WO2021249463A1 - 双环化合物及其应用 - Google Patents
双环化合物及其应用 Download PDFInfo
- Publication number
- WO2021249463A1 WO2021249463A1 PCT/CN2021/099316 CN2021099316W WO2021249463A1 WO 2021249463 A1 WO2021249463 A1 WO 2021249463A1 CN 2021099316 W CN2021099316 W CN 2021099316W WO 2021249463 A1 WO2021249463 A1 WO 2021249463A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tetrahydro
- difluoro
- trifluoromethyl
- indol
- fluorophenyl
- Prior art date
Links
- -1 Bicyclic compound Chemical class 0.000 title claims description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 478
- 238000002360 preparation method Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 106
- 150000002367 halogens Chemical class 0.000 claims description 105
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 48
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 44
- 125000004043 oxo group Chemical group O=* 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 239000000651 prodrug Substances 0.000 claims description 34
- 229940002612 prodrug Drugs 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 31
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 239000013522 chelant Substances 0.000 claims description 25
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 16
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 15
- 229910052805 deuterium Inorganic materials 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 208000006542 von Hippel-Lindau disease Diseases 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 6
- HJDMPKDROSFLTO-UHFFFAOYSA-N 3-fluoro-5-(3-methylsulfonyl-4-oxo-6,7-dihydro-5H-indol-1-yl)benzonitrile Chemical compound CS(C(C1=C2CCCC1=O)=CN2C1=CC(C#N)=CC(F)=C1)(=O)=O HJDMPKDROSFLTO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 206010018338 Glioma Diseases 0.000 claims description 5
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 206010027191 meningioma Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 208000028591 pheochromocytoma Diseases 0.000 claims description 5
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 5
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 4
- OWTPKELUPCGLEE-UHFFFAOYSA-N 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=CC=C1 OWTPKELUPCGLEE-UHFFFAOYSA-N 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010061332 Paraganglion neoplasm Diseases 0.000 claims description 4
- 208000007312 paraganglioma Diseases 0.000 claims description 4
- JQPIJXGXGZVAAE-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(CCC1)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC(F)=C1 JQPIJXGXGZVAAE-UHFFFAOYSA-N 0.000 claims description 3
- FARZICHMFLAREO-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C=C2)=C1N2C1=CC(F)=CC(F)=C1 FARZICHMFLAREO-UHFFFAOYSA-N 0.000 claims description 3
- MYJSTICDELZOLB-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-3-ethenyl-5,5-difluoro-6,7-dihydro-4H-indol-4-ol Chemical compound C=CC(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1 MYJSTICDELZOLB-UHFFFAOYSA-N 0.000 claims description 3
- BMODBEUQGLTKPH-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-6,7-dihydro-4H-indole-3-carbonitrile Chemical compound N#CC(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1 BMODBEUQGLTKPH-UHFFFAOYSA-N 0.000 claims description 3
- NRHGFLQQJZLCBB-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-3-(2-methylpyrazol-3-yl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound CN1N=CC=C1C1=CN(CC(C=C2)=CC=C2F)C(CCC2)=C1C2O NRHGFLQQJZLCBB-UHFFFAOYSA-N 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000000172 Medulloblastoma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- VRCADQNIMFDTJC-KRWDZBQOSA-N (4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-thiophen-2-yl-6,7-dihydro-4H-indol-4-ol Chemical compound O[C@H](C(CC1)(F)F)C(C(C2=CC=CS2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 VRCADQNIMFDTJC-KRWDZBQOSA-N 0.000 claims description 2
- PUJOXDUJMBSJHZ-ZDUSSCGKSA-N (4S)-1-[3-(difluoromethyl)-4-fluorophenyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound O[C@H](C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)F)=C1F PUJOXDUJMBSJHZ-ZDUSSCGKSA-N 0.000 claims description 2
- ARAIKDHPAOUXQU-LBPRGKRZSA-N (4S)-2-bromo-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound O[C@H](C(CC1)(F)F)C(C(C(F)(F)F)=C2Br)=C1N2C1=CC(F)=CC(F)=C1 ARAIKDHPAOUXQU-LBPRGKRZSA-N 0.000 claims description 2
- ZZCHORMZYBEKTO-LBPRGKRZSA-N (4S)-2-chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound O[C@H](C(CC1)(F)F)C(C(C(F)(F)F)=C2Cl)=C1N2C1=CC(Cl)=CC(F)=C1 ZZCHORMZYBEKTO-LBPRGKRZSA-N 0.000 claims description 2
- JZMRIIVZCYSWEI-SMDDNHRTSA-N (4S,5S)-1-[3-(difluoromethyl)-4-fluorophenyl]-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound O[C@H]([C@H](CC1)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)F)=C1F JZMRIIVZCYSWEI-SMDDNHRTSA-N 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- DPPHNCGGFCAZGX-UHFFFAOYSA-N 1,1-difluorocyclobutane Chemical compound FC1(F)CCC1 DPPHNCGGFCAZGX-UHFFFAOYSA-N 0.000 claims description 2
- KJWMRCRZANYIHY-UHFFFAOYSA-N 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=NC=C1 KJWMRCRZANYIHY-UHFFFAOYSA-N 0.000 claims description 2
- NDZGMQADMPWFCX-UHFFFAOYSA-N 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C2=C1N(C(C1)CC1(F)F)C=C2C(F)(F)F NDZGMQADMPWFCX-UHFFFAOYSA-N 0.000 claims description 2
- DBZXLNRYBJTPOL-UHFFFAOYSA-N 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydro-4H-indol-4-ol Chemical compound CS(C1=CN(C(C2)CC2(F)F)C(CCC2(F)F)=C1C2O)(=O)=O DBZXLNRYBJTPOL-UHFFFAOYSA-N 0.000 claims description 2
- GMHXICRGHXMWCU-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(F)=C1F GMHXICRGHXMWCU-UHFFFAOYSA-N 0.000 claims description 2
- SDABYVFSRPBZQJ-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(Cl)=C1 SDABYVFSRPBZQJ-UHFFFAOYSA-N 0.000 claims description 2
- QRPVETFUGMTZMF-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-3-(2-methylpyrazol-3-yl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound CN1N=CC=C1C(C1=C2CCCC1O)=CN2C1=CC(F)=CC(F)=C1 QRPVETFUGMTZMF-UHFFFAOYSA-N 0.000 claims description 2
- DNITXUIJGQNYGU-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC(F)=C1 DNITXUIJGQNYGU-UHFFFAOYSA-N 0.000 claims description 2
- JERWFADLNHKHPA-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC(F)=C1 JERWFADLNHKHPA-UHFFFAOYSA-N 0.000 claims description 2
- FQXQWPCLLDVWCD-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydro-4H-indol-4-ol Chemical compound CS(C(C(C1O)=C2CCC1(F)F)=CN2C1=CC(F)=CC(F)=C1)(=O)=O FQXQWPCLLDVWCD-UHFFFAOYSA-N 0.000 claims description 2
- HRPPKBFEGQKJGV-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydroindol-4-one Chemical compound CS(C(C(C1=O)=C2CCC1(F)F)=CN2C1=CC(F)=CC(F)=C1)(=O)=O HRPPKBFEGQKJGV-UHFFFAOYSA-N 0.000 claims description 2
- RVGBIKZHDMQGOU-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-3-thiophen-2-yl-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CC=CS2)=C2)=C1N2C1=CC(F)=CC(F)=C1 RVGBIKZHDMQGOU-UHFFFAOYSA-N 0.000 claims description 2
- QRVVPKIZYIAERA-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-5,5-difluoro-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C=C2)=C1N2C1=CC(F)=CC(F)=C1 QRVVPKIZYIAERA-UHFFFAOYSA-N 0.000 claims description 2
- KVMJRHSYGWBOCO-UHFFFAOYSA-N 1-(3-amino-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound NC1=CC(F)=CC(N2C(CCC(C3O)F)=C3C(C(F)(F)F)=C2)=C1 KVMJRHSYGWBOCO-UHFFFAOYSA-N 0.000 claims description 2
- ATFMLOOMNFNRJX-UHFFFAOYSA-N 1-(3-bromo-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Br)=CC(F)=C1 ATFMLOOMNFNRJX-UHFFFAOYSA-N 0.000 claims description 2
- HWNVNQKNKSAKPV-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(Cl)=C1F HWNVNQKNKSAKPV-UHFFFAOYSA-N 0.000 claims description 2
- NGSGKLGYFIDMQK-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-3,5,5-trifluoro-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 NGSGKLGYFIDMQK-UHFFFAOYSA-N 0.000 claims description 2
- MPIPQIGLOBBYJG-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 MPIPQIGLOBBYJG-UHFFFAOYSA-N 0.000 claims description 2
- SZPNIABXSPDHEE-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-5H-indol-4-one Chemical compound O=C(CCC1)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 SZPNIABXSPDHEE-UHFFFAOYSA-N 0.000 claims description 2
- UXOYIFSWPIRDJF-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-3-cyclopropyl-5,5-difluoro-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2CC2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 UXOYIFSWPIRDJF-UHFFFAOYSA-N 0.000 claims description 2
- OLOORRKKNFGRFF-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1,3-thiazol-4-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CSC=N2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 OLOORRKKNFGRFF-UHFFFAOYSA-N 0.000 claims description 2
- ZIBYEVAZJIVBHI-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1,3-thiazol-5-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CN=CS2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 ZIBYEVAZJIVBHI-UHFFFAOYSA-N 0.000 claims description 2
- CYHGNZGOSJKPLS-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methylpyrrol-2-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound CN1C(C(C(C2O)=C3CCC2(F)F)=CN3C2=CC(Cl)=CC(F)=C2)=CC=C1 CYHGNZGOSJKPLS-UHFFFAOYSA-N 0.000 claims description 2
- BRYIHISMNPXMAI-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(2-methylpyrazol-3-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound CN1N=CC=C1C(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1 BRYIHISMNPXMAI-UHFFFAOYSA-N 0.000 claims description 2
- QFZKDXTUPJDCSE-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(5-methyl-1H-pyrazol-3-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound CC1=CC(C(C(C2O)=C3CCC2(F)F)=CN3C2=CC(Cl)=CC(F)=C2)=NN1 QFZKDXTUPJDCSE-UHFFFAOYSA-N 0.000 claims description 2
- BFTRWLDQFMWUCQ-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-2-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CC=CO2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 BFTRWLDQFMWUCQ-UHFFFAOYSA-N 0.000 claims description 2
- VTZGCLSJRIAYQC-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=COC=C2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 VTZGCLSJRIAYQC-UHFFFAOYSA-N 0.000 claims description 2
- CVBIKHPMENRAHN-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C2=COC=C2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 CVBIKHPMENRAHN-UHFFFAOYSA-N 0.000 claims description 2
- GXKOXOAJXPCBRD-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OCC(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1 GXKOXOAJXPCBRD-UHFFFAOYSA-N 0.000 claims description 2
- BDCLUKYZPPQCHA-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 BDCLUKYZPPQCHA-UHFFFAOYSA-N 0.000 claims description 2
- AZKSCEQYCRYJAH-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 AZKSCEQYCRYJAH-UHFFFAOYSA-N 0.000 claims description 2
- ZYQBIFFHWXVMJT-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(I)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 ZYQBIFFHWXVMJT-UHFFFAOYSA-N 0.000 claims description 2
- QOJHKUOAIFGVHA-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(I)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 QOJHKUOAIFGVHA-UHFFFAOYSA-N 0.000 claims description 2
- GFAPAROTKTYTCU-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methyl-6,7-dihydro-4H-indol-4-ol Chemical compound CC(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1 GFAPAROTKTYTCU-UHFFFAOYSA-N 0.000 claims description 2
- CGUUWCILGCLKGI-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methylsulfonyl-6,7-dihydro-4H-indol-4-ol Chemical compound CS(C(C(C1O)=C2CCC1(F)F)=CN2C1=CC(Cl)=CC(F)=C1)(=O)=O CGUUWCILGCLKGI-UHFFFAOYSA-N 0.000 claims description 2
- DDFJGEUKJOPXOC-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CC=CC=C2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 DDFJGEUKJOPXOC-UHFFFAOYSA-N 0.000 claims description 2
- QKNNNIUTYLXKJY-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C2=CC=CC=C2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 QKNNNIUTYLXKJY-UHFFFAOYSA-N 0.000 claims description 2
- LNQMPIPTKMPYJW-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-thiophen-3-yl-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C2=CSC=C2)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 LNQMPIPTKMPYJW-UHFFFAOYSA-N 0.000 claims description 2
- DCTDHRBRZDQVLW-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(C(C(C1)F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 DCTDHRBRZDQVLW-UHFFFAOYSA-N 0.000 claims description 2
- MKTWEYSHUZAICE-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-methylsulfonyl-4,5,6,7-tetrahydroindol-4-ol Chemical compound CS(C(C(C(C1F)O)=C2CC1F)=CN2C1=CC(Cl)=CC(F)=C1)(=O)=O MKTWEYSHUZAICE-UHFFFAOYSA-N 0.000 claims description 2
- LJJCBSJMEYRCHC-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(C(CC1F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 LJJCBSJMEYRCHC-UHFFFAOYSA-N 0.000 claims description 2
- LZSDVNZRPOGMMF-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(C(CC1)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CC(F)=C1 LZSDVNZRPOGMMF-UHFFFAOYSA-N 0.000 claims description 2
- HBWNBSNLVRNMGC-UHFFFAOYSA-N 1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-6,7-dihydro-4H-indole-3-carbonitrile Chemical compound N#CC(C(C1O)=C2CCC1(F)F)=CN2C(C=C1)=CC(C#N)=C1F HBWNBSNLVRNMGC-UHFFFAOYSA-N 0.000 claims description 2
- QCFIUXHYHHFZSR-UHFFFAOYSA-N 1-(4-chloro-3-nitrophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound [O-][N+](C(C=C(C=C1)N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1Cl)=O QCFIUXHYHHFZSR-UHFFFAOYSA-N 0.000 claims description 2
- UXWRVWAVTRSPBT-UHFFFAOYSA-N 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC=C1Cl UXWRVWAVTRSPBT-UHFFFAOYSA-N 0.000 claims description 2
- WPEWRWXEHCUZEO-UHFFFAOYSA-N 1-(4-chlorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(C(C(C1)F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC=C1Cl WPEWRWXEHCUZEO-UHFFFAOYSA-N 0.000 claims description 2
- QNSOTWXVUZVTAL-UHFFFAOYSA-N 1-(5-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(Cl)=CN=C1 QNSOTWXVUZVTAL-UHFFFAOYSA-N 0.000 claims description 2
- OKRGIUJNBJDTSU-UHFFFAOYSA-N 1-(benzenesulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(CCC1)C(C(C(F)(F)F)=C2)=C1N2S(C1=CC=CC=C1)(=O)=O OKRGIUJNBJDTSU-UHFFFAOYSA-N 0.000 claims description 2
- QBDUOCZKUFASIV-UHFFFAOYSA-N 1-(benzenesulfonyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2S(C1=CC=CC=C1)(=O)=O QBDUOCZKUFASIV-UHFFFAOYSA-N 0.000 claims description 2
- IOXAGCSADXETRE-UHFFFAOYSA-N 1-(benzenesulfonyl)-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2S(C1=CC=CC=C1)(=O)=O IOXAGCSADXETRE-UHFFFAOYSA-N 0.000 claims description 2
- ZLCYJHSPFMVCOR-UHFFFAOYSA-N 1-[(3-chloro-5-fluorophenyl)methyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C2=C1N(CC1=CC(Cl)=CC(F)=C1)C=C2C(F)(F)F ZLCYJHSPFMVCOR-UHFFFAOYSA-N 0.000 claims description 2
- KDKTZLWYBVNOHG-UHFFFAOYSA-N 1-[(3-chloro-5-fluorophenyl)methyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C2=C1N(CC1=CC(Cl)=CC(F)=C1)C=C2C(F)(F)F KDKTZLWYBVNOHG-UHFFFAOYSA-N 0.000 claims description 2
- VBTXQVQGYKRJBK-VQHVLOKHSA-N 1-[(E)-2-cyclohexylethenyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C2=C1N(/C=C/C1CCCCC1)C=C2C(F)(F)F VBTXQVQGYKRJBK-VQHVLOKHSA-N 0.000 claims description 2
- NCSSPPSLGGISNS-VQHVLOKHSA-N 1-[(E)-2-cyclohexylethenyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C2=C1N(/C=C/C1CCCCC1)C=C2C(F)(F)F NCSSPPSLGGISNS-VQHVLOKHSA-N 0.000 claims description 2
- HCEKBNQYTJYPLR-UHFFFAOYSA-N 1-[3-(difluoromethyl)-4-fluorophenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(CCC1)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)F)=C1F HCEKBNQYTJYPLR-UHFFFAOYSA-N 0.000 claims description 2
- KDYUYUYPCUGEFD-UHFFFAOYSA-N 1-[3-(difluoromethyl)-4-fluorophenyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)F)=C1F KDYUYUYPCUGEFD-UHFFFAOYSA-N 0.000 claims description 2
- OJMAGSKYUKCFRE-UHFFFAOYSA-N 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C2=C1N(C1CCCCC1)C=C2C(F)(F)F OJMAGSKYUKCFRE-UHFFFAOYSA-N 0.000 claims description 2
- OTXQDMGXYWAYRC-UHFFFAOYSA-N 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C2=C1N(C1CCCCC1)C=C2C(F)(F)F OTXQDMGXYWAYRC-UHFFFAOYSA-N 0.000 claims description 2
- CFMITBQBUDXBKU-UHFFFAOYSA-N 2-chloro-4-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC(C=CC(N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1)=C1)=C1Cl CFMITBQBUDXBKU-UHFFFAOYSA-N 0.000 claims description 2
- MAPWVLGAYPAROJ-UHFFFAOYSA-N 2-chloro-5-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC(C=C(C=C1)N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1Cl MAPWVLGAYPAROJ-UHFFFAOYSA-N 0.000 claims description 2
- FFMKLYPHOLTRRV-UHFFFAOYSA-N 2-cyano-5-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzoic acid Chemical compound N#CC(C=CC(N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1)=C1)=C1C(O)=O FFMKLYPHOLTRRV-UHFFFAOYSA-N 0.000 claims description 2
- TYMVYFSDXWCFCZ-UHFFFAOYSA-N 2-fluoro-5-[4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-1-yl]benzonitrile Chemical compound N#CC(C=C(C=C1)N2C(CCCC3O)=C3C(C(F)(F)F)=C2)=C1F TYMVYFSDXWCFCZ-UHFFFAOYSA-N 0.000 claims description 2
- JLLLOUWOUGZUBF-UHFFFAOYSA-N 2-fluoro-5-[5-fluoro-4-oxo-3-(trifluoromethyl)-6,7-dihydro-5H-indol-1-yl]benzaldehyde Chemical compound O=CC(C=C(C=C1)N(C=C2C(F)(F)F)C(CCC3F)=C2C3=O)=C1F JLLLOUWOUGZUBF-UHFFFAOYSA-N 0.000 claims description 2
- MJFBAFHGZZAFKF-UHFFFAOYSA-N 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydroindol-7-ol Chemical compound OC(C(C(C1)F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=CN2C(F)(F)F MJFBAFHGZZAFKF-UHFFFAOYSA-N 0.000 claims description 2
- ZXYCNSHHDRLGMT-UHFFFAOYSA-N 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-5,7-dihydro-4H-indol-7-ol Chemical compound OC(C(CC1)(F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=CN2C(F)(F)F ZXYCNSHHDRLGMT-UHFFFAOYSA-N 0.000 claims description 2
- VMDZCFTYFMITGP-UHFFFAOYSA-N 3-(5,5-difluoro-4-hydroxy-3-methylsulfonyl-6,7-dihydro-4H-indol-1-yl)-5-fluorobenzonitrile Chemical compound CS(C(C(C1O)=C2CCC1(F)F)=CN2C1=CC(F)=CC(C#N)=C1)(=O)=O VMDZCFTYFMITGP-UHFFFAOYSA-N 0.000 claims description 2
- LDKFUPVYEMBUON-UHFFFAOYSA-N 3-[3-(difluoromethyl)-5,5-difluoro-4-hydroxy-6,7-dihydro-4H-indol-1-yl]-5-fluorobenzonitrile Chemical compound N#CC1=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)F)=C2)=CC(F)=C1 LDKFUPVYEMBUON-UHFFFAOYSA-N 0.000 claims description 2
- CYXYMVWEZSHYMC-UHFFFAOYSA-N 3-[3-(difluoromethylsulfonyl)-5,5-difluoro-4-hydroxy-6,7-dihydro-4H-indol-1-yl]-5-fluorobenzonitrile Chemical compound N#CC1=CC(N2C(CCC(C3O)(F)F)=C3C(S(C(F)F)(=O)=O)=C2)=CC(F)=C1 CYXYMVWEZSHYMC-UHFFFAOYSA-N 0.000 claims description 2
- UYPGMKDIAVUMBA-UHFFFAOYSA-N 3-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]-5-fluorobenzonitrile Chemical compound N#CC1=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=CC(F)=C1 UYPGMKDIAVUMBA-UHFFFAOYSA-N 0.000 claims description 2
- MNXWEGXJLNUMKO-UHFFFAOYSA-N 3-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC1=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=CC=C1 MNXWEGXJLNUMKO-UHFFFAOYSA-N 0.000 claims description 2
- OOCYTSALXHBEBS-UHFFFAOYSA-N 3-chloro-5-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC1=CC(Cl)=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1 OOCYTSALXHBEBS-UHFFFAOYSA-N 0.000 claims description 2
- HWSKBAWSQHPVHO-UHFFFAOYSA-N 3-fluoro-5-(4-hydroxy-3-methylsulfonyl-4,5,6,7-tetrahydroindol-1-yl)benzonitrile Chemical compound CS(C(C1=C2CCCC1O)=CN2C1=CC(C#N)=CC(F)=C1)(=O)=O HWSKBAWSQHPVHO-UHFFFAOYSA-N 0.000 claims description 2
- BNUSZXUWTSZETQ-UHFFFAOYSA-N 3-fluoro-5-(5-fluoro-4-hydroxy-3-methylsulfonyl-4,5,6,7-tetrahydroindol-1-yl)benzonitrile Chemical compound CS(C(C(C1O)=C2CCC1F)=CN2C1=CC(C#N)=CC(F)=C1)(=O)=O BNUSZXUWTSZETQ-UHFFFAOYSA-N 0.000 claims description 2
- VJQRROXUYCCQHE-UHFFFAOYSA-N 3-fluoro-5-[4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-1-yl]benzonitrile Chemical compound N#CC1=CC(F)=CC(N2C(CCCC3O)=C3C(C(F)(F)F)=C2)=C1 VJQRROXUYCCQHE-UHFFFAOYSA-N 0.000 claims description 2
- LAIFACPEYLVLCO-UHFFFAOYSA-N 3-fluoro-5-[4-oxo-3-(trifluoromethyl)-6,7-dihydro-5H-indol-1-yl]benzonitrile Chemical compound N#CC1=CC(F)=CC(N(C=C2C(F)(F)F)C(CCC3)=C2C3=O)=C1 LAIFACPEYLVLCO-UHFFFAOYSA-N 0.000 claims description 2
- RYZWDZMBOZZANL-UHFFFAOYSA-N 3-fluoro-5-[5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-1-yl]benzonitrile Chemical compound N#CC1=CC(F)=CC(N2C(CCC(C3O)F)=C3C(C(F)(F)F)=C2)=C1 RYZWDZMBOZZANL-UHFFFAOYSA-N 0.000 claims description 2
- FKBIOZPUWQJQEK-UHFFFAOYSA-N 4-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]-2-fluorobenzonitrile Chemical compound N#CC(C=CC(N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1)=C1)=C1F FKBIOZPUWQJQEK-UHFFFAOYSA-N 0.000 claims description 2
- OIPSSBYSXNSWHH-UHFFFAOYSA-N 4-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzene-1,2-dicarbonitrile Chemical compound N#CC(C(C#N)=C1)=CC=C1N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1 OIPSSBYSXNSWHH-UHFFFAOYSA-N 0.000 claims description 2
- CXVCOQAOWMBPBR-UHFFFAOYSA-N 4-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC(C=C1)=CC=C1N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1 CXVCOQAOWMBPBR-UHFFFAOYSA-N 0.000 claims description 2
- PHPCFGOXOSIFMX-UHFFFAOYSA-N 4-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]pyridine-2-carbonitrile Chemical compound N#CC1=NC=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1 PHPCFGOXOSIFMX-UHFFFAOYSA-N 0.000 claims description 2
- DQWXLBHALGRYJR-UHFFFAOYSA-N 5,5-difluoro-1-(2-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=CC=C1)=C1F DQWXLBHALGRYJR-UHFFFAOYSA-N 0.000 claims description 2
- SLCIMUJOJHCAQU-UHFFFAOYSA-N 5,5-difluoro-1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=NC=C1 SLCIMUJOJHCAQU-UHFFFAOYSA-N 0.000 claims description 2
- AMOAUBZHJNPOFX-UHFFFAOYSA-N 5,5-difluoro-1-(2-methoxypyridin-4-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound COC1=NC=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1 AMOAUBZHJNPOFX-UHFFFAOYSA-N 0.000 claims description 2
- HHUVRDUWYHJMPC-UHFFFAOYSA-N 5,5-difluoro-1-(3-fluoro-5-hydroxyphenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC(O)=C1 HHUVRDUWYHJMPC-UHFFFAOYSA-N 0.000 claims description 2
- NGCCTTRQANEQKE-UHFFFAOYSA-N 5,5-difluoro-1-(3-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC=C1 NGCCTTRQANEQKE-UHFFFAOYSA-N 0.000 claims description 2
- LTJININOLSNABD-UHFFFAOYSA-N 5,5-difluoro-1-(3-methylsulfonylphenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound CS(C1=CC=CC(N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1)(=O)=O LTJININOLSNABD-UHFFFAOYSA-N 0.000 claims description 2
- SHRONZVDINPEBR-UHFFFAOYSA-N 5,5-difluoro-1-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound CC(C=C(C=C1)N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1F SHRONZVDINPEBR-UHFFFAOYSA-N 0.000 claims description 2
- HVKXMAYQNLTIGA-UHFFFAOYSA-N 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC=C1F HVKXMAYQNLTIGA-UHFFFAOYSA-N 0.000 claims description 2
- PFURHCJELWCJRH-UHFFFAOYSA-N 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indole-4-carbonitrile Chemical compound N#CC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC=C1F PFURHCJELWCJRH-UHFFFAOYSA-N 0.000 claims description 2
- DFWDPMSDTSSMOX-UHFFFAOYSA-N 5,5-difluoro-1-(4-methylphenyl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound CC(C=C1)=CC=C1N1C(CCC(C2O)(F)F)=C2C(C(F)(F)F)=C1 DFWDPMSDTSSMOX-UHFFFAOYSA-N 0.000 claims description 2
- MOMGYOUDVFNGSZ-UHFFFAOYSA-N 5,5-difluoro-1-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=NC=C1F MOMGYOUDVFNGSZ-UHFFFAOYSA-N 0.000 claims description 2
- DTPXVUPFQLCXHC-UHFFFAOYSA-N 5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CN=C1 DTPXVUPFQLCXHC-UHFFFAOYSA-N 0.000 claims description 2
- FURCIOBOSFGHFP-UHFFFAOYSA-N 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=NC(F)=CC=C1 FURCIOBOSFGHFP-UHFFFAOYSA-N 0.000 claims description 2
- RVNWFINYFHIZTG-UHFFFAOYSA-N 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=N1)=CC=C1F RVNWFINYFHIZTG-UHFFFAOYSA-N 0.000 claims description 2
- WEUAMFWMPKHLFO-UHFFFAOYSA-N 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=CO1 WEUAMFWMPKHLFO-UHFFFAOYSA-N 0.000 claims description 2
- JFARSGFPICCMAL-UHFFFAOYSA-N 5,5-difluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CC(C(F)(F)F)=C1 JFARSGFPICCMAL-UHFFFAOYSA-N 0.000 claims description 2
- JWLZDZSCFDWMMJ-UHFFFAOYSA-N 5,5-difluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)(F)F)=C1F JWLZDZSCFDWMMJ-UHFFFAOYSA-N 0.000 claims description 2
- CBHZZIQNSXYTGD-UHFFFAOYSA-N 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=CC=C1 CBHZZIQNSXYTGD-UHFFFAOYSA-N 0.000 claims description 2
- BOOSNZWFERMCOZ-UHFFFAOYSA-N 5,5-difluoro-1-pyridin-3-yl-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=CN=C1 BOOSNZWFERMCOZ-UHFFFAOYSA-N 0.000 claims description 2
- JOTYLYOHFYNKJK-UHFFFAOYSA-N 5,5-difluoro-1-pyridin-4-yl-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=NC=C1 JOTYLYOHFYNKJK-UHFFFAOYSA-N 0.000 claims description 2
- XIKGVAJBFPZQFV-UHFFFAOYSA-N 5,5-difluoro-1-thiophen-3-yl-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CSC=C1 XIKGVAJBFPZQFV-UHFFFAOYSA-N 0.000 claims description 2
- BEKQWPGPBQTEFO-UHFFFAOYSA-N 5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1F)=CC(F)=C1F BEKQWPGPBQTEFO-UHFFFAOYSA-N 0.000 claims description 2
- WNNVIBHQBPHBTO-UHFFFAOYSA-N 5,5-difluoro-3-iodo-1-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(I)=C2)=C1N2C1=CC=C(C(F)(F)F)C=C1 WNNVIBHQBPHBTO-UHFFFAOYSA-N 0.000 claims description 2
- PGJNPMOXOZCQJA-UHFFFAOYSA-N 5,5-difluoro-3-iodo-1-[4-(trifluoromethyl)phenyl]-6,7-dihydroindol-4-one Chemical compound O=C(C(CC1)(F)F)C(C(I)=C2)=C1N2C1=CC=C(C(F)(F)F)C=C1 PGJNPMOXOZCQJA-UHFFFAOYSA-N 0.000 claims description 2
- VJPWMMFXJAEPAX-UHFFFAOYSA-N 5,6-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydroindol-4-ol Chemical compound OC(C(C(C1)F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC(F)=CN=C1 VJPWMMFXJAEPAX-UHFFFAOYSA-N 0.000 claims description 2
- IBEPYXPQJCPEFF-AWEZNQCLSA-N 5-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]-2-fluorobenzonitrile Chemical compound N#CC(C=C(C=C1)N2C(CCC([C@H]3O)(F)F)=C3C(C(F)(F)F)=C2)=C1F IBEPYXPQJCPEFF-AWEZNQCLSA-N 0.000 claims description 2
- ZBHUZNXLAJPPQU-ZDUSSCGKSA-N 5-[(4S)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]pyridine-3-carbonitrile Chemical compound N#CC1=CN=CC(N2C(CCC([C@H]3O)(F)F)=C3C(C(F)(F)F)=C2)=C1 ZBHUZNXLAJPPQU-ZDUSSCGKSA-N 0.000 claims description 2
- ARKMATGMFRLQOS-HNNXBMFYSA-N 5-[(4S)-5,5-difluoro-4-hydroxy-3-methylsulfonyl-6,7-dihydro-4H-indol-1-yl]-2-fluorobenzonitrile Chemical compound CS(C(C([C@@H]1O)=C2CCC1(F)F)=CN2C(C=C1)=CC(C#N)=C1F)(=O)=O ARKMATGMFRLQOS-HNNXBMFYSA-N 0.000 claims description 2
- IBEPYXPQJCPEFF-UHFFFAOYSA-N 5-[5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]-2-fluorobenzonitrile Chemical compound N#CC(C=C(C=C1)N2C(CCC(C3O)(F)F)=C3C(C(F)(F)F)=C2)=C1F IBEPYXPQJCPEFF-UHFFFAOYSA-N 0.000 claims description 2
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 claims description 2
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- PQFJFDGEIOJXLD-VQHVLOKHSA-N O=C(C(CC1)(F)F)C2=C1N(/C=C/C1=CC=CC=C1)C=C2C(F)(F)F Chemical compound O=C(C(CC1)(F)F)C2=C1N(/C=C/C1=CC=CC=C1)C=C2C(F)(F)F PQFJFDGEIOJXLD-VQHVLOKHSA-N 0.000 claims description 2
- ZROQSNSDMCNSQH-UHFFFAOYSA-N OC(C(C(C1)F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=NN2C(F)(F)F Chemical compound OC(C(C(C1)F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=NN2C(F)(F)F ZROQSNSDMCNSQH-UHFFFAOYSA-N 0.000 claims description 2
- UEISTYSCPNNHRV-UHFFFAOYSA-N OC(C(CC1)(F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=NN2C(F)(F)F Chemical compound OC(C(CC1)(F)F)C2=C1C(C1=CC(Cl)=CC(F)=C1)=NN2C(F)(F)F UEISTYSCPNNHRV-UHFFFAOYSA-N 0.000 claims description 2
- DINJXGNFUSTVIU-VQHVLOKHSA-N OC(C(CC1)(F)F)C2=C1N(/C=C/C1=CC=CC=C1)C=C2C(F)(F)F Chemical compound OC(C(CC1)(F)F)C2=C1N(/C=C/C1=CC=CC=C1)C=C2C(F)(F)F DINJXGNFUSTVIU-VQHVLOKHSA-N 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 210000002249 digestive system Anatomy 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 206010061311 nervous system neoplasm Diseases 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 210000004994 reproductive system Anatomy 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 208000008846 Neurocytoma Diseases 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 2
- 201000010881 cervical cancer Diseases 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 201000008361 ganglioneuroma Diseases 0.000 claims 2
- 206010017758 gastric cancer Diseases 0.000 claims 2
- 201000007270 liver cancer Diseases 0.000 claims 2
- 208000014018 liver neoplasm Diseases 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 201000002528 pancreatic cancer Diseases 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- 206010038038 rectal cancer Diseases 0.000 claims 2
- 201000001275 rectum cancer Diseases 0.000 claims 2
- 201000000849 skin cancer Diseases 0.000 claims 2
- 201000011549 stomach cancer Diseases 0.000 claims 2
- 206010046766 uterine cancer Diseases 0.000 claims 2
- 208000037979 autoimmune inflammatory disease Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 214
- 230000015572 biosynthetic process Effects 0.000 description 166
- 238000003786 synthesis reaction Methods 0.000 description 166
- 239000012043 crude product Substances 0.000 description 157
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 98
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 89
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
- 239000004698 Polyethylene Substances 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 75
- 238000004440 column chromatography Methods 0.000 description 61
- 239000000243 solution Substances 0.000 description 61
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 238000003756 stirring Methods 0.000 description 41
- 239000011734 sodium Substances 0.000 description 40
- 238000004809 thin layer chromatography Methods 0.000 description 37
- 239000012267 brine Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 235000008504 concentrate Nutrition 0.000 description 17
- 239000012141 concentrate Substances 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 239000005457 ice water Substances 0.000 description 16
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000012046 mixed solvent Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- NLMQHXUGJIAKTH-UHFFFAOYSA-N 4-hydroxyindole Chemical compound OC1=CC=CC2=C1C=CN2 NLMQHXUGJIAKTH-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 206010021143 Hypoxia Diseases 0.000 description 12
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- 239000012279 sodium borohydride Substances 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 9
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 230000007954 hypoxia Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 102100030907 Aryl hydrocarbon receptor nuclear translocator Human genes 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000793115 Homo sapiens Aryl hydrocarbon receptor nuclear translocator Proteins 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 5
- LZGZCPQPZQJUEN-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1H-indol-4-ol Chemical compound N1CCC2C(C=CC=C12)O LZGZCPQPZQJUEN-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- QWQBQRYFWNIDOC-UHFFFAOYSA-N (3,5-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC(F)=C1 QWQBQRYFWNIDOC-UHFFFAOYSA-N 0.000 description 4
- XYQDHVBKUNNLGZ-UHFFFAOYSA-N (3-chloro-5-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC(Cl)=C1 XYQDHVBKUNNLGZ-UHFFFAOYSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 4
- JWYPXFQCCVZJKH-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indol-4-ol Chemical compound OC1CCCC2=C1C=CN2 JWYPXFQCCVZJKH-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 4
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000005257 alkyl acyl group Chemical group 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000001146 hypoxic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- OLKIYJDSLMKNLC-UHFFFAOYSA-N (3-cyano-4-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C(C#N)=C1 OLKIYJDSLMKNLC-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- 0 *C1CCCCC1 Chemical compound *C1CCCCC1 0.000 description 2
- JXUKFFRPLNTYIV-UHFFFAOYSA-N 1,3,5-trifluorobenzene Chemical compound FC1=CC(F)=CC(F)=C1 JXUKFFRPLNTYIV-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- YBGOLOJQJWLUQP-UHFFFAOYSA-O 7-(dimethylamino)-4-hydroxy-3-oxophenoxazin-10-ium-1-carboxylic acid Chemical compound OC(=O)C1=CC(=O)C(O)=C2OC3=CC(N(C)C)=CC=C3[NH+]=C21 YBGOLOJQJWLUQP-UHFFFAOYSA-O 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 2
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WSTOVLQLTOEWSI-UHFFFAOYSA-N (3,5-difluorophenyl)hydrazine Chemical compound NNC1=CC(F)=CC(F)=C1 WSTOVLQLTOEWSI-UHFFFAOYSA-N 0.000 description 1
- YABSTJQEBSKPCG-UHFFFAOYSA-N (4-fluoro-3-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C(C=O)=C1 YABSTJQEBSKPCG-UHFFFAOYSA-N 0.000 description 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KASJZXHXXNEULX-UHFFFAOYSA-N 1,5,6,7-tetrahydroindol-4-one Chemical compound O=C1CCCC2=C1C=CN2 KASJZXHXXNEULX-UHFFFAOYSA-N 0.000 description 1
- FOJZOGCRYQAXMU-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-4-hydroxy-4,5,6,7-tetrahydroindole-3-carbonitrile Chemical compound N#CC(C1=C2CCCC1O)=CN2C1=CC(F)=CC(F)=C1 FOJZOGCRYQAXMU-UHFFFAOYSA-N 0.000 description 1
- RFMKYBJEAPHEQI-UHFFFAOYSA-N 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indole Chemical compound FC(C(C(CC(CC1)(F)F)=C1N1C2=CC(Cl)=CC(F)=C2)=C1F)(F)F RFMKYBJEAPHEQI-UHFFFAOYSA-N 0.000 description 1
- PKSAHOPFPPAUOD-UHFFFAOYSA-N 1-(bromomethyl)-3-chloro-5-fluorobenzene Chemical compound FC1=CC(Cl)=CC(CBr)=C1 PKSAHOPFPPAUOD-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- PUJOXDUJMBSJHZ-UHFFFAOYSA-N 1-[3-(difluoromethyl)-4-fluorophenyl]-5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C(C=C1)=CC(C(F)F)=C1F PUJOXDUJMBSJHZ-UHFFFAOYSA-N 0.000 description 1
- IWFKMNAEFPEIOY-UHFFFAOYSA-N 1-fluoro-3,5-dimethoxybenzene Chemical compound COC1=CC(F)=CC(OC)=C1 IWFKMNAEFPEIOY-UHFFFAOYSA-N 0.000 description 1
- HLXOVAMYQUFLPE-UHFFFAOYSA-N 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1N=CC=C1B1OC(C)(C)C(C)(C)O1 HLXOVAMYQUFLPE-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- MBTGBRYMJKYYOE-UHFFFAOYSA-N 2,6-difluoropyridine Chemical compound FC1=CC=CC(F)=N1 MBTGBRYMJKYYOE-UHFFFAOYSA-N 0.000 description 1
- FUSFWUFSEJXMRQ-UHFFFAOYSA-N 2-bromo-1,1-dimethoxyethane Chemical compound COC(CBr)OC FUSFWUFSEJXMRQ-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- GFOBNDWRJRFBCW-AWEZNQCLSA-N 2-fluoro-5-[(4S)-4,5,5-trifluoro-3-(trifluoromethyl)-6,7-dihydro-4H-indol-1-yl]benzonitrile Chemical compound N#CC(C=C(C=C1)N2C(CCC([C@H]3F)(F)F)=C3C(C(F)(F)F)=C2)=C1F GFOBNDWRJRFBCW-AWEZNQCLSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- CQXZSEXZQVKCHW-UHFFFAOYSA-N 3,5-difluorobenzonitrile Chemical compound FC1=CC(F)=CC(C#N)=C1 CQXZSEXZQVKCHW-UHFFFAOYSA-N 0.000 description 1
- ONZQYZKCUHFORE-UHFFFAOYSA-N 3-bromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)CBr ONZQYZKCUHFORE-UHFFFAOYSA-N 0.000 description 1
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 1
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Substances CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- VXWDVCBACKACOV-UHFFFAOYSA-N 5,5-difluoro-3-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-indol-4-ol Chemical compound OC(C(CC1)(F)F)C(C(C(F)(F)F)=C2)=C1N2C1=CC=C(C(F)(F)F)C=C1 VXWDVCBACKACOV-UHFFFAOYSA-N 0.000 description 1
- QHFZEKILWZFDHG-UHFFFAOYSA-N 5,5-difluoro-3-(trifluoromethyl)-6,7-dihydro-1H-indol-4-one Chemical compound O=C(C(CC1)(F)F)C2=C1NC=C2C(F)(F)F QHFZEKILWZFDHG-UHFFFAOYSA-N 0.000 description 1
- LGJAKBSRKIMODY-UHFFFAOYSA-N 5,5-difluoro-3-iodo-6,7-dihydro-1H-indol-4-one Chemical compound O=C(C(CC1)(F)F)C2=C1NC=C2I LGJAKBSRKIMODY-UHFFFAOYSA-N 0.000 description 1
- SUSABQXGTIPNRT-UHFFFAOYSA-N 5,6-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydroindol-4-one Chemical compound O=C(C(C(C1)F)F)C2=C1NC=C2C(F)(F)F SUSABQXGTIPNRT-UHFFFAOYSA-N 0.000 description 1
- ZRLDEURARYTBKB-UHFFFAOYSA-N 5-[5,5-difluoro-4-oxo-3-(trifluoromethyl)-6,7-dihydroindol-1-yl]-2-fluorobenzaldehyde Chemical compound O=CC(C=C(C=C1)N(C=C2C(F)(F)F)C(CCC3(F)F)=C2C3=O)=C1F ZRLDEURARYTBKB-UHFFFAOYSA-N 0.000 description 1
- HHTRAISBAAXRKZ-UHFFFAOYSA-N 5-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(F)C(C#N)=C1 HHTRAISBAAXRKZ-UHFFFAOYSA-N 0.000 description 1
- URSMCGHEFBTVNT-UHFFFAOYSA-N 5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydroindol-4-one Chemical compound O=C(C(CC1)F)C2=C1NC=C2C(F)(F)F URSMCGHEFBTVNT-UHFFFAOYSA-N 0.000 description 1
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- SBBIDMJQUFGIJC-UHFFFAOYSA-N CC(C)[S+](C(C)C)C(C)C(CC1)c([n](C)cc2I)c2C1=O Chemical compound CC(C)[S+](C(C)C)C(C)C(CC1)c([n](C)cc2I)c2C1=O SBBIDMJQUFGIJC-UHFFFAOYSA-N 0.000 description 1
- IFTRQJLVEBNKJK-UHFFFAOYSA-N CCC1CCCC1 Chemical compound CCC1CCCC1 IFTRQJLVEBNKJK-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 125000000815 N-oxide group Chemical group 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IVOSSEGQMHTCQY-UHFFFAOYSA-N O=C(CCC1)c2c1[nH]cc2I Chemical compound O=C(CCC1)c2c1[nH]cc2I IVOSSEGQMHTCQY-UHFFFAOYSA-N 0.000 description 1
- ZBURYHPKODOOLM-UHFFFAOYSA-N O=C(CCC1)c2c1[n](C1CCCCC1)cc2C(F)(F)F Chemical compound O=C(CCC1)c2c1[n](C1CCCCC1)cc2C(F)(F)F ZBURYHPKODOOLM-UHFFFAOYSA-N 0.000 description 1
- GBIGSGGRNVNBRC-UHFFFAOYSA-N O=C(CCC1)c2c1[n](C1CCCCC1)cc2I Chemical compound O=C(CCC1)c2c1[n](C1CCCCC1)cc2I GBIGSGGRNVNBRC-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 101150046474 Vhl gene Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- ZAFJDLVZVINKSX-UHFFFAOYSA-N azane butane-1,1,1-triol Chemical compound N.CCCC(O)(O)O ZAFJDLVZVINKSX-UHFFFAOYSA-N 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 208000010572 basal-like breast carcinoma Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
- OHHPZPDQZMUTCA-UHFFFAOYSA-N cyclohexyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CCCCC1 OHHPZPDQZMUTCA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical class [H]C([H])([H])* 0.000 description 1
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical compound [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- WRSXUNSJGJUKHE-UHFFFAOYSA-N indazole Chemical compound C1=CC=C[C]2C=NN=C21 WRSXUNSJGJUKHE-UHFFFAOYSA-N 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229940045996 isethionic acid Drugs 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- RWYUPXPKZMQREC-UHFFFAOYSA-N methyl 3-bromo-1h-pyrrole-2-carboxylate Chemical compound COC(=O)C=1NC=CC=1Br RWYUPXPKZMQREC-UHFFFAOYSA-N 0.000 description 1
- LDTLDBDUBGAEDT-UHFFFAOYSA-N methyl 3-sulfanylpropanoate Chemical compound COC(=O)CCS LDTLDBDUBGAEDT-UHFFFAOYSA-N 0.000 description 1
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 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
- 201000008383 nephritis Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- HKKDKUMUWRTAIA-UHFFFAOYSA-N nitridooxidocarbon(.) Chemical group [O]C#N HKKDKUMUWRTAIA-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 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
- 239000012363 selectfluor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K9/00—Screening of apparatus or components against electric or magnetic fields
- H05K9/0007—Casings
- H05K9/0054—Casings specially adapted for display applications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/192—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
- C07D243/36—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings containing an indole or hydrogenated indole ring system
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F1/00—Details not covered by groups G06F3/00 - G06F13/00 and G06F21/00
- G06F1/16—Constructional details or arrangements
- G06F1/1601—Constructional details related to the housing of computer displays, e.g. of CRT monitors, of flat displays
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F1/00—Details not covered by groups G06F3/00 - G06F13/00 and G06F21/00
- G06F1/16—Constructional details or arrangements
- G06F1/1613—Constructional details or arrangements for portable computers
- G06F1/1633—Constructional details or arrangements of portable computers not specific to the type of enclosures covered by groups G06F1/1615 - G06F1/1626
- G06F1/1656—Details related to functional adaptations of the enclosure, e.g. to provide protection against EMI, shock, water, or to host detachable peripherals like a mouse or removable expansions units like PCMCIA cards, or to provide access to internal components for maintenance or to removable storage supports like CDs or DVDs, or to mechanically mount accessories
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F1/00—Details not covered by groups G06F3/00 - G06F13/00 and G06F21/00
- G06F1/16—Constructional details or arrangements
- G06F1/18—Packaging or power distribution
- G06F1/181—Enclosures
- G06F1/182—Enclosures with special features, e.g. for use in industrial environments; grounding or shielding against radio frequency interference [RFI] or electromagnetical interference [EMI]
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
- H05K5/00—Casings, cabinets or drawers for electric apparatus
- H05K5/02—Details
- H05K5/03—Covers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to a bicyclic compound, compositions and preparations containing such compounds, and methods of using and preparing such compounds.
- HIFs Hypoxia inducible factors
- HIF-1 ⁇ HIF-1 ⁇ , HIF-2 ⁇ , HIF-3 ⁇
- HIF-1 ⁇ HIF-1 ⁇
- HIF-1 ⁇ is always in the nucleus, while HIF ⁇ is located in the cytoplasm.
- VHL Volt-Lindau Syndrome
- ubiquitinase ubiquitination labeling and other pathways and finally be degraded by the proteasome.
- HIF ⁇ hypoxia response element
- HRE hypoxia response element
- HIF-2 ⁇ mediates the occurrence and development of tumors mainly include: 1. Under conditions such as hypoxia or VHL mutations, the metabolic pathway of HIF-2 ⁇ is blocked, accumulates into the nucleus, and forms heterodimers with HIF-1 ⁇ . It then activates the hypoxia response element (HRE), regulates the up-regulation of downstream VEGFA, CXCR4, Cyclin D1 and other cancer-related genes, and promotes tumor angiogenesis; 2. HIF-2 ⁇ also participates in the conduction of immunosuppressive signals by up-regulating the expression of CD73, so it is targeted HIF-2 ⁇ can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells and NK cells.
- HRE hypoxia response element
- VHL protein is an important part of E3 ubiquitin ligase, which mediates protein degradation by the proteasome.
- VHL gene has a 57% high mutation rate or 98% loss of heterozygosity in renal cell carcinoma (RCC), which leads to pseudohypoxia and induces the activation of HIF-2 ⁇ into the nucleus.
- RRCC renal cell carcinoma
- clear cell renal cell carcinoma (ccRCC) accounts for 70%-75% of primary renal cell malignancies, and more than 90% of ccRCC patients have VHL protein defects.
- HIF-2 ⁇ When gliomas are not vascularized, the unstable blood supply leads to a hypoxic microenvironment, which induces high local expression of HIF-2 ⁇ and promotes tumor growth.
- the mutation rate of AA at positions 529-532 of HIF-2 ⁇ is as high as 81%, which directly affects the hydroxylation and degradation of HIF-2 ⁇ and makes HIF-2 ⁇ continue to be activated.
- HIF-2 ⁇ and HIF-1 ⁇ are the key factors leading to downstream activation, and the PAS binding domain of the two is the binding site for the formation of heterodimers.
- Peloton's R&D team developed HIF based on this PT2977, a small molecule inhibitor of -2 ⁇ , exerts an anti-tumor effect by inhibiting the binding of HIF-2 ⁇ and HIF-1 ⁇ .
- the present invention first provides a compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,
- X 1 and X 2 are each independently selected from C or N;
- X 3 is CR f or NR f ;
- X 4 is CR j or NR j ;
- X 1 , X 2 , X 3 and X 4 is N;
- R 1 is selected from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl, 5-18 membered hetero Aryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group; wherein, the 5-18 membered heteroaryl group and 3-10 membered heterocyclic group optionally contain 1, 2, or 3 independently Heteroatoms selected from N, O and S; the C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 2 -C 10 alkynyl group, C 1 -C 10 alkoxy group, C 6- C 10 aryl, 5-18 membered heteroaryl, C 3 -C 10 cycloalkyl and 3-10 membered heterocyclic group may optionally be substituted by one or more halogen, -OH, -CN, oxo, Amino, C 1
- R 4 and R 5 are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl, and 3-6 membered heterocyclic group; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane Group, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclic group may optionally be substituted by one or more halogens, -CN, -OH , Amino, C 1 -C 5 alkyl, C 2 -C 6 alkenyl and/or C 1 -C 5 haloalkyl substituted; or R 4 and R 5 together with
- R 6 is selected from H, -CN, halogen, -OH, -NO 2 , -NH 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl , C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclic group; the C 1 -C 6 alkyl, C 1 -C 6 alkane Oxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and 3-6 membered heterocyclic group may be optionally substituted by one or Multiple H, halogen, -CN, -OH, amino, oxo, C 1 -C 5 alkyl, C 2 -C 6 alkenyl and/or C 1
- R 6 and R 5 together with the C atom to which they are connected form a substituted or unsubstituted C 3 -C 4 cycloalkyl group
- R d and R e are each independently selected from H, halo, cyano, -NR a R b, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl; or R d and R e together form an oxo base;
- R f is selected from absent, H, -CN, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 10 cycloalkyl, oxo, -NR a R b ;
- the C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group and C 3 -C 10 cycloalkyl group may optionally be substituted by one or more H, halogen, -CN, -OH, amino, C 1 -C 5 substituted by alkyl, C 2 -C 6 alkenyl and/or C 1 -C 5 haloalkyl;
- R a , R b and R c are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2- C 10 alkenyl, C 2- C 10 alkynyl, C 3- C 10 cycloalkyl, 3-10 membered heterocyclic group, C 6- C 10 aryl or 5-10 membered heteroaryl;
- n 1, 2 or 3;
- n 0, 1, 2, 3, or 4.
- X 1 and X 2 are each independently selected from C or N;
- X 3 is CR f or NR f ;
- X 4 is CR j or NR j ;
- X 1 , X 2 , X 3 and X 4 is N;
- R 1 is selected from substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl , 5-18 membered heteroaryl group, C 3 -C 10 cycloalkyl group, 3-10 membered heterocyclic group; wherein the 5-18 membered heteroaryl group and 3-10 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; said R 1 may optionally be substituted by one or more halogen, hydroxyl, cyano, oxo, amino, C 1-6 alkyl , C 2-6 alkenyl, C 3-5 cycloalkyl, C 2-6 alkynyl or C 1-6 haloalkyl;
- R 2 is selected from H, -OH, amino, C 1 -C 10 alkoxy, -OC 1 -C 3 alkyl acyl or -NR a R b ;
- R 3 is selected from H, -OH, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, -OC 1-3 alkyl acyl or C 2 -C 10 alkynyl ; Or R 2 and R 3 together form an oxo group;
- R 4 and R 5 are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R 4 and R 5 together with the C atom to which they are attached form a substitution Or unsubstituted cyclopropyl;
- R 6 is selected from H, -CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; or two R 6 together with the C atom to which they are attached form a substituted or unsubstituted C 3- C 5 cycloalkyl or 3-5 membered heterocyclic group;
- R 6 and R 5 together with the C atom to which they are connected form a substituted or unsubstituted C 3 -C 4 cycloalkyl group
- R d and R e are each independently selected from H, halo, cyano, -NR a R b, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl; or R d and R e together form an oxo base;
- R f is selected from H, -CN, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 10 cycloalkyl, oxo, -NR a R b ;
- R a , R b and R c are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3- C 10 cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl;
- n 0, 1, 2, 3, or 4.
- X 1 and X 2 are C or N;
- X 3 is CR f or NR f ;
- X 4 is CR j or NR j ;
- X 1 , X 2 and X 4 is N;
- R 1 is selected from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl, C 5 -C 18 Heteroaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclic group; wherein, the C 5 -C 18 heteroaryl and C 3 -C 10 heterocyclic group optionally contain 1, 2, or 3 heteroatoms independently selected from N, O and S; the C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 2 -C 10 alkynyl group, C 1 -C 10 alkoxy group , C 6 -C 10 aryl, C 5 -C 18 heteroaryl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocyclic group can be optionally substituted by H, halogen, hydroxyl, cyano, oxygen Substit
- R 2 is selected from H, -OH, oxo, amino, C 1 -C 10 alkoxy, -OC 1-3 alkyl acyl or -NR a R b ;
- R 3 is selected from H, -OH, oxo, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl or -OC 1-3 alkyl acyl;
- R 4 and R 5 are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 5 cycloalkyl and C 3 -C 6 heterocyclyl; or R 4 and R 5 together with the C atom to which they are connected form a substituted or unsubstituted cyclopropyl base;
- R 6 is selected from H, -CN, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 2 -C 10 alkenyl, C 2- C 10 alkynyl, C 3 -C 5 cycloalkyl and C 3 -C 6 heterocyclyl; or two R 6 together with the C atom to which they are connected form a substituted or unsubstituted C 3 -C 5 cycloalkane Group or C 3 -C 5 heterocyclic group;
- R 6 and R 5 together with the C atom to which they are connected form a substituted or unsubstituted C 3 -C 4 cycloalkyl group
- R d and R e are each independently selected from H, halo, cyano, -NR a R b, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl; or R d and R e together form an oxo base;
- R f is selected from absent, H, -CN, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 10 cycloalkyl, oxo, -NR a R b ;
- R a , R b and R c are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3- C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 10 aryl or C 5 -C 10 heteroaryl;
- n 0, 1, 2, 3, or 4.
- the compound is represented by formula (II):
- X 1 and X 2 have and only one is N, and the other is C.
- the compound is represented by formula (III-1) or formula (III-2):
- the compound is represented by formula (III-A-1), formula (III-A-2) or formula (III-A-3),
- R 2 is halogen, -CN or -OH.
- R 2 is F, -CN or -OH.
- R 2 is halogen
- R 2 is -CN.
- R 2 is -OH.
- R 2 and R 3 together form an oxo group.
- R 3 is selected from H, deuterium, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and the C 1 -C 10 alkyl and C 2 -C 10 alkenyl may Optionally substituted by H, halogen, -CN, -OH, amino, C 1 -C 5 haloalkyl; or R 2 and R 3 together form an oxo group.
- R 3 is selected from H, deuterium, C 1 -C 3 alkyl, C 2 -C 5 alkenyl, and the C 1 -C 3 alkyl and C 2 -C 5 alkenyl may Optionally substituted by H, halogen, -CN, -OH, amino, C 1 -C 5 haloalkyl.
- R 3 is selected from H, deuterium, or C 1 -C 3 alkyl, and the C 1 -C 3 alkyl and C 2 -C 5 alkenyl can be optionally substituted by H, halogen, -CN, -OH, amino, C 1 -C 5 haloalkyl substituted.
- R 3 is selected from H, deuterium, or C 1 -C 3 alkyl.
- R 3 is H or deuterium.
- R 3 is H.
- R 2 is -OH, -CN or halogen
- R 3 is H or deuterium; or R 2 and R 3 together form an oxo group.
- R 2 is -OH, -CN or -F, and R 3 is H or deuterium; or R 2 and R 3 together form an oxo group.
- R 2 is -OH, and R 3 is H or deuterium; or R 2 and R 3 together form an oxo group.
- the compound is represented by formula (IV-1) or formula (IV-2),
- X 1 and X 2 have and only one is N, and the other is C.
- R 4 and R 5 are each independently selected from H, halogen or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl may be optionally substituted by H, halogen, -CN , -OH, amino or oxo group.
- R 4 and R 5 are each independently selected from H, halogen, or C 1 -C 6 alkyl.
- R 4 and R 5 are each independently selected from H or halogen.
- R 4 and R 5 are independently selected from H or F, respectively.
- X 4 is CR j .
- the compound is represented by formula (V),
- X 1 and X 2 have and only one is N, and the other is C.
- L is a bond
- the compound is represented by formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4) or formula (VI-5):
- X 3 is CR f .
- R f is selected from H, -CN, -NH 2 , halogen, C 1 -C 3 alkyl, cyclopropyl or C 1 -C 3 haloalkyl, the C 1 -C 3 Alkyl, cyclopropyl or C 1 -C 3 haloalkyl can optionally be substituted by H, halogen, -CN, -OH, amino, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1- C 3 substituted by haloalkyl.
- X 3 is CR f
- R f is selected from H, -CN, halogen, C 1 -C 3 alkyl or cyclopropyl.
- R f is H, -CN, halogen, C 1 -C 6 alkyl, or C 1 -C 3 haloalkyl.
- R f is H, -CN, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
- R f is H, -CN or halogen.
- R f is H or halogen.
- R f is H, -CN, -F, -Cl, -Br or -CF 3 .
- R f is H.
- R 6 is H, -CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, the C 1 -C 6
- the alkyl group, C 1 -C 6 alkoxy group or C 1 -C 6 haloalkyl group may be optionally substituted by H, halogen, -CN, -OH, oxo, or amino.
- R 6 is H, halogen, or C 1 -C 6 alkyl, and the C 1 -C 6 alkyl may be optionally substituted by H, halogen, -CN, -OH, oxo , Amino substituted.
- R 6 is H, halogen, or C 1 -C 6 alkyl.
- R 6 is H, halogen, or C 1 -C 3 alkyl.
- R 6 is H or halogen.
- R 6 is H, F, Cl or Br.
- R 6 is H or F.
- two R 6 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl group.
- R 1 is a C 6 -C 10 aryl group, a 5-18 membered heteroaryl group or a C 3 -C 10 cycloalkyl group, and the 5-18 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S.
- R 1 is a C 6 -C 10 aryl group or a 5-18 membered heteroaryl group, and the 5-18 membered heteroaryl group optionally contains 1, 2, or 3 independently selected from Heteroatoms of N, O and S.
- R 1 is a C 6 -C 10 aryl group or a 5-18 membered heteroaryl group, and the 5-18 membered heteroaryl group optionally contains 1, 2, or 3 independently selected from N, O and S heteroatoms, the C 6 -C 10 aryl group or 5-18 membered heteroaryl group may optionally be substituted by one or more H, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 3-5 cycloalkyl or C 1-6 haloalkyl substituted.
- R 1 is a C 6 -C 10 aryl group or a 5-18 membered heteroaryl group, and the 5-18 membered heteroaryl group optionally contains 1, 2, or 3 independently selected from N, O and S heteroatoms, the C 6 -C 10 aryl group or 5-18 membered heteroaryl group may be optionally substituted by one or more halogen, cyano and/or C 1-6 haloalkyl .
- R 1 is a benzene ring, a 5-6 membered heteroaryl group or a C 3 -C 6 cycloalkyl group, and the 5-6 membered heteroaryl group optionally contains 1, 2, or 3, respectively Heteroatoms independently selected from N, O and S, the benzene ring, 5-6 membered heteroaryl group or C 3 -C 6 cycloalkyl group may be optionally substituted by one or more halogens, -CN and/or C 1 -C 4 haloalkyl substituted.
- R 1 is a benzene ring or a 5-6 membered heteroaryl group, which optionally contains 1, 2 or 3 heteroatoms selected from N, O or S .
- R 1 is a benzene ring or a 6-membered heteroaryl group, which optionally contains 1, 2 or 3 N heteroatoms.
- R 1 is a benzene ring or a pyridine ring.
- the R 1 is a benzene ring, and the benzene ring may be optionally substituted with one or more halogen, -CN and/or C 1 -C 4 haloalkyl.
- the R 1 is a benzene ring, and the benzene ring may be optionally substituted by one or more halogens, -CN, -CHF 2 , -CF 3 , -CH 2 CHF 2 and/or -Replaced by CH 2 CF 3 .
- the R 1 is a benzene ring, and the benzene ring may be optionally substituted with one or more halogens and/or -CN.
- the R 1 is a pyridine ring, and the pyridine ring may be optionally substituted with one or more halogen, -CN and/or C 1 -C 4 haloalkyl.
- the R 1 is a pyridine ring, and the pyridine ring may be optionally substituted with one or more halogen, cyano and/or trifluoromethyl.
- the 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S;
- the C 1 -C 10 alkyl groups, C 2 -C 10 alkenyl groups, C 1 -C 10 haloalkyl groups, C 3 -C 10 cycloalkyl groups, C 6 -C 10 aryl groups, 5-10 membered heteroaryl groups may optionally be substituted by one Or
- the Ra , R b and R c are each independently H or C 1 -C 4 alkyl.
- the C 3 -C 5 cycloalkyl group, 5-membered heteroaryl group It can be optionally substituted by one or more halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and/or C 1 -C 3 haloalkyl;
- the 5-membered heteroaryl group is optional Ground contains 1, 2 or 3 heteroatoms independently selected from N, O and S;
- the Ra and R b are each independently selected from H, C 1 -C 4 alkyl;
- the R c is selected from H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
- the R c is selected from H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
- the R j is selected from C 1 -C 4 haloalkyl, cyano or 5-membered heteroaryl, and the C 5 heteroaryl optionally contains 1, 2 or 3 independently Heteroatoms selected from N, O and S; the C 5 heteroaryl group may be optionally substituted by H, halogen or C 1 -C 3 alkyl.
- the R j is C 1 -C 4 haloalkyl.
- the R j is a C 1 -C 4 fluoroalkyl group.
- the R j is -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 or -CH 2 CF 3 .
- the R j is -CF 3 .
- the R a and R b are each independently selected from H, C 1 -C 4 alkyl.
- the R c is selected from H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
- the R j is selected from
- the compound is represented by formula (VII):
- R 1 is selected from C 6 -C 10 aryl, 5-18 membered heteroaryl, C 3 -C 10 cycloalkyl, wherein the 5-18 membered heteroaryl and 3-10 membered heterocyclic group are arbitrarily Contain 1, 2 or 3 heteroatoms independently selected from N, O and S;
- R 2 is -OH, -CN or halogen, and R 3 is H or deuterium; or R 2 and R 3 together form an oxo group;
- R 4 and R 5 are each independently H or halogen
- R 6 is H, halogen or C 1 -C 6 alkyl
- R f is H, -CN, halogen, C 1 -C 6 alkyl or C 1 -C 3 haloalkyl;
- the Ra and R b are each independently selected from H or C 1 -C 4 alkyl;
- the R c is selected from H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
- the present invention further provides a compound or a pharmaceutically acceptable salt thereof, and the compound refers to:
- the present invention also provides a method for preparing the compound.
- the compound described in formula (I) or the compound described in the specific embodiment of the present invention can be prepared by using known organic synthesis techniques, for example, using a preparation similar to the specific embodiment. Method.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose.
- pharmaceutically acceptable excipients such as hydroxypropyl methylcellulose.
- the weight ratio of the compound to the excipient is about 0.001-10.
- the present invention also provides a method for treating a subject suffering from a disease or disorder mediated by HIF-2 ⁇ , which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the disease or condition is selected from VHL syndrome, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, renal disorders, viral infections, and obesity.
- the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs.
- the disease or condition is cancer, including hematological cancers, lymphomas, multiple myeloma, tumors of the digestive system, tumors of the reproductive system, brain tumors, tumors of the nervous system.
- the disease or disorder is glioma, pheochromocytoma, paraganglioma, colon, rectum, prostate (e.g., castrate resistant prostate cancer), lung cancer (e.g., non-small cell Lung cancer and/or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (e.g. basal or basal-like breast cancer and/or triple negative breast cancer), skin (e.g. melanoma), Tumors or cancers of the nervous system (including the brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma, and medulloblastoma).
- the nervous system including the brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma, and medulloblastoma.
- the disease or condition is VHL syndrome. In certain aspects, the disease or condition is kidney cancer. In certain aspects, the subject is a human.
- the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
- the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases or disorders mediated by HIF-2 ⁇ .
- the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treatment. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject suffering from a disease or condition mediated by HIF-2 ⁇ .
- halogen refers to fluorine, chlorine, bromine or iodine.
- Preferred halogen groups refer to fluorine, chlorine and bromine.
- alkyl includes linear or branched saturated monovalent hydrocarbon groups.
- alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
- the "C 1 -C 6 "in the C 1 -C 6 alkyl group refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched chain.
- alkoxy refers to an oxyether formed from the above-mentioned linear, branched or cyclic alkyl group.
- alkylene refers to a divalent alkyl linking group.
- alkylene refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound.
- C 1 -C 4 in the C 1 -C 4 alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.
- haloalkyl refers to an alkyl group in which one or more H has been replaced by a halogen atom.
- haloalkoxy refers to the group -O-haloalkyl.
- oxo or "oxo” refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when connected to a heteroatom group.
- aromatic ring means having aromatic characteristics (having (4n+2) non-localized ⁇ electrons, where n is Integer) carbocyclic or heterocyclic polyunsaturated ring.
- aryl refers to a substituted or unsubstituted, stable 6 to 10 ring carbon atom aromatic hydrocarbon group, which may contain one aromatic ring or multiple aromatic rings (for example, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
- heteroaryl refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S.
- the "5-18 membered” in the 5-18 membered heteroaryl group refers to a heteroaryl group composed of 5-18 carbon atoms or N, O or S ring-forming atoms. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl and the like.
- cycloalkyl refers to a ring system having at least one cyclized alkyl group.
- C 3 -C 10 in the term C 3 -C 10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
- Cycloalkyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, fused rings, etc.).
- cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused to cyclized alkyl rings. Part, such as benzo or thienyl derivatives of cyclohexane, etc.
- cycloalkenyl refers to a ring system having at least one cyclized alkenyl group with one or more carbon-carbon double bonds in the cycloalkenyl group.
- C 3 -C 10 in the term C 3 -C 10 cycloalkenyl group means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
- Cycloalkenyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.).
- cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl also includes those having one or more fused rings with cyclized alkenyl Part of the aromatic ring, such as benzo or thienyl derivatives of the cyclohexene ring.
- heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, and the heteroatom is selected from N, O and/or S.
- the heterocyclic group may include a single ring or a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
- the heterocyclic group can be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom.
- heterocyclic group also includes moieties having one or more aromatic rings fused with a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. .
- heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc. .
- composition in the present invention is intended to include products containing specific amounts of specific components, as well as any products obtained directly or indirectly from specific amounts of specific components. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound are also the content of the present invention. Moreover, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
- the "compound” of the present invention includes the compound of formula (I) and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometrically different Conformers, isotopically labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.
- the “enantiomers” are a pair of non-superimposable stereoisomers that are mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture.
- the conventional RS system is used (for example (1S, 2S) specifies a single stereoisomer with two chiral centers of known relative and absolute configuration).
- Optically active (R)- and (S)-isomers can be prepared by synthesis using optically active raw materials or chiral reagents, or they can be resolved using conventional techniques (for example, separation on a chiral SFC or HPLC column ).
- the “diastereomers” are stereoisomers having at least two asymmetric atoms, but they are not mirror images of each other.
- the stereochemistry on each chiral carbon can be designated by R or S.
- the resolved compounds with unknown absolute configuration can be named (+) or (-) according to the direction (right-handed or left-handed) they rotate the plane-polarized light at the wavelength of the sodium D line.
- the resolved compound can be defined by the corresponding retention time of the corresponding enantiomer/diastereomer of chiral HPLC.
- the compounds of the present invention may contain one or more chiral centers, and may generate diastereomers and optical isomers therefrom.
- the above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound, so it can exist in different isomeric forms.
- the present invention includes all possible stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof, such as racemic mixtures, optically pure forms and isomer mixtures in any ratio . Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention.
- the product obtained may be a mixture of stereoisomers.
- the prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention.
- the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, the term "administration" in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or the prodrug compound disclosed in the present invention that can be converted in vivo after administration to a subject although it is not clearly disclosed.
- the conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
- any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select a suitable substituent or substitution form to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.
- the present invention includes any possible solvate and polymorph.
- the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
- water, ethanol, propanol, acetone and similar solvents can all be used.
- pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
- the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium and sodium.
- Non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
- non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol and so on.
- ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -
- the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluor
- citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
- the pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
- a pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
- the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
- the compound represented by formula (I) of the present invention can be used as an active component and mixed with a drug carrier to form a drug combination Things.
- the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient.
- the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
- the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier which constitutes one or more necessary ingredients.
- the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Then, the product can be easily prepared into the desired appearance.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
- the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
- Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- Liquid carriers include syrup, peanut oil, olive oil and water.
- the gas carrier includes carbon dioxide and nitrogen.
- any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
- standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
- Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compressing or molding one or more auxiliary components or adjuvants together.
- the active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets.
- the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
- each tablet contains about 0.05 mg to 5 g of active ingredient
- each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
- a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
- the unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
- the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
- a suitable surfactant such as hydroxypropyl cellulose may be included.
- glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared.
- a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
- the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
- the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion.
- the final injection form must be sterile, and for easy injection, it must be easy to flow.
- the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
- the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
- the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
- these preparations can be prepared by conventional processing methods.
- an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above-mentioned compound to prepare an emulsion or ointment having the desired consistency.
- the pharmaceutical composition provided by the present invention can be made into a form that takes a solid as a carrier and is suitable for rectal administration.
- the preferred dosage form is a suppository in which the mixture forms a unit dose.
- Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or molten excipients, then cooling and moulding.
- the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc.
- other adjuvants can also include penetration enhancers that regulate the isotonic pressure of the drug and blood.
- the pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
- the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
- the specific dosage level for any particular patient will depend on many factors, including age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs and acceptance The severity of the specific disease being treated.
- DMSO dimethyl sulfoxide
- K 2 CO 3 potassium carbonate
- LDA lithium diisopropylamide
- LiHMDS Lithium bis(trimethylsilyl)amide
- m-CPBA m-chloroperoxybenzoic acid
- Na 2 SO 4 sodium sulfate
- NBS N-bromosuccinimide
- NFSI N-fluorobisbenzenesulfonamide
- NIS N-iodosuccinimide
- NMP N-methylpyrrolidone
- PE petroleum ether
- Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
- Pd(dppf)Cl 2 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
- Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
- TBAF Tetrabutylammonium fluoride
- TEA Triethylamine
- THF Tetrahydrofuran
- Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
- 1,3-dimethoxy-5-fluorobenzene (15.6g) was dissolved in tert-butanol (25mL) and tetrahydrofuran (15mL), added to the liquid ammonia solution (650mL), and added in batches Lithium metal (1.75g), blue solution below -65 degrees, stir for 3 hours, add solid ammonium chloride until the blue color disappears, heat up to allow the liquid ammonia to volatilize and remove, add petroleum ether to dilute the residue, wash with water, wash with saturated brine, dry and concentrate
- the target product M6-11 (10 g) was obtained.
- the compound M6-13 (7.24 g) was dissolved in dichloromethane (100 mL), the temperature was lowered to zero, trifluoroacetic acid (5 mL) was added, the mixture was stirred at room temperature overnight, concentrated, and the target product M6-14 (5 g) was obtained by column chromatography.
- Example 1 and Example 2 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indole- 4-ketone (compound A13) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indole-4 - Synthesis of alcohol (compound A2)
- Example 28 and Example 29 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetra Hydrogen-4H-indol-4-one (compound A19) and 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)- Synthesis of 4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A3)
- Example 33 and Example 34 1-(3,5-Difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indole-4- Ketone (compound A12) and 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (chemical Synthesis of compound A4)
- compound M1-1 (2.91g) was dissolved in THF (40mL), cooled to -78°C, and 1.0M LiHMDS tetrahydrofuran solution (28mL) was slowly dropped into it. After stirring for half an hour, NFSI( 6.6 g) tetrahydrofuran solution (40 mL), kept stirring at -78°C for two hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution to the reaction mixture, extracted twice with ethyl acetate, washed twice with saturated brine, dried and concentrated to obtain the crude compound 4-1 (2.8 g), which was directly used in the next reaction.
- the crude compound 4-1 (2.8 g) was dissolved in a mixed solvent of THF (20 mL)/water (20 mL), K 2 CO 3 (2.76 g) was added at room temperature, and stirring was continued for three hours.
- the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain a crude product.
- Example 35 and Example 36 1-Cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indyl Dolin-4-one (compound A20) and 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole- Synthesis of 4-alcohol (Compound A5)
- the target compound 5-3 can be prepared.
- the target compound A20 can be prepared by using a preparation method similar to that in Step 3 of Intermediate M1, replacing compound M1-2 with compound 5-3.
- the target compound A5 can be prepared.
- Example 38 and Example 39 3-Fluoro-5-(3-(methylsulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl) Benzoonitrile (compound A24) and 3-fluoro-5-(4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indole-1- Synthesis of benzonitrile (compound A8)
- the compound 8 can be obtained by using a preparation method similar to that of compound A2, replacing compound A13 with compound 8-4.
- Example 69 and Example 70 5-(7,7-Difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindole Dalazin-3-yl)-2-fluorobenzonitrile (compound D79) and (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl) Yl)-5,6,7,8-tetrahydroindolazin-3-yl)-2-fluorobenzonitrile (Compound D76)
- Example 1 Using a preparation method similar to that of Example 1 to Example 70, for example, Replace with And so on, the following examples were obtained.
- the crude compound D49-4 (0.73 g) was dissolved in a mixed solvent of THF (20 mL)/water (20 mL), K 2 CO 3 (0.48 g) was added at room temperature, and stirring was continued for three hours.
- the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain a crude product.
- the crude compound D50-1 (550 mg) was dissolved in a mixed solvent of THF (10 mL)/water (10 mL), K 2 CO 3 (375 mg) was added at room temperature, and stirring was continued for three hours.
- the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain a crude product.
- compound 1-2 (106 mg) was dissolved in acetonitrile (5 mL), added with NCS (50 mg), stirred at 80°C for 2 hours, extracted with ethyl acetate, and the organic layer was washed with brine and dried over Na 2 SO 4 After concentration, the crude product was obtained.
- Example 1 Through different raw materials and/or intermediates, the following examples were obtained using preparation methods similar to those in Example 1 to Example 108.
- Example 196 and Example 197 (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7- Tetrahydro-1H-indol-1-yl)benzonitrile (compound D54, hypothetical) and (R)-2-fluoro-5-(4,5,5-trifluoro) -3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (compound D55, hypothetical) become
- the 786-O cells grown in the logarithmic phase were seeded in a 96-well plate at a cell concentration of 65,000 cells per milliliter of culture medium, 180ul per well. Dilute the compound to the corresponding concentration, and add 20 ul of the compound solution of different concentrations to the corresponding cell wells so that the final concentration of the compound is (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. Culturing 24h, cell culture supernatants were taken, using an ELISA assay kit VEGFA concentration (available from Abeam), and finally terminate the reaction, and absorbance of each well plate reader at 450nm wavelength measured by GraphPadPrism calculated IC 50. At the same time, CellTiter-Glo reagent was used to determine cell viability.
- IC 50 data exemplary embodiments are provided in Table 1, wherein, A represents IC 50 ⁇ 0.5 ⁇ M; B represents 0.5 ⁇ M ⁇ IC 50 ⁇ 1.5 ⁇ M; C represents 1.5 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M, D represents the IC 50> 1.5 ⁇ M. Table 1
- Example number IC 50 ( ⁇ M) Example number IC 50 ( ⁇ M) 5 B 109 A 6 B 116 0.0277 7 0.0307 120 0.0389 12 0.0675 121 0.031 13 A 122 0.0426 15 0.0188 124 0.0085 19 A 125 0.034 20 A 130 A twenty two 0.0554 131 A twenty four A 132 A 29 C 133 B 37 A 134 A 41 B 137 0.0421 48 0.0456 139 A 51 B 141 A 53 A 142 A 54 B 145 C 64 A 148 A 68 A 154 A 69 0.0442 156 0.0156 70 0.0454 160 0.0461 71 0.0138 164 A 75 A 167 A 76 A 168 0.0084 77 0.0162 170 B 88 D 173 0.0178 90 D 174 B 92 D 178 A 93 D 179 B 95 0.0145 180 B 96 A 181 C 97 A 190 B 100 A 193 A 103 0.0441 196 A 104 0.0062 197 A
- the luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) with Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2 ⁇ reporter cells (786-O-HIF2 ⁇ -Luc cells).
- RPMI MEDIUM 1640 purchased from In
- Use Echo550 non-contact sonic pipetting system, purchased from Labcyte
- the concentrations are 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively.
- the cells were cultured at 37°C and 5% CO 2 for 18-20 hours; Steady-Glo TM Luciferase Assay System (purchased from Promega) was added to a 384-well plate, 25 ⁇ l/well; the luminescence value was detected with Envision.
- % Inhibition is calculated according to each well RLU (Record Luminescence) signal values, and fitting calculation of IC 50 through the corresponding compound Graphpad 8.0.
- IC 50 data exemplary embodiments are provided in Table 2, wherein, A represents IC 50 ⁇ 0.5 ⁇ M; B represents 0.5 ⁇ M ⁇ IC 50 ⁇ 1.5 ⁇ M; C represents 1.5 ⁇ M ⁇ IC 50 ⁇ 10 ⁇ M, D represents the IC 50> 1.5 ⁇ M.
- Example number IC 50 ( ⁇ M) Example number IC 50 ( ⁇ M) 7 0.0577 106 A 12 A 116 0.0532 15 A 120 0.0757 19 A 121 0.0985 20 A 124 A 37 A 125 A 48 A 131 A 64 A 148 A
- the compound was formulated with 5% DMSO, 5% Solutol and 90% NaCl.
- SD rats and Balb/c mice were selected for administration.
- the intravenous dose was 1 mg/kg and the oral dose was 5 mg/kg, respectively at 5 min, 15 min, 30 min, 1h, 2h, 4h, 7h, 24h Take blood from the orbit. After blood collection, centrifuge at 4000 rpm for 10 min, take the supernatant, add 200 ⁇ L of internal standard solution to 30 ⁇ L of supernatant for precipitation, vortex and centrifuge at 12000 rpm for 10 min, take 100 ⁇ L of supernatant solution and purified water in a 1:1 ratio for mixing and injection.
- the compound concentration in the plasma is detected by a high performance liquid-mass spectrometer, and the compound concentration in the plasma sample is quantitatively analyzed by the internal standard quantification method. After the compound concentration is measured, Winnonln software is used to calculate related pharmacokinetic parameters including Cmax and AUC. It is found through experiments that the exemplary compounds of the present invention have better PK properties in vivo.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Theoretical Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- General Engineering & Computer Science (AREA)
- Computer Hardware Design (AREA)
- Epidemiology (AREA)
- Microelectronics & Electronic Packaging (AREA)
- General Physics & Mathematics (AREA)
- Human Computer Interaction (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Electromagnetism (AREA)
- Power Engineering (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
实施例编号 | IC 50(μM) | 实施例编号 | IC 50(μM) |
5 | B | 109 | A |
6 | B | 116 | 0.0277 |
7 | 0.0307 | 120 | 0.0389 |
12 | 0.0675 | 121 | 0.031 |
13 | A | 122 | 0.0426 |
15 | 0.0188 | 124 | 0.0085 |
19 | A | 125 | 0.034 |
20 | A | 130 | A |
22 | 0.0554 | 131 | A |
24 | A | 132 | A |
29 | C | 133 | B |
37 | A | 134 | A |
41 | B | 137 | 0.0421 |
48 | 0.0456 | 139 | A |
51 | B | 141 | A |
53 | A | 142 | A |
54 | B | 145 | C |
64 | A | 148 | A |
68 | A | 154 | A |
69 | 0.0442 | 156 | 0.0156 |
70 | 0.0454 | 160 | 0.0461 |
71 | 0.0138 | 164 | A |
75 | A | 167 | A |
76 | A | 168 | 0.0084 |
77 | 0.0162 | 170 | B |
88 | D | 173 | 0.0178 |
90 | D | 174 | B |
92 | D | 178 | A |
93 | D | 179 | B |
95 | 0.0145 | 180 | B |
96 | A | 181 | C |
97 | A | 190 | B |
100 | A | 193 | A |
103 | 0.0441 | 196 | A |
104 | 0.0062 | 197 | A |
106 | A | 200 | 0.0056 |
107 | A | 201 | D |
108 | A | 202 | D |
实施例编号 | IC 50(μM) | 实施例编号 | IC 50(μM) |
7 | 0.0577 | 106 | A |
12 | A | 116 | 0.0532 |
15 | A | 120 | 0.0757 |
19 | A | 121 | 0.0985 |
20 | A | 124 | A |
37 | A | 125 | A |
48 | A | 131 | A |
64 | A | 148 | A |
69 | 0.067 | 156 | 0.0705 |
70 | 0.0842 | 167 | 0.0699 |
75 | A | 168 | 0.0305 |
95 | 0.0376 | 173 | 0.0159 |
103 | A | 196 | A |
104 | 0.0220 | 200 | 0.0335 |
Claims (32)
- 一种式(I)所示的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其中,L为键、-O-、-NH-、-(CR dR e) n-、-S-、-S(=O)-、-S(=O) 2-、-C=C-、-C≡C-或C 3-C 5环烷基;X 1和X 2分别独立地选自C或N;X 3为CR f或NR f;X 4为CR j或NR j;且X 1、X 2、X 3和X 4至少有一个为N;R 1选自C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、C 3-C 10环烷基、3-10元杂环基;其中,所述5-18元杂芳基和3-10元杂环基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 6-C 10芳基、5-18元杂芳基、C 3-C 10环烷基和3-10元杂环基可任选地被一个或多个卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 3-C 5环烷基、C 2-C 6炔基、C 1-C 6卤代烷基、-C 1-C 6亚烷基-OR c、-C 0-C 6亚烷基-C=O-R c、-NO 2、-OR c、-SR c、-NR aR b、-C(=O)R c、-C(=O)OR c、-C(=O)NR aR b、-NC(=O)R c、-S(=O)R c、-S(=O) 2R c、-S(=O) 2NR aR b、-S(=O)(=NR a)R b、-P(=O)R aR b和/或-P(=S)R aR b所取代;R 2选自H、氘、卤素、-CN、-OH、=N-OH、C 1-C 5卤代烷基、氨基、C 1-C 10烷氧基、-O-C(=O)-C 1-3烷基、-C(=O)-O-C 1-3烷基或-NR aR b;R 3选自H、氘、卤素、-CN、-OH、=N-OH、C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(=O)-C 1-3烷基、-C(=O)-O-C 1-3烷基或C 2-C 10 炔基,所述C 1-C 10烷基、C 2-C 10烯基、C 1-C 5卤代烷基、C 1-C 10烷氧基、-O-C(=O)-C 1-3烷基、-C(=O)-O-C 1-3烷基可任选地被一个或多个H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 2-C 6烯基和/或C 1-C 5卤代烷基所取代;或R 2与R 3共同形成氧代基;R 4和R 5分别独立地选自H、卤素、-OH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基;所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个卤素、-CN、-OH、氨基、C 1-C 5烷基、C 2-C 6烯基和/或C 1-C 5卤代烷基所取代;或R 4和R 5与连同其所连接的C原子共同形成取代或未被取代的环丙基;R 6选自H、-CN、卤素、-OH、-NO 2,-NH 2、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基;所述C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 5环烷基和3-6元杂环基可任选地被一个或多个H、卤素、-CN、-OH、氨基、氧代基、C 1-C 5烷基、C 2-C 6烯基和/或C 1-C 5卤代烷基所取代;或两个R 6一起连同其所连接的C原子共同形成取代或未取代的C 3-C 5环烷基或3-5元杂环基;或R 6与R 5连同其所连接的C原子共同形成取代或未取代的C 3-C 4环烷基;R d和R e分别独立地选自H、卤素、氰基、-NR aR b、C 1-C 10烷基或C 3-C 10环烷基;或R d和R e共同形成氧代基;R f选自不存在、H、-CN、卤素、C 1-C 10烷基、C 1-C 10卤代烷基、C 3-C 10环烷基、氧代基、-NR aR b;所述C 1-C 10烷基、C 1-C 10卤代烷基和C 3-C 10环烷基可任选地被一个或多个H、卤素、-CN、-OH、氨基、C 1-C 5烷基、C 2-C 6烯基和/或C 1-C 5卤代烷基所取代;R j选自H、-NO 2、-CN、卤素、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10卤代烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 10芳基、5-10元杂芳基、-C 1-C 6亚烷基-OR c、-OR c、-SR c、-NR aR b、-C(=O)R c、-C(=O)OR c、-C(=O)NR aR b、-NC(=O)R c、-S(=O)R c、-S(=O) 2R c、-S(=O) 2NR aR b或-S(=O)(=NR a)R b、P(=O)R aR b、P(=S)R aR b;其中,所述5-10元杂芳基和3-10元杂环基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10卤代烷基、C 3-C 10环烷基、3-10元 杂环基、C 6-C 10芳基和5-10元杂芳基可任选地任选地被一个或多个卤素、羟基、氨基、P(=O)Me 2、P(=S)Me 2、-S(=O) 2-C 1-C 3烷基、-S(=O) 2-C 3-C 5环烷基、-S(=O)-C 1-C 3烷基、-S(=O)-C 3-C 5环烷基、氰基、C 1-C 6烷基、C 1-C 6烷氧基和/或C 1-C 6卤代烷基所取代。R a、R b和R c分别独立地选自H、C 1-C 10烷基、C 1-C 10卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 10环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基;n为1、2或3;m为0、1、2、3或4。
- 根据权利要求1或2所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R 2选自卤素、-CN、-OH、=N-OH。
- 根据权利要求1-3任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R 3选自H、氘、C 1-C 10烷基、C 2-C 10烯基,所述C 1-C 10烷基和C 2-C 10烯基可任选地被H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基所取代;或R 2与R 3共同形成氧代基。
- 根据权利要求1-4任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R 3选自H、氘或C 1-C 3烷基,所述C 1-C 3烷基和C 2-C 5烯基可任选地被H、卤素、-CN、-OH、氨基、C 1-C 5卤代烷基所取代;或R 2与R 3共同形成氧代基。
- 根据权利要求1-5任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 4和R 5分别独立地选自H、卤素或C 1-C 6烷基,所述C 1-C 6烷基可任选地被H、卤素、-CN、-OH、氨基或氧代基所取代。
- 根据权利要求1-6任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 4和R 5分别独立地选自H或卤素。
- 根据权利要求1-9任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,L为键、-CH 2-、-S(=O) 2-、-C=C-、-C=O-、-C≡C-或C 3-C 5环烷基。
- 根据权利要求1-10任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,X 3为CR f。
- 根据权利要求1-11任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,L为键。
- 根据权利要求1-13任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 6为H、-CN、卤素、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基,所述C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基可任选地被一个或多个H、卤素、-CN、-OH、氧代基和/或氨基所取代。
- 根据权利要求1-14任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 6为H、卤素或C 1-C 6烷基,所述C 1-C 6烷基可任选地被一个或多个H、卤素、-CN、-OH、氧代基和/或氨基所取代。
- 根据权利要求1-15任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R f选自H、-CN、卤素、-NH 2、C 1-C 3烷基、环丙基或C 1-C 3卤代烷基,所述C 1-C 3烷基、环丙基或C 1-C 3卤代烷基可任选地被一个或多个H、卤素、-CN、-OH、氨基、C 1-C 3烷基、C 2-C 4烯基和/或C 1-C 3卤代烷基所取代。
- 根据权利要求1-16任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R f选自H、-CN、卤素、C 1-C 3烷基或C 1-C 3卤代烷基。
- 根据权利要求1-17任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R 1为C 6-C 10芳基、5-18元杂芳基或C 3-C 10环烷基;所述5-18元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子。
- 根据权利要求1-18任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 1为C 6-C 8芳基、5-8元杂芳基或C 3-C 6环烷基,所述5-8元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子,所述C 6-C 8芳基、5-8元杂芳基或C 3-C 6环烷基可任选地被被一个或多个卤素、-OH、-CN、氧代基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、-C 1-C 6亚烷基-OR c、-C 0-C 6亚烷基-C=O-R c、-NO 2、C(=O)OR c和/或-S(=O) 2R c所取代。
- 根据权利要求1-19任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,R 1为苯环、5-6元杂芳基或C 3-C 6环烷基,所述5-6元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述苯环、5-6元杂芳基或C 3-C 6环烷基可任选地被一个或多个卤素、-CN和/或C 1-C 4卤代烷基所取代。
- 根据权利要求1-20任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R j选自H、-CN、卤素、C 1-C 10烷基、C 2-C 10烯基、C 1-C 10卤代烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基、-S(=O)R c、-C 1-C 6亚烷基-OR c、-S(=O) 2R c或P(=O)R aR b;所述5-10元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述C 1-C 10烷基、C 2-C 10烯基、C 1-C 10卤代烷基、C 3-C 10环烷基、C 6-C 10芳基、5-10元杂芳基可任选地被一个或多个卤素、羟基、P(=O)Me 2、P(=S)Me 2、-S(=O) 2-C 1-C 3烷基、-S(=O) 2-C 3-C 5环烷基、-S(=O)-C 1-C 3烷基、-S(=O)-C 3-C 5环烷基、氰基、C 1-C 6烷基和/或C 1-C 6卤代烷基所取代;所述R a和R b分别独立地选自H、C 1-C 4烷基;所述R c选自H、C 1-C 3烷基或C 1-C 3卤代烷基。
- 根据权利要求1-21任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R j选自H、卤素、-CN、C 1-C 4卤代烷基、C 3-C 5环烷基、5元杂芳基、S(=O)R c、-S(=O) 2R c、-S(=O)(=NR a)R b或P(=O)Me 2,所述5元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述C 3-C 5环烷基、5元杂芳基可任选地被一个或多个卤素、羟基、C 1-C 3烷基、C 1-C 3烷氧基和/或C 1-C 3卤代烷基所取代;所述R a和R b分别独立地选自H、C 1-C 4烷基;所述R c选自H、C 1-C 3烷基或C 1-C 3卤代烷基。
- 根据权利要求1-22任一所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述R j选自C 1-C 4卤代烷基、氰基、-S(=O) 2R c或5元杂芳基,所述5元杂芳基任意地含有1、2或3个分别独立地选自N、O和S的杂原子;所述5元杂芳基可任选地被一个或多个卤素C 1-C 3烷基和/或C 1-C 3卤代烷基所取代;所述R c选自H、C 1-C 3烷基或C 1-C 3卤代烷基。
- 根据权利要求1所述的化合物,或其立体异构体、互变异构体、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂合物,其特征在于,所述化合物选自:1-(3-氯-5-氟苯基)-5,5-二氟-3-碘-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3-氯-5-氟苯基)-5,5-二氟-3-碘-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-3-碘-1-(4-(三氟甲基)苯基)-1,5,6,7-四氢-4H-吲哚-4-酮;5,5-二氟-3-碘-1-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇;5-(5,5-二氟-4-羟基-3-碘-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-苯基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;5,5-二氟-1-苯基-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;3-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;5,5-二氟-1-(4-氟-3-甲氧基苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯苯)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(3-氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(5-氯吡啶-3-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(2-氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3,5-二氯苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(4-氯苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-溴-5-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(吡啶-3-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(3-氟-5-(三氟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-3-(三氟甲基)-1-(4-(三氟甲基)苯基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(p-甲苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(3-氟-5-羟基苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苄基)-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3-氯-5-氟苄基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-苯基-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-醇;1-((3,3-二氟环丁基)甲基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)(3,3-二氟环丁基)甲酮;1-(3,5-二氟苯基)-5,5-二氟-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3,5-二氟苯基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇;1-环己基-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;1-环己基-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-氟-5-(3-(甲磺酰基)-4-氧-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;3-氟-5-(4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3,5-二氟苯基)-4-羟基-4,5,6,7-四氢-1H-吲哚-3-氰;3-氟-5-(4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3-氯-5-氟苯基)-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;3-氟-5-(4-氧-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3,3-二氟环丁基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,3-二氟环丁基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇;2-氟-5-(4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3,5-二氟苯基)-3-(1-甲基-1H-吡唑-5-基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-1-(3-氯-5-氟苯基)-5,5-二氟-3-(噻吩-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(4-氟苄基)-3-(1-甲基-1H-吡唑-5-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-5,5-二氟-3-(噻吩-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(1-甲基-1H-吡咯-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-3-环丙基-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(呋喃-2-基)-4,5,6,7-四氢-1H-吲哚-4-醇;5-(5,5-二氟-4-羟基-3-(噻唑-5-基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯甲腈;1-(3-氯-5-氟苯基)-5,5-二氟-3-(呋喃-3-基)-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3-氯-5-氟苯基)-5,5-二氟-3-(呋喃-3-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(1H-吡唑-3-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(5-甲基-1H-吡唑-3-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(1-甲基-1H-吡唑-5-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(噻吩-3-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-甲基-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(噻唑-4-基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(噻唑-5-基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-1-(3,5-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-3-(二氟甲基)-5,5-二氟-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-乙烯基-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(羟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-(3-氯-5-氟苯基)-7-氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;5-(7,7-二氟-8-羟基-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-3-基)-2-对氟苯甲腈;(S)-5-(7,7-二氟-8-羟基-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-3-基)-2-对氟苯甲腈;3-(3-氯-5-氟苯基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚基-8-醇;7-氟-3-苯基-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;3-(3,5-二氟苯基)-7-氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;7-氟-3-(4-氟-3-(三氟甲基)苯基)-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;2-氟-5-(7-氟-8-羟基-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-3-基)苯甲腈;3-(3,5-二氟苯基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;3-(7,7-二氟-8-羟基-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-3-基)-5-对氟苯甲腈;(E)-3-(2-环己基乙烯基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;3-(环丙基乙炔基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;7,7-二氟-1-(三氟甲基)-3-(3,4,5-三氟苯基)-5,6,7,8-四氢吲哚嗪-8-醇;7,7-二氟-3-(4-氟-3-(三氟甲基)苯基)-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;3-(3-(二氟甲基)-4-氟苯基)-7,7-二氟-1-(三氟甲基)-6,7-二氢吲哚嗪-8(5H)-酮;7,7-二氟-1-(三氟甲基)-3-(3,4,5-三氟苯基)-6,7-二氢吲哚嗪-8(5H)-酮;7,7-二氟-3-(4-氟-3-(三氟甲基)苯基)-1-(三氟甲基)-6,7-二氢吲哚嗪-8(5H)-酮;7,7-二氟-3-(1-苯基环丙基)-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;7,7-二氟-3-(苯基乙炔基)-1-(三氟甲基)-5,6,7,8-四氢吲哚嗪-8-醇;(1-(3-氯-5-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-基)二甲基氧膦;(S)-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯甲腈;1-(3-氯-5-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-腈;1-(3-氯-5-氟苯基)-5,6-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(4-氟-3-(羟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(6-氟吡啶-2-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5-(5,5-二氟-4-羟基-4-甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;5-(5,5-二氟-4-羟基-6,6-二甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;2-氟-5-(5-氟-4-羟基-6,6-二甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;(4S,5S)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(4R,5R)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(4S,5R)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(4R,5S)-1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-2,5,5-三氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-2-氯-1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-(二氟甲基)-4-氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈;3-(3-(二氟甲基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈;3-(3-((二氟甲基)磺酰基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-1-基)-5-氟苯甲腈;1-(3-氯-5-氟苯基)-3,5,5-三氟-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-2-氰;(R)-1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-1,5,6,7-四氢-4H-吲哚-4-酮;3-(3-氯-5-氟苯基)-6,6-二氟-1-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-7-醇;1-(3-氯-4-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈;5,5-二氟-1-(1-甲基-1H-吡咯-2-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;2-氯-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二甲腈;5,5-二氟-1-(呋喃-2-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;2-氰基-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲酸;2-乙酰基-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3-氯-5-氟苯基)-5,6-二氟-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(4-氯苯基)-5,6-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;2-氟-5-((4S)-5-氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;5,6-二氟-1-(5-氟吡啶-3-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(5-氟吡啶-3-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-5-(5,5-二氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯腈;1-(3-氯-5-氟苯基)-5,5-二氟-3-((S)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-((R)-甲基亚砜基)-4,5,6,7-四氢-1H-吲哚-4-醇;2-氯-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(4-氯-3-硝基苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-氟-5-(5-氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;1-(3-氨基-5-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,7-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5-氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5-氟-2-甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氯-5-氟苯基)-5,5-二氟-3-苯基-1,5,6,7-四氢-4H-吲哚-4-酮;1-(3-氯-5-氟苯基)-5,5-二氟-3-苯基-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-2-溴-1-(3,5-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(噻吩-3-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-3-(三氟甲基)-1-(3,4,5-三氟苯基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3,5-二氯-4-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;3-(3-氯-5-氟苯基)-6,7-二氟-1-(三氟甲基)-5,6,7,8-四氢吲哚基-8-醇;3-(3-氯-5-氟苯基)-6,7-二氟-1-(三氟甲基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇;3-(3-氯-5-氟苯基)-5,6-二氟-1-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-7-醇;3-(3-氯-5-氟苯基)-5,6-二氟-1-(三氟甲基)-4,5,6,7-四氢-1H-吲哒唑-7-醇;3-氯-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-甲氧基苯甲腈;5,5-二氟-1-(4-氟-3-(三氟甲基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-(三氟甲基)苯甲腈;5,5-二氟-1-(3-氟-4-甲氧基苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(吡啶-4-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(4-氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(3-(甲磺酰基)苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(2-甲氧基吡啶-4-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)吡啶甲腈;1-(3,4-二氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(2-氟吡啶-4-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(3-氰基-4-氟苯基)-5,5-二氟-4-羟基-4,5,6,7-四氢-1H-吲哚-3-腈;(S)-4-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)邻苯二甲腈;1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(4-氟-3-甲基苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(6-氟吡啶-3-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5,5-二氟-1-(5-氟吡啶-2-基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;1-(2-氯吡啶-4-基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(R)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇(R)-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;5-(5,5-二氟-4-羟基-3-(三氟甲基)-4-乙烯基-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;(S)-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)烟腈;5,5-二氟-1-(4-氟苯基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-甲腈;5-(5,5-二氟-4-羟基-6-甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;5-((4S)-5,5-二氟-4-羟基-6-甲基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;(E)-5,5-二氟-1-苯乙烯基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(E)-5,5-二氟-1-苯乙烯基-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;1-(苯磺酰基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(E)-1-(2-环己基乙烯基)-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;5,5-二氟-1-(苯磺酰基)-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;5,5-二氟-1-(苯磺酰基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(E)-1-(2-环己基乙烯基)-5,5-二氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;5-(5,5-二氟-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;5-(5,5-二氟-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-氟苯甲醛;1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;2-氟-5-(5-氟-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲醛;1-(3-(二氟甲基)-4-氟苯基)-5-氟-3-(三氟甲基)-1,5,6,7-四氢-4H-吲哚-4-酮;3-氟-5-(5-氟-4-羟基-3-(甲磺酰基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;3-(3-氯-5-氟苯基)-7,7-二氟-1-(三氟甲基)-5,6,7,8-四氢咪唑并[1,5-a]吡啶-8-醇;3-(3-氯-5-氟苯基)-6,6-二氟-1-(三氟甲基)-4,5,6,7-四氢-1H-吲哒唑-7-醇;(S)-1-(3,5-二氟苯基)-5,5-二氟-3-(甲磺酰基)-2-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-4-醇;(S)-2-氟-5-(4,5,5-三氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;(R)-2-氟-5-(4,5,5-三氟-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)苯甲腈;(Z)-5-(5,5-二氟-4-(羟基亚氨基)-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基)-2-对氟苯甲腈;或(S)-5-(5,5-二氟-4-羟基-3-(三氟甲基)-4,5,6,7-四氢-1H-吲哚-1-基-4-d)-2-对氟苯甲腈。
- 一种药物组合物,其特征在于,包含治疗有效量的至少一种权利要求1-24任一所述的化合物和至少一种药学上可接受的辅料。
- 权利要求1-24任一所述的化合物或权利要求25所述的药物组合物在制备用于治疗由HIF-2α介导的疾病的药物中的应用。
- 根据权利要求26所述的应用,其特征在于,所述的疾病是VHL综合征、自身免疫疾病、炎性疾病和/或癌症。
- 根据权利要求27所述的应用,其特征在于,所述的癌症选自血液学癌症、淋巴瘤、多发性骨髓瘤、消化系统肿瘤、生殖系统肿瘤、脑瘤、神经系统肿瘤赘瘤。
- 根据权利要求28所述的应用,其特征在于,所述癌症选自胶质瘤、嗜铬细胞瘤、副神经节瘤、结肠癌、直肠癌、前列腺癌、肺癌、胰腺癌、肝癌、肾癌、子宫颈癌、子宫癌、胃癌、卵巢癌、乳腺癌、皮肤癌、脑癌、脑脊膜瘤、神经细胞瘤、脑膜瘤和髓母细胞瘤。
- 一种治疗和/或预防由HIF-2α介导的疾病的方法,其特征在于,向治疗对象施用治疗有效量的权利要求1-24任一项所述的化合物或权利要求25所述的药物组合物。
- 根据权利要求30所述的方法,其特征在于,所述HIF-2α介导的疾病是癌症。
- 根据权利要求31所述的方法,其特征在于,所述的癌症选自胶质瘤、嗜铬细胞瘤、副神经节瘤、结肠癌、直肠癌、前列腺癌、肺癌、胰腺癌、肝癌、肾癌、子宫颈癌、子宫癌、胃癌、卵巢癌、乳腺癌、皮肤癌、脑癌、脑脊膜瘤、神经细胞瘤、脑膜瘤和髓母细胞瘤。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022576169A JP2023529471A (ja) | 2020-06-11 | 2021-06-10 | 二環化合物及びその使用 |
US18/009,362 US20230219890A1 (en) | 2020-06-11 | 2021-06-10 | Bicyclic compounds and use thereof |
CN202180037614.5A CN115884966A (zh) | 2020-06-11 | 2021-06-10 | 双环化合物及其应用 |
CN202310446687.0A CN117126097A (zh) | 2020-06-11 | 2021-06-10 | 双环化合物及其应用 |
CA3186769A CA3186769A1 (en) | 2020-06-11 | 2021-06-10 | Bicyclic compounds and use thereof |
AU2021287852A AU2021287852A1 (en) | 2020-06-11 | 2021-06-10 | Bicyclic compound and application thereof |
KR1020237001302A KR20230027161A (ko) | 2020-06-11 | 2021-06-10 | 비시클릭 화합물 및 이의 응용 |
EP21820923.7A EP4166542A1 (en) | 2020-06-11 | 2021-06-10 | Bicyclic compound and application thereof |
IL298966A IL298966A (en) | 2020-06-11 | 2021-06-10 | A bicyclic compound and its application |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2020095654 | 2020-06-11 | ||
CNPCT/CN2020/095654 | 2020-06-11 | ||
CN2020112063 | 2020-08-28 | ||
CNPCT/CN2020/112063 | 2020-08-28 | ||
CN202110610887.6 | 2021-06-01 | ||
CN202110610887 | 2021-06-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021249463A1 true WO2021249463A1 (zh) | 2021-12-16 |
Family
ID=78845383
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/099316 WO2021249463A1 (zh) | 2020-06-11 | 2021-06-10 | 双环化合物及其应用 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20230219890A1 (zh) |
EP (1) | EP4166542A1 (zh) |
JP (1) | JP2023529471A (zh) |
KR (1) | KR20230027161A (zh) |
CN (2) | CN115884966A (zh) |
AU (1) | AU2021287852A1 (zh) |
CA (1) | CA3186769A1 (zh) |
IL (1) | IL298966A (zh) |
TW (1) | TW202214563A (zh) |
WO (1) | WO2021249463A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023077046A1 (en) * | 2021-10-29 | 2023-05-04 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha and methods of use thereof |
WO2023078369A1 (zh) * | 2021-11-02 | 2023-05-11 | 贝达药业股份有限公司 | 双环化合物及其应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011115804A1 (en) * | 2010-03-17 | 2011-09-22 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
CN105530923A (zh) * | 2013-09-09 | 2016-04-27 | 佩洛通治疗公司 | 芳基醚及其用途 |
WO2016145032A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
WO2016144826A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
WO2018031680A1 (en) * | 2016-08-10 | 2018-02-15 | Fronthera U.S. Pharmaceuticals Llc | Novel compounds, uses and methods for their preparation |
US20190151347A1 (en) * | 2017-11-20 | 2019-05-23 | University Of Georgia Research Foundation, Inc. | Compositions and methods of modulating hif-2a; to improve muscle generation and repair |
WO2019219731A1 (en) * | 2018-05-18 | 2019-11-21 | Merck Patent Gmbh | Thiophene derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL275478B1 (en) * | 2017-12-20 | 2024-02-01 | Betta Pharmaceuticals Co Ltd | A preparation that functions as a bromodomain protein inhibitor, and the composition |
WO2019233456A1 (zh) * | 2018-06-08 | 2019-12-12 | 贝达药业股份有限公司 | Erk抑制剂及其应用 |
-
2021
- 2021-06-10 TW TW110121101A patent/TW202214563A/zh unknown
- 2021-06-10 WO PCT/CN2021/099316 patent/WO2021249463A1/zh unknown
- 2021-06-10 US US18/009,362 patent/US20230219890A1/en active Pending
- 2021-06-10 JP JP2022576169A patent/JP2023529471A/ja active Pending
- 2021-06-10 CN CN202180037614.5A patent/CN115884966A/zh active Pending
- 2021-06-10 IL IL298966A patent/IL298966A/en unknown
- 2021-06-10 AU AU2021287852A patent/AU2021287852A1/en active Pending
- 2021-06-10 KR KR1020237001302A patent/KR20230027161A/ko active Search and Examination
- 2021-06-10 CN CN202310446687.0A patent/CN117126097A/zh active Pending
- 2021-06-10 CA CA3186769A patent/CA3186769A1/en active Pending
- 2021-06-10 EP EP21820923.7A patent/EP4166542A1/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011115804A1 (en) * | 2010-03-17 | 2011-09-22 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
CN105530923A (zh) * | 2013-09-09 | 2016-04-27 | 佩洛通治疗公司 | 芳基醚及其用途 |
WO2016145032A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
WO2016144826A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
WO2018031680A1 (en) * | 2016-08-10 | 2018-02-15 | Fronthera U.S. Pharmaceuticals Llc | Novel compounds, uses and methods for their preparation |
US20190151347A1 (en) * | 2017-11-20 | 2019-05-23 | University Of Georgia Research Foundation, Inc. | Compositions and methods of modulating hif-2a; to improve muscle generation and repair |
WO2019219731A1 (en) * | 2018-05-18 | 2019-11-21 | Merck Patent Gmbh | Thiophene derivatives |
Non-Patent Citations (1)
Title |
---|
"Design of Prodrugs", 1985, ELSEVIER |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023077046A1 (en) * | 2021-10-29 | 2023-05-04 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha and methods of use thereof |
WO2023078369A1 (zh) * | 2021-11-02 | 2023-05-11 | 贝达药业股份有限公司 | 双环化合物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
TW202214563A (zh) | 2022-04-16 |
AU2021287852A1 (en) | 2023-02-02 |
CN115884966A (zh) | 2023-03-31 |
JP2023529471A (ja) | 2023-07-10 |
CA3186769A1 (en) | 2021-12-16 |
CN117126097A (zh) | 2023-11-28 |
US20230219890A1 (en) | 2023-07-13 |
KR20230027161A (ko) | 2023-02-27 |
EP4166542A1 (en) | 2023-04-19 |
IL298966A (en) | 2023-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108430998A (zh) | 氮杂双环衍生物及其制备方法和用途 | |
WO2018149284A1 (zh) | 激酶抑制剂及其制备方法和用途 | |
TW201835070A (zh) | 芳香烴受體(AhR)調節劑化合物 | |
WO2020063792A1 (zh) | 吲哚类大环衍生物、其制备方法及其在医药上的应用 | |
WO2016150255A1 (zh) | 稠环衍生物、其制备方法、中间体、药物组合物及应用 | |
WO2022100623A1 (zh) | 氮取代杂环噻吩类化合物及其用途 | |
WO2020007322A1 (zh) | 一种靶向降解bet蛋白的化合物及其应用 | |
WO2021218755A1 (zh) | Shp2抑制剂及其组合物和应用 | |
HUE030067T2 (en) | Bicyclic pyrazinone derivatives | |
WO2021249463A1 (zh) | 双环化合物及其应用 | |
WO2022100625A1 (zh) | 氮取代氨基碳酸酯噻吩类化合物及其用途 | |
WO2023072273A1 (zh) | 作为cbl-b抑制剂的并环化合物 | |
WO2022063115A1 (zh) | 双环化合物及其应用 | |
AU2022320004A1 (en) | Organic pyridine-pyrazole compounds and their uses | |
WO2021227906A1 (zh) | 一种作为cdk抑制剂的吡啶乙酰胺类衍生物、其制备方法及用途 | |
WO2022171088A1 (zh) | 吡唑并[3,4-d]嘧啶-3-酮衍生物 | |
WO2020156162A1 (zh) | Mek抑制剂及其在医药上的应用 | |
WO2021254416A1 (zh) | 茚酮类化合物及其应用 | |
WO2021254417A1 (zh) | 双环类化合物及其应用 | |
WO2023078369A1 (zh) | 双环化合物及其应用 | |
WO2024067463A1 (zh) | 苯并[7]环烯类衍生物、包含其的药物组合物及其医药用途 | |
WO2024114680A1 (zh) | 杂环化合物、药物组合物及其应用 | |
WO2024067802A1 (zh) | 蛋白酪氨酸磷酸酶抑制剂及其制备方法和医药用途 | |
WO2022089219A1 (zh) | 芳基酰胺化合物、包含其的药物组合物及其制备方法和用途 | |
WO2023134713A1 (zh) | 氮杂并环衍生物、其药物组合物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21820923 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2022576169 Country of ref document: JP Kind code of ref document: A Ref document number: 3186769 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2021820923 Country of ref document: EP Effective date: 20230111 |
|
ENP | Entry into the national phase |
Ref document number: 2021287852 Country of ref document: AU Date of ref document: 20210610 Kind code of ref document: A |