WO2022262350A1 - 取代二芳基类化合物其制备方法和用途 - Google Patents
取代二芳基类化合物其制备方法和用途 Download PDFInfo
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- WO2022262350A1 WO2022262350A1 PCT/CN2022/082764 CN2022082764W WO2022262350A1 WO 2022262350 A1 WO2022262350 A1 WO 2022262350A1 CN 2022082764 W CN2022082764 W CN 2022082764W WO 2022262350 A1 WO2022262350 A1 WO 2022262350A1
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- methyl
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- ethoxy
- methoxy
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229910001389 inorganic alkali salt Inorganic materials 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- AJDUTMFFZHIJEM-UHFFFAOYSA-N n-(9,10-dioxoanthracen-1-yl)-4-[4-[[4-[4-[(9,10-dioxoanthracen-1-yl)carbamoyl]phenyl]phenyl]diazenyl]phenyl]benzamide Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2NC(=O)C(C=C1)=CC=C1C(C=C1)=CC=C1N=NC(C=C1)=CC=C1C(C=C1)=CC=C1C(=O)NC1=CC=CC2=C1C(=O)C1=CC=CC=C1C2=O AJDUTMFFZHIJEM-UHFFFAOYSA-N 0.000 description 1
- RUGBMQVCMWSXJP-UHFFFAOYSA-N n-[3-(oxiran-2-ylmethoxy)phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(OCC2OC2)=C1 RUGBMQVCMWSXJP-UHFFFAOYSA-N 0.000 description 1
- OQAKYHCGYGLHAZ-UHFFFAOYSA-N n-[4-(oxiran-2-ylmethoxy)phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1OCC1OC1 OQAKYHCGYGLHAZ-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001043 yellow dye Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- 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
- C07D295/084—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a class of substituted diaryl compounds, a preparation method thereof, a pharmaceutical preparation and a medical application thereof.
- the technical problem solved by the present invention is to provide a class of substituted diaryl compounds and their pharmaceutically acceptable salts, their optical isomers, their preparation methods, pharmaceutical compositions and their application in the preparation of drugs for treating cancer.
- the present invention provides the following technical solutions:
- the first aspect of the technical solution of the present invention is to provide the compound shown in general formula (I) or its pharmaceutically acceptable salt, its optical isomer:
- R 1 is -OC 2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, -CH 3
- R 2 is -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , -CH(CH 3 ) 2
- R 3 is -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , -OCH 3
- R 4 is -H, -Br, -CF 3 , -Cl
- R 5 is -H, -Cl, -I, -Br,
- the above-mentioned compound or its pharmaceutically acceptable salt, its optical isomer said
- R 1 is -H, -CH(CH 3 ) 2 , -Br, -Cl
- R 2 is -F, -Br, -Cl, -H, -CH(CH 3 ) 2 , -CF 3
- R 3 is -H, -CH 3 , -Cl, -Br, -C 14 H 29
- R 4 is -H, -Br, -CF 3 , -Cl
- R 5 is -H, -Cl, -I, -Br,
- R 1 is -H;
- R 2 is -CF 3 ;
- R 3 is -Br;
- R 4 is -H;
- R 5 is -H;
- R 1 is -H;
- R 2 is -H;
- R 3 is -C 14 H 29 ;
- R 4 is -H;
- R 5 is -H;
- R 1 is -H;
- R 2 is -H;
- R 3 is -Cl;
- R 4 is -Br;
- R 5 is -H;
- R 1 is -Br;
- R 2 is -H;
- R 3 is -Br;
- R 4 is -H;
- R 5 is -Br;
- R 1 is -H
- R 2 is -CF 3
- R 3 is -Br
- R 4 is -H
- R 5 is -H
- R 1 is -H;
- R 2 is -H;
- R 3 is -C 14 H 29 ;
- R 4 is -H;
- R 5 is -H;
- R 1 is -Br;
- R 2 is -H;
- R 3 is -Br;
- R 4 is -H;
- R 5 is -Br;
- R 1 is -H;
- R 2 is -CF 3 ;
- R 3 is -Br;
- R 4 is -H;
- R 5 is -H;
- R 1 is -Br;
- R 2 is -H;
- R 3 is -Br;
- R 4 is -H;
- R 5 is -Br;
- the pharmaceutically acceptable salts of any of the above-mentioned compounds of the present invention are organic acid salts, inorganic acid salts, organic alkali salts or inorganic alkali salts, wherein organic acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid , succinic acid, tartaric acid, citric acid, fumaric acid; inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; organic bases include meglumine, glucosamine; inorganic bases include sodium, potassium, barium, calcium, magnesium , zinc, lithium alkaline compounds.
- any of the above-mentioned compounds of the present invention is a racemate, and its optical isomer is a levorotatory or dextrorotatory form.
- the second aspect of the technical solution of the present invention is to provide the preparation method of the compound described in the first aspect, and the compound of general formula (I) of the present invention can be prepared by the following method:
- R 1 is -OC 2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, -CH 3
- R 2 is -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , -CH(CH 3 ) 2
- R 3 is -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , -OCH 3
- R 4 is -H, -Br, -CF 3 , -Cl
- R 5 is -H, -Cl, -I, -Br,
- the third aspect of the technical solution of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising the compound described in the first aspect, a pharmaceutically acceptable salt thereof, an optical isomer thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
- the pharmaceutical composition is any dosage form that is clinically or pharmaceutically acceptable, preferably an oral preparation or an injection
- the fourth aspect of the technical solution of the present invention is to provide the application of the compound in the first aspect and the pharmaceutical composition in the third aspect in the preparation of a drug for treating cancer.
- the cancer is lung cancer or ovarian cancer or melanoma or colon cancer.
- the clinical administration of the compound of the present invention can be oral administration, injection and the like.
- the clinically used dose of the compound of the present invention is 0.01-1000 mg/day, which may also deviate from this range according to the severity of the disease or different dosage forms.
- the present invention provides a series of compounds with novel structure and anti-cancer effect, which are effective for lung cancer or ovarian cancer or melanoma or colon cancer.
- the synthesis of the target compound of the embodiment of the present invention is to dissolve substituted phenoxymethyloxirane (7) (1.0mmol) and compound (5) (1.2mmol) in isopropanol (15mL), under nitrogen protection , adding a catalytic amount of pyridine, heating to reflux for 6h, TLC detection of raw materials disappeared.
- the reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
- Compound (5) is synthesized from vanillin (1) through 4 steps of reaction.
- Substituted phenoxymethyloxirane (7) is synthesized by nucleophilic substitution reactions between phenols with different substitutions on the benzene ring and epibromohydrin.
- the series of compounds obtained are shown in the following table:
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-ethoxyphenoxy)methyl)oxirane (7-1).
- the reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
- Example 2-58 The preparation method of compound CHJ02029-CHJ05004 in Example 2-58 is the same as Example 1, the difference is that different compound 5 and compound 7 are used for synthesis, and the raw materials of compound 5 and compound 7 used in each example are listed in the corresponding examples. recorded.
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2,6-dichlorophenoxy)methyl)oxirane (7-2).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2,5-bis(trifluoromethyl)phenoxy)methyl)oxirane (7-4).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromophenoxy)methyl)oxirane (7-5).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-bromophenoxy)methyl)oxirane (7-6).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-isopropylphenoxy)methyl)oxirane (7-7).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-bromo-2-methoxyphenoxy)methyl)oxirane (7-8).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-methoxy-4-propylphenoxy)methyl)oxirane (7-9).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-pentadecylphenoxy)methyl)oxirane (7-10).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2,3-dichlorophenoxy)methyl)oxirane (7-11).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-bromophenoxy)methyl)oxirane (7-12).
- Example 13 1-(3-isopropylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl ) (methyl) amino) propan-2-ol (CHJ03015) synthesis
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-isopropylphenoxy)methyl)oxirane (7-13).
- IR (KBr, cm -1 ): 2952, 2925, 2871, 2844, 2792, 2360, 2340, 1606, 1588,1513,1486,1460,1418,1366,1320,1262,1233,1286,1138,1088,1037,1003,980,940,870,804,789,754,700 .
- _ _ H + :485.3379.found:485.3296.
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-methoxyphenoxy)methyl)oxirane (7-14).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((5-bromo-2-fluorophenoxy)methyl)oxirane (7-15).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3,4-dimethoxyphenoxy)methyl)oxirane (7-16).
- Example 17 1-(3-bromo-4-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy) Synthesis of benzyl)(methyl)amino)propan-2-ol (CHJ03043)
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromo-4-chlorophenoxy)methyl)oxirane (7-17).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3,5-dichlorophenoxy)methyl)oxirane (7-20).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromo-4-fluorophenoxy)methyl)oxirane (7-21).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2,4,6-tribromophenoxy)methyl)oxirane (7-22).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromo-5-fluorophenoxy)methyl)oxirane (7-23).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-chlorophenoxy)methyl)oxirane (7-24).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-(trifluoromethyl)phenoxy)methyl)oxirane (7-25).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-iodophenoxy)methyl)oxirane (7-27).
- Example 28 1-(4-bromo-2,6-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethyl) Synthesis of oxy)benzyl)(methyl)amino)propan-2-ol (CHJ04033)
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-bromo-5-fluorophenoxy)methyl)oxirane (7-30).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was N-(3-(oxiran-2-ylmethoxy)phenyl)acetamide (7-31).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2,4-dichlorophenoxy)methyl)oxirane (7-32).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((5-bromo-2-methylphenoxy)methyl)oxirane (7-33).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was N-(4-(oxiran-2-ylmethoxy)phenyl)acetamide (7-34).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-(trifluoromethyl)phenoxy)methyl)oxirane (7-35).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-chlorophenoxy)methyl)oxirane (7-36).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((4-methoxyphenoxy)methyl)oxirane (7-37).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-chlorophenoxy)methyl)oxirane (7-38).
- Compound 5 used was 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).
- Compound 7 used was 2-((2-methoxyphenoxy)methyl)oxirane (7-39).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18).
- Example 41 1-(2-Bromo-5)-(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(pyrrolidinyl-1-yl)ethyl) Synthesis of oxy)benzyl)(methyl)amino)propan-2-ol (CHJ04065)
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((3,5-dichlorophenoxy)methyl)oxirane (7-20).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((2,4,6-tribromophenoxy)methyl)oxirane (7-22).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).
- Compound 5 used was 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).
- Compound 7 used was 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29).
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((2-isopropylphenoxy)methyl)oxirane (7-7).
- Example 48 1-(2-Bromo-5-(trifluoromethyl)phenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-(methoxybenzyl base) (methyl) amino) propan-2-ol (CHJ04090) synthesis
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19).
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((3-bromo-4-fluorophenoxy)methyl)oxirane (7-21).
- Example 51 1-(4-Bromo-3)-(trifluoromethyl)phenoxy)-3-((4-(2-(diethylamino)ethoxy)-3(methoxybenzyl base) (methyl) amino) propan-2-ol (CHJ04093) synthesis
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3).
- Compound 5 used was N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).
- Compound 7 used was 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((4-bromophenoxy)methyl)oxirane (7-12).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((3-bromo-4-chlorophenoxy)methyl)oxirane (7-17).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18).
- Compound 5 used was 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).
- Compound 7 used was 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29).
- the compounds of the present invention inhibit the growth of tumor cells
- Cell lines human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cell lines, all purchased from the Cell Bank of the Chinese Academy of Sciences, using DMEM containing 15% fetal bovine serum ( High Glucose) culture medium, cultured in a 37°C, 5% CO2 incubator.
- DMEM fetal bovine serum ( High Glucose) culture medium
- MTT is an oxidative yellow dye with a chemical name of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazoliumbromide[3-(4,5-dimethyl Thiazole-2)-2,5-diphenyltetrazolium bromide.
- MTT method is also called MTT colorimetric method. It can detect the survival and growth of cells. The method is simple and easy to operate. It is often used to screen substances with cytotoxic activity. The basic principle of its detection is that succinate dehydrogenase can reduce exogenous MTT, so that MTT is reduced to water-insoluble blue-purple crystal formazan (Formazan), which is deposited in cells.
- Succinate dehydrogenase is present in the mitochondria of living cells, but not in dead cells. Thus, this chromogenic reaction can only occur in living cells [56] . Then, the blue-purple crystalline formazan in the cells was dissolved with dimethyl sulfoxide (DMSO), and its absorbance was measured with a microplate reader, thus indirectly reflecting the number of living cells. Within a certain range of cell numbers, the amount of formed blue-purple crystal formazan is positively correlated with the number of living cells.
- DMSO dimethyl sulfoxide
- the MTT method has the advantages of high efficiency, accuracy, simplicity, economy, and good repeatability. It has been widely used in the screening of antineoplastic drugs, the activity detection of medical bioactive factors, the determination of cytotoxic activity and the determination of tumor radiosensitivity.
- MTT solution Preparation of 5mg/mL MTT solution: Weigh 500.0mg of MTT powder, dissolve it in warm 100mL PBS, filter it with a microporous membrane of 0.22 ⁇ m pore size to remove bacteria, and distribute small doses into centrifuge tubes after autoclaving Store in a freezer at -20°C, protected from light.
- the cryopreservation tube containing the tumor cells was taken out of the liquid nitrogen, quickly placed in a 37°C incubator, and kept shaking until it melted. After wiping the edge of the cap of the cryovial with 75% alcohol, pipette the cell suspension into a 10mL centrifuge tube, and add 5mL of culture medium. Centrifuge at low speed (25°C, 3000r/min, 5min), discard the supernatant, add culture medium and repeat the centrifugation and washing once. After adding an appropriate amount of medium to dilute, blow the cells with a pipette to make a suspension, transfer them to a culture bottle, and place them in a 37°C, 5% CO 2 cell incubator for culture. The culture medium was replaced the next day, and placed in a 37°C, 5% CO 2 cell incubator to continue culturing.
- Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells are all adherent cells. According to the growth rate of tumor cells, adherent tumor cells in logarithmic growth phase Wash, digest with 0.25% EDTA trypsin, adjust the cell number to 1 ⁇ 10 5 /mL, inoculate in 96-well plate, 100 ⁇ L per well, culture in CO 2 incubator at 37°C, and administer after 24 hours. Different concentrations of drugs (CHJ series compounds) were added to the administration group, and five dosage groups were set up for each drug, respectively 100, 10, 1, 0.1, 0.01 ⁇ mol/L, and three replicate wells were set for each concentration. Set blank control, DMSO (0.8%) solvent control and cisplatin positive control. After culturing in a 5% CO 2 incubator at 37°C for 48 hours, the OD value was measured by the MTT method, and the cell inhibition rate was calculated.
- CHJ series compounds Different concentration
- Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells were cultured for 48 hours, then terminated, and then 10 ⁇ L of 0.5% MTT solution was added to each well and placed in a CO 2 incubator After 4 hours, remove the liquid in each well, then add 0.2mL of DMSO solution, oscillate fully on the shaker at low frequency to fully dissolve the blue-purple crystal formazan, place it in a microplate reader, and test at a wavelength of 490nm Record the OD value, calculate the average OD value of three parallel wells with different concentrations, and calculate the cell inhibition rate and IC50 value of each test drug at different concentrations according to the average value.
- Inhibition rate (%) [1-OD value of test product/OD value of negative control group] ⁇ 100%
Abstract
本发明涉及药物化学领域，具体涉及一类取代二芳基类化合物式(I)、其制备方法、并包含其药物制剂及其医药用途。药理试验结果表明，本发明的取代二芳基类化合物对人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均具有良好的抑制作用。
Description
本发明涉及药物化学领域，具体涉及一类取代二芳基类化合物、其制备方法、并包含其药物制剂及其医药用途。
1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇，CAS号2125657-10-3，分子式C
28H
42N
2O
5，结构式为：
目前公开的文献资料仅有该化合物的理化性质，未见其药理作用公开,更未见其具有抗肿瘤作用的文献报道。
发明内容
本发明解决的技术问题是提供一类取代二芳基类化合物及其药学上可接受的盐、其光学异构体、其制备方法、药物组合物以及其在制备治疗癌症药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供如通式(I)所示的化合物或其药学上可接受的盐、其光学异构体：
其中，R
1为-OC
2H
5,-H,-CH(CH
3)
2,-Br,-CF
3,-OCH
3,-F,-Cl,-CH
3
R
2为-F,-CF
3,-Br,-NHCOCH
3,-Cl,-H,-OCH
3,-CH(CH
3)
2
R
3为-H,-CH
3,-Cl,-Br,-NHCOCH
3,-C
3H
7,-F,-C
14H
29,-OCH
3
R
4为-H,-Br,-CF
3,-Cl
R
5为-H,-Cl,-I,-Br,
R
6为
优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述
R
1为-H,-CH(CH
3)
2,-Br,-Cl
R
2为-F,-Br,-Cl,-H,-CH(CH
3)
2，-CF
3
R
3为-H,-CH
3,-Cl,-Br,-C
14H
29
R
4为-H,-Br,-CF
3,-Cl
R
5为-H,-Cl,-I,-Br,
R
6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述
R
1为-H；R
2为-CF
3；R
3为-Br；R
4为-H；R
5为-H；
R
6为
或
R
1为-H；R
2为-H；R
3为-C
14H
29；R
4为-H；R
5为-H；
R
6为
或
R
1为-H；R
2为-H；R
3为-Cl；R
4为-Br；R
5为-H；
R
6为
或
R
1为-Br；R
2为-H；R
3为-Br；R
4为-H；R
5为-Br；
R
6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述R
1为-H；R
2为-CF
3；R
3为-Br；R
4为-H；R
5为-H；
R
6为
或
R
1为-H；R
2为-H；R
3为-C
14H
29；R
4为-H；R
5为-H；
R
6为
或
R
1为-Br；R
2为-H；R
3为-Br；R
4为-H；R
5为-Br；
R
6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述
R
1为-H；R
2为-CF
3；R
3为-Br；R
4为-H；R
5为-H；
R
6为
或
R
1为-Br；R
2为-H；R
3为-Br；R
4为-H；R
5为-Br；
R
6为
本发明上述任一化合物药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐，其中有机酸包括乙酸、三氟乙酸、甲磺酸、甲苯磺酸、马来酸、琥珀酸、酒石酸、柠檬酸、富马酸；无机酸包括盐酸、氢溴酸、硝酸、硫酸、磷酸；有机碱包括葡甲胺、氨基葡萄糖；无机碱包括钠、钾、钡、钙、镁、锌、锂的碱性化合物。
本发明上述任一化合物均为消旋体，其光学异构体为其左旋体或右旋体。
本发明技术方案的第二方面是提供第一方面所述化合物的制备方法，本发明的通式(I)化合物可用下述方法制备：
其中，R
1为-OC
2H
5,-H,-CH(CH
3)
2,-Br,-CF
3,-OCH
3,-F,-Cl,-CH
3
R
2为-F,-CF
3,-Br,-NHCOCH
3,-Cl,-H,-OCH
3,-CH(CH
3)
2
R
3为-H,-CH
3,-Cl,-Br,-NHCOCH
3,-C
3H
7,-F,-C
14H
29,-OCH
3
R
4为-H,-Br,-CF
3,-Cl
R
5为-H,-Cl,-I,-Br,
R
6为
通式(I)系列化合物的合成：将取代苯氧基甲基环氧乙烷(7)(1.0mmol)和化合物(5)(1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶，加热回流6h，TLC检测原料消失。反应液用乙酸乙酯稀释，有机相用依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)得目标化合物(I)，产率80％—90％。
本发明技术方案的第三方面是提供包含第一方面所述化合物的药物组合物其药学上可接受的盐、其光学异构体与一种或多种药用载体和/或赋形剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂
本发明技术方案的第四方面是提供包含第一方面所述化合物以及第三方面所述药物组合物在制备治疗癌症药物中的应用。所述癌症为肺癌或卵巢癌或黑色素瘤或结肠癌。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。本发明的化合物临床所用剂量为0.01-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
有益技术效果：本发明提供了一系列结构全新的具有抗癌功效的化合物，该化合物对肺癌或卵巢癌或黑色素瘤或结肠癌有效。
下面具体实施方式来对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不以此限制本发明。
本发明实施例目标化合物的合成，是将取代苯氧基甲基环氧乙烷(7)(1.0mmol)和化合物(5)(1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶，加热回流6h，TLC检测原料消失。反应液用乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)得目标化合物。
化合物(5)是由香草醛(1)为原料，经过4步反应合成的。
得到的4种化合物(5)如下表所示：
表1化合物(5)的具体结构
取代苯氧基甲基环氧乙烷(7)是由苯环上含有不同取代的苯酚与环氧溴丙烷发生亲核取代反应来合成，得到的该系列化合物如下表所示：
表2化合物(7)的具体结构
实施例1：1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(SAMS10)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-乙氧基苯氧基)甲基)环氧乙烷(7-1)。
将2-((2-乙氧基苯氧基)甲基)环氧乙烷(7-1)(194mg,1.0mmol)和1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)(354mg,1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶(8.0μL,0.1mmol)，加热回流6h，TLC检测(展开剂：二氯甲烷-甲醇＝10:1)原料消失。反应液用乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)，得无色油状物(437.9mg,90％)。
1H NMR(CDCl
3,600MHz)δ(ppm):6.89(m,7H),4.09(m,7H),3.84(s,3H),3.59(d,J＝19.80Hz,1H),3.47(d,J＝19.80Hz,1H),3.05(d,J＝17.40Hz,2H),2.90(t,J＝9.60Hz,2H),2.61(m,2H),2.28(s,3H),2.19(m,2H),1.66(d,J＝21.0Hz,2H),1.38(m,6H),0.94(d,J＝8.40Hz,3H).
13C NMR(CDCl
3,150MHz)δ(ppm):149.49,149.39,148.72,147.33,131.62,122.12,121.27,121.10,115.80,113.84,113.16,112.48,72.91,66.61(2C),64.51,62.45,59.60,57.25,55.94,54.37(2C),42.43,33.84(2C),30.39,21.76,14.93.IR(KBr,cm
-1):2924,2871,2851,2794,2360,2340,1592,1512,1494,1460,1419,1368,1321,1272,1217,1138,1035,980,863,803,772,670.HRMS(ESI):m/z calcd for C
28H
43N
2O
5(M+H)
+:487.3172.found:487.3199.
实施例2-58中化合物CHJ02029-CHJ05004的制备方法同实施例1，区别在于使用不同的化合物5和化合物7合成，具体每个实施例中使用的化合物5和化合物7原料在相应实施例中有记载。
实施例2：1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02029)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,6-二氯苯氧基)甲基)环氧乙烷(7-2)。
无色油状物，产率88％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.36(d,J＝8.0Hz,2H),7.08(t,J＝8.0Hz,1H),7.01(s,1H),6.87(m,2H),4.15(m,3H),3.99(m,2H),3.80(s,3H),3.59(m,2H),3.14(d,J＝11.20Hz,2H),2.92(t,J＝5.60Hz,2H),2.74(m,1H),2.59(dd,J＝12.80,7.60Hz,1H),2.32(m,5H),1.70(d,J＝12.80Hz,2H),1.45(s,1H),1.30(m,2H),0.95(d,J＝6.4Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):151.27,149.68,147.30,131.70,129.04,128.89(3C),125.31,121.62,113.84,113.09,75.76,67.86,66.25,62.02,59.27,56.86,55.00,53.81(2C),41.86,33.04(2C),29.92,20.60.IR(KBr,cm
-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1511,1475,1455,1367,1286,1262,1230,1127,1036,979,937,863,807,670.HRMS(ESI):m/z calcd for C
26H
37Cl
2N
2O
4(M+H)
+:511.2130.found:511.2047.
实施例3：1-(4-溴-3-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02049)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
无色油状物，产率87％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.64(d,J＝8.80Hz,1H),7.26(s,1H),7.02(d,J＝8.80Hz,1H),6.95(s,1H),6.83(q,J＝8.0Hz,2H),4.08(m,4H),3.91(m,1H),3.75(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.62(dd,J＝12.40,5.60Hz,1H),2.48(dd,J＝12.40,6.40Hz,1H),2.32(s,3H),2.17(t,J＝11.60Hz,2H),1.66(d,J＝12.40Hz,2H),1.39(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):158.33,149.62,147.45,135.7(2C),131.91,121.46(2C),118.91,114.35,114.29,113.48,113.06,70.99,67.29,66.69,62.29,58.70,57.12,54.94,54.00(2C),42.25,33.48(2C),33.25,20.75.IR(KBr,cm
-1):2926,2872,2849,2793,2370,2323,1684,1651,1556,1512,1474,1455,1419,1367,1330,1313,1260,1235,1139,1035,980,936,879,809,753.HRMS(ESI):m/z calcd for C
27H
37BrF
3N
2O
4(M+H)
+:589.1889.found:589.2404.
实施例4：1-(2,5-双(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02050)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,5-双(三氟甲基)苯氧基)甲基)环氧乙烷(7-4)。
白色固体，产率85％，mp:70-72℃，
1H NMR(CD
3OD,400MHz)δ(ppm):7.77(d,J＝8.0Hz,1H),7.46(s,1H),7.38(d,J＝8.0Hz,1H),6.96(s,1H),6.83(q,J＝8.0Hz,2H),4.13(m,5H),3.76(s,3H),3.51(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.63(m,2H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.66(d,J＝12.40Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):157.29,149.66,147.41,131.89,127.72,127.67,121.67,121.40,116.72,116.68,113.59,112.97,109.94,109.90,71.45,67.17,66.71,62.28,59.06,57.11,54.90,53.98(2C),41.93,33.46(2C),30.24,20.73.IR(KBr,cm
-1):3562,3354,2945,2877,2831,2800,1624,1595,1517,1463,1435,1330,1259,1232,1174,1132,1087,1043,1022,962,910,866,833,804,750,673.HRMS(ESI):m/z calcd for C
28H
37F
6N
2O
4(M+H)
+:579.2658.found:579.2549.
实施例5：1-(3-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03001)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴苯氧基)甲基)环氧乙烷(7-5)。
无色油状物，产率86％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.10(m,3H),6.82(m,4H),4.14(m,3H),3.94(d,J＝4.80Hz,2H),3.85(s,3H),3.62(d,J＝13.60Hz,1H),3.45(d,J＝13.20Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.0Hz,2H),2.62(m,1H),2.49(dd,J＝12.40,3.60Hz,1H),2.29(s,3H),2.11(t,J＝11.60Hz,2H),1.64(d,J＝12.40Hz,2H),1.30(m,3H),0.93(d,J＝4.0Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):159.54,149.44,147.60,131.18,130.53,124.07, 122.76,121.30,117.86,113.58,112.97,112.49,70.63,66.81,66.04,62.37,59.25,57.40,55.97,54.49(2C),42.26,34.19(2C),30.57,21.87.IR(KBr,cm
-1):2947,2924,2871,2846,2792,2360,2340,1651,1591,1572,1512,1476,1463,1459,1368,1324,1283,1261,1229,1157,1138,1090,1035,991,936,861,804,800,674.HRMS(ESI):m/z calcd for C
26H
38BrN
2O
4(M+H)
+:521.2015.found:521.1945.
实施例6：1-(2-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03003)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴苯氧基)甲基)环氧乙烷(7-6)。
无色油状物，产率90％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.52(d,J＝7.60Hz,1H),7.23(d,J＝8.0Hz,1H),6.85(m,5H),4.14(t,J＝6.0Hz,3H),4.03(d,J＝4.40Hz,2H),3.84(s,3H),3.72(q,J＝7.20Hz,1H),3.63(d,J＝12.80Hz,1H),3.47(d,J＝12.80Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.72(m,1H),2.59(dd,J＝12.0,3.60Hz,1H),2.31(s,3H),2.11(t,J＝11.20Hz,2H),1.64(d,J＝12.40Hz,2H),1.27(m,3H),0.93(d,J＝6.0Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.10,149.41,147.54,133.30,131.32,128.46,122.19,121.33,113.54,112.94,112.52,112.41,71.39,66.74,66.25,62.47,59.35,58.43,57.39,55.96,54.47,42.43,34.17,30.57,21.86,18.45.IR(KBr,cm
-1):2947,2924,2871,2844,2792,2361,2340,1589,1513,1480,1462,1417,1368,1323,1276,1261,1232,1158,1138,1084,1053,1030,979,939,872,806,749.HRMS(ESI):m/zcalcd for C
26H
38BrN
2O
4(M+H)
+:521.2015.found:521.1943.
实施例7：1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03004)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-异丙基苯氧基)甲基)环氧乙烷(7-7)。
无色油状物，产率87％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.2(d,J＝7.60Hz,1H),7.13(t,J＝7.60Hz,1H),6.92(t,J＝7.20Hz,1H),6.82(m,4H),4.14(m,3H),3.99(m,2H),3.84(s,3H),3.65(d,J＝13.20Hz,1H),3.45(d,J＝12.80Hz,1H),3.26(m,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.69(m,1H),2.53(dd,J＝12.0,3.20Hz,1H),2.31(s,3H),2.11(t,J＝11.2Hz,2H),1.64(d,J＝12.0Hz,2H),1.30(m,3H),1.19(d,J＝6.80Hz,6H),0.96(d,J＝6.0Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.82,149.43,147.56,137.05,131.31,126.55,126.07,121.26,120.89,112.93,112.45,111.30,70.34,66.78,66.35,62.47,59.67,57.40,55.94,54.48(2C),42.36,34.19(2C),30.57,26.90,22.64(2C),21.88.IR(KBr,cm
-1):2950,2925,2870,2792,2360,2340,1597,1513,1491,1452,1418,1365,1323,1261,1238,1193,1138,1088,1033,1030,980,937,878,822,805,751.HRMS(ESI):m/z calcd for C
29H
45N
2O
4(M+H)
+:485.3379.found:485.3330.
实施例8：1-(4-溴-2-甲氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03005)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-2-甲氧基苯氧基)甲基)环氧乙烷(7-8)。
无色油状物，产率90％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.06(s,1H),7.00(d,J＝8.40Hz,1H),6.95(s,1H),6.83(m,3H),4.10(m,3H),3.96(dd,J＝9.60,5.60Hz,1H),3.85(dd,J＝9.60,5.60Hz,1H),3.77(d,J＝12.0Hz,6H),3.53(m,2H),3.06(d,J＝11.60Hz,2H),2.83(t,J＝5.88Hz,2H),2.63(dd,J＝13.44,5.60Hz,1H),2.49(dd,J＝13.44,6.80Hz,1H),2.31(s,3H),2.20(t,J＝11.60Hz,2H),1.67(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.94(d,J＝6.40Hz,3H).
13C NMR(CD
3OD,100MHz)δ(ppm):150.42,149.62,147.91,147.36,131.88,123.29,121.47,115.25,114.88,113.54,113.05,112.79,71.91,67.50,66.61,62.22,58.89,57.07,55.34,54.94,53.96(2C),42.13,33.39(2C),30.18,20.71.IR(KBr,cm
-1):2946,2924,2843,2792,2360,2340,1589,1556,1539,1506,1459,1418,1398,1364,1324,1255,1225,1183,1136,1084,1029,936, 857,797,670.HRMS(ESI):m/z calcd for C
27H
40BrN
2O
5(M+H)
+:551.2101.found:551.2094.
实施例9：1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇(CHJ03011)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-甲氧基-4-丙基苯氧基)甲基)环氧乙烷(7-9)。
白色固体，产率83％，mp:45-47℃，
1H NMR(CD
3OD,400MHz)δ(ppm):6.97(s,1H),6.87(d,J＝8.0Hz,1H),6.80(m,3H),6.69(d,J＝8.0Hz,1H),4.10(m,3H),3.96(dd,J＝9.60,3.60Hz,1H),3.84(dd,J＝9.60,6.40Hz,1H),3.78(d,J＝13.60Hz,6H),3.54(m,2H),3.05(d,J＝11.60Hz,2H),2.82(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,5.20Hz,1H),2.51(q,J＝7.20Hz,3H),2.30(s,3H),2.19(t,J＝11.60Hz,2H),1.63(m,4H),1.40(s,1H),1.28(m,2H),0.94(d,J＝7.20Hz,6H).
13C NMR(CD
3OD,100MHz)δ(ppm):149.66,149.33,147.40,146.45,136.10,131.85,121.50,120.41,113.95,113.60,113.07,112.54,72.26,67.62,66.67,62.16,59.08,57.08,55.14,54.96,53.97(2C),42.01,37.26,33.41(2C),30.19,24.48,20.71,12.68.IR(KBr,cm
-1):2922,2868,2791,2360,2340,1597,1516,1458,1419,1371,1330,1261,1230,1138,1091,1031,970,850,804,750,646,553,489.HRMS(ESI):m/zcalcd for C
30H
47N
2O
5(M+H)
+:515.3485.found:515.3423.
实施例10：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-十五烷基苯氧基)丙-2-醇(CHJ03012)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-十五烷基苯氧基)甲基)环氧乙烷(7-10)。
白色固体，产率85％，mp:40-42℃，
1H NMR(CD
3OD,400MHz)δ(ppm):7.13(t,J＝7.60Hz,1H),6.97(s,1H),6.84(m,2H),6.72(m,3H),4.11(m,3H),3.98(m,1H),3.86(m,1H),3.76(s, 3H),3.55(m,2H),3.05(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.59(m,4H),2.30(m,3H),2.18(t,J＝11.60Hz,2H),1.64(m,4H),1.28(s,27H),0.94(d,J＝6.40Hz,3H),0.89(t,J＝6.0Hz,3H).
13C NMR(CD
3OD,100MHz)δ(ppm):159.02,149.69,147.42,144.23,131.93,128.79,121.47,120.62,114.35,113.65,113.08,111.38,70.34,67.53,66.71,62.22,59.19,57.11,54.98,53.98(2C),53.38,42.07,35.56,33.43(2C),31.67,31.21,30.21,29.35(6C),29.20,29.07,28.91,22.33,20.72,13.04.IR(KBr,cm
-1):2924,2852,2794,2360,2340,1591,1514,1458,1367,1325,1263,1151,1085,1035,937,869,806,775,694.HRMS(ESI):m/z calcd for C
41H
69N
2O
4(M+H)
+:653.5257.found:653.5163.
实施例11：1-(2,3-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03013)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,3-二氯苯氧基)甲基)环氧乙烷(7-11)。
无色油状物，产率88％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.20(t,J＝8.11Hz,1H),7.08(t,J＝8.08Hz,1H),6.96(m,2H),6.82(q,J＝8.05Hz,2H),4.05(m,5H),3.75(s,3H),3.52(s,2H),3.03(d,J＝11.43Hz,2H),2.80(t,J＝5.65Hz,2H),2.69(dd,J＝12.82,5.4Hz,1H),2.56(dd,J＝12.73,7.02Hz,1H),2.32(s,3H),2.17(t,J＝11.7Hz,2H),1.65(d,J＝12.71Hz,2H),1.38(s,1H),1.27(m,2H),0.93(d,J＝6.28Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):155.92,149.65,147.41,133.15,131.90,127.52,121.91,121.45,121.32,113.56,113.03,111.43,71.63,67.36,66.65,62.35,58.90,57.11,54.97,53.97(2C),42.20,33.46(2C),30.22,20.76.IR(KBr,cm
-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1511,1475,1455,1367,1286,1262,1230,1127,1036,979,937,863,807,670.HRMS(ESI):m/z calcd for C
26H
37Cl
2N
2O
4(M+H)
+:511.2130.found:511.2095.
实施例12：1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴苯氧基)甲基)环氧乙烷(7-12)。
无色油状物，产率81％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.35(d,J＝8.0Hz,2H),6.95(s,1H),6.82(m,4H),4.10(t,J＝5.60Hz,2H),4.05(m,1H),3.95(dd,J＝9.60,3.20Hz,1H),3.84(dd,J＝9.60,6.0Hz,1H),3.77(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.83,6.0Hz,1H),2.48(dd,J＝12.80,7.20Hz,1H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.93(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):158.28,149.64,147.44,131.89(2C),131.89,121.49,116.19(2C),113.56,113.10,112.35,70.66,67.42,66.70,62.27,58.96,57.12,54.88,53.99(2C),42.21,33.47(2C),30.23,20.76.IR(KBr,cm
-1):2947,2925,2871,2844,2792,2360,2331,1591,1556,1512,1489,1458,1418,1368,1322,1285,1245,1157,1074,1034,980,937,879,863,821,756,647.HRMS(ESI):m/z calcd for C
26H
38BrN
2O
4(M+H)
+:521.2015.found:521.1975.
实施例13：1-(3-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03015)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-异丙基苯氧基)甲基)环氧乙烷(7-13)。
无色油状物，产率89％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.15(t,J＝7.60Hz,1H),6.97(s,1H),6.82(m,4H),6.69(d,J＝8.0Hz,1H),4.10(m,3H),3.97(m,1H),3.86(m,1H),3.76(s,3H),3.54(m,2H),3.03(d,J＝11.20Hz,2H),2.82(m,3H),2.63(dd,J＝12.80,5.60Hz,1H),2.51(dd,J＝12.40,6.8Hz,1H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.24(m,8H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):159.09,150.37,149.68，147.44，131.90，128.90，121.47，118.55，113.62，113.09，112.54，111.36，70.39，67.54，66.74， 62.21,59.25,57.12,54.99(3C),42.05,34.05,33.46(2C),30.23,23.03(2C),20.75.IR(KBr,cm
-1):2952,2925,2871,2844,2792,2360,2340,1606,1588,1513,1486,1460,1418,1366,1320,1262,1233,1286,1138,1088,1037,1003,980,940,870,804,789,754,700.HRMS(ESI):m/zcalcd for C
29H
45N
2O
4(M+H)
+:485.3379.found:485.3296.
实施例14：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-甲氧基苯氧基)甲基)环氧乙烷(7-14)。
无色油状物，产率83％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.13(t,J＝8.0Hz,1H),6.96(s,1H),6.83(m,2H),6.48(m,3H),4.09(m,3H),3.96(dd,J＝9.60,6.80Hz,1H),3.85(dd,J＝9.20,6.0Hz,1H),3.75(d,J＝7.60Hz,6H),3.52(m,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,5.60Hz,1H),2.49(dd,J＝12.80,7.20Hz,2H),2.30(s,3H),2.16(t,J＝11.60Hz,2H),1.65(dd,J＝12.40Hz,2H),1.40(s,1H),1.27(m,2H),0.93(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):160.97,160.23,149.65,147.42,131.90,129.48,121.46,113.58,113.05,106.35,106.02,100.65,70.42,67.48,66.69,62.23,59.13,57.12,54.98,54.28,53.99(2C),42.10,33.46(2C),30.23,20.76.IR(KBr,cm
-1):2947,2925,2872,2837,2792,2360,2340,1593,1559,1513,1492,1455,1418,1368,1334,1287,1264,1231,1201,1154,1083,1036,980,940,834,807,762,687.HRMS(ESI):m/z calcd for C
27H
41N
2O
5(M+H)
+:473.3015.found:473.2947.
实施例15：1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((5-溴-2-氟苯氧基)甲基)环氧乙烷(7-15)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.23(d,J＝7.20Hz,1H),7.02(m,3H),6.85(dd,J＝22.0,8.0Hz,2H),4.09(m,4H),3.94(dd,J＝10.0,5.60Hz,1H),3.78(s,3H),3.50(m,2H),3.05(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.63(dd,J＝12.80,5.60Hz,1H),2.50(dd,J＝12.85,6.51Hz,1H),2.31(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝13.20Hz,2H),1.41(s,1H),1.28(m,2H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):150.62,149.66,147.40,131.94,123.66,123.59,121.44,118.06,117.16,116.96,115.94,113.59,112.97,72.04,67.36,66.68,62.24,58.85,57.10,54.98,53.98(2C),42.10,33.44(2C),30.22,20.72.IR(KBr,cm
-1):2947,2925,2872,2845,2794,2360,2340,1607,1511,1459,1417,1404,1369,1323,1303,1262,1231,1138,1117,1090,1020,962,935,877,837,803,755,627.HRMS(ESI):m/zcalcd for C
26H
37BrFN
2O
4(M+H)
+:539.1921.found:539.1911.
实施例16：1-(3,4-二甲氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03019)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,4-二甲氧基苯氧基)甲基)环氧乙烷(7-16)。
无色油状物，产率87％，
1H NMR(CD
3OD,400MHz)δ(ppm):6.97(s,1H),6.84(m,3H),6.54(s,1H),6.40(d,J＝8.55Hz,1H),4.08(m,3H),3.93(dd,J＝9.57,3.33Hz,1H),3.83(m,1H),3.77(d,J＝8.88Hz,9H),3.52(q,J＝12.85Hz,2H),3.05(d,J＝11.47Hz,2H),2.82(t,J＝5.55Hz,2H),2.62(dd,J＝12.84,5.5Hz,1H),2.49(dd,J＝12.77,7.05Hz,1H),2.31(s,3H),2.19(t,J＝11.69Hz,2H),1.66(d,J＝12.59Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.29Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):153.95,150.09,149.63,147.39,143.54,131.88,121.48,113.57,113.07,112.86,104.22,100.91,70.91,67.53,66.61,62.22,59.10,57.08,55.91,54.97(2C),53.97(2C),42.12,33.39(2C),30.18,20.72.IR(KBr,cm
-1):2926,2871,2850,2794,2360,2340,1700,1651,1611,1596,1513,1418,1368,1320,1261,1229,1199,1162,1138,1029,981,943,875,804,764.HRMS(ESI):m/zcalcd for C
28H
43N
2O
6(M+H)
+:503.3121.found:503.2817.
实施例17：1-(3-溴-4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03043)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-氯苯氧基)甲基)环氧乙烷(7-17)。
无色油状物，产率89％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.30(m,1H),7.17(s,1H),6.81(m,4H),4.11(m,3H),3.91(m,2H),3.84(s,3H),3.61(d,J＝12.0Hz,1H),3.45(d,J＝12.80Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.61(m,1H),2.47(dd,J＝12.40,3.60Hz,1H),2.29(s,3H),2.11(t,J＝11.20Hz,2H),1.63(d,J＝12.40Hz,2H),1.29(m,3H),0.93(d,J＝6.0Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.74,149.48,147.66,131.13,130.47,126.18,122.53,121.31,119.57,115.31,113.07,112.55,71.00,66.93,65.99,62.37,59.10,57.39,55.99,54.50(2C),42.29,34.21(2C),30.56,21.87.IR(KBr,cm
-1):2923,2846,2360,2340,1700,1651,1613,1590,1559,1539,1511,1470,1460,1418,1373,1337,1288,1262,1229,1157,1138,1083,1035,931,859,805,669.HRMS(ESI):m/z calcd for C
26H
37BrClN
2O
4(M+H)
+:555.1625.found:555.1610.
实施例18：1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04010)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
无色油状物，产率82％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.15(d,J＝8.40Hz,1H),7.09(s,1H),6.96(s,1H),6.82(m,3H),4.11(t,J＝5.60Hz,2H),4.04(m,1H),3.95(m,1H),3.83(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H), 2.60(dd,J＝12.40,5.60Hz,1H),2.48(dd,J＝13.20,6.80Hz,1H),2.30(d,J＝2.40Hz,6H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):157.77,149.67,147.44,131.94,130.79,129.42,124.18,121.46,117.97,113.65,113.61,113.06,70.79,67.42,66.75,62.25,59.98,57.13,55.00,53.99(2C),42.14,33.47(2C),30.24,20.74,20.50.IR(KBr,cm
-1):2946,2923,2871,2792,2360,2340,1651,1604,1579,1539,1511,1492,1458,1418,1368,1323,1289,1262,1236,1158,1138,1086,1030,1003,932,866,838,806,757,671.HRMS(ESI):m/zcalcd for C
27H
40BrN
2O
4(M+H)
+:535.2171.found:535.2149.
实施例19：1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04011)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.71(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.40Hz,1H),6.95(s,1H),6.82(q,J＝8.0Hz,3H),4.09(m,5H),3.74(s,3H),3.53(s,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.72(dd,J＝12.40,4.80Hz,1H),2.58(dd,J＝12.80,6.40Hz,1H),2.33(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):155.81,149.65,147.39,133.69,131.95,121.42,118.16,118.12,116.09,113.57,112.96,109.59,109.55,71.58,67.30,66.67,62.39,58.82,57.10,54.91,53.97(2C),42.13,33.45(2C),30.22,20.73.IR(KBr,cm
-1):3560,3354,2927,2868,2818,1591,1516,1462,1421,1371,1332,1255,1226,1165,1130,1080,1041,1020,935,904,862,802,752.HRMS(ESI):m/z calcd for C
27H
37BrF
3N
2O
4(M+H)
+:589.1889.found:589.1827.
实施例20：1-(3,5-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04012)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,5-二氯苯氧基)甲基)环氧乙烷(7-20)。
无色油状物，产率88％，
1H NMR(CD
3OD,400MHz)δ(ppm):6.96(d,J＝9.60Hz,2H),6.84(m,4H),4.10(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.48(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝6.40Hz,2H),2.60(dd,J＝12.80,6.0Hz,1H),2.46(dd,J＝12.80,6.40Hz,1H),2.31(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.75Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):160.34,149.66,147.46,135.12,131.94,121.46,120.38,113.52,113.42(3C),113.04,70.04,67.26,66.70,62.29,58.68,57.13,54.99,54.00(2C),42.25,33.47(2C),30.24,20.75.IR(KBr,cm
-1):2948,2925,2872,2843,2793,2360,2340,1590,1571,1513,1442,1424,1368,1323,1303,1262,1192,1157,1138,1039,980,938,853,831,800,756,670.HRMS(ESI):m/z calcd for C
26H
37Cl
2N
2O
4(M+H)
+:511.2130.found:511.2075.
实施例21：1-(3-溴-4-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04020)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-氟苯氧基)甲基)环氧乙烷(7-21)。
无色油状物，产率90％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.10(m,2H),6.95(s,1H),6.84(m,3H),4.10(m,3H),3.96(m,1H),3.84(m,1H),3.77(s,3H),3.50(q,J＝12.0Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.20Hz,2H),2.60(dd,J＝12.80,6.0Hz,1H),2.47(dd,J＝11.20,6.80Hz,1H),2.31(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.41(s,1H),1.28(m,2H),0.93(d,J＝6.0Hz,3H).
13C NMR(CD
3OD,100MHz)δ(ppm):155.71,149.65,147.44, 131.92,121.47,118.73,116.32,116.08,114.95,114.88,113.55,113.07,71.29,67.38,66.71,62.27,58.86,57.12,55.01,54.00(2C),42.21,33.47(2C),30.23,20.76.IR(KBr,cm
-1):2947,2925,2872,2843,2793,2360,2340,1591,1513,1493,1458,1418,1368,1322,1262,1220,1203,1157,1138,1088,1035,979,938,862,840,806,774.HRMS(ESI):m/z calcd for C
26H
37BrFN
2O
4(M+H)
+:539.1921.found:539.1888.
实施例22：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,4,6-三溴苯氧基)甲基)环氧乙烷(7-22)。
无色油状物，产率90％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.75(s,2H),6.98(s,1H),6.85(m,2H),4.10(t,J＝5.69Hz,2H),4.22(m,1H),4.12(t,J＝5.61Hz,2H),3.79(s,3H),3.54(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.72(dd,J＝13.20,5.20Hz,1H),2.54(dd,J＝12.80,7.20Hz,1H),2.32(s,3H),2.16(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.39(s,1H),1.30(m,2H),0.93(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):152.75,149.67,147.45,134.96(3C),131.75,121.55,118.54,117.13,113.66,113.14,75.83,67.96,66.75,62.14,59.34,57.11,55.06,53.99(2C),42.08,33.48(2C),30.24,20.77.IR(KBr,cm
-1):2923,2846,2360,2340,1700,1651,1613,1590,1559,1539,1511,1470,1460,1418,1373,1337,1288,1262,1229,1157,1138,1083,1035,931,859,805.HRMS(ESI):m/z calcd for C
26H
36Br
3N
2O
4(M+H)
+:677.0225.found:677.0256.
实施例23：1-(3-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04023)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-5-氟苯氧基)甲基)环氧乙烷(7-23)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):6.95(s,1H),6.85(m,4H),6.65(d,J＝10.80Hz,1H),4.11(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.60(dd,J＝12.40,5.60Hz,1H),2.46(dd,J＝12.80,6.40Hz,1H),2.31(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.93(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):164.64,162.18,161.02,149.65,147.45,131.93,122.34,121.46,113.83,113.29,110.85,101.17,71.09,67.25,66.68,62.28,58.72,57.12,55.00,53.99(2C),42.23,33.46(2C),30.23,20.76.IR(KBr,cm
-1):2947,2925,2872,2841,2792,2360,2340,1605,1583,1512,1454,1418,1367,1318,1280,1263,1231,1280,1263,1231,1146,1084,1039,980,941,833.HRMS(ESI):m/z calcd for C
26H
37BrFN
2O
4(M+H)
+:539.1921.found:539.1879.
实施例24：1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04024)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-氯苯氧基)甲基)环氧乙烷(7-24)。
无色油状物，产率83％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.21(t,J＝8.40Hz,1H),6.88(m,6H),4.09(m,3H),3.98(m,1H),3.86(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,1H),3.03(d,J＝11.20Hz,1H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,6.80Hz,2H),2.49(dd,J＝12.80,6.80Hz,2H),2.30(s,3H),2.16(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.39(s,1H),1.28(m,2H),0.93(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):159.91,149.66,147.45,134.44,131.93,130.12,121.47,120.46,114.57,113.58,113.06,112.81,70.71,67.38,66.72,62.26,58.98,57.13,55.00,53.99(2C),42.16,33.48(2C),30.24,20.76.IR(KBr,cm
-1):2947,2925,2872,2843,2792,2360,2340,1651,1595,1580,1539,1511,1470,1459,1419,1367,1326,1283,1260,1231,1192,1157,1138,1091,1036,979,935,870,807,770,681.HRMS(ESI):m/z calcd for C
26H
38ClN
2O
4(M+H)
+:477.2520.found:477.2476.
实施例25：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-(三氟甲基)苯氧基)丙-2-醇(CHJ04025)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-25)。
无色油状物，产率83％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.44(t,J＝8.0Hz,1H),7.17(m,3H),6.97(s,1H),6.85(m,2H),4.09(m,4H),3.93(m,1H),3.76(s,3H),3.53(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.63(dd,J＝12.40,5.20Hz,1H),2.51(dd,J＝12.80,6.80Hz,1H),2.31(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.93(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):159.32,149.66,147.45,131.92,131.39,131.55,130.01,121.46,117.96,116.91,113.57,113.06,110.96,70.71,67.38,66.72,62.26,58.98,57.13,55.00,53.99(2C),42.16,33.48(2C),30.24,20.76.IR(KBr,cm
-1):2947,2926,2873,2845,2794,2360,2340,1651,1593,1557,1539,1513,1493,1453,1419,1367,1330,1289,1262,1234,1165,1096,1065,1037,979,934,880,794,753,698.HRMS(ESI):m/z calcd for C
27H
38F
3N
2O
4(M+H)
+:511.2784.found:511.2765.
实施例26：1-(3,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04026)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率81％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.36(d,J＝9.20Hz,1H),7.05(s,1H),6.95(s,1H),6.84(m,3H),4.10(t,J＝5.60Hz,2H),4.04(m,1H),3.97(m,1H),3.86(m,1H),3.77(s,3H),3.50(q,J＝12.80Hz,1H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd，J＝12.80，6.0Hz，1H)，2.47(dd，J＝12.80，6.80Hz，1H)，2.31(s，3H)，2.16(t，J＝11.60Hz， 2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).
13C NMR(CD
3OD,100MHz)δ(ppm):158.36,149.64,147.45,132.25,131.93,130.48,123.33,121.47,116.16,114.57,113.52,113.07,70.99,67.33,66.70,62.29,58.76,57.13,54.98,54.00(2C),42.26,33.48(2C),30.24,20.76.IR(KBr,cm
-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1570,1539,1511,1475,1455,1419,1367,1286,1262,1230,1191,1156,1127,1092,1036,979,937,861,807,757,670.HRMS(ESI):m/z calcd for C
26H
37Cl
2N
2O
4(M+H)
+:511.2130.found:511.2115.
实施例27：1-(2-碘苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04027)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-碘苯氧基)甲基)环氧乙烷(7-27)。
无色油状物，产率90％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.72(d,J＝7.60Hz,1H),7.30(t,J＝8.0Hz,1H),6.96(s,1H),6.90(d,J＝8.40Hz,1H),6.83(q,J＝8.0Hz,2H),6.70(t,J＝7.60Hz,1H),4.09(m,3H),3.98(m,2H),3.74(s,3H),3.55(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.74(d,J＝5.20Hz,1H),2.64(dd,J＝12.80,7.60Hz,1H),2.32(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):157.53,149.66,147.40,139.11,131.94,129.30,122.32,121.47,113.60,113.07,112.12,85.66,71.22,67.40,62.42,59.28,57.11,55.00,53.97(3C),42.07,33.47(2C),30.23,20.75.IR(KBr,cm
-1):2946,2923,2871,2844,2792,2360,2340,1584,1513,1471,1441,1418,1368,1323,1261,1231,1192,1158,1138,1084,1050,1030,1019,979,962,938,873,822,806,749.HRMS(ESI):m/z calcd for C
26H
38IN
2O
4(M+H)
+:569.1876.found:569.1842.
实施例28：1-(4-溴-2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04033)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率84％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.56(s,2H),6.97(s,1H),6.85(m,2H),4.16(m,1H),4.12(t,J＝5.60Hz,2H),3.99(m,2H),3.79(s,3H),3.52(m,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.67(dd,J＝13.20,4.80Hz,1H),2.55(dd,J＝13.20,7.60Hz,1H),2.30(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):150.93,149.67,147.43,131.79,131.46(3C),129.99,121.50,116.13,113.67,113.08,76.07,67.97,66.71,62.14,59.26,57.09,55.02,53.97(2C),42.01,33.44(2C),30.21,20.76.IR(KBr,cm
-1):2947,2924,2872,2840,2794,2360,2340,1544,1511,1459,1419,1375,1320,1259,1231,1193,1158,1138,1084,1031,994,933,856,803.HRMS(ESI):m/z calcd for C
26H
36BrCl
2N
2O
4(M+H)
+:589.1236.found:589.1220.
实施例29：1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04034)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.12(s,1H),7.02(s,1H),6.95(s,1H),6.91(s,1H),6.83(m,2H),4.10(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.48(m,2H),3.04(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.60(dd,J＝12.40,6.0Hz,1H),2.46(dd,J＝12.40,6.0Hz,1H),2.31(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝12.80Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):160.39,149.66,147.44,135.27,131.85,123.18,122.49,121.46,116.33,113.87,113.54,113.04,71.04, 67.26,66.67,62.29,58.67,57.11,55.01,53.99(2C),42.26,33.45(2C),30.22,20.74.IR(KBr,cm
-1):2947,2926,2870,2840,2793,2360,2331,1588,1563,1539,1512,1459,1437,1420,1367,1335,1319,1301,1230,1259,1190,1156,1138,1091,1038,978,930,912,864,831,770,670.HRMS(ESI):m/z calcd for C
26H
37BrClN
2O
4(M+H)
+:555.1625.found:555.1600.
实施例30：1-(2-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04036)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴-5-氟苯氧基)甲基)环氧乙烷(7-30)。
无色油状物，产率82％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.48(m,1H),6.95(s,1H),6.82(m,3H),6.63(t,J＝8.40Hz,1H),4.11(t,J＝5.6Hz,3H),4.01(m,2H),3.76(s,3H),3.53(s,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.71(dd,J＝12.80,5.20Hz,1H),2.58(dd,J＝12.80,7.20Hz,1H),2.32(s,3H),2.18(t,J＝11.60Hz,2H),1.66(d,J＝12.80Hz,2H),1.41(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):164.01,161.58,156.35,149.65,147.40,133.34,131.93,121.47,113.59,107.89,106.05,101.44,71.52,67.28,66.65,62.36,58.95,57.09,54.96,53.96(2C),42.01,33.43(2C),30.21,20.73.IR(KBr,cm
-1):3529,3277,3088,2929,2852,2796,2769,2428,1681,1604,1514,1477,1452,1417,1371,1286,1259,1224,1151,1101,1037,960,871,833,790,748,609,451.HRMS(ESI):m/z calcd for C
26H
37BrFN
2O
4(M+H)
+:539.1921.found:539.1914.
实施例31：N-(3-(2-羟基-3-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04058)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为N-(3-(环氧乙烷-2-基甲氧基)苯基)乙酰胺(7-31)。
白色固体，产率90％，mp:60-62℃，
1H NMR(CD
3OD,400MHz)δ(ppm):7.27(s,1H),7.17(t,J＝8.0Hz,1H),7.05(m,2H),6.86(m,2H),6.63(d,J＝8.0Hz,1H),4.11(m,3H),3.97(m,1H),3.87(m,1H),3.78(s,3H),3.55(s,2H),3.13(d,J＝11.20Hz,2H),2.91(t,J＝5.20Hz,1H),2.65(dd,J＝12.40,6.80Hz,1H),2.53(dd,J＝12.40,6.80Hz,1H),2.32(m,5H),2.11(s,3H),1.70(d,J＝13.20Hz,2H),1.46(s,1H),1.32(m,3H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):170.23,159.35,149.61,147.25,139.66,131.87,129.11,121.58,113.73,113.06,112.11,109.83,106.29,70.42,67.37,66.13,62.12,59.09,56.86,55.00,53.79(2C),42.01,33.02(2C),29.92,22.53,20.59.IR(KBr,cm
-1):2924,2852,2360,2340,1699,1670,1651,1616,1556,1540,1510,1491,1458,1419,1373,1286,1265,1230,1198,1156,1083,1034,980,871,768,686,669.HRMS(ESI):m/z calcd for C
28H
42N
3O
5(M+H)
+:500.3124.found:500.3071.
实施例32：1-(2,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04059)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,4-二氯苯氧基)甲基)环氧乙烷(7-32)。
无色油状物，产率81％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.37(s,1H),7.23(d,J＝8.40Hz,1H),7.00(d,J＝8.80Hz,1H),6.94(s,1H),6.82(q,J＝8.0Hz,2H),4.11(t,J＝5.60Hz,3H),4.00(m,2H),3.75(s,3H),3.52(s,2H),3.06(d,J＝11.60Hz,2H),2.82(t,J＝5.60Hz,2H),2.69(dd,J＝12.80,5.60Hz,1H),2.54(dd,J＝12.80,6.80Hz,1H),2.32(s,3H),2.19(t,J＝12.0Hz,2H),1.67(d,J＝12.80Hz,2H),1.41(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):153.47,149.61,147.37,131.88,129.29,127.46,125.32,123.37,121.45,114.33,113.50,112.98,71.53,67.36,66.58,62.33,58.86,57.07,54.92,53.96(2C),42.19,33.41(2C),30.20,20.73.IR(KBr,cm
-1):2947,2924,2872,2845,2360,2339,1590,1513,1484,1458,1419,1389,1368,1323,1290,1263,1232,1156,1060,1028,1007,938,867,846,804,745,653.HRMS(ESI):m/z calcd for C
26H
37Cl
2N
2O
4(M+H)
+:511.2130.found:511.2120.
实施例33：1-(5-溴-2-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨 基)丙-2-醇(CHJ04060)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((5-溴-2-甲基苯氧基)甲基)环氧乙烷(7-33)。
无色油状物，产率82％，
1H NMR(CD
3OD,400MHz)δ(ppm):6.97(m,4H),6.82(q,J＝8.0Hz,2H),4.10(t,J＝5.20Hz,3H),3.97(dd,J＝9.60,2.80Hz,1H),3.89(dd,J＝9.20,5.2Hz,1H),3.74(s,3H),3.51(q,J＝12.8Hz,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.20Hz,2H),2.66(dd,J＝12.80,6.0Hz,1H),2.49(dd,J＝12.80,6.0Hz,1H),2.33(s,3H),2.18(t,J＝11.60Hz,2H),2.05(s,3H),1.66(d,J＝12.80Hz,2H),1.41(s,1H),1.27(m,2H),0.94(d,J＝6.0Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):157.70,149.65,147.37,131.99,131.30,125.78,122.88,121.36,119.06,113.96,113.48,112.83,70.39,67.47,66.64,62.41,58.80,57.10,54.91,53.98(2C),42.28,33.45(2C),30.23,20.72,14.59.IR(KBr,cm
-1):2947,2923,2871,2844,2360,2340,1592,1555,1513,1491,1458,1417,1398,1373,1260,1239,1191,1129,1084,1034,984,939,870,836,800,756.HRMS(ESI):m/z calcd for C
27H
40BrN
2O
4(M+H)
+:535.2171.found:535.2170.
实施例34：N-(4-(2-羟基-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04061)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为N-(4-(环氧乙烷-2-基甲氧基)苯基)乙酰胺(7-34)。
白色固体，产率90％，mp:60-62℃,
1H NMR(CD
3OD,400MHz)δ(ppm):7.41(d,J＝8.0Hz,2H),6.98(s,1H),6.86(m,4H),4.14(m,3H),3.96(m,1H),3.85(m,1H),3.78(s,3H),3.54(d,J＝5.60Hz,2H),3.14(d,J＝11.20Hz,2H),2.92(t,J＝5.20Hz,1H),2.64(dd,J＝12.80,7.20Hz,1H),2.52(dd,J＝12.80,7.20Hz,1H),2.32(m,5H),2.09(s,3H),1.70(d,J＝13.20Hz,2H),1.46(s,1H), 1.32(m,3H),0.95(d,J＝6.40Hz,3H).
13CNMR(CD
3OD,100MHz)δ(ppm):170.23,159.35,149.61,147.25,139.66,131.87,129.11,121.58,113.73,113.06,112.11,109.83,106.29,70.42,67.37,66.13,62.12,59.09,56.86,55.00,53.79(2C),42.01,33.02(2C),29.92,22.53,20.59.IR(KBr,cm
-1):2922,2848,2362,2340,2044,1681,1602,1548,1512,1460,1417,1369,1325,1259,1240,1136,1031,931,819,750,686,669.HRMS(ESI):m/z calcd for C
28H
42N
3O
5(M+H)
+:500.3124.found:500.3074.
实施例35：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-(三氟甲基)苯氧基)丙-2-醇(CHJ04082)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-(三氟甲基)苯氧基)甲基)环氧乙烷(7-35)。
无色油状物，产率83％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.55(d,J＝7.60Hz,1H),7.47(t,J＝8.0Hz,1H),7.00(t,J＝8.40Hz,2H),6.81(m,3H),4.10(m,5H),3.84(s,3H),3.62(d,J＝12.80Hz,1H),3.47(d,J＝12.80Hz,1H),3.00(d,J＝10.80Hz,2H),2.86(t,J＝6.0Hz,2H),2.68(m,1H),2.59(m,1H),2.30(s,3H),2.15(t,J＝10.80Hz,2H),1.64(d,J＝12.0Hz,2H),1.31(m,3H),0.93(d,J＝5.60Hz,3H).
13C NMR(CDCl
3,100MHz)δ(ppm):156.61,149.49,147.54,133.28,131.37,127.08,121.34(2C),120.33(2C),113.18,112.96,112.61,70.86,66.82,66.17,62.45,59.40,57.34,55.95,54.43(2C),42.43,34.08(2C),30.50,21.81.IR(KBr,cm
-1):2939,2873,2841,2794,2362,1602,1510,1460,1363,1323,1269,1132,1033,974,948,879,808,758,650.HRMS(ESI):m/z calcd for C
27H
38F
3N
2O
4(M+H)
+:511.2784.found:511.2741.
实施例36：1-(4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04083)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-氯苯氧基)甲基)环氧乙烷(7-36)。
无色油状物，产率90％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.22(d,J＝15.2Hz,2H),6.81(m,5H),4.16(t,J＝6.0Hz,2H),4.09(m,1H),3.92(d,J＝4.40Hz,2H),3.84(s,3H),3.62(d,J＝13.20Hz,1H),3.45(d,J＝13.20Hz,1H),2.99(d,J＝10.8Hz,2H),2.85(t,J＝6.0Hz,2H),2.63(t,J＝11.60Hz,1H),2.50(m,1H),2.29(s,3H),2.14(t,J＝10.80Hz,2H),1.64(d,J＝12.40Hz,2H),1.32(m,3H),0.93(d,J＝5.60Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.41,149.51,147.62,131.25,129.30(2C),125.84,121.32,115.88(2C),113.16,112.59,70.74,66.91,66.11,62.37,59.29,57.36,55.99,54.47(2C),42.28,34.12(2C),30.52,21.83.IR(KBr,cm
-1):2947,2925,2872,2843,2792,2360,2325,1651,1595,1539,1511,1492,1458,1418,1367,1322,1283,1246,1157,1138,1092,1035,1008,824,672.HRMS(ESI):m/z calcd for C
26H
38ClN
2O
4(M+H)
+:477.2520.found:477.2471.
实施例37：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-甲氧基苯氧基)丙-2-醇(CHJ04084)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-甲氧基苯氧基)甲基)环氧乙烷(7-37)。
无色油状物，产率90％，
1HNMR(CDCl
3,400MHz)δ(ppm):6.82(m,7H),4.17(t,J＝6.0Hz,2H),4.09(m,1H),3.91(d,J＝4.40Hz,2H),3.84(s,3H),3.76(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),3.01(d,J＝12.40Hz,2H),2.86(t,J＝6.0Hz,2H),2.63(t,J＝11.20Hz,1H),2.51(m,1H),2.28(s,3H),2.16(t,J＝11.20Hz,2H),1.65(d,J＝12.0Hz,2H),1.31(m,3H),0.93(d,J＝5.48Hz,3H).
13C NMR(CDCl
3,100MHz)δ(ppm):154.01,152.97,149.49,147.52,131.40,121.31,115.55(2C),114.64(2C),113.17,112.57,71.16,66.78,66.29,62.37,59.53,57.34,55.98,55.73,54.43(2C),42.25,34.04(2C),30.48,21.80.IR(KBr,cm
-1):2947,2925,2871,2834,2792,2360,2325,1595,1510,1459,1418,1368,1322,1262,1231,1156,1138,1036,980,937,878,824,748.HRMS(ESI):m/z calcd for C
27H
41N
2O
5(M+H)
+:473.3015.found:473.2975.
实施例38：1-(2-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2- 醇(CHJ04085)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-氯苯氧基)甲基)环氧乙烷(7-38)。
无色油状物，产率83％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.34(d,J＝8.0Hz,1H),7.19(t,J＝7.60Hz,1H),6.86(m,5H),4.15(t,J＝6.0Hz,3H),4.03(d,J＝4.40Hz,2H),3.84(s,3H),3.63(d,J＝13.2Hz,1H),3.47(d,J＝13.2Hz,1H),3.00(d,J＝13.14Hz,2H),2.85(t,J＝6.40Hz,2H),2.70(m,1H),2.58(m,1H),2.30(s,3H),2.13(t,J＝11.22Hz,2H),1.64(d,J＝12.06Hz,2H),1.30(m,3H),0.93(d,J＝5.80Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):154.31,149.41,147.52,131.30,130.25,127.69,123.15,121.72,121.34,113.80,112.97,112.53,71.46,66.64,66.24,62.42,59.34,57.36,55.95,54.41(2C),42.40,34.08(2C),30.58,21.83.IR(KBr,cm
-1):2925,2872,2845,2792,2360,2325,1591,1512,1486,1455,1418,1368,1322,1276,1258,1232,1158,1137,1084,1061,980,937,877,807,749,693.HRMS(ESI):m/z calcd for C
26H
38ClN
2O
4(M+H)
+:477.2520.found:477.2506.
实施例39：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基苯氧基)丙-2-醇(CHJ04086)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-甲氧基苯氧基)甲基)环氧乙烷(7-39)。
无色油状物，产率85％，
1H NMR(CDCl
3,400MHz)δ(ppm):6.86(m,7H),4.16(t,J＝6.0Hz,3H),4.02(m,2H),3.84(s,6H),3.60(d,J＝13.20Hz,1H),3.47(d,J＝13.20Hz,1H),3.03(d,J＝11.20Hz,2H),2.87(t,J＝6.0Hz,2H),2.63(m,1H),2.54(m,1H),2.28(s,3H),2.16(t,J＝10.8Hz,2H),1.65(d,J＝12.0Hz,2H),1.33(m,3H),0.94(d,J＝5.60Hz,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):149.80,149.37,148.39,147.38,131.50,121.78,121.30,120.93,114.58,112.97,112.50, 112.04,72.39,66.46,66.41,62.38,59.50,57.31,55.88(2C),54.33(2C),42.35,33.89(2C),30.45,21.77.IR(KBr,cm
-1):2925,2872,2838,2792,2360,2340,1593,1556,1510,1458,1418,1368,1328,1250,1226,1258,1157,1125,1090,1030,980,939,876,807,744.HRMS(ESI):m/z calcd for C
27H
41N
2O
5(M+H)
+:473.3015.found:473.2972.
实施例40：1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04064)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
无色油状物，产率80％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.15(d,J＝8.40Hz,1H),7.09(s,1H),6.98(s,1H),6.83(m,3H),4.13(t,J＝5.20Hz,2H),4.05(m,1H),3.96(m,1H),3.82(m,4H),3.54(m,2H),3.04(t,J＝5.20Hz,2H),2.83(s,4H),2.61(dd,J＝12.40,5.6Hz,1H),2.49(dd,J＝12.80,6.80Hz,1H),2.30(d,J＝6.80Hz,6H),1.87(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):157.76,149.69,147.25,132.08,130.80,129.43,124.18,121.47,117.94,113.75,113.64,112.98,70.76,67.36,67.27,62.21,58.95,54.94,54.50,54.23(2C),42.08,22.77(2C),20.50.IR(KBr,cm
-1):2924,2873,2850,2793,2360,2339,1604,1513,1492,1459,1418,1369,1325,1263,1235,1139,1031,976,928,863,805,750,669.HRMS(ESI):m/z calcd for C
25H
36BrN
2O
4(M+H)
+:507.1858.found:507.1858.
实施例41：1-(2-溴-5)-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04065)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率82％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.71(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H),6.97(s,1H),6.84(m,2H),4.10(m,5H),3.75(s,3H),3.55(s,2H),3.07(t,J＝5.20Hz,2H),2.87(s,4H),2.73(dd,J＝12.80,4.80Hz,1H),2.60(dd,J＝12.40,6.40Hz,1H),2.34(s,3H),1.89(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):155.80,149.68,147.16,133.70,132.16,130.42,121.44,118.14,116.09,113.78,112.88,109.57,71.55,67.09,62.34,58.80,54.86,54.45,54.22(2C),42.08,23.39,22.76(2C),12.54.IR(KBr,cm
-1):2968,2938,2879,2793,2361,2323,1734,1700,1518,1492,1459,1419,1398,1328,1268,1252,1167,1137,1080,1035,977,935,906,861,748,670.HRMS(ESI):m/z calcd for C
25H
33BrF
3N
2O
4(M+H)
+:561.1576.found:561.1569.
实施例42：1-(3，5-二氯苯氧基)-3-((3-甲氧基-4-(2(吡咯烷基-1-乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04066)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3,5-二氯苯氧基)甲基)环氧乙烷(7-20)。
无色油状物，产率84％，
1H NMR(CD
3OD,400MHz)δ(ppm):6.98(d,J＝3.60Hz,2H),6.87(m,3H),6.82(d,J＝8.40Hz,1H),4.13(t,J＝4.80Hz,2H),4.03(m,2H),3.88(m,1H),3.79(s,3H),3.52(q,J＝12.80Hz,2H),3.06(t,J＝5.20Hz,2H),2.85(s,4H),2.62(dd,J＝12.40,6.0Hz,1H),2.47(dd,J＝12.40,6.40Hz,1H),2.32(s,3H),1.88(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):160.34,149.67,147.23,135.12,132.16,121.46,120.37,113.68,113.40(3C),112.94,71.00,67.21,67.17,62.25,58.63,54.92,54.48,54.24(2C),42.20,22.76(2C).IR(KBr,cm
-1):2933,2877,2843,2787,2361,2340,1591,1514,1454,1421,1330,1290,1261,1230,1165,1130,1089,1028,964,908,875,808,752,692,661,617.HRMS(ESI):m/z calcd for C
24H
33Cl
2N
2O
4(M+H)
+:483.1817.found:483.1801.
实施例43：1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇(CHJ04068)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((2,4,6-三溴苯氧基)甲基)环氧乙烷(7-22)。
白色固体，产率84％，mp:60-70℃，
1H NMR(CD
3OD,400MHz)δ(ppm):7.76(s,2H),6.99(s,1H),6.86(m,2H),4.23(m,1H),4.11(t,J＝5.20Hz,2H),3.97(s,2H),3.79(s,3H),3.54(q,J＝12.80Hz,2H),2.94(t,J＝5.60Hz,2H),2.72(s,5H),2.55(dd,J＝12.80,7.60Hz,1H),2.32(s,3H),1.83(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):152.74,149.66,147.42,134.96(2C),134.96,131.75,121.53,118.54,117.14,113.56,113.07,75.82,67.94,67.68,62.12,59.35,55.01,54.58,54.23(2C),42.05,22.83(2C).IR(KBr,cm
-1):3103,2924,2873,2808,1695,1597,1514,1435,1371,1334,1253,1138,1031,989,852,798,734,684,570.HRMS(ESI):m/z calcd for C
24H
32Br
3N
2O
4(M+H)
+:648.9912.found:648.9938.
实施例44：1-(3，4-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04072)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.37(d,J＝8.80Hz,1H),7.06(s,1H),6.96(s,1H),6.85(m,3H),4.11(t,J＝5.20Hz,2H),4.04(m,1H),3.98(m,1H),3.86(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,2H),2.97(t,J＝5.20Hz,2H),2.76(s,4H),2.61(dd,J＝12.80,6.0Hz,1H),2.47(dd,J＝12.80,6.80Hz,1H),2.32(s,3H),1.85(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):158.36,149.64,147.37,132.25,131.99,130.48,123.32,121.45,116.13,114.57,113.50,112.99,70.96,67.30,62.27,58.73,54.92,54.56,54.24(2C),53.40,42.22,22.81(2C).IR(KBr,cm
-1):2926,2875,2851,2802,2361,2340,1736,1651,1593,1563,1512，1475，1462，1418，1368，1328，1284，1262，1230，1127，1035，976，932，902，860，805，752， 671.HRMS(ESI):m/z calcd for C
24H
33Cl
2N
2O
4(M+H)
+:483.1817.found:483.1790.
实施例45：1-(4-溴-2，6-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04074)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率85％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.59(s,2H),7.00(s,1H),6.91(d,J＝8.04Hz,1H),6.85(d,J＝8.09Hz,1H),4.16(m,3H),4.00(m,2H),3.81(s,3H),3.56(d,J＝6.47Hz,2H),3.09(t,J＝5.24Hz,2H),2.89(s,4H),2.69(dd,J＝5.54,4.71Hz,1H),2.57(dd,J＝12.76,7.5Hz,1H),2.32(s,3H),1.90(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):150.90,149.71,147.19,131.98,131.46(3C),129.99,121.53,116.16,113.92,113.01,76.00,67.88,67.09,62.06,59.18,54.95,54.44,54.23(2C),41.93,22.75(2C).IR(KBr,cm
-1):2953,2920,2866,2765,1726,1651,1593,1516,1458,1419,1373,1327,1261,1230,1136,1085,1028,964,875,842,800,752,557.HRMS(ESI):m/z calcd for C
24H
32BrCl
2N
2O
4(M+H)
+:561.0923.found:561.0882.
实施例46：1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04075)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
无色油状物，产率87％，
1H NMR(CD
3OD,400MHz)δ(ppm):7.13(s,1H),7.03(s,1H),6.98(s,1H),6.90(m,2H),6.82(d,J＝8.08Hz,1H),4.15(t,J＝5.54Hz,2H),4.03(m,2H),3.88(m,1H),3.80(s,3H),3.52(q,J＝12.86Hz,2H),3.12(t,J＝5.24Hz,2H),2.92(s,4H),2.62(dd,J＝12.72,6.12Hz,1H),2.48(dd,J＝12.71,6.44Hz,1H),2.33(s,3H),1.91(s,4H).
13CNMR(CD
3OD,100MHz)δ(ppm):160.38,149.69,147.13,135.27,132.25,123.18,122.49,121.48,116.32,113.84(2C),112.93,70.99,67.18,62.23,58.61,54.94,54.42,54.25(2C),42.19,22.74(2C),12.54.IR(KBr,cm
-1):2974,2934,2379,2309,1716,1651,1593,1557,1539,1510,1475,1419,1393,1339,1231,1124,1038,854,670,520.HRMS(ESI):m/z calcd for C
24H
33BrClN
2O
4(M+H)
+:527.1312.found:527.1275.
实施例47：1-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基)(甲基)氨基)-3-(2-异丙基苯氧基)丙-2-醇(CHJ04089)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((2-异丙基苯氧基)甲基)环氧乙烷(7-7)。
无色油状物，产率82％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.20(d,J＝7.60Hz,1H),7.13(t,J＝8.0Hz,1H),6.93(t,J＝7.20Hz,1H),6.82(m,4H),4.11(m,3H),3.98(m,2H),3.84(s,3H),3.65(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),3.26(m,1H),2.94(t,J＝6.80Hz,2H),2.66(m,5H),2.54(m,1H),2.31(s,3H),1.20(d,J＝7.20Hz,6H),1.08(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.82,149.38,147.59,137.05,131.20,126.55,126.07,121.26,120.89,112.69,112.41,111.30,70.35,67.24,66.34,62.47,59.66,55.94,51.66,47.85(2C),42.36,26.89,22.63(2C),11.78(2C).IR(KBr,cm
-1):3035,2965,2933,2871,2360,1598,1513,1491,1451,1417,1368,1286,1261,1239,1197,1139,1088,1034,983,938,881,823,751.HRMS(ESI):m/z calcd for C
27H
43N
2O
4(M+H)
+:459.3223.found:459.3166.
实施例48：1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04090)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率81％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.63(d,J＝8.40Hz,1H),7.10(m,2H),6.81(m,3H),4.11(m,5H),3.84(s,3H),3.65(d,J＝12.80Hz,1H),3.47(d,J＝13.20Hz,1H),2.94(t,J＝6.80Hz,2H),2.67(m,5H),2.55(m,1H),2.32(s,3H),1.08(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.44,149.39,147.63,133.70(2C),131.09,121.31(2C),118.73,116.43,112.73,112.45,109.89,71.63,67.28,66.10,62.48,58.95,55.94,51.65,47.85(2C),42.42,11.77(2C).IR(KBr,cm
-1):2969,2936,2876,2837,2360,2340,1651,1597,1539,1512,1488,1461,1420,1329,1296,1263,1231,1169,1128,1081,1036,979,934,857,814,751,656,565.HRMS(ESI):m/z calcd for C
25H
35BrF
3N
2O
4(M+H)
+:563.1732.found:563.1676.
实施例49：1-(3,4-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04091)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率85％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.31(d,J＝8.8Hz,1H),7.00(s,1H),6.80(m,4H),4.09(m,3H),3.91(m,2H),3.85(s,3H),3.62(d,J＝12.80Hz,1H),3.45(d,J＝12.80Hz,1H),2.95(t,J＝6.40Hz,2H),2.67(m,5H),2.47(m,1H),2.29(s,3H),1.08(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.83,149.37,147.63,132.81,131.03,130.65,124.20,121.31,116.45,114.63,112.73,112.46,70.97,67.20,65.97,62.37,59.08,55.96,51.65,47.80(2C),42.28,11.70(2C).IR(KBr,cm
-1):2970,2936,2874,2832,2360,2326,1700,1651,1593,1559,1539,1511,1475,1459,1418,1337,1285,1263,1230,1158,1126,1090,1126,1035,930,865,806,671.HRMS(ESI):m/z calcd for C
24H
35Cl
2N
2O
4(M+H)
+:485.1974.found:485.1904.
实施例50：1-(3-溴-4-氟苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04092)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((3-溴-4-氟苯氧基)甲基)环氧乙烷(7-21)。
无色油状物，产率82％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.09(m,1H),7.02(t,J＝8.80Hz,1H),6.81(m,4H),4.09(m,3H),3.90(m,2H),3.85(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.95(t,J＝6.40Hz,2H),2.67(m,5H),2.47(m,1H),2.29(s,3H),1.09(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.25,149.38,147.62,131.06,121.3(2C),119.02(2C),116.52,114.98,112.58,109.01,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm
-1):2969,2936,2875,2832,2360,2340,1651,1592,1556,1539,1511,1493,1459,1418,1373,1333,1262,1220,1203,1158,1139,1092,1036,929,864,805,752.HRMS(ESI):m/z calcd for C
24H
35BrFN
2O
4(M+H)
+:513.1764.found:513.1710.
实施例51：1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
无色油状物，产率83％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.57(d,J＝8.80Hz,1H),7.24(s,1H),6.92(d,J＝8.80Hz,1H),6.82(m,3H),4.11(t,J＝6.40Hz,3H),3.96(m,2H),3.84(s,3H),3.63(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.97(t,J＝6.4Hz,2H),2.67(m,5H),2.48(m,1H),2.30(s,3H),1.10(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.82,149.40,147.62,135.72(2C),131.02,121.32(2C),118.88(2C),114.64,112.77,110.18,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm
-1):2969,2936,2875,2800,2360,2340,1603,1512,1475,1462,1419,1373,1330,1313,1260,1233,1171,1139,1097,1036,1017，980，932，880，810，752，702.HRMS(ESI):m/z calcd for C
25H
35BrF
3N
2O
4(M+H)
+:563.1732. found:563.1695.
实施例:52：1-(4-溴-2,6-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04094)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率87％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.44(s,2H),6.81(m,3H),4.06(m,5H),3.84(s,3H),3.61(d,J＝12.80Hz,1H),3.49(d,J＝12.80Hz,1H),2.96(t,J＝6.80Hz,2H),2.69(m,5H),2.59(m,1H),2.28(s,3H),1.09(t,J＝7.20Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):150.74,149.36,147.52,131.62(3C),131.24,130.16,121.30,116.51,112.76,112.45,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm
-1):2966,2935,2875,2800,2362,2340,1597,1548,1514,1456,1375,1328,1261,1134,1031,995,929,854,802,748,702,569.HRMS(ESI):m/z calcd for C
24H
34BrCl
2N
2O
4(M+H)
+:563.1079.found:563.1039.
实施例53：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴-3-三氟甲基)苯氧基)丙-2-醇(CHJ04097)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
白色固体，产率85％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.64(s,1H),7.56(d,J＝8.80Hz,1H),7.23(s,1H),7.10(s,1H),7.05(s,1H),6.92(d,J＝8.8Hz,1H),6.84(s,1H),6.74(m,2H),4.34(m,2H),4.24(m,2H),4.10(m,1H),3.96(m,2H),3.84(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.62(t,J＝11.20Hz,1H),2.49(m,1H),2.30(s,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.80,149.88,146.88,137.64,135.73,132.45,130.69,129.26,121.25,119.59,118.87,114.63,114.58,114.18,112.82,110.21,70.88,68.92,66.00,62.35,59.07,55.95,46.69,42.35.IR(KBr,cm
-1):3111, 2929,2877,2787,2362,2340,1600,1514,1473,1419,1321,1261,1230,1170,1138,1093,1026,962,908,871,810,759,663.HRMS(ESI):m/z calcd for C
24H
28BrF
3N
3O
4(M+H)
+:558.1215.found:558.1172.
实施例54：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇(CHJ04099)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
白色固体，产率90％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.62(d,J＝12.40Hz,2H),7.08(m,4H),6.85(s,1H),6.78(d,J＝8.0Hz,1H),6.71(d,J＝8.0Hz,1H),4.34(m,2H),4.23(m,2H),4.09(m,3H),3.83(s,3H),3.64(d,J＝12.80Hz,1H),3.47(d,J＝13.20Hz,1H),2.73(t,J＝11.60Hz,1H),2.55(m,1H),2.32(s,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):155.41,149.90,146.85,137.67,133.71,132.57,130.71,129.39,122.28,121.25,119.58,118.81,116.41,114.19,112.80,109.89,71.55,68.94,66.15,62.45,58.93,55.94,46.65,42.52.IR(KBr,cm
-1):3118,2879,2845,2787,2362,2340,1676,1595,1516,1460,1421,1388,1332,1290,1259,1138,1114,1085,1029,964,906,819,752.HRMS(ESI):m/z calcd for C
24H
28BrF
3N
3O
4(M+H)
+:558.1215.found:558.1160.
实施例55：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇(CHJ05001)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((4-溴苯氧基)甲基)环氧乙烷(7-12)。
白色固体，产率85％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.63(s,1H),7.35(d,J＝8.40Hz,2H),7.08(d,J＝14.80Hz,2H),6.78(m,5H),4.34(m,2H),4.23(m,2H),4.09(m,1H),3.92(d,J＝4.40 Hz,2H),3.83(s,3H),3.61(d,J＝13.20Hz,1H),3.45(d,J＝12.80Hz,1H),2.62(t,J＝11.60Hz,1H),2.49(m,1H),2.29(s,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.89,149.88,146.84,137.67,132.56,132.24(2C),129.38,121.23,119.58,116.36(2C),114.19,113.12,112.81,70.60,68.95,66.12,62.34,59.31,55.96,46.65,42.34.IR(KBr,cm
-1):3111,2931,2879,2843,2771,2362,2340,1712,1587,1514,1487,1456,1419,1355,1325,1242,1139,1099,1064,1028,999,960,910,883,858,819,754,692,663,615.HRMS(ESI):m/z calcd for C
23H
29BrN
3O
4(M+H)
+:490.1341.found:490.1341.
实施例56：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇(CHJ05002)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-4-氯苯氧基)甲基)环氧乙烷(7-17)。
白色固体，产率90％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.63(s,1H),7.30(d,J＝8.80Hz,1H),7.16(s,1H),7.08(d,J＝16.0Hz,2H),6.78(m,4H),4.34(m,2H),4.23(m,2H),4.09(m,1H),3.92(m,2H),3.84(s,3H),3.61(d,J＝13.2Hz,1H),3.45(d,J＝13.2Hz,1H),2.61(t,J＝11.60Hz,1H),2.48(m,1H),2.29(s,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.73,149.89,146.87,137.67,132.50,130.48,129.37,126.16,122.52,121.24,119.55(2C),115.30,114.19,112.81,70.74,68.95,66.04,62.35,59.12,55.97,46.66,42.37.IR(KBr,cm
-1):3113,2927,2877,2845,2785,2362,2340,1589,1564,1512,1467,1419,1384,1323,1261,1239,1141,1089,1029,960,906,858,808,754,666.HRMS(ESI):m/z calcd for C
23H
28BrClN
3O
4(M+H)
+:524.0952.found:524.0916.
实施例57：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-甲基苯氧基)丙-2-醇(CHJ05003)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
白色固体，产率90％,
1H NMR(CDCl
3,400MHz)δ(ppm):7.64(s,1H),7.10(s,3H),7.06(s,1H),6.86(s,1H),6.73(m,3H),4.34(m,2H),4.24(m,2H),4.09(m,1H),3.92(m,2H),3.84(s,3H),3.61(d,J＝12.80Hz,1H),3.46(d,J＝13.20Hz,1H),2.62(t,J＝12.0Hz,1H),2.48(m,1H),2.30(d,J＝10.40Hz,6H).
13CNMR(CDCl
3,100MHz)δ(ppm):157.34,149.86,146.83,137.67,132.49,130.99,130.04,129.37,124.80,121.24,119.60,118.30,114.15,113.90,112.77,70.68,68.93,66.11,62.33,59.30,55.96,46.64,42.30,21.84.IR(KBr,cm
-1):3112,2924,2877,2844,2777,2361,2340,1605,1564,1511,1492,1454,1418,1264,1239,1226,1158,1141,1091,1029,962,896,866,815,800,764,739,658,614.HRMS(ESI):m/z calcd for C
24H
31BrN
3O
4(M+H)
+:504.1498.found:504.1460.
实施例58：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-5-氯苯氧基)丙-2-醇(CHJ05004)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
白色固体，产率88％，
1H NMR(CDCl
3,400MHz)δ(ppm):7.63(s,1H),7.10(s,2H),7.06(s,1H),6.96(s,1H),6.84(s,2H),6.73(m,2H),4.35(m,2H),4.24(m,2H),4.07(m,1H),3.93(m,2H),3.84(s,3H),3.61(d,J＝12.94Hz,1H),3.45(d,J＝13.35Hz,1H),2.60(t,J＝11.55Hz,1H),2.47(m,1H),2.29(s,3H).
13CNMR(CDCl
3,100MHz)δ(ppm):159.85,149.91,146.89,137.67,135.53,132.46,129.39 124.03,122.83,121.24,119.58,116.57,114.21(2C),112.79,70.90,68.95,65.96,62.35,59.05,55.97,46.66,42.37.HRMS(ESI):m/z calcd for C
23H
28BrClN
3O
4(M+H)
+:524.0952.found:524.0913.
本发明化合物对肿瘤细胞生长抑制活性实验
1、实验材料
将CHJ系列化合物用二甲基亚砜(DMSO，终浓度0.4％)溶解，用含15％胎牛血清 RPMI-1640培养基配制成1mg/mL备用，在进行分组给药时，用该培养基进行倍数稀释至所需浓度。
实验试剂
细胞株：人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞系，均购买于中国科学院细胞库，使用含15％胎牛血清的DMEM(High Glucose)培养基，置于37℃，5％的CO
2培养箱内培养。
2、实验方法
2.1 MTT实验原理及配制方法
MTT是一种具有氧化性的黄色染料，化学名为3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazoliumbromide[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐。MTT法又叫MTT比色法，可检测细胞的存活和生长，方法简单，易于操作，常用于筛选具有细胞毒活性的物质。其检测基本原理为琥珀酸脱氢酶能够还原外源性MTT，使MTT被还原为不溶于水的蓝紫色结晶甲瓒(Formazan)，该结晶沉积于细胞中。琥珀酸脱氢酶存在于活细胞的线粒体中，死细胞中则无此酶。因而，该显色反应只能在活细胞中发生
[56]。然后将细胞中的蓝紫色结晶甲瓒用二甲基亚砜(DMSO)溶解，用酶标仪测定其吸光度，从而间接地反映活细胞的数量。在一定的细胞数范围内，形成的蓝紫色结晶甲瓒的量与活细胞数量成正相关。
MTT法具有高效、准确、简便、经济、重复性好等优点，已被广泛应用于抗肿瘤药物筛选、医学生物活性因子活性检测、细胞毒活性试验测定以及肿瘤放射敏感性的测定。
5mg/mL的MTT溶液配制：称取MTT粉末500.0mg，溶于温的100mL PBS中，用0.22μm孔径的微孔滤膜过滤除去细菌得滤液，小剂量分装于高压灭菌后的离心管中，置于-20℃下冷冻避光保存。
2.2细胞培养及实验方法
将保存有肿瘤细胞的冻存管从液氮中取出，迅速放入37℃恒温箱中，不停摇动，直到融化。用75％酒精擦拭冻存管盖边缘后，吸取细胞悬液转入10mL离心管中，补加5mL培养基。低速离心(25℃，3000r/min，5min)，弃上清，加培养基再重复离心清洗一次。加适量培养基稀释后，用吸管将细胞吹散制成悬液，转入培养瓶中，置于37℃、5％的CO
2细胞培养箱中 培养。次日更换培养液，置于37℃、5％的CO
2细胞培养箱中继续培养。
人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均为贴壁细胞，根据肿瘤细胞生长速率，将处于对数生长期的贴壁肿瘤细胞洗涤，经0.25％的EDTA胰酶消化，调整细胞数为1×10
5/mL接种于96孔板内，每孔100μL，37℃下于CO
2孵箱内培养，24h后给药。给药组加入不同浓度药物(CHJ系列化合物)，每个药物设置5个剂量组，分别为100、10、1、0.1、0.01μmol/L，每个浓度设三个复孔。设置空白对照、DMSO(0.8％)溶剂对照和顺铂阳性对照。于37℃，5％的CO
2培养箱内培养48h后，用MTT法测定OD值，计算细胞抑制率。
2.3 IC
50值的计算
人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞培养48h后，终止，然后每个孔中加入10μL 0.5％MTT溶液放置于CO
2培养箱中，4h后，除去每个孔中的液体，再分别加入0.2mL的DMSO溶液，在摇床上低频充分振荡，使蓝紫色结晶的甲瓒充分溶解，置于酶标仪中，于490nm波长处记录OD值，计算不同浓度的三个平行孔的平均OD值，根据平均值计算不同浓度下的每一种受试药物的细胞抑制率以及IC
50值。
抑制率(％)＝[1-供试品OD值/阴性对照组OD值]×100％
3、实验结果
目标化合物抗癌细胞增殖的IC
50值
通过观察上述实验数据发现，目标化合物中绝大多数对人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均具有良好的抑制作用。并且从数据中可以看出，化合物右侧为四甲基哌啶时的化合物在抗癌方面普遍要比右侧为四氢吡咯、二乙胺基和吡咯的化合物活性要好。化合物左侧增加疏水侧链长度时(CHJ03011和CHJ03012)仍然具有很好的抗癌效果，但在左侧芳环引入大极性化合物时(CHJ04068和CHJ04061)，可以明显的降低化合物的抗癌活性。值得注意的是左侧芳环有3个Br原子取代的化合物(CHJ04022和CHJ04068)活性最好，其活性与对照品顺铂相当。
Claims (10)
- 通式(I)所示化合物或其药学上可接受的盐、其光学异构体,
其中，R 1为-OC 2H 5,-H,-CH(CH 3) 2,-Br,-CF 3,-OCH 3,-F,-Cl,-CH 3R 2为-F,-CF 3,-Br,-NHCOCH 3,-Cl,-H,-OCH 3,-CH(CH 3) 2R 3为-H,-CH 3,-Cl,-Br,-NHCOCH 3,-C 3H 7,-F,-C 14H 29,-OCH 3R 4为-H,-Br,-CF 3,-ClR 5为-H,-Cl,-I,-Br,R 6为
- 如权利要求1所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述R 1为-H,-CH(CH 3) 2,-Br,-ClR 2为-F,-Br,-Cl,-H,-CH(CH 3) 2，-CF 3R 3为-H,-CH 3,-Cl,-Br,-C 14H 29R 4为-H,-Br,-CF 3,-ClR 5为-H,-Cl,-I,-Br,R 6为
- 如权利要求2所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述R 1为-H；R 2为-CF 3；R 3为-Br；R 4为-H；R 5为-H；R 6为
或R 1为-H；R 2为-H；R 3为-C 14H 29；R 4为-H；R 5为-H；R 6为
或R 1为-H；R 2为-H；R 3为-Cl；R 4为-Br；R 5为-H；R 6为
或R 1为-Br；R 2为-H；R 3为-Br；R 4为-H；R 5为-Br；R 6为
- 如权利要求3所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述R 1为-H；R 2为-CF 3；R 3为-Br；R 4为-H；R 5为-H；R 6为
或R 1为-H；R 2为-H；R 3为-C 14H 29；R 4为-H；R 5为-H；R 6为
或R 1为-Br；R 2为-H；R 3为-Br；R 4为-H；R 5为-Br；R 6为
- 如权利要求3所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述R 1为-H；R 2为-CF 3；R 3为-Br；R 4为-H；R 5为-H；R 6为
- 如权利要求3所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述R 1为-Br；R 2为-H；R 3为-Br；R 4为-H；R 5为-Br；R 6为
- 权利要求1-6任一权利要求所述的化合物或其药学上可接受的盐、其光学异构体的制备方法，包括如下步骤：
其中，R 1为-OC 2H 5,-H,-CH(CH 3) 2,-Br,-CF 3,-OCH 3,-F,-Cl,-CH 3R 2为-F,-CF 3,-Br,-NHCOCH 3,-Cl,-H,-OCH 3,-CH(CH 3) 2R 3为-H,-CH 3,-Cl,-Br,-NHCOCH 3,-C 3H 7,-F,-C 14H 29,-OCH 3R 4为-H,-Br,-CF 3,-ClR 5为-H,-Cl,-I,-Br,R 6为
通式(I)系列化合物的合成：将取代苯氧基甲基环氧乙烷(7)和化合物(5)溶于异丙醇，于氮气保护下，加入催化量的吡啶，加热回流6h，TLC检测原料消失；反应液用乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离得到目标化合物。 - 一种药物组合物，其特征在于，含有权利要求1-6任一项的化合物或其药学上可接受的盐、其光学异构体和药学上可接受的载体或赋形剂。
- 权利要求1-6任一项的化合物或其药学上可接受的盐、其光学异构体或权利要求8的药物组合物在制备治疗癌症药物中的应用。
- 根据权利要求9的应用，其特征在于，所述癌症为肺癌或卵巢癌或黑色素瘤或结肠癌。
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