CN113387873A - 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
- Publication number
- CN113387873A CN113387873A CN202110658765.4A CN202110658765A CN113387873A CN 113387873 A CN113387873 A CN 113387873A CN 202110658765 A CN202110658765 A CN 202110658765A CN 113387873 A CN113387873 A CN 113387873A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- ppm
- ethoxy
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 diaryl compound Chemical class 0.000 title abstract description 51
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 201000005202 lung cancer Diseases 0.000 claims abstract description 8
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 110
- 230000015572 biosynthetic process Effects 0.000 claims description 61
- 238000003786 synthesis reaction Methods 0.000 claims description 61
- 125000001246 bromo group Chemical group Br* 0.000 claims description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- FQYUMYWMJTYZTK-UHFFFAOYSA-N Phenyl glycidyl ether Chemical class C1OC1COC1=CC=CC=C1 FQYUMYWMJTYZTK-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000003733 ovarian melanoma Diseases 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 230000009982 effect on human Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 144
- 229940125898 compound 5 Drugs 0.000 description 59
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 58
- 238000005160 1H NMR spectroscopy Methods 0.000 description 58
- 239000012230 colorless oil Substances 0.000 description 45
- YRJZCKLHYZZRFQ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CNC)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CNC)=C2)=C2OC)CC1 YRJZCKLHYZZRFQ-UHFFFAOYSA-N 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 229910014263 BrF3 Inorganic materials 0.000 description 7
- PGBNTOIOOBKWFK-UHFFFAOYSA-N 1-[4-(2-imidazol-1-ylethoxy)-3-methoxyphenyl]-N-methylmethanamine Chemical compound COC1=CC(CNC)=CC=C1OCCN1C=NC=C1 PGBNTOIOOBKWFK-UHFFFAOYSA-N 0.000 description 6
- RPIZUYCMTZXIIS-UHFFFAOYSA-N N,N-diethyl-2-[2-methoxy-4-(methylaminomethyl)phenoxy]ethanamine Chemical compound CCN(CC)CCOC1=CC=C(CNC)C=C1OC RPIZUYCMTZXIIS-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 5
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 5
- QVPLNQPFNVLICQ-UHFFFAOYSA-N FC(C(C=C1)=CC(OCC2OC2)=C1Br)(F)F Chemical compound FC(C(C=C1)=CC(OCC2OC2)=C1Br)(F)F QVPLNQPFNVLICQ-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- DJOGZXNBSUIGKG-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]oxirane Chemical compound CCOC1=CC=CC=C1OCC1OC1 DJOGZXNBSUIGKG-UHFFFAOYSA-N 0.000 description 3
- NRLJEEOYPXGFOM-UHFFFAOYSA-N 2-[(3,4-dichlorophenoxy)methyl]oxirane Chemical compound C1=C(Cl)C(Cl)=CC=C1OCC1OC1 NRLJEEOYPXGFOM-UHFFFAOYSA-N 0.000 description 3
- WHKWPBIEAHWUNN-UHFFFAOYSA-N 2-[(3-bromo-5-chlorophenoxy)methyl]oxirane Chemical compound ClC1=CC(Br)=CC(OCC2OC2)=C1 WHKWPBIEAHWUNN-UHFFFAOYSA-N 0.000 description 3
- MQRCREFNDBMBLS-UHFFFAOYSA-N 2-[[4-bromo-3-(trifluoromethyl)phenoxy]methyl]oxirane Chemical compound C1=C(Br)C(C(F)(F)F)=CC(OCC2OC2)=C1 MQRCREFNDBMBLS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DMLJMSSKQWHCGS-UHFFFAOYSA-N Cc1ccc(OCC2CO2)cc1Br Chemical compound Cc1ccc(OCC2CO2)cc1Br DMLJMSSKQWHCGS-UHFFFAOYSA-N 0.000 description 3
- KDGYKWFRBVQMLL-UHFFFAOYSA-N ClC(C=C(C=C1Cl)Br)=C1OCC1OC1 Chemical compound ClC(C=C(C=C1Cl)Br)=C1OCC1OC1 KDGYKWFRBVQMLL-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 3
- PISMICRVSLSVKX-UHFFFAOYSA-N 1-(2-ethoxyphenoxy)-3-[[3-methoxy-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]methyl-methylamino]propan-2-ol Chemical compound CCOC1=CC=CC=C1OCC(CN(C)CC2=CC(=C(C=C2)OCCN3CCC(CC3)C)OC)O PISMICRVSLSVKX-UHFFFAOYSA-N 0.000 description 2
- NXJGWHGJPITYOJ-UHFFFAOYSA-N 2-[(2,4,6-tribromophenoxy)methyl]oxirane Chemical compound BrC1=CC(Br)=CC(Br)=C1OCC1OC1 NXJGWHGJPITYOJ-UHFFFAOYSA-N 0.000 description 2
- RTJWCOIBFLXONL-UHFFFAOYSA-N 2-[(2-propan-2-ylphenoxy)methyl]oxirane Chemical compound CC(C)C1=CC=CC=C1OCC1OC1 RTJWCOIBFLXONL-UHFFFAOYSA-N 0.000 description 2
- WINSUAJGKBCXIF-UHFFFAOYSA-N 2-[(3,5-dichlorophenoxy)methyl]oxirane Chemical compound ClC1=CC(Cl)=CC(OCC2OC2)=C1 WINSUAJGKBCXIF-UHFFFAOYSA-N 0.000 description 2
- JWMKKOLXHRXCPZ-UHFFFAOYSA-N 2-[(3-bromo-4-fluorophenoxy)methyl]oxirane Chemical compound C1=C(Br)C(F)=CC=C1OCC1OC1 JWMKKOLXHRXCPZ-UHFFFAOYSA-N 0.000 description 2
- YKUYKENINQNULY-UHFFFAOYSA-N 2-[(4-bromophenoxy)methyl]oxirane Chemical compound C1=CC(Br)=CC=C1OCC1OC1 YKUYKENINQNULY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- XOORIIIWKGUPRG-UHFFFAOYSA-N CCN(CC)CCOC(C=CC(CN(C)CC(C)O)=C1)=C1OC Chemical compound CCN(CC)CCOC(C=CC(CN(C)CC(C)O)=C1)=C1OC XOORIIIWKGUPRG-UHFFFAOYSA-N 0.000 description 2
- BPNOMIJUPAQBLG-UHFFFAOYSA-N ClC(C=CC(OCC1OC1)=C1)=C1Br Chemical compound ClC(C=CC(OCC1OC1)=C1)=C1Br BPNOMIJUPAQBLG-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 2
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000005811 Viola adunca Nutrition 0.000 description 2
- 240000009038 Viola odorata Species 0.000 description 2
- 235000013487 Viola odorata Nutrition 0.000 description 2
- 235000002254 Viola papilionacea Nutrition 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- QLANKMCBLWCBIM-UHFFFAOYSA-N 1-[[3-methoxy-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]methyl-methylamino]-3-(3-methoxyphenoxy)propan-2-ol Chemical compound CC1CCN(CC1)CCOC2=C(C=C(C=C2)CN(C)CC(COC3=CC=CC(=C3)OC)O)OC QLANKMCBLWCBIM-UHFFFAOYSA-N 0.000 description 1
- RRCQPUHFRYGLIF-UHFFFAOYSA-N 1-[[3-methoxy-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]methyl-methylamino]-3-(4-methoxyphenoxy)propan-2-ol Chemical compound CC1CCN(CC1)CCOC2=C(C=C(C=C2)CN(C)CC(COC3=CC=C(C=C3)OC)O)OC RRCQPUHFRYGLIF-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BGOUOFHQLQPABA-UHFFFAOYSA-N 2-[(2,3-dichlorophenoxy)methyl]oxirane Chemical compound ClC1=CC=CC(OCC2OC2)=C1Cl BGOUOFHQLQPABA-UHFFFAOYSA-N 0.000 description 1
- NTMMJCXPHYKNSP-UHFFFAOYSA-N 2-[(2,4-dichlorophenoxy)methyl]oxirane Chemical compound ClC1=CC(Cl)=CC=C1OCC1OC1 NTMMJCXPHYKNSP-UHFFFAOYSA-N 0.000 description 1
- VOYMDUMUZXIMNN-UHFFFAOYSA-N 2-[(2,6-dichlorophenoxy)methyl]oxirane Chemical compound ClC1=CC=CC(Cl)=C1OCC1OC1 VOYMDUMUZXIMNN-UHFFFAOYSA-N 0.000 description 1
- WAFWSOVUHCJOOY-UHFFFAOYSA-N 2-[(2-bromo-5-fluorophenoxy)methyl]oxirane Chemical compound FC1=CC=C(Br)C(OCC2OC2)=C1 WAFWSOVUHCJOOY-UHFFFAOYSA-N 0.000 description 1
- CFPYDAOUKFUDEY-UHFFFAOYSA-N 2-[(2-bromophenoxy)methyl]oxirane Chemical compound BrC1=CC=CC=C1OCC1OC1 CFPYDAOUKFUDEY-UHFFFAOYSA-N 0.000 description 1
- IYFFPRFMOMGBGB-UHFFFAOYSA-N 2-[(2-chlorophenoxy)methyl]oxirane Chemical compound ClC1=CC=CC=C1OCC1OC1 IYFFPRFMOMGBGB-UHFFFAOYSA-N 0.000 description 1
- DCTQHUBQXSEMEW-UHFFFAOYSA-N 2-[(2-iodophenoxy)methyl]oxirane Chemical compound IC1=CC=CC=C1OCC1OC1 DCTQHUBQXSEMEW-UHFFFAOYSA-N 0.000 description 1
- UASPPRLOUSJLJY-UHFFFAOYSA-N 2-[(2-methoxy-4-propylphenoxy)methyl]oxirane Chemical compound COC1=CC(CCC)=CC=C1OCC1OC1 UASPPRLOUSJLJY-UHFFFAOYSA-N 0.000 description 1
- RJNVSQLNEALZLC-UHFFFAOYSA-N 2-[(2-methoxyphenoxy)methyl]oxirane Chemical compound COC1=CC=CC=C1OCC1OC1 RJNVSQLNEALZLC-UHFFFAOYSA-N 0.000 description 1
- NXZRPCSZNMYJTR-UHFFFAOYSA-N 2-[(3,4-dimethoxyphenoxy)methyl]oxirane Chemical compound C1=C(OC)C(OC)=CC=C1OCC1OC1 NXZRPCSZNMYJTR-UHFFFAOYSA-N 0.000 description 1
- IAYLDVSLWMFGMD-UHFFFAOYSA-N 2-[(3-bromo-5-fluorophenoxy)methyl]oxirane Chemical compound FC1=CC(Br)=CC(OCC2OC2)=C1 IAYLDVSLWMFGMD-UHFFFAOYSA-N 0.000 description 1
- MJDGHPATEBXUTI-UHFFFAOYSA-N 2-[(3-bromophenoxy)methyl]oxirane Chemical compound BrC1=CC=CC(OCC2OC2)=C1 MJDGHPATEBXUTI-UHFFFAOYSA-N 0.000 description 1
- QMWAQHTYWDAKBC-UHFFFAOYSA-N 2-[(3-chlorophenoxy)methyl]oxirane Chemical compound ClC1=CC=CC(OCC2OC2)=C1 QMWAQHTYWDAKBC-UHFFFAOYSA-N 0.000 description 1
- UCGYCLBMTBEQQM-UHFFFAOYSA-N 2-[(3-methoxyphenoxy)methyl]oxirane Chemical compound COC1=CC=CC(OCC2OC2)=C1 UCGYCLBMTBEQQM-UHFFFAOYSA-N 0.000 description 1
- QXZRQBKRDAWMJD-UHFFFAOYSA-N 2-[(3-propan-2-ylphenoxy)methyl]oxirane Chemical compound CC(C)C1=CC=CC(OCC2OC2)=C1 QXZRQBKRDAWMJD-UHFFFAOYSA-N 0.000 description 1
- SWDJUBPTLWORCW-UHFFFAOYSA-N 2-[(4-bromo-2-methoxyphenoxy)methyl]oxirane Chemical compound COC1=CC(Br)=CC=C1OCC1OC1 SWDJUBPTLWORCW-UHFFFAOYSA-N 0.000 description 1
- KSLSZOOZWRMSAP-UHFFFAOYSA-N 2-[(4-chlorophenoxy)methyl]oxirane Chemical compound C1=CC(Cl)=CC=C1OCC1OC1 KSLSZOOZWRMSAP-UHFFFAOYSA-N 0.000 description 1
- AVWGFHZLPMLKBL-UHFFFAOYSA-N 2-[(4-methoxyphenoxy)methyl]oxirane Chemical compound C1=CC(OC)=CC=C1OCC1OC1 AVWGFHZLPMLKBL-UHFFFAOYSA-N 0.000 description 1
- ZXYKRDJIEKFRTD-UHFFFAOYSA-N 2-[(4-pentadecylphenoxy)methyl]oxirane Chemical compound C1=CC(CCCCCCCCCCCCCCC)=CC=C1OCC1OC1 ZXYKRDJIEKFRTD-UHFFFAOYSA-N 0.000 description 1
- GRHYGTLYRAOWLM-UHFFFAOYSA-N 2-[(5-bromo-2-fluorophenoxy)methyl]oxirane Chemical compound FC1=CC=C(Br)C=C1OCC1OC1 GRHYGTLYRAOWLM-UHFFFAOYSA-N 0.000 description 1
- RKCRMVILALALDZ-UHFFFAOYSA-N 2-[[2-(trifluoromethyl)phenoxy]methyl]oxirane Chemical compound FC(F)(F)C1=CC=CC=C1OCC1OC1 RKCRMVILALALDZ-UHFFFAOYSA-N 0.000 description 1
- NBXFAQFMTDGEQN-UHFFFAOYSA-N 2-[[3-(trifluoromethyl)phenoxy]methyl]oxirane Chemical compound FC(F)(F)C1=CC=CC(OCC2OC2)=C1 NBXFAQFMTDGEQN-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- FIEINNZXASUFNA-UHFFFAOYSA-N CC(C)C1=CC=CC(OCC(CN(C)CC(C=C2)=CC(OC)=C2OCCN2CCC(C)CC2)O)=C1 Chemical compound CC(C)C1=CC=CC(OCC(CN(C)CC(C=C2)=CC(OC)=C2OCCN2CCC(C)CC2)O)=C1 FIEINNZXASUFNA-UHFFFAOYSA-N 0.000 description 1
- DNSIHRYLHSVDDH-UHFFFAOYSA-N CC(C=CC(OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1)O)=C1)=C1Br Chemical compound CC(C=CC(OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1)O)=C1)=C1Br DNSIHRYLHSVDDH-UHFFFAOYSA-N 0.000 description 1
- YOPJGXNJHBRAPQ-UHFFFAOYSA-N CC(C=CC(OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1CCCC1)O)=C1)=C1Br Chemical compound CC(C=CC(OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1CCCC1)O)=C1)=C1Br YOPJGXNJHBRAPQ-UHFFFAOYSA-N 0.000 description 1
- TXJNLBIXIALJCQ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Br)=CC(Br)=C2)=C2Br)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Br)=CC(Br)=C2)=C2Br)O)=C2)=C2OC)CC1 TXJNLBIXIALJCQ-UHFFFAOYSA-N 0.000 description 1
- RGKPHXPXXUQVLZ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Cl)=CC(Br)=C2)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Cl)=CC(Br)=C2)=C2Cl)O)=C2)=C2OC)CC1 RGKPHXPXXUQVLZ-UHFFFAOYSA-N 0.000 description 1
- CBUIMNFODOMVNU-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Cl)=CC=C2)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C(Cl)=CC=C2)=C2Cl)O)=C2)=C2OC)CC1 CBUIMNFODOMVNU-UHFFFAOYSA-N 0.000 description 1
- CIVPOUQCJIQIJE-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C(F)(F)F)C=C2)=C2Br)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C(F)(F)F)C=C2)=C2Br)O)=C2)=C2OC)CC1 CIVPOUQCJIQIJE-UHFFFAOYSA-N 0.000 description 1
- LJEUKFXVLGUFIG-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C=C2)Br)=C2F)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C=C2)Br)=C2F)O)=C2)=C2OC)CC1 LJEUKFXVLGUFIG-UHFFFAOYSA-N 0.000 description 1
- KLUKGBZUNDTFGB-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C=C2)F)=C2Br)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C(C=C2)F)=C2Br)O)=C2)=C2OC)CC1 KLUKGBZUNDTFGB-UHFFFAOYSA-N 0.000 description 1
- DLDBLGAERUSECN-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Br)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Br)=C2Cl)O)=C2)=C2OC)CC1 DLDBLGAERUSECN-UHFFFAOYSA-N 0.000 description 1
- BUMVCMJNGKFCBE-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Br)=C2F)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Br)=C2F)O)=C2)=C2OC)CC1 BUMVCMJNGKFCBE-UHFFFAOYSA-N 0.000 description 1
- KLBMSZHWTNTLDC-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(C(F)(F)F)=C2Br)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(C(F)(F)F)=C2Br)O)=C2)=C2OC)CC1 KLBMSZHWTNTLDC-UHFFFAOYSA-N 0.000 description 1
- IQGBYPXBKOKCFT-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Cl)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(Cl)=C2Cl)O)=C2)=C2OC)CC1 IQGBYPXBKOKCFT-UHFFFAOYSA-N 0.000 description 1
- HFOHYFQZKBKZMW-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(OC)=C2OC)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC(OC)=C2OC)O)=C2)=C2OC)CC1 HFOHYFQZKBKZMW-UHFFFAOYSA-N 0.000 description 1
- MCBHIWZNHGPLDD-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC=C2Cl)O)=C2)=C2OC)CC1 MCBHIWZNHGPLDD-UHFFFAOYSA-N 0.000 description 1
- XLFVPLMLKNMROC-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC=C2NC(C)=O)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=C2)=CC=C2NC(C)=O)O)=C2)=C2OC)CC1 XLFVPLMLKNMROC-UHFFFAOYSA-N 0.000 description 1
- OPKBEMMWELXXRU-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC(Br)=C2)=C2OC)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC(Br)=C2)=C2OC)O)=C2)=C2OC)CC1 OPKBEMMWELXXRU-UHFFFAOYSA-N 0.000 description 1
- ROIVDDBJRZJJOQ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC(Cl)=C2)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC(Cl)=C2)=C2Cl)O)=C2)=C2OC)CC1 ROIVDDBJRZJJOQ-UHFFFAOYSA-N 0.000 description 1
- SPZQTJKUPAVFQJ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2Br)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2Br)O)=C2)=C2OC)CC1 SPZQTJKUPAVFQJ-UHFFFAOYSA-N 0.000 description 1
- HQSDIBZHMWXJEL-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2Cl)O)=C2)=C2OC)CC1 HQSDIBZHMWXJEL-UHFFFAOYSA-N 0.000 description 1
- DXAZYQOCOIPOQU-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2OC)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2)=C2OC)O)=C2)=C2OC)CC1 DXAZYQOCOIPOQU-UHFFFAOYSA-N 0.000 description 1
- PUVPQQRIDJJJTQ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2Cl)=C2Cl)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC(C=CC=C2Cl)=C2Cl)O)=C2)=C2OC)CC1 PUVPQQRIDJJJTQ-UHFFFAOYSA-N 0.000 description 1
- WWCQBWXEXKKXKT-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C(F)(F)F)C=CC(C(F)(F)F)=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C(F)(F)F)C=CC(C(F)(F)F)=C2)O)=C2)=C2OC)CC1 WWCQBWXEXKKXKT-UHFFFAOYSA-N 0.000 description 1
- XMCAAUCAOYCFTC-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C(F)(F)F)C=CC=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C(F)(F)F)C=CC=C2)O)=C2)=C2OC)CC1 XMCAAUCAOYCFTC-UHFFFAOYSA-N 0.000 description 1
- RHSBFFNYXFAHPF-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C)C=CC(Br)=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=C(C)C=CC(Br)=C2)O)=C2)=C2OC)CC1 RHSBFFNYXFAHPF-UHFFFAOYSA-N 0.000 description 1
- STEUIXKQJIFLES-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=C(C)C=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=C(C)C=C2)O)=C2)=C2OC)CC1 STEUIXKQJIFLES-UHFFFAOYSA-N 0.000 description 1
- WEBPAEYMTLUWBR-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC(Cl)=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC(Cl)=C2)O)=C2)=C2OC)CC1 WEBPAEYMTLUWBR-UHFFFAOYSA-N 0.000 description 1
- JNFHEWVFNBTRLJ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC(F)=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC(F)=C2)O)=C2)=C2OC)CC1 JNFHEWVFNBTRLJ-UHFFFAOYSA-N 0.000 description 1
- ODYJKSWZHVRRKG-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Br)=CC=C2)O)=C2)=C2OC)CC1 ODYJKSWZHVRRKG-UHFFFAOYSA-N 0.000 description 1
- PPLLRVYGEAQYPV-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(C(F)(F)F)=CC=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(C(F)(F)F)=CC=C2)O)=C2)=C2OC)CC1 PPLLRVYGEAQYPV-UHFFFAOYSA-N 0.000 description 1
- ZHRMBRBSEXJBGZ-UHFFFAOYSA-N CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Cl)=CC(Cl)=C2)O)=C2)=C2OC)CC1 Chemical compound CC1CCN(CCOC(C=CC(CN(C)CC(COC2=CC(Cl)=CC(Cl)=C2)O)=C2)=C2OC)CC1 ZHRMBRBSEXJBGZ-UHFFFAOYSA-N 0.000 description 1
- PWCZXUUAICGKJE-UHFFFAOYSA-N CCCCCCCCCCCCCCCC(C=C1)=CC=C1OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1CCC(C)CC1)O Chemical compound CCCCCCCCCCCCCCCC(C=C1)=CC=C1OCC(CN(C)CC(C=C1)=CC(OC)=C1OCCN1CCC(C)CC1)O PWCZXUUAICGKJE-UHFFFAOYSA-N 0.000 description 1
- SDTSVLCIWZZPSC-UHFFFAOYSA-N CCN(CC)CCOC(C=CC(CN(C)CC(COC1=C(C(C)C)C=CC=C1)O)=C1)=C1OC Chemical compound CCN(CC)CCOC(C=CC(CN(C)CC(COC1=C(C(C)C)C=CC=C1)O)=C1)=C1OC SDTSVLCIWZZPSC-UHFFFAOYSA-N 0.000 description 1
- DFRNFTHSCBXYAZ-UHFFFAOYSA-N CN(CC(COC(C=C1)=CC(Br)=C1Cl)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 Chemical compound CN(CC(COC(C=C1)=CC(Br)=C1Cl)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 DFRNFTHSCBXYAZ-UHFFFAOYSA-N 0.000 description 1
- TXZNKKBZKRBWNR-UHFFFAOYSA-N CN(CC(COC(C=C1)=CC=C1Br)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 Chemical compound CN(CC(COC(C=C1)=CC=C1Br)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 TXZNKKBZKRBWNR-UHFFFAOYSA-N 0.000 description 1
- TZAXYIVNHZVKNF-UHFFFAOYSA-N CN(CC(COC1=CC(Br)=CC(Cl)=C1)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 Chemical compound CN(CC(COC1=CC(Br)=CC(Cl)=C1)O)CC(C=C1)=CC(OC)=C1OCCN1C=NC=C1 TZAXYIVNHZVKNF-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- PBNWVLRCAKJLHL-UHFFFAOYSA-N Cc1ccc(Br)cc1OCC1CO1 Chemical compound Cc1ccc(Br)cc1OCC1CO1 PBNWVLRCAKJLHL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- HEQSMGLXQYFOGW-UHFFFAOYSA-N FC(C1=CC(OCC2OC2)=C(C(F)(F)F)C=C1)(F)F Chemical compound FC(C1=CC(OCC2OC2)=C(C(F)(F)F)C=C1)(F)F HEQSMGLXQYFOGW-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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
- 108010019160 Pancreatin Proteins 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 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
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 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
- 238000007664 blowing Methods 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
- 230000010261 cell growth Effects 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 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
- 239000000706 filtrate Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 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
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002372 labelling Methods 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
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 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
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229940055695 pancreatin Drugs 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
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 238000005303 weighing 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
- 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
- C07C217/64—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 further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- 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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/82—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
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。式(I)：
Description
技术领域
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。
背景技术
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C28H42N2O5，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，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6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
R1为-H,-CH(CH3)2,-Br,-Cl
R2为-F,-Br,-Cl,-H,-CH(CH3)2，-CF3
R3为-H,-CH3,-Cl,-Br,-C14H29
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6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
R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-Cl；R4为-Br；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6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
R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6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
R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6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，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6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。
具体实施方式
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(CDCl3,600MHz)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(CDCl3,150MHz)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 C28H43N2O5(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(CD3OD,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(CD3OD,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 C26H37Cl2N2O4(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(CD3OD,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 (CD3OD,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 forC27H37BrF3N2O4(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(CD3OD,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(CD3OD,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 C28H37F6N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C26H38BrN2O4(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(CDCl3,400MHz)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 (CDCl3,100MHz)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 C26H38BrN2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C29H45N2O4(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(CD3OD,400MHz)δ(ppm):7.06(s,1H),7.00(d,J＝8.40 Hz,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＝5.88 Hz,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(CD3OD,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 C27H40BrN2O5(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(CD3OD,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＝11.60 Hz,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＝7.20 Hz,6H).13C NMR(CD3OD,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 C30H47N2O5(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(CD3OD,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(CD3OD,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 C41H69N2O4(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(CD3OD,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(CD3OD,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 C26H37Cl2N2O4(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(CD3OD,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(CD3OD,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 C26H38BrN2O4(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(CD3OD,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(CD3OD,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 C29H45N2O4(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(CD3OD,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(CD3OD,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 C27H41N2O5(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(CD3OD,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(CD3OD,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 forC26H37BrFN2O4(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(CD3OD,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(CD3OD,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/zcalcdfor C28H43N2O6(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C26H37BrClN2O4(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(CD3OD,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(CD3OD,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 C27H40BrN2O4(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(CD3OD,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(CD3OD,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 C27H37BrF3N2O4(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(CD3OD,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＝12.80,6.40 Hz,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(CD3OD,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 C26H37Cl2N2O4(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(CD3OD,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(CD3OD,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 C26H37BrFN2O4(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(CD3OD,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(CD3OD,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 C26H36Br3N2O4(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(CD3OD,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＝12.40,5.60 Hz,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＝12.80 Hz,2H),1.40(s,1H),1.29(m,2H),0.93(d,J＝6.0Hz,3H).13CNMR(CD3OD,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 C26H37BrFN2O4(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(CD3OD,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(CD3OD,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 C26H38ClN2O4(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(CD3OD,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＝12.80,6.80 Hz,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(CD3OD,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 C27H38F3N2O4(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(CD3OD,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 (CD3OD,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 C26H37Cl2N2O4(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(CD3OD,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(CD3OD,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 C26H38IN2O4(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(CD3OD,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＝13.20,7.60 Hz,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(CD3OD,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/zcalcd for C26H36BrCl2N2O4(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(CD3OD,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(CD3OD,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 forC26H37BrClN2O4(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(CD3OD,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(CD3OD,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 C26H37BrFN2O4(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(CD3OD,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(CD3OD,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 calcdfor C28H42N3O5(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(CD3OD,400MHz)δ(ppm):7.37(s,1H),7.23(d,J＝8.40 Hz,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(CD3OD, 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 forC26H37Cl2N2O4(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(CD3OD,400MHz)δ(ppm):6.97(m,4H),6.82(q,J＝8.0 Hz,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(CD3OD,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/zcalcd for C27H40BrN2O4(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(CD3OD,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(CD3OD,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 C28H42N3O5(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(CDCl3,400MHz)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＝12.80 Hz,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(CDCl3,100MHz)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 forC27H38F3N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C26H38ClN2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C27H41N2O5(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C26H38ClN2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C27H41N2O5(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(CD3OD,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(CD3OD,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 C25H36BrN2O4(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(CD3OD,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＝12.40,6.40 Hz,1H),2.34(s,3H),1.89(s,4H).13CNMR(CD3OD,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 C25H33BrF3N2O4(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(CD3OD,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(CD3OD,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 C24H33Cl2N2O4(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(CD3OD,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(CD3OD,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 C24H32Br3N2O4(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(CD3OD,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(CD3OD,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 C24H33Cl2N2O4(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(CD3OD,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(CD3OD,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 forC24H32BrCl2N2O4(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(CD3OD,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(CD3OD,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 C24H33BrClN2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C27H43N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C25H35BrF3N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 calcdfor C24H35Cl2N2O4(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(CDCl3,400MHz)δ(ppm):7.09(m,1H),7.02(t,J＝8.80 Hz,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＝7.20 Hz,6H).13CNMR(CDCl3,100MHz)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 forC24H35BrFN2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C25H35BrF3N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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/zcalcd for C24H34BrCl2N2O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C24H28BrF3N3O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C24H28BrF3N3O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C23H29BrN3O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 calcdfor C23H28BrClN3O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C24H31BrN3O4(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(CDCl3,400MHz)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(CDCl3,100MHz)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 C23H28BrClN3O4(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CO2培养箱内培养。
2、实验方法
2.1MTT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CO2细胞培养箱中 培养。次日更换培养液，置于37℃、5％的CO2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1×105/mL接种于96孔板内，每孔100μL，37℃下于CO2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CO2培养箱内培养48h后，用MTT法测定OD值，计 算细胞抑制率。
2.3 IC50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CO2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IC50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IC50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)
1.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，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
2.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R1为-H,-CH(CH3)2,-Br,-Cl
R2为-F,-Br,-Cl,-H,-CH(CH3)2，-CF3
R3为-H,-CH3,-Cl,-Br,-C14H29
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
3.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R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-Cl；R4为-Br；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
4.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R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
5.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R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
6.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R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
7.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，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6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。
8.一种药物组合物，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。
9.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。
10.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。
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110658765.4A CN113387873B (zh) | 2021-06-15 | 2021-06-15 | 取代二芳基类化合物其制备方法和用途 |
| CN202211071077.9A CN115385847B (zh) | 2021-06-15 | 2021-06-15 | 多取代二芳基类化合物及其制备方法和应用 |
| PCT/CN2022/082764 WO2022262350A1 (zh) | 2021-06-15 | 2022-03-24 | 取代二芳基类化合物其制备方法和用途 |
| JP2023576389A JP2024522403A (ja) | 2021-06-15 | 2022-03-24 | 置換ジアリール化合物、その製造方法及び用途 |
| US18/540,293 US20240166602A1 (en) | 2021-06-15 | 2023-12-14 | Substituted diaryl compound as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110658765.4A CN113387873B (zh) | 2021-06-15 | 2021-06-15 | 取代二芳基类化合物其制备方法和用途 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211071077.9A Division CN115385847B (zh) | 2021-06-15 | 2021-06-15 | 多取代二芳基类化合物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113387873A true CN113387873A (zh) | 2021-09-14 |
| CN113387873B CN113387873B (zh) | 2022-09-20 |
Family
ID=77620822
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110658765.4A Active CN113387873B (zh) | 2021-06-15 | 2021-06-15 | 取代二芳基类化合物其制备方法和用途 |
| CN202211071077.9A Active CN115385847B (zh) | 2021-06-15 | 2021-06-15 | 多取代二芳基类化合物及其制备方法和应用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211071077.9A Active CN115385847B (zh) | 2021-06-15 | 2021-06-15 | 多取代二芳基类化合物及其制备方法和应用 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20240166602A1 (zh) |
| JP (1) | JP2024522403A (zh) |
| CN (2) | CN113387873B (zh) |
| WO (1) | WO2022262350A1 (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114848640A (zh) * | 2022-06-13 | 2022-08-05 | 山东第一医科大学(山东省医学科学院) | 化合物在制备抗炎药物中的应用 |
| CN114957126A (zh) * | 2022-05-11 | 2022-08-30 | 北京安德兴石油技术有限公司 | 一种油田酸化压裂用助排剂及其合成方法 |
| CN114957108A (zh) * | 2022-05-11 | 2022-08-30 | 北京安德兴石油技术有限公司 | 油田酸化压裂助排剂 |
| WO2022262350A1 (zh) * | 2021-06-15 | 2022-12-22 | 山东第一医科大学(山东省医学科学院) | 取代二芳基类化合物其制备方法和用途 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1154392A (en) * | 1991-01-11 | 1992-08-17 | Laboratoires Glaxo S.A. | Acridine derivatives |
| US20070111998A1 (en) * | 2005-10-13 | 2007-05-17 | Orchid Research Laboratories, Ltd. | Novel heterocyclic compounds as pSTAT3/IL-6 inhibitors |
| WO2009060282A2 (en) * | 2007-11-06 | 2009-05-14 | Orchid Research Laboratories Limited | Stilbene derivatives as pstat3/il-6 inhibitors |
| WO2009151569A2 (en) * | 2008-06-09 | 2009-12-17 | Combinatorx, Incorporated | Beta adrenergic receptor agonists for the treatment of b-cell proliferative disorders |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9751830B2 (en) * | 2010-03-15 | 2017-09-05 | The Trustees Of The University Of Pennsylvania | Inhibitors of the tumor necrosis factor receptor complex |
| CN105753724A (zh) * | 2016-01-27 | 2016-07-13 | 中国药科大学 | 用于杀伤癌细胞的几种化合物 |
| JP6780163B2 (ja) * | 2016-04-18 | 2020-11-04 | 小胞体ストレス研究所株式会社 | 小胞体ストレス応答と統合的ストレス応答を制御する新規なｅＩＦ２αのリン酸化促進剤 |
| CN110330452A (zh) * | 2019-06-12 | 2019-10-15 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | 四氢吡咯烷类化合物或其药学上可接受的盐及其制备方法和应用 |
| CN113387873B (zh) * | 2021-06-15 | 2022-09-20 | 山东第一医科大学(山东省医学科学院) | 取代二芳基类化合物其制备方法和用途 |
| CN113387872B (zh) * | 2021-06-15 | 2022-04-19 | 山东第一医科大学(山东省医学科学院) | 化合物的制备方法及其应用 |
| CN114605315A (zh) * | 2022-03-22 | 2022-06-10 | 山东第一医科大学(山东省医学科学院) | 化合物的旋光异构体及其制备方法和应用 |
| CN114848640B (zh) * | 2022-06-13 | 2023-04-07 | 山东第一医科大学(山东省医学科学院) | 化合物在制备抗炎药物中的应用 |
-
2021
- 2021-06-15 CN CN202110658765.4A patent/CN113387873B/zh active Active
- 2021-06-15 CN CN202211071077.9A patent/CN115385847B/zh active Active
-
2022
- 2022-03-24 JP JP2023576389A patent/JP2024522403A/ja active Pending
- 2022-03-24 WO PCT/CN2022/082764 patent/WO2022262350A1/zh active Application Filing
-
2023
- 2023-12-14 US US18/540,293 patent/US20240166602A1/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1154392A (en) * | 1991-01-11 | 1992-08-17 | Laboratoires Glaxo S.A. | Acridine derivatives |
| US20070111998A1 (en) * | 2005-10-13 | 2007-05-17 | Orchid Research Laboratories, Ltd. | Novel heterocyclic compounds as pSTAT3/IL-6 inhibitors |
| WO2009060282A2 (en) * | 2007-11-06 | 2009-05-14 | Orchid Research Laboratories Limited | Stilbene derivatives as pstat3/il-6 inhibitors |
| WO2009151569A2 (en) * | 2008-06-09 | 2009-12-17 | Combinatorx, Incorporated | Beta adrenergic receptor agonists for the treatment of b-cell proliferative disorders |
Non-Patent Citations (1)
| Title |
|---|
| 无: "化合物结构", 《STN-REGISTRY》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262350A1 (zh) * | 2021-06-15 | 2022-12-22 | 山东第一医科大学(山东省医学科学院) | 取代二芳基类化合物其制备方法和用途 |
| CN114957126A (zh) * | 2022-05-11 | 2022-08-30 | 北京安德兴石油技术有限公司 | 一种油田酸化压裂用助排剂及其合成方法 |
| CN114957108A (zh) * | 2022-05-11 | 2022-08-30 | 北京安德兴石油技术有限公司 | 油田酸化压裂助排剂 |
| CN114957126B (zh) * | 2022-05-11 | 2023-09-29 | 滨州乾坤化工机械有限公司 | 一种油田酸化压裂用助排剂及其合成方法 |
| CN114957108B (zh) * | 2022-05-11 | 2023-11-03 | 东营施普瑞石油工程技术有限公司 | 油田酸化压裂助排剂 |
| CN114848640A (zh) * | 2022-06-13 | 2022-08-05 | 山东第一医科大学(山东省医学科学院) | 化合物在制备抗炎药物中的应用 |
| CN114848640B (zh) * | 2022-06-13 | 2023-04-07 | 山东第一医科大学(山东省医学科学院) | 化合物在制备抗炎药物中的应用 |
| WO2023241140A1 (zh) * | 2022-06-13 | 2023-12-21 | 山东第一医科大学(山东省医学科学院) | 化合物在制备抗炎药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115385847A (zh) | 2022-11-25 |
| CN115385847B (zh) | 2023-09-29 |
| US20240166602A1 (en) | 2024-05-23 |
| CN113387873B (zh) | 2022-09-20 |
| WO2022262350A1 (zh) | 2022-12-22 |
| JP2024522403A (ja) | 2024-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113387873B (zh) | 取代二芳基类化合物其制备方法和用途 | |
| JPH0623193B2 (ja) | 新規なジスタマイシンａ同族体、その製造方法およびそれを含有する医薬組成物 | |
| CN109311891B (zh) | 作为jak抑制剂的吡咯并嘧啶化合物的结晶 | |
| JP6746613B2 (ja) | ウレア誘導体、またはその薬理学的に許容される塩 | |
| KR20210018557A (ko) | 피롤 유도체의 결정 및 그 제조 방법 | |
| US20100298402A1 (en) | Stilbene derivatives as pstat3/il-6 inhibitors | |
| JP2000503999A (ja) | ジスタマイシン誘導体、その調製方法、および抗腫瘍および抗ウイルス剤としてのその使用 | |
| EA002273B1 (ru) | Производные дистамицина, способ их получения и применение в качестве противоопухолевых агентов | |
| JP2022549923A (ja) | Ｎヘテロ五員環含有カプシドタンパク質集合阻害剤の結晶形及びその使用 | |
| CN103183682B (zh) | C-10位脲基取代的青蒿素衍生物及其制备方法和用途 | |
| WO2013107428A1 (zh) | 7-位取代的汉防己乙素衍生物、及其制备方法和应用 | |
| US11236073B2 (en) | ODM-201 crystalline form, preparation method therefor, and pharmaceutical composition thereof | |
| CN113387957A (zh) | 螺环吲哚酮-吡咯烷碳酸酯化合物和其组合物、制备方法及用途 | |
| CN110105356B (zh) | 一种氮杂吲哚类化合物及其制备方法和用途 | |
| KR20120101017A (ko) | 6-치환 1-메틸-1ｈ-벤즈이미다졸 유도체의 제조법 및 그 제조 중간체 | |
| CN111094241B (zh) | 一种氧代吡啶酰胺类衍生物的晶型及其制备方法 | |
| KR20120007848A (ko) | 엘로티닙 다이클로로아세트산염 및 이를 포함하는 항암제 조성물 | |
| CN115322158A (zh) | 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物 | |
| CN114075227B (zh) | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 | |
| WO2003045953A1 (fr) | Cristaux de derive de taxane et procede de production associe | |
| WO2021233133A1 (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
| CN109553604B (zh) | 4-氨基嘧啶衍生物作cxcr4抑制剂及其应用 | |
| CN113149977A (zh) | 一类呼吸道合胞病毒抑制剂的合成与用途 | |
| EP3498712B1 (en) | Spirocyclic indolone polyethylene glycol carbonate compound, composition, preparation method and use thereof | |
| CN114057716B (zh) | 苯并氮杂卓酮类化合物及其盐、其制备方法及医药用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |