WO2022007903A1 - 一种能够抑制并降解雄激素受体的化合物及其药物组合物和药学上的应用 - Google Patents
一种能够抑制并降解雄激素受体的化合物及其药物组合物和药学上的应用 Download PDFInfo
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- WO2022007903A1 WO2022007903A1 PCT/CN2021/105275 CN2021105275W WO2022007903A1 WO 2022007903 A1 WO2022007903 A1 WO 2022007903A1 CN 2021105275 W CN2021105275 W CN 2021105275W WO 2022007903 A1 WO2022007903 A1 WO 2022007903A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 117
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 108010080146 androgen receptors Proteins 0.000 title description 31
- 102000001307 androgen receptors Human genes 0.000 title description 31
- 230000002401 inhibitory effect Effects 0.000 title description 8
- 230000000593 degrading effect Effects 0.000 title description 2
- 239000013078 crystal Substances 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 239000000651 prodrug Chemical class 0.000 claims abstract description 29
- 229940002612 prodrug Drugs 0.000 claims abstract description 29
- 239000012453 solvate Chemical class 0.000 claims abstract description 29
- 239000002207 metabolite Chemical class 0.000 claims abstract description 28
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 17
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 229910052731 fluorine Inorganic materials 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 80
- 229910052794 bromium Inorganic materials 0.000 claims description 72
- 229910052801 chlorine Inorganic materials 0.000 claims description 72
- 229910052740 iodine Inorganic materials 0.000 claims description 71
- -1 cyclopropylazepinyl Chemical group 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 47
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 41
- 125000005842 heteroatom Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000003003 spiro group Chemical group 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical compound C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 claims description 9
- ZJPNBMKYNNIDJC-UHFFFAOYSA-N 2-cyclohexyl-1H-azepine Chemical compound C1CCCCC1C1=CC=CC=CN1 ZJPNBMKYNNIDJC-UHFFFAOYSA-N 0.000 claims description 9
- 230000015556 catabolic process Effects 0.000 claims description 9
- 238000006731 degradation reaction Methods 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 230000014509 gene expression Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- RHRLGFPTYKGJPR-UHFFFAOYSA-N 1-cyclobutylpiperidine Chemical compound C1CCC1N1CCCCC1 RHRLGFPTYKGJPR-UHFFFAOYSA-N 0.000 claims description 3
- WYANFTXHKVXPFJ-UHFFFAOYSA-N 1-cyclopentylpiperidine Chemical compound C1CCCC1N1CCCCC1 WYANFTXHKVXPFJ-UHFFFAOYSA-N 0.000 claims description 3
- JUBXTBVKELTJEX-UHFFFAOYSA-N 1-cyclopropylpiperidine Chemical compound C1CC1N1CCCCC1 JUBXTBVKELTJEX-UHFFFAOYSA-N 0.000 claims description 3
- KNLOUXALILBKPY-UHFFFAOYSA-N 5,8-diazabicyclo[4.2.0]octane Chemical compound C1CCNC2CNC21 KNLOUXALILBKPY-UHFFFAOYSA-N 0.000 claims description 3
- DSSKLTAHHALFRW-UHFFFAOYSA-N N-cyclohexylpiperidine Chemical compound C1CCCCC1N1CCCCC1 DSSKLTAHHALFRW-UHFFFAOYSA-N 0.000 claims description 3
- NQESILKODDIQJD-UHFFFAOYSA-N O1NC=CC=C1.N1CCCCC1 Chemical compound O1NC=CC=C1.N1CCCCC1 NQESILKODDIQJD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 125000000477 aza group Chemical group 0.000 claims description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 5
- 125000005843 halogen group Chemical group 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 191
- 238000006243 chemical reaction Methods 0.000 description 74
- 239000000243 solution Substances 0.000 description 64
- 239000000460 chlorine Substances 0.000 description 57
- 230000002829 reductive effect Effects 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
- 239000012043 crude product Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 0 CC(*)N1CC(C)C1 Chemical compound CC(*)N1CC(C)C1 0.000 description 33
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
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- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- 238000001308 synthesis method Methods 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 12
- 108091008715 AR-FL Proteins 0.000 description 11
- HXOTVNAOPQHDEQ-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-iodopyrazol-1-yl)-2-methylpropanamide Chemical compound CC(C)(C(NC(C=C1)=CC(C(F)(F)F)=C1C#N)=O)N1N=CC(I)=C1 HXOTVNAOPQHDEQ-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
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- LVHOEJMKTKXNAH-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutane-1-carboxamide Chemical compound N#CC(C=C1)=C(C(F)(F)F)C=C1NC(C1(CCC1)N1N=CC(C#CC(C2)CN2C(C2)CN2C(C=C2C(N3C(CCC(N4)=O)C4=O)=O)=CC=C2C3=O)=C1)=O LVHOEJMKTKXNAH-UHFFFAOYSA-N 0.000 description 9
- WKCISRMXSDRFQR-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-2-[4-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]-2-methylpropanamide Chemical compound CC(C)(C(NC(C=C1)=CC(C(F)(F)F)=C1C#N)=O)N1N=CC(C#CC(C2)CN2C(C=C2C(N3C(CCC(N4)=O)C4=O)=O)=CC=C2C3=O)=C1 WKCISRMXSDRFQR-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
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- NEEXEJUMTZZLTQ-UHFFFAOYSA-N N#CC(C=C1)=C(C(F)(F)F)C=C1NC(C1(CCC1)N1N=CC(C2CCN(CC(C=C3)=CN3C(C=C3C(N4C(CCC(N5)=O)C5=O)=O)=CC=C3C4=O)CC2)=C1)=O Chemical compound N#CC(C=C1)=C(C(F)(F)F)C=C1NC(C1(CCC1)N1N=CC(C2CCN(CC(C=C3)=CN3C(C=C3C(N4C(CCC(N5)=O)C5=O)=O)=CC=C3C4=O)CC2)=C1)=O NEEXEJUMTZZLTQ-UHFFFAOYSA-N 0.000 description 8
- UTVNAZSZXPAUSJ-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutane-1-carboxamide Chemical compound N#CC(C=C1)=C(C(F)(F)F)C=C1NC(C1(CCC1)N1N=CC(C#CC(C2)CN2C(C=C2C(N3C(CCC(N4)=O)C4=O)=O)=CC=C2C3=O)=C1)=O UTVNAZSZXPAUSJ-UHFFFAOYSA-N 0.000 description 8
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- 238000000034 method Methods 0.000 description 8
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- 125000003396 thiol group Chemical class [H]S* 0.000 description 8
- KLZAHUJTOHCAGX-DETIRCLXSA-N 2-[4-[1-[(3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]piperidin-4-yl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropanamide Chemical compound CC(C)(C(NC(C=C1)=CC(C(F)(F)F)=C1C#N)=O)N1N=CC(C(CC2)CCN2C(C2)C[C@@H]3[C@H]2CNC3)=C1 KLZAHUJTOHCAGX-DETIRCLXSA-N 0.000 description 7
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- 229960000583 acetic acid Drugs 0.000 description 7
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- AHHALPZTMLZRFL-UHFFFAOYSA-N tert-butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1C#CC1=CNN=C1)=O AHHALPZTMLZRFL-UHFFFAOYSA-N 0.000 description 7
- BBKNAKDKYGLEKG-UHFFFAOYSA-N tert-butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1N(C1)CC1C#CC1=CN(C2(CCC2)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O BBKNAKDKYGLEKG-UHFFFAOYSA-N 0.000 description 7
- NSPSFSOMUZBHPB-UHFFFAOYSA-N tert-butyl 4-(1h-pyrazol-4-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CNN=C1 NSPSFSOMUZBHPB-UHFFFAOYSA-N 0.000 description 7
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- XMYHJUPBYREXHW-UHFFFAOYSA-N tert-butyl 4-[1-[1-[4-cyano-3-(trifluoromethyl)anilino]-2-methyl-1-oxopropan-2-yl]pyrazol-4-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C1=CN(C(C)(C)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O XMYHJUPBYREXHW-UHFFFAOYSA-N 0.000 description 7
- TXJZGBNZYYZAQB-UHFFFAOYSA-N tert-butyl 7-[4-[1-[1-[4-cyano-3-(trifluoromethyl)anilino]-2-methyl-1-oxopropan-2-yl]pyrazol-4-yl]piperidin-1-yl]-2-azaspiro[3.5]nonane-2-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1(CC1)CCC1N(CC1)CCC1C1=CN(C(C)(C)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O TXJZGBNZYYZAQB-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
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- UBWQGQVHAIBOMW-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-[4-[1-(1H-pyrrol-3-ylmethyl)piperidin-4-yl]pyrazol-1-yl]propanamide Chemical compound CC(C)(C(NC(C=C1)=CC(C(F)(F)F)=C1C#N)=O)N1N=CC(C2CCN(CC3=CNC=C3)CC2)=C1 UBWQGQVHAIBOMW-UHFFFAOYSA-N 0.000 description 6
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- TZOZEFROZVMDME-UHFFFAOYSA-N tert-butyl 3-[2-[1-[1-[4-cyano-3-(trifluoromethyl)anilino]-2-methyl-1-oxopropan-2-yl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1C#CC1=CN(C(C)(C)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O TZOZEFROZVMDME-UHFFFAOYSA-N 0.000 description 6
- RHPSCFZLRLQYHQ-UHFFFAOYSA-N tert-butyl 4-[2-[1-[1-[4-cyano-3-(trifluoromethyl)anilino]-2-methyl-1-oxopropan-2-yl]pyrazol-4-yl]ethynyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C#CC1=CN(C(C)(C)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O RHPSCFZLRLQYHQ-UHFFFAOYSA-N 0.000 description 6
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- GGNDIMLSSMWKDR-DTORHVGOSA-N tert-butyl (3ar,6as)-5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate Chemical compound C1C(=O)C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21 GGNDIMLSSMWKDR-DTORHVGOSA-N 0.000 description 1
- MVBJELSNUFREQL-UHFFFAOYSA-N tert-butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1C#CC1=CN(C(C)=O)N=C1)=O MVBJELSNUFREQL-UHFFFAOYSA-N 0.000 description 1
- QQBUAKATDZITBF-UHFFFAOYSA-N tert-butyl 3-[3-[2-[1-[1-[4-cyano-3-(trifluoromethyl)anilino]-2-methyl-1-oxopropan-2-yl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(N(C1)CC1N(C1)CC1C#CC1=CN(C(C)(C)C(NC(C=C2)=CC(C(F)(F)F)=C2C#N)=O)N=C1)=O QQBUAKATDZITBF-UHFFFAOYSA-N 0.000 description 1
- YQTBNGOMJGLOSE-UHFFFAOYSA-N tert-butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]piperidin-1-yl]methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N1CC(CN(CC2)CCC2C2=CN(C3(CCC3)C(NC(C=C3)=CC(C(F)(F)F)=C3C#N)=O)N=C2)CC1)=O YQTBNGOMJGLOSE-UHFFFAOYSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- INUWDZDWSJJFSQ-UHFFFAOYSA-N tert-butyl 4-ethynylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C#C)CC1 INUWDZDWSJJFSQ-UHFFFAOYSA-N 0.000 description 1
- KHCPHQZPEYFYRA-UHFFFAOYSA-N tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CCC(=O)CC2 KHCPHQZPEYFYRA-UHFFFAOYSA-N 0.000 description 1
- QUERMGFVJPRMJL-UHFFFAOYSA-N tert-butyl azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1 QUERMGFVJPRMJL-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
提供了一种通式B-L-K (I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体,以及在AR相关疾病如前列腺癌中的用途。
Description
本发明涉及一种通式(I)的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在AR相关疾病如前列腺癌中的用途。
前列腺癌是一种多发现于早期的癌症,其发病原因常常与遗传因素、高脂肪饮食及内分泌有关。通常来说,发达国家的前列腺癌发病率高于发展中国家。2016年,中国的前列腺癌新发患者12万人,到2030年预计新发患者将达到23.7万人,同时市场份额也将达到48亿美元。对于早期的前列腺癌患者可采用根治性治疗方法,且生存时间较长,而癌细胞转移的晚期患者则采用去势结合抗雄激素药物疗法,且病情会发展为去势抵抗性前列腺癌。临床研究显示,大部分去抵抗性前列腺癌的患者体内雄激素受体(Androgen receptor,AR)过度表达,抑制雄激素受体(Androgen receptor,AR)信号对激素难治性前列腺患者有显著的疗效,因此抑制雄激素受体(Androgen receptor,AR)是一种直接阻断该通路的有效手段。
雄激素受体(Androgen receptor,AR)是一种激素核受体,结构上可划分为N-端活化区域(NTD)、DNA结合区域(DBD)和配体结合区域(LTD),能够调节诱发前列腺癌的基因表达,因此,抑制雄激素受体是治疗前列腺癌的有效方法。目前上市的雄激素受体抑制剂如恩杂鲁胺、比卡鲁胺等主要是通过与雄激素受体的配体结合区域(LTD)作用发挥抑制效果,但部分患者在治疗过程中会出现由于LTD片段缺失的雄激素受体剪切突变体(Androgen receptor splice variants,AR-Vs)导致的耐药现象。临床前研究表明,雄激素受体剪切突变体能加快恩杂鲁胺耐药的前列腺癌进展,如何解决其耐药问题成为临床医学的关注点。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物,此类化合物能够被细胞的蛋白酶体识别,引起靶向蛋白的降解,能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体,使PROTAC技术应用于各种疾病的治疗成为可能,该技术近年来同时得 到了广泛的关注。
因此,有必要开发新型的雄激素受体(Androgen receptor,AR)或/和AR剪切突变体抑制剂和E3泛素连接酶的PROTAC药物,用于治疗与雄激素受体相关的肿瘤疾病。
发明内容
本发明开发了一种结构新颖的、药效好、生物利用度高、更安全的AR或/和AR剪切突变体抑制剂,用于治疗AR相关疾病如前列腺癌。
本发明提供一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,化合物选自通式(I)所示的化合物,
B-L-K (I);
B
1选自取代或未取代的如下基团之一:6元芳基或6元杂芳基,当被取代时,任选进一步被0至4个R
b1所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
B
2选自取代或未取代的如下基团之一:5-10元杂环基或-NHC(=O)-,当被取代时,任选进一步被0至4个选自R
b2所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;
B
3选自取代或未取代的5-6元芳基或键,当所述5-6元芳基被取代时,任选进一步被0至4个R
b2所取代;
R
b1、R
b2各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、-C(=O)NH
2、-C(=O)NH-C
1-4烷基、-C(=O)N(C
1-4烷基)
2、C
1-4烷基或C
1-4烷氧基,所述的烷基或者烷氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;
R
b3、R
b4各自独立的选自H或C
1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
或R
b3、R
b4与其相连接的碳原子共同形成C
3-6环烷基或C
3-6杂单环,所述的环烷基或杂单环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环含有1至4个选自O、S、N的杂原子;
B
1选自取代或未取代的如下基团之一:6元芳基或6元杂芳基,当被取代时,任选进一步被0至4个R
b1所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
B
2选自取代或未取代的如下基团之一:5-10元杂环基或-NHC(=O)-,当被取代时,任选进一步被0至4个选自R
b2所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;
B
3选自取代或未取代的苯基或键,当所述苯基被取代时,任选进一步被0至4个R
b2所取代;
R
b1、R
b2各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、-C(=O)NH
2、-C(=O)NH-CH
3、-C(=O)N(CH
3)
2、甲基、乙基、丙基、异丙基、甲氧基或乙氧基,所述的甲基、乙基、丙基、异丙基、甲氧基或乙氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;
R
b3、R
b4各自独立的选自H或C
1-3烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
或R
b3、R
b4与其相连接的碳原子共同形成C
3-6环烷基或C
3-6杂单环,所述的环烷基或杂单环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环含有1至4个选自O、S、N的杂原子;
在某些实施方案中,L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O、C≡C或者键;
Cy1、Cy2、Cy3、Cy4各自独立的选自键、4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH
2、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子;
在某些实施方案中,L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O、C≡C或者键;
Cy1、Cy2、Cy3和Cy4各自独立的选自键、4-7元含氮杂单环、5-10元含氮杂并环、7-10元杂桥环或6-12元含氮杂螺环,所述杂单环、杂并环、杂桥环或杂螺环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH
2、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂桥环或杂螺环含有1至4个选自O、S、N的杂原子;
在某些实施方案中,L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O、C≡C或者键;
Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、氮杂环己基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环 丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、COOH、CN、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代;
在某些实施方案中,L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O、C≡C或者键;
在某些实施方案中,L选自
L的左侧与B连接,Cy1、Cy2各自独立的选自取代的或者未取代的如下基团之一:
当被取代时,任选进一步被0至4个选自H、F、CF
3、甲基、oxo、羟甲基、COOH、CN或NH
2的取代基所取代;
在某些实施方案中,L选自
L的左侧与B连接,Cy1、Cy2各自独立的选自取代的或者未取代的如下基团之一:
当被取代时,任选进一步被0至4个选自H、F、CF
3、甲基、oxo、羟甲基、COOH、CN或NH
2的取代基所取代;
环E或F各自的独立的选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
M
1选自键、-CH
2-C(=O)NH-或-C(=O)CH
2NH-;
M
2选自-NHC(=O)-C
1-6烷基或-NHC(=O)-C
3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
M
3选自-NH-或-O-;
R
k6选自C
1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C
1-6烷基或C
3-6环烷基的取代基所取代;
R
k7各自独立的选自H、F、Cl、Br、I、OH、SH、C
1-6烷基、C
1-6烷氧基、C
1-6烷硫基或C
1-6烷基甲酰氧基,所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k8、R
k9各自独立的选自H、C
1-6烷基或C
3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k10选自5-6元杂芳基,所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF
3、CN、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基、C
1-4烷氧基或C
3-6环烷基的取代基所取代;
G选自6-10元芳基或5-10元杂芳基,所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF
3、CN、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基、C
1-4烷氧基或C
3-6环烷基的取代基所取代;
p1或p2各自独立的选自0、1、2、3或4;
R
k2各自独立的选自CH
2或C=O;
R
k1、R
k3或R
k4各自独立的选自H、CH
3、F、Cl、Br、I、OH或NH
2;
M
1选自键、-CH
2-C(=O)NH-或-C(=O)CH
2NH-;
M
2选自-NHC(=O)-甲基、-NHC(=O)-乙基、-NHC(=O)-环丙基、-NHC(=O)-环丁基、-NHC(=O)-环戊基或-NHC(=O)-环已基,所述的甲基、乙基、环丙基、环丁基、环戊基或环已基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k6选自甲基、乙基、丙基、异丙基、叔丁基、异丁基或仲丁基;
R
k7各自独立的选自H、F、OH、SH、甲基、甲氧基或-SCH
3;
R
k8、R
k9各自独立的选自H、甲基、乙基、环丙基或环丁基;
p1或p2各自独立的选自0、1或2;
作为本发明的第一种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
B-L-K (I);
L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH
2、O、C≡C或者键;
Cy1、Cy2、Cy3、Cy4各自独立的选自键、4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH
2、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂 原子;
B
1选自取代或未取代的如下基团之一:6元芳基或6元杂芳基,当被取代时,任选进一步被0至4个R
b1所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
B
2选自取代或未取代的如下基团之一:5-10元杂环基或-NHC(=O)-,当被取代时,任选进一步被0至4个选自R
b2所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;
B
3选自取代或未取代的5-6元芳基或键,当所述5-6元芳基被取代时,任选进一步被0至4个R
b2所取代;
R
b1、R
b2各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、-C(=O)NH
2、-C(=O)NH-C
1-4烷基、-C(=O)N(C
1-4烷基)
2、C
1-4烷基或C
1-4烷氧基,所述的烷基或者烷氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;
R
b3、R
b4各自独立的选自H或C
1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
或R
b3、R
b4与其相连接的碳原子共同形成C
3-6环烷基或C
3-6杂单环,所述的环烷基或杂单环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环含有1至4个选自O、S、N的杂原子;
环E或F各自的独立的选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;
R
k2各自独立的选自CH
2、C=O、S=O、SO
2;
R
k1、R
k3或R
k4各自独立的选自H、F、Cl、Br、I、OH、NH
2、CF
3、CN、COOH、C
1-4烷基或C
1-4烷氧基;
M
1选自键、-CH
2-C(=O)NH-或-C(=O)CH
2NH-;
M
2选自-NHC(=O)-C
1-6烷基或-NHC(=O)-C
3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
M
3选自-NH-或-O-;
R
k6选自C
1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C
1-6烷基或C
3-6环烷基的取代基所取代;
R
k7各自独立的选自H、F、Cl、Br、I、OH、SH、C
1-6烷基、C
1-6烷氧基或C
1-6烷硫基、C
1-6烷基甲酰氧基,所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k8、R
k9各自独立的选自H、C
1-6烷基或C
3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k10选自5-6元杂芳基,所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF
3、CN、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基、C
1-4烷氧基或C
3-6环烷基的取代基所取代;
G选自6-10元芳基或5-10元杂芳基,所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF
3、CN、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基、C
1-4烷氧基或C
3-6环烷基的取代基所取代;
p1或p2各自独立的选自0、1、2、3或4。
作为本发明的第二种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
Cy1、Cy2、Cy3和Cy4各自独立的选自键、4-7元含氮杂单环、5-10元含氮杂并环、7-10元杂桥环或6-12元含氮杂螺环,所述杂单环、杂并环、杂桥环或杂螺环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH
2、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代,所述的杂单环、杂并环、杂桥环或杂螺环含有1至4个选自O、S、N的杂原子;
其他基团的定义同第一种方案。
作为本发明的第三种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
Cy1、Cy2、Cy3和Cy4各自独立的选自键或者取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、氮杂环己基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环 丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、
当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、COOH、CN、oxo、C
1-4烷基、卤素取代的C
1-4烷基、羟基取代的C
1-4烷基或C
1-4烷氧基的取代基所取代
R
b1、R
b2各自独立的选自H、F、Cl、Br、I、OH、NH
2、CN、CF
3、-C(=O)NH
2、-C(=O)NH-CH
3、-C(=O)N(CH
3)
2、甲基、乙基、丙基、异丙基、甲氧基或乙氧基,所述的甲基、乙基、丙基、异丙基、甲氧基或乙氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;
R
k2各自独立的选自CH
2或C=O;
R
k1、R
k3或R
k4各自独立的选自H、CH
3、F、Cl、Br、I、OH或NH
2;
M
1选自键、-CH
2-C(=O)NH-或-C(=O)CH
2NH-;
M
2选自-NHC(=O)-甲基、-NHC(=O)-乙基、-NHC(=O)-环丙基、-NHC(=O)-环丁基、-NHC(=O)-环戊基或-NHC(=O)-环已基,所述的甲基、乙基、环丙基、环丁基、环戊基或环已基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH
2、C
1-4烷基或C
1-4烷氧基的取代基所取代;
R
k6选自甲基、乙基、丙基、异丙基、叔丁基、异丁基或仲丁基;
R
k7各自独立的选自H、F、OH、SH、甲基、甲氧基或-SCH
3;
R
k8、R
k9各自独立的选自H、甲基、乙基、环丙基或环丁基;
p1或p2各自独立的选自0、1或2;
其他基团的定义同第二种方案。
作为本发明的第四种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其他定义同第三种方案。
作为本发明的第五种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其他基团的定义同第四种方案。
作为本发明的第六种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其他基团的定义同第五种方案。
作为本发明的第七种实施方案,通式(I)或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其他基团的定义同第六种方案。
作为本发明的一种实施方案,通式(I)所示的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自如下结构之一:
本发明涉及一种药物组合物,包括本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及要学上可接受的载体。
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与AR活性或表达量相关疾病的药物中的应用。
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解AR相关疾病的药物中的应用。
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。
本发明涉及的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的应用,其特征在于,所述的疾病选自前列腺癌。
合成方法:
通式(Z-1)与通式(Z-2)发生亲核取代反应生成通式(Z-3),即通式(Z-3′),当R
1为氨基保护基时,通式(Z-3′)进行脱保护得到对应通式(Z-4),通式(Z-4)再与通式(Z-5)发生亲核取代反应得到通式(Z-6),即通式(I);通式(Z-4)与通式(Z-7)发生亲核取代或还原胺化反应生成通式(Z-8),当R
4为氨基保护基时,通式(Z-8)进行脱保护得到对应通式(Z-9),通式(Z-9)再与通式(Z-5)发生亲核取代反应得到通式(Z-10),即通式(I);
通式(Z-9)与通式(Z-11)发生亲核取代或还原胺化反应生成通式(Z-12),当R
6为氨基保护基时,通式(Z-12)进行脱保护得到对应通式(Z-13),通式(Z-13)再与通式(Z-5)发生亲核取代反应得到通式(Z-14),即通式(I);
通式(Z-13)与通式(Z-15)发生亲核取代或还原胺化反应生成通式(Z-16),当R
8为氨基保护基时,通式(Z-16)进行脱保护得到对应通式(Z-17),通式(Z-17)再与通式(Z-5)发生亲核取代反应得到通式(Z-18),即通式(I)。
通式(Z-5)合成方法见WO2017197056;
R
1选自H、(=O)、-CHO、F、Cl、Br、I或氨基保护基(优选Boc);
R
2选自NH
2、F、Cl、Br、I、OTf、OH;
R
3、R
4、R
5、R
6、R
7、R
8各自独立的选自H、(=O)、-CHO、H、F、Cl、Br、I、OTf或氨基保护基(优选Boc)。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一 步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素包括
17F和
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;所述的烷基可以任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C
1-6烷基、C
1-6羟基烷基、C
1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代,本文中出现的烷基,其定义与本定义一致。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷氧基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基,其定义与本定义一致。
“环烷基”是指3至20个碳原子的直链或支链饱和环状脂肪族烃基,优选为3至10个碳原子的环烷基。非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基。所述的环烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的环烷基,其定义与本定义一致。
“杂环基”或”杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、 呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、=O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基,其定义与本定义一致。
“螺环”是指取代的或未取代的单环之间共用一个碳原子(称螺原子)的5至20元多环基团,其可以包含0至5个双键,且可以含有0至5个选自N、O或S(=O)
n的杂原子。优选为6至14元,进一步优选为6至12元,更优选6至10元,其非限定性实例包括:
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的螺环,其定义与本定义一致。
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团,其中一个或多个环可以含有0个或多个双键,且可以是取代的或未取代,并环体系中的各个环可以含0至5个选自N、S(=O)
n或O的杂原子(n选自0、1或2)。优选为5至20元,进一步优选为5至14元,更有选5至12元,再进一步优选5至10元。非限定性实 例包括:
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的并环,其定义与本定义一致。
“桥环”是指任意两个不直接连接的碳原子的多环基团,可以含有0个或多个双键,且可以是取代的或未取代的,并环体系中的任意环可以含0至5个选自N、S(=O)
n或O杂原子或基团(其中n为1、1、2)。环原子包含5至20个原子,优选为5至14个原子,进一步优选5至12个,在进一步优选5至10个。非限定性实例包括
金刚烷。当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的桥环,其定义与本定义一致。
“杂单环”是指单环体系的“杂环基”或“杂环”,本文中出现的杂单环,其定义与本定义一致。
“杂并环”是指含有杂原子的“并环”。本文中出现的杂并环,其定义与本定义一致。
“杂螺环”是指含有杂原子的“螺环”。本文中出现的杂螺环,其定义与本定义一致。
“杂桥环”是指含有杂原子的“桥环”。本文中出现的杂桥环,其定义与本定义一致。
“杂芳基”或“杂芳环”是指取代或未取代的5至14元芳香环,且含有1至5个选自N、O或S(=O)
n杂原子或基团,优选5至10元杂芳香环,进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并咪唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH
2)
m-C(=O)-R
a、-O-(CH
2)
m-C(=O)-R
a、-(CH
2)
m-C(=O)-NR
bR
c、-(CH
2)
mS(=O)
nR
a、-(CH
2)
m-烯基-R
a、OR
d或-(CH
2)
m-炔基-R
a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR
bR
c等基团,其中R
b与R
c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环 基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,R
b与R
c可形成五或六元环烷基或杂环基。R
a与R
d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂芳基或杂芳环,其定义与本定义一致。
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代,X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。
X-Y元的环(X为整数,且3≤X<Y,Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环,“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“DC
50”是指降解50%蛋白时的剂量。
“IC
50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。
以下结合实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
为了完成本发明的目的,根据本邻域技术人员已知的有机合成技术,从市售的化学品和/或化学文献中描述的化合物开始,制备本文所述反应中使用的化合物“商业上可用的化学品”是从标准的商业来源获得的,包括上海阿拉丁生化科技股份有限公司,上海麦克林生化科技有限公司,Sigma-Aldrich,阿法埃莎(中国)化学有限公司,梯希爱(上海)化成工业发展有限公司,安耐吉化学,上海泰坦科技股份有限公司,科龙化工,百灵威科技有限公司等。
本领域的参考书和专著,详细介绍了可用于制备本文所述化合物的反应物的合成,或提供了描述该制备方法的文章以供参考。这些参考书和专著包括:“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983;H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,New York,1992;J.March,“Advanced Organic Chemistry:Reactions,Mechanisms and Structure”,4th Ed.,Wiley Interscience,New York,1992;Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3 527-29074-5;Hoffman,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN: 3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55 volumes;and“Chemistry of Functional Groups”John Wiley&Sons,in 73 volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引,可以选择性地识别特定和类似的反应物,这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备,其中许多标准化学供应工厂(例如,上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的,起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的,供应商包括:泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10
-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
DMSO:二甲基亚砜;DIPEA:N,N'-二异丙基乙胺;DCE:二氯乙烷;DCM:二氯甲烷;DIPEA:N,N-二异丙基乙胺。
中间体A的合成:
4-(1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(中间体A)
tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate
第一步:4-(三氟甲基磺酰氧基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A2)
tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate
将N-Boc-4-哌啶酮(A1)(5.21g,26.1mmol)溶解在26mL四氢呋喃中,氮气保护下冷却至-78℃,慢慢滴加1mol/L双三甲基硅基氨基锂的四氢呋喃溶液(28.5mL),加完后反应继续在-78℃搅拌1h,随后滴加N-苯基双(三氟甲烷磺酰)亚胺(10.2g,28.6mmol)的四氢呋喃溶液(26mL),加完后自然升至室温反应3h。滴加20mL饱和碳酸氢钠溶液淬灭反应,加入50mL乙酸乙酯,分液,有机层用20mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=100/0-9/1),得4-(三氟甲基磺酰氧基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A2)(7.80g,产率:90%)。
第二步:4-(1H-吡唑-4-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A3)
tert-butyl 4-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
将4-(三氟甲基磺酰氧基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A2)(1.00g,3.02mmol)溶解在5mL乙腈中,依次加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-1H-吡唑(0.761g,3.92mmol)、5mL饱和碳酸氢钠水溶液和Pd(dppf)Cl
2·CH
2Cl
2(122mg,0.16mmol),于110℃微波反应30min。将反应冷却至室温,加入20mL水,用乙酸乙酯萃取(20mL×2),合并有机层,有机层用20mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4/1-1/1),得4-(1H-吡唑-4-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A3)(0.420g,产率:56%)。
1H NMR(400MHz,CDCl
3)δ7.61(s,2H),5.92(s,1H),4.07–4.00(m,2H),3.62(t,2H),2.46–2.37(m,2H),1.48(s,9H).
LCMS m/z=250.3[M+1]
+
第三步:4-(1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(中间体A)
tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate
将4-(1H-吡唑-4-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(A3)(0.400g,1.60mmol)溶解在10mL无水乙醇中,加入200mg 10%钯碳,置换氢气三次,于氢气球氛围下40℃反应5h。将反应液垫硅藻土过滤,将滤液减压浓缩,得到4-(1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(中间体A)(0.4g,收率:>99%)。
1H NMR(400MHz,CDCl
3)δ8.94(s,1H),7.43(s,2H),4.30–4.00(m,2H),2.83(t,2H),2.74–2.63(m,1H),1.96–1.84(m,2H),1.60–1.39(m,11H).
中间体B的合成:
3-乙炔基-[1,3'-双环丁]-1'-甲酸叔丁酯(中间体B)
tert-butyl 3-ethynyl-[1,3'-biazetidine]-1'-carboxylate
第一步:3-乙炔基氮杂环丁烷(B2)的盐酸盐
3-ethynylazetidine hydrochloride
将3-乙炔基氮杂环丁-甲酸叔丁酯(B1)(2.77g,15.28mmol)加入盛有40mL 3mol/L盐酸乙酸乙酯溶液的250mL单口圆底烧瓶中,室温搅拌反应4h。将反应液减压浓缩,得粗品3-乙炔基氮杂环丁烷(B2)的盐酸盐(1.74g)。
LCMS m/z=82.2[M+1]
+
第二步:3-乙炔基-[1,3'-双环丁]-1'-甲酸叔丁酯(中间体B)
tert-butyl 3-ethynyl-[1,3'-biazetidine]-1'-carboxylate
称取上述粗品3-乙炔基氮杂环丁烷(B2)的盐酸盐(1.74g)于250mL单口圆底烧瓶中,用100mL 1,2-二氯乙烷溶解,加入3mL三乙胺,然后依次加入3-氧代氮杂环丁-1-甲酸叔丁酯(6.33g,37.00mmol)、醋酸(3.11g,51.80mmol)和6g无水硫酸钠,加 热至60℃反应2h。将反应液降至室温,分批次加入三乙酰氧基硼氢化钠(18.82g,88.79mmol),室温反应16h。反应完毕,向反应液中加入50mL水,分层,有机相依次用50mL饱和碳酸氢钠溶液、50mL水和50mL饱和食盐水各洗涤一次,无水硫酸钠干燥,过滤,减压浓缩,粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4/1),得3-乙炔基-[1,3'-双环丁]-1'-甲酸叔丁酯(中间体B)(3.33g,从化合物B1算两步产率:92%)。
LCMS m/z=237.2[M+1]
+
中间体1的合成:
N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide
第一步:4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(1A)
tert-butyl 4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate
将2-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(合成方法见WO2020063407)(4.0g,11.9mmol)溶于50mL乙腈中,加入4-(1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(中间体A)(2.5g,9.9mmol)及碳酸铯(6.5g,19.9mmol),反应于50℃下搅拌1h。将反应液减压浓缩,加入100mL乙酸乙酯稀释,用100mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=2:1),得4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(1A)(3.7g,收率: 74%)。
第二步:N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide
将4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(1A)(3.7g,7.3mmol)溶解到50mL DCM中,加入15mL三氟乙酸,室温搅拌3h。将反应液减压浓缩,加入50mL二氯甲烷稀释,加入饱和碳酸氢钠溶液调pH至9.0,分离有机相,有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)(2.9g,收率:98%)。
LCMS m/z=406.3[M+1]
+
中间体2的合成:
N-(4-氰基-3-(三氟甲基)苯基)-1-(4-(哌啶-4-基)-1H-吡唑-1-基)环丁-1-甲酰胺(中间体2)
N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide
第一步:4-[1-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]哌啶-1-甲酸叔丁酯(2A)
tert-butyl 4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl] piperidine-1-carboxylate
将4-(1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(中间体A)(0.145g,0.576mmol)溶解在5mL乙腈中,依次加入1-溴-N-(4-氰基-3-(三氟甲基)苯基)环丁-1-甲酰胺(合成方法见WO2020063407)(0.200g,0.576mmol)和碳酸铯(0.207g,0.635mmol),反应于80℃搅拌3h。将反应液冷却至室温,加入20mL乙酸乙酯和10mL水,分液,有机层用无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4:1),得4-[1-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]哌啶-1-甲酸叔丁酯(2A)(0.060g,产率:20%)。
1H NMR(400MHz,CDCl
3)δ9.14(s,1H),8.00–7.96(m,1H),7.81–7.70(m,2H),7.60(s,1H),7.39(s,1H),4.23–4.12(m,2H),3.10–2.99(m,2H),2.87–2.61(m,5H),2.27–2.14(m,1H),2.14–2.04(m,1H),1.94–1.85(m,2H),1.58–1.40(m,11H).
第二步:N-(4-氰基-3-(三氟甲基)苯基)-1-(4-(哌啶-4-基)-1H-吡唑-1-基)环丁-1-甲酰胺(中间体2)
N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide
将4-[1-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]哌啶-1-甲酸叔丁酯(2A)(1.50g,2.90mmol)溶解在10mL二氯甲烷中,加入4mL三氟乙酸,室温反应20min。将反应液减压浓缩,向残留物中加入50mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9,分液,有机层用无水硫酸钠干燥,减压浓缩,得N-(4-氰基-3-(三氟甲基)苯基)-1-(4-(哌啶-4-基)-1H-吡唑-1-基)环丁-1-甲酰胺(中间体2)(1.20g,产率:>99%)。
LCMS m/z=418.2[M+1]
+
实施例1:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧 代异吲哚啉-5-基)八氢环戊[c]吡咯-5-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物1)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:(3aR,6aS)-5-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)六氢环戊[c]吡咯-2(1H)-甲酸叔丁酯(1a)
tert-butyl(3aR,6aS)-5-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)(202mg,0.50mmol)溶于15mL DCE中,加入(3aR,6aS)-5-氧代六氢环戊[c]吡咯-2(1H)-甲酸叔丁酯(225mg,1.00mmol),室温搅拌0.5h后,加入三乙酰氧基硼氢化钠 (318mg,1.50mmol),室温搅拌16h。向反应液中缓慢加入20mL饱和碳酸氢钠水溶液,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得(3aR,6aS)-5-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)六氢环戊[c]吡咯-2(1H)-甲酸叔丁酯(1a)(0.25g,收率:81%)。
LCMS m/z=615.4[M+1]
+
第二步:N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-((3aR,6aS)-八氢环戊[c]吡咯-5-基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(1b)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide
将(3aR,6aS)-5-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)六氢环戊[c]吡咯-2(1H)-甲酸叔丁酯(1a)(0.25g,0.41mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将反应体系减压浓缩,残留物用30mL 4mol/L NaOH水溶液溶解,DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-((3aR,6aS)-八氢环戊[c]吡咯-5-基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(1b)(0.18g)。
LCMS m/z=515.3[M+1]
+
第三步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)八氢环戊[c]吡咯-5-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物1)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-((3aR,6aS)-八氢环戊[c]吡咯 -5-基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(1b)(0.18g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(145mg,0.53mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,固体用10mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)八氢环戊[c]吡咯-5-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物1)(140mg,从化合物1a算两步收率:44%)。
1H NMR(400MHz,CDCl
3)δ9.78(s,1H),8.57(br.s,1H),7.99–7.90(m,1H),7.80–7.68(m,2H),7.64(d,1H),7.60(s,1H),7.45(s,1H),7.00–6.95(m,1H),6.69(dd,1H),4.92(dd,1H),3.66–3.52(m,2H),3.44–3.32(m,2H),3.19–3.03(m,2H),2.92–2.63(m,6H),2.59–2.45(m,1H),2.35–2.21(m,2H),2.18–2.01(m,3H),1.97–1.85(m,8H),1.84–1.62(m,2H),1.60–1.47(m,2H).
LCMS m/z=771.3[M+1]
+
实施例2:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)吡咯-3-基)甲基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物2)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:3-((4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(2a)
tert-butyl 3-((4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)(202mg,0.50mmol)溶于15mL DCE中,加入3-甲酰基吡咯-1-甲酸叔丁酯(200mg,1.00mmol),室温搅拌0.5h后,加入三乙酰氧基硼氢化钠(318mg,1.5mmol),室温搅拌16h。向反应液中缓慢加入20mL饱和碳酸氢钠水溶液,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得3-((4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(2a)(260mg,收率:88%)。
LCMS m/z=589.2[M+1]
+
第二步:N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(2b)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide
将3-((4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)甲基)吡咯-1-甲酸叔丁酯(2a)(0.26g,0.44mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将反应体系直接旋干,残留物用30mL 4mol/L NaOH水溶液溶解,DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(2b)(0.20g)。
LCMS m/z=489.2[M+1]
+
第三步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)吡咯-3-基)甲基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物2)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo isoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(1-(吡咯-3-基甲基)哌啶-4-基)-1H-吡唑-1-基)丙酰胺(2b)(0.18g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(153mg,0.55mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,用10mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)吡咯-3-基)甲基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物2)(150mg,从化合物2a算两步收率:51%)。
1H NMR(400MHz,CDCl
3)δ9.79(s,1H),8.22(s,1H),7.99–7.93(m,1H),7.81–7.69(m,2H),7.68–7.60(m,2H),7.48(s,1H),6.95(d,1H),6.68(dd,1H),4.93(dd,1H),3.65–3.35(m,3H),3.30–3.15(m,1H),3.12–2.59(m,6H),2.59–2.32(m,3H),2.30–2.05(m,3H),1.98–1.80(m,9H),1.76–1.52(m,3H).
LCMS m/z=745.3[M+1]
+
实施例3:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物3)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:7-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(3a)
tert-butyl 7-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)(202mg,0.50mmol)溶于15mL DCE中,加入7-氧代-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(240mg,1.00mmol),室温搅拌0.5h后,加入三乙酰氧基硼氢化钠(318mg,1.5mmol),室温搅拌16h。向反应液中缓慢加入20mL饱和碳酸氢钠水溶液,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=20:1),得7-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(3a)(200mg,收率:64%)。
LCMS m/z=629.4[M+1]
+
第二步:2-(4-(1-(2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(3b)
2-(4-(1-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide
将7-(4-(1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)哌啶-1-基)-2-氮杂螺[3.5]壬-2-甲酸叔丁酯(3a)(0.20g,0.32mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将反应体系直接减压浓缩,残留物用30mL 4mol/L NaOH水溶液溶解,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品2-(4-(1-(2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(3b)(0.15g)。
LCMS m/z=529.3[M+1]
+
第三步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物3)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品2-(4-(1-(2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(3b)(0.15g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(118mg,0.43mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,用10mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2-氮杂螺[3.5]壬-7-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物3)(120mg,从化合物3a算两步收率:48%)。
1H NMR(400MHz,CDCl
3)δ9.78(s,1H),8.22(br.s,1H),7.97–7.93(m,1H),7.81–7.69(m,2H),7.66–7.59(m,2H),7.46(s,1H),6.76(d,1H),6.49(dd,1H),4.93(dd,1H),3.73(s,2H),3.68(s,2H),3.16–2.95(m,2H),2.93–2.67(m,3H),2.59–2.46(m,1H),2.44–2.24(m,2H),2.16–2.02(m,3H),2.00–1.84(m,10H),1.80–1.52(m,5H),1.45–1.31(m,2H).
LCMS m/z=785.3[M+1]
+
实施例4:
N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-[[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]吡咯-3-基]甲基]-4-哌啶基]吡唑-1-基]环丁甲酰胺(化合物4)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pyrrolidin-3-yl]methyl]-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide
第一步:3-[[[4-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]-1-哌啶基]甲基]吡咯-1-甲酸叔丁酯(4a)
tert-butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]-1-piperidyl]methyl]pyrrolidine-1-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-1-(4-(哌啶-4-基)-1H-吡唑-1-基)环丁-1-甲酰胺(中间体2)(0.100g,0.240mmol)溶解在3mL 1,2-二氯乙烷中,依次加入N-Boc-3-吡咯甲醛(0.0955g,0.479mmol)、冰醋酸(0.036g,0.599mmol)和三乙酰氧基硼氢化钠(0.102g,0.481mmol),加完后室温反应16h。滴加饱和碳酸氢钠溶液调pH至9,分液,水层用 20mL二氯甲烷萃取,合并有机层,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(DCM/MeOH(v/v)=100/0-97/3),得3-[[[4-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]-1-哌啶基]甲基]吡咯-1-甲酸叔丁酯(4a)(0.08g,产率:56%)。
LCMS m/z=601.3[M+1]
+
第二步:N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-(吡咯-3-基甲基)-4-哌啶基]吡唑-1-基]环丁甲酰胺(4b)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-(pyrrolidin-3-ylmethyl)-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide
将3-[[[4-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]-1-哌啶基]甲基]吡咯-1-甲酸叔丁酯(4a)(0.08g,0.133mmol)溶解在2mL二氯甲烷中,加入1mL三氟乙酸,室温反应1h。将反应液减压浓缩,向残留物加入20mL二氯甲烷,用饱和碳酸氢钠调pH至9,分液,水层再用10mL二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,减压浓缩,得粗品N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-(吡咯-3-基甲基)-4-哌啶基]吡唑-1-基]环丁甲酰胺(4b)(0.0667g)。
LCMS m/z=501.3[M+1]
+
第三步:N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-[[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]吡咯-3-基]甲基]-4-哌啶基]吡唑-1-基]环丁甲酰胺(化合物4)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pyrrolidin-3-yl]methyl]-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide
将上述粗品N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-(吡咯-3-基甲基)-4-哌啶基]吡唑-1-基]环丁甲酰胺(4b)(0.060g,0.12mmol)溶于3mL二甲基亚砜中,加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.036g,0.13mmol)、二异丙基乙胺(0.031g,0.24mmol),反应于90℃搅拌2h。将反应液冷却至室温,加入 5mL水,搅拌2分钟,过滤,滤饼用10mL水洗涤,收集滤饼,滤饼用二氯甲烷(30mL)溶解,饱和氯化钠水溶液洗涤(10mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品用硅胶柱色谱分离提纯(甲醇/二氯甲烷(v/v)=0:1-1:19),得N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[1-[[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]吡咯-3-基]甲基]-4-哌啶基]吡唑-1-基]环丁甲酰胺(化合物4)(0.040g,产率:44%)。
1H NMR(400MHz,CDCl
3)δ9.01(s,1H),8.17(s,1H),7.98–7.92(m,1H),7.79–7.68(m,2H),7.68–7.57(m,2H),7.41(s,1H),6.95(d,1H),6.72–6.65(m,1H),4.94(dd,1H),3.66–3.46(m,2H),3.45–3.37(m,1H),3.28–3.15(m,1H),3.09–2.97(m,3H),2.95–2.65(m,6H),2.60–2.32(m,3H),2.30–1.76(m,9H),1.75–1.60(m,1H),1.37–1.20(m,2H).
LCMS m/z=757.3[M+1]
+
实施例5:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物5)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
将N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基)-1H-吡唑-1-基)丙酰胺(中间体1)(0.1g,0.25mmol)溶于5mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(90mg,0.33mmol),反应于85℃搅拌3h。将反应液冷却至室温,加入30mL水,过滤,收集固体,固体用10mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物5)(90mg,收率:54%)。
1H NMR(400MHz,CDCl
3)δ9.82(s,1H),8.12(br.s,1H),7.96–7.93(m,1H),7.82– 7.66(m,3H),7.63(s,1H),7.48(s,1H),7.31(d,1H),7.08(dd,1H),4.94(dd,1H),4.08–3.98(m,2H),3.16–3.04(m,2H),2.94–2.67(m,4H),2.19–2.01(m,3H),1.92(s,6H),1.78–1.65(m,2H).
LCMS m/z=662.2[M+1]
+
实施例6:
N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁甲酰胺(化合物6)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide
第一步:N-[4-氰基-3-(三氟甲基)苯基]-1-(4-碘吡唑-1-基)环丁甲酰胺(6b)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-(4-iodopyrazol-1-yl)cyclobutanecarboxamide
将4-碘-1H-吡唑(6a)(0.559g,2.88mmol)溶解在10mL乙腈中,依次加入1-溴-N-(4-氰基-3-(三氟甲基)苯基)环丁-1-甲酰胺(合成方法见WO2020063407)(1.00g,2.88mmol)和碳酸铯(1.03g,3.16mmol),80℃微波反应1h。将反应液冷却至室温,加入20mL乙酸乙酯和10mL水,分液,有机层用无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=9/1),得N-[4-氰基-3-(三氟甲基)苯基]-1-(4-碘吡唑 -1-基)环丁甲酰胺(6b)(0.130g,产率:10%)。
第二步:3-[3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(6c)
tert-butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate
将N-[4-氰基-3-(三氟甲基)苯基]-1-(4-碘吡唑-1-基)环丁甲酰胺(6b)(0.100g,0.217mmol)溶解在3mL二氯甲烷中,加入三乙胺(0.0660g,0.652mmol),氮气保护下依次加入PdCl
2(PPh
3)
2(0.0150g,0.0213mmol)、碘化亚铜(0.0062g,0.0326mmol),再慢慢滴加3-乙炔基-[1,3'-双环丁]-1'-甲酸叔丁酯(中间体B)(0.0770g,0.326mmol)的二氯甲烷溶液(1mL),加完后室温反应16h。加入5mL水和10mL二氯甲烷,分液,有机层用5mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(乙酸乙酯),得3-[3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(6c)(0.0350g,产率28%)。
第三步:1-[4-[2-[1-(氮杂环丁-3-基)氮杂环丁-3-基]乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁甲酰胺(6d)
1-[4-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide
将3-[3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(6c)(0.030g,0.053mmol)溶解在5mL二氯甲烷中,加入2mL三氟乙酸,室温反应1h。将反应液减压浓缩,向残留物中加入20mL二氯甲烷,用饱和碳酸氢钠溶液调pH至9,分液,水层再用10mL二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,减压浓缩,得粗品1-[4-[2-[1-(氮杂环丁-3-基)氮杂环丁-3-基] 乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁甲酰胺(6d)(0.020g)。
LCMS m/z=469.2[M+1]
+
第四步:N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁甲酰胺(化合物6)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide
将上述粗品1-[4-[2-[1-(氮杂环丁-3-基)氮杂环丁-3-基]乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁甲酰胺(6d)(0.020g)溶于二甲基亚砜(3mL)中,加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.013g,0.047mmol)和二异丙基乙胺(0.011g,0.085mmol),反应于90℃搅拌2h。将反应液冷却至室温,加入5mL水,搅拌2min,过滤,滤饼用10mL水洗涤,收集滤饼,滤饼用二氯甲烷(30mL)溶解,用10mL饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,粗品用硅胶柱色谱分离提纯(甲醇/二氯甲烷(v/v)=0:1-1:19),得N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁甲酰胺(化合物6)(0.020g,从化合物6c算两步产率:52%)。
1H NMR(400MHz,CDCl
3)δ8.11–7.97(m,2H),7.95–7.87(m,1H),7.80–7.74(m,1H),7.72–7.64(m,2H),7.58–7.50(m,1H),6.83–6.77(m,1H),6.58–6.51(m,1H),4.93(dd,1H),4.20–3.26(m,10H),2.94–2.67(m,4H),2.56–2.45(m,1H),2.44–2.28(m,2H),2.28–2.17(m,1H),2.17–2.08(m,1H),2.06–1.96(m,1H).
LCMS m/z=725.2[M+1]
+
实施例7:
N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁烷甲酰胺(化合物7)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide
第一步:3-[2-(1-(乙酰基吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7b)
tert-butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate
将1-乙酰基-4-碘-1H-吡唑(7a)(0.200g,0.847mmol)溶解在3mL二氯甲烷中,加入三乙胺(0.257g,2.54mmol),氮气保护下依次加入PdCl
2(PPh
3)
2(0.06g,0.0855mmol)和碘化亚铜(0.0242g,0.127mmol),再慢慢滴入3-乙炔基-1-氮杂环丁烷甲酸叔丁酯(0.200g,1.10mmol)的二氯甲烷溶液(1mL),加完后室温反应16h。向反应体系中加入5mL水和10mL二氯甲烷,分液,有机层用5mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=5/1),得3-[2-(1-(乙酰基吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7b)(0.190g,产率:78%)。
1H NMR(400MHz,CDCl
3)δ8.27(s,1H),7.69(s,1H),4.23–4.16(m,2H),4.04–3.96(m,2H),3.56–3.45(m,1H),2.69(s,3H),1.45(s,9H).
第二步:3-[2-(1H-吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7c)
tert-butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate
将3-[2-(1-(乙酰基吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7b)(0.190g,0.657mmol)溶解在5mL无水甲醇中,加入碳酸钾(0.182g,1.32mmol),室温搅拌5min。向反应液中加入10mL水和20mL乙酸乙酯,分液,有机层用10mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得粗品3-[2-(1H-吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7c)(0.150g)。
第三步:3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-甲酸叔丁酯(7d)
tert-butyl 3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate
将上述粗品3-[2-(1H-吡唑-4-基)乙炔基]氮杂环丁-1-甲酸叔丁酯(7c)(0.142g)溶解在10mL乙腈中,加入1-溴-N-(4-氰基-3-(三氟甲基)苯基)环丁-1-甲酰胺(合成方法见WO2020063407)(0.200g,0.576mmol)、碳酸铯(0.207g,0.635mmol),于80℃微波反应1h。将反应液冷却至室温,加入5mL水和10mL乙酸乙酯,分液,有机层用10mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=9/1),得3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-甲酸叔丁酯(7d)(0.130g,从化合物7b算两步产率:41%)。
第四步:1-[4-[2-(氮杂环丁-3-基)乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁烷甲酰胺(7e)
1-[4-[2-(azetidin-3-yl)ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide
将3-[2-[1-[1-[[4-氰基-3-(三氟甲基)苯基]氨基甲酰基]环丁基]吡唑-4-基]乙炔基]氮杂环丁-1-甲酸叔丁酯(7d)(0.050g,0.097mmol)溶解在5mL二氯甲烷中,加入2mL三氟乙酸,室温反应1h。将反应液减压浓缩,向残留物中加入20mL二氯甲烷,用饱和碳酸氢钠溶液调pH至10,分液,水层再用10mL二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,减压浓缩,得粗品1-[4-[2-(氮杂环丁-3-基)乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁烷甲酰胺(7e)(0.040g)。
LCMS m/z=414.1[M+1]
+
第五步:N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁烷甲酰胺(化合物7)
N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide
将上述粗品1-[4-[2-(氮杂环丁-3-基)乙炔基]吡唑-1-基]-N-[4-氰基-3-(三氟甲基)苯基]环丁烷甲酰胺(7e)(0.030g)溶于二甲基亚砜(3mL)中,加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(0.022g,0.080mmol)、二异丙基乙胺(0.019g,0.15mmol),反应于90℃搅拌2h。将反应液冷却至室温,加入5mL水,搅拌2min,过滤,滤饼用10mL水洗涤,收集滤饼,滤饼用二氯甲烷(30mL)溶解,有机相用10mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=3/7),得N-[4-氰基-3-(三氟甲基)苯基]-1-[4-[2-[1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]氮杂环丁-3-基]乙炔基]吡唑-1-基]环丁烷甲酰胺(化合物7)(0.010g,从化合物7d算两步产率:21%)。
1H NMR(400MHz,CDCl
3)δ8.83(s,1H),8.23(s,1H),7.97–7.91(m,1H),7.83–7.61(m,5H),6.80(d,1H),6.55(dd,1H),4.94(dd,1H),4.40–4.31(m,2H),4.11–4.00(m,2H), 3.87–3.74(m,1H),3.11–2.99(m,2H),2.96–2.67(m,5H),2.26–1.96(m,3H).
LCMS m/z=670.3[M+1]
+
实施例8:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1'-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-[1,3'-二氮杂丁]-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物8)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-碘-1H-吡唑-1-基)-2-甲基丙酰胺(8a)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanamide
将2-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(合成方法见WO2020063407)(1.72g,5.13mmol)溶于35mL乙腈中,加入4-碘-1H-吡唑(6a)(1.0g,5.15mmol)与碳酸铯(3.36g,10.30mmol),反应于50℃搅拌3h。将反应液冷却至室温,加入50mL水,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-碘-1H-吡唑-1-基)-2-甲基丙酰胺(8a)(1.5g,收率:65%)。
1H NMR(400MHz,DMSO-d
6)δ10.06(s,1H),8.26(d,1H),8.18(s,1H),8.15(dd,1H),8.08(d,1H),7.62(s,1H),1.81(s,6H).
LCMS m/z=449.0[M+1]
+
第二步:3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)-[1,3'-二氮杂环丁]-1'-甲酸叔丁酯(8b)
tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)-[1,3'-biazetidine]-1'-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-(4-碘-1H-吡唑-1-基)-2-甲基丙酰胺(8a)(224mg,0.50mmol)溶解在10mL二氯甲烷中,加入三乙胺(150mg,1.48mmol),氮气保护下依次加入PdCl
2(PPh
3)
2(35mg,0.05mmol)和碘化亚铜(10mg,0.05mmol),再慢慢滴入3-乙炔基-[1,3'-双环丁]-1'-甲酸叔丁酯(中间体B)(178mg,0.75mmol)的二氯甲烷溶液(2mL),加完后室温反应16h。向反应液中加入15mL水和10mL二氯甲烷,分液,有机层用5mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,所得粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1),得3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)-[1,3'-二氮杂环丁]-1'-甲酸叔丁酯(8b)(260mg,产率:93%)。
LCMS m/z=557.3[M+1]
+
第三步:2-(4-([1,3'-二氮杂环丁]-3-基乙炔基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(8c)
2-(4-([1,3'-biazetidin]-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide
将3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)-[1,3'-二氮杂环丁]-1'-甲酸叔丁酯(8b)(0.24g,0.43mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将反应体系直接减压浓缩,残留物用20mL 4mol/L NaOH水溶液溶解,用DCM萃取(40ml×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品2-(4-([1,3'-二氮杂环丁]-3-基乙炔基)-1H-吡唑-1-基)-N-(4- 氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(8c)(0.18g)。
LCMS m/z=457.1[M+1]
+
第四步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1'-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-[1,3'-二氮杂丁]-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物8)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品2-(4-([1,3'-二氮杂环丁]-3-基乙炔基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(8c)(0.18g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(181mg,0.66mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,用20mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1'-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-[1,3'-二氮杂丁]-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物8)(18mg,从化合物8b算两步收率:6%)。
1H NMR(400MHz,CDCl
3)δ9.47(s,1H),8.31(s,1H),7.96–7.90(m,1H),7.84–7.70(m,4H),7.64(d,1H),6.78(d,1H),6.52(dd,1H),4.92(dd,1H),4.11–4.01(m,2H),3.96–3.84(m,2H),3.83–3.63(m,3H),3.58–3.47(m,1H),3.39–3.25(m,2H),2.94–2.64(m,3H),2.17–2.07(m,1H),1.92(s,6H).
LCMS m/z=713.3[M+1]
+
实施例9:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物9)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)氮杂环丁-1-甲酸叔丁酯(9a)
tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-(4-碘-1H-吡唑-1-基)-2-甲基丙酰胺(8a)(224mg,0.50mmol)溶解在10mL二氯甲烷中,加入三乙胺(150mg,1.48mmol),氮气保护下依次加入PdCl
2(PPh
3)
2(35mg,0.05mmol)和碘化亚铜(10mg,0.05mmol),再慢慢滴入3-乙炔基氮杂环丁-1-甲酸叔丁酯(136mg,0.75mmol)的二氯甲烷溶液(2mL),加完后室温反应16h。向反应液中加入15mL水和10mL二氯甲烷,分液,有机层用5mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1),得3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)氮杂环丁-1-甲酸叔丁酯(9a)(230mg,产率:92%)。
第二步:2-(4-(氮杂环丁-3-基乙炔基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(9b)
2-(4-(azetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide
将3-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)氮杂环丁-1-甲酸叔丁酯(9a)(0.23g,0.46mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将体系直接减压浓缩,残留物用20mL 4mol/L NaOH水溶液溶解,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品2-(4-(氮杂环丁-3-基乙炔基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(9b)(0.18g)。
LCMS m/z=402.1[M+1]
+
第三步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物9)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品2-(4-(氮杂环丁-3-基乙炔基)-1H-吡唑-1-基)-N-(4-氰基-3-(三氟甲基)苯基)-2-甲基丙酰胺(9b)(0.17g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(180mg,0.65mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,用20mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁-3-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物9)(80mg,从化合物9a算两步收率:28%)。
1H NMR(400MHz,CDCl
3)δ9.49(s,1H),8.04(s,1H),7.95–7.90(m,1H),7.84–7.70(m,4H),7.67(d,1H),6.80(d,1H),6.56(dd,1H),4.94(dd,1H),4.40–4.32(m,2H),4.10–4.02(m,2H),3.86–3.75(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.92(s,6H).
LCMS m/z=658.2[M+1]
+
实施例10:
N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物10)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
第一步:4-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)哌啶-1-甲酸叔丁酯(10a)
tert-butyl 4-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)piperidine-1-carboxylate
将N-(4-氰基-3-(三氟甲基)苯基)-2-(4-碘-1H-吡唑-1-基)-2-甲基丙酰胺(8a)(224mg,0.50mmol)溶解在10mL二氯甲烷中,加入三乙胺(150mg,1.48mmol),氮气保护下依次加入PdCl
2(PPh
3)
2(35mg,0.05mmol)和碘化亚铜(10mg,0.05mmol),再慢慢滴入4-乙炔基哌啶-1-甲酸叔丁酯(170mg,0.81mmol)的二氯甲烷溶液(2mL),加完后室温反应16h。向反应液中加入15mL水和10mL二氯甲烷,分液,有机层用5mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=4:1),得4-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)哌啶-1-甲酸叔丁酯(10a)(200mg,产率:76%)。
第二步:N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基乙炔基)-1H-吡唑-1-基)丙酰胺(10b)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-ylethynyl)-1H-pyrazol-1-yl)propanamide
将4-((1-(1-((4-氰基-3-(三氟甲基)苯基)氨基)-2-甲基-1-氧代丙-2-基)-1H-吡唑-4-基)乙炔基)哌啶-1-甲酸叔丁酯(10a)(0.20g,0.38mmol)溶解到10mL DCM中,加入6mL三氟乙酸,室温搅拌3h。反应完后将反应体系直接减压浓缩,残留物用20mL 4mol/L NaOH水溶液溶解,用DCM萃取(40mL×3),有机相用50mL水洗涤,无水硫酸钠干燥,减压浓缩,得粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基乙炔基)-1H-吡唑-1-基)丙酰胺(10b)(0.16g)。
LCMS m/z=430.2[M+1]
+
第三步:N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物10)
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide
将上述粗品N-(4-氰基-3-(三氟甲基)苯基)-2-甲基-2-(4-(哌啶-4-基乙炔基)-1H-吡唑-1-基)丙酰胺(10b)(0.15g)溶于10mL DMSO中,加入0.5mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(145mg,0.53mmol),反应于80℃搅拌5h。将反应液冷却至室温,加入20mL水,过滤,收集固体,用20mL水洗涤,固体用50mL二氯甲烷溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)=15:1),得N-(4-氰基-3-(三氟甲基)苯基)-2-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)乙炔基)-1H-吡唑-1-基)-2-甲基丙酰胺(化合物10)(45mg,从化合物10a算两步收率:18%)。
1H NMR(400MHz,CDCl
3)δ9.49(s,1H),8.13(s,1H),7.96–7.90(m,1H),7.82–7.65(m,5H),7.30(d,1H),7.10(dd,1H),4.94(dd,1H),3.78–3.68(m,2H),3.39–3.28(m,2H), 2.96–2.66(m,4H),2.18–1.99(m,3H),1.92(s,6H),1.88–1.78(m,2H).
LCMS m/z=686.2[M+1]
+
生物测试例
1.抑制VCaP细胞增殖实验
前列腺癌细胞VCaP购置于ATCC,细胞培养基为1640+10%FBS,培养于37℃,5%CO
2孵箱中。第一天收集处于指数生长期的细胞,用1%css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板,使细胞为7500个/孔,铺板同时铺T0孔,培养3天。培养结束后,加入终浓度为0.1nM的R1881和不同浓度的化合物,置于孵箱中培养继续孵育7天。加药当天,同时使用CellTiter-Glo试剂盒检测T
0板,记为RLU
0。培养结束后,每孔吸出100μL培养基后,按照CellTiter-Glo试剂盒(Promega,G7573)操作说明,每孔加入50μL预先融化并平衡到室温的CellTiter-Glo试剂,用微孔板震荡器混匀2分钟,于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。结果按照式(1)处理,计算出化合物各个浓度的抑制率,并使用origin9.2软件,计算抑制率为50%时化合物的浓度GI
50值。其中RLU
compound为药物处理组的读数,RLU
control为溶剂对照组的平均值。
Inhibition%=[1-(RLU
compound-RLU
0)/(RLU
control-RLU
0)]×100% 式(1)
抑制VCaP细胞增殖的GI
50值结果见表1。
表1本发明化合物抑制VCaP细胞的GI
50值
序号 | 化合物编号 | GI 50(μM) |
1 | 化合物2 | 4.79 |
2 | 化合物3 | 3.09 |
3 | 化合物4 | 1.81 |
4 | 化合物5 | 1.91 |
5 | 化合物6 | 1.69 |
6 | 化合物7 | 0.47 |
7 | 化合物8 | 3.96 |
8 | 化合物9 | 0.18 |
9 | 化合物10 | 0.33 |
结论:本发明化合物对前列腺细胞VCaP具有抑制作用。
2.大鼠药代动力学测试
实验目的:本试验通过单剂量静脉和灌胃给予受试物于SD大鼠,测定大鼠血浆中受试物的浓度,评价受试物在大鼠体内药代特征和生物利用度。
试验动物:雄性SD大鼠,200~250g,6~8周龄,6只/化合物。购于成都达硕实验动物有限公司。
试验方法:试验当天,6只SD大鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
表2
*剂量以游离碱计。
取样:于给药前及给药后异氟烷麻醉经眼眶取血0.1mL,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。
G1和G2组采集血浆时间点:0,5min,15min,30min,1,2,4,6,8,24h。
分析检测前,所有样品存于-80℃。用LC-MS/MS对样品进行定量分析。
表3本发明化合物在大鼠血浆中药代动力学参数
*注:i.g.(灌胃)给予化合物;
结论:运用本发明化合物在大鼠体内具有一定的口服生物利用度。
3.抑制22RV1细胞增殖实验
前列腺癌细胞22RV1购置于ATCC,细胞培养基为RPMI 1640+10%FBS,培养于37℃,5%CO
2孵箱中。第一天收集处于指数生长期的细胞,用1%css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板,使细胞为2000个/孔,孵育过夜。第二天加入不同浓度的化合物,置于孵箱中培养继续孵育7天。培养结束后,按照CellTiter-Glo试剂盒(Promega,G7573)操作说明,每孔加入50μL预先融化并平衡到室温的CellTiter-Glo试剂,用微孔板震荡器混匀2分钟,于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。结果按照式(2)处理,计算出化合物各个浓度的抑制率,并使用origin9.2软件,采用DoseResp函数计算化合物抑制率为50%的IC
50值。其中RLU
compound为药物处理组的读数,RLU
control为DMSO溶剂对照组的平均值。
Inhibition%=[1-RLU
compound/RLU
control]×100% 式(2)
抑制22RV1细胞增殖的IC
50值结果见表4。
表4本发明化合物抑制22RV1细胞的IC50值
序号 | 化合物编号 | IC 50(μM) |
1 | 化合物9 | 0.078 |
结论:本发明化合物对前列腺细胞22RV1具有抑制作用。
4. 22RV1细胞中全长AR(AR-FL)及AR剪切突变体(AR-Vs)的降解实验
前列腺癌细胞22RV1购置于ATCC,细胞培养基为1640+10%FBS,培养于37℃,5%CO
2孵箱中。第一天收集处于指数生长期的细胞,用1%css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板,6孔板每孔1mL,细胞数量为100000个/孔。次日加入含待测化合物的1%css-FBS无酚红培养基,其中一个孔加入0.2%DMSO的1%css-FBS无酚红培养基作为DMSO溶媒对照,6孔板培养于37℃,5%CO
2孵箱中。24小时后,胰酶消化,收集细胞于1.5mL离心管,向每孔加入15μL RIPA裂解液(含1X蛋白酶抑制剂混合物(Protease Inhibitor cocktail)),于冰上裂解15分钟后,12000g,4℃,离心10分钟。收集上清蛋白样品,用BCA法进行蛋白定量。使用全自动蛋白质表达定量分析检测AR-FL及AR-Vs,实验过程如下,将待测蛋白浓度稀释至1mg/mL。取4μL稀释后的蛋白样品加入1μL 5×Master Mix(试剂盒提供),将配制好的样品放在95℃变性5分钟,放在冰上待用。使用Antibody Diluent II(试剂盒提供)稀释一抗,一抗为AR(CST,5153S)与β-actin(CST,3700),稀释比例分别为1:20和1:200。二抗为1:1混合羊抗小鼠和羊抗兔二抗,显色液为1:1混合的Lumino-S和Peroxide。按照试剂盒说明书将配制好的试剂依次加入检测板内,上机检测。Western条带处理使用全自动蛋白质表达定量分析软件“Compass for SW”根据信号值自动模拟western条带。根据式(1)(2)计算不同药物浓度下,AR-FL(1)或AR-Vs(2)相对于溶媒对照的降解率。其中AR-FL
compound为给药组AR-FL相对峰面积,AR-FL
solvent为溶媒对照组AR-FL相对峰面积。AR-Vs
compound为给药组AR-Vs相对峰面积,AR-Vs
solvent为溶媒对照组AR-Vs相对峰面积。
AR-FL降解率=(1-AR-FL
compound/AR-FL
solvent)×100% 式(1)
AR-Vs降解率=(1-AR-Vs
compound/AR-Vs
solvent)×100% 式(2)
DC
50计算:按照式(1)或(2)处理,使用OriginPro2015软件计算并采用DoseResp函数分析AR-FL或AR-Vs降解率为50%时的化合物浓度DC
50值。
结论:本发明化合物对前列腺细胞22RV1中AR-FL或AR-Vs具有一定的降解作用。
Claims (12)
- 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,化合物选自通式(I)所示的化合物,B-L-K(I);L选自-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;Ak1、Ak2、Ak3、Ak4和Ak5各自独立的选自CH 2、O、C≡C或者键;Cy1、Cy2、Cy3、Cy4各自独立的选自键、4-7元杂单环、5-10元杂并环、6-12元杂螺环、7-10元杂桥环、4-7元单环烷基、5-10元并环烷基、6-12元螺环烷基、7-10元桥环烷基、5-10元杂芳基或6-10元芳基,所述芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环任选进一步被0至4个选自H、F、Cl、Br、I、OH、COOH、CN、NH 2、oxo、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代,所述的杂芳基、杂单环、杂并环、杂螺环或杂桥环含有1至4个选自O、S、N的杂原子;B 1选自取代或未取代的如下基团之一:6元芳基或6元杂芳基,当被取代时,任选进一步被0至4个R b1所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;B 2选自取代或未取代的如下基团之一:5-10元杂环基或-NHC(=O)-,当被取代时,任选进一步被0至4个选自R b2所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;B 3选自取代或未取代的5-6元芳基或键,当所述5-6元芳基被取代时,任选进一步被0至4个R b2所取代;R b1、R b2各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基,所述的烷基或者烷氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;R b3、R b4各自独立的选自H或C 1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;或R b3、R b4与其相连接的碳原子共同形成C 3-6环烷基或C 3-6杂单环,所述的环烷基或杂单环任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、C 1-4烷基或C 1-4烷氧 基的取代基所取代,所述的杂单环含有1至4个选自O、S、N的杂原子;环E或F各自的独立的选自苯环或者5-6元的杂芳环,所述的杂芳环含有1至2个选自O、S、N的杂原子;R k2各自独立的选自CH 2、C=O、S=O、SO 2;R k1、R k3或R k4各自独立的选自H、F、Cl、Br、I、OH、NH 2、CF 3、CN、COOH、C 1-4烷基或C 1-4烷氧基;M 1选自键、-CH 2-C(=O)NH-或-C(=O)CH 2NH-;M 2选自-NHC(=O)-C 1-6烷基或-NHC(=O)-C 3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;M 3选自-NH-或-O-;R k6选自C 1-6烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C 1-6烷基或C 3-6环烷基的取代基所取代;R k7各自独立的选自H、F、Cl、Br、I、OH、SH、C 1-6烷基、C 1-6烷氧基或C 1-6烷硫基、C 1-6烷基甲酰氧基,所述的烷基、烷氧基或烷硫基任选进一步被0至4个选自H、F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k8、R k9各自独立的选自H、C 1-6烷基或C 3-6环烷基,所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k10选自5-6元杂芳基,所述的杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF 3、CN、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代;G选自6-10元芳基或5-10元杂芳基,所述的芳基或者杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、OH、CF 3、CN、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代;p1或p2各自独立的选自0、1、2、3或4。
- 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中Cy1、Cy2、Cy3和Cy4各自独立的选自键或取代的或者未取代的如下基团之一:氮杂环丁基、氮杂环戊基、氮杂环己基、哌啶、吗啉、哌嗪、环丙基并氮杂环丁基、环丙基并氮杂环戊基、环丙基并氮杂环己基、环丙基并哌啶、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环已基、环丁基并哌啶、环戊基并氮杂环丁基、环戊基并氮杂环戊基、环戊基并氮杂环已基、环戊基并哌啶、环已基并氮杂环丁基、环已基并氮杂环戊基、环已基并氮杂环已基、环己基并哌啶、氮杂环丁基并氮杂环丁基、氮杂环丁基并氮杂环戊基、氮杂环丁基并氮杂环已基、氮杂环丁基并哌啶、氮杂环戊基并氮杂环丁基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环已基、氮杂环戊基并哌啶、氮杂环已基并氮杂环丁基、氮杂环已基并氮杂环戊基、氮杂环已基并氮杂环已基、氮杂环己基并哌啶、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环已基、环戊基螺氮杂环丁基、环戊基螺氮杂环戊基、环戊基螺氮杂环已基、环已基螺氮杂环丁基、环已基螺氮杂环戊基、环已基螺氮杂环已基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺氮杂环戊基、氮杂环丁基螺氮杂环已基、氮杂环戊基螺氮杂环丁基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环已基、氮杂环已基螺氮杂环丁基、氮杂环已基螺氮杂环戊基、氮杂环已基螺氮杂环已基、环丁基螺哌啶、环戊基螺哌啶、环己基螺哌啶、氮杂环丁基螺哌啶、氮杂环戊基螺哌啶、氮杂环己基螺哌啶、当被取代时,任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、COOH、CN、oxo、C 1-4烷基、卤素取代的C 1-4烷基、羟基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代;R b1、R b2各自独立的选自H、F、Cl、Br、I、OH、NH 2、CN、CF 3、-C(=O)NH 2、-C(=O)NH-CH 3、-C(=O)N(CH 3) 2、甲基、乙基、丙基、异丙基、甲氧基或乙氧基,所述的甲基、乙基、丙基、异丙基、甲氧基或乙氧基任选进一步被0至4个选自H、F、Cl、Br、I或OH的取代基所取代;R k2各自独立的选自CH 2或C=O;R k1、R k3或R k4各自独立的选自H、CH 3、F、Cl、Br、I、OH或NH 2;M 1选自键、-CH 2-C(=O)NH-或-C(=O)CH 2NH-;M 2选自-NHC(=O)-甲基、-NHC(=O)-乙基、-NHC(=O)-环丙基、-NHC(=O)-环丁基、-NHC(=O)-环戊基或-NHC(=O)-环已基,所述的甲基、乙基、环丙基、环丁基、环戊基或环已基任选进一步被0至4个选自H、F、Cl、Br、I、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代;R k6选自甲基、乙基、丙基、异丙基、叔丁基、异丁基或仲丁基;R k7各自独立的选自H、F、OH、SH、甲基、甲氧基或-SCH 3;R k8、R k9各自独立的选自H、甲基、乙基、环丙基或环丁基;p1或p2各自独立的选自0、1或2。
- 一种药物组合物,包括权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体。
- 根据权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与AR活性或表达量相关疾病的药物中的应用。
- 根据权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与抑制或降解AR相关疾病的药物中的应用。
- 根据权利要求11所述的应用,其特征在于,所述的疾病选自前列腺癌。
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WO2024012570A1 (zh) * | 2022-07-15 | 2024-01-18 | 西藏海思科制药有限公司 | 一种含氮杂环衍生物及其组合物和药学上的应用 |
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WO2024012570A1 (zh) * | 2022-07-15 | 2024-01-18 | 西藏海思科制药有限公司 | 一种含氮杂环衍生物及其组合物和药学上的应用 |
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