CN116813603A - 一种选择性雌激素受体α降解化合物及其制备方法和应用 - Google Patents
一种选择性雌激素受体α降解化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN116813603A CN116813603A CN202310649767.6A CN202310649767A CN116813603A CN 116813603 A CN116813603 A CN 116813603A CN 202310649767 A CN202310649767 A CN 202310649767A CN 116813603 A CN116813603 A CN 116813603A
- Authority
- CN
- China
- Prior art keywords
- compound
- hydroxy
- benzo
- hydroxyphenyl
- dmso
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 106
- 108010007005 Estrogen Receptor alpha Proteins 0.000 title claims abstract description 20
- 102100038595 Estrogen receptor Human genes 0.000 title claims abstract description 20
- 230000015556 catabolic process Effects 0.000 title claims abstract description 19
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- -1 (4-ethoxyphenyl) (6-hydroxy-2- (4-hydroxyphenyl) benzo [ b ] thiophen-3-yl) methanone derivative Chemical class 0.000 claims abstract description 57
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 206010006187 Breast cancer Diseases 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 208000026310 Breast neoplasm Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 230000000593 degrading effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- WGDVDMKNSDCNGB-UHFFFAOYSA-N 6-methoxy-1-benzothiophene Chemical compound COC1=CC=C2C=CSC2=C1 WGDVDMKNSDCNGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 abstract description 10
- 229940095743 selective estrogen receptor modulator Drugs 0.000 abstract description 8
- 206010059866 Drug resistance Diseases 0.000 abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 233
- 238000005481 NMR spectroscopy Methods 0.000 description 74
- 239000007787 solid Substances 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 38
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 18
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 125000003118 aryl group Chemical group 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 125000001188 haloalkyl group Chemical group 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 8
- 125000005605 benzo group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229940011871 estrogen Drugs 0.000 description 7
- 239000000262 estrogen Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 229960004622 raloxifene Drugs 0.000 description 7
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 229960001603 tamoxifen Drugs 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229960002258 fulvestrant Drugs 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 5
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 5
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 108010038795 estrogen receptors Proteins 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 4
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 4
- 102000007594 Estrogen Receptor alpha Human genes 0.000 description 4
- 239000002033 PVDF binder Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 4
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100029951 Estrogen receptor beta Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010041356 Estrogen Receptor beta Proteins 0.000 description 2
- 230000035519 G0 Phase Effects 0.000 description 2
- 230000010190 G1 phase Effects 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 2
- 230000037182 bone density Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000009261 endocrine therapy Methods 0.000 description 2
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 108091008039 hormone receptors Proteins 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 101000882584 Homo sapiens Estrogen receptor Proteins 0.000 description 1
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 1
- 208000033830 Hot Flashes Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000006718 epigenetic regulation Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940125944 selective estrogen receptor degrader Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- PIEFOIGZJZFQQJ-UHFFFAOYSA-N tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CCO)C1 PIEFOIGZJZFQQJ-UHFFFAOYSA-N 0.000 description 1
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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)
Abstract
本发明公开了一种选择性雌激素受体α降解化合物及其制备方法和应用，具体涉及医药化学技术领域。所述降解化合物为(4‑乙氧基苯基)(6‑羟基‑2‑(4‑羟基苯基)苯并[b]噻吩‑3‑基)甲酮衍生物。本发明的衍生物可以规避AI/SERM治疗后导致耐药的问题，并且本发明的衍生物结合亲和力更高，降解能力更强，口服生物利用度更高。
Description
技术领域
本发明涉及医药化学技术领域，具体涉及一种选择性雌激素受体α降解化合物及其制备方法和应用。
背景技术
乳腺癌是全球最常见的三种恶性肿瘤之一，其死亡率居女性恶性肿瘤之首。2012年，全球约有170万人被诊断出患有乳腺癌，其中约50万人死于乳腺癌乳腺癌是一种多病因疾病，其发生的确切机制尚不清楚。遗传因素、生活方式以及环境因素都可能造成乳腺癌的发生。根据患者的肿瘤癌变程度，早期乳腺癌患者的治疗主要采取手术切除治疗、放射治疗和全身治疗。手术切除治疗主要是采取手术治疗手段对恶性肿瘤组织以及受影响的腋窝淋巴结组织进行切除。全身治疗包括对乳腺癌患者进行内分泌药物治疗、化疗以及靶向治疗等。晚期乳腺癌主要分为局部晚期乳腺癌和转移性乳腺癌。局部晚期乳腺癌患者是不能采取手术切除的治疗手段，仅能对患者进行放射治疗以及全身治疗。晚期乳腺癌是一种可治疗但不可治愈的疾病。晚期乳腺癌患者通常需要采取化疗以及全身治疗等手段缓解疾病症状以及延长预期寿命。
雌激素是一种胆固醇类的激素，具有促进骨骼密度的增长、脑功能和性器官的发育以及调节月经周期的功能。除此之外，雌激素还能够协助细胞的增殖分裂和基因的表观遗传来调节乳腺组织的发育。雌激素受体(EstrogenReceptor，ER)是一种蛋白质分子，主要存在于靶细胞的细胞膜、细胞质和细胞核内。当雌激素与ER特异性结合时会形成激素-受体复合物，从而发挥其生物学功能。ER有雌激素受体α(Estrogen Receptor alpha，Erα)和雌激素受体β(Estrogen Receptorbeta，Erβ)两种结构亚型，均能通过基因调控参与细胞的增殖与分化。ERα在促进人体骨骼生产、脑认知系统以及人生殖系统发育完善等方面发挥着至关重要的作用。ERβ在疾病的预防以及治疗等方面发挥着至关重要的作用。
根据药物的作用机制，目前临床上ERα阳性乳腺癌有三种类型的内分泌治疗小分子药物，通常需要与其他非雌激素受体相作用的抗癌药物进行联合使用。
①芳香化酶抑制剂：AIs是一种参与睾酮转化为雌二醇的关键酶，能够抑制雌二醇的形成，减少雌激素与雌激素受体结合，从而阻止ER信号的传递。然而，长期服用AIs药物治疗的ERα乳腺癌患者，在接受治疗2-3年后会产生耐药性，同时患者的骨骼密度也会受到损伤。常见的芳香化酶抑制剂包括：依西美坦(Aromasin)、阿那曲唑(Arimidex)和来曲唑(Femara)。
②选择性雌激素受体调节剂：SERM是一类能与ER受体结合形成一个不活跃的复合物，从而阻止ER信号传递的化合物。他莫昔芬(Tamoxifen)是内分泌治疗的重要药物。他莫昔芬的分子结构与雌激素类似，能够与体内的雌激素、孕激素相互竞争与乳腺癌细胞的激素受体结合，从而抑制体内正常雌激素发挥作用。然而，在使用他莫昔芬治疗ERα阳性乳腺癌的同时，他莫昔芬在子宫内会表现激动剂作用，使患者罹患子宫内膜癌风险上升。此外，长期服用SERMs治疗的ERα阳性乳腺癌患者，在接受治疗2-3年后也会产生耐药性。常见的选择性雌激素受体调节剂包括：他莫昔芬和雷洛昔芬(Raloxifene)。
③选择性雌激素受体降解剂：SERD是一类能够在蛋白水平降解ER受体并阻断ER信号传递的新型化合物。氟维司群(Fulvestrant，8)是2002年由阿斯利康公司(AstraZeneca)开发的首款SERDs，经美国FDA批准上市，用于治疗绝经后的妇女在接受AI/SERM治疗后耐药的ERα阳性乳腺癌患者。氟维司群能够与ER结合，促使其发生泛素化降解，从而阻断ER信号传递。氟维司群是目前临床上治疗AI/SERM耐药性ERα阳性乳腺癌患者最有效的药物。然而，氟维司群在临床上需要采取高剂量给药，并且肌肉注射的方式限制了药品的保存运输以及病人的依从性。多年来，AI/SERM一直是晚期ERα阳性乳腺癌的重要治疗药物，但由于ESR1突变以及其他生长信号通路的串扰引起的对药物的耐药限制了其临床应用。
发明内容
为此，本发明提供一种选择性雌激素受体α降解化合物及其制备方法和应用，以解决现有治疗药物因耐药性限制了其应用的问题。
虽然氟维司群因其自身副作用及给药方式的原因在临床应用中受到了许多限制，并且其临床给药剂量亦无确切定论，但是氟维司群在临床治疗方案中的成功应用表明靶向ERα可以成为规避AI/SERM治疗后导致耐药的有效手段，因此激发了国内外研究热潮。目前在临床研究中也涌现了一些结合亲和力更高、降解能力更强及口服生物利用度更高的非甾体类候选化合物。
为了实现上述目的，本发明提供如下技术方案：
根据本发明第一方面提供的一种选择性雌激素受体α降解化合物，所述降解化合物为(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
2.根据权利要求1所述的一种选择性雌激素受体α降解化合物，其特征在于，所述降解化合物为通式(Ⅰ)的化合物或其药学上可接受的盐：
其中，A环为
R1、R2和R3选自氢、C1-5烷基、C3-6环烷基、C1-5烷酰基、C1-5烷磺酰基、C1-5不饱和烷基、C1-6不饱和烷酰基、卤素取代C1-5烷酰基、羟基取代C1-5烷基、C1-5环烷基取代酰基。
进一步的，本发明的典型通式(I)化合物包括，但不仅限于以下化合物：
进一步的，所述降解化合物为通式(Ⅰ)所示化合物或其可药用的盐的溶剂化物、异构体、酯、代谢物，或其前药。
根据本发明第二方面提供的一种选择性雌激素受体α降解化合物的制备方法，所述方法包括以6-甲氧基苯并噻吩为起始原料，在溶剂和催化剂的作用下制备(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
根据本发明第三方面提供的(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物在制备治疗ERα介导的相关疾病的药物中的应用。
本发明还提供通式(I)合物的药物组合物可用于预防或治疗与ERα相关的病症的用途和方法。
根据本发明第四方面提供的(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物在制备治疗细胞增殖紊乱相关疾病的药物中的应用。
进一步的，所述疾病为实体瘤疾病，所述实体瘤疾病为乳腺癌、前列腺癌、膀胱癌、肾癌、食道癌、颈癌、胰腺癌、结直肠癌、胃癌中的一种或几种。
根据本发明第五方面提供的一种选择性雌激素受体α降解药物，所述药物包括(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
进一步的，所述药物包括通式(I)化合物或其药学上可接受的盐、载体、助剂、赋形剂或稀释剂。
进一步的，所述药物包含给药治疗有效量的通式化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物，或其前药。
进一步的，所述药物还包括药学常用辅料。
本发明具有如下优点：
本发明的衍生物可以规避AI/SERM治疗后导致耐药的问题，并且本发明的衍生物结合亲和力更高，降解能力更强，口服生物利用度更高。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地，下面描述中的附图仅仅是示例性的，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图引伸获得其它的实施附图。
本说明书所绘示的结构、比例、大小等，均仅用以配合说明书所揭示的内容，以供熟悉此技术的人士了解与阅读，并非用以限定本发明可实施的限定条件，故不具技术上的实质意义，任何结构的修饰、比例关系的改变或大小的调整，在不影响本发明所能产生的功效及所能达成的目的下，均应仍落在本发明所揭示的技术内容得能涵盖的范围内。
图1为本发明实验例2提供的化合物B29和雷诺昔芬在MCF-7细胞上Western Blot分析；
图2为本发明实验例2提供的化合物B29和雷诺昔芬在T47D细胞上Western Blot分析；
图3为本发明实施例2提供的化合物B29和雷诺昔芬诱导MCF-7细胞G0/G1周期阻滞图；
图4为本发明实施例2提供的化合物B29和雷诺昔芬对HUVEC细胞迁移影响图。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
除非另有规定，本文使用的所有技术和科学术语具有与本领域技术人员的通常理解相同含义。如果任何给定取代基的数量没有规定，则可以存在一个或多个取代基，比如“卤代烷基”可以含有一个或多个相同或不同的卤素。如果化学结构和化学名称出现矛盾，则是以其化学结构为准。对于任何保护基团、氨基酸和其他化合物的缩写，一般以常用的工人缩写表示，或根据IUPAC命名规则表示。
术语“烷基”指饱和的脂肪烃基团，包括1至5个碳原子的直链和支链基团。本说明书中，“烷基”主要包括1-5个碳的直链或支链，比如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基等。“烷基”还包括3-6个碳的环状烷基，比如环丙级、环己基、环戊基、环己基等。烷基可以是被取代的或未取代的、当被取代时，取代基可以在任何使用的连接点上被取代，优选一个或多个基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“烯基”指由碳和氢原子组成的至少含有一个双键的直链或支链的烃链基团，并通过单间或双键与分子的其余部分链接。优选2-6个碳原子，甚至更优选2-4个碳原子。非限制性实施例包括乙烯基、丙烯基、丁烯基、戊烯基、戊二烯基、己烯基、烯基可以是苯取代或非取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“炔基”指由碳和氢组成的至少含有一个三键的直链或支链的烃链基团，并通过单键或三键与分子的其余部分链接。优选2-6个碳原子，甚至更有选2-4个碳原子。非限制性实施例包括乙炔基、丙炔基、丁炔基、戊炔基、己炔基。炔基可以是取代或非取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基、环烷基的定义如上、非限定性实例包括甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“烷硫基”包括C1-10直链或支链的烷基连接到二价的硫原子上，其中烷基基团如上所述。在一些实施例中，烷硫基是较低级的C1-3的烷硫基，例如甲硫基、乙硫基、丙硫基等。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代物，具体是指基团-NRR’,其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是NH2。
术语“卤素”包括氟、氯、溴、碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN。
术语“环烷基”指饱和或不饱和单环或多环环状取代基，优选包括3至7个碳原子。单环环烷基的非限制性实施例包括环丙级、环己基、环戊基、环己基、环己烯基、环己二烯等。环烷基可以是取代或非取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或硫的杂原子，优选杂环基包含5至7个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代或未取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“芳基”指具有共轭的π电子体系的全碳单环或稠环基团，优选5至7元，最优选苯基。芳基可以是完全芳香族的基团，例如苯基、萘基、蒽基、菲基等。芳基可以是取代的或未取代的，当被取代时，取代基可以是一个或多个一下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、羟基、氰基、环烷基、芳基、杂芳基、卤代烷基等。
术语“卤代烷基”指其中一个或多个氢原子被卤素取代的烷基，其中烷基的定义如上所述。非限定性实例包括氯甲基、三氟甲基、氯乙基、氯丙基、氯丁基等。
本说明书的“任选取代”指未取代或被一个或多个取代基取代，优选自卤素原子、烷基、烯基、炔基、卤代烷基、烷氧基、芳基、卤代芳基、芳烷基、烷基氨基、烷基酰基、氰基或杂环基等。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐，优选无机盐、药学上可接受的无毒的酸形成的盐，包括但不限于，与氨基反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、硝酸盐,有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、盐酸盐、油酸盐、硬脂酸盐、抗坏血酸盐、甲酸盐、硼酸盐、樟脑酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、苹果酸盐等。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但不限于，水、异丙醇、乙醇、甲醇、二甲基亚砜、乙酸乙酯、乙酸等。
术语“异构体”是指化学组成相同但是原子或基团在空间排列上不同的化合物，包括非对映异构体、对映异构体、区域异构体、结构异构体、旋转异构体、互变异构体等。
术语“酯”是指含有羟基的式(I)化合物可形成体内可降解的酯。这样的酯是在人体或动物体内水解产生母体醇的药学上可接受的酯，包括但不限于，磷酸基、烷酰基、苯甲酰基、苯甲乙酰基等。
术语“代谢物”是指当该化合物被代谢时形成的化合物的衍生物。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰胺化、脱酰胺作用、酯化、脱脂作用、酶裂解等方法得到。
术语“前药”包括可以在体内代谢的部分的化合物。通常，前药通过酯酶活通过其他机理在体内代谢成活性药物。例如，本发明里的一个化合物包含羟基，就可以将其酰化得到前体药物形式的化合物。
4-Iodoanisole：4-碘苯甲醚
4-Fluorobenzoyl chloride：4-氟苯甲酰氯
Halogenated hydrocarbons：
Raloxifene：雷诺昔芬
本发明提供(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物的制备：
(一)以商业可得的化合物6-甲氧基苯并噻吩为起始原料，Tween-80/H2O(2wt％)为溶剂，在CF3COOAg，Pd(OAc)2催化下与4-碘苯甲醚，密封体系并置换氮气，常温搅拌48h。TLC监测反应结束后，反应混合物用乙酸乙酯稀释，并于硅藻土垫上过滤，滤液依次用水和盐水洗涤，Na2CO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到化合物2。
化合物2与4-氟苯甲酰氯溶于DCM中，并边搅拌边缓慢加入AlCl3，待加完后常温搅拌4h。TLC监测反应结束后，用H2O淬灭，反应混合物经萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化得到化合物3。
合成工艺路线如下：
试剂与条件：(a)4-Iodoanisole，CF3COOAg，TFA，Pd(OAc)2，Tween-80/H2O(2wt％)，N2，48h；(b)4-Fluorobenzoyl chloride，AlCl3，DCM，回流，4h。
(二)化合物3与N-Boc-4-羟基吡咯烷在碳酸铯的作用下，115℃加热搅拌过夜反应。TLC监测反应结束后，反应混合物经萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化得到化合物4a。
化合物4a溶于DCM中，并边搅拌边缓慢加入三氟乙酸，待加完后常温搅拌15分钟，脱BOC得到化合物5a。
化合物5a与不同的脂肪链卤代烃在碱性条件下115℃加热搅拌8小时。TLC监测反应结束后，反应混合物萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化分别得到化合物6a。
化合物6a先置于冷井中快速降到0℃后，用注射器缓慢加入BBr3，此过程15分钟内完成，低温搅拌半小时。TLC监测反应结束后，用H2O淬灭，反应混合物萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化分别得到化合物B1-B10。化合物B11-B21以类似于化合物B1-B10的合成路线得到。
合成工艺路线如下：
试剂与条件：(c)Cs2CO3，DMF，115℃，24h；(d)TFA，DCM，15min；(e)Halogenatedhydrocarbons，Cs2CO3，DMF，115℃，8h；(f)BBr3，DCM，0℃，0.5h。
(三)将化合物5a和Et3N溶于DCM中，置于冰浴中10分钟后，用注射剂缓慢加入酰氯，在冰浴条件下反应30分钟。TLC监测反应结束后，反应混合物萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化分别得到化合物7a。
化合物7a先置于冷井中快速降到0℃后，用注射器缓慢加入BBr3，此过程15分钟内完成，低温搅拌半小时。TLC监测反应结束后，用H2O淬灭，反应混合物萃取、干燥、浓缩、制作分离柱后，通过硅胶快速柱色谱纯化分别得到化合物B22-B29。
化合物B30-B38、B39-B42和化合物B43-B44以类似于化合物B22-B29的合成路线得到。
合成工艺路线如下：
试剂与条件：(c)Cs2CO3，DMF，115℃，24h；(d)TFA，DCM，15min；(e)Et3N，DCM，0℃，0.5h；(f)BBr3，DCM，0℃，0.5h。
实施例1--中间体
化合物2：
将化合物6-甲氧基苯并[b]噻吩(16.4g，0.1mol)溶于Tween-80/H2O(40ml，2wt％)溶液中，然后依次搅拌加入CF3COOAg(33.1g，0.15mol)、三氟乙酸(22.8g，0.2mol)以及4-碘苯甲醚(0.2mol)，最后加入催化剂Pd(OAc)2(1.1g，0.005mol)后，封闭体系并抽真空进行氮气保护，在室温下搅拌48小时。TLC监测反应完全后，反应混合物用乙酸乙酯(10ml)稀释，在硅藻土垫上过滤，滤液依次用盐水和乙酸乙酯洗涤并进行萃取，有机相经无水Na2SO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到淡黄色固体2(18.9g，70％yield))。1HNMR(400MHz,DMSO)δ7.70–7.61(m,4H),7.53(d,J＝2.4Hz,1H),7.05–6.97(m,3H),3.83(s,3H),3.80(s,3H)。
化合物3：
将化合物2(4.1g，15mmol，1equiv)溶于80ml DCM溶液中，缓慢加入AlCl3(2.6g，19.5mmol，1.3equiv)，待降至室温后，用注射器缓慢的打入对氟苯甲酰氯(2.14ml，18mmol，1.2equiv)后，加热搅拌回流4小时。TLC监测反应完全后，先将通过旋转蒸发仪除去大部分DCM，用1M稀盐酸淬灭AlCl3，待淬灭完成降至室温，反应混合液依次用盐水和乙酸乙酯洗涤并进行萃取，有机相经无水Na2SO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到淡黄色固体3(5.3g，90％yield))。1H NMR(400MHz，DMSO)δ7.79–7.73(m,2H),7.68(d,J＝2.4Hz,1H),7.47(d,J＝8.9Hz,1H),7.30–7.26(m,2H),7.22–7.15(m,2H),7.04(dd,J＝8.9,2.4Hz,1H),6.90–6.83(m,2H),3.85(s,3H),3.71(s,3H)。
化合物4a：
将化合物3(4g，10.2mmol，1equiv)倒入200ml的圆底烧瓶中，加入适量的DMF搅拌使其溶解，加入碳酸铯(13.5g，40.5mmol，4equiv)充分搅拌五分钟，缓慢加入(R)-3-羟基吡咯烷-1-羧酸叔丁酯(2.1g，11.22mmol，1.1equiv),加热至115℃反应24小时。TLC监测反应完全后，旋转蒸发仪除去大部分DMF，反应残余液依次用盐水和乙酸乙酯洗涤并进行萃取，有机相经无水Na2SO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到淡黄色固体4a(2.86g，50％yield))。1H NMR(400MHz,DMSO)δ7.69–7.65(m,3H),7.38–7.29(m,3H),7.00(dd,J＝8.9,2.4Hz,1H),6.95–6.87(m,4H),3.84(s,3H),3.71(s,3H),3.52(dd,J＝7.2,4.2Hz,1H),3.45–3.39(m,1H),3.33–3.20(m,2H),2.10(d,J＝9.4Hz,1H),1.99(s,1H),1.38(d,J＝7.3Hz,9H).
化合物4b：
化合物4b合成方法同化合物4a。淡黄色固体，产率46％。1H NMR(400MHz,DMSO)δ7.70–7.62(m,3H),7.39(dd,J＝8.9,1.9Hz,1H),7.34–7.27(m,2H),7.01(dt,J＝9.0,2.3Hz,1H),6.90(dd,J＝23.4,8.9,2.0Hz,4H),4.61(td,J＝8.2,7.4,3.8Hz,1H),3.85(d,J＝1.9Hz,3H),3.71(d,J＝2.0Hz,3H),3.61(dd,J＝12.8,6.4Hz,2H),3.17(t,J＝10.9Hz,2H),1.85(dd,J＝12.1,7.1Hz,2H),1.48(d,J＝9.8Hz,2H),1.40(d,J＝2.0Hz,9H).
化合物4c：
将化合物3(4g，10.2mmol，1equiv)倒入200ml的圆底烧瓶中，加入适量的DMF搅拌使其溶解，加入碳酸铯(13.5g，40.5mmol，4equiv)充分搅拌五分钟，缓慢加入3-(2-羟乙基)氮杂环丁烷-1-羧酸叔丁酯(2.25g，11.22mmol，1.1equiv),加热至115℃反应24小时。TLC监测反应完全后，旋转蒸发仪除去大部分DMF，反应残余液依次用盐水和乙酸乙酯洗涤并进行萃取，有机相经无水Na2SO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到淡黄色固体4a(2.5g，43％yield))。1H NMR(400MHz,DMSO)δ7.71–7.66(m,3H),7.32(dd,J＝8.9,2.8Hz,3H),7.00(dd,J＝8.9,2.4Hz,1H),6.95–6.88(m,4H),4.14(d,J＝6.5Hz,2H),3.93(s,2H),3.84(s,3H),3.72(s,3H),3.64(s,2H),2.92(td,J＝7.8,3.7Hz,1H),1.37(s,9H).
化合物5a：
将化合物4a(4g，8.95mmol，1equiv)倒入100ml的圆底烧瓶中，加入适量的DCM搅拌使其溶解，用注射器缓慢的打入TFA(1.37ml，2equiv)，常温搅拌15分钟。TLC监测反应完全后，旋转蒸发仪除去大部分TFA，用饱和NaHCO3溶液中和TFA调至PH值呈弱碱性(PH值为8)，反应液依次用盐水和乙酸乙酯洗涤并进行萃取，有机相经无水Na2SO3干燥并减压蒸发，粗残余物通过硅胶快速柱色谱纯化得到淡黄色固体5a(3.9g，95％yield)。1H NMR(400MHz,DMSO)δ7.66(dd,J＝5.6,3.1Hz,3H),7.37–7.30(m,3H),7.01(dd,J＝8.9,2.4Hz,1H),6.89(dd,J＝8.8,3.4Hz,4H),4.88(tt,J＝4.9,2.2Hz,1H),3.85(s,3H),3.71(s,3H),3.03(dd,J＝12.4,5.3Hz,1H),2.89–2.73(m,3H),1.98(dt,J＝14.3,7.1Hz,1H),1.73–1.65(m,1H).
化合物5b：
5b合成方法同5a。淡黄色固体，产率95％。1H NMR(400MHz,DMSO)δ7.69–7.63(m,3H),7.36(d,J＝8.8Hz,1H),7.34–7.28(m,2H),7.00(dd,J＝8.9,2.4Hz,1H),6.96–6.87(m,4H),4.54(d,J＝8.8,4.2Hz,1H),3.84(s,3H),3.71(s,3H),2.99(dt,J＝12.9,4.6Hz,2H),2.69(dd,J＝12.7,9.6,3.1Hz,2H),1.94–1.88(m,2H),1.52(dt,J＝13.8,9.1,4.7Hz,2H),1.37–1.19(m,1H).
化合物5c：
化合物5c合成方法同5a。淡黄色固体，产率95％。1H NMR(400MHz,DMSO)δ8.84(s,2H),7.75–7.70(m,2H),7.67(d,J＝2.4Hz,1H),7.33(d,J＝8.8Hz,3H),7.03–6.96(m,3H),6.93–6.88(m,2H),4.16(d,J＝5.6Hz,2H),4.05(tt,J＝14.3,6.7Hz,6H),3.88(d,J＝7.2Hz,1H),3.85(s,3H),3.84–3.79(m,1H),3.72(s,3H),3.19(d,J＝8.0,3.6Hz,1H).
实施例2
化合物B1：
(R)-(4-((1-allylpyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(B1)
淡黄色固体；产率49％。1H NMR(400MHz,DMSO-d6)δ9.78(s,2H),7.66(dd,J＝8.9,3.1Hz,2H),7.35(d,J＝2.2Hz,1H),7.29(dd,J＝8.8,3.7Hz,1H),7.17(d,J＝8.4Hz,2H),6.94(d,J＝8.8Hz,2H),6.87(dd,J＝8.7,2.3Hz,1H),6.71–6.66(m,2H),6.14(dd,J＝16.8,4.8,2.4Hz,1H),5.66(dd,J＝12.1,10.3,2.4Hz,1H),5.11(dt,J＝29.2,3.4Hz,1H),3.77–3.66(m,1H),3.59(ddd,J＝14.1,9.4,5.6Hz,2H),3.43–3.36(m,2H),2.14(ddd,J＝36.3,27.2,16.3,6.3Hz,2H).13CNMR(101MHz,DMSO)δ193.01,164.00,163.93,161.58,161.52,158.35,158.34,155.93,141.27,141.19,139.74,132.74,132.34,130.51,130.45,130.27,130.24,130.11,130.09,129.88,129.67,127.53,127.47,124.26,123.85,116.17,116.14,115.71,107.61,77.22,75.60,51.98,51.60,49.09,44.51,44.04,31.39,29.62,15.63.
实施例3
化合物B2：
(R)-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-(prop-2-yn-1-yl)pyrrolidin-3-yl)oxy)phenyl)methanone(B2)
淡黄色固体；产率56％。1H NMR(400MHz,DMSO)δ7.69–7.62(m,2H),7.35(d,J＝2.3Hz,1H),7.27(d,J＝8.7Hz,1H),7.20–7.13(m,2H),6.93–6.83(m,3H),6.71–6.65(m,2H),5.02(t,J＝5.5Hz,1H),3.26–3.10(m,4H),3.02(ddd,J＝8.6,6.4,4.0Hz,3H),2.13–2.05(m,1H),1.90–1.83(m,1H).13C NMR(101MHz,DMSO)δ193.02,161.68,158.35,155.93,141.14,139.67,132.69,132.30,130.35,130.21,130.06,124.21,123.78,116.16,115.78,107.61,77.71,51.73,44.90,32.17.
实施例4
化合物B3：
(R)-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-methylpyrrolidin-3-yl)oxy)phenyl)methanone(B3)
淡黄色固体；产率68％。1H NMR(400MHz,DMSO)δ9.77(d,J＝19.8Hz,2H),7.67(d,J＝8.3Hz,2H),7.37(s,1H),7.28(d,J＝8.7Hz,1H),7.16(d,J＝8.5Hz,2H),6.94(d,J＝8.6Hz,2H),6.88(d,J＝8.8Hz,1H),6.71(t,J＝6.8Hz,2H),4.13(s,1H),3.17(s,4H),2.79(s,3H),2.00(dd,J＝13.6,6.9Hz,2H).
实施例5
化合物B4：
(R)-(4-((1-ethylpyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(B4)
淡黄色固体；产率70％。1H NMR(400MHz,DMSO)δ7.66–7.62(m,2H),7.32(d,J＝2.3Hz,1H),7.25(d,J＝8.7Hz,1H),7.18–7.14(m,2H),6.85(dd,J＝9.2,2.8Hz,3H),6.69–6.64(m,2H),4.87(td,J＝6.5,5.8,3.0Hz,1H),2.73(dd,J＝10.6,6.0Hz,1H),2.67(td,J＝8.1,5.3Hz,1H),2.59(dd,J＝10.5,2.7Hz,1H),2.42–2.36(m,2H),2.36–2.17(m,3H),1.72–1.65(m,1H),1.00(t,J＝7.2Hz,3H).
实施例6
化合物B5：
(R)-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-propylpyrrolidin-3-yl)oxy)phenyl)methanone(B5)
淡黄色固体；产率56％。1H NMR(400MHz,DMSO)δ7.63(d,J＝8.6Hz,2H),7.33(d,J＝2.2Hz,1H),7.25(d,J＝8.8Hz,1H),7.16(d,J＝8.4Hz,2H),6.85(dd,J＝8.8,3.0Hz,3H),6.66(d,J＝8.3Hz,2H),2.76(dd,J＝10.5,6.1Hz,1H),2.65(q,J＝7.8Hz,1H),2.57(dd,J＝10.6,2.8Hz,1H),2.33(dt,J＝14.4,7.3Hz,3H),2.23(dd,J＝13.4,6.6Hz,1H),1.68(dd,J＝13.5,7.7Hz,1H),1.40(p,J＝7.4Hz,2H),1.23(d,J＝4.9Hz,1H),1.07(dt,J＝14.0,7.0Hz,1H),0.85(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)δ193.04,162.23,158.57,156.11,140.91,139.68,132.65,132.29,130.17,130.10,130.00,124.08,123.78,116.18,115.74,115.53,107.59,77.21,60.14,57.82,52.83,32.12,21.78,12.38.
实施例7
化合物B6：
(R)-(4-((1-butylpyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)ben zo[b]thiophen-3-yl)methanone(B6)
淡黄色固体；产率49％。1H NMR(400MHz,DMSO)δ9.77(s,2H),7.66(d,J＝8.8Hz,2H),7.34(d,J＝2.2Hz,1H),7.27(d,J＝8.7Hz,1H),7.21–7.12(m,2H),6.93(d,J＝8.8Hz,2H),6.85(dd,J＝8.8,2.3Hz,1H),6.67(d,J＝8.4Hz,2H),5.06(d,J＝7.0Hz,1H),3.97(dt,J＝9.5,6.3Hz,2H),3.65–3.51(m,1H),2.07(d,J＝47.6Hz,2H),1.52(dt,J＝13.6,6.9Hz,2H),1.30(ddd,J＝30.0,15.0,7.6Hz,2H),0.88(dq,J＝14.4,7.4Hz,3H).13C NMR(101MHz,DMSO)δ193.02,161.59,158.40,155.96,154.74,141.13,139.72,132.71,132.33,130.44,130.22,130.16,130.09,124.20,123.81,116.16,115.69,114.87,107.59,77.07,76.19,64.67,51.99,51.53,44.45,44.01,31.14,30.98,30.31,19.08,15.63,14.06.
实施例8
化合物B7：
(R)-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-isopropylpyrroli din-3-yl)oxy)phenyl)methanone(B7)
淡黄色固体；产率56％。1H NMR(400MHz,DMSO)δ9.79(s,2H),7.64(d,J＝8.4Hz,2H),7.34(d,J＝2.2Hz,1H),7.27(d,J＝8.8Hz,1H),7.17(d,J＝8.4Hz,2H),6.86(d,J＝8.6Hz,3H),6.68(d,J＝8.3Hz,2H),4.89(s,1H),2.87(t,J＝8.2Hz,1H),2.78–2.66(m,2H),2.43(d,J＝25.9Hz,2H),2.27–2.19(m,1H),1.72(dd,J＝13.7,7.3Hz,1H),1.01(dd,J＝6.4,2.6Hz,6H).13C NMR(101MHz,DMSO)δ193.03,162.12,158.36,155.93,140.98,139.68,132.72,132.31,130.19,130.13,130.04,124.22,123.80,116.14,115.70,115.57,107.59,77.05,57.63,54.42,50.22,31.95,21.56,21.41.
实施例9
化合物B8：
(R)-(4-((1-(2-fluoroethyl)pyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphen yl)benzo[b]thiophen-3-yl)methanone(B8)
淡黄色固体；产率40％。1H NMR(400MHz,DMSO)δ9.76(d,J＝19.3Hz,2H),7.69–7.63(m,2H),7.34(d,J＝2.2Hz,1H),7.27(d,J＝8.8Hz,1H),7.19–7.15(m,2H),6.96–6.91(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),5.08(d,J＝10.8Hz,1H),4.28(q,J＝5.9,4.5Hz,2H),3.64(dt,J＝10.9,5.7Hz,2H),3.55–3.36(m,4H),2.22–2.11(m,1H),2.03(s,1H).13C NMR(101MHz,DMSO)δ193.02,192.44,161.60,161.54,158.62,158.34,155.91,154.08,153.97,152.67,141.16,139.72,132.73,132.45,132.34,131.04,130.43,130.34,130.23,130.10,124.24,123.83,116.24,116.15,115.70,107.60,101.09,76.18,66.88,65.47,65.39,64.77,59.87,52.06,51.64,44.58,44.15,31.81,31.11,30.31,15.63.
实施例10
化合物B9：
(4-(((3R)-1-(2-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyph enyl)benzo[b]thiophen-3-yl)methanone(B9)
淡黄色固体；产率35％。1H NMR(400MHz,DMSO)δ9.79(s,2H),7.67(d,J＝8.6Hz,2H),7.36(d,J＝2.2Hz,1H),7.28(d,J＝8.7Hz,1H),7.17(d,J＝8.4Hz,2H),6.94(d,J＝8.6Hz,2H),6.87(dd,J＝8.7,2.3Hz,1H),6.68(d,J＝8.4Hz,2H),5.18(d,J＝5.3Hz,1H),4.11(s,1H),3.30–3.13(m,6H),2.54(s,1H),2.20(dp,J＝14.4,5.2,4.7Hz,1H),2.03(d,J＝14.1Hz,1H).
实施例11
化合物B10：
(R)-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyph enyl)benzo[b]thiophen-3-yl)methanone(B10)
/>
淡黄色固体；产率32％。1H NMR(400MHz,DMSO)δ9.76(d,J＝19.3Hz,2H),7.66(d,J＝8.6Hz,2H),7.34(d,J＝2.2Hz,1H),7.27(d,J＝8.7Hz,1H),7.20–7.14(m,2H),6.93(d,J＝8.8Hz,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.70–6.65(m,2H),5.07(s,1H),4.08(d,J＝6.9Hz,2H),3.62–3.55(m,2H),3.47–3.36(m,4H),2.17–1.97(m,4H).13C NMR(101MHz,DMSO)δ193.03,192.45,161.70,161.58,158.60,158.32,155.89,152.66,141.48,141.18,139.71,132.81,132.72,132.45,132.34,130.42,130.34,130.23,130.18,130.09,124.24,123.82,123.72,123.05,116.24,116.15,115.69,107.60,101.09,77.09,76.21,63.01,62.34,57.71,51.54,44.02,32.46,32.17,31.56,31.11,30.30.
实施例12
化合物B11：
(4-((1-ethylpiperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thio phen-3-yl)methanone(B11)
淡黄色固体；产率62％。1H NMR(400MHz,DMSO)δ9.79(s,2H),7.63(d,J＝8.5Hz,2H),7.33(d,J＝2.2Hz,1H),7.26(d,J＝8.7Hz,1H),7.16(d,J＝8.1Hz,2H),6.91(d,J＝8.6Hz,2H),6.85(dd,J＝8.7,2.2Hz,1H),6.67(d,J＝8.2Hz,2H),4.45–4.40(m,1H),2.65(d,J＝12.2Hz,2H),2.31(q,J＝6.9Hz,2H),2.15(t,J＝10.4Hz,2H),1.92–1.85(m,2H),1.57(dt,J＝12.8,4.5Hz,2H),0.98(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ192.98,162.08,158.39,155.95,140.99,139.69,132.71,132.34,130.20,130.16,129.94,124.20,123.81,116.14,115.77,115.71,107.59,73.37,51.93,50.18,30.85,12.68.
实施例13
化合物B12：
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-propylpiperidin-4-yl)oxy)phenyl)methanone(B12)
淡黄色固体；产率61％。1H NMR(400MHz,DMSO)δ9.75(d,J＝16.6Hz,2H),7.65–7.60(m,2H),7.34(d,J＝1.9Hz,1H),7.27(dd,J＝8.7,1.4Hz,1H),7.16(dd,J＝8.6,1.5Hz,2H),6.90(d,J＝8.4Hz,2H),6.85(dt,J＝8.9,1.9Hz,1H),6.69–6.65(m,2H),4.42(dt,J＝9.0,4.7Hz,1H),2.67–2.60(m,2H),2.18(dt,J＝27.8,8.9Hz,4H),1.92–1.85(m,2H),1.59(dd,J＝15.4,7.1Hz,2H),1.44–1.38(m,2H),0.86–0.81(m,3H).13C NMR(101MHz,DMSO)δ192.96,162.06,158.34,155.92,141.01,139.70,132.75,132.33,130.20,130.18,129.95,124.25,123.82,116.12,115.76,115.68,107.58,73.32,60.12,50.60,30.86,20.21,12.30.
实施例14
化合物B13：
(4-((1-butylpiperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thio phen-3-yl)methanone(B13)
淡黄色固体；产率64％。1H NMR(400MHz,DMSO)δ9.76(d,J＝19.9Hz,2H),7.34(d,J＝2.3Hz,1H),7.27(d,J＝8.8Hz,1H),7.19–7.14(m,2H),6.94–6.89(m,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.70–6.65(m,2H),4.45(s,1H),2.67(s,2H),2.26(d,J＝34.7Hz,4H),1.90(s,2H),1.59(s,2H),1.39(q,J＝7.6Hz,2H),1.28(dd,J＝15.1,7.8Hz,2H),0.88(t,J＝7.3Hz,3H).
实施例15
化合物B14：
(4-((1-allylpiperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thio phen-3-yl)methanone(B14)
淡黄色固体；产率57％。1H NMR(400MHz,DMSO)δ9.78(s,2H),7.67(d,J＝8.6Hz,2H),7.34(d,J＝2.2Hz,1H),7.25(dd,J＝8.7,2.5Hz,1H),7.17(d,J＝8.5Hz,2H),6.93(d,J＝8.6Hz,2H),6.85(dd,J＝8.8,2.3Hz,1H),6.67(d,J＝8.3Hz,2H),4.61(q,J＝6.6Hz,1H),4.34(dt,J＝23.9,8.7Hz,1H),4.17(dd,J＝6.5,2.4Hz,2H),4.10–3.99(m,2H),3.71(ddd,J＝15.6,10.0,5.5Hz,1H),3.06–2.99(m,1H),1.47(dd,J＝6.7,2.1Hz,3H),1.09(t,J＝7.0Hz,2H).13C NMR(101MHz,DMSO)δ192.94,162.09,158.33,155.90,140.93,139.69,137.76,136.77,132.75,132.32,130.19,129.93,124.25,123.82,117.61,116.51,116.13,115.77,115.68,107.58,73.56,67.15,47.17,45.74,36.30,31.31.
实施例16
化合物B15：
(4-((1-(but-3-en-1-yl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(B15)
淡黄色固体；产率57％。1H NMR(400MHz,DMSO)δ9.79(s,2H),7.66–7.60(m,2H),7.33(d,J＝2.2Hz,1H),7.30–7.25(m,1H),7.19–7.13(m,2H),6.93(dd,J＝8.4,6.3Hz,2H),6.85(dt,J＝8.8,2.6Hz,1H),6.67(d,J＝8.4Hz,2H),4.42(td,J＝8.8,4.5Hz,1H),3.18(dd,J＝4.9,2.5Hz,2H),2.65(dd,J＝11.2,5.6Hz,2H),2.36–2.26(m,2H),1.91(d,J＝12.3Hz,2H),1.79(d,J＝2.4Hz,2H),1.58(dtd,J＝12.9,9.3,3.7Hz,2H).13C NMR(101MHz,DMSO)δ192.95,162.06,158.35,155.92,140.95,139.69,132.74,132.33,130.20,129.97,124.25,123.83,116.13,115.80,115.69,107.59,80.90,75.38,49.47,46.98,30.84,3.57.
实施例17
化合物B16：
2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenox-y)piperidin-1-yl)acetonitrile(B16)
淡黄色固体；产率52％。1H NMR(400MHz,DMSO)δ9.78(s,1H),9.73(s,1H),7.67–7.61(m,2H),7.34(d,J＝2.2Hz,1H),7.28(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.97–6.92(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),4.49(dt,J＝8.4,4.3Hz,1H),3.73(s,2H),2.72–2.66(m,2H),2.44–2.36(m,2H),1.94(d,J＝12.4Hz,2H),1.64(dd,J＝8.5,4.2Hz,2H).
实施例18
化合物B17：
3-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pi peridin-1-yl)propanenitrile(B17)
淡黄色固体；产率59％。1H NMR(400MHz,DMSO)δ9.76(s,2H),7.67–7.61(m,2H),7.34(d,J＝2.2Hz,1H),7.28(d,J＝8.7Hz,1H),7.20–7.14(m,2H),6.95–6.89(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.71–6.65(m,2H),4.46(dt,J＝8.4,4.3Hz,1H),2.66(t,J＝6.3Hz,4H),2.58(d,J＝6.4Hz,2H),2.34–2.25(m,2H),1.90(d,J＝12.6Hz,2H),1.60(qd,J＝10.4,9.2,4.8Hz,2H).
实施例19
化合物B18：
(4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(B18)
淡黄色固体；产率52％。1H NMR(400MHz,DMSO)δ9.76(d,J＝19.6Hz,2H),7.66–7.60(m,2H),7.34(d,J＝2.3Hz,1H),7.27(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.94–6.89(m,2H),6.85(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),4.57(t,J＝4.9Hz,1H),4.45(t,J＝5.0Hz,2H),2.70(s,2H),2.58(s,2H),2.35–2.26(m,2H),1.90(d,J＝12.5Hz,2H),1.59(d,J＝9.9Hz,2H).
实施例20
化合物B19：
(4-((1-(3-fluoropropyl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophen-3-yl)methanone(B19)
淡黄色固体；产率39％。1H NMR(400MHz,DMSO)δ9.79(dd,J＝17.0,7.8Hz,2H),7.66(dd,J＝9.1,7.3Hz,2H),7.35(t,J＝2.5Hz,1H),7.29(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.97(d,J＝8.9Hz,2H),6.87(dd,J＝8.8,2.2Hz,1H),6.71–6.65(m,2H),4.66(s,1H),4.23(d,J＝8.2Hz,2H),3.59(d,J＝9.0Hz,2H),3.51(d,J＝7.1Hz,2H),3.17(d,J＝5.1Hz,2H),2.44(q,J＝8.3Hz,2H),2.08(d,J＝6.7Hz,2H),1.85(d,J＝14.7Hz,2H).13C NMR(101MHz,DMSO)δ192.93,161.19,158.39,155.98,141.44,139.69,132.70,132.66,132.33,130.60,130.26,130.22,130.11,130.02,124.21,123.80,116.12,115.99,115.88,115.74,107.60,56.18,25.53,13.72.
实施例21
化合物B20：
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)methanone(B20)
淡黄色固体；产率56％。1H NMR(400MHz,DMSO)δ9.77(d,J＝19.2Hz,2H),7.67–7.61(m,2H),7.34(d,J＝2.3Hz,1H),7.27(d,J＝8.8Hz,1H),7.19–7.14(m,2H),6.95–6.89(m,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.70–6.65(m,2H),4.45(s,1H),4.36(t,J＝5.1Hz,2H),2.73(s,2H),2.44(s,2H),2.34(dd,J＝4.0,2.1Hz,2H),1.90(s,2H),1.61(s,2H).
实施例22
化合物B21：
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-(3-hydroxypropyl)piperidin-4-yl)oxy)phenyl)methanone(B21)
淡黄色固体；产率57％。1H NMR(400MHz,DMSO)δ9.79(s,2H),7.66–7.61(m,2H),7.34(d,J＝2.2Hz,1H),7.28(d,J＝8.7Hz,1H),7.19–7.15(m,2H),6.94–6.89(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),4.46(s,1H),3.44(q,J＝6.7Hz,4H),2.73–2.63(m,2H),2.38(s,2H),1.90(s,2H),1.59(h,J＝7.8,6.3Hz,4H).13C NMR(101MHz,DMSO)δ192.96,161.99,158.36,155.94,141.05,139.69,132.73,132.33,130.20,130.16,130.02,124.24,123.82,116.13,115.80,115.70,107.59,59.79,55.32,50.52,30.58,30.01.
实施例23
化合物B22：
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)propan-1-one(B22)
淡黄色固体；产率70％。1H NMR(400MHz,DMSO)δ9.83(s,2H),7.66(dd,J＝8.7,3.2Hz,2H),7.34(d,J＝2.3Hz,1H),7.28(dd,J＝8.7,7.0Hz,1H),7.16(d,J＝8.2Hz,2H),6.93(dt,J＝8.9,1.9Hz,2H),6.86(dd,J＝8.7,2.1Hz,1H),6.67(dt,J＝8.6,1.9Hz,2H),5.14–5.03(m,1H),3.64–3.44(m,4H),2.27–2.18(m,2H),2.15–1.89(m,2H),0.96(q,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ193.03,171.94,171.78,161.62,161.57,158.48,158.45,156.01,141.29,141.13,139.72,132.68,132.33,130.47,130.39,130.27,130.22,130.07,130.04,124.16,123.82,116.19,116.14,115.74,115.69,107.60,77.31,75.81,51.74,51.40,44.28,43.78,31.43,31.14,29.81,27.33,27.15,19.00,9.31,9.27.
实施例24
化合物B23：
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)-2,2-dimethylpropan-1-one(B23)
淡黄色固体；产率72％。1H NMR(400MHz,DMSO)δ9.82(s,2H),7.68–7.61(m,2H),7.33(d,J＝2.0Hz,1H),7.27(d,J＝8.6Hz,1H),7.18–7.12(m,2H),6.96–6.90(m,2H),6.85(dt,J＝8.7,2.0Hz,1H),6.69–6.62(m,2H),5.04(s,1H),3.59(d,J＝76.5Hz,4H),2.16–1.96(m,2H),1.13(s,9H).13C NMR(101MHz,DMSO)δ193.03,175.79,161.60,158.50,156.04,141.27,139.74,132.67,132.35,130.42,130.24,130.02,124.13,123.82,116.17,115.75,115.71,107.60,45.85,38.70,27.63.
实施例25
化合物B24：
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-one(B24)
淡黄色固体；产率69％。1H NMR(400MHz,DMSO)δ9.81(s,2H),7.69–7.63(m,2H),7.33(d,J＝2.2Hz,1H),7.27(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.92(dd,J＝9.0,2.0Hz,2H),6.85(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),5.12–5.03(m,1H),3.78–3.56(m,2H),2.26–2.12(m,2H),2.11–2.02(m,2H),1.09(t,J＝7.0Hz,2H),0.97(d,J＝14.5Hz,9H).13CNMR(101MHz,DMSO)δ193.05,193.02,170.25,170.06,161.64,161.60,158.51,158.48,156.03,141.17,141.11,139.72,132.67,132.34,130.44,130.40,130.22,130.08,130.05,124.13,123.81,116.20,116.16,115.73,115.70,107.60,77.34,75.73,52.53,51.31,46.26,46.05,45.16,43.72,31.54,31.26,31.14,30.06,30.02,29.82,19.01,15.63.
实施例26
化合物B25:
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)prop-2-en-1-one(B25)
淡黄色固体；产率72％。1H NMR(400MHz,DMSO)δ9.78(s,2H),7.66(dd,J＝8.9,3.1Hz,2H),7.35(d,J＝2.2Hz,1H),7.29(dd,J＝8.8,3.7Hz,1H),7.17(d,J＝8.3Hz,2H),6.94(d,J＝8.8Hz,2H),6.87(dd,J＝8.7,2.3Hz,1H),6.71–6.66(m,2H),6.63–6.49(m,1H),6.14(ddd,J＝16.8,4.8,2.4Hz,1H),5.66(ddd,J＝12.1,10.3,2.4Hz,1H),5.11(dt,J＝29.2,3.4Hz,1H),3.59(ddd,J＝14.3,9.5,5.6Hz,2H),3.51–3.23(m,4H),2.26–2.00(m,2H).13C NMR(101MHz,DMSO)δ193.01,164.00,163.93,161.58,161.52,158.35,158.34,155.93,141.27,141.19,139.74,132.74,132.34,130.51,130.45,130.27,130.24,130.11,130.09,129.88,129.67,127.53,127.47,124.26,123.85,116.17,116.14,115.71,107.61,77.22,75.60,51.98,51.60,49.09,44.51,44.04,31.39,29.62,15.63.
实施例27
化合物B26:
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)but-3-en-1-one(B26)
淡黄色固体；产率72％。1H NMR(400MHz,DMSO)δ9.47(s,2H),7.66(d,J＝8.4Hz,2H),7.34(d,J＝2.2Hz,1H),7.27(d,J＝8.7Hz,1H),7.17(d,J＝8.2Hz,2H),6.90(ddd,J＝30.8,8.9,2.3Hz,3H),6.74–6.62(m,3H),6.24(ddd,J＝23.5,15.1,2.0Hz,1H),5.10(d,J＝31.8Hz,1H),3.8–3.66(m,1H),3.62(t,J＝10.7Hz,1H),3.55(td,J＝8.6,5.1Hz,2H),2.15(dddd,J＝44.5,12.2,8.7,4.4Hz,2H),1.88–1.76(m,3H).13C NMR(101MHz,DMSO)δ193.05,193.02,164.30,164.20,161.60,161.55,158.37,158.34,155.93,141.20,140.77,140.71,139.73,132.73,132.35,130.48,130.42,130.24,130.10,124.24,123.85,123.65,116.17,116.14,115.70,107.59,79.62,77.24,75.62,51.91,51.47,44.41,43.90,31.40,29.66,18.11,18.07.
实施例28
化合物B27:
(R)-1-(3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pyrrolidin-1-yl)-2-methylprop-2-en-1-one(B27)
淡黄色固体；产率70％。1H NMR(400MHz,DMSO)δ9.78(s,2H),7.65(t,J＝7.9Hz,2H),7.33(d,J＝2.2Hz,1H),7.27(dd,J＝8.9,3.8Hz,1H),7.19–7.12(m,2H),6.93(t,J＝9.0Hz,2H),6.85(dd,J＝8.7,2.3Hz,1H),6.66(dd,J＝8.6,2.4Hz,2H),5.28–5.05(m,3H),3.80–3.60(m,2H),3.46–3.41(m,2H),2.15(ddt,J＝13.6,9.2,4.7Hz,1H),2.03(t,J＝11.0Hz,1H),1.81(d,J＝28.2Hz,3H).13C NMR(101MHz,DMSO)δ193.01,169.99,169.88,161.63,161.51,158.50,156.05,141.50,141.34,141.14,139.74,132.68,132.33,130.47,130.24,130.06,124.14,123.82,116.92,116.85,116.18,115.73,107.60,76.86,75.85,65.39,56.52,53.74,51.50,46.60,43.71,31.66,29.73,20.20,20.10,19.03,15.63.
实施例29
化合物B28:
(R)-(4-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)oxy)phenyl)(6-hydroxy-2-(4-hyd roxyphenyl)benzo[b]thiophen-3-yl)methanone(B28)
淡黄色固体；产率76％。1H NMR(400MHz,DMSO)δ7.66(d,J＝8.6Hz,2H),7.34(d,J＝2.2Hz,1H),7.27(dd,J＝8.8,6.3Hz,1H),7.16(d,J＝8.5Hz,2H),6.94(dd,J＝8.6,5.2Hz,2H),6.85(dd,J＝8.7,2.2Hz,1H),6.70–6.64(m,2H),5.11(d,J＝43.7Hz,1H),3.83–3.63(m,2H),3.53(dd,J＝10.9,7.2Hz,2H),2.31–2.04(m,2H),1.79–1.65(m,1H),0.72(qd,J＝9.4,8.3,4.4Hz,4H).13C NMR(101MHz,DMSO)δ193.05,171.70,171.53,161.62,161.57,158.52,158.49,156.04,141.25,141.13,139.73,132.67,132.35,130.48,130.41,130.26,130.22,130.07,130.03,124.13,123.82,116.20,116.16,115.74,115.70,107.60,77.24,75.75,56.53,52.06,51.64,44.55,44.07,31.33,31.13,29.75,19.00,12.43,12.30,7.69,7.61,7.50.
实施例30
化合物B29:
2-chloro-1-((R)-3-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbon yl)phenoxy)pyrrolidin-1-yl)propan-1-one(B29)
淡黄色固体；产率70％。1H NMR(400MHz,DMSO)δ9.83–9.70(m,2H),7.67(d,J＝8.3Hz,2H),7.35(d,J＝2.2Hz,1H),7.28(dt,J＝8.8,3.0Hz,1H),7.20–7.14(m,2H),6.94(dd,J＝8.7,3.6Hz,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.68(dt,J＝8.8,2.4Hz,2H),5.13(d,J＝39.1Hz,1H),4.90–4.70(m,1H),3.80(tt,J＝33.0,12.6Hz,2H),3.65–3.48(m,2H),2.14(ddd,J＝50.4,27.8,10.6Hz,2H),1.53–1.44(m,3H).13C NMR(101MHz,DMSO)δ193.01,167.57,167.36,167.30,167.22,161.47,158.35,155.95,141.48,141.34,139.81,132.81,132.38,130.62,130.56,130.53,130.29,130.11,124.32,123.90,116.16,115.71,107.62,77.21,75.52,65.40,52.16,52.03,51.96,44.54,41.70,31.44,29.66,21.71,21.11,21.05,21.02,15.61.
实施例31
化合物B30:
2-chloro-1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)ph enoxy)piperidin-1-yl)ethan-1-one(B30)
淡黄色固体；产率70％。1H NMR(400MHz,DMSO)δ9.78(d,J＝18.2Hz,2H),7.68–7.62(m,2H),7.35(d,J＝2.2Hz,1H),7.30(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.98–6.93(m,2H),6.87(dd,J＝8.8,2.3Hz,1H),6.70–6.65(m,2H),4.70(dq,J＝7.4,3.8Hz,1H),4.39(s,2H),3.83–3.76(m,1H),3.65(d,J＝13.3Hz,1H),3.48–3.40(m,2H),2.00–1.87(m,2H),1.66–1.48(m,2H).
实施例32
化合物B31:
2-bromo-1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)piperidin-1-yl)ethan-1-one(B31)
淡黄色固体；产率72％。1H NMR(400MHz,DMSO)δ9.76(s,2H),7.68–7.62(m,2H),7.34(d,J＝2.3Hz,1H),7.30(d,J＝8.7Hz,1H),7.20–7.14(m,2H),6.96(dt,J＝9.0,3.2Hz,2H),6.87(dd,J＝8.7,2.3Hz,1H),6.71–6.65(m,2H),4.75–4.68(m,1H),4.09(s,1H),3.81(s,2H),3.17(s,3H),1.93(d,J＝18.4Hz,2H),1.64–1.48(m,2H).
实施例33
化合物B32:
3-chloro-1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)piperidin-1-yl)propan-1-one(B32)
淡黄色固体；产率69％。1H NMR(400MHz,DMSO)δ9.81(d,J＝18.3Hz,2H),7.67–7.61(m,2H),7.36(d,J＝2.1Hz,1H),7.29(dd,J＝8.7,1.8Hz,1H),7.19–7.13(m,2H),6.98–6.92(m,2H),6.87(dt,J＝8.8,2.0Hz,1H),6.68(dd,J＝8.6,1.8Hz,2H),4.69(dq,J＝8.4,4.7,4.1Hz,1H),3.85–3.75(m,3H),3.66(d,J＝13.4Hz,1H),3.25(t,J＝11.6Hz,2H),2.85(dd,J＝7.6,5.8Hz,2H),1.88(d,J＝24.5Hz,2H),1.60–1.43(m,2H).
实施例34
化合物B33:
4-chloro-1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbon-yl)phenoxy)piperidin-1-yl)butan-1-one(B33)
淡黄色固体；产率71％。1H NMR(400MHz,DMSO)δ9.89–9.78(m,2H),7.64(d,J＝8.4Hz,2H),7.36(q,J＝1.9Hz,1H),7.29(dd,J＝8.8,5.9Hz,1H),7.15(dt,J＝8.7,2.2Hz,2H),6.95(dd,J＝8.6,6.5Hz,2H),6.87(dq,J＝8.8,1.9Hz,1H),6.72–6.65(m,2H),4.75–4.63(m,1H),4.26(t,J＝7.1Hz,1H),3.81(d,J＝8.6Hz,1H),3.66(t,J＝6.6Hz,1H),3.30–3.13(m,2H),3.03(s,1H),2.48–2.32(m,2H),2.17–2.05(m,2H),1.97–1.78(m,3H),1.51(dd,J＝39.6,9.1Hz,1H).13C NMR(101MHz,DMSO)δ192.94,192.91,169.96,161.79,161.35,158.47,156.05,141.46,141.20,139.66,132.67,132.64,132.33,130.47,130.24,130.18,130.09,130.02,124.17,123.79,116.14,116.12,115.86,115.75,107.60,72.61,69.88,68.74,45.51,42.32,40.70,38.65,31.16,30.49,29.77,28.49,27.89,27.28,22.21.
实施例35
化合物B34:
1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)piperidin-1-yl)-3,3-dimethylbutan-1-one(B34)
淡黄色固体；产率76％。1H NMR(400MHz,DMSO)δ9.76(s,2H),7.66–7.62(m,2H),7.34(d,J＝2.3Hz,1H),7.29(d,J＝8.7Hz,1H),7.18–7.14(m,2H),6.97–6.92(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.69–6.65(m,2H),4.72–4.67(m,1H),3.87–3.81(m,2H),3.17(d,J＝3.7Hz,2H),1.90(d,J＝12.5Hz,2H),1.50(q,J＝6.6,3.8Hz,2H),1.19(s,9H).13C NMR(101MHz,DMSO)δ192.90,175.38,161.77,158.35,155.93,141.30,139.73,132.76,132.34,130.27,130.20,130.14,124.29,123.88,116.11,115.84,115.69,107.58,72.68,49.08,42.07,38.56,31.08,28.52.
实施例36
化合物B35:
(4-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyp henyl)benzo[b]thiophen-3-yl)methanone(B35)
淡黄色固体；产率77％。1H NMR(400MHz,DMSO)δ9.77(s,2H),7.67–7.62(m,2H),7.34(d,J＝2.2Hz,1H),7.30(d,J＝8.7Hz,1H),7.19–7.13(m,2H),7.00–6.94(m,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.71–6.64(m,2H),4.70(dd,J＝8.6,4.7Hz,1H),3.89(d,J＝34.4Hz,3H),3.51(s,2H),3.29–3.14(m,2H),2.10–1.78(m,4H),1.52(d,J＝43.7Hz,2H).13CNMR(101MHz,DMSO)δ192.92,171.40,161.81,158.37,155.94,141.23,139.72,132.74,132.35,130.26,130.20,130.13,124.26,123.86,116.12,115.86,115.70,107.59,72.76,65.39,42.40,31.48,30.49,15.63,10.78,7.34.
实施例37
化合物B36:
4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-N,N-dimethylpiperidine-1-carboxamide(B36)
淡黄色固体；产率62％。1H NMR(400MHz,DMSO)δ9.75(d,J＝16.9Hz,2H),7.66–7.61(m,2H),7.34(d,J＝2.3Hz,1H),7.29(d,J＝8.8Hz,1H),7.18–7.13(m,2H),6.96–6.91(m,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.69–6.64(m,2H),4.64–4.59(m,1H),3.48–3.39(m,2H),2.97(t,J＝11.1Hz,2H),2.72(s,6H),1.89(d,J＝11.8Hz,2H),1.55(dd,J＝12.2,7.4Hz,2H).
实施例38
化合物B37:
1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)piperidin-1-yl)prop-2-en-1-one(B37)
淡黄色固体；产率68％。1H NMR(400MHz,DMSO)δ9.75(d,J＝17.4Hz,2H),7.64(d,J＝8.8Hz,2H),7.34(d,J＝2.2Hz,1H),7.29(d,J＝8.7Hz,1H),7.19–7.14(m,2H),6.98–6.93(m,2H),6.87–6.84(m,1H),6.83–6.76(m,1H),6.69–6.64(m,2H),6.09(dd,J＝16.7,2.4Hz,1H),5.66(dd,J＝10.5,2.4Hz,1H),4.70(t,J＝3.8Hz,1H),3.83(d,J＝24.3Hz,2H),3.45–3.39(m,2H),1.91(s,2H),1.53(s,2H).13C NMR(101MHz,DMSO)δ192.92,164.76,161.77,158.33,155.91,141.25,139.71,132.74,132.35,130.27,130.21,130.13,128.85,127.68,124.28,123.87,116.11,115.87,115.70,107.59,89.66,72.52,42.56,31.46,31.15,30.47.
实施例39
化合物B38:
1-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)pip eridin-1-yl)-2-methylprop-2-en-1-one(B38)
淡黄色固体；产率74％。1H NMR(400MHz,DMSO)δ9.80(s,2H),7.66–7.61(m,2H),7.33(d,J＝2.2Hz,1H),7.29(d,J＝8.8Hz,1H),7.18–7.13(m,2H),6.97–6.92(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.69–6.64(m,2H),5.15(t,J＝1.8Hz,1H),4.98(s,1H),4.70(tt,J＝7.9,3.8Hz,1H),3.71(s,2H),3.45(s,2H),1.94–1.87(m,2H),1.85(s,3H),1.55(t,J＝10.5Hz,2H).
实施例40
化合物B39:
(4-((1-(ethylsulfonyl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)be nzo[b]thiophen-3-yl)methanone(B39)
淡黄色固体；产率59％。1H NMR(400MHz,DMSO)δ7.67–7.62(m,2H),7.34(d,J＝2.3Hz,1H),7.30(d,J＝8.8Hz,1H),7.18–7.14(m,2H),6.95(d,J＝8.8Hz,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.69–6.65(m,2H),4.64(dq,J＝7.6,3.8Hz,1H),3.16(td,J＝8.4,4.1Hz,2H),3.07(q,J＝7.4Hz,2H),1.95(ddt,J＝14.0,7.3,3.7Hz,2H),1.66(dtd,J＝12.1,8.0,3.7Hz,2H),1.21(t,J＝7.4Hz,3H),1.10(t,J＝7.0Hz,2H).
实施例41
化合物B40:
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-(propylsulfonyl)piper idin-4-yl)oxy)phenyl)methanone(B40)
淡黄色固体；产率67％。1H NMR(400MHz,DMSO)δ9.76(s,2H),7.67–7.62(m,2H),7.34(d,J＝2.2Hz,1H),7.29(d,J＝8.8Hz,1H),7.18–7.13(m,2H),6.97–6.92(m,2H),6.86(dd,J＝8.7,2.3Hz,1H),6.69–6.64(m,2H),4.63(dt,J＝7.8,4.3Hz,1H),3.15(ddd,J＝12.0,8.1,3.5Hz,2H),3.05–2.99(m,2H),1.98–1.91(m,2H),1.72–1.62(m,4H),1.06(t,J＝7.0Hz,2H),0.99(t,J＝7.4Hz,3H).
实施例42
化合物B41:
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-((1-(isobutylsulfonyl)pip eridin-4-yl)oxy)phenyl)methanone(B41)
淡黄色固体；产率64％。1H NMR(400MHz,DMSO)δ9.75(d,J＝17.8Hz,2H),7.64(d,J＝8.5Hz,2H),7.34(d,J＝2.2Hz,1H),7.29(d,J＝8.7Hz,1H),7.16(d,J＝8.2Hz,2H),6.95(dd,J＝8.9,3.4Hz,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.67(d,J＝8.3Hz,2H),5.08(t,J＝7.0Hz,1H),4.76–4.68(m,1H),3.89–3.71(m,2H),3.38(q,J＝7.0Hz,4H),1.93(d,J＝35.1Hz,2H),1.66(d,J＝6.4Hz,3H),1.50(dd,J＝17.0,10.0Hz,2H),1.09(t,J＝7.0Hz,3H).
实施例43
化合物B42:
(4-((1-(cyclopropylsulfonyl)piperidin-4-yl)oxy)phenyl)(6-hydroxy-2-(4-hydroxyph enyl)benzo[b]thiophen-3-yl)methanone(B42)
淡黄色固体；产率74％。1H NMR(400MHz,DMSO)δ7.67–7.62(m,2H),7.34(d,J＝2.3Hz,1H),7.30(d,J＝8.8Hz,1H),7.19–7.14(m,2H),6.98–6.93(m,2H),6.86(dd,J＝8.8,2.3Hz,1H),6.69–6.63(m,2H),4.64(dq,J＝7.4,3.8Hz,1H),3.19(td,J＝8.5,4.2Hz,2H),2.64–2.58(m,1H),1.98(ddt,J＝13.8,7.4,3.5Hz,2H),1.69(dtd,J＝12.2,8.0,3.7Hz,2H),1.10(t,J＝7.0Hz,2H),0.96(ddt,J＝17.0,5.3,2.3Hz,4H).
实施例44
化合物B43
2-chloro-1-(3-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]
thiophene-3-carbonyl)phenoxy)ethyl)azetidin-1-yl)ethan-1-one(B43)
淡黄色固体；产率74％。1H NMR(400MHz,DMSO)δ9.76(s,2H),7.67(d,J＝8.7Hz,2H),7.34(d,J＝2.2Hz,1H),7.26(d,J＝8.8Hz,1H),7.20–7.14(m,2H),6.94(d,J＝8.7Hz,2H),6.85(dd,J＝8.8,2.3Hz,1H),6.71–6.65(m,2H),4.29(t,J＝8.6Hz,1H),4.17(d,J＝6.5Hz,2H),4.11(s,2H),4.03–3.97(m,2H),3.70(dd,J＝10.0,5.5Hz,1H),3.17(d,J＝3.5Hz,2H),3.05–2.98(m,1H).13C NMR(101MHz,DMSO)δ193.05,171.95,166.17,163.20,163.15,158.33,155.93,140.95,139.74,132.74,132.31,130.39,130.19,130.11,124.25,123.78,116.19,115.70,114.99,107.62,69.86,69.62,60.21,53.02,50.93,49.08,40.46,28.90,28.20.
实施例45
化合物B44:
2-chloro-1-(3-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]
thiophene-3-carb-onyl)phenoxy)ethyl)azetidin-1-yl)propan-1-one(B44)
淡黄色固体；产率68％。1H NMR(400MHz,DMSO)δ9.78(s,2H),7.67(d,J＝8.6Hz,2H),7.34(d,J＝2.2Hz,1H),7.25(dd,J＝8.7,2.5Hz,1H),7.17(d,J＝8.5Hz,2H),6.93(d,J＝8.6Hz,2H),6.85(dd,J＝8.7,2.3Hz,1H),6.67(d,J＝8.3Hz,2H),4.61(q,J＝6.6Hz,1H),4.34(dt,J＝23.9,8.7Hz,1H),4.17(dd,J＝6.5,2.4Hz,2H),4.10–3.99(m,2H),3.71(ddd,J＝15.6,10.0,5.5Hz,1H),3.06–2.99(m,1H),1.47(dd,J＝6.7,2.1Hz,3H),1.09(t,J＝7.0Hz,2H).
实验例1
本实验例用于分析本发明化合物的生物活性：
(一)CCK8法测试体外抗肿瘤活性
使用含10％FBS和1％双抗的完全MEM培养基培养MCF-7细胞，实验前先将培养基替换为含10％FBS和1％双抗的无酚红1640培养基，在此条件下培养2d。然后将MCF-7细胞以2000个细胞/孔的密度接种在96孔板中，每孔加入100μL细胞悬液，培养24h后，按照设定浓度进行加药，并设置正常组与空白对照组。加药后在37℃孵箱中培养5d。五天后每孔加入20μL CCK8试剂，在孵箱中继续培养1-2h后，使用酶标仪测定各孔光吸收值，波长设定为450nm，记录数值。抑制率＝(1-(加药组-空白组)/(正常组-空白组))×100％，重复三次取平均值。IC50值使用Graphpad软件计算。
(二)细胞周期的流式检测
实验前先将MCF-7细胞培养基替换为含10％FBS和1％双抗的无酚红1640培养基，在此条件下培养2d。然后以2×105个细胞/孔铺板于六孔板中，待24h后细胞完全贴壁，加入相应浓度的化合物。作用48h后收集细胞，PBS清洗后加入75％的冰乙醇固定。固定过夜的细胞先用PBS清洗2次后加入提前配好的PI，室温避光染色10min。染色后使用滤网过滤，过滤后即可使用细胞流式仪进行周期分析。
(三)体外细胞划痕实验
HUVEC细胞使用含有10％FBS和1％双抗的DMEM培养基培养，将处于对数生长期的细胞铺板至六孔板中，待细胞长为单层时，将培养基替换为双无的DMEM培养基饥饿12h。然后使用200μL枪尖进行划痕，并弃去上清。划痕后使用PBS进行洗涤，弃去上清，将培养基替换为完全培养基，并按照设定浓度加入相应化合物。此时在显微镜下进行拍照记录，记为0h，并在24h、48h时间梯度下进行拍照观察。
(四)Western Blot分析
实验前先将MCF-7细胞培养基替换为含10％FBS和1％双抗的无酚红1640培养基，在此条件下培养2d。然后将细胞铺板至六孔板中，24h后按照设定浓度加入对应化合物，在孵箱中孵育48h。48h后提取细胞总蛋白。使用10％的SDS/PAGE凝胶进行电泳分离，电泳分离后在250V电压下转膜90min，然后使用5％脱脂牛奶室温封闭2h，封闭完的PVDF膜使用PBST溶液洗涤后至于预先配置好的一抗中，孵育盒4℃摇动孵育过夜。将孵育了一抗的PVDF膜置于PBST中清洗30min，每隔5min更换一次，然后将PVDF膜转移至二抗孵育盒中室温孵育1h。孵育过二抗的PVDF膜使用PBST重复清洗30min，同样的，每隔5min换一次液。显影液工作液A:B＝1:1配置混匀后，避光存放，PVDF膜清洗完毕后滴加显影液，ECL(Rio-Rad)化学发光显影照相。
受试化合物对MCF-7细胞和T47D细胞的抑制率结果见表1所示；
优选化合物在MCF-7细胞和T47D细胞以及正常细胞上的IC50值见表2所示。
表1
/>
表2
/>
结果表明，本发明的大部分受试化合物MCF-7细胞和T47D细胞的抑制率细胞增殖具有较好的抑制活性，是一种新型的、潜在的和具备治疗ERα阳性介导的相关疾病潜力的抑制剂。
实验例2
选用化合物B29为代表进行ERα蛋白的降解作用进行免疫印迹实验，雷诺昔芬作为对比试验，实验选择MCF-7和T47D细胞进行。由图1和图2结果表明，优选化合物B29能够可以显著降解ERα蛋白，且在同等浓度下，降解能力优于雷诺昔芬。
由图3可见，雷洛昔芬能诱导MCF-7细胞G0/G1期阻滞，干扰细胞正常的周期进程，从而抑制肿瘤细胞的增殖。为了验证化合物B29是否也能引起细胞周期阻滞，将不同浓度的化合物B29作用于MCF-7细胞，48h后进行处理，然后使用流式细胞仪进行细胞周期分析实验。结果表明，化合物B29作用下，能够呈浓度依赖性的将MCF-7细胞阻滞在G0/G1期，无法进行进一步的有丝分裂，细胞将不能顺利进行细胞增殖，从而抑制肿瘤细胞生长。
图4可见，将不同浓度的化合物B29作用于HUVEC细胞，同时将10μM浓度的雷洛昔芬同样作用于HUVEC细胞，通过比较，发现Raloxifene/B29作用后，细胞划痕间伤口愈合距离百分比明显高于对照组；说明Raloxifene/B29可以抑制人脐静脉内皮细胞HUVEC细胞的迁移。
虽然，上文中已经用一般性说明及具体实施例对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (9)
1.一种选择性雌激素受体α降解化合物，其特征在于，所述降解化合物为(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
2.根据权利要求1所述的一种选择性雌激素受体α降解化合物，其特征在于，所述降解化合物为通式(Ⅰ)的化合物或其药学上可接受的盐：
其中，A环为
R1、R2和R3选自氢、C1-5烷基、C3-6环烷基、C1-5烷酰基、C1-5烷磺酰基、C1-5不饱和烷基、C1-6不饱和烷酰基、卤素取代C1-5烷酰基、羟基取代C1-5烷基、C1-5环烷基取代酰基。
3.根据权利要求2所述的一种选择性雌激素受体α降解化合物，其特征在于，所述降解化合物为通式(Ⅰ)所示化合物或其可药用的盐的溶剂化物、异构体、酯、代谢物，或其前药。
4.一种选择性雌激素受体α降解化合物的制备方法，其特征在于，所述方法包括以6-甲氧基苯并噻吩为起始原料，在溶剂和催化剂的作用下制备(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
5.(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物在制备治疗ERα介导的相关疾病的药物中的应用。
6.(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物在制备治疗细胞增殖紊乱相关疾病的药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述疾病为实体瘤疾病，所述实体瘤疾病为乳腺癌、前列腺癌、膀胱癌、肾癌、食道癌、颈癌、胰腺癌、结直肠癌、胃癌中的一种或几种。
8.一种选择性雌激素受体α降解药物，其特征在于，所述药物包括(4-乙氧基苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮衍生物。
9.根据权利要求8所述的降解药物，其特征在于，所述药物还包括药学常用辅料。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310649767.6A CN116813603A (zh) | 2023-06-02 | 2023-06-02 | 一种选择性雌激素受体α降解化合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310649767.6A CN116813603A (zh) | 2023-06-02 | 2023-06-02 | 一种选择性雌激素受体α降解化合物及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116813603A true CN116813603A (zh) | 2023-09-29 |
Family
ID=88113668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310649767.6A Pending CN116813603A (zh) | 2023-06-02 | 2023-06-02 | 一种选择性雌激素受体α降解化合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116813603A (zh) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133040A (zh) * | 1993-10-12 | 1996-10-09 | 辉瑞大药厂 | 作为雌激素激动剂的苯并噻吩及其有关化合物 |
| US5567828A (en) * | 1995-06-07 | 1996-10-22 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side |
| EP0747376A1 (en) * | 1995-06-07 | 1996-12-11 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side chains |
| EP0747380A1 (en) * | 1995-06-07 | 1996-12-11 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side chains |
| WO1999015521A1 (en) * | 1997-09-23 | 1999-04-01 | Eli Lilly And Company | Benzothiophenes |
| US5981570A (en) * | 1996-09-27 | 1999-11-09 | Eli Lilly And Company | Benzothiophene compounds, compositions, and methods |
| WO2012084711A1 (en) * | 2010-12-24 | 2012-06-28 | Msd Oss B.V. | N-substituted azetidine derivatives |
| CN107406424A (zh) * | 2014-12-18 | 2017-11-28 | 豪夫迈·罗氏有限公司 | 雌激素受体调节剂及其用途 |
| CN112041307A (zh) * | 2018-02-06 | 2020-12-04 | 伊利诺伊大学评议会 | 作为选择性雌激素受体降解剂的取代的苯并噻吩类似物 |
-
2023
- 2023-06-02 CN CN202310649767.6A patent/CN116813603A/zh active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133040A (zh) * | 1993-10-12 | 1996-10-09 | 辉瑞大药厂 | 作为雌激素激动剂的苯并噻吩及其有关化合物 |
| US5567828A (en) * | 1995-06-07 | 1996-10-22 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side |
| EP0747376A1 (en) * | 1995-06-07 | 1996-12-11 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side chains |
| EP0747380A1 (en) * | 1995-06-07 | 1996-12-11 | Eli Lilly And Company | Compounds and compositions with nitrogen-containing non-basic side chains |
| US5981570A (en) * | 1996-09-27 | 1999-11-09 | Eli Lilly And Company | Benzothiophene compounds, compositions, and methods |
| WO1999015521A1 (en) * | 1997-09-23 | 1999-04-01 | Eli Lilly And Company | Benzothiophenes |
| WO2012084711A1 (en) * | 2010-12-24 | 2012-06-28 | Msd Oss B.V. | N-substituted azetidine derivatives |
| CN107406424A (zh) * | 2014-12-18 | 2017-11-28 | 豪夫迈·罗氏有限公司 | 雌激素受体调节剂及其用途 |
| CN112041307A (zh) * | 2018-02-06 | 2020-12-04 | 伊利诺伊大学评议会 | 作为选择性雌激素受体降解剂的取代的苯并噻吩类似物 |
Non-Patent Citations (3)
| Title |
|---|
| CHENGFENG BAI, ET AL.: "Benzothiophene derivatives as selective estrogen receptor covalent antagonists: Design, synthesis and anti-ERα activities", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 47, 6 September 2021 (2021-09-06), pages 116395 - 116408, XP086798414, DOI: 10.1016/j.bmc.2021.116395 * |
| ROMAGNOLI ROMEO, ET AL.: "Concise synthesis and biological evaluation of 2-Aryl-3-Anilinobenzo[b]thiophene derivatives as potent apoptosis-inducing agents", BIOORGANIC CHEMISTRY,, vol. 112, 31 December 2021 (2021-12-31), pages 104919 - 104933 * |
| TAKUJI SHODA, ET AL.: "Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 24, 31 December 2016 (2016-12-31), pages 2914 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2719428C2 (ru) | Индазольные соединения в качестве ингибиторов киназы fgfr, их получение и применение | |
| JP2019059783A (ja) | １，４−二置換ピリダジン誘導体およびｓｍｎ欠損に関連する状態を処置するためのその使用 | |
| CA2720552C (en) | Acylthiourea compound or salt thereof, and use thereof | |
| JP6506322B2 (ja) | 新規な抗不安薬化合物 | |
| KR20180071274A (ko) | 테트라히드로-1H-피리도[3,4-b]인돌 항에스트로겐 약물 | |
| CN115175679A (zh) | 治疗雌激素受体相关疾病的方法 | |
| WO2001083456A1 (fr) | Derives d'heteroaryle condenses | |
| JP6695275B2 (ja) | ３−置換カルボニル−ナフト［２，３−ｂ］フラン誘導体又はその薬学的に許容される塩 | |
| CN107849050B (zh) | 化合物 | |
| EA023173B1 (ru) | Ингибиторы киназы и способ лечения злокачественной опухоли с их помощью | |
| KR101760651B1 (ko) | 피롤일 치환된 다이하이드로인돌 2 온 유도체, 그의 제조 방법 및 용도 | |
| WO2013060179A1 (zh) | 酰基四氢-β-咔啉类化合物及其衍生物、用途及其制备方法 | |
| CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
| EA028035B1 (ru) | Производные пиразолопирролидин-4-она и их применение при лечении заболевания | |
| WO2022206723A1 (zh) | 杂环类衍生物、其制备方法及其医药上的用途 | |
| JP5649652B2 (ja) | 置換ヒドラジド類化合物及びその応用 | |
| US20220177485A1 (en) | Camptothecin derivative, preparation method therefor and application thereof | |
| CN107151233B (zh) | 含腙的嘧啶类衍生物及其用途 | |
| KR20210142554A (ko) | Ron 돌연변이와 관련된 비소세포 폐암 예방 또는 치료용 약학 조성물 및 이를 이용한 방법 | |
| KR20210142553A (ko) | Ron 돌연변이와 관련된 소세포 폐암 예방 또는 치료용 약학 조성물 및 이를 이용한 방법 | |
| CN110467616B (zh) | 含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物的制备及应用 | |
| WO2009100655A1 (zh) | 芳环并三嗪类衍生物及其应用 | |
| CN116813603A (zh) | 一种选择性雌激素受体α降解化合物及其制备方法和应用 | |
| CN115368366A (zh) | 嘧啶并吡唑类化合物及其应用 | |
| WO1999061414A1 (fr) | Nouveaux derives de guanidine substitues et procede de production de ces derniers |
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 |