.8, 150.6, 138.7, 137.1, 135.8, 135.7, 130.9, 130.3, 130.1, 129.4, 128.6, 122.3, 117.9, 115.6, 115.1, 112.9, 69.9, 59.1, 52.2, 47.0, 30.3, 30.1, 29.0, 23.8, 23.5.
Embodiment 21：The preparation of compound 22
The reaction of intermediate 4 and 1- (2,4- dichlorophenyl) piperazine, building-up process is the same as embodiment 4.It is solid to obtain 63.8 mg whites Body, yield：65%.M.p.: 135-136oC (HCl salt); MS (ESI, m/z): 495.0 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.16 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d,J = 8.0 Hz, 2H), 7.25 – 7.15 (m, 2H), 7.02 (dd, J = 8.0, 1.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.76 – 6.61 (m, 2H), 4.99 (s, 2H), 3.69 (t, J = 12.0 Hz, 4H), 3.50 – 2.97 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9, 149.3, 138.7, 137.1, 135.8, 134.6, 130.4, 130.1, 129.3, 128.6, 128.3, 128.0, 126.6, 119.7, 115.2, 112.9, 69.9, 59.1, 52.9, 48.4, 30.3, 30.1, 29.0, 23.8, 23.5.
Embodiment 22：The preparation of compound 23
The reaction of intermediate 4 and 1- (5- chloro-2-methyls phenyl) piperazine, building-up process is the same as embodiment 4.65.4 mg without Color oily liquids, yield：60%.M.p.: 147-148oC (HCl salt); MS (ESI, m/z): 475.1 [M+1]+;1H NMR (400 MHz, CDCl3) δ in ppm: 13.21 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.14 – 6.93 (m, 4H), 6.75 – 6.64 (m, 2H), 5.00 (s, 2H), 3.66 (br s, 4H), 3.43 – 2.94 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H), 2.23 (s, 3H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.6, 150.2, 138.4, 136.9, 135.6, 132.4, 132.3, 130.8, 130.1, 129.8, 129.1, 128.3, 124.9, 120.6, 114.9, 112.6, 69.7, 58.8, 52.8, 48.6, 30.1, 29.8, 28.7, 23.5, 23.2, 17.4.
Embodiment 23：The preparation of compound 24
The reaction of intermediate 4 and 1- (4- bromophenyls) piperazine, building-up process is the same as embodiment 4.81.4 mg white solids are obtained, Yield：70%.M.p.: 169-170oC (HCl salt); MS (ESI, m/z): 506.9 [M+2]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 11.48 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.70 (m, 2H), 5.01 (s, 2H), 3.83 (d, J = 10.7 Hz, 2H), 3.61 (d,J = 10.7 Hz, 2H), 3.40 – 3.03 (m, 8H), 2.66 (br s, 2H), 2.61 (br s, 2H), 1.68 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, DMSO-d 6) δ in ppm: 156.0, 148.7, 137.5, 136.5, 135.9, 131.6, 129.6, 128.7, 127.9, 117.9, 114.5, 112.5, 111.2, 68.7, 55.9, 50.3, 45.0, 29.0, 28.9, 27.9, 22.9, 22.6.
Embodiment 24：The preparation of compound 25
The reaction of intermediate 4 and 1- (2- trifluoromethyls) piperazine, building-up process is the same as embodiment 4.Obtain 79.5 mg whites Solid, yield：70%.M.p.: 159-160oC (HCl salt); MS (ESI, m/z): 495.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.08 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.62 – 7.49 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 – 7.27 (m, 3H), 6.96 (d, J = 8.3 Hz, 1H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H), 3.80 (t, J = 10.7 Hz, 2H), 3.62 (d, J = 10.7 Hz, 2H), 3.40 – 2.94 (m, 8H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.76 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9, 150.3, 138.7, 137.1, 135.9, 133.8, 130.3, 130.1, 129.4, 128.6, 127.6, 127.6, 126.9, 125.3, 115.2, 112.9, 70.0, 59.1, 53.2, 50.3, 30.3, 30.1, 29.0, 23.8, 23.5.
Embodiment 25：The preparation of compound 26
The reaction of intermediate 4 and 1- (4- trifluoromethyls) piperazine, building-up process is the same as embodiment 4.Obtain 68.1 mg whites Solid, yield：60%.M.p.: 166-167oC (HCl salt); MS (ESI, m/z): 495.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 13.39 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40 (d,J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 8.0 Hz, 3H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H), 3.90 – 3.60 (m, 6H), 3.33 (br s, 2H), 3.24 (br s, 2H), 3.00 (br s, 2H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.77 (dt, J = 6.5, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.6, 151.6, 138.4, 136.9, 135.4, 130.1, 129.9, 129.0, 128.3, 126.9, 116.2, 114.9, 112.6, 69.6, 58.8, 51.8, 45.9, 30.0, 29.8, 28.7, 23.5, 23.2.
Embodiment 26：The preparation of compound 27
The reaction of intermediate 4 and 4- Phenylpiperidines, building-up process is the same as embodiment 4.Obtain 68.4 mg white solids, yield： 70%。M.p.: 146-147 oC (HCl salt); MS (ESI, m/z): 426.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ in ppm: 12.55 (s, 1H), 7.38 (d, J = 7.0 Hz, 2H), 7.35 – 7.20 (m, 7H), 6.96 (d, J = 8.2 Hz, 1H), 6.78 – 6.60 (m, 2H), 4.98 (s, 2H), 3.74 (br s, 2H), 3.32 (br s, 2H), 3.20 (br s, 2H), 2.84 – 2.68 (m, 8H), 2.14 – 1.95 (m, 3H), 1.78 (dt, J = 6.4, 3.4 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ in ppm: 156.9, 143.2, 138.7, 137.0, 136.1, 130.3, 130.1, 129.4, 129.2, 128.5, 127.6, 127.2, 115.2, 112.9, 70.0, 59.3, 54.0, 41.1, 30.6, 30.5, 30.1, 29.0, 23.8, 23.5.
Embodiment 27：The preparation of compound 28
The reaction of intermediate 4 and 4- phenyl -4- hydroxy piperidines, building-up process is the same as embodiment 4.83.1 mg white solids are obtained, Yield：82%.M.p.: 194-195oC (HCl salt); MS (ESI, m/z): 442.1 [M+1]+; 1H NMR (400 MHz, DMSO-d 6) δ in ppm: 1H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 7.52 (d, J = 7.0 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.33 – 7.19 (m, 5H), 6.96 (d, J = 8.2 Hz, 1H), 6.77 – 6.62 (m, 2H), 4.98 (s, 2H), 3.57 – 3.05 (m, 8H), 2.82 (br s, 2H), 2.73 (br s, 2H), 2.69 (br s, 2H), 1.98 (d, J = 11.6 Hz, 2H), 1.76 (t, J = 2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 156.6, 145.9, 138.3, 136.7, 135.7, 130.0, 129.8, 129.0, 128.7, 128.2, 127.8, 124.6, 114.8, 112.6, 69.6, 69.4, 58.6, 49.3, 35.4, 30.2, 29.8, 28.6, 23.5, 23.2.
Embodiment 28：Extracorporeal anti-tumor cytoactive is tested
1. material：
1.1 CCK-8 kits are purchased from Japanese colleague's chemistry institute.
The preparation of 1.2 target cells：Human prostate cancer cell line PC-3, LNCaP, DU145 and normal prostatic epithelium Cell WPMY-1 recovery and culture.
A. human prostate cancer cell line PC-3, LNCaP, DU145 and normal prostate are taken out from liquid nitrogen container respectively The cold of epithelial cell WPMY-1 deposits pipe, inserts rapidly in 37 DEG C of water baths, is kept stirred and is allowed to dissolve rapidly, and sterile working moves into In centrifuge tube;
B. respectively plus DMEM complete culture solutions are trained completely to the centrifuge tube of PC-3 cells and WPMY-1 cells to 10 mL, F12 Base is supported to the centrifuge tube of LNCaP cells to 10 mL, the centrifuge tube of 1640 complete mediums to DU145 cells to 10 mL, 1000 Rmp centrifuges 5 min, abandons supernatant.
C.PC-3, WPMY-1 cell add DMEM complete medium 3-4 mL piping and druming cell is moved into blake bottle after mixing respectively In, LNCaP cells, which add 3-4 mL F12 complete mediums to blow and beat, makes cell be moved into after mixing in blake bottle, and DU145 cells add 3-4 mL 1640 complete mediums piping and druming makes cell be moved into after mixing in blake bottle, 5% CO2, 37 DEG C of cultures；
D. cell growth status is observed, changes nutrient solution, sub-bottle in time.
1.3 cell count：
A. exponential phase cell is chosen, pancreatin digestion, complete medium terminates corresponding to difference, moves into centrifuge tube, Add corresponding complete medium to 10 mL；
B. 10 μ L cell suspensions are taken to instill in the groove of tally side, the cell that four big lattice are counted under microscope is total Number divided by 4, multiplies 104, cell number as contained by every milliliter of nutrient solution；
C. cell number is adjusted to 1 × 105 cells/mL 。
1.4 ether-type aryl bridged piperazine derivatives solution allocations：
Ether-type aryl bridged piperazine derivatives are taken to add DMSO solvents, adjustment initial concentration is 10 mmol, and configuration concentration is 1 mmol It is stand-by, 4 DEG C of preservations.
2. test method
Each hole of 2.1 96 orifice plates is added on human prostate cancer cell line PC-3, LNCaP, DU145 and normal prostate Skin
The μ L of cell WPMY-1 100（1×105 cells/mL）, 37 DEG C of overnight incubations.
2.2 abandon liquid, add the μ L of study subject 100 of various concentrations, control plus the μ L of DMEM complete mediums 100, continue Cultivate 24 h..
2.3 each holes add the μ L of CCK-8 detection reagents 10, continue to cultivate 20 min to 1 h.
Determined under the nm of 2.4 ELIASA 450 per hole OD values.
2.5 calculate inhibiting rate：
Inhibition rate of tumor cell %=[(mean OD value of the mean OD value of control group measure-dosing group measure)/control The mean OD value of group measure] × 100%.
2.6 are mapped with inhibiting rate to the logarithm of drug concentration, try to achieve IC50Value：
Using lgc as abscissa, inhibiting rate is ordinate, tries to achieve IC50Value.
The extracorporeal anti-tumor cytoactive result of the compounds of this invention is as shown in the table：

Claims (4)

1. ether-type aryl bridged piperazine derivatives, it is characterised in that：For the change with following 5-7,9-14,16-19,21-23,25 structures Compound,
。
2. the preparation method of ether-type aryl bridged piperazine derivatives as claimed in claim 1, it is characterised in that：Comprise the following steps： Raw material 4- (bromoethane) phenylacetic acid first（1）Intermediate 2 is reduced into by borane dimethyl sulphide complex compound, secondly intermediate 2 exists With 5 under base catalysis, 6,7,8- tetralols react to obtain intermediate 3, again intermediate 3 under base catalysis with to toluene sulphur Acyl chloride reaction generates the intermediate 4 of hydroxyl protection；Last intermediate 4 and corresponding aryl piperazines class compound generation nucleophilic displacement of fluorine are anti- Corresponding compound 5-7,9-14,16-19,21-23,25 should be obtained；Reaction equation is as follows：
；
The intermediate 2 alkali used with the reaction of 5,6,7,8- tetralols is potassium carbonate；Intermediate 3 with to toluene sulphur Alkali used in acyl chloride reaction is triethylamine.
3. the salt of ether-type aryl bridged piperazine derivatives as claimed in claim 1, it is characterised in that：Including hydrobromate, hydriodate, Hydrochloride, perchlorate, sulfate, maleate, fumarate, malate, tartrate, citrate, benzoate, Mandelate, mesylate, esilate, benzene sulfonate, oxalates, phosphate, succinate or lactate.
4. purposes of the ether-type aryl bridged piperazine derivatives as claimed in claim 1 in antiprostate cancer is prepared.
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