CN115087486A - 取代的双环和三环脲和酰胺、其类似物及其使用方法 - Google Patents
取代的双环和三环脲和酰胺、其类似物及其使用方法 Download PDFInfo
- Publication number
- CN115087486A CN115087486A CN202080095887.0A CN202080095887A CN115087486A CN 115087486 A CN115087486 A CN 115087486A CN 202080095887 A CN202080095887 A CN 202080095887A CN 115087486 A CN115087486 A CN 115087486A
- Authority
- CN
- China
- Prior art keywords
- oxo
- fluorophenyl
- isoquinolin
- chloro
- tetrahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 253
- 235000013877 carbamide Nutrition 0.000 title description 20
- 150000003672 ureas Chemical class 0.000 title description 5
- 125000002619 bicyclic group Chemical group 0.000 title description 4
- 150000001408 amides Chemical class 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 202
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 62
- 208000037262 Hepatitis delta Diseases 0.000 claims abstract description 24
- 241000724709 Hepatitis delta virus Species 0.000 claims abstract description 24
- 208000015181 infectious disease Diseases 0.000 claims abstract description 23
- -1 isoindolin-2-yl Chemical group 0.000 claims description 375
- 150000001875 compounds Chemical class 0.000 claims description 279
- 125000000217 alkyl group Chemical group 0.000 claims description 110
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims description 106
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 102
- 230000015572 biosynthetic process Effects 0.000 claims description 88
- 239000008194 pharmaceutical composition Substances 0.000 claims description 58
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 44
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 239000004202 carbamide Substances 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 150000003254 radicals Chemical class 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 21
- 239000003112 inhibitor Substances 0.000 claims description 20
- USEGMRQULIIIFR-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CCCO)=O USEGMRQULIIIFR-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 229940124765 capsid inhibitor Drugs 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 108090000623 proteins and genes Proteins 0.000 claims description 14
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 13
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 13
- 230000008685 targeting Effects 0.000 claims description 13
- 208000006454 hepatitis Diseases 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 150000001721 carbon Chemical group 0.000 claims description 11
- 231100000283 hepatitis Toxicity 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- YWZVBTGLHUDHRQ-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-(6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CC(C)C)=O YWZVBTGLHUDHRQ-UHFFFAOYSA-N 0.000 claims description 10
- SNCAKWRQRPQPSY-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C3=CC=CC=C3C1=2)=O)C)=O SNCAKWRQRPQPSY-UHFFFAOYSA-N 0.000 claims description 10
- 108091034117 Oligonucleotide Proteins 0.000 claims description 10
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 9
- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 230000003308 immunostimulating effect Effects 0.000 claims description 9
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 229940002612 prodrug Drugs 0.000 claims description 9
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 8
- 230000000368 destabilizing effect Effects 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 208000002672 hepatitis B Diseases 0.000 claims description 7
- 108090000565 Capsid Proteins Proteins 0.000 claims description 6
- 108091036055 CccDNA Proteins 0.000 claims description 6
- 102100023321 Ceruloplasmin Human genes 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 230000003612 virological effect Effects 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
- BKGUJEZHQHPTJD-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1F)N(C(=O)NC1(CC1)C(F)(F)F)C)=O BKGUJEZHQHPTJD-UHFFFAOYSA-N 0.000 claims description 5
- AHISYTFRZNMJHT-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F AHISYTFRZNMJHT-GOSISDBHSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 229960001438 immunostimulant agent Drugs 0.000 claims description 5
- ZRAKIAHSFGGPNQ-QGZVFWFLSA-N 1-(3-cyano-4-fluorophenyl)-3-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(=O)N[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O ZRAKIAHSFGGPNQ-QGZVFWFLSA-N 0.000 claims description 4
- DYMHACPYSMBQTG-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1F)N(C(=O)NC1=CC=C(C=C1)F)C)=O DYMHACPYSMBQTG-UHFFFAOYSA-N 0.000 claims description 4
- REBNSCKSPQTBIX-UHFFFAOYSA-N 1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)CC(C)C REBNSCKSPQTBIX-UHFFFAOYSA-N 0.000 claims description 4
- MINRWLGPRMXKGG-UHFFFAOYSA-N 1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1)N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)=O MINRWLGPRMXKGG-UHFFFAOYSA-N 0.000 claims description 4
- DZQHZRKKFSPUJO-GOSISDBHSA-N 1-[(1S)-5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COC[C@H]2N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F)F)=O DZQHZRKKFSPUJO-GOSISDBHSA-N 0.000 claims description 4
- OPLSPORMUKRDIF-GOSISDBHSA-N 1-[(1S)-5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COC[C@H]2N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F)F)=O OPLSPORMUKRDIF-GOSISDBHSA-N 0.000 claims description 4
- DHPYSRINHBTFAV-LJQANCHMSA-N 1-[(1S)-6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)[C@@H](COC2)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C DHPYSRINHBTFAV-LJQANCHMSA-N 0.000 claims description 4
- XJKCAKQHCWXYDO-LJQANCHMSA-N 1-[(1S)-6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)[C@@H](COC2)N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C XJKCAKQHCWXYDO-LJQANCHMSA-N 0.000 claims description 4
- GUOGJILWXHCHIM-GOSISDBHSA-N 1-[(1S)-8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)CCO)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F GUOGJILWXHCHIM-GOSISDBHSA-N 0.000 claims description 4
- KLRHAWGGSZFJNC-GOSISDBHSA-N 1-[(1S)-8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KLRHAWGGSZFJNC-GOSISDBHSA-N 0.000 claims description 4
- HKGLDNQVMIZZKY-CYBMUJFWSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1(CC1)C(F)(F)F)C)F HKGLDNQVMIZZKY-CYBMUJFWSA-N 0.000 claims description 4
- ZMBBOGVDLFILGU-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O ZMBBOGVDLFILGU-UHFFFAOYSA-N 0.000 claims description 4
- KNVCGSMEEFVXNG-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(6-methoxy-1,2,3,4-tetrahydrophenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CCCC2=NC(=C3C=CC=CC3=C12)OC)=O KNVCGSMEEFVXNG-UHFFFAOYSA-N 0.000 claims description 4
- WVOJXEIFDLJXJR-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,10-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CCCC=2NC(C3=CC(=CC(=C3C1=2)F)F)=O)=O WVOJXEIFDLJXJR-UHFFFAOYSA-N 0.000 claims description 4
- KELBMUDITFJNBW-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-4,6-dioxo-2,5-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COC(C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O KELBMUDITFJNBW-UHFFFAOYSA-N 0.000 claims description 4
- PTTWQPVEJMXILW-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CCCC=2NC(C3=CC(=C(C=C3C1=2)F)F)=O)=O PTTWQPVEJMXILW-UHFFFAOYSA-N 0.000 claims description 4
- ULFFFRCRAVBKJP-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)C1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ULFFFRCRAVBKJP-UHFFFAOYSA-N 0.000 claims description 4
- UGMDUOMEUZTMDI-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OCCO)=O UGMDUOMEUZTMDI-LJQANCHMSA-N 0.000 claims description 4
- UXCKRBIRFTYFEO-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OC)=O UXCKRBIRFTYFEO-GOSISDBHSA-N 0.000 claims description 4
- KLGDZXZPMCXCJR-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(5-methyl-6-oxo-1,2,3,4-tetrahydrophenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2N(C(C3=CC=CC=C3C1=2)=O)C)C)=O KLGDZXZPMCXCJR-UHFFFAOYSA-N 0.000 claims description 4
- SNCAKWRQRPQPSY-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1R)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)C)=O SNCAKWRQRPQPSY-GOSISDBHSA-N 0.000 claims description 4
- SNCAKWRQRPQPSY-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1S)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)C)=O SNCAKWRQRPQPSY-SFHVURJKSA-N 0.000 claims description 4
- NKUYFBCXQNADMO-MRXNPFEDSA-N 3-(3-chloro-4-hydroxyphenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1O)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NKUYFBCXQNADMO-MRXNPFEDSA-N 0.000 claims description 4
- XGSYTOPAJUKUGM-QGZVFWFLSA-N 3-(3-chloro-4-methoxyphenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1OC)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O XGSYTOPAJUKUGM-QGZVFWFLSA-N 0.000 claims description 4
- HLPOMOGOSUFNIQ-GOSISDBHSA-N 3-(4-chloro-3-cyanophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)C#N HLPOMOGOSUFNIQ-GOSISDBHSA-N 0.000 claims description 4
- ZATVRHZDBXQQCA-QGZVFWFLSA-N 3-(4-chloro-3-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)F ZATVRHZDBXQQCA-QGZVFWFLSA-N 0.000 claims description 4
- ATZAALIEVIHFRP-GOSISDBHSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1S)-8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ATZAALIEVIHFRP-GOSISDBHSA-N 0.000 claims description 4
- NKCDCEYERXHNER-LJQANCHMSA-N N-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)N1CC2=CC=CC=C2C1)C)F NKCDCEYERXHNER-LJQANCHMSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 208000029570 hepatitis D virus infection Diseases 0.000 claims description 4
- 239000003022 immunostimulating agent Substances 0.000 claims description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- FGZMIMISQGSJKF-UHFFFAOYSA-N 1-(3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1CC(C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C FGZMIMISQGSJKF-UHFFFAOYSA-N 0.000 claims description 3
- MOXKMIOWFIKXSO-MRXNPFEDSA-N 1-(3-chloro-4-fluorophenyl)-3-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)N[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O MOXKMIOWFIKXSO-MRXNPFEDSA-N 0.000 claims description 3
- NQFNPDLMZOQDFX-MRXNPFEDSA-N 1-(3-chloro-4-fluorophenyl)-3-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)N[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O NQFNPDLMZOQDFX-MRXNPFEDSA-N 0.000 claims description 3
- OCUXGNPCNQAHTR-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C)C)F OCUXGNPCNQAHTR-UHFFFAOYSA-N 0.000 claims description 3
- KTXCGNFZHJVNNQ-UHFFFAOYSA-N 1-[6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCN)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KTXCGNFZHJVNNQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- WULIWRMNZLVONY-QGZVFWFLSA-N 3-(3,4-dichlorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1Cl)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O WULIWRMNZLVONY-QGZVFWFLSA-N 0.000 claims description 3
- MGHPVSLDRSRYFC-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(CC(C)C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MGHPVSLDRSRYFC-UHFFFAOYSA-N 0.000 claims description 3
- DTQMZAIGKXIBMP-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methylurea Chemical compound FC=1C=C(C=CC=1F)NC(N(C)C1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O DTQMZAIGKXIBMP-UHFFFAOYSA-N 0.000 claims description 3
- RYBWBFUHLFPRNM-UHFFFAOYSA-N 3-(3,5-dichloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)Cl)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RYBWBFUHLFPRNM-UHFFFAOYSA-N 0.000 claims description 3
- OGYKARXNZGRZLF-UHFFFAOYSA-N 3-(3-chloro-4,5-difluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O OGYKARXNZGRZLF-UHFFFAOYSA-N 0.000 claims description 3
- HRMHNGLZRUWGHR-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-(5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O HRMHNGLZRUWGHR-UHFFFAOYSA-N 0.000 claims description 3
- XXOVWGPFHRUTPE-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-(6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O XXOVWGPFHRUTPE-UHFFFAOYSA-N 0.000 claims description 3
- LRKXULYGPJCLEA-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCC=2NC(C=3C=CC=CC=3C=21)=O)CCCO)=O LRKXULYGPJCLEA-UHFFFAOYSA-N 0.000 claims description 3
- GLUQNFMNUALIIA-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCCC=2NC(C3=CC=CC=C3C=21)=O)CCCO)=O GLUQNFMNUALIIA-UHFFFAOYSA-N 0.000 claims description 3
- IBYIRYJIURZFDK-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-4-hydroxy-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COC(C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)O)=O IBYIRYJIURZFDK-UHFFFAOYSA-N 0.000 claims description 3
- ZOGVHAJBIUZCJV-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZOGVHAJBIUZCJV-UHFFFAOYSA-N 0.000 claims description 3
- VIMJYCMJWXPZGL-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-hydroxy-2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)(C)O)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O VIMJYCMJWXPZGL-UHFFFAOYSA-N 0.000 claims description 3
- QIRKVVHJYOMCAC-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O QIRKVVHJYOMCAC-UHFFFAOYSA-N 0.000 claims description 3
- LUNARCYFNAWKCV-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O LUNARCYFNAWKCV-UHFFFAOYSA-N 0.000 claims description 3
- ZRKMKDRBAHXBCH-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)C1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ZRKMKDRBAHXBCH-UHFFFAOYSA-N 0.000 claims description 3
- ZOGVHAJBIUZCJV-XHXSEOGJSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-1-deuterio-8,9-difluoro-6-oxo-4,5-dihydro-2H-pyrano[3,4-c]isoquinolin-1-yl]-1-(trideuteriomethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C([2H])([2H])[2H])[C@@]1(COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)[2H])=O ZOGVHAJBIUZCJV-XHXSEOGJSA-N 0.000 claims description 3
- RORDHOAUIKYOBT-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N(C(C=3C=C(C(=CC=3C=21)F)F)=O)CCO)=O RORDHOAUIKYOBT-GOSISDBHSA-N 0.000 claims description 3
- ZOGVHAJBIUZCJV-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZOGVHAJBIUZCJV-QGZVFWFLSA-N 0.000 claims description 3
- LUNARCYFNAWKCV-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O LUNARCYFNAWKCV-QGZVFWFLSA-N 0.000 claims description 3
- WBCQYAGTGJWCRP-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)CC)=O WBCQYAGTGJWCRP-UHFFFAOYSA-N 0.000 claims description 3
- WBCQYAGTGJWCRP-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)CC)=O WBCQYAGTGJWCRP-GOSISDBHSA-N 0.000 claims description 3
- ZXVJFVZZXKYRBL-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O ZXVJFVZZXKYRBL-UHFFFAOYSA-N 0.000 claims description 3
- XIYAWXMPHNJHKJ-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCCC=2NC(C3=CC=CC=C3C=21)=O)C)=O XIYAWXMPHNJHKJ-UHFFFAOYSA-N 0.000 claims description 3
- OBPAWLSEXVDLRD-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O OBPAWLSEXVDLRD-UHFFFAOYSA-N 0.000 claims description 3
- RQNWYIRJNIRWTK-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RQNWYIRJNIRWTK-UHFFFAOYSA-N 0.000 claims description 3
- SJAJPXBWVTZCEU-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O SJAJPXBWVTZCEU-GOSISDBHSA-N 0.000 claims description 3
- MTKBPHCDBOXYCO-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MTKBPHCDBOXYCO-GOSISDBHSA-N 0.000 claims description 3
- LPSCYOZISIOMSV-UHFFFAOYSA-N 3-(4-fluoro-3-methylphenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)urea Chemical compound FC1=C(C=C(C=C1)NC(N(CC(C)C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C LPSCYOZISIOMSV-UHFFFAOYSA-N 0.000 claims description 3
- GRPILJRHSJYCLC-UHFFFAOYSA-N 3-(4-fluoro-3-methylphenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C GRPILJRHSJYCLC-UHFFFAOYSA-N 0.000 claims description 3
- FSPQWLPQEYIOSQ-UHFFFAOYSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC(C=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)F FSPQWLPQEYIOSQ-UHFFFAOYSA-N 0.000 claims description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- REEQWHGGBNYTJR-UHFFFAOYSA-N 1-(3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1CC(C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C REEQWHGGBNYTJR-UHFFFAOYSA-N 0.000 claims description 2
- TZPHZOOZRQGILK-UHFFFAOYSA-N 1-(3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1CC(C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C TZPHZOOZRQGILK-UHFFFAOYSA-N 0.000 claims description 2
- CFFHMXPMBYKEGH-UHFFFAOYSA-N 1-(3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1CC(C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C CFFHMXPMBYKEGH-UHFFFAOYSA-N 0.000 claims description 2
- MOXKMIOWFIKXSO-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-3-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)NC1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O MOXKMIOWFIKXSO-UHFFFAOYSA-N 0.000 claims description 2
- NQFNPDLMZOQDFX-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-3-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)NC1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O NQFNPDLMZOQDFX-UHFFFAOYSA-N 0.000 claims description 2
- MOXKMIOWFIKXSO-INIZCTEOSA-N 1-(3-chloro-4-fluorophenyl)-3-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)N[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O MOXKMIOWFIKXSO-INIZCTEOSA-N 0.000 claims description 2
- NQFNPDLMZOQDFX-INIZCTEOSA-N 1-(3-chloro-4-fluorophenyl)-3-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(=O)N[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O NQFNPDLMZOQDFX-INIZCTEOSA-N 0.000 claims description 2
- ZRAKIAHSFGGPNQ-UHFFFAOYSA-N 1-(3-cyano-4-fluorophenyl)-3-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(=O)NC1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O ZRAKIAHSFGGPNQ-UHFFFAOYSA-N 0.000 claims description 2
- ZRAKIAHSFGGPNQ-KRWDZBQOSA-N 1-(3-cyano-4-fluorophenyl)-3-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(=O)N[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O ZRAKIAHSFGGPNQ-KRWDZBQOSA-N 0.000 claims description 2
- KLRHAWGGSZFJNC-UHFFFAOYSA-N 1-(8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KLRHAWGGSZFJNC-UHFFFAOYSA-N 0.000 claims description 2
- OQRGNWRXVLUVPQ-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)F OQRGNWRXVLUVPQ-UHFFFAOYSA-N 0.000 claims description 2
- HKGLDNQVMIZZKY-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1(CC1)C(F)(F)F)C)F HKGLDNQVMIZZKY-UHFFFAOYSA-N 0.000 claims description 2
- WQHWZGCCSRADAC-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methyl-3-phenylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC=CC=C1)C)F WQHWZGCCSRADAC-UHFFFAOYSA-N 0.000 claims description 2
- JKIWJOXVUWQVEC-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)F)C)F JKIWJOXVUWQVEC-UHFFFAOYSA-N 0.000 claims description 2
- GOMOHGDDROPFOK-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC=C(C=C1)F)C)F GOMOHGDDROPFOK-UHFFFAOYSA-N 0.000 claims description 2
- XJIGWNSPVFROME-UHFFFAOYSA-N 1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNCC(C2=3)N(C(=O)NC2=CC(=C(C=C2)F)F)C)=O)C=1)F XJIGWNSPVFROME-UHFFFAOYSA-N 0.000 claims description 2
- XGMHIFUVYDEDFV-UHFFFAOYSA-N 1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-ethyl-3-(4-fluoro-3-methylphenyl)urea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C)CC XGMHIFUVYDEDFV-UHFFFAOYSA-N 0.000 claims description 2
- HYAZMEUKQRIMTH-UHFFFAOYSA-N 1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(3-cyano-4-fluorophenyl)-1-ethylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C#N)CC HYAZMEUKQRIMTH-UHFFFAOYSA-N 0.000 claims description 2
- VOHKMSYWSQBQGR-UHFFFAOYSA-N 1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C#N)C VOHKMSYWSQBQGR-UHFFFAOYSA-N 0.000 claims description 2
- GYPBLEKRVXKBRN-UHFFFAOYSA-N 1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C)C GYPBLEKRVXKBRN-UHFFFAOYSA-N 0.000 claims description 2
- REEQWHGGBNYTJR-IBGZPJMESA-N 1-[(1R)-3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@@H](C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C REEQWHGGBNYTJR-IBGZPJMESA-N 0.000 claims description 2
- TZPHZOOZRQGILK-IBGZPJMESA-N 1-[(1R)-3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@@H](C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C TZPHZOOZRQGILK-IBGZPJMESA-N 0.000 claims description 2
- CFFHMXPMBYKEGH-FQEVSTJZSA-N 1-[(1R)-3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@@H](C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C CFFHMXPMBYKEGH-FQEVSTJZSA-N 0.000 claims description 2
- DZQHZRKKFSPUJO-SFHVURJKSA-N 1-[(1R)-5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COC[C@@H]2N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F)F)=O DZQHZRKKFSPUJO-SFHVURJKSA-N 0.000 claims description 2
- OPLSPORMUKRDIF-SFHVURJKSA-N 1-[(1R)-5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COC[C@@H]2N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F)F)=O OPLSPORMUKRDIF-SFHVURJKSA-N 0.000 claims description 2
- DHPYSRINHBTFAV-IBGZPJMESA-N 1-[(1R)-6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)[C@H](COC2)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C DHPYSRINHBTFAV-IBGZPJMESA-N 0.000 claims description 2
- XJKCAKQHCWXYDO-IBGZPJMESA-N 1-[(1R)-6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)[C@H](COC2)N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C XJKCAKQHCWXYDO-IBGZPJMESA-N 0.000 claims description 2
- HFWAHSBKIHFQKV-IBGZPJMESA-N 1-[(1R)-6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCN)=O HFWAHSBKIHFQKV-IBGZPJMESA-N 0.000 claims description 2
- KTXCGNFZHJVNNQ-IBGZPJMESA-N 1-[(1R)-6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCN)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KTXCGNFZHJVNNQ-IBGZPJMESA-N 0.000 claims description 2
- GUOGJILWXHCHIM-SFHVURJKSA-N 1-[(1R)-8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)CCO)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F GUOGJILWXHCHIM-SFHVURJKSA-N 0.000 claims description 2
- NZFJPIKHAUEKJP-IBGZPJMESA-N 1-[(1R)-8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OCCO)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F NZFJPIKHAUEKJP-IBGZPJMESA-N 0.000 claims description 2
- ORNXUDOPPYEPMU-IBGZPJMESA-N 1-[(1R)-8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCO)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ORNXUDOPPYEPMU-IBGZPJMESA-N 0.000 claims description 2
- HVSCTHBPWHCJCD-SFHVURJKSA-N 1-[(1R)-8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NC)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F HVSCTHBPWHCJCD-SFHVURJKSA-N 0.000 claims description 2
- KLRHAWGGSZFJNC-SFHVURJKSA-N 1-[(1R)-8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KLRHAWGGSZFJNC-SFHVURJKSA-N 0.000 claims description 2
- OQRGNWRXVLUVPQ-INIZCTEOSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)F OQRGNWRXVLUVPQ-INIZCTEOSA-N 0.000 claims description 2
- HKGLDNQVMIZZKY-ZDUSSCGKSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1(CC1)C(F)(F)F)C)F HKGLDNQVMIZZKY-ZDUSSCGKSA-N 0.000 claims description 2
- WQHWZGCCSRADAC-KRWDZBQOSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-phenylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC=CC=C1)C)F WQHWZGCCSRADAC-KRWDZBQOSA-N 0.000 claims description 2
- JKIWJOXVUWQVEC-KRWDZBQOSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)F)C)F JKIWJOXVUWQVEC-KRWDZBQOSA-N 0.000 claims description 2
- OCUXGNPCNQAHTR-SFHVURJKSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)C)F OCUXGNPCNQAHTR-SFHVURJKSA-N 0.000 claims description 2
- GOMOHGDDROPFOK-KRWDZBQOSA-N 1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC=C(C=C1)F)C)F GOMOHGDDROPFOK-KRWDZBQOSA-N 0.000 claims description 2
- XJIGWNSPVFROME-KRWDZBQOSA-N 1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)NC2=CC(=C(C=C2)F)F)C)=O)C=1)F XJIGWNSPVFROME-KRWDZBQOSA-N 0.000 claims description 2
- BKGUJEZHQHPTJD-CQSZACIVSA-N 1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C=C2C(NC=3CCC[C@H](C=3C2=CC=1F)N(C(=O)NC1(CC1)C(F)(F)F)C)=O BKGUJEZHQHPTJD-CQSZACIVSA-N 0.000 claims description 2
- DYMHACPYSMBQTG-GOSISDBHSA-N 1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C=C2C(NC=3CCC[C@H](C=3C2=CC=1F)N(C(=O)NC1=CC=C(C=C1)F)C)=O DYMHACPYSMBQTG-GOSISDBHSA-N 0.000 claims description 2
- XGMHIFUVYDEDFV-IBGZPJMESA-N 1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethyl-3-(4-fluoro-3-methylphenyl)urea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)CC XGMHIFUVYDEDFV-IBGZPJMESA-N 0.000 claims description 2
- HYAZMEUKQRIMTH-IBGZPJMESA-N 1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-ethylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C#N)CC HYAZMEUKQRIMTH-IBGZPJMESA-N 0.000 claims description 2
- VOHKMSYWSQBQGR-SFHVURJKSA-N 1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C#N)C VOHKMSYWSQBQGR-SFHVURJKSA-N 0.000 claims description 2
- GYPBLEKRVXKBRN-SFHVURJKSA-N 1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)C GYPBLEKRVXKBRN-SFHVURJKSA-N 0.000 claims description 2
- REBNSCKSPQTBIX-IBGZPJMESA-N 1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)CC(C)C REBNSCKSPQTBIX-IBGZPJMESA-N 0.000 claims description 2
- MINRWLGPRMXKGG-QGZVFWFLSA-N 1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=C2C(NC=3CCC[C@H](C=3C2=CC=1)N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)=O MINRWLGPRMXKGG-QGZVFWFLSA-N 0.000 claims description 2
- REEQWHGGBNYTJR-LJQANCHMSA-N 1-[(1S)-3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@H](C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C REEQWHGGBNYTJR-LJQANCHMSA-N 0.000 claims description 2
- FGZMIMISQGSJKF-HXUWFJFHSA-N 1-[(1S)-3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@H](C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C FGZMIMISQGSJKF-HXUWFJFHSA-N 0.000 claims description 2
- TZPHZOOZRQGILK-LJQANCHMSA-N 1-[(1S)-3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@H](C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C TZPHZOOZRQGILK-LJQANCHMSA-N 0.000 claims description 2
- CFFHMXPMBYKEGH-HXUWFJFHSA-N 1-[(1S)-3-acetyl-8-fluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@H](C=2C3=C(C(NC=2C1)=O)C=C(C=C3)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C CFFHMXPMBYKEGH-HXUWFJFHSA-N 0.000 claims description 2
- HFWAHSBKIHFQKV-LJQANCHMSA-N 1-[(1S)-6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCN)=O HFWAHSBKIHFQKV-LJQANCHMSA-N 0.000 claims description 2
- ORNXUDOPPYEPMU-LJQANCHMSA-N 1-[(1S)-8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCO)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ORNXUDOPPYEPMU-LJQANCHMSA-N 0.000 claims description 2
- HVSCTHBPWHCJCD-GOSISDBHSA-N 1-[(1S)-8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NC)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F HVSCTHBPWHCJCD-GOSISDBHSA-N 0.000 claims description 2
- OQRGNWRXVLUVPQ-MRXNPFEDSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)F OQRGNWRXVLUVPQ-MRXNPFEDSA-N 0.000 claims description 2
- WQHWZGCCSRADAC-QGZVFWFLSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methyl-3-phenylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC=CC=C1)C)F WQHWZGCCSRADAC-QGZVFWFLSA-N 0.000 claims description 2
- JKIWJOXVUWQVEC-QGZVFWFLSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)F)C)F JKIWJOXVUWQVEC-QGZVFWFLSA-N 0.000 claims description 2
- GOMOHGDDROPFOK-QGZVFWFLSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC=C(C=C1)F)C)F GOMOHGDDROPFOK-QGZVFWFLSA-N 0.000 claims description 2
- XJIGWNSPVFROME-QGZVFWFLSA-N 1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-3-(3,4-difluorophenyl)-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)NC2=CC(=C(C=C2)F)F)C)=O)C=1)F XJIGWNSPVFROME-QGZVFWFLSA-N 0.000 claims description 2
- BKGUJEZHQHPTJD-AWEZNQCLSA-N 1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methyl-3-[1-(trifluoromethyl)cyclopropyl]urea Chemical compound FC=1C=C2C(NC=3CCC[C@@H](C=3C2=CC=1F)N(C(=O)NC1(CC1)C(F)(F)F)C)=O BKGUJEZHQHPTJD-AWEZNQCLSA-N 0.000 claims description 2
- DYMHACPYSMBQTG-SFHVURJKSA-N 1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-3-(4-fluorophenyl)-1-methylurea Chemical compound FC=1C=C2C(NC=3CCC[C@@H](C=3C2=CC=1F)N(C(=O)NC1=CC=C(C=C1)F)C)=O DYMHACPYSMBQTG-SFHVURJKSA-N 0.000 claims description 2
- XGMHIFUVYDEDFV-LJQANCHMSA-N 1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethyl-3-(4-fluoro-3-methylphenyl)urea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)CC XGMHIFUVYDEDFV-LJQANCHMSA-N 0.000 claims description 2
- HYAZMEUKQRIMTH-LJQANCHMSA-N 1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-ethylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C#N)CC HYAZMEUKQRIMTH-LJQANCHMSA-N 0.000 claims description 2
- VOHKMSYWSQBQGR-GOSISDBHSA-N 1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C#N)C VOHKMSYWSQBQGR-GOSISDBHSA-N 0.000 claims description 2
- GYPBLEKRVXKBRN-GOSISDBHSA-N 1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound ClC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)C GYPBLEKRVXKBRN-GOSISDBHSA-N 0.000 claims description 2
- MINRWLGPRMXKGG-KRWDZBQOSA-N 1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methyl-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=C2C(NC=3CCC[C@@H](C=3C2=CC=1)N(C(=O)NC1=CC(=C(C(=C1)F)F)F)C)=O MINRWLGPRMXKGG-KRWDZBQOSA-N 0.000 claims description 2
- DZQHZRKKFSPUJO-UHFFFAOYSA-N 1-[5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COCC2N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F)F)=O DZQHZRKKFSPUJO-UHFFFAOYSA-N 0.000 claims description 2
- OPLSPORMUKRDIF-UHFFFAOYSA-N 1-[5-(2-aminoethyl)-8,9-difluoro-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCN1C(C=2C=C(C(=CC=2C2=C1COCC2N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F)F)=O OPLSPORMUKRDIF-UHFFFAOYSA-N 0.000 claims description 2
- DHPYSRINHBTFAV-UHFFFAOYSA-N 1-[6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)C(COC2)N(C(=O)NC1=CC(=C(C=C1)F)Cl)C DHPYSRINHBTFAV-UHFFFAOYSA-N 0.000 claims description 2
- XJKCAKQHCWXYDO-UHFFFAOYSA-N 1-[6-(2-aminoethoxy)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound NCCOC1=NC2=C(C=3C=C(C(=CC1=3)F)F)C(COC2)N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C XJKCAKQHCWXYDO-UHFFFAOYSA-N 0.000 claims description 2
- HFWAHSBKIHFQKV-UHFFFAOYSA-N 1-[6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-(3-chloro-4-fluorophenyl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCN)=O HFWAHSBKIHFQKV-UHFFFAOYSA-N 0.000 claims description 2
- GUOGJILWXHCHIM-UHFFFAOYSA-N 1-[8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)CCO)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F GUOGJILWXHCHIM-UHFFFAOYSA-N 0.000 claims description 2
- NZFJPIKHAUEKJP-UHFFFAOYSA-N 1-[8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OCCO)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F NZFJPIKHAUEKJP-UHFFFAOYSA-N 0.000 claims description 2
- ORNXUDOPPYEPMU-UHFFFAOYSA-N 1-[8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCO)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ORNXUDOPPYEPMU-UHFFFAOYSA-N 0.000 claims description 2
- HVSCTHBPWHCJCD-UHFFFAOYSA-N 1-[8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NC)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F HVSCTHBPWHCJCD-UHFFFAOYSA-N 0.000 claims description 2
- IMZFVBGJEGUVRI-UHFFFAOYSA-N 1-ethyl-3-(4-fluoro-3-methylphenyl)-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound C(C)N(C(=O)NC1=CC(=C(C=C1)F)C)C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O IMZFVBGJEGUVRI-UHFFFAOYSA-N 0.000 claims description 2
- IMZFVBGJEGUVRI-IBGZPJMESA-N 1-ethyl-3-(4-fluoro-3-methylphenyl)-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(C)N(C(=O)NC1=CC(=C(C=C1)F)C)[C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O IMZFVBGJEGUVRI-IBGZPJMESA-N 0.000 claims description 2
- IMZFVBGJEGUVRI-LJQANCHMSA-N 1-ethyl-3-(4-fluoro-3-methylphenyl)-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(C)N(C(=O)NC1=CC(=C(C=C1)F)C)[C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O IMZFVBGJEGUVRI-LJQANCHMSA-N 0.000 claims description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
- WULIWRMNZLVONY-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1Cl)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O WULIWRMNZLVONY-UHFFFAOYSA-N 0.000 claims description 2
- WULIWRMNZLVONY-KRWDZBQOSA-N 3-(3,4-dichlorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1Cl)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O WULIWRMNZLVONY-KRWDZBQOSA-N 0.000 claims description 2
- GVPGTAHGJZMEKW-MRXNPFEDSA-N 3-(3,4-difluorophenyl)-1-(2-methylpropyl)-1-[(5R)-2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O GVPGTAHGJZMEKW-MRXNPFEDSA-N 0.000 claims description 2
- GVPGTAHGJZMEKW-INIZCTEOSA-N 3-(3,4-difluorophenyl)-1-(2-methylpropyl)-1-[(5S)-2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O GVPGTAHGJZMEKW-INIZCTEOSA-N 0.000 claims description 2
- GVPGTAHGJZMEKW-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-(2-methylpropyl)-1-[2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O GVPGTAHGJZMEKW-UHFFFAOYSA-N 0.000 claims description 2
- MGHPVSLDRSRYFC-FQEVSTJZSA-N 3-(3,4-difluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MGHPVSLDRSRYFC-FQEVSTJZSA-N 0.000 claims description 2
- DTQMZAIGKXIBMP-GOSISDBHSA-N 3-(3,4-difluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound FC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O DTQMZAIGKXIBMP-GOSISDBHSA-N 0.000 claims description 2
- MGHPVSLDRSRYFC-HXUWFJFHSA-N 3-(3,4-difluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MGHPVSLDRSRYFC-HXUWFJFHSA-N 0.000 claims description 2
- DTQMZAIGKXIBMP-SFHVURJKSA-N 3-(3,4-difluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound FC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O DTQMZAIGKXIBMP-SFHVURJKSA-N 0.000 claims description 2
- UZLNTDGJEDMQGP-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-ethyl-1-(6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O UZLNTDGJEDMQGP-UHFFFAOYSA-N 0.000 claims description 2
- UZLNTDGJEDMQGP-LJQANCHMSA-N 3-(3,4-difluorophenyl)-1-ethyl-1-[(1R)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O UZLNTDGJEDMQGP-LJQANCHMSA-N 0.000 claims description 2
- UZLNTDGJEDMQGP-IBGZPJMESA-N 3-(3,4-difluorophenyl)-1-ethyl-1-[(1S)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O UZLNTDGJEDMQGP-IBGZPJMESA-N 0.000 claims description 2
- WOHNJNAZLQERDE-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-methyl-1-(5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O WOHNJNAZLQERDE-UHFFFAOYSA-N 0.000 claims description 2
- QWLHTKGAAUJQSI-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-methyl-1-(5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O QWLHTKGAAUJQSI-UHFFFAOYSA-N 0.000 claims description 2
- MQORKMWXVISFAL-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-methyl-1-(6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O MQORKMWXVISFAL-UHFFFAOYSA-N 0.000 claims description 2
- GVDMCPXVZKCXAC-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-1-methyl-1-(9-oxo-5,12-dioxa-8-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-3-yl)urea Chemical compound FC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C3=C(C=21)CCOC3)=O)C)=O GVDMCPXVZKCXAC-UHFFFAOYSA-N 0.000 claims description 2
- WOHNJNAZLQERDE-QGZVFWFLSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(10R)-5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O WOHNJNAZLQERDE-QGZVFWFLSA-N 0.000 claims description 2
- QWLHTKGAAUJQSI-QGZVFWFLSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(10R)-5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O QWLHTKGAAUJQSI-QGZVFWFLSA-N 0.000 claims description 2
- WOHNJNAZLQERDE-KRWDZBQOSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(10S)-5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O WOHNJNAZLQERDE-KRWDZBQOSA-N 0.000 claims description 2
- QWLHTKGAAUJQSI-KRWDZBQOSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(10S)-5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O QWLHTKGAAUJQSI-KRWDZBQOSA-N 0.000 claims description 2
- UXNGYMRWKHMKHG-INIZCTEOSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(14R)-8-oxo-4,12-dioxa-9-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-14-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)COCC3)=O)C)=O UXNGYMRWKHMKHG-INIZCTEOSA-N 0.000 claims description 2
- UXNGYMRWKHMKHG-MRXNPFEDSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(14S)-8-oxo-4,12-dioxa-9-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-14-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)COCC3)=O)C)=O UXNGYMRWKHMKHG-MRXNPFEDSA-N 0.000 claims description 2
- MQORKMWXVISFAL-GOSISDBHSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(1R)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O MQORKMWXVISFAL-GOSISDBHSA-N 0.000 claims description 2
- MQORKMWXVISFAL-SFHVURJKSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(1S)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O MQORKMWXVISFAL-SFHVURJKSA-N 0.000 claims description 2
- GVDMCPXVZKCXAC-INIZCTEOSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(3R)-9-oxo-5,12-dioxa-8-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-3-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)CCOC3)=O)C)=O GVDMCPXVZKCXAC-INIZCTEOSA-N 0.000 claims description 2
- GVDMCPXVZKCXAC-MRXNPFEDSA-N 3-(3,4-difluorophenyl)-1-methyl-1-[(3S)-9-oxo-5,12-dioxa-8-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-3-yl]urea Chemical compound FC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)CCOC3)=O)C)=O GVDMCPXVZKCXAC-MRXNPFEDSA-N 0.000 claims description 2
- RYBWBFUHLFPRNM-INIZCTEOSA-N 3-(3,5-dichloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)Cl)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RYBWBFUHLFPRNM-INIZCTEOSA-N 0.000 claims description 2
- RYBWBFUHLFPRNM-MRXNPFEDSA-N 3-(3,5-dichloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)Cl)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RYBWBFUHLFPRNM-MRXNPFEDSA-N 0.000 claims description 2
- OGYKARXNZGRZLF-INIZCTEOSA-N 3-(3-chloro-4,5-difluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O OGYKARXNZGRZLF-INIZCTEOSA-N 0.000 claims description 2
- OGYKARXNZGRZLF-MRXNPFEDSA-N 3-(3-chloro-4,5-difluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=C(C=1F)F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O OGYKARXNZGRZLF-MRXNPFEDSA-N 0.000 claims description 2
- ZOGVHAJBIUZCJV-LCJPYDMBSA-N 3-(3-chloro-4-fluorophenyl)-1-(1-deuterio-8,9-difluoro-6-oxo-4,5-dihydro-2H-pyrano[3,4-c]isoquinolin-1-yl)-1-(trideuteriomethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C([2H])([2H])[2H])C1(COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)[2H])=O ZOGVHAJBIUZCJV-LCJPYDMBSA-N 0.000 claims description 2
- HRMHNGLZRUWGHR-HXUWFJFHSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1R)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O HRMHNGLZRUWGHR-HXUWFJFHSA-N 0.000 claims description 2
- XXOVWGPFHRUTPE-FQEVSTJZSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1R)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O XXOVWGPFHRUTPE-FQEVSTJZSA-N 0.000 claims description 2
- YWZVBTGLHUDHRQ-OAQYLSRUSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1R)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CC(C)C)=O YWZVBTGLHUDHRQ-OAQYLSRUSA-N 0.000 claims description 2
- HRMHNGLZRUWGHR-FQEVSTJZSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1S)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O HRMHNGLZRUWGHR-FQEVSTJZSA-N 0.000 claims description 2
- XXOVWGPFHRUTPE-HXUWFJFHSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1S)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)CC(C)C)=O XXOVWGPFHRUTPE-HXUWFJFHSA-N 0.000 claims description 2
- YWZVBTGLHUDHRQ-NRFANRHFSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(1S)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CC(C)C)=O YWZVBTGLHUDHRQ-NRFANRHFSA-N 0.000 claims description 2
- ZMBBOGVDLFILGU-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(5R)-2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O ZMBBOGVDLFILGU-MRXNPFEDSA-N 0.000 claims description 2
- HQWTUWKTKWTPBX-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(5R)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CC(C)C)=O HQWTUWKTKWTPBX-QGZVFWFLSA-N 0.000 claims description 2
- ZMBBOGVDLFILGU-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(5S)-2-oxo-4-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]pyridin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCC=2NC(C=C(C=21)C(F)(F)F)=O)CC(C)C)=O ZMBBOGVDLFILGU-INIZCTEOSA-N 0.000 claims description 2
- HQWTUWKTKWTPBX-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[(5S)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CC(C)C)=O HQWTUWKTKWTPBX-KRWDZBQOSA-N 0.000 claims description 2
- HQWTUWKTKWTPBX-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(2-methylpropyl)-1-[2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CC(C)C)=O HQWTUWKTKWTPBX-UHFFFAOYSA-N 0.000 claims description 2
- SPXHXPSGLKGPGT-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(3,3-dimethyl-6-oxo-1,2,4,5-tetrahydrophenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CC(CC=2NC(C3=CC=CC=C3C1=2)=O)(C)C)=O SPXHXPSGLKGPGT-UHFFFAOYSA-N 0.000 claims description 2
- GLUQNFMNUALIIA-OAQYLSRUSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(11R)-5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCCC=2NC(C3=CC=CC=C3C=21)=O)CCCO)=O GLUQNFMNUALIIA-OAQYLSRUSA-N 0.000 claims description 2
- GLUQNFMNUALIIA-NRFANRHFSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(11S)-5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCCC=2NC(C3=CC=CC=C3C=21)=O)CCCO)=O GLUQNFMNUALIIA-NRFANRHFSA-N 0.000 claims description 2
- USEGMRQULIIIFR-HXUWFJFHSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(1R)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CCCO)=O USEGMRQULIIIFR-HXUWFJFHSA-N 0.000 claims description 2
- LRKXULYGPJCLEA-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(1S)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)CCCO)=O LRKXULYGPJCLEA-IBGZPJMESA-N 0.000 claims description 2
- USEGMRQULIIIFR-FQEVSTJZSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(1S)-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C3=CC=CC=C3C1=2)=O)CCCO)=O USEGMRQULIIIFR-FQEVSTJZSA-N 0.000 claims description 2
- BAKGRTCBOOOOPO-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(5R)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CCCO)=O BAKGRTCBOOOOPO-MRXNPFEDSA-N 0.000 claims description 2
- BAKGRTCBOOOOPO-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(5S)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CCCO)=O BAKGRTCBOOOOPO-INIZCTEOSA-N 0.000 claims description 2
- BAKGRTCBOOOOPO-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)CCCO)=O BAKGRTCBOOOOPO-UHFFFAOYSA-N 0.000 claims description 2
- YIQJEBQAUPTAGO-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(7,8-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C(=C(C=CC=3C=21)F)F)=O)=O YIQJEBQAUPTAGO-UHFFFAOYSA-N 0.000 claims description 2
- OPXAPWCDOLFDON-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(7,8-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CCCC=2NC(C3=C(C(=CC=C3C1=2)F)F)=O)=O OPXAPWCDOLFDON-UHFFFAOYSA-N 0.000 claims description 2
- YRKOWTARMBPQPB-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,10-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=C(C=3C=21)F)F)=O)=O YRKOWTARMBPQPB-UHFFFAOYSA-N 0.000 claims description 2
- GIQGJZXOVSTXHG-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-3,6-dioxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CS(CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O GIQGJZXOVSTXHG-UHFFFAOYSA-N 0.000 claims description 2
- GAPDCRVBJBBICD-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O GAPDCRVBJBBICD-UHFFFAOYSA-N 0.000 claims description 2
- AHISYTFRZNMJHT-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COCC3N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F AHISYTFRZNMJHT-UHFFFAOYSA-N 0.000 claims description 2
- UXCKRBIRFTYFEO-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OC)=O UXCKRBIRFTYFEO-UHFFFAOYSA-N 0.000 claims description 2
- OPGKEPUSGUQLIX-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O OPGKEPUSGUQLIX-UHFFFAOYSA-N 0.000 claims description 2
- YMKKWNUBGUBNOE-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O YMKKWNUBGUBNOE-UHFFFAOYSA-N 0.000 claims description 2
- LDTDCLJHWQGTKL-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LDTDCLJHWQGTKL-UHFFFAOYSA-N 0.000 claims description 2
- ARTKFTSGIPAQHN-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)C1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O ARTKFTSGIPAQHN-UHFFFAOYSA-N 0.000 claims description 2
- URPRGLAEHNFRJB-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O URPRGLAEHNFRJB-UHFFFAOYSA-N 0.000 claims description 2
- OMTBNDJLWQCWFR-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)C1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O OMTBNDJLWQCWFR-UHFFFAOYSA-N 0.000 claims description 2
- JHVCIOQILSMSFO-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O JHVCIOQILSMSFO-UHFFFAOYSA-N 0.000 claims description 2
- SWNKMRUDSVHTCF-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-3,6-dioxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CS(CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O SWNKMRUDSVHTCF-UHFFFAOYSA-N 0.000 claims description 2
- KXLKHUKYUCBEGA-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O KXLKHUKYUCBEGA-UHFFFAOYSA-N 0.000 claims description 2
- MORMMLZKCHJTBL-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MORMMLZKCHJTBL-UHFFFAOYSA-N 0.000 claims description 2
- PXQGTNCAVDFQMW-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O PXQGTNCAVDFQMW-UHFFFAOYSA-N 0.000 claims description 2
- SDCGFNQYCPLKCK-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O SDCGFNQYCPLKCK-UHFFFAOYSA-N 0.000 claims description 2
- IDINEURTQBDPEC-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O IDINEURTQBDPEC-UHFFFAOYSA-N 0.000 claims description 2
- ZOGVHAJBIUZCJV-OTPRCQSWSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-1-deuterio-8,9-difluoro-6-oxo-4,5-dihydro-2H-pyrano[3,4-c]isoquinolin-1-yl]-1-(trideuteriomethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C([2H])([2H])[2H])[C@]1(COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)[2H])=O ZOGVHAJBIUZCJV-OTPRCQSWSA-N 0.000 claims description 2
- KNVCGSMEEFVXNG-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-6-methoxy-1,2,3,4-tetrahydrophenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC2=NC(=C3C=CC=CC3=C12)OC)=O KNVCGSMEEFVXNG-LJQANCHMSA-N 0.000 claims description 2
- YIQJEBQAUPTAGO-HNNXBMFYSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-7,8-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C(=C(C=CC=3C=21)F)F)=O)=O YIQJEBQAUPTAGO-HNNXBMFYSA-N 0.000 claims description 2
- OPXAPWCDOLFDON-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-7,8-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC=2NC(C3=C(C(=CC=C3C1=2)F)F)=O)=O OPXAPWCDOLFDON-MRXNPFEDSA-N 0.000 claims description 2
- YRKOWTARMBPQPB-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,10-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=C(C=3C=21)F)F)=O)=O YRKOWTARMBPQPB-INIZCTEOSA-N 0.000 claims description 2
- WVOJXEIFDLJXJR-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,10-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC=2NC(C3=CC(=CC(=C3C1=2)F)F)=O)=O WVOJXEIFDLJXJR-QGZVFWFLSA-N 0.000 claims description 2
- XXKAEXYKKAEBRY-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O XXKAEXYKKAEBRY-IBGZPJMESA-N 0.000 claims description 2
- GAPDCRVBJBBICD-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O GAPDCRVBJBBICD-SFHVURJKSA-N 0.000 claims description 2
- KELBMUDITFJNBW-HNNXBMFYSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-4,6-dioxo-2,5-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COC(C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O KELBMUDITFJNBW-HNNXBMFYSA-N 0.000 claims description 2
- RORDHOAUIKYOBT-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N(C(C=3C=C(C(=CC=3C=21)F)F)=O)CCO)=O RORDHOAUIKYOBT-SFHVURJKSA-N 0.000 claims description 2
- AHISYTFRZNMJHT-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)Cl)C)F AHISYTFRZNMJHT-SFHVURJKSA-N 0.000 claims description 2
- UGMDUOMEUZTMDI-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OCCO)=O UGMDUOMEUZTMDI-IBGZPJMESA-N 0.000 claims description 2
- DPSSEZRIIPCNNQ-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCO)=O DPSSEZRIIPCNNQ-IBGZPJMESA-N 0.000 claims description 2
- KCRAVLVAVBMOAY-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NC)=O KCRAVLVAVBMOAY-SFHVURJKSA-N 0.000 claims description 2
- UXCKRBIRFTYFEO-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OC)=O UXCKRBIRFTYFEO-SFHVURJKSA-N 0.000 claims description 2
- DAOJPJYOVOCZQN-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylsulfonylethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCS(=O)(=O)C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O DAOJPJYOVOCZQN-IBGZPJMESA-N 0.000 claims description 2
- OPGKEPUSGUQLIX-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O OPGKEPUSGUQLIX-SFHVURJKSA-N 0.000 claims description 2
- ZOGVHAJBIUZCJV-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZOGVHAJBIUZCJV-KRWDZBQOSA-N 0.000 claims description 2
- YMKKWNUBGUBNOE-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O YMKKWNUBGUBNOE-KRWDZBQOSA-N 0.000 claims description 2
- LDTDCLJHWQGTKL-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LDTDCLJHWQGTKL-KRWDZBQOSA-N 0.000 claims description 2
- PTTWQPVEJMXILW-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC=2NC(C3=CC(=C(C=C3C1=2)F)F)=O)=O PTTWQPVEJMXILW-GOSISDBHSA-N 0.000 claims description 2
- ARTKFTSGIPAQHN-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O ARTKFTSGIPAQHN-SFHVURJKSA-N 0.000 claims description 2
- URPRGLAEHNFRJB-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O URPRGLAEHNFRJB-KRWDZBQOSA-N 0.000 claims description 2
- OMTBNDJLWQCWFR-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O OMTBNDJLWQCWFR-IBGZPJMESA-N 0.000 claims description 2
- JHVCIOQILSMSFO-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O JHVCIOQILSMSFO-SFHVURJKSA-N 0.000 claims description 2
- CFPYADAPAWAWKM-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O CFPYADAPAWAWKM-IBGZPJMESA-N 0.000 claims description 2
- KXLKHUKYUCBEGA-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O KXLKHUKYUCBEGA-SFHVURJKSA-N 0.000 claims description 2
- VIMJYCMJWXPZGL-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-hydroxy-2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)(C)O)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O VIMJYCMJWXPZGL-IBGZPJMESA-N 0.000 claims description 2
- MORMMLZKCHJTBL-FQEVSTJZSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MORMMLZKCHJTBL-FQEVSTJZSA-N 0.000 claims description 2
- QIRKVVHJYOMCAC-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O QIRKVVHJYOMCAC-IBGZPJMESA-N 0.000 claims description 2
- LUNARCYFNAWKCV-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O LUNARCYFNAWKCV-KRWDZBQOSA-N 0.000 claims description 2
- PXQGTNCAVDFQMW-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O PXQGTNCAVDFQMW-KRWDZBQOSA-N 0.000 claims description 2
- ZRKMKDRBAHXBCH-OAQYLSRUSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ZRKMKDRBAHXBCH-OAQYLSRUSA-N 0.000 claims description 2
- ULFFFRCRAVBKJP-HXUWFJFHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)[C@@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ULFFFRCRAVBKJP-HXUWFJFHSA-N 0.000 claims description 2
- PXYPBAXHXPBTIS-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O PXYPBAXHXPBTIS-GOSISDBHSA-N 0.000 claims description 2
- IDINEURTQBDPEC-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O IDINEURTQBDPEC-KRWDZBQOSA-N 0.000 claims description 2
- SPXHXPSGLKGPGT-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-3,3-dimethyl-6-oxo-1,2,4,5-tetrahydrophenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CC(CC=2NC(C3=CC=CC=C3C1=2)=O)(C)C)=O SPXHXPSGLKGPGT-IBGZPJMESA-N 0.000 claims description 2
- KNVCGSMEEFVXNG-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-6-methoxy-1,2,3,4-tetrahydrophenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC2=NC(=C3C=CC=CC3=C12)OC)=O KNVCGSMEEFVXNG-IBGZPJMESA-N 0.000 claims description 2
- YIQJEBQAUPTAGO-OAHLLOKOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-7,8-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C(=C(C=CC=3C=21)F)F)=O)=O YIQJEBQAUPTAGO-OAHLLOKOSA-N 0.000 claims description 2
- OPXAPWCDOLFDON-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-7,8-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC=2NC(C3=C(C(=CC=C3C1=2)F)F)=O)=O OPXAPWCDOLFDON-INIZCTEOSA-N 0.000 claims description 2
- YRKOWTARMBPQPB-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,10-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=C(C=3C=21)F)F)=O)=O YRKOWTARMBPQPB-MRXNPFEDSA-N 0.000 claims description 2
- WVOJXEIFDLJXJR-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,10-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC=2NC(C3=CC(=CC(=C3C1=2)F)F)=O)=O WVOJXEIFDLJXJR-KRWDZBQOSA-N 0.000 claims description 2
- XXKAEXYKKAEBRY-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O XXKAEXYKKAEBRY-LJQANCHMSA-N 0.000 claims description 2
- GAPDCRVBJBBICD-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O GAPDCRVBJBBICD-GOSISDBHSA-N 0.000 claims description 2
- KELBMUDITFJNBW-OAHLLOKOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-4,6-dioxo-2,5-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COC(C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O KELBMUDITFJNBW-OAHLLOKOSA-N 0.000 claims description 2
- DPSSEZRIIPCNNQ-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCO)=O DPSSEZRIIPCNNQ-LJQANCHMSA-N 0.000 claims description 2
- KCRAVLVAVBMOAY-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NC)=O KCRAVLVAVBMOAY-GOSISDBHSA-N 0.000 claims description 2
- DAOJPJYOVOCZQN-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylsulfonylethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCS(=O)(=O)C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O DAOJPJYOVOCZQN-LJQANCHMSA-N 0.000 claims description 2
- OPGKEPUSGUQLIX-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O OPGKEPUSGUQLIX-GOSISDBHSA-N 0.000 claims description 2
- YMKKWNUBGUBNOE-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O YMKKWNUBGUBNOE-QGZVFWFLSA-N 0.000 claims description 2
- LDTDCLJHWQGTKL-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LDTDCLJHWQGTKL-QGZVFWFLSA-N 0.000 claims description 2
- PTTWQPVEJMXILW-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC=2NC(C3=CC(=C(C=C3C1=2)F)F)=O)=O PTTWQPVEJMXILW-SFHVURJKSA-N 0.000 claims description 2
- ARTKFTSGIPAQHN-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O ARTKFTSGIPAQHN-GOSISDBHSA-N 0.000 claims description 2
- URPRGLAEHNFRJB-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-chloro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)Cl)=O)=O URPRGLAEHNFRJB-QGZVFWFLSA-N 0.000 claims description 2
- OMTBNDJLWQCWFR-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O OMTBNDJLWQCWFR-LJQANCHMSA-N 0.000 claims description 2
- JHVCIOQILSMSFO-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-cyano-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)C#N)=O)=O JHVCIOQILSMSFO-GOSISDBHSA-N 0.000 claims description 2
- CFPYADAPAWAWKM-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O CFPYADAPAWAWKM-LJQANCHMSA-N 0.000 claims description 2
- KXLKHUKYUCBEGA-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O KXLKHUKYUCBEGA-GOSISDBHSA-N 0.000 claims description 2
- VIMJYCMJWXPZGL-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-hydroxy-2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)(C)O)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O VIMJYCMJWXPZGL-LJQANCHMSA-N 0.000 claims description 2
- MORMMLZKCHJTBL-HXUWFJFHSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MORMMLZKCHJTBL-HXUWFJFHSA-N 0.000 claims description 2
- QIRKVVHJYOMCAC-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O QIRKVVHJYOMCAC-LJQANCHMSA-N 0.000 claims description 2
- PXQGTNCAVDFQMW-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O PXQGTNCAVDFQMW-QGZVFWFLSA-N 0.000 claims description 2
- SDCGFNQYCPLKCK-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O SDCGFNQYCPLKCK-QGZVFWFLSA-N 0.000 claims description 2
- ZRKMKDRBAHXBCH-NRFANRHFSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-(2-methylpropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CC(C)C)[C@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ZRKMKDRBAHXBCH-NRFANRHFSA-N 0.000 claims description 2
- ULFFFRCRAVBKJP-FQEVSTJZSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-(3-hydroxypropyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCCO)[C@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O ULFFFRCRAVBKJP-FQEVSTJZSA-N 0.000 claims description 2
- PXYPBAXHXPBTIS-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O PXYPBAXHXPBTIS-SFHVURJKSA-N 0.000 claims description 2
- IDINEURTQBDPEC-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O IDINEURTQBDPEC-QGZVFWFLSA-N 0.000 claims description 2
- RORDHOAUIKYOBT-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8,9-difluoro-5-(2-hydroxyethyl)-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N(C(C=3C=C(C(=CC=3C=21)F)F)=O)CCO)=O RORDHOAUIKYOBT-UHFFFAOYSA-N 0.000 claims description 2
- UGMDUOMEUZTMDI-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)OCCO)=O UGMDUOMEUZTMDI-UHFFFAOYSA-N 0.000 claims description 2
- DPSSEZRIIPCNNQ-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8,9-difluoro-6-(2-hydroxyethylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NCCO)=O DPSSEZRIIPCNNQ-UHFFFAOYSA-N 0.000 claims description 2
- KCRAVLVAVBMOAY-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8,9-difluoro-6-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1COCC=2N=C(C=3C=C(C(=CC=3C=21)F)F)NC)=O KCRAVLVAVBMOAY-UHFFFAOYSA-N 0.000 claims description 2
- CFPYADAPAWAWKM-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O CFPYADAPAWAWKM-UHFFFAOYSA-N 0.000 claims description 2
- JEAMGCQDRKRWRI-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O JEAMGCQDRKRWRI-UHFFFAOYSA-N 0.000 claims description 2
- BDFFELJZQCEBOO-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O BDFFELJZQCEBOO-UHFFFAOYSA-N 0.000 claims description 2
- WBCQYAGTGJWCRP-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)CC)=O WBCQYAGTGJWCRP-SFHVURJKSA-N 0.000 claims description 2
- BDFFELJZQCEBOO-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O BDFFELJZQCEBOO-SFHVURJKSA-N 0.000 claims description 2
- JEAMGCQDRKRWRI-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1S)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O JEAMGCQDRKRWRI-IBGZPJMESA-N 0.000 claims description 2
- BDFFELJZQCEBOO-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O BDFFELJZQCEBOO-GOSISDBHSA-N 0.000 claims description 2
- YXSJLNDTCDICHF-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(3-methyl-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CC(CC=2NC(C3=CC=CC=C3C1=2)=O)C)C)=O YXSJLNDTCDICHF-UHFFFAOYSA-N 0.000 claims description 2
- NDPIKJFBWBZNMD-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O NDPIKJFBWBZNMD-UHFFFAOYSA-N 0.000 claims description 2
- MMMHNBYHCIWMTH-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O MMMHNBYHCIWMTH-UHFFFAOYSA-N 0.000 claims description 2
- VSLHUJPODXYPPD-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O VSLHUJPODXYPPD-UHFFFAOYSA-N 0.000 claims description 2
- HNHWMFCCPXJOAH-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(7-oxo-11-oxa-3-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),4-trien-13-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C3=C(C=21)SC=C3)=O)C)=O HNHWMFCCPXJOAH-UHFFFAOYSA-N 0.000 claims description 2
- ORONKDOSFFCHAQ-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(7-oxo-11-oxa-4-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2,5-trien-13-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C(C=21)=CSC=3)=O)C)=O ORONKDOSFFCHAQ-UHFFFAOYSA-N 0.000 claims description 2
- ZDZHQKJBMWEWHF-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(7-oxo-11-oxa-5-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),3-trien-13-yl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C3=C(C=21)C=CS3)=O)C)=O ZDZHQKJBMWEWHF-UHFFFAOYSA-N 0.000 claims description 2
- NDPIKJFBWBZNMD-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(10R)-5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O NDPIKJFBWBZNMD-QGZVFWFLSA-N 0.000 claims description 2
- MMMHNBYHCIWMTH-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(10R)-5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O MMMHNBYHCIWMTH-QGZVFWFLSA-N 0.000 claims description 2
- NDPIKJFBWBZNMD-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(10S)-5-oxo-1,2,4,6,7,8,9,10-octahydropyrano[3,4-c]quinolin-10-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C3=C(C(NC=2CCC1)=O)COCC3)C)=O NDPIKJFBWBZNMD-KRWDZBQOSA-N 0.000 claims description 2
- MMMHNBYHCIWMTH-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(10S)-5-oxo-1,3,4,6,7,8,9,10-octahydropyrano[4,3-c]quinolin-10-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C3=C(C(NC=2CCC1)=O)CCOC3)C)=O MMMHNBYHCIWMTH-KRWDZBQOSA-N 0.000 claims description 2
- XIYAWXMPHNJHKJ-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(11R)-5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCCC=2NC(C3=CC=CC=C3C=21)=O)C)=O XIYAWXMPHNJHKJ-LJQANCHMSA-N 0.000 claims description 2
- XIYAWXMPHNJHKJ-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(11S)-5-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-11-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCCC=2NC(C3=CC=CC=C3C=21)=O)C)=O XIYAWXMPHNJHKJ-IBGZPJMESA-N 0.000 claims description 2
- HNHWMFCCPXJOAH-AWEZNQCLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13R)-7-oxo-11-oxa-3-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),4-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)SC=C3)=O)C)=O HNHWMFCCPXJOAH-AWEZNQCLSA-N 0.000 claims description 2
- ORONKDOSFFCHAQ-HNNXBMFYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13R)-7-oxo-11-oxa-4-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2,5-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C(C=21)=CSC=3)=O)C)=O ORONKDOSFFCHAQ-HNNXBMFYSA-N 0.000 claims description 2
- ZDZHQKJBMWEWHF-AWEZNQCLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13R)-7-oxo-11-oxa-5-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),3-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)C=CS3)=O)C)=O ZDZHQKJBMWEWHF-AWEZNQCLSA-N 0.000 claims description 2
- HNHWMFCCPXJOAH-CQSZACIVSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13S)-7-oxo-11-oxa-3-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),4-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)SC=C3)=O)C)=O HNHWMFCCPXJOAH-CQSZACIVSA-N 0.000 claims description 2
- ORONKDOSFFCHAQ-OAHLLOKOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13S)-7-oxo-11-oxa-4-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2,5-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C(C=21)=CSC=3)=O)C)=O ORONKDOSFFCHAQ-OAHLLOKOSA-N 0.000 claims description 2
- ZDZHQKJBMWEWHF-CQSZACIVSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(13S)-7-oxo-11-oxa-5-thia-8-azatricyclo[7.4.0.02,6]trideca-1(9),2(6),3-trien-13-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)C=CS3)=O)C)=O ZDZHQKJBMWEWHF-CQSZACIVSA-N 0.000 claims description 2
- KRPSEBXDWRZJPU-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(14R)-8-oxo-4,12-dioxa-9-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-14-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)COCC3)=O)C)=O KRPSEBXDWRZJPU-INIZCTEOSA-N 0.000 claims description 2
- KRPSEBXDWRZJPU-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(14S)-8-oxo-4,12-dioxa-9-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-14-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)COCC3)=O)C)=O KRPSEBXDWRZJPU-MRXNPFEDSA-N 0.000 claims description 2
- KLGDZXZPMCXCJR-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1R)-5-methyl-6-oxo-1,2,3,4-tetrahydrophenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2N(C(C3=CC=CC=C3C1=2)=O)C)C)=O KLGDZXZPMCXCJR-LJQANCHMSA-N 0.000 claims description 2
- ZXVJFVZZXKYRBL-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1R)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O ZXVJFVZZXKYRBL-QGZVFWFLSA-N 0.000 claims description 2
- OBPAWLSEXVDLRD-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1R)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O OBPAWLSEXVDLRD-KRWDZBQOSA-N 0.000 claims description 2
- VSLHUJPODXYPPD-GOSISDBHSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1R)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O VSLHUJPODXYPPD-GOSISDBHSA-N 0.000 claims description 2
- KLGDZXZPMCXCJR-IBGZPJMESA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1S)-5-methyl-6-oxo-1,2,3,4-tetrahydrophenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2N(C(C3=CC=CC=C3C1=2)=O)C)C)=O KLGDZXZPMCXCJR-IBGZPJMESA-N 0.000 claims description 2
- ZXVJFVZZXKYRBL-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1S)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O ZXVJFVZZXKYRBL-KRWDZBQOSA-N 0.000 claims description 2
- OBPAWLSEXVDLRD-QGZVFWFLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1S)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O OBPAWLSEXVDLRD-QGZVFWFLSA-N 0.000 claims description 2
- VSLHUJPODXYPPD-SFHVURJKSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(1S)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)C)=O VSLHUJPODXYPPD-SFHVURJKSA-N 0.000 claims description 2
- WCEFQDWNTYJJOD-CQSZACIVSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(5R)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)C)=O WCEFQDWNTYJJOD-CQSZACIVSA-N 0.000 claims description 2
- WCEFQDWNTYJJOD-AWEZNQCLSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(5S)-2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)C)=O WCEFQDWNTYJJOD-AWEZNQCLSA-N 0.000 claims description 2
- WCEFQDWNTYJJOD-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[2-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-quinolin-5-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C1C=2C(=CC(NC=2CCC1)=O)C(F)(F)F)C)=O WCEFQDWNTYJJOD-UHFFFAOYSA-N 0.000 claims description 2
- NKUYFBCXQNADMO-UHFFFAOYSA-N 3-(3-chloro-4-hydroxyphenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1O)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NKUYFBCXQNADMO-UHFFFAOYSA-N 0.000 claims description 2
- NKUYFBCXQNADMO-INIZCTEOSA-N 3-(3-chloro-4-hydroxyphenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1O)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NKUYFBCXQNADMO-INIZCTEOSA-N 0.000 claims description 2
- XGSYTOPAJUKUGM-UHFFFAOYSA-N 3-(3-chloro-4-methoxyphenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1OC)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O XGSYTOPAJUKUGM-UHFFFAOYSA-N 0.000 claims description 2
- XGSYTOPAJUKUGM-KRWDZBQOSA-N 3-(3-chloro-4-methoxyphenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1OC)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O XGSYTOPAJUKUGM-KRWDZBQOSA-N 0.000 claims description 2
- JBUFKVJMCVXGDM-UHFFFAOYSA-N 3-(3-chloro-5-fluorophenyl)-1-methyl-1-(6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound ClC=1C=C(C=C(C=1)F)NC(N(C1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O JBUFKVJMCVXGDM-UHFFFAOYSA-N 0.000 claims description 2
- JBUFKVJMCVXGDM-KRWDZBQOSA-N 3-(3-chloro-5-fluorophenyl)-1-methyl-1-[(1R)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=C(C=1)F)NC(N([C@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O JBUFKVJMCVXGDM-KRWDZBQOSA-N 0.000 claims description 2
- JBUFKVJMCVXGDM-QGZVFWFLSA-N 3-(3-chloro-5-fluorophenyl)-1-methyl-1-[(1S)-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=C(C=1)F)NC(N([C@@H]1COCC=2NC(C=3C=CC=CC=3C=21)=O)C)=O JBUFKVJMCVXGDM-QGZVFWFLSA-N 0.000 claims description 2
- QSEQPPKSPMIDNJ-UHFFFAOYSA-N 3-(3-chlorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O QSEQPPKSPMIDNJ-UHFFFAOYSA-N 0.000 claims description 2
- QSEQPPKSPMIDNJ-KRWDZBQOSA-N 3-(3-chlorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O QSEQPPKSPMIDNJ-KRWDZBQOSA-N 0.000 claims description 2
- QSEQPPKSPMIDNJ-QGZVFWFLSA-N 3-(3-chlorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O QSEQPPKSPMIDNJ-QGZVFWFLSA-N 0.000 claims description 2
- MCQWOAFBYLOPRU-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-3,6-dioxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1CS(CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O MCQWOAFBYLOPRU-UHFFFAOYSA-N 0.000 claims description 2
- IJSSTGGMZPBHQB-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O IJSSTGGMZPBHQB-UHFFFAOYSA-N 0.000 claims description 2
- ZVHQDCRLMSGPSX-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZVHQDCRLMSGPSX-UHFFFAOYSA-N 0.000 claims description 2
- MSWFJWFFLHAFDY-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-ethylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O MSWFJWFFLHAFDY-UHFFFAOYSA-N 0.000 claims description 2
- SJAJPXBWVTZCEU-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O SJAJPXBWVTZCEU-UHFFFAOYSA-N 0.000 claims description 2
- NBUBNEVYRYFFTD-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NBUBNEVYRYFFTD-UHFFFAOYSA-N 0.000 claims description 2
- LIDNZFYJRJNUEB-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LIDNZFYJRJNUEB-UHFFFAOYSA-N 0.000 claims description 2
- IEJWLQWXVYFDBM-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-3,6-dioxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1CS(CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O IEJWLQWXVYFDBM-UHFFFAOYSA-N 0.000 claims description 2
- LOTJAYZEIKBPCW-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O LOTJAYZEIKBPCW-UHFFFAOYSA-N 0.000 claims description 2
- MTKBPHCDBOXYCO-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MTKBPHCDBOXYCO-UHFFFAOYSA-N 0.000 claims description 2
- NDSQUOITXOOHLC-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O NDSQUOITXOOHLC-UHFFFAOYSA-N 0.000 claims description 2
- BMFZPPCCNYWSFS-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O BMFZPPCCNYWSFS-UHFFFAOYSA-N 0.000 claims description 2
- YNXCMABPWYJUGK-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O YNXCMABPWYJUGK-UHFFFAOYSA-N 0.000 claims description 2
- WMOVXZDKGUMTDK-FQEVSTJZSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O WMOVXZDKGUMTDK-FQEVSTJZSA-N 0.000 claims description 2
- IJSSTGGMZPBHQB-IBGZPJMESA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O IJSSTGGMZPBHQB-IBGZPJMESA-N 0.000 claims description 2
- ZVHQDCRLMSGPSX-NRFANRHFSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZVHQDCRLMSGPSX-NRFANRHFSA-N 0.000 claims description 2
- MSWFJWFFLHAFDY-IBGZPJMESA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O MSWFJWFFLHAFDY-IBGZPJMESA-N 0.000 claims description 2
- SJAJPXBWVTZCEU-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O SJAJPXBWVTZCEU-SFHVURJKSA-N 0.000 claims description 2
- NBUBNEVYRYFFTD-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NBUBNEVYRYFFTD-SFHVURJKSA-N 0.000 claims description 2
- LIDNZFYJRJNUEB-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LIDNZFYJRJNUEB-SFHVURJKSA-N 0.000 claims description 2
- OCJAQXZIYLEUCV-FQEVSTJZSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O OCJAQXZIYLEUCV-FQEVSTJZSA-N 0.000 claims description 2
- LOTJAYZEIKBPCW-IBGZPJMESA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O LOTJAYZEIKBPCW-IBGZPJMESA-N 0.000 claims description 2
- RQNWYIRJNIRWTK-NRFANRHFSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RQNWYIRJNIRWTK-NRFANRHFSA-N 0.000 claims description 2
- MTKBPHCDBOXYCO-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O MTKBPHCDBOXYCO-SFHVURJKSA-N 0.000 claims description 2
- NDSQUOITXOOHLC-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O NDSQUOITXOOHLC-SFHVURJKSA-N 0.000 claims description 2
- BMFZPPCCNYWSFS-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O BMFZPPCCNYWSFS-SFHVURJKSA-N 0.000 claims description 2
- YNXCMABPWYJUGK-SFHVURJKSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O YNXCMABPWYJUGK-SFHVURJKSA-N 0.000 claims description 2
- WMOVXZDKGUMTDK-HXUWFJFHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O WMOVXZDKGUMTDK-HXUWFJFHSA-N 0.000 claims description 2
- IJSSTGGMZPBHQB-LJQANCHMSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C(=C3)F)F)=O IJSSTGGMZPBHQB-LJQANCHMSA-N 0.000 claims description 2
- ZVHQDCRLMSGPSX-OAQYLSRUSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O ZVHQDCRLMSGPSX-OAQYLSRUSA-N 0.000 claims description 2
- MSWFJWFFLHAFDY-LJQANCHMSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-ethylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O MSWFJWFFLHAFDY-LJQANCHMSA-N 0.000 claims description 2
- NBUBNEVYRYFFTD-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1CSCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O NBUBNEVYRYFFTD-GOSISDBHSA-N 0.000 claims description 2
- LIDNZFYJRJNUEB-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C(=C3)F)F)=O LIDNZFYJRJNUEB-GOSISDBHSA-N 0.000 claims description 2
- OCJAQXZIYLEUCV-HXUWFJFHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O OCJAQXZIYLEUCV-HXUWFJFHSA-N 0.000 claims description 2
- LOTJAYZEIKBPCW-LJQANCHMSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-3-methyl-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CN(C1)C)=O)C=C(C=C3)F)=O LOTJAYZEIKBPCW-LJQANCHMSA-N 0.000 claims description 2
- RQNWYIRJNIRWTK-OAQYLSRUSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(CC(C)C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O RQNWYIRJNIRWTK-OAQYLSRUSA-N 0.000 claims description 2
- NDSQUOITXOOHLC-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydrothiopyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1CSCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O NDSQUOITXOOHLC-GOSISDBHSA-N 0.000 claims description 2
- BMFZPPCCNYWSFS-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O BMFZPPCCNYWSFS-GOSISDBHSA-N 0.000 claims description 2
- YNXCMABPWYJUGK-GOSISDBHSA-N 3-(3-cyano-4-fluorophenyl)-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O YNXCMABPWYJUGK-GOSISDBHSA-N 0.000 claims description 2
- WMOVXZDKGUMTDK-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-[8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O WMOVXZDKGUMTDK-UHFFFAOYSA-N 0.000 claims description 2
- OCJAQXZIYLEUCV-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-[8-fluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C=C3)F)=O OCJAQXZIYLEUCV-UHFFFAOYSA-N 0.000 claims description 2
- MWUQLJAABCFGBD-UHFFFAOYSA-N 3-(3-cyano-4-fluorophenyl)-1-ethyl-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O MWUQLJAABCFGBD-UHFFFAOYSA-N 0.000 claims description 2
- MWUQLJAABCFGBD-IBGZPJMESA-N 3-(3-cyano-4-fluorophenyl)-1-ethyl-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O MWUQLJAABCFGBD-IBGZPJMESA-N 0.000 claims description 2
- MWUQLJAABCFGBD-LJQANCHMSA-N 3-(3-cyano-4-fluorophenyl)-1-ethyl-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]urea Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)CC)=O MWUQLJAABCFGBD-LJQANCHMSA-N 0.000 claims description 2
- HLPOMOGOSUFNIQ-UHFFFAOYSA-N 3-(4-chloro-3-cyanophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)C#N HLPOMOGOSUFNIQ-UHFFFAOYSA-N 0.000 claims description 2
- HLPOMOGOSUFNIQ-SFHVURJKSA-N 3-(4-chloro-3-cyanophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)C#N HLPOMOGOSUFNIQ-SFHVURJKSA-N 0.000 claims description 2
- ZATVRHZDBXQQCA-UHFFFAOYSA-N 3-(4-chloro-3-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)F ZATVRHZDBXQQCA-UHFFFAOYSA-N 0.000 claims description 2
- ZATVRHZDBXQQCA-KRWDZBQOSA-N 3-(4-chloro-3-fluorophenyl)-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound ClC1=C(C=C(C=C1)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)F ZATVRHZDBXQQCA-KRWDZBQOSA-N 0.000 claims description 2
- KQEMJBHTJRTDPB-UHFFFAOYSA-N 3-(4-fluoro-3-methylphenyl)-1-(9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)C1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O)C KQEMJBHTJRTDPB-UHFFFAOYSA-N 0.000 claims description 2
- LPSCYOZISIOMSV-NRFANRHFSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound FC1=C(C=C(C=C1)NC(N(CC(C)C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C LPSCYOZISIOMSV-NRFANRHFSA-N 0.000 claims description 2
- GRPILJRHSJYCLC-SFHVURJKSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C GRPILJRHSJYCLC-SFHVURJKSA-N 0.000 claims description 2
- KQEMJBHTJRTDPB-SFHVURJKSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1R)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)[C@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O)C KQEMJBHTJRTDPB-SFHVURJKSA-N 0.000 claims description 2
- LPSCYOZISIOMSV-OAQYLSRUSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)urea Chemical compound FC1=C(C=C(C=C1)NC(N(CC(C)C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C LPSCYOZISIOMSV-OAQYLSRUSA-N 0.000 claims description 2
- GRPILJRHSJYCLC-GOSISDBHSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)C GRPILJRHSJYCLC-GOSISDBHSA-N 0.000 claims description 2
- KQEMJBHTJRTDPB-GOSISDBHSA-N 3-(4-fluoro-3-methylphenyl)-1-[(1S)-9-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC1=C(C=C(C=C1)NC(N(C)[C@@H]1COCC=2NC(C=3C=CC(=CC=3C=21)F)=O)=O)C KQEMJBHTJRTDPB-GOSISDBHSA-N 0.000 claims description 2
- ATZAALIEVIHFRP-UHFFFAOYSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-(8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ATZAALIEVIHFRP-UHFFFAOYSA-N 0.000 claims description 2
- LMYPOZRHKVEGHC-UHFFFAOYSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F LMYPOZRHKVEGHC-UHFFFAOYSA-N 0.000 claims description 2
- XYGSELMCYXWGRX-UHFFFAOYSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-(8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl)-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNCC(C2=3)N(C(=O)NC2=CC(=C(C=C2)F)C(F)F)C)=O)C=1)F XYGSELMCYXWGRX-UHFFFAOYSA-N 0.000 claims description 2
- ATZAALIEVIHFRP-SFHVURJKSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1R)-8,9-difluoro-5-methyl-6-oxo-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F ATZAALIEVIHFRP-SFHVURJKSA-N 0.000 claims description 2
- LMYPOZRHKVEGHC-KRWDZBQOSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F LMYPOZRHKVEGHC-KRWDZBQOSA-N 0.000 claims description 2
- XYGSELMCYXWGRX-KRWDZBQOSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)NC2=CC(=C(C=C2)F)C(F)F)C)=O)C=1)F XYGSELMCYXWGRX-KRWDZBQOSA-N 0.000 claims description 2
- FSPQWLPQEYIOSQ-KRWDZBQOSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1R)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC(C=1C=C(C=CC=1F)NC(N(C)[C@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)F FSPQWLPQEYIOSQ-KRWDZBQOSA-N 0.000 claims description 2
- LMYPOZRHKVEGHC-QGZVFWFLSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F LMYPOZRHKVEGHC-QGZVFWFLSA-N 0.000 claims description 2
- XYGSELMCYXWGRX-QGZVFWFLSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)NC2=CC(=C(C=C2)F)C(F)F)C)=O)C=1)F XYGSELMCYXWGRX-QGZVFWFLSA-N 0.000 claims description 2
- FSPQWLPQEYIOSQ-QGZVFWFLSA-N 3-[3-(difluoromethyl)-4-fluorophenyl]-1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-methylurea Chemical compound FC(C=1C=C(C=CC=1F)NC(N(C)[C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)F FSPQWLPQEYIOSQ-QGZVFWFLSA-N 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- GZKDJFLRXDZBOI-UHFFFAOYSA-N 5-bromo-N-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound BrC=1C=C2CN(CC2=CC=1)C(=O)N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O GZKDJFLRXDZBOI-UHFFFAOYSA-N 0.000 claims description 2
- GZKDJFLRXDZBOI-IBGZPJMESA-N 5-bromo-N-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound BrC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O GZKDJFLRXDZBOI-IBGZPJMESA-N 0.000 claims description 2
- CDSZOCIZMOWDFD-IBGZPJMESA-N 5-bromo-N-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)Br)C)=O)C=1)F CDSZOCIZMOWDFD-IBGZPJMESA-N 0.000 claims description 2
- CDSZOCIZMOWDFD-LJQANCHMSA-N 5-bromo-N-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)Br)C)=O)C=1)F CDSZOCIZMOWDFD-LJQANCHMSA-N 0.000 claims description 2
- WOCZDBKFCSWULZ-UHFFFAOYSA-N 5-chloro-N-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound ClC=1C=C2CN(CC2=CC=1)C(=O)N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O WOCZDBKFCSWULZ-UHFFFAOYSA-N 0.000 claims description 2
- WOCZDBKFCSWULZ-IBGZPJMESA-N 5-chloro-N-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound ClC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O WOCZDBKFCSWULZ-IBGZPJMESA-N 0.000 claims description 2
- KDCOSORSZBQIPF-IBGZPJMESA-N 5-chloro-N-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)Cl)C)=O)C=1)F KDCOSORSZBQIPF-IBGZPJMESA-N 0.000 claims description 2
- WOCZDBKFCSWULZ-LJQANCHMSA-N 5-chloro-N-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound ClC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O WOCZDBKFCSWULZ-LJQANCHMSA-N 0.000 claims description 2
- KDCOSORSZBQIPF-LJQANCHMSA-N 5-chloro-N-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)Cl)C)=O)C=1)F KDCOSORSZBQIPF-LJQANCHMSA-N 0.000 claims description 2
- MCQWOAFBYLOPRU-CVCYQNGTSA-N C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O MCQWOAFBYLOPRU-CVCYQNGTSA-N 0.000 claims description 2
- IEJWLQWXVYFDBM-OKXSDPAFSA-N C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O IEJWLQWXVYFDBM-OKXSDPAFSA-N 0.000 claims description 2
- MCQWOAFBYLOPRU-UPTQXZAWSA-N C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O MCQWOAFBYLOPRU-UPTQXZAWSA-N 0.000 claims description 2
- IEJWLQWXVYFDBM-DRKIFQHWSA-N C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O Chemical compound C(#N)C=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O IEJWLQWXVYFDBM-DRKIFQHWSA-N 0.000 claims description 2
- IBYIRYJIURZFDK-DNVCBOLYSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CO[C@H](C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CO[C@H](C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)O)=O IBYIRYJIURZFDK-DNVCBOLYSA-N 0.000 claims description 2
- YXSJLNDTCDICHF-HXPMCKFVSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[C@H](CC=2NC(C3=CC=CC=C3C1=2)=O)C)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[C@H](CC=2NC(C3=CC=CC=C3C1=2)=O)C)=O YXSJLNDTCDICHF-HXPMCKFVSA-N 0.000 claims description 2
- GIQGJZXOVSTXHG-INZIPBBXSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O GIQGJZXOVSTXHG-INZIPBBXSA-N 0.000 claims description 2
- SWNKMRUDSVHTCF-ZQHDKMAOSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O SWNKMRUDSVHTCF-ZQHDKMAOSA-N 0.000 claims description 2
- IBYIRYJIURZFDK-HNAYVOBHSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CO[C@H](C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1CO[C@H](C=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)O)=O IBYIRYJIURZFDK-HNAYVOBHSA-N 0.000 claims description 2
- YXSJLNDTCDICHF-BUXKBTBVSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[C@H](CC=2NC(C3=CC=CC=C3C1=2)=O)C)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[C@H](CC=2NC(C3=CC=CC=C3C1=2)=O)C)=O YXSJLNDTCDICHF-BUXKBTBVSA-N 0.000 claims description 2
- GIQGJZXOVSTXHG-MYGHRHJXSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O)=O GIQGJZXOVSTXHG-MYGHRHJXSA-N 0.000 claims description 2
- SWNKMRUDSVHTCF-ZOKDDAQRSA-N ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@H]1C[S@](CC=2NC(C=3C=C(C=CC=3C=21)F)=O)=O)=O SWNKMRUDSVHTCF-ZOKDDAQRSA-N 0.000 claims description 2
- IKOFUHBBMICHFN-UHFFFAOYSA-N N-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-5-fluoro-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C=C2CN(CC2=CC=1)C(=O)N(C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O IKOFUHBBMICHFN-UHFFFAOYSA-N 0.000 claims description 2
- IKOFUHBBMICHFN-IBGZPJMESA-N N-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-5-fluoro-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O IKOFUHBBMICHFN-IBGZPJMESA-N 0.000 claims description 2
- NKCDCEYERXHNER-IBGZPJMESA-N N-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)N1CC2=CC=CC=C2C1)C)F NKCDCEYERXHNER-IBGZPJMESA-N 0.000 claims description 2
- QRAHHLFSYHCPJN-IBGZPJMESA-N N-[(1R)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-5-(trifluoromethyl)-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@@H]3N(C(=O)N1CC2=CC=C(C=C2C1)C(F)(F)F)C)F QRAHHLFSYHCPJN-IBGZPJMESA-N 0.000 claims description 2
- XLFPUNKSEDXHDB-IBGZPJMESA-N N-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-5-fluoro-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)F)C)=O)C=1)F XLFPUNKSEDXHDB-IBGZPJMESA-N 0.000 claims description 2
- CDWPBANHNMESDD-IBGZPJMESA-N N-[(1R)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@@H](C2=3)N(C(=O)N2CC3=CC=CC=C3C2)C)=O)C=1)F CDWPBANHNMESDD-IBGZPJMESA-N 0.000 claims description 2
- IKOFUHBBMICHFN-LJQANCHMSA-N N-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-5-fluoro-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O IKOFUHBBMICHFN-LJQANCHMSA-N 0.000 claims description 2
- QRAHHLFSYHCPJN-LJQANCHMSA-N N-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-5-(trifluoromethyl)-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)N1CC2=CC=C(C=C2C1)C(F)(F)F)C)F QRAHHLFSYHCPJN-LJQANCHMSA-N 0.000 claims description 2
- XLFPUNKSEDXHDB-LJQANCHMSA-N N-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-5-fluoro-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)N2CC3=CC=C(C=C3C2)F)C)=O)C=1)F XLFPUNKSEDXHDB-LJQANCHMSA-N 0.000 claims description 2
- CDWPBANHNMESDD-LJQANCHMSA-N N-[(1S)-8,9-difluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound FC=1C(=CC2=C(C(NC=3CNC[C@H](C2=3)N(C(=O)N2CC3=CC=CC=C3C2)C)=O)C=1)F CDWPBANHNMESDD-LJQANCHMSA-N 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000006769 halocycloalkoxy group Chemical group 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 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 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 288
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 187
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 159
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- 238000005481 NMR spectroscopy Methods 0.000 description 123
- 239000000243 solution Substances 0.000 description 72
- 238000003786 synthesis reaction Methods 0.000 description 70
- 238000004808 supercritical fluid chromatography Methods 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 53
- 239000002904 solvent Substances 0.000 description 53
- 238000004458 analytical method Methods 0.000 description 52
- 238000009472 formulation Methods 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- 239000004480 active ingredient Substances 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 30
- 239000007787 solid Substances 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- 239000000463 material Substances 0.000 description 22
- XVIPJBUXMFLHSI-UHFFFAOYSA-N 2-chloro-1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1Cl XVIPJBUXMFLHSI-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000004615 ingredient Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 230000008569 process Effects 0.000 description 19
- 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 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 17
- 230000000670 limiting effect Effects 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 229940126179 compound 72 Drugs 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 230000001225 therapeutic effect Effects 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
- GSPVRZNJFVHSTO-UHFFFAOYSA-N O=C1C=CC2=CN=CCC2=C1 Chemical compound O=C1C=CC2=CN=CCC2=C1 GSPVRZNJFVHSTO-UHFFFAOYSA-N 0.000 description 14
- GPVPDRHTRGTSIH-UHFFFAOYSA-N isoquinolin-6-ol Chemical compound C1=NC=CC2=CC(O)=CC=C21 GPVPDRHTRGTSIH-UHFFFAOYSA-N 0.000 description 14
- 239000003755 preservative agent Substances 0.000 description 14
- PXYPBAXHXPBTIS-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-phenanthridin-1-yl)-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1CCCC=2NC(C3=CC(=CC=C3C1=2)F)=O)=O PXYPBAXHXPBTIS-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 13
- 210000000234 capsid Anatomy 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 12
- 239000005695 Ammonium acetate Substances 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 235000019257 ammonium acetate Nutrition 0.000 description 12
- 229940043376 ammonium acetate Drugs 0.000 description 12
- 229940126540 compound 41 Drugs 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- JAOBVXMYFIESNC-SNVBAGLBSA-N (1S)-8,9-difluoro-1-(methylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3NC)F JAOBVXMYFIESNC-SNVBAGLBSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- PDGSFRLUEWTBMU-UHFFFAOYSA-N 2,3,4,5-tetrahydrophenanthridine-1,6-dione Chemical compound N1C(=O)C2=CC=CC=C2C2=C1CCCC2=O PDGSFRLUEWTBMU-UHFFFAOYSA-N 0.000 description 9
- WAIXYWFQVYMVAT-UHFFFAOYSA-N 8-fluoro-1-(methylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1)NC)=O WAIXYWFQVYMVAT-UHFFFAOYSA-N 0.000 description 9
- DPMFNMXKPYIAPN-UHFFFAOYSA-N 8-fluoro-2,3,4,5-tetrahydrophenanthridine-1,6-dione Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1)=O)=O DPMFNMXKPYIAPN-UHFFFAOYSA-N 0.000 description 9
- 108010010803 Gelatin Proteins 0.000 description 9
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000008273 gelatin Substances 0.000 description 9
- 229920000159 gelatin Polymers 0.000 description 9
- 235000019322 gelatine Nutrition 0.000 description 9
- 235000011852 gelatine desserts Nutrition 0.000 description 9
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 210000003491 skin Anatomy 0.000 description 9
- 238000013268 sustained release Methods 0.000 description 9
- 239000012730 sustained-release form Substances 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- ZDQCLDBVVQUHDH-UHFFFAOYSA-N 6h-isoquinolin-5-one Chemical compound N1=CC=C2C(=O)CC=CC2=C1 ZDQCLDBVVQUHDH-UHFFFAOYSA-N 0.000 description 8
- XLLCOFZRBKDHQI-UHFFFAOYSA-N 8,9-difluoro-1-(methylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1F)NC)=O XLLCOFZRBKDHQI-UHFFFAOYSA-N 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 108020004459 Small interfering RNA Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
- 239000002270 dispersing agent Substances 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 230000036961 partial effect Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- 239000000375 suspending agent Substances 0.000 description 8
- RHFNHLPBXXSVPC-UHFFFAOYSA-N 1-(2-methylpropylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound C(C(C)C)NC1CCCC=2NC(C3=CC=CC=C3C1=2)=O RHFNHLPBXXSVPC-UHFFFAOYSA-N 0.000 description 7
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 7
- 239000003963 antioxidant agent Substances 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 7
- 239000002738 chelating agent Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 238000007911 parenteral administration Methods 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- 239000001993 wax Substances 0.000 description 7
- 239000000080 wetting agent Substances 0.000 description 7
- GLPGPCBQLDKRRK-UHFFFAOYSA-N 8-fluoro-1-(2-methylpropylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3NCC(C)C GLPGPCBQLDKRRK-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010074708 B7-H1 Antigen Proteins 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 108020004638 Circular DNA Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004429 atom Chemical group 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
- 238000000576 coating method Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 235000010356 sorbitol Nutrition 0.000 description 6
- 239000000600 sorbitol Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 210000000434 stratum corneum Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 235000015112 vegetable and seed oil Nutrition 0.000 description 6
- 239000008158 vegetable oil Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 239000003039 volatile agent Substances 0.000 description 6
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 5
- ZKZLJOZQTFHFFC-UHFFFAOYSA-N 1-(3-hydroxypropylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound OCCCNC1CCCC=2NC(C3=CC=CC=C3C1=2)=O ZKZLJOZQTFHFFC-UHFFFAOYSA-N 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 5
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 description 5
- JGMGVXPLHPTKPR-UHFFFAOYSA-N 3,4-dihydro-2H-cyclopenta[c]isoquinoline-1,5-dione Chemical compound C1(CCC=2NC(C=3C=CC=CC=3C=21)=O)=O JGMGVXPLHPTKPR-UHFFFAOYSA-N 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 5
- VNWXNMOSINWZPA-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-2H-phenanthridin-1-one Chemical compound COC=1N=C2CCCC(C2=C2C=CC=CC=12)=O VNWXNMOSINWZPA-UHFFFAOYSA-N 0.000 description 5
- NBYOALZMOPHPMA-UHFFFAOYSA-N 8,10-difluoro-1-(methylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=C(C=1)F)NC)=O NBYOALZMOPHPMA-UHFFFAOYSA-N 0.000 description 5
- GHQGAULSYVPPBH-UHFFFAOYSA-N 8,10-difluoro-2,3,4,5-tetrahydrophenanthridine-1,6-dione Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=C(C=1)F)=O)=O GHQGAULSYVPPBH-UHFFFAOYSA-N 0.000 description 5
- UQAQBTLWLROJEE-UHFFFAOYSA-N 8-fluoro-1-(2-methylpropylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1)NCC(C)C)=O UQAQBTLWLROJEE-UHFFFAOYSA-N 0.000 description 5
- HTMJSJBEHKUECV-UHFFFAOYSA-N 8-fluoro-1-(3-hydroxypropylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1)NCCCO)=O HTMJSJBEHKUECV-UHFFFAOYSA-N 0.000 description 5
- ZJLPRBHOUKXKLF-UHFFFAOYSA-N 8-fluoro-1-(methylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3NC ZJLPRBHOUKXKLF-UHFFFAOYSA-N 0.000 description 5
- 229940126657 Compound 17 Drugs 0.000 description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- 241000792859 Enema Species 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- 239000007920 enema Substances 0.000 description 5
- 229940095399 enema Drugs 0.000 description 5
- 229960000980 entecavir Drugs 0.000 description 5
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 229940093915 gynecological organic acid Drugs 0.000 description 5
- 210000000987 immune system Anatomy 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 235000010445 lecithin Nutrition 0.000 description 5
- 239000000787 lecithin Substances 0.000 description 5
- 229940067606 lecithin Drugs 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000004006 olive oil Substances 0.000 description 5
- 235000008390 olive oil Nutrition 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 235000005985 organic acids Nutrition 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- UYMCNKBLWIZQGB-UHFFFAOYSA-N phenyl n-(3-chloro-4-fluorophenyl)carbamate Chemical compound C1=C(Cl)C(F)=CC=C1NC(=O)OC1=CC=CC=C1 UYMCNKBLWIZQGB-UHFFFAOYSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000012258 stirred mixture Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- VKHHBEKDPDCZIC-UHFFFAOYSA-N (3-chloro-4-fluorophenyl) carbamate Chemical compound C(N)(OC1=CC(=C(C=C1)F)Cl)=O VKHHBEKDPDCZIC-UHFFFAOYSA-N 0.000 description 4
- LGLXQNBLFHJCKP-UHFFFAOYSA-N 1-(methylamino)-2,3,4,5-tetrahydro-1H-phenanthridin-6-one Chemical compound CNC1CCCC=2NC(C3=CC=CC=C3C1=2)=O LGLXQNBLFHJCKP-UHFFFAOYSA-N 0.000 description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 4
- WUCDESMTRFBDTO-UHFFFAOYSA-N 4,5-dihydropyrano[3,4-c]isoquinoline-1,6-dione Chemical compound C1(COCC=2NC(C=3C=CC=CC=3C=21)=O)=O WUCDESMTRFBDTO-UHFFFAOYSA-N 0.000 description 4
- NALNKQBHCNZSSU-UHFFFAOYSA-N 5-methyl-3,4-dihydro-2H-phenanthridine-1,6-dione Chemical compound CN1C=2CCCC(C=2C2=CC=CC=C2C1=O)=O NALNKQBHCNZSSU-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IHLBQWVMEWCRGP-OODIQHKMSA-N COC=1N=C2CCCC(C2=C2C=CC=CC=12)N([S@](=O)C(C)(C)C)C Chemical compound COC=1N=C2CCCC(C2=C2C=CC=CC=12)N([S@](=O)C(C)(C)C)C IHLBQWVMEWCRGP-OODIQHKMSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 4
- 101150065749 Churc1 gene Proteins 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- BVSMVMAHOBDTKT-LJQANCHMSA-N FC=1C(=CC=2C3=C(N=C(C=2C=1)OCCNC(OCC1=CC=CC=C1)=O)COC[C@H]3NC)F Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OCCNC(OCC1=CC=CC=C1)=O)COC[C@H]3NC)F BVSMVMAHOBDTKT-LJQANCHMSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 4
- 235000019483 Peanut oil Nutrition 0.000 description 4
- 102100038239 Protein Churchill Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 125000004404 heteroalkyl group Chemical group 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- 229940057995 liquid paraffin Drugs 0.000 description 4
- 239000006194 liquid suspension Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000006072 paste Substances 0.000 description 4
- 239000000312 peanut oil Substances 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- 239000007901 soft capsule Substances 0.000 description 4
- 239000004334 sorbic acid Substances 0.000 description 4
- 235000010199 sorbic acid Nutrition 0.000 description 4
- 229940075582 sorbic acid Drugs 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 229960004556 tenofovir Drugs 0.000 description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 229910052720 vanadium Inorganic materials 0.000 description 4
- LMOZCGSYNKTCDP-ADLMAVQZSA-N (1S)-8,9-difluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]amino]-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N[C@H](C)C1=CC=C(C=C1)OC)F LMOZCGSYNKTCDP-ADLMAVQZSA-N 0.000 description 3
- VPEUXKKHMUCDPW-KZULUSFZSA-N (1S)-8-fluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]amino]-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N[C@H](C)C1=CC=C(C=C1)OC VPEUXKKHMUCDPW-KZULUSFZSA-N 0.000 description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 3
- CCPCZZTZWCIVLT-UHFFFAOYSA-N 1-(2-methylpropylamino)-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-5-one Chemical compound C(C(C)C)NC1CCC=2NC(C=3C=CC=CC=3C=21)=O CCPCZZTZWCIVLT-UHFFFAOYSA-N 0.000 description 3
- DYYVUMASWHJUHN-UHFFFAOYSA-N 1-(3-hydroxypropylamino)-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-5-one Chemical compound OCCCNC1CCC=2NC(C=3C=CC=CC=3C=21)=O DYYVUMASWHJUHN-UHFFFAOYSA-N 0.000 description 3
- LRFMEWORDIODOX-UHFFFAOYSA-N 1-(ethylamino)-8-fluoro-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound C(C)NC1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O LRFMEWORDIODOX-UHFFFAOYSA-N 0.000 description 3
- HRTUVDWAHRHGSN-UHFFFAOYSA-N 1-(methylamino)-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-5-one Chemical compound CNC1CCC=2NC(C=3C=CC=CC=3C=21)=O HRTUVDWAHRHGSN-UHFFFAOYSA-N 0.000 description 3
- NZFJPIKHAUEKJP-LJQANCHMSA-N 1-[(1S)-8,9-difluoro-6-(2-hydroxyethoxy)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OCCO)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F NZFJPIKHAUEKJP-LJQANCHMSA-N 0.000 description 3
- QLOBMZKAOAACPA-UHFFFAOYSA-N 1-fluoro-4-isocyanato-2-methylbenzene Chemical compound CC1=CC(N=C=O)=CC=C1F QLOBMZKAOAACPA-UHFFFAOYSA-N 0.000 description 3
- MXZOCYJMJUBAOH-UHFFFAOYSA-N 11-(3-hydroxypropylamino)-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-5-one Chemical compound OCCCNC1CCCCC=2NC(C3=CC=CC=C3C=21)=O MXZOCYJMJUBAOH-UHFFFAOYSA-N 0.000 description 3
- DPWPYEATGBFEFF-UHFFFAOYSA-N 11-(methylamino)-6,7,8,9,10,11-hexahydrocyclohepta[c]isoquinolin-5-one Chemical compound CNC1CCCCC=2NC(C3=CC=CC=C3C=21)=O DPWPYEATGBFEFF-UHFFFAOYSA-N 0.000 description 3
- NHXDCVFTXJVUGK-UHFFFAOYSA-N 4,5-difluoro-2-iodobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1I NHXDCVFTXJVUGK-UHFFFAOYSA-N 0.000 description 3
- JAOINXWEFKZYIL-UHFFFAOYSA-N 4-(1-methyl-2-oxoquinolin-4-yl)oxy-n-(4-methylpyridin-2-yl)butanamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC1=CC=NC(NC(=O)CCCOC=2C3=CC=CC=C3N(C)C(=O)C=2)=C1 JAOINXWEFKZYIL-UHFFFAOYSA-N 0.000 description 3
- 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 3
- JRGSDODHCFFYAZ-UHFFFAOYSA-N 8,9-difluoro-2,3,4,5-tetrahydrophenanthridine-1,6-dione Chemical compound FC=1C=C2C(NC=3CCCC(C=3C2=CC=1F)=O)=O JRGSDODHCFFYAZ-UHFFFAOYSA-N 0.000 description 3
- BKGZFCJPIPDTSX-UHFFFAOYSA-N 8-fluoro-1-(3-hydroxypropylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3NCCCO BKGZFCJPIPDTSX-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 235000019489 Almond oil Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NAAUOQXDZJVQMJ-RYDFDWSBSA-N COC=1N=C2CCCC(C2=C2C=CC=CC=12)N[S@](=O)C(C)(C)C Chemical compound COC=1N=C2CCCC(C2=C2C=CC=CC=12)N[S@](=O)C(C)(C)C NAAUOQXDZJVQMJ-RYDFDWSBSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 108091006905 Human Serum Albumin Proteins 0.000 description 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 3
- 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 3
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 3
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 239000008168 almond oil Substances 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- ISLNCCCLBUMHQQ-UHFFFAOYSA-N isoquinoline-1,5-dione Chemical compound O=C1N=CC=C2C(=O)C=CC=C21 ISLNCCCLBUMHQQ-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001627 lamivudine Drugs 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000007909 melt granulation Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- SMIQVIXGQSMHKF-UHFFFAOYSA-N oxane-3,5-dione Chemical compound O=C1COCC(=O)C1 SMIQVIXGQSMHKF-UHFFFAOYSA-N 0.000 description 3
- 239000003961 penetration enhancing agent Substances 0.000 description 3
- NHLIEUJLUQIYMN-UHFFFAOYSA-N phenyl n-(3-cyano-4-fluorophenyl)carbamate Chemical compound C1=C(C#N)C(F)=CC=C1NC(=O)OC1=CC=CC=C1 NHLIEUJLUQIYMN-UHFFFAOYSA-N 0.000 description 3
- 125000005541 phosphonamide group Chemical group 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 3
- 229910001958 silver carbonate Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 229960002180 tetracycline Drugs 0.000 description 3
- 229930101283 tetracycline Natural products 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 230000007442 viral DNA synthesis Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UPCHIKZLKUVJHY-SPLOXXLWSA-N (1S)-1-[ethyl-[(1R)-1-(4-methoxyphenyl)ethyl]amino]-8-fluoro-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound C(C)N([C@@H]1COCC=2NC(C=3C=C(C=CC=3C=21)F)=O)[C@H](C)C1=CC=C(C=C1)OC UPCHIKZLKUVJHY-SPLOXXLWSA-N 0.000 description 2
- PDTNLVMVYUKLQO-MPBGBICISA-N (1S)-8,9-difluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]-methylamino]-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C)[C@H](C)C1=CC=C(C=C1)OC)F PDTNLVMVYUKLQO-MPBGBICISA-N 0.000 description 2
- RPPXNKAQTQHBGZ-LLVKDONJSA-N (1S)-8,9-difluoro-5-methyl-1-(methylamino)-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@H]3NC)F RPPXNKAQTQHBGZ-LLVKDONJSA-N 0.000 description 2
- NWPBSEJXHNTRDR-ZUOKHONESA-N (1S)-8-fluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]-methylamino]-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C)[C@H](C)C1=CC=C(C=C1)OC NWPBSEJXHNTRDR-ZUOKHONESA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-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
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- PISHPAJOGZXLCG-UHFFFAOYSA-N 1,2,3-trifluoro-5-isocyanatobenzene Chemical compound FC1=CC(N=C=O)=CC(F)=C1F PISHPAJOGZXLCG-UHFFFAOYSA-N 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 2
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 2
- LQKNUYPNFMZLDD-UHFFFAOYSA-N 1-(methylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound CNC1COCC=2NC(C=3C=CC=CC=3C=21)=O LQKNUYPNFMZLDD-UHFFFAOYSA-N 0.000 description 2
- OCUXGNPCNQAHTR-GOSISDBHSA-N 1-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-3-(4-fluoro-3-methylphenyl)-1-methylurea Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C)C)F OCUXGNPCNQAHTR-GOSISDBHSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- ARGCQEVBJHPOGB-UHFFFAOYSA-N 2,5-dihydrofuran Chemical compound C1OCC=C1 ARGCQEVBJHPOGB-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-MICDWDOJSA-N 2-deuterioacetonitrile Chemical compound [2H]CC#N WEVYAHXRMPXWCK-MICDWDOJSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- XPFMQYOPTHMSJJ-UHFFFAOYSA-N 5-fluoro-2-iodobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC=C1I XPFMQYOPTHMSJJ-UHFFFAOYSA-N 0.000 description 2
- KBWHMZSWXRVOCB-UHFFFAOYSA-N 7,8,9,10-tetrahydro-6H-cyclohepta[c]isoquinoline-5,11-dione Chemical compound C1=C2C3=C(NC(C2=CC=C1)=O)CCCCC3=O KBWHMZSWXRVOCB-UHFFFAOYSA-N 0.000 description 2
- FGBDZHFABKWLSK-CRIUFTBBSA-N 8,9-difluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]-methylamino]-5-methyl-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COCC3N(C)[C@H](C)C1=CC=C(C=C1)OC)F FGBDZHFABKWLSK-CRIUFTBBSA-N 0.000 description 2
- STNUAYXRCIZXPS-UHFFFAOYSA-N 8,9-difluoro-4,5-dihydropyrano[3,4-c]isoquinoline-1,6-dione Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3=O)F STNUAYXRCIZXPS-UHFFFAOYSA-N 0.000 description 2
- WOYXRPJKLFYGIY-UHFFFAOYSA-N 8,9-difluoro-6-methoxy-4H-pyrano[3,4-c]isoquinolin-1-one Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COCC3=O)F WOYXRPJKLFYGIY-UHFFFAOYSA-N 0.000 description 2
- GKEVPGXHNDVIEB-ILRUXTBWSA-N 8,9-difluoro-6-methoxy-N-[(1R)-1-(4-methoxyphenyl)ethyl]-N-methyl-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-amine Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COCC3N(C)[C@H](C)C1=CC=C(C=C1)OC)F GKEVPGXHNDVIEB-ILRUXTBWSA-N 0.000 description 2
- KCGBXFNBSDRAHS-UHFFFAOYSA-N 8,9-difluoro-6-methoxy-N-methyl-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-amine Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COCC3NC)F KCGBXFNBSDRAHS-UHFFFAOYSA-N 0.000 description 2
- UFWAAETUQMPHEX-UHFFFAOYSA-N 8-fluoro-1-[(2-hydroxy-2-methylpropyl)amino]-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3NCC(C)(C)O UFWAAETUQMPHEX-UHFFFAOYSA-N 0.000 description 2
- HWPSSOSHTJELTA-UHFFFAOYSA-N 8-fluoro-4,5-dihydropyrano[3,4-c]isoquinoline-1,6-dione Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COCC3=O HWPSSOSHTJELTA-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 2
- 229940123014 DNA polymerase inhibitor Drugs 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 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
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 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 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 229930182821 L-proline Natural products 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 108091081021 Sense strand Proteins 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229960001997 adefovir Drugs 0.000 description 2
- 229960003205 adefovir dipivoxil Drugs 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000003240 coconut oil Substances 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000000112 colonic effect Effects 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- DBOVMTXPZWVYAQ-UHFFFAOYSA-N cycloheptane-1,3-dione Chemical compound O=C1CCCCC(=O)C1 DBOVMTXPZWVYAQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 235000021472 generally recognized as safe Nutrition 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000003752 hydrotrope Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 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 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 239000002563 ionic surfactant Substances 0.000 description 2
- 230000002262 irrigation Effects 0.000 description 2
- 238000003973 irrigation Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-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
- 229960003639 laurocapram Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Chemical class 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229940055577 oleyl alcohol Drugs 0.000 description 2
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 2
- 229960003930 peginterferon alfa-2a Drugs 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical group NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 230000000541 pulsatile effect Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- GYESAYHWISMZOK-UHFFFAOYSA-N quinolin-5-ol Chemical compound C1=CC=C2C(O)=CC=CC2=N1 GYESAYHWISMZOK-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000006104 solid solution Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229960005311 telbivudine Drugs 0.000 description 2
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 2
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 2
- 229960004946 tenofovir alafenamide Drugs 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 2
- GFJBVRZNXHSCKR-UHFFFAOYSA-N tert-butyl N-(8,9-difluoro-4-hydroxy-6-methoxy-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl)-N-methylcarbamate Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)C(OCC3N(C(OC(C)(C)C)=O)C)O)F GFJBVRZNXHSCKR-UHFFFAOYSA-N 0.000 description 2
- QLVSYMKEIMWOIL-UHFFFAOYSA-N tert-butyl N-(8,9-difluoro-6-methoxy-4-oxo-1,2-dihydropyrano[3,4-c]isoquinolin-1-yl)-N-methylcarbamate Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)C(OCC3N(C(OC(C)(C)C)=O)C)=O)F QLVSYMKEIMWOIL-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- 230000007486 viral budding Effects 0.000 description 2
- 230000029302 virus maturation Effects 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- FGBDZHFABKWLSK-ZUOKHONESA-N (1S)-8,9-difluoro-1-[[(1R)-1-(4-methoxyphenyl)ethyl]-methylamino]-5-methyl-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COC[C@H]3N(C)[C@H](C)C1=CC=C(C=C1)OC)F FGBDZHFABKWLSK-ZUOKHONESA-N 0.000 description 1
- KCGBXFNBSDRAHS-LLVKDONJSA-N (1S)-8,9-difluoro-6-methoxy-N-methyl-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-amine Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)OC)COC[C@H]3NC)F KCGBXFNBSDRAHS-LLVKDONJSA-N 0.000 description 1
- JTDGKQNNPKXKII-SSDOTTSWSA-N (1r)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@@H](C)N)C=C1 JTDGKQNNPKXKII-SSDOTTSWSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-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
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-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
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-M 1,1-dioxo-1,2-benzothiazol-3-olate Chemical compound C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-M 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- YBWJVFMNWMLZEN-UHFFFAOYSA-N 1,2-difluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1F YBWJVFMNWMLZEN-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- CZLMRJZAHXYRIX-UHFFFAOYSA-N 1,3-dioxepane Chemical compound C1CCOCOC1 CZLMRJZAHXYRIX-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- 125000000196 1,4-pentadienyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])=C([H])[H] 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- FGZMIMISQGSJKF-FQEVSTJZSA-N 1-[(1R)-3-acetyl-8,9-difluoro-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-3-(3-cyano-4-fluorophenyl)-1-methylurea Chemical compound C(C)(=O)N1C[C@@H](C=2C3=C(C(NC=2C1)=O)C=C(C(=C3)F)F)N(C(=O)NC1=CC(=C(C=C1)F)C#N)C FGZMIMISQGSJKF-FQEVSTJZSA-N 0.000 description 1
- KTXCGNFZHJVNNQ-LJQANCHMSA-N 1-[(1S)-6-(2-aminoethylamino)-8,9-difluoro-2,4-dihydro-1H-pyrano[3,4-c]isoquinolin-1-yl]-3-[3-(difluoromethyl)-4-fluorophenyl]-1-methylurea Chemical compound FC=1C(=CC=2C3=C(N=C(C=2C=1)NCCN)COC[C@H]3N(C(=O)NC1=CC(=C(C=C1)F)C(F)F)C)F KTXCGNFZHJVNNQ-LJQANCHMSA-N 0.000 description 1
- REBNSCKSPQTBIX-LJQANCHMSA-N 1-[(1S)-8-fluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-1-(2-methylpropyl)-3-(3,4,5-trifluorophenyl)urea Chemical compound FC=1C=CC=2C3=C(NC(C=2C=1)=O)COC[C@H]3N(C(=O)NC1=CC(=C(C(=C1)F)F)F)CC(C)C REBNSCKSPQTBIX-LJQANCHMSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- PQDCXGBIHHYOHN-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(CN)O.CC(C)(CN)O PQDCXGBIHHYOHN-UHFFFAOYSA-N 0.000 description 1
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 1
- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical group CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- KBOFTBQUYXDFEF-UHFFFAOYSA-N 2-bromo-3,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC(F)=C1Br KBOFTBQUYXDFEF-UHFFFAOYSA-N 0.000 description 1
- XYRDQHNCDBDNSF-UHFFFAOYSA-N 2-chloro-4-isocyanato-1-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1Cl XYRDQHNCDBDNSF-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- MFUVCHZWGSJKEQ-UHFFFAOYSA-N 3,4-dichlorphenylisocyanate Chemical compound ClC1=CC=C(N=C=O)C=C1Cl MFUVCHZWGSJKEQ-UHFFFAOYSA-N 0.000 description 1
- VMUXSMXIQBNMGZ-UHFFFAOYSA-N 3,4-dihydrocoumarin Chemical compound C1=CC=C2OC(=O)CCC2=C1 VMUXSMXIQBNMGZ-UHFFFAOYSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- LRKXULYGPJCLEA-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-[(1R)-5-oxo-1,2,3,4-tetrahydrocyclopenta[c]isoquinolin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCC=2NC(C=3C=CC=CC=3C=21)=O)CCCO)=O LRKXULYGPJCLEA-LJQANCHMSA-N 0.000 description 1
- DAOJPJYOVOCZQN-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-(8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl)-1-(2-methylsulfonylethyl)urea Chemical compound ClC=1C=C(C=CC=1F)NC(N(CCS(=O)(=O)C)C1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O)=O DAOJPJYOVOCZQN-UHFFFAOYSA-N 0.000 description 1
- SPXHXPSGLKGPGT-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-3,3-dimethyl-6-oxo-1,2,4,5-tetrahydrophenanthridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1CC(CC=2NC(C3=CC=CC=C3C1=2)=O)(C)C)=O SPXHXPSGLKGPGT-LJQANCHMSA-N 0.000 description 1
- SDCGFNQYCPLKCK-KRWDZBQOSA-N 3-(3-chloro-4-fluorophenyl)-1-[(1R)-8-fluoro-6-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)[C@@H]1C=2C3=C(C(NC=2CNC1)=O)C=C(C=C3)F)=O SDCGFNQYCPLKCK-KRWDZBQOSA-N 0.000 description 1
- XXKAEXYKKAEBRY-UHFFFAOYSA-N 3-(3-chloro-4-fluorophenyl)-1-[8,9-difluoro-3-(2-hydroxyethyl)-6-oxo-1,2,4,5-tetrahydrobenzo[c][1,7]naphthyridin-1-yl]-1-methylurea Chemical compound ClC=1C=C(C=CC=1F)NC(N(C)C1C=2C3=C(C(NC=2CN(C1)CCO)=O)C=C(C(=C3)F)F)=O XXKAEXYKKAEBRY-UHFFFAOYSA-N 0.000 description 1
- JEAMGCQDRKRWRI-LJQANCHMSA-N 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-[(1R)-6-oxo-2,3,4,5,7,8,9,10-octahydro-1H-phenanthridin-1-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1CCCC=2NC(C=3CCCCC=3C1=2)=O)CC)=O JEAMGCQDRKRWRI-LJQANCHMSA-N 0.000 description 1
- JENLWMXGRQCIOZ-INIZCTEOSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(3R)-9-oxo-5,12-dioxa-8-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-3-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@H]1COCC=2NC(C3=C(C=21)CCOC3)=O)C)=O JENLWMXGRQCIOZ-INIZCTEOSA-N 0.000 description 1
- JENLWMXGRQCIOZ-MRXNPFEDSA-N 3-(3-chloro-4-fluorophenyl)-1-methyl-1-[(3S)-9-oxo-5,12-dioxa-8-azatricyclo[8.4.0.02,7]tetradeca-1(10),2(7)-dien-3-yl]urea Chemical compound ClC=1C=C(C=CC=1F)NC(N([C@@H]1COCC=2NC(C3=C(C=21)CCOC3)=O)C)=O JENLWMXGRQCIOZ-MRXNPFEDSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 1
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 1
- JOWXBGIZDALBJW-UHFFFAOYSA-N 3h-dioxepine Chemical compound C1OOC=CC=C1 JOWXBGIZDALBJW-UHFFFAOYSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 1
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CTUXTQBAHKCUIH-UHFFFAOYSA-N 4h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)N=CCC2=C1 CTUXTQBAHKCUIH-UHFFFAOYSA-N 0.000 description 1
- GZKDJFLRXDZBOI-LJQANCHMSA-N 5-bromo-N-[(1S)-8,9-difluoro-6-oxo-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-1-yl]-N-methyl-1,3-dihydroisoindole-2-carboxamide Chemical compound BrC=1C=C2CN(CC2=CC=1)C(=O)N(C)[C@@H]1COCC=2NC(C=3C=C(C(=CC=3C=21)F)F)=O GZKDJFLRXDZBOI-LJQANCHMSA-N 0.000 description 1
- LWYPJZCSMWHVPY-UHFFFAOYSA-N 5-fluoro-2-(3-hydroxy-5-oxo-2H-pyran-4-yl)benzoic acid Chemical compound FC=1C=CC(=C(C(=O)O)C=1)C1=C(COCC1=O)O LWYPJZCSMWHVPY-UHFFFAOYSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JAOBVXMYFIESNC-UHFFFAOYSA-N 8,9-difluoro-1-(methylamino)-1,2,4,5-tetrahydropyrano[3,4-c]isoquinolin-6-one Chemical compound FC=1C(=CC=2C3=C(NC(C=2C=1)=O)COCC3NC)F JAOBVXMYFIESNC-UHFFFAOYSA-N 0.000 description 1
- QIGLIZHRPFCQBH-UHFFFAOYSA-N 8,9-difluoro-3,4-dihydro-2H-benzo[c]chromene-1,6-dione Chemical compound FC=1C(=CC2=C(C(OC=3CCCC(C2=3)=O)=O)C=1)F QIGLIZHRPFCQBH-UHFFFAOYSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 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
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000010471 Chronic Hepatitis D Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-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
- 230000004543 DNA replication Effects 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241001050985 Disco Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 244000239659 Eucalyptus pulverulenta Species 0.000 description 1
- RPPXNKAQTQHBGZ-UHFFFAOYSA-N FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COCC3NC)F Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)C)COCC3NC)F RPPXNKAQTQHBGZ-UHFFFAOYSA-N 0.000 description 1
- BNXLPBKPEIMTDO-UHFFFAOYSA-N FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)CCNC(OCC1=CC=CC=C1)=O)COCC3NC)F Chemical compound FC=1C(=CC=2C3=C(N(C(C=2C=1)=O)CCNC(OCC1=CC=CC=C1)=O)COCC3NC)F BNXLPBKPEIMTDO-UHFFFAOYSA-N 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 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
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- 230000004075 alteration Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 108010006523 asialoglycoprotein receptor Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- OTKPPUXRIADSGD-PPRNARJGSA-N avoparcina Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2C([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@H](N)C2)OC2=CC=C(C=C2)[C@@H](O)[C@H](C(N[C@H](C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](NC)C=1C=CC(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)=CC=1)[C@H]1C[C@@H](N)[C@@H](O)[C@H](C)O1 OTKPPUXRIADSGD-PPRNARJGSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000004718 beta keto acids Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000003686 blood clotting factor concentrate Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000011449 brick Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 125000004369 butenyl group Chemical group C(=CCC)* 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
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 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
- 235000012000 cholesterol Nutrition 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
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 229960005338 clevudine Drugs 0.000 description 1
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- ZWAJLVLEBYIOTI-UHFFFAOYSA-N cyclohexene oxide Chemical compound C1CCCC2OC21 ZWAJLVLEBYIOTI-UHFFFAOYSA-N 0.000 description 1
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohexene oxide Natural products O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- LOGSONSNCYTHPS-UHFFFAOYSA-N cyclopentane-1,3-dione Chemical compound O=C1CCC(=O)C1 LOGSONSNCYTHPS-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- DMSHWWDRAYHEBS-UHFFFAOYSA-N dihydrocoumarin Natural products C1CC(=O)OC2=C1C=C(OC)C(OC)=C2 DMSHWWDRAYHEBS-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229950006528 elvucitabine Drugs 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 244000309457 enveloped RNA virus Species 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- XGZNHFPFJRZBBT-UHFFFAOYSA-N ethanol;titanium Chemical compound [Ti].CCO.CCO.CCO.CCO XGZNHFPFJRZBBT-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- MFFXVVHUKRKXCI-UHFFFAOYSA-N ethyl iodoacetate Chemical compound CCOC(=O)CI MFFXVVHUKRKXCI-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 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
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 229940113174 imidurea Drugs 0.000 description 1
- 229940126546 immune checkpoint molecule Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 238000009126 molecular therapy Methods 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
- 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
- 239000002105 nanoparticle Substances 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 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
- 239000011236 particulate material Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- OVMZDPUWIKZVIX-UHFFFAOYSA-N phenyl n-(4-chloro-3-cyanophenyl)carbamate Chemical compound C1=C(C#N)C(Cl)=CC=C1NC(=O)OC1=CC=CC=C1 OVMZDPUWIKZVIX-UHFFFAOYSA-N 0.000 description 1
- KDGPOUYSABMLPS-UHFFFAOYSA-N phenyl n-(4-chloro-3-fluorophenyl)carbamate Chemical compound C1=C(Cl)C(F)=CC(NC(=O)OC=2C=CC=CC=2)=C1 KDGPOUYSABMLPS-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 125000004585 polycyclic heterocycle group Chemical group 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 230000035935 pregnancy 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
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 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
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 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
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000017610 release of virus from host Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940048842 sodium xylenesulfonate Drugs 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
-
- 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
-
- 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
- A61K31/436—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 six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/4365—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 having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
- C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D227/08—Oxygen atoms
- C07D227/087—One doubly-bound oxygen atom in position 2, e.g. lactams
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本公开内容包括可用于治疗或预防患者中的乙型肝炎病毒(HBV)和/或丁型肝炎病毒(HDV)感染的取代的芳基甲基脲、取代的杂芳基甲基脲或其类似物,以及包括它们的组合物。
Description
相关申请的交叉引用
根据35 U.S.C.§119(e),本申请要求2019年12月20日提交的美国临时申请号62/951,299和2020年6月9日提交的63/036,687的优先权,该申请的全部内容通过引用以其整体并入本文。
背景技术
乙型肝炎是世界上最流行的疾病之一,被美国过敏和传染病研究所(NIAID)列为高度优先感兴趣的领域。尽管大多数人会在急性症状后解决感染,但是大约30%的病例会变成慢性病。据估计,全世界有3.5-4亿人患有慢性乙型肝炎,每年导致50-100万人死亡,这主要是由于肝细胞癌、肝硬化和/或其他并发症的发展。
目前已批准用于治疗慢性乙型肝炎的药物数量有限,包括抑制α-干扰素的两种制剂(标准和聚乙二醇化的)和抑制乙型肝炎病毒(HBV)DNA聚合酶的五种核苷/核苷酸类似物(拉米夫定、阿德福韦、恩替卡韦、替比夫定和替诺福韦)。目前,一线治疗的选择是恩替卡韦、替诺福韦和/或聚乙二醇干扰素α-2a。然而,聚乙二醇干扰素α-2a仅在三分之一的治疗患者中达到了理想的血清学里程碑,并且经常伴有严重的副作用。恩替卡韦和替诺福韦是有效的HBV抑制剂,但需要长期或可能终生施用以持续抑制HBV复制,并可能由于耐药病毒的出现而最终失败。因此,迫切需要为慢性乙型肝炎引入新型、安全和有效的疗法。
HBV是属于嗜肝病毒科的非致细胞病变型嗜肝DNA病毒。前基因组(pg)RNA是HBVDNA逆转录复制的模板。pg RNA与病毒DNA聚合酶一起衣壳化为核衣壳对于随后的病毒DNA合成至关重要。抑制pg RNA衣壳化可能会阻止HBV复制,并为HBV治疗提供新的治疗方法。衣壳抑制剂通过直接或间接抑制衣壳蛋白的表达和/或功能发挥作用:例如,它可以抑制衣壳装配、诱导非衣壳聚合物形成、促进过量的衣壳装配或衣壳装配方向错误、影响衣壳稳定和/或抑制RNA衣壳化。衣壳抑制剂还可以通过在复制过程中的一个或多个下游事件中抑制衣壳功能来发挥作用,这些事件比如但不限于病毒DNA合成、松环DNA(rcDNA)转运入细胞核中、共价闭合的环状DNA(cccDNA)的形成、病毒成熟、出芽和/或释放。
在临床上,抑制pg RNA衣壳化或更普遍地抑制核衣壳装配可以提供某些治疗优势。在一方面,抑制pg RNA衣壳化可以通过向无法耐受或无法从当前药物中获益的患者亚群提供选择来补充当前的药物。在另一方面,基于其独特的抗病毒机制,对pg RNA衣壳化的抑制可有效地抵抗对当前可用的DNA聚合酶抑制剂具有抗性的HBV变体。在另一方面,pgRNA衣壳化抑制剂与DNA聚合酶抑制剂的联合治疗可以协同抑制HBV复制并防止耐药性的出现,因此为慢性乙型肝炎感染提供了更有效的治疗。
丁型肝炎病毒(HDV)是仅在HBV存在时才能繁殖的一种小的环状包膜RNA病毒。具体而言,HDV需要HBV表面抗原蛋白自我繁殖。与单独感染HBV相比,感染HBV和HDV会导致更严重的并发症。这些并发症包括在急性感染中经历肝衰竭的可能性更大,并迅速发展为肝硬化,并且增加在慢性感染中发展为肝癌的机会。与乙型肝炎结合时,丁型肝炎在所有肝炎感染中死亡率最高。HDV的传播途径与HBV相似。感染主要限于处于HBV感染的高风险人群,特别是注射吸毒者和接受凝血因子浓缩物的人群。
当前,没有有效的可用于治疗急性或慢性丁型肝炎的抗病毒疗法。每周给予干扰素-α,持续12至18个月是丁型肝炎的唯一许可疗法。对该疗法的反应有限,因为仅约四分之一的患者在治疗后6个月无法检测到血清HDV RNA。
在临床上,抑制pg RNA衣壳化或更普遍地抑制核衣壳装配可能为乙型肝炎和/或丁型肝炎的治疗提供某些治疗优势。在一方面,抑制pg RNA衣壳化可以通过向无法耐受或无法从当前药物中获益的患者亚群提供选择来补充当前的药物。在另一方面,基于其独特的抗病毒机制,对pg RNA衣壳化的抑制可有效地抵抗对当前可用的DNA聚合酶抑制剂具有抗性的HBV和/或HDV变体。在另一方面,pg RNA衣壳化抑制剂与DNA聚合酶抑制剂的联合治疗可以协同抑制HBV和/或HDV复制并防止耐药性的出现,因此为慢性乙型肝炎和/或丁型肝炎感染提供了更有效的治疗。
因此,本领域中需要鉴定可用于在受试者中治疗和/或预防HBV和/或HDV感染的新型化合物。在某些实施方式中,新型化合物抑制HBV和/或HDV核衣壳装配。在其他实施方式中,新型化合物可用于HBV和/或HBV-HDV感染的患者、有被HBV和/或HBV-HDV感染的风险的患者和/或感染了耐药性HBV和/或HDV的患者中。本公开内容解决了这一需求。
发明内容
本公开内容提供了式(I)的化合物或其盐、溶剂化物、前药、立体异构体、互变异构体或同位素标记的衍生物,或其任何混合物:
其中R1、R4、R5、R6、X、Y和A环如本文其他地方所定义。
本公开内容进一步提供了包括至少一种本公开内容的化合物和药学上可接受的载体的药物组合物。
本公开内容进一步提供了在受试者中治疗、减轻和/或预防乙型肝炎病毒(HBV)感染的方法。本公开内容进一步提供了在HBV-感染的受试者中直接或间接抑制病毒衣壳蛋白的表达和/或功能的方法。在某些实施方式中,该方法包括向需要其的受试者施用治疗有效量的至少一种本公开内容的化合物和/或至少一种本公开内容的药物组合物。
附图说明
附图通过示例而非限制的方式一般地图解了本申请的各种实施方式。
图1图解了具有50%热椭球的化合物72的ORTEP图。
具体实施方式
在某些方面,本公开内容涉及发现可用于在受试者中治疗、减轻和/或预防乙型肝炎病毒(HBV)和/或丁型肝炎病毒(HDV)感染和相关病症的某些取代的脲和酰胺。在某些非限制性实施方式中,本公开内容的化合物是病毒衣壳抑制剂。
定义
如本文所使用的,以下每个术语在本节中具有与其相关的含义。除非另有定义,否则本文使用的所有技术和科学术语通常具有与本公开内容所属领域的普通技术人员通常所理解的相同的含义。通常,本文所用的命名法以及动物药理学、药物科学,分离科学和有机化学中的实验室程序是本领域众所周知的和常用的。应当理解,只要本教导仍然可操作,步骤的顺序或用于执行某些动作的顺序是不重要的。章节标题的任何使用均旨在帮助阅读文件,而不应理解为限制性的;与章节标题相关的信息可能发生在该特定章节之内或之外。该文件中引用的所有出版物、专利和专利文件都通过引用以其整体并入本文,如同通过引用将其单独并入。
在本申请中,在叙述元素或组分被包括在所列举的元素或组分的列表中和/或选自所列举的元素或组分的列表的情况下,应当理解,该元素或组分可以是所列举的元素或组分中的任一个并且可以选自所列举的元件或组分中的两个或更多个。
在本文描述的方法中,可以以任何顺序执行动作,除非明确地陈述了时间或操作序列。此外,指定的动作可以同时执行,除非明确的声明语言陈述了它们是分开执行的。例如,可以在单个操作中同时进行要求保护的X动作和要求保护的Y动作,并且所得过程将落入要求保护的过程的字面范围内。
在本文中,除非上下文另外明确指出,否则术语“一(a)”、“一(an)”或“所述(the)”用于包括一个或多个。除非另有说明,否则术语“或(or)”用于表示非排他性的“或”。陈述“A和B中的至少一个”或“A或B中的至少一个”具有与“A、B或A和B”相同的含义。
如本文中所使用的,术语“约(about)”将被本领域普通技术人员理解,并且将在使用它的上下文中在某种程度上变化。如本文中所使用的,当“约”指代可测量值比如量、时间持续时间等时,旨在涵盖与指定值具有±20%、±10%、±5%、±1%或±0.1%的变化,因为这样的变化适合执行所公开的方法。
如本文所使用的,除非另有说明,否则单独或与其他术语组合使用的术语“烯基”是指具有规定数目的碳原子的稳定的单不饱和或二不饱和直链或支链烃基。实例包括乙烯基、丙烯基(或烯丙基)、丁烯基(crotyl)、异戊烯基、丁二烯基、1,3-戊二烯基、1,4-戊二烯基以及更高的同系物和异构体。代表烯烃的官能团的实例为-CH2-CH=CH2。
如本文所使用的,除非另有说明,否则单独或与其他术语组合使用的术语“烷氧基(alkoxy)”是指经由氧原子连接到分子的其余部分的如本文其他地方所定义的具有指定数目的碳原子的烷基,诸如例如甲氧基、乙氧基、1-丙氧基、2-丙氧基(或异丙氧基)和更高的同系物和异构体。具体实例是(C1-C3)烷氧基,比如,但不限于乙氧基和甲氧基。
如本文所使用的,除非另有说明,术语“烷基(alkyl)”本身或作为另一取代基的一部分是指具有指定数目的碳原子(即,C1-C10表示1至10个碳原子)的直链或支链烃,并且包括直链、支链或环状取代基。实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、新戊基、己基和环丙基甲基。具体实施方式是(C1-C6)烷基,比如,但不限于乙基、甲基、异丙基、异丁基、正戊基、正己基和环丙基甲基。
如本文所使用的,除非另有说明,否则单独或与其他术语组合使用的术语“炔基(alkynyl)”是指具有规定数目的碳原子的具有碳-碳三键的稳定的直链或支链烃基。非限制性实例包括乙炔基和丙炔基,以及更高的同系物和异构体。术语“炔丙基(propargylic)”是指以-CH2-C≡CH为例的基团。术语“均炔丙基(homopropargylic)”是指以-CH2CH2-C≡CH为例的基团。
如本文所使用的,术语“芳族”是指具有一个或多个多不饱和环并且具有芳族特征,即具有(4n+2)个离域的π(pi)电子(其中‘n’是整数)的碳环或杂环。
如本文所使用的,除非另有说明,否则单独或与其他术语组合使用的术语“芳基”是指含有一个或多个环(通常为一个、两个或三个环)的碳环芳族系统,其中这些环可以以侧链方式连接在一起,比如联苯,或者可以稠合,比如萘。实例包括苯基、蒽基和萘基。芳基还包括例如与一个或多个饱和或部分饱和的碳环(例如,双环[4.2.0]八-1,3,5-三烯基或茚满基)稠合的苯环或萘环,其可以在芳环和/或饱和或部分饱和的环的一个或多个碳原子处被取代。
如本文所使用的,术语“芳基-(C1-C6)烷基”是指其中1至6个碳亚烷基链连接至芳基的官能团,例如,-CH2CH2-苯基或-CH2-苯基(或苄基)。具体实例是芳基-CH2-和芳基-CH(CH3)-。术语“取代的芳基-(C1-C6)烷基”是指其中芳基被取代的芳基-(C1-C6)烷基官能团。具体实例是取代的芳基(CH2)-。类似地,术语“杂芳基-(C1-C6)烷基”是指其中1至3个碳亚烷基链连接至杂芳基的官能团,例如,-CH2CH2-吡啶基。具体实例是杂芳基-(CH2)-。术语“取代的杂芳基-(C1-C6)烷基”是指其中杂芳基被取代的杂芳基-(C1-C6)烷基官能团。具体实例是取代的杂芳基-(CH2)-。
在一方面,与受试者有关的术语“共同施用的(co-administered)”和“共同施用(co-administration)”是指向受试者施用本公开内容的化合物和/或组合物以及也可以治疗或预防本文考虑的疾病或紊乱的化合物和/或组合物。在某些实施方式中,作为单一治疗方法的一部分,共同施用的化合物和/或组合物单独施用或以任何种类的组合施用。可以以任何种类的组合将共同施用的化合物和/或组合物配制成各种固体、凝胶和液体制剂的固体和液体的混合物以及溶液。
如本文所使用的,除非另有说明,术语“环烷基(cycloalkyl)”本身或作为另一取代基的一部分是指具有指定数目的碳原子的环链烃(即,C3-C6是指包括由3至6个碳原子组成的环基团的环状基团)并且包括直链、支链或环状取代基。(C3-C6)环烷基的实例是环丙基、环丁基、环戊基和环己基。环烷基环可以任选地被取代。环烷基的非限制性实例包括:环丙基、2-甲基-环丙基、环丙烯基、环丁基、2,3-二羟基环丁基、环丁烯基、环戊基、环戊烯基、环戊二烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、2,5-二甲基环戊基、3,5-二氯环己基、4-羟基环己基、3,3,5-三甲基环己-1-基、八氢戊烯基、八氢-1H-茚基、3a,4,5,6,7,7a-六氢-3H-茚-4-基、十氢薁基(azulenyl);双环[6.2.0]癸基、十氢萘基和十二氢-1H-芴基。术语“环烷基”还包括双环烃环,其非限制性实例包括双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.1.1]庚烷基、1,3-二甲基[2.2.1]庚烷-2-基、双环[2.2.2]辛烷基和双环[3.3.3]十一烷酰基(undecanyl)。
如本文所使用的,“疾病”是受试者的健康状态,其中受试者不能维持体内稳态,并且如果疾病没有得到改善,则受试者的健康继续恶化。
如本文所使用的,受试者中的“紊乱(disorder)”是其中受试者能够维持稳态的健康状态,但是其中受试者的健康状态比没有紊乱时的健康状态不利。如果不及时治疗,紊乱不一定会导致受试者的健康状态进一步下降。
如本文所使用的,术语“卤离子(halide)”是指带有负电荷的卤素原子。卤化物阴离子是氟离子(F-)、氯离子(Cl-)、溴离子(Br-)和碘离子(I-)。
如本文所使用的,除非另有说明,术语“卤基(halo)”或“卤素(halogen)”单独或作为另一取代基的一部分是指氟原子、氯原子、溴原子或碘原子。
如本文所使用的,除非另有说明,术语“杂烯基(heteroalkenyl)”本身或与另一术语组合是指由规定数目的碳原子和选自O、N和S的一个或两个杂原子组成的稳定的直链或支链单不饱和或二不饱和烃基,并且其中氮原子和硫原子可任选地被氧化,和氮杂原子可任选地被季铵化。可以连续放置至多两个杂原子。实例包括-CH=CH-O-CH3、-CH=CH-CH2-OH、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3和-CH2-CH=CH-CH2-SH。
如本文所使用的,除非另有说明,术语“杂烷基(heteroalkyl)”本身或与另一术语组合是指由规定数目的碳原子和选自O、N和S的一个或两个杂原子组成的稳定的直链或支链烷基,并且其中氮原子和硫原子可以任选地被氧化,和氮杂原子可以任选地被季铵化。杂原子(一个或多个)可位于杂烷基的任何位置,包括在杂烷基的其余部分和其连接的片段之间,以及连接至杂烷基中最远端的碳原子。实例包括:-OCH2CH2CH3、-CH2CH2CH2OH、-CH2CH2NHCH3、-CH2SCH2CH3和-CH2CH2S(=O)CH3。至多两个杂原子可以是连续的,诸如例如-CH2NH-OCH3或-CH2CH2SSCH3。
如本文所使用的,术语“杂芳基(heteroaryl)”或“杂芳族(heteroaromatic)”是指具有芳族特性的杂环。多环杂芳基可以包括一个或多个部分饱和的环。实例包括四氢喹啉和2,3-二氢苯并呋喃基。
如本文所使用的,除非另有说明,否则术语“杂环(heterocycle)”或“杂环基(heterocyclyl)”或“杂环的(heterocyclic)”本身或作为另一取代基的一部分是指包括碳原子和选自N、O和S的至少一个杂原子的未取代或取代的、稳定的单环或多环杂环系统,并且其中氮和硫杂原子可以任选地被氧化,和氮原子可以任选地被季铵化。除非另有说明,杂环系统可以连接在提供稳定结构的任何杂原子或碳原子上。杂环本质上可以是芳族的或非芳族的。在某些实施方式中,杂环是杂芳基。
非芳族杂环的实例包括单环基团,比如氮丙啶、环氧乙烷、硫杂丙环(thiirane)、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、吡咯烷、吡咯啉、咪唑啉、吡唑烷、二氧戊环、环丁砜、2,3-二氢呋喃、2,5-二氢呋喃、四氢呋喃、四氢噻吩(thiophane)、哌啶、1,2,3,6-四氢吡啶、1,4-二氢吡啶、哌嗪、吗啉、硫代吗啉、吡喃、2,3-二氢吡喃、四氢吡喃、1,4-二噁烷、1,3-二噁烷、高哌嗪、高哌啶、1,3-二氧杂环庚烷、4,7-二氢-1,3-二噁庚(dioxepin)和环氧己烷(hexamethyleneoxide)。
杂芳基的实例包括吡啶基、吡嗪基、嘧啶基(比如,但不限于2-和4-嘧啶基)、哒嗪基、噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、异噻唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-三唑基、四唑基、1,2,3-噻唑基、1,2,3-噁二唑基、1,3,4-噻唑基和1,3,4-噁二唑基。
多环杂环的实例包括吲哚基(比如,但不限于3-、4-、5-、6-和7-吲哚基)、二氢吲哚基、喹啉基、四氢喹啉基、异喹啉基(比如,但不限于1-和5-异喹啉基)、1,2,3,4-四氢异喹啉基、噌啉基(cinnolinyl)、喹喔啉基(比如,但不限于2-和5-喹喔啉基)、喹唑啉基、酞嗪基、1,8-二氮杂萘基、1,4-苯并二噁烷基、香豆素、二氢香豆素、1,5-二氮杂萘基、苯并呋喃基(比如,但不限于3-、4-、5-、6-和7-苯并呋喃基)、2,3-二氢苯并呋喃基、1,2-苯并噁唑基、苯并噻吩基(比如,但不限于3-、4-、5-、6-和7-苯并噻吩基)、苯并噁唑基、苯并噻唑基(比如,但不限于2-苯并噻唑基和5-苯并噻唑基)、嘌呤基、苯并咪唑基、苯并三唑基、硫代黄嘌呤基(thioxanthinyl)、咔唑基、咔啉基、吖啶基、吡咯啶基(pyrrolizidinyl)和喹嗪啶基(quinolizidinyl)。
杂环基和杂芳基部分的上述列举旨在是代表性的,而不是限制性的。
如本文所使用的,术语“药物组合物”或“组合物”是指在本公开内容中有用的至少一种化合物与药学上可接受的载体的混合物。药物组合物促进将化合物施用至受试者。
如本文所使用的,术语“药学上可接受的”是指不消除本公开内容中有用的化合物的生物活性或特性并且相对无毒的材料,比如载体或稀释剂,即可以在不引起不良生物效应或不会以有害方式与包含其的组合物的任何组分相互作用的情况下将该材料施用至受试者。
如本文所使用的,术语“药学上可接受的载体”是指参与在受试者中或向受试者携带或运输本公开内容中有用的化合物使得它可以执行预期的功能的药学上可接受的材料、组合物或载体,比如液体或固体填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或封装材料。典型地,将这种构建体从一个器官或身体的一部分携带或运输到另一器官或身体的一部分。在与制剂的其他成分(包括本公开内容中有用的化合物)相容的意义上,每种载体必须是“可接受的”,并且对受试者无害。可用作药学上可接受的载体的材料的的一些实例包括:糖,比如乳糖、葡萄糖和蔗糖;淀粉,比如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,比如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉末状黄蓍胶;麦芽;明胶;滑石;赋形剂,比如可可脂和栓剂蜡;油,比如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,比如丙二醇;多元醇,比如甘油、山梨糖醇、甘露糖醇和聚乙二醇;酯,比如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,比如氢氧化镁和氢氧化铝;表面活性剂;藻酸;无热原水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;和药物制剂中使用的其他无毒的相容性物质。如本文所使用的,“药学上可接受的载体”还包括与本公开内容中有用的化合物的活性相容的并且是受试者生理上可接受的任何和所有包衣、抗细菌和抗真菌剂,以及吸收延迟剂等。补充活性化合物也可以并入组合物中。“药学上可接受的载体”可以进一步包括在本公开内容中有用的化合物的药学上可接受的盐。在本公开内容的实践中使用的药物组合物中可以包含的其他另外的成分是本领域已知的,并且在例如《雷明顿药物科学》(Genaro,Ed.,Mack Publishing Co.,1985,Easton,PA)中描述,其通过引用并入本文。
如本文所使用的,措词“药学上可接受的盐”是指由包括无机酸、无机碱、有机酸、无机碱、溶剂化物(包括水合物)和其包合物(clathrate)的药学上可接受的无毒酸和/或碱制备的施用化合物的盐。
如本文所使用的,化合物的“药学上有效量”、“治疗有效量”或“有效量”是足以向施用化合物的受试者提供有益作用的化合物的量。
如本文所使用的,术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”是指在开始施用药剂或化合物时在未发展出这种症状的受试者中避免或延迟与疾病或病症相关的症状的发作。疾病、病症和紊乱在本文可互换使用。
如本文所使用的术语“特异性结合(specifically bind)”或“特异性结合(specifically binds)”是指第一分子优先结合第二分子(例如,特定受体或酶),但不一定仅结合该第二分子。
如本文所使用的,术语“受试者(subject)”和“个体(individual)”和“患者(patient)”可以互换使用,并且可以指人类或非人类哺乳动物或鸟类。非人类哺乳动物包括例如牲畜和宠物,比如绵羊、牛科、猪科、犬科、猫科和鼠科哺乳动物。在某些实施方式中,受试者是人类。
如本文所使用的,术语“取代的”是指原子或原子团已取代氢作为连接至另一基团的取代基。
如本文所使用的,术语“取代的烷基”、“取代的环烷基”、“取代的烯基”或“取代的炔基”是指如本文其他地方所定义的烷基、环烷基、烯基或炔基,其被独立地选自卤素、-OH、烷氧基、四氢-2-H-吡喃基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、1-甲基-咪唑-2-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、-C(=O)OH、-C(=O)O(C1-C6)烷基、三氟甲基、-C≡N、-C(=O)NH2、-C(=O)NH(C1-C6)烷基、-C(=O)N((C1-C6)烷基)2、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-C(=NH)NH2和-NO2的一个、两个或三个取代基取代,在某些实施方式中含有独立地选自卤素、-OH、烷氧基、-NH2、三氟甲基、-N(CH3)2和-C(=O)OH的一个或两个取代基,在某些实施方式中独立地选自卤素、烷氧基和-OH。取代的烷基的实例包括但不限于2,2-二氟丙基、2-羧基环戊基和3-氯丙基。
对于芳基、芳基-(C1-C3)烷基和杂环基,应用于这些基团的环的术语“取代的”是指在允许这种取代的地方的任何取代水平,即单、二、三、四或五取代。取代基是独立选择的,并且取代可以在任何化学可及的位置。在某些实施方式中,取代基的数目在1和4之间变化。在其他实施方式中,取代基的数目在1和3之间变化。在另一个实施方式中,取代基的数目在1和2之间变化。在又其他实施方式中,取代基独立地选自C1-C6烷基、-OH、C1-C6烷氧基、卤素、氨基、乙酰氨基和硝基。如本文所使用的,当取代基是烷基或烷氧基时,碳链可以是支链、直链或环状的。
除非另有说明,当两个取代基一起形成具有指定数目的环原子的环时(例如,R2和R3与它们所连接的氮一起形成具有3至7个环成员的环),该环可以具有碳原子和任选地一个或多个(例如,1至3个)独立地选自氮、氧或硫的另外的杂原子。该环可以是饱和的或部分饱和的,并且可以任选地被取代。
每当术语或其前缀根中的任一个出现在取代基的名称中时,该名称应解释为包括本文提供的那些限制。例如,每当术语“烷基”或“芳基”或其前缀根中的任一个出现在取代基(例如芳基烷基、烷基氨基)的名称中时,该名称应解释为包括本文其他地方分别对“烷基”和“芳基”给出的那些限制。
在某些实施方式中,化合物的取代基以组或范围公开。具体期望该描述包括这些组和范围的成员的每个和每一个单独的子组合。例如,术语“C1-6烷基”明确地旨在单独公开C1、C2、C3、C4、C5、C6、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5和C5-C6烷基。
本文所用的术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指通过向受试者施用药剂或化合物来降低受试者经历疾病或病症的症状的频率或严重程度。
本文使用的某些缩写如下:cccDNA,共价闭合的环状DNA;DAD,二极管阵列探测器;DCE,1,2-二氯乙烷;DCM,二氯甲烷;DIEA或DIPEA,二异丙基乙胺;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;EtOAc,乙酸乙酯;HATU,氮杂苯并三唑四甲基脲六氟磷酸盐;HBsAg,HBV表面抗原;HBV,乙型肝炎病毒;HDV,丁型肝炎病毒;HPLC,高压液相色谱法;IPA,异丙醇(2-丙醇);LCMS,液相色谱质谱法;LG,离去基团;NARTI或NRTI,逆转录酶抑制剂;NBS,N-溴代琥珀酰亚胺;NMR,核磁共振;NtARTI或NtRTI,核苷酸类似物逆转录酶抑制剂;PCC,氯铬酸吡啶鎓盐;pg RNA,前基因组RNA;rcDNA,松弛环状DNA;RT,保留时间;sAg,表面抗原;SFC,超临界流体色谱法;STAB,三乙酰氧基硼氢化钠;TFA,三氟乙酸;THF,四氢呋喃;TLC,薄层色谱法;TMSOTf,三甲基甲硅烷基三氟甲基磺酸盐。
范围:在整篇公开内容中,可以以范围格式来呈现本公开内容的各个方面。应当理解,范围格式的描述仅是为了方便和简洁,而不应被解释为对本公开内容范围的僵化限制。因此,应该将范围的描述视为已明确公开了所有可能的子范围以及该范围内的各个数值。例如,对范围比如从1至6的描述应视为已明确公开了子范围,比如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等,以及该范围内的单个数值,例如,1、2、2.7、3、4、5、5.3和6。例如,“约0.1%至约5%”或“约0.1%至5%”的范围应视为不仅包括约0.1%至约5%,而且还包括指示范围内的单个值(例如,1%、2%、3%和4%)和子范围(例如,0.1%至0.5%、1.1%至2.2%、3.3%至4.4%)。除非另外指出,否则陈述“约X至Y”具有与“约X至约Y”相同的含义。同样,除非另外指出,否则陈述“约X、Y或Z”与“约X、约Y或约Z”具有相同的含义。无论范围的广度如何,这都适用。
化合物
本公开内容包括式(I)的化合物或其盐、溶剂化物、前药、同位素标记的衍生物、立体异构体(比如,在非限制性实例中,对映异构体或非对映异构体和/或其任何混合物,比如,在非限制性实例中,以任何比例的其对映异构体和/或非对映异构体的混合物)、互变异构体和任何混合物,和/或其几何异构体和任何混合物:
其中:
X、Y以及X与Y之间的键是这样的:
X是NR7,Y是C(=O),并且X与Y之间的键是单键,或
X是N,Y是CR10,并且X与Y之间的键是双键,
其中:
在(Ai)中,R8a和R8b任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aii)中,R8a和R8b、或R8c和R8d任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiii)中,R8c和R8d、或R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiv)中,R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
或者,A环不存在,吡啶-2-酮环的3位被R8a取代,并且所述吡啶-2-酮环的4位被R8b取代;
R2选自任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的苄基、任选地取代的杂芳基和-(CH2)(任选地取代的杂芳基);
R3选自H和C1-C6烷基;
R4选自H、C1-C6烷基和C3-C8环烷基,其中烷基或环烷基被选自C1-C6烷基、C3-C8环烷基、卤素、氰基、-OH、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷氧基、C3-C8卤代环烷氧基、任选地取代的苯基、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)OR9、-OC(=O)R9、-SR9、-S(=O)R9、-S(=O)2R9、-S(=O)2NR9R9、-N(R9)S(=O)2R9、-N(R9)C(=O)R9、-C(=O)NR9R9和-NR9R9的至少一个任选地取代;
R5选自H和任选地取代的C1-C6烷基;
R6是–(CH2)p-Q-(CH2)q-,
其中p和q独立地为0、1、2或3,和
Q是键(不存在)、-O-、-OCH(OH)-、-CH(OH)O-、-S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-、-C(=O)-、-C(=O)O-或-OC(=O)-,
其中选择p和q,使得:
如果Q是键(不存在),则2≤(p+q)≤4,
如果Q是-O-、S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-或-C(=O)-,则1≤(p+q)≤3,
如果Q是-C(=O)O-、-OC(=O)-、-OCH(OH)-或-CH(OH)O-,则0≤(p+q)≤2,并且
其中R6中的每个CH2任选地独立地被一个或两个甲基取代;
R7选自H、任选地取代的C1-C6烷基和任选地取代的C3-C8环烷基;
R8a、R8b、R8c、R8d、R8e、R8f、R8g和R8h的每次出现独立地选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷氧基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基;
R9的每次出现独立地选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基和任选地取代的杂芳基;
R10选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基);
R11选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的杂芳基和任选地取代的C1-C6酰基。
在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是
在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是在某些实施方式中,式(I)的化合物是
在某些实施方式中,Q是键且B基团是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是键且B基团是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是键且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是C=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是C=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S=O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是O且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是NR11且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是CH(OH)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是C(=O)且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是-C(=O)O-且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的CH2任选地被一个或两个甲基取代。
在某些实施方式中,Q是-C(=O)O-且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S=O且B环是其中B环中的CH2任选地被一个或两个甲基取代。在某些实施方式中,Q是S(=O)2且B环是其中B环中的CH2任选地被一个或两个甲基取代。
在某些实施方式中,Q是-C(=O)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OC(=O)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OCH(OH)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-CH(OH)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是-C(=O)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OC(=O)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OCH(OH)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-CH(OH)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,Q是-C(=O)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OC(=O)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-OCH(OH)-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。在某些实施方式中,Q是-CH(OH)O-且B环是其中B环中的每个CH2任选地独立地被一个或两个甲基取代。
在某些实施方式中,在本文所述的任何实施例中,其中B环包括与环碳连接的羟基,所述环碳任选地是叔的,被所述羟基和甲基取代(即,在本文中其他地方示例的H原子被甲基取代以提供-C(CH3)(OH)-)。作为非限制性实例,在某些实施方式中,本公开内容考虑B环是
在某些实施方式中,烷基、烯基、炔基或环烷基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、卤素、氰基(-CN)、-ORa、任选地取代的苯基(因此在非限制性实例中产生任选地取代的苯基-(C1-C3烷基),比如但不限于苄基或取代的苄基)、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa和-N(Ra)(Ra)的至少一个取代基任选地取代,其中Ra的每次出现独立地为H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的芳基或任选地取代的杂芳基或两个Ra基团与它们所键连的N结合以形成杂环。
在某些实施方式中,芳基或杂芳基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、苯基、C1-C6羟烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、-N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、酰基和C1-C6烷氧基羰基的至少一个取代基任选地取代,其中Rb的每次出现独立地为H、C1-C6烷基或C3-C8环烷基,其中在Rb中,烷基或环烷基被选自卤素、-OH、C1-C6烷氧基和杂芳基的至少一个任选地取代;或两个相邻碳原子上的取代基结合以形成-O(CH2)1-3O-。
在某些实施方式中,芳基或杂芳基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、苯基、C1-C6羟烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、-ORb、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb和-N(Rb)S(=O)2Rb的至少一个取代基任选地取代,其中Rb的每次出现独立地为H、C1-C6烷基或C3-C8环烷基,其中在Rb中,烷基或环烷基被选自卤素、-OH、C1-C6烷氧基和杂芳基的至少一个任选地取代;或两个相邻碳原子上的取代基结合以形成-O(CH2)1-3O-。
在某些实施方式中,烷基、烯基、炔基、环烷基、杂芳基、杂环基、芳基或苄基任选地独立地被选自C1-C6烷基;C1-C6烷氧基;C1-C6卤代烷基;C1-C6卤代烷氧基;-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、卤素、-OH;-CN;苯氧基、-NHC(=O)H、-NHC(=O)C1-C6烷基、-C(=O)NH2、-C(=O)NHC1-C6烷基、-C(=O)N(C1-C6烷基)(C1-C6烷基)、四氢吡喃基、吗啉基、-C(=O)CH3、-C(=O)CH2OH、-C(=O)NHCH3、-C(=O)CH2OMe或其N-氧化物的至少一个基团取代。
在某些实施方式中,杂芳基的每次出现独立地选自喹啉基、咪唑并[1,2-a]吡啶基、吡啶基、嘧啶基、吡嗪基、咪唑基、噻唑基、吡唑基、异噁唑基、噁二唑基(包括1,2,3-、1,2,4-、1,2,5-和1,3,4-噁二唑)和三唑基(比如1,2,3-三唑基和1,2,4-三唑基)。
在某些实施方式中,杂环基的每次出现独立地选自四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吡咯烷基、吗啉基、硫代吗啉基、1-氧桥-硫代吗啉基、1,1-二氧桥-硫代吗啉基、噁唑烷基、氮杂环丁烷基及其相应的氧代类似物(其中亚甲基环基被羰基取代)。
在某些实施方式中,R1是-NR2R3。在某些实施方式中,R1是其中R8a、R8b、R8c、R8d、R8e、R8f、R8g和R8h的每次出现是独立选择的并且在本文中其他地方所限定。在某些实施方式中,在R1中,R8b和R8c中的至少一个是卤素。在某些实施方式中,在R1中,R8b和R8c中的至少一个是F。在某些实施方式中,在R1中,R8b和R8c中的至少一个是Cl。在某些实施方式中,R1是异二氢吲哚-2-基(R8a-R8h=H)。在某些实施方式中,R1是R8b-卤素异二氢吲哚-2-基。在某些实施方式中,R1是R8c-卤素异二氢吲哚-2-基。在某些实施方式中,R1是R8b-卤素-R8c-卤素异二氢吲哚-2-基,其中R8b和R8b中的卤素是独立选择的。
在某些实施方式中,R2是任选地取代的C3-C8环烷基。
在某些实施方式中,R2选自任选地取代的苯基、任选地取代的苄基和-(CH2)(任选地取代的杂芳基),其中苯基、苄基或杂芳基被选自C1-C6烷基(比如例如,甲基、乙基和异丙基)、卤素(比如例如,F、Cl、Br和I)、C1-C3卤代烷基(比如例如,一氟甲基、二氟甲基和三氟甲基)和–CN的至少一个任选地取代。
在某些实施方式中,R2选自:苯基、3-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3,5-二氟苯基、2,4,5-三氟苯基、3,4,5-三氟苯基、3,4-二氯苯基、3-氯-4-氟苯基、4-氯-3-氟苯基、4-氯-3-甲基苯基、3-氯-4-甲基苯基、4-氟-3-甲基苯基、3-氟-4-甲基苯基、4-氯-3-甲氧基苯基、3-氯-4-甲氧基苯基、4-氟-3-甲氧基苯基、3-氟-4-甲氧基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3-三氟甲基-4-氟苯基、4-三氟甲基-3-氟苯基、3-氰基苯基、4-氰基苯基、3-氰基-4-氟苯基、4-氰基-3-氟苯基、3-二氟甲基-4-氟苯基、4-二氟甲基-3-氟苯基、苯并[d][1,3]二氧戊环-5-基、2,3-二氢苯并[b][1,4]二噁烯-6-基、苄基、3-氟苄基、4-氟苄基、3-氯苄基、4-氯苄基、2-吡啶基、4-甲基-2-吡啶基、5-甲基-2-吡啶基、6-甲基-2-吡啶基、3-吡啶基、2-甲基-3-吡啶基、3-甲基-3-吡啶基、4-吡啶基、2-甲基-4-吡啶基和6-甲基-4-吡啶基。在其他实施方式中,R2是3,4-二氟苯基。在又其他实施方式中,R2是3-氯-4-氟苯基。在又其他实施方式中,R2是4-氯-3-氟苯基。在又其他实施方式中,R2是3-氟-4-甲基苯基。在又其他实施方式中,R2是4-氟-3-甲基苯基。在又其他实施方式中,R2是3-氰基-4-氟苯基。在又其他实施方式中,R2是3-二氟甲基-4-氟苯基。
在某些实施方式中,R3的每次出现独立地选自H和甲基。在其他实施方式中,R3是H。在又其他实施方式中,R3是甲基。
在某些实施方式中,R4选自H、甲基、乙基、异丙基、正丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、异丙基甲基、-(CH2)2-6OH,-(CH2)2-6O(C1-C6烷基)、任选地取代的苄基和任选地取代的苯基。
在某些实施方式中,R5选自H和甲基。在其他实施方式中,R5是H。在其他实施方式中,R5是甲基。
在某些实施方式中,当Q是-O-、-S-、-S(=O)-、-S(=O)2-或-NR11时,p独立地为1或2。
在某些实施方式中,R6是选自-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2OCH(OH)-、-CH(OH)OCH2-、-CH2OC(=O)-、-C(=O)OCH2-、-CH2SCH2-、-CH2S(=O)CH2-、-CH2S(=O)2CH2-、-CH2NHCH2-、-CH2N(CH3)CH2-、-CH2N[C(=O)CH3]CH2-、-CH2N[CH2CH2OH]CH2-、-CH2CH2CH2CH2-、-CH2OCH2CH2-和-CH2CH2OCH2-的二价基团,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。
在某些实施方式中,R6是-CH2CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2CH2CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2OCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2OCH(OH)-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH(OH)OCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2OC(=O)-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-C(=O)OCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2SCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2S(=O)CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2S(=O)2CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2NHCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2N(CH3)CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2N[C(=O)CH3]CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2N[CH2CH2OH]CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2CH2CH2CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2OCH2CH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。在某些实施方式中,R6是-CH2CH2OCH2-,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。
在某些实施方式中,R6是选自-CH2CH2-、-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-、-CH(CH3)CH(CH3)-、-CH(CH3)C(CH3)2-、-C(CH3)2CH(CH3)-和-C(CH3)2C(CH3)2-的二价基团。
在某些实施方式中,R6是选自-CH2OCH2-、-CH(CH3)OCH2-、-CH2OCH(CH3)-、-CH(CH3)OCH(CH3)-、-C(CH3)2OCH2-、-CH2OC(CH3)2-、-C(CH3)2OCH(CH3)-、-CH(CH3)OC(CH3)2-和C(CH3)2OC(CH3)2-的二价基团。
在某些实施方式中,R6是选自-CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-CH(CH3)CH(CH3)CH2-、-CH(CH3)CH2CH(CH3)-、-CH2CH(CH3)CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-、-CH(CH3)CH(CH3)CH(CH3)-、-C(CH3)2CH(CH3)CH2-、-C(CH3)2CH2CH(CH3)-、-CH(CH3)C(CH3)2CH2-、-CH2C(CH3)2CH(CH3)-、-CH(CH3)CH2C(CH3)2-、-CH2CH(CH3)C(CH3)2-、-C(CH3)2CH(CH3)CH(CH3)-、-C(CH3)2C(CH3)2CH2-、-C(CH3)2CH2C(CH3)2-、-CH(CH3)C(CH3)2CH(CH3)-,CH2C(CH3)2C(CH3)2-、-CH(CH3)CH(CH3)C(CH3)2-、-CH(CH3)C(CH3)2C(CH3)2-、-C(CH3)2CH(CH3)C(CH3)2-、-C(CH3)2C(CH3)2CH(CH3)-和-C(CH3)2C(CH3)2C(CH3)2-的二价基团。
在某些实施方式中,R6是选自-CH2OCH2CH2-、-CH(CH3)OCH2CH2-、-CH2OCH(CH3)CH2-、-CH2OCH2CH(CH3)-、-CH(CH3)OCH(CH3)CH2-、-CH(CH3)OCH2CH(CH3)-、-CH2OCH(CH3)CH(CH3)-、-C(CH3)2OCH2CH2-、-CH2OC(CH3)2CH2-、-CH2OCH2C(CH3)2-、-CH(CH3)OCH(CH3)CH(CH3)-、-C(CH3)2OCH(CH3)CH2-、-C(CH3)2OCH2CH(CH3)-、-CH(CH3)OC(CH3)2CH2-、-CH2OC(CH3)2CH(CH3)-、-CH(CH3)OCH2C(CH3)2-、-CH2OCH(CH3)C(CH3)2-、-C(CH3)2OCH(CH3)CH(CH3)-、-C(CH3)2OC(CH3)2CH2-、-C(CH3)2OCH2C(CH3)2-、-CH(CH3)OC(CH3)2CH(CH3)-、-CH2OC(CH3)2C(CH3)2-、-CH(CH3)OCH(CH3)C(CH3)2-、-CH(CH3)OC(CH3)2C(CH3)2-、-C(CH3)2OCH(CH3)C(CH3)2-、-C(CH3)2OC(CH3)2CH(CH3)-和-C(CH3)2OC(CH3)2C(CH3)2-的二价基团。
在某些实施方式中,R6是选自-CH2CH2OCH2-、-CH(CH3)CH2OCH2-、-CH2CH(CH3)OCH2-、-CH2CH2OCH(CH3)-、-CH(CH3)CH(CH3)OCH2-、-CH(CH3)CH2OCH(CH3)-、-CH2CH(CH3)OCH(CH3)-、-C(CH3)2CH2OCH2-、-CH2C(CH3)2OCH2-、-CH2CH2OC(CH3)2-、-CH(CH3)CH(CH3)OCH(CH3)-、-C(CH3)2CH(CH3)OCH2-、-C(CH3)2CH2OCH(CH3)-、-CH(CH3)C(CH3)2OCH2-、-CH2C(CH3)2OCH(CH3)-、-CH(CH3)CH2OC(CH3)2-、-CH2CH(CH3)OC(CH3)2-、-C(CH3)2CH(CH3)OCH(CH3)-、-C(CH3)2C(CH3)2OCH2-、-C(CH3)2CH2OC(CH3)2-、-CH(CH3)C(CH3)2OCH(CH3)-、-CH2C(CH3)2OC(CH3)2-、-CH(CH3)CH(CH3)OC(CH3)2-、-CH(CH3)C(CH3)2OC(CH3)2-、-C(CH3)2CH(CH3)OC(CH3)2-、-C(CH3)2C(CH3)2OCH(CH3)-和-C(CH3)2C(CH3)2OC(CH3)2-的二价基团。
在某些实施方式中,R7是H。在其他实施方式中,R7是甲基。在又其他实施方式中,R7是乙基。在又其他实施方式中,R7是1-(2,2,2-三氟乙基)。在又其他实施方式中,R7是1-丙基。在又其他实施方式中,R7是异丙基。在又其他实施方式中,R7是环丙基。在又其他实施方式中,R7是1-(2-羟基)乙基。在又其他实施方式中,R7是1-(2-甲氧基)乙基。在又其他实施方式中,R7是1-(3-羟基)丙基。在又其他实施方式中,R7是1-(3-甲氧基)丙基。在又其他实施方式中,R7是三唑基甲基。
在某些实施方式中,R10是H。在其他实施方式中,R10是甲氧基。在又其他实施方式中,R10是乙氧基。在又其他实施方式中,R10是甲基。在又其他实施方式中,R10是乙基。在又其他实施方式中,R10是2-羟基乙氧基。在又其他实施方式中,R10是氨基。在又其他实施方式中,R10是甲氨基。在又其他实施方式中,R10是乙氨基。在又其他实施方式中,R10是二甲氨基。在又其他实施方式中,R10是(2-羟乙基)氨基。在又其他实施方式中,R10是2-氨乙基)氨基。在又其他实施方式中,R10是三唑基。在又其他实施方式中,R10是三唑基甲氧基。在又其他实施方式中,R10是(N-甲基三唑基)甲基。在又其他实施方式中,R10是三唑基甲氨基。在又其他实施方式中,R10是(N-甲基三唑基)甲氨基。在又其他实施方式中,R10是CN。在又其他实施方式中,R10是羟甲基。在又其他实施方式中,R10是羧基。在又其他实施方式中,R10是氨基羰基。在又其他实施方式中,R10是甲氨基羰基。在又其他实施方式中,R10是二甲氨基羰基。在又其他实施方式中,R10是甲基磺酰基。在又其他实施方式中,R10是吡啶基甲氧基。
在某些实施方式中,本公开内容的化合物为本文中公开的任何化合物,或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物、互变异构体和/或互变异构体的任何混合物。
在某些实施方式中,化合物是选自表3中的至少一种,或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物、互变异构体和/或互变异构体的任何混合物。
在某些实施方式中,化合物是下列的至少一种:
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(3-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物、互变异构体和/或互变异构体的任何混合物。
在某些实施方式中,化合物是下列的至少一种:
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(R)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(R)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(R)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(R)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(S)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(R)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(R)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物、互变异构体和/或互变异构体的任何混合物。
本公开内容的化合物可以具有一个或多个立构中心,并且每个立构中心可以以(R)或(S)构型独立存在。在某些实施方式中,本文所述的化合物以旋光或外消旋形式存在。本文所述的化合物包括具有本文所述的治疗有用特性的外消旋、旋光、区域异构和立体异构形式或其组合。旋光形式的制备以任何合适的方式实现,作为非限制性实例,包括通过用重结晶技术外消旋形式的解析、由旋光原材料合成、手性合成或使用手性固定相进行色谱分离。本文由外消旋式说明的化合物进一步代表两种对映异构体或其任何混合物,或者在存在两个或更多个手性中心的情况下,代表所有非对映异构体或其任何混合物。
在某些实施方式中,本公开内容的化合物以互变异构体存在。所有互变异构体均包括在本文所述的化合物的范围内。
本文所述的化合物还包括同位素标记的化合物,其中一个或多个原子被具有相同原子序数但原子质量或原子质量数不同于通常在自然界发现的原子质量或原子质量数的原子替代。适于包含在本文所述的化合物中的同位素的实例包括但不限于2H、3H、11C、13C、14C、36Cl、18F、123I、125I、13N、15N、15O、17O、18O、32P和35S。在某些实施方式中,用较重的同位素比如氘取代提供更高的化学稳定性。可通过任何合适的方法或使用合适的同位素标记的试剂代替否则采用未标记的试剂的方法制备同位素标记的化合物。
在某些实施方式中,本文所述的化合物通过其他方式标记,包括但不限于使用发色团或荧光部分、生物发光标记或化学发光标记。
在本文提供的所有实施方式中,合适的任选取代基的实例不旨在限制要求保护的发明的范围。本公开内容的化合物可以包含本文提供的任何取代基或取代基的组合。
盐
本文所述的化合物可与酸或碱形成盐,并且这种盐包括在本公开内容中。术语“盐”包括在本公开内容的方法中有用的游离酸或碱的加成盐。术语“药学上可接受的盐”是指具有在药学应用中有用的范围内的毒性特征的盐。在某些实施方式中,盐是药学上可接受的盐。然而,药学上不可接受的盐可以具有比如高结晶度的性质,其在本公开内容的实践中具有实用性,诸如例如在本公开内容的方法中有用的化合物的合成、纯化或配制过程中的实用性。
合适的药学上可接受的酸加成盐可以由无机酸或有机酸制备。无机酸的实例包括硫酸盐、硫酸氢盐(hydrogen sulfate)、盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸(包括磷酸氢盐和磷酸二氢盐)。合适的有机酸可以选自脂族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类的有机酸,其实例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、扑酸(或帕莫酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、磺胺酸、2-羟基乙磺酸、三氟甲磺酸、对甲苯磺酸、环己基氨基磺酸、硬脂酸、海藻酸、β-羟基丁酸、水杨酸、半乳糖二酸、半乳糖醛酸、甘油膦酸和糖精(例如,糖精盐(saccharinate)、糖酸盐(saccharate))。相对于本公开内容的任何化合物,盐可以由1摩尔当量、1或多于1摩尔当量的酸或碱的部分组成。
本公开内容的化合物的合适的药学上可接受的碱加成盐包括例如铵盐和金属盐,包括碱金属、碱土金属和过渡金属盐,诸如例如钙、镁、钾、钠和锌盐。药学上可接受的碱加成盐还包括由碱性胺诸如例如N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(或N-甲葡糖胺)和普鲁卡因制备的有机盐。所有这些盐可以通过例如使合适的酸或碱与化合物反应而由相应的化合物制备。
联合治疗
在一个方面,本公开内容的化合物与用于治疗HBV和/或HDV感染的一种或多种另外的试剂组合用于本公开内容的方法中。这些另外的试剂可以包括本文鉴定的化合物或组合物,或已知用于治疗、预防或减轻HBV和/或HDV感染的症状的化合物(例如,商业上可获得的化合物)。
用于治疗HBV和/或HDV感染的一种或多种另外的试剂的非限制性实例包括:(a)逆转录酶抑制剂;(b)衣壳抑制剂;(c)cccDNA形成抑制剂;(d)RNA去稳定剂;(e)靶向HBV基因组的寡聚核苷酸;(f)免疫刺激剂,比如检查点抑制剂(例如,PD-L1抑制剂);和(g)靶向HBV基因转录体的GalNAc-siRNA缀合物。
(a)逆转录酶抑制剂
在某些实施方式中,逆转录酶抑制剂为逆转录酶抑制剂(NARTI或NRTI)。在其他实施方式中,逆转录酶抑制剂为核苷酸类似物逆转录酶抑制剂(NtARTI或NtRTI)。
报道的逆转录酶抑制剂包括但不限于恩替卡韦、克拉夫定、替比夫定、拉米夫定、阿德福韦和替诺福韦、替诺福韦二吡呋酯(tenofovir disoproxil)、替诺福韦艾拉酚胺、阿德福韦酯(adefovir dipovoxil)、(1R,2R,3R,5R)-3-(6-氨基-9H-9-嘌呤基)-2-氟-5-(羟甲基)-4-亚甲基环戊-1-醇(描述于美国专利号8,816,074中,通过引用以其整体并入本文)、恩曲他滨、阿巴卡韦、依维他滨(elvucitabine)、更昔洛韦、洛布卡韦、泛昔洛韦、喷昔洛韦和氨多索韦(amdoxovir)。
报道的逆转录酶抑制剂进一步包括但不限于恩替卡韦、拉米夫定和(1R,2R,3R,5R)-3-(6-氨基-9H-9-嘌呤基)-2-氟-5-(羟甲基)-4-亚甲基环戊-1-醇。
报道的逆转录酶抑制剂进一步包括但不限于上面提到的逆转录酶抑制剂的共价结合的氨基磷酸酯或膦酰胺部分,或如例如美国专利号8,816,074、美国专利申请公开号US2011/0245484 A1和US 2008/0286230A1中描述的,所有这些通过引用以其整体并入本文。
报道的逆转录酶抑制剂进一步包括但不限于包括氨基磷酸酯部分的核苷酸类似物,诸如例如((((1R,3R,4R,5R)-3-(6-氨基-9H-嘌呤-9-基)-4-氟-5-羟基-2-亚甲基环戊基)甲氧基)甲基(苯氧基)磷酰基)-(D或L)-丙氨酸酯和((((1R,2R,3R,4R)-3-氟-2-羟基-5-亚甲基-4-(6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基)甲氧基)甲基(苯氧基)磷酰基)-(D或L)-丙氨酸酯。还包括其单独的非对映异构体,其包括例如((R)-(((1R,3R,4R,5R)-3-(6-氨基-9H-嘌呤-9-基)-4-氟-5-羟基-2-亚甲基环戊基)甲氧基)甲基(苯氧基)磷酰基)-(D或L)-丙氨酸酯和((S)-(((1R,3R,4R,5R)-3-(6-氨基-9H-嘌呤-9-基)-4-氟-5-羟基-2-亚甲基环戊基)甲氧基)甲基(苯氧基)磷酰基)-(D或L)-丙氨酸酯。
报道的逆转录酶抑制剂进一步包括但不限于包括膦酰胺部分的化合物,诸如例如替诺福韦艾拉酚胺,以及在美国专利申请公开号US 2008/0286230 A1中描述的那些,通过引用以其整体并入本文。在例如,美国专利号8,816,074以及美国专利申请公开号US 2011/0245484 A1和US 2008/0286230 A1中描述了用于制备含有立体选择性氨基磷酸酯或膦酰胺的活性物的方法,其全部通过引用以其整体并入本文。
(b)衣壳抑制剂
如本文所描述的,术语“衣壳抑制剂”包括能够直接或间接抑制衣壳蛋白的表达和/或功能的化合物。例如,衣壳抑制剂可以包括但不限于抑制衣壳装配、诱导非衣壳聚合物形成、促进过量的衣壳装配或衣壳装配方向错误、影响衣壳稳定和/或抑制RNA(pgRNA)衣壳化的任何化合物。衣壳抑制剂还包括在复制过程的下游事件(一个或多个)(例如,病毒DNA合成、松环DNA(rcDNA)转运到细胞核、共价闭合环状DNA(cccDNA)形成、病毒成熟、出芽和/或释放等)中抑制衣壳功能的任何化合物。例如,在某些实施方式中,该抑制剂可检测地抑制衣壳蛋白的表达水平或生物活性,例如使用本文所述的测定法所测量的。在某些实施方式中,抑制剂将rcDNA和病毒生命周期下游产物的水平抑制至少5%、至少10%、至少20%、至少50%、至少75%或至少90%。
报道的衣壳抑制剂包括但不限于在国际专利申请公开号WO 2013006394、WO2014106019和WO2014089296中描述的化合物,其全部通过引用以其整体并入本文。
报道的衣壳抑制剂还包括但不限于下述化合物和其药学上可接受的盐和/或溶剂化物:Bay-41-4109(参见国际专利申请公开号WO 2013144129)、AT-61(参见国际专利申请公开号WO 1998033501;和King等人,1998,Antimicrob.Agents Chemother.42(12):3179–3186)、DVR-01和DVR-23(参见国际专利申请公开号WO 2013006394;和Campagna等人,2013,J.Virol.87(12):6931,其全部通过引用以其整体并入本文。
另外,报道的衣壳抑制剂包括但不限于在美国专利申请公开号US 2015/0225355、US 2015/0132258、US 2016/0083383、US 2016/0052921、US 2019/0225593和国际专利申请公开号WO 2013096744、WO 2014165128、WO 2014033170、WO 2014033167、WO 2014033176、WO 2014131847、WO 2014161888、WO 2014184350、WO 2014184365、WO 2015059212、WO2015011281、WO 2015118057、WO 2015109130、WO 2015073774、WO 2015180631、WO2015138895、WO 2016089990、WO 2017015451、WO 2016183266、WO 2017011552、WO2017048950、WO2017048954、WO 2017048962、WO 2017064156、WO 2018052967、WO2018172852、WO 2020023710中一般和具体地描述的那些,并通过引用以其整体并入本文。
(c)cccDNA形成抑制剂
共价封闭的环状DNA(cccDNA)在病毒rcDNA的细胞核中产生,并用作病毒mRNA的转录模板。如本文所描述的,术语“cccDNA形成抑制剂”包括能够直接或间接抑制cccDNA的形成和/或稳定性的化合物。例如,cccDNA形成抑制剂可以包括但不限于抑制衣壳解体,rcDNA进入细胞核和/或将rcDNA转化为cccDNA的任何化合物。例如,在某些实施方式中,抑制剂可抑制地抑制cccDNA的形成和/或稳定性,例如使用本文所述的测定法所测量的。在某些实施方式中,抑制剂将cccDNA的形成和/或稳定性抑制至少5%、至少10%、至少20%、至少50%、至少75%或至少90%。
报道的cccDNA形成抑制剂包括但不限于在国际专利申请公开号WO 2013130703中描述的化合物,并且通过引用以其整体并入本文。
另外,报道的cccDNA形成抑制剂包括但不限于在美国专利申请公开号US 2015/0038515 A1中一般和具体描述的那些,并且通过引用以其整体并入本文。
(d)RNA去稳定剂
如本文所使用的,术语“RNA去稳定剂”是指在哺乳动物细胞培养物中或在活的人类受试者中减少HBV RNA总量的分子或其盐或溶剂化物。在非限制性实例中,RNA去稳定剂减少了编码以下一种或多种以下HBV蛋白的RNA转录体(一种或多种)的量:表面抗原,核心蛋白,RNA聚合酶和e抗原。在某些实施方式中,RNA去稳定剂使哺乳动物细胞培养物中或活的人类受试者中的HBV RNA的总量减少至少5%、至少10%、至少20%、至少50%、至少75%或至少90%。
报道的RNA去稳定剂包括在美国专利号8,921,381中描述的化合物,以及在美国专利申请公开号US 2015/0087659和US 2013/0303552中描述的化合物,其全部通过引用以其整体并入本文。
另外,报道的RNA去稳定剂包括但不限于在国际专利申请公开号WO 2015113990、WO 2015173164、US 2016/0122344、WO 2016107832、WO 2016023877、WO 2016128335、WO2016177655、WO 2016071215、WO 2017013046、WO 2017016921、WO 2017016960、WO2017017042、WO 2017017043、WO 2017102648、WO 2017108630、WO 2017114812、WO2017140821、WO 2018085619中一般和具体地描述的那些,并且通过引用以其整体并入本文。
(e)靶向HBV基因组的寡聚核苷酸
报道的靶向HBV基因组的寡聚核苷酸包括但不限于Arrowhead-ARC-520(参见美国专利号8,809,293;和Wooddell等人,2013,Molecular Therapy 21(5):973–985,其全部通过引用以其整体并入本文)。
在某些实施方式中,寡聚核苷酸可以设计为靶向HBV基因组的一个或多个基因和/或转录体。靶向HBV基因组的寡聚核苷酸还包括但不限于分离的双链siRNA分子,每个siRNA分子包括有义链和与有义链杂交的反义链。在某些实施方式中,siRNA靶向HBV基因组的一个或多个基因和/或转录体。
(f)免疫刺激剂
检查点抑制剂
如本文所描述的,术语“检查点抑制剂”包括能够抑制作为免疫系统调节剂(例如,刺激或抑制免疫系统活性)的免疫检查点分子的任何化合物。例如,一些检查点抑制剂阻断抑制性检查点分子,从而刺激免疫系统功能,比如刺激针对癌细胞的T细胞活性。检查点抑制剂的非限制性实例是PD-L1抑制剂。
如本文所描述的,术语“PD-L1抑制剂”包括能够直接或间接抑制程序性死亡配体1(PD-L1)蛋白的表达和/或功能的任何化合物。PD-L1,也称为分化簇274(CD274)或B7同系物1(B7-H1),是在抑制妊娠期间的免疫系统适应性臂、组织同种异体移植、自身免疫性疾病和肝炎中起重要作用的1型跨膜蛋白。PD-L1与其受体、抑制性检查点分子PD-1(在激活的T细胞、B细胞和骨髓细胞上发现)结合,以便调节免疫系统适应性臂的激活或抑制。在某些实施方式中,PD-L1抑制剂将PD-L1的表达和/或功能抑制至少5%、至少10%、至少20%、至少50%、至少75%或至少90%。
报道的PD-L1抑制剂包括但不限于下述专利申请出版物之一中所述的化合物:US2018/0057455;US 2018/0057486;WO 2017/106634;WO 2018/026971;WO 2018/045142;WO2018/118848;WO 2018/119221;WO 2018/119236;WO 2018/119266;WO 2018/119286;WO2018/121560;WO 2019/076343;WO 2019/087214;并且通过引用以其整体并入本文。
(g)靶向HBV基因转录体的GalNAc-siRNA缀合物
“GalNAc”是N-乙酰基半乳糖胺的缩写,和“siRNA”是小干扰RNA的缩写。在本公开内容的实践中有用的GalNAc-siRNA缀合物中,将靶向HBV基因转录体的siRNA与GalNAc共价结合。尽管不希望受到理论的束缚,但据信GalNAc与肝细胞上的脱唾液酸糖蛋白受体结合,从而促进siRNA靶向感染HBV的肝细胞。siRNA进入感染的肝细胞,并通过RNA干扰现象刺激HBV基因转录体的破坏。
在本公开内容的这一方面的实践中有用的GalNAc-siRNA缀合物的实例在公开的国际申请PCT/CA2017/050447(2017年10月19日公开的PCT申请公开号WO/2017/177326)中阐述,其通过引用以其整体并入本文。
例如,可以使用合适的方法,诸如例如Sigmoid-Emax方程式(Holford&Scheiner,1981,Clin.Pharmacokinet.6:429-453)、Loewe可加性方程式(Loewe&Muischnek,1926,Arch.Exp.Pathol Pharmacol.114:313-326)和中值效应方程式(Chou&Talalay,1984,Adv.Enzyme Regul.22:27-55)计算协同效应。本文别处提及的每个方程式可以应用于实验数据以生成相应的曲线,以帮助评估药物组合的效果。与本文其他地方提及的方程式相关的相应曲线分别是浓度-效果曲线、等效线图曲线和组合指数曲线。
合成
本公开内容进一步提供了制备本公开内容的化合物的方法。本教导的化合物可以通过使用本领域技术人员已知的标准合成方法和程序,根据本文概述的程序,由商业上可获得的起始原料、文献中已知的化合物或容易制备的中间体制备。可从相关的科学文献或本领域的标准教科书中容易地获得用于制备有机分子以及官能团转化和操纵的标准合成方法和程序。
应当理解,除非另有说明,在给出典型的或优选的工艺条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)的情况下,也可以使用其他工艺条件。最佳反应条件可以随所使用的特定反应物或溶剂而变化,但是这种条件可以由本领域技术人员通过常规优化程序来确定。有机合成领域的技术人员将认识到,出于优化本文所述化合物的形成的目的,可以改变所呈现的合成步骤的性质和顺序。
可以根据本领域中已知的任何合适的方法来监测本文描述的过程。例如,产物形成可以通过光谱方法(spectroscopic means),比如核磁共振光谱法(例如,1H或13C)、红外光谱法、分光光度法(例如紫外可见)、质谱法,或通过色谱法比如高效液相色谱法(HPLC)、气相色谱法(GC)、凝胶渗透色谱发的(GPC)或薄层色谱法(TLC)来监测。
化合物的制备可以涉及各种化学基团的保护和脱保护。保护和脱保护的需要以及合适保护基团的选择可以由本领域技术人员容易地确定。保护基团的化学性质可以在例如Greene等人,Protective Groups in Organic Synthesis,第2版(Wiley&Sons,1991)中找到,出于所有目的通过引用将其全部公开内容并入本文。
本文所述的反应或方法可以在有机合成领域的技术人员可以容易选择的合适溶剂中进行。在进行反应的温度下,即在溶剂的冷冻温度至溶剂的沸腾温度的范围内的温度下,合适的溶剂通常与反应物、中间体和/或产物基本上不反应。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。取决于特定的反应步骤,可以选择用于特定反应步骤的合适溶剂。
式(I)的化合物可以例如根据方案1中概述的合成方法(其中,在某些实施方式中,Y是O或NH),由可商购的或先前记载的起始材料制备。
方案1
双环或三环酮IV可以由1,3-二酮II和羧酸衍生物III在存在金属催化剂比如但不限于碘化铜的情况下通过偶联反应(在非限制性实例中,当III中的LG为卤素或TfO-基团时)或通过醛醇型缩合(当III是β-酮酸或β-酮酯时),随后使生成的中间体(分离的或原位的)与氨或胺反应,然后任选通过烷基化制备。在后一种情况下,O-烷基化提供酮VII。在非限制性实例中,N-烷基化酮VII(Y=NH)也可以由酮IV(R7=H),通过用POCl3处理,随后用合适的氨或胺对所得氯化物进行亲核置换来制备。酮IV和VII与胺缩合,并将所得中间体亚胺与还原剂反应,比如但不限于硼氢化钠,或碳基亲核试剂比如但不限于格氏试剂或烷基/芳基锂以提供胺V或V-B的试剂。在某些实施方式中,伯胺R'NH2可以是外消旋的、非外消旋的或纯对映异构体的,并且可以用于影响亚胺还原或碳基亲核试剂加成的立体化学结果。所得仲胺可以进一步与醛和还原剂比如但不限于三乙酰氧基硼氢化钠反应,并且可以除去R'基团以提供V或V-B。可选地,IV和VII可以与伯亚磺酰胺反应形成亚磺酰亚胺,其随后与还原剂比如但不限于硼氢化钠,或碳基亲核试剂比如但不限于格氏试剂或烷基/芳基锂反应。在某些实施方式中,伯亚磺酰胺可以是外消旋的、非外消旋的或纯对应异构体的,并且可以用于影响亚磺酰亚胺还原的立体化学结果。所得仲亚磺酰胺可以在碱比如但不限于氢化钠的存在下用亲电子试剂比如但不限于烷基卤进一步官能化,并且可以除去磺酰胺基以提供V或V-B。V或V-B与各种亲电子试剂(例如异氰酸酯或氨基甲酸苯酯VI)的官能化提供I或I-B。
本文其他地方并入的方案举例说明了本公开内容的代表性化合物的合成。可以以与使用适当取代的中间体和试剂举例说明的那些类似的方式合成类似的化合物。
方法
本公开内容提供了在受试者中治疗、减轻和/或预防肝炎病毒感染的方法。在某些实施方式中,感染包括乙型肝炎病毒(HBV)感染。在其他实施方式中,该方法包括向需要其的受试者施用治疗有效量的至少一种本公开内容的化合物和/或组合物。在又其他实施方式中,至少一种本公开内容的化合物是施用至受试者的唯一抗病毒剂。在又其他实施方式中,将至少一种化合物在药学上可接受的组合物中施用至受试者。在又其他实施方式中,进一步向受试者施用用于治疗肝炎感染的至少一种另外的药剂。在又其他实施方式中,至少一种另外的药剂包括选自逆转录酶抑制剂、衣壳抑制剂、cccDNA形成抑制剂、RNA去稳定剂、靶向HBV基因组的寡聚核苷酸、免疫刺激剂比如检查点抑制剂(例如,PD-L1抑制剂);和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。在又其他实施方式中,向受试者共同施用至少一种化合物和至少一种另外的药剂。在又其他实施方式中,至少一种化合物和至少一种另外的药剂是共同配制的。
本公开内容进一步提供了在受试者中直接或间接抑制病毒衣壳蛋白的表达和/或功能的方法。在某些实施方式中,该方法包括向需要其的受试者施用治疗有效量的至少一种本公开内容的化合物和/或组合物。在其他实施方式中,将至少一种化合物在药学上可接受的组合物中施用至受试者。在又其他实施方式中,至少一种本公开内容的化合物是施用至受试者的唯一抗病毒剂。在又其他实施方式中,进一步向受试者施用用于治疗HBV感染的至少一种另外的药剂。在又其他实施方式中,至少一种另外的药剂包括选自逆转录酶抑制剂、衣壳抑制剂、cccDNA形成抑制剂、RNA去稳定剂、靶向HBV基因组的寡聚核苷酸、免疫刺激剂比如检查点抑制剂(例如,PD-L1抑制剂);和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。在又其他实施方式中,向受试者共同施用至少一种化合物和至少一种另外的药剂。在又其他实施方式中,至少一种化合物和至少一种另外的药剂是共同配制的。
在某些实施方式中,受试者是哺乳动物。在其他实施方式中,哺乳动物是人。
药物组合物和制剂
本公开内容提供了包括至少一种本公开内容的化合物或其盐或溶剂化物的药物组合物,其用于实践本公开内容的方法。这样的药物组合物可由适合施用至受试者的形式的至少一种本公开内容的化合物或盐或溶剂化物组成,或药物组合物可以包括至少一种本公开内容的化合物或其盐或溶剂化物以及一种或多种药学上可接受的载体、一种或多种另外的成分或这些的任何组合。如本领域众所周知的,至少一种本公开内容的化合物可以以生理学上可接受的盐的形式,比如与生理学上可接受的阳离子或阴离子组合存在于药物组合物中。
在某些实施方式中,可以施用用于实践本公开内容的方法的药物组合物以递送在1ng/kg/天和100mg/kg/天之间的剂量。在其他实施方式中,可以施用用于实践本公开内容的药物组合物以递送在1ng/kg/天和1,000mg/kg/天之间的剂量。
本公开内容的药物组合物中的活性成分、药学上可接受的载体和任何另外的成分的相对量将变化,这取决于所治疗的受试者的身份、体型(size)和病症,并且进一步取决于该组合物被施用的途径。举例来说,组合物可以包括在0.1%至100%(w/w)之间的活性成分。
用于本公开内容的方法中的药物组合物可以适当地开发用于经鼻、吸入、口服、直肠、阴道、胸膜、腹膜、肠胃外、局部、经皮、经肺、鼻内、含服、眼内、硬膜外、鞘内、静脉内或另一施用途径。可以将在本公开内容的方法中使用的组合物直接施用至哺乳动物或鸟类的中枢神经系统的大脑、脑干或任何其他部分。其他考虑的制剂包括设计(project)的纳米颗粒、微球、脂质体制剂、包被的颗粒、聚合物缀合物、含有活性成分的重新密封的红细胞以及基于免疫学的制剂。
在某些实施方式中,本公开内容的组合物是药物基质的一部分,其允许处理不溶性材料并改善其生物利用度、开发控释或缓释产品以及产生均质组合物。举例来说,可以使用热熔挤出、固溶体、固体分散体、尺寸减小技术、分子复合物(例如,环糊精等)、微粒以及颗粒和制剂包衣方法来制备药物基质。非晶相或结晶相可用于这种工艺中。
施用途径(一种或多种)对技术人员来说是显而易见的,并且将取决于许多因素,包括所治疗的疾病的类型和严重程度、所治疗的兽医或人类患者的类型和年龄等。
本文描述的药物组合物的制剂可以通过药理学和制药学领域中已知的或以后开发的任何方法来制备。通常,这种制备方法包括以下步骤:使活性成分与载体或一种或多种其他辅助成分结合,并且然后,如果必要或期望,将产品成型或包装成所需的单剂量或多剂量单位。
如本文所使用的,“单位剂量”是包括预定量的活性成分的离散量的药物组合物。活性成分的量通常等于将被施用至受试者的活性成分的剂量或这样的剂量的方便部分,诸如例如这样的剂量的一半或三分之一。单位剂型可以是单次日剂量或多次日剂量之一(例如,每天约1-4次或更多次)。当使用多次日剂量时,每次给药的单位剂型可以相同或不同。
尽管本文提供的药物组合物的描述主要针对适合于对人类进行伦理施用的药物组合物,但是技术人员将理解,这种组合物通常适合于施用至各种动物。为了使组合物适合于向各种动物施用,适合于向人施用的药物组合物的改进是众所周知的,并且普通技术的兽医药理师可以仅通过普通的实验来设计和进行这种改进。预期向其施用本公开内容的药物组合物的受试者包括但不限于人和其他灵长类动物,哺乳动物,包括与商业相关的哺乳动物,比如牛、猪、马、绵羊、猫和狗。
在某些实施方式中,使用一种或多种药学上可接受的赋形剂或载体配制本公开内容的组合物。在某些实施方式中,本公开内容的药物组合物包括治疗有效量的至少一种本公开内容的化合物和药学上可接受的载体。有用的药学上可接受的载体包括但不限于甘油、水、盐水、乙醇、重组人白蛋白(例如,)、可溶凝胶(例如,)和其他药学上可接受的盐溶液,比如磷酸盐和有机酸的盐。在Remington’s Pharmaceutical Sciences(1991,Mack Publication Co.,New Jersey)中描述了这些和其他药学上可接受的载体的实例。
载体可以是溶剂或分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)、重组人白蛋白、可溶明胶、其合适的混合物和植物油。例如,可以通过使用包衣比如卵磷脂,通过在存在分散体的情况下维持所需的粒径以及通过使用表面活性剂来维持合适的流动性。可以通过各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、抗坏血酸、硫柳汞等,来防止微生物的作用。在许多情况下,组合物中包括等渗剂,例如糖、氯化钠或多元醇,比如甘露糖醇和山梨糖醇。可以通过在组合物中包含延迟吸收的试剂例如单硬脂酸铝或明胶来实现可注射组合物的延长吸收。
制剂可以与常规赋形剂混合使用,即适合于口服、肠胃外、经鼻、吸入、静脉内、皮下、经皮肠内或本领域已知的任何其他合适的施用方式的药学上可接受的有机或无机载体物质。可以对药物制剂进行灭菌,并且如果需要,可以与辅助剂例如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压缓冲剂的盐、着色剂、调味剂和/或赋予香气的物质等混合。在需要时,它们也可以与其他活性剂,例如其他镇痛剂、抗焦虑剂或催眠剂组合。如本文所使用的,“另外的成分”包括但不限于可用作药物载体的一种或多种成分。
本公开内容的组合物可以包括按组合物的总重量计约0.005%至2.0%的防腐剂。在暴露于环境中的污染物的情况下,防腐剂用于防止变质。根据本公开内容有用的防腐剂的实例包括但不限于选自苄醇、山梨酸、对羟基苯甲酸、咪脲及其任何组合的那些。一种这样的防腐剂是约0.5%至2.0%的苄醇和0.05-0.5%的山梨酸的组合。
该组合物可以包括抑制化合物降解的抗氧化剂和螯合剂。对于某些化合物,抗氧化剂是BHT、BHA、α-生育酚和抗坏血酸,按组合物的总重量计,其示例性范围为按重量计约0.01%至0.3%,或BHT范围为按重量计0.03%至0.1%。按组合物的总重量计,螯合剂存在的量可以是按重量计0.01%至0.5%。按组合物的总重量计,示例性螯合剂包括在约0.01%至0.20%的重量范围内或在按重量计0.02%至0.10%的范围内的乙二胺四乙酸盐(例如乙二胺四乙酸二钠)和柠檬酸。螯合剂可用于螯合组合物中的金属离子,这可能对制剂的保存期限有害。对于某些化合物,尽管BHT和乙二胺四乙酸二钠分别是示例性的抗氧化剂和螯合剂,但是如本领域技术人员所知,可以用其他合适的和等同的抗氧化剂和螯合剂替代。
可以使用常规方法制备液体悬浮液,以使活性成分悬浮在水性或油性媒介物中。水性媒介物包括例如水和等渗盐水。油性媒介物包括例如杏仁油、油性酯、乙醇、植物油比如花生油、橄榄油、芝麻油或椰子油、分馏的植物油和矿物油比如液体石蜡。液体悬浮液可以进一步包括一种或多种另外的成分,包括但不限于悬浮剂、分散剂或润湿剂、乳化剂、缓和剂、防腐剂、缓冲剂、盐、调味剂、着色剂和甜味剂。油性悬浮液可以进一步包括增稠剂。已知的悬浮剂包括但不限于山梨糖醇糖浆剂、氢化可食用脂肪、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶、阿拉伯树胶和纤维素衍生物比如羧甲基纤维素钠、甲基纤维素、羟丙甲基纤维素。已知的分散剂或润湿剂包括但不限于天然存在的磷脂比如卵磷脂,烯化氧与脂肪酸、与长链脂族醇、与源自脂肪酸和己糖醇的偏酯或与源自脂肪酸和己糖醇酐的偏酯(例如,分别是聚氧乙烯硬脂酸酯、十七碳亚乙氧基鲸蜡醇、聚氧乙烯山梨醇单油酸酯和聚氧乙烯山梨聚糖单油酸酯)的缩合产物。已知的乳化剂包括但不限于卵磷脂、阿拉伯胶和离子或非离子表面活性剂。已知的防腐剂包括但不限于对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、抗坏血酸和山梨酸。已知的甜味剂包括例如甘油、丙二醇、山梨糖醇、蔗糖和糖精。
可以以与液体悬浮液基本相同的方式制备活性成分在水性或油性溶剂中的液体溶液,主要区别在于活性成分是溶解而不是悬浮在溶剂中。如本文所使用的,“油性”液体是包括含碳液体分子并且展现出比水小的极性的液体。本公开内容的药物组合物的液体溶液可包含关于液体悬浮液描述的每种组分,应当理解,悬浮剂不一定会帮助活性成分溶解在溶剂中。水性溶剂包括例如水和等渗盐水。油性溶剂包括例如杏仁油、油性酯、乙醇、植物油比如花生油、橄榄油、芝麻油或椰子油、分馏的植物油和矿物油比如液体石蜡。
可以使用已知方法制备本公开内容的药物制剂的粉末状和颗粒制剂。这样的制剂可以直接施用至受试者,例如用于形成片剂、填充胶囊,或通过向其中添加水性或油性媒介物来制备水性或油性悬浮液或溶液。这些制剂中的每一种可以进一步包括分散剂或润湿剂、悬浮剂、离子和非离子表面活性剂和防腐剂中的一种或多种。这些制剂中还可以包括另外的赋形剂,比如填充剂和甜味剂、调味剂或着色剂。
本公开内容的药物组合物也可以水包油乳剂或油包水乳剂的形式制备、包装或出售。油相可以是植物油比如橄榄油或花生油,矿物油比如液体石蜡,或这些的组合。这样的组合物可以进一步包含一种或多种乳化剂,比如天然存在的树胶比如阿拉伯树胶或黄蓍树胶;天然存在的磷脂,例如大豆或卵磷脂;源自脂肪酸和己糖醇酐的组合的酯或偏酯,比如山梨聚糖单油酸酯,以及这种偏酯与环氧乙烷的缩合产物,比如聚氧乙烯山梨聚糖单油酸酯。这些乳剂还可以包含另外的成分,包括例如甜味剂或调味剂。
用化学组成物浸渍或涂覆材料的方法在本领域中是已知的,并且包括但不限于将化学组成物沉积或结合到表面上的方法,在合成材料(即,比如使用生理学上可降解的材料)期间将化学组成物结合到材料结构中的方法,以及将水性或油性溶液或悬浮液吸收到吸收性材料中的方法,随后进行干燥或不进行干燥。混合组分的方法包括本领域技术人员已知的物理研磨、在固体和悬浮液制剂中使用丸粒以及在透皮贴剂中混合。
施用/给药
给药方案可能会影响有效量的构成。可以在疾病或紊乱发作之前或之后将治疗制剂施用至患者。此外,可以每天或顺序施用几种分开的剂量以及交错剂量,或者可以连续输注该剂量,或者可以是推注注射。此外,治疗制剂的剂量可以根据治疗或预防情况的紧急程度成比例地增加或减少。
可以使用已知的程序,以有效治疗本文考虑的疾病或紊乱的剂量和时间段将本公开内容的组合物施用至患者,比如哺乳动物,比如人。实现治疗效果所必需的治疗化合物的有效量可以根据以下因素而变化,比如所采用的特定化合物的活性;施用时间;该化合物的排泄速率;治疗的持续时间;与该化合物组合使用的其他药物、化合物或材料;疾病或紊乱的状态,所治疗患者的年龄、性别、体重、状况、一般健康状况以及既往病史,以及医学领域众所周知的类似因素。可以调整剂量方案以提供最佳的治疗反应。例如,如治疗状况的紧急情况所指示,可以每天施用数个分开的剂量或可以成比例地减少剂量。本公开内容的治疗化合物的有效剂量范围的非限制性实例为每天约0.01mg/kg至100mg/kg体重。本领域普通技术人员将能够研究相关因素并确定治疗化合物的有效量而无需过度实验。
可以将该化合物每天几次频繁地施用至动物,或者可以更不频繁地施用,比如每天一次、每周一次、每两周一次、每月一次或甚至更不频繁地,比如每几个月一次,甚至一年一次或更低。应当理解,在非限制性实例中,每天给药的化合物的量可以每天、每隔一天、每2天、每3天、每4天或每5天施用一次。例如,每隔一天施用一次,可以在星期一开始5mg的每日剂量,在星期三施用第一个随后5mg的每日剂量,在星期五施用第二个随后5mg的每日剂量,等等。剂量的频率对技术人员而言是显而易见的,并且取决于许多因素,比如但不限于所治疗的疾病的类型和严重程度以及动物的类型和年龄。
可以改变本公开内容的药物组合物中活性成分的实际剂量水平,以便获得有效实现特定患者、组合物和给药方式所需的治疗反应的活性成分的量,而对患者是无毒的。
具有本领域普通技术的医生,例如医师或兽医,可以容易地确定和开处方所需的有效量的药物组合物。例如,医师或兽医可以以低于所需要的水平开始在药物组合物中使用的本公开内容化合物的剂量,以便获得所需的治疗效果并逐渐增加剂量,直到获得所需的效果。
在具体实施方式中,以剂量单位形式配制化合物对于施用的容易性和剂量的均匀性是特别有利的。如本文所使用的剂量单位形式是指适合作为待治疗患者的单位剂量的物理上离散的单位;每个单位都包含预定量的治疗化合物,该化合物经计算可与所需的药物媒介物结合以产生所需的治疗效果。本公开内容的剂量单位形式由以下决定并直接取决于(a)治疗化合物的独特特征和要实现的特定治疗效果,以及(b)在配制/配制用于治疗患者的疾病或紊乱的这种治疗化合物的领域中固有的局限性。
在某些实施方式中,本公开内容的组合物以每天1-5次或更多次的范围内的剂量施用至患者。在其他实施方式中,本公开内容的组合物以包括但不限于每天一次、每两天一次、每三天一次至一周一次以及每两周一次的剂量范围施用至患者。对于本领域技术人员而言显而易见的是,本公开内容的各种组合组合物的施用频率将因受试者而异,这取决于许多因素,包括但不限于年龄、待治疗的疾病或紊乱、性别、整体健康状况和其他因素。因此,本公开内容不应被解释为限于任何特定的剂量方案,并且将由主治医师考虑到患者的所有其他因素来确定要施用至任何患者的精确剂量和组成。
用于施用的本公开内容的化合物可以在以下范围内:约1μg至约7,500mg、约20μg至约7,000mg、约40μg至约6,500mg、约80μg至约6,000mg、约100μg至约5,500mg、约200μg至约5,000mg、约400μg至约4,000mg、约800μg至约3,000mg、约1mg至约2,500mg、约2mg至约2,000mg、约5mg至约1,000mg、约10mg至约750mg、约20mg至约600mg、约30mg至约500mg、约40mg至约400mg、约50mg至约300mg、约60mg至约250mg、约70mg至约200mg、约80mg至约150mg和它们之间的任何完整增量和部分增量。
在一些实施方式中,本公开内容的化合物的剂量为约0.5μg和约5,000mg。在一些实施方式中,本文描述的组合物中使用的本公开内容的化合物的剂量小于约5,000mg、或小于约4,000mg、或小于约3,000mg、或小于约2,000mg、或小于约1,000mg、或小于约800mg、或小于约600mg、或小于约500mg、或小于约200mg、或小于约50mg。类似地,在一些实施方式中,如本文描述的第二化合物的剂量小于约1,000mg、或小于约800mg、或小于约600mg、或小于约500mg、或小于约400mg、或小于约300mg、或小于约200mg、或小于约100mg、或小于约50mg、或小于约40mg、或小于约30mg、或小于约25mg、或小于约20mg、或小于约15mg、或小于约10mg、或小于约5mg、或小于约2mg、或小于约1mg、或小于约0.5mg、以及其任何完全增量和部分增量。
在某些实施方式中,本公开内容涉及包装的药物组合物,其包含单独地或与第二种药物组合地容纳治疗有效量的本公开内容化合物的容器;以及使用该化合物治疗、预防或减轻患者的疾病或紊乱的一种或多种症状的说明书。
术语“容器”包括用于容纳药物组合物或用于管理稳定性或水吸收的任何接受器(receptacle)。例如,在某些实施方式中,容器是包含药物组合物的包装,比如存在于双室中的液体(溶液和悬浮液)、半固体、冻干固体、溶液和粉末或冻干制剂。在其他实施方式中,容器不是包含药物组合物的包装,即,容器是接受器,比如包含包装的药物组合物或未包装的药物组合物以及药物组合物使用说明书的盒子或小瓶。此外,包装技术是本领域众所周知的。应当理解,药物组合物的使用说明书可以包含在含有药物组合物的包装上,并且因此,说明书与包装的产品形成增加的功能关系。然而,应当理解,说明书中可能包含有关该化合物执行其预期功能的能力,例如治疗、预防或减轻患者的疾病或紊乱的信息。
施用
本公开内容任何组合物的给药途径包括吸入、口服、经鼻、直肠、肠胃外、舌下、经皮、经粘膜(例如舌下、舌、(经)含服、(经)尿道、阴道(例如,经阴道和阴道周围)、鼻(内)和((经)直肠)、膀胱内、肺内、十二指肠内、胃内、鞘内、硬膜外、胸膜内、腹膜内、皮下、肌内、皮内、动脉内、静脉内、支气管内、吸入和局部施用。
合适的组合物和剂型包括例如片剂、胶囊、囊片、丸剂、软胶囊、锭剂、乳剂、分散剂、悬浮剂、溶液、糖浆剂、颗粒剂、珠剂、透皮贴剂、凝胶剂、粉末、丸粒、乳浆剂(magma)、锭剂、乳膏、糊剂、膏药、洗剂、片剂(discs)、栓剂、用于经鼻或口服施用的液体喷雾剂、用于吸入的干粉或雾化制剂、用于膀胱内施用的组合物和制剂等。应当理解,可用于本公开内容的制剂和组合物不限于本文描述的特定制剂和组合物。
口服施用
对于口服施用,特别地合适的是片剂、锭剂、液体、滴剂、胶囊、囊片和软胶囊。其他适合口服施用的制剂包括但不限于粉末或颗粒制剂、水性或油性悬浮剂、水性或油性溶液、糊剂、凝胶剂、牙膏、漱口剂、包衣剂、口腔冲洗剂或乳剂。可以根据本领域已知的任何方法来制备预期用于口服使用的组合物,并且这种组合物可以包含选自适合用于制造片剂的惰性、无毒、通常被认为是安全的(GRAS)药学上的赋形剂的一种或多种试剂。这种赋形剂包括例如惰性稀释剂比如乳糖;制粒剂和崩解剂,例如玉米淀粉;粘合剂,比如淀粉;和润滑剂,比如硬脂酸镁。
片剂可以是未被涂覆的,或者可以使用已知方法涂覆,以在受试者的胃肠道中实现延迟崩解,从而提供活性成分的持续释放和吸收。举例来说,可以使用比如单硬脂酸甘油酯或二硬脂酸甘油酯的材料涂覆片剂。进一步举例来说,可以使用在美国专利号4,256,108;4,160,452;和4,265,874中描述的方法涂覆片剂以形成渗透控释片。片剂可以进一步包含甜味剂、调味剂、着色剂、防腐剂或这些的某种组合以提供药学上鲜美(elegant)且可口的制剂。包括活性成分的硬胶囊可以使用生理学上可降解的组合物例如明胶来制备。胶囊包括活性成分,并且可以进一步包括另外的成分,包括例如惰性固体稀释剂,比如碳酸钙、磷酸钙或高岭土。
包括活性成分的硬胶囊可以使用生理学上可降解的组合物比如明胶来制备。这种硬胶囊包括活性成分,并且可以进一步包含另外的成分,包括例如惰性固体稀释剂,比如碳酸钙、磷酸钙或高岭土。
包括活性成分的软胶囊可以使用生理学上可降解的组合物比如来自动物胶原或羟丙甲纤维素(纤维素的改性形式)的明胶来制备,并使用明胶、水和增塑剂比如山梨糖醇或甘油的任选的混合物制造。这样的软胶囊包括可以与水或油介质比如花生油、液体石蜡或橄榄油混合的活性成分。
对于口服施用,本公开内容的化合物可以是通过常规方法与药学上可接受的赋形剂比如粘合剂;填充剂;润滑剂;崩解剂;或润湿剂制备的片剂或胶囊的形式。如果期望的,可以使用合适的方法和包衣材料比如可获得自Colorcon,West Point,Pa.(例如,OY型、OYC型、有机肠溶型OY-P型、水性肠溶型OY-A型、OY-PM型和White,32K18400)的膜包衣系统涂覆片剂。应当理解,可以使用其他公司的类似类型的膜涂层或聚合产物。
包括活性成分的片剂可以例如通过将活性成分任选地与一种或多种另外的成分一起压制或模制来制备。制备压制片剂可以通过在合适的装置中压制自由流动形式的活性成分比如粉末或颗粒制剂,任选地与一种或多种粘合剂、润滑剂、赋形剂、表面活性剂和分散剂混合。模制片剂可以通过在合适的装置中模制活性成分、药学上可接受的载体和至少足以润湿混合物的液体的混合物来制备。用于制造片剂的药学上可接受的赋形剂包括但不限于惰性稀释剂、制粒剂和崩解剂、粘合剂和润滑剂。已知的分散剂包括但不限于马铃薯淀粉和羟甲基淀粉钠。已知的表面活性剂包括但不限于月桂基硫酸钠。已知的稀释剂包括但不限于碳酸钙、碳酸钠、乳糖、微晶纤维素、磷酸钙、磷酸氢钙和磷酸钠。已知的制粒剂和崩解剂包括但不限于玉米淀粉和藻酸。已知的粘合剂包括但不限于明胶、阿拉伯胶、预糊化的玉米淀粉、聚乙烯吡咯烷酮和羟丙基甲基纤维素。已知的润滑剂包括但不限于硬脂酸镁、硬脂酸、二氧化硅和滑石。
制粒技术在制药领域是众所周知的,用于改性活性成分的起始粉末或其他颗粒材料。通常将粉末与粘合剂材料混合成较大的永久性自由流动的附聚物或颗粒,称为“制粒”。例如,使用溶剂的“湿法”制粒工艺的一般特征是,将粉末与粘合剂材料混合,并在一定条件下用水或有机溶剂润湿,形成湿的粒状物料,然后必须将溶剂从中蒸发。
熔融制粒通常包括使用在室温下为固体或半固体的材料(即,具有相对较低的软化或熔点范围)在基本上没有添加水或其他液体溶剂的情况下促进粉末或其他材料的制粒。当加热到熔点范围内的温度时,低熔点固体液化以充当粘合剂或制粒介质。液化的固体将其自身散布在与之接触的粉末状材料的表面上,并在冷却后形成固体颗粒状物质,在其中将初始物质粘合在一起。然后可以将所得的熔融制粒提供给压片机或封装以制备口服剂型。熔融制粒通过形成固体分散体或固溶体来改善活性物质(即,药物)的溶解速率和生物利用度。
美国专利号5,169,645公开了具有改善的流动特性的可直接压缩的含蜡颗粒。当蜡在熔体中与某些改善流动性的添加剂混合,然后将混合物冷却并制粒时,可得到颗粒。在某些实施方式中,在蜡(一种或多种)和添加剂(一种或多种)的熔融组合物中只有蜡本身熔融,并且在其他情况下,蜡(一种或多种)和添加剂(一种或多种)二者都将熔融。
本公开内容还包括多层片剂,其包括提供用于延迟释放在本公开内容的方法中有用的一种或多种化合物的层,和提供用于立即释放在本公开内容的方法中有用的一种或多种化合物的其他层。使用蜡/pH敏感的聚合物混合物,可以获得胃不溶性组合物,其中捕获(entrap)了活性成分,从而确保了其延迟释放。
用于口服施用的液体制剂可以是溶液、糖浆剂或悬浮剂的形式。液体制剂可以通过常规方式用药学上可接受的添加剂比如悬浮剂(例如,山梨糖醇糖浆剂、甲基纤维素或氢化可食用脂肪);乳化剂(例如,卵磷脂或阿拉伯胶);非水性媒介物(例如,杏仁油、油性酯或乙醇);和防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)制备。适用于口服施用的本公开内容的药物组合物的液体制剂可以以液体形式或干燥产物的形式制备、包装和出售,该干燥产物旨在在使用前用水或另一种合适的载体重构。
肠胃外施用
如本文所使用的,药物组合物的“肠胃外施用”包括特征在于对受试者的组织进行物理破坏和通过组织中的破坏施用药物组合物的任何施用途径。因此肠胃外施用包括但不限于通过注射组合物施用药物组合物、通过外科切口施用组合物、通过穿透组织的非外科伤口施用组合物等方式施用药物组合物。特别地,预期肠胃外施用包括但不限于皮下、静脉内、腹膜内、肌内、胸骨内注射和肾透析输注技术。
适用于肠胃外施用的药物组合物的制剂包括与药学上可接受的载体,比如无菌水或无菌等渗盐水组合的活性成分。这样的制剂可以以适合于推注施用或连续施用的形式制备、包装或出售。可注射制剂可以在单位剂型,比如在含有防腐剂的安瓿或多剂量容器中制备、包装或出售。还可以在装置比如患者自控的镇痛(PCA)装置中制备、包装或出售可注射制剂。肠胃外施用的制剂包括但不限于混悬剂、溶液、在油性或水性媒介物中的乳剂、膏剂和可植入的缓释或生物可降解的制剂。这样的制剂可以进一步包含一种或多种另外的成分,包括但不限于悬浮剂、稳定剂或分散剂。在用于肠胃外施用的制剂的一个实施方式中,活性成分以干燥(即,粉末或颗粒)形式提供,以与合适的媒介物(例如,无菌无热原水)重构,然后肠胃外施用重构的组合物。
药物组合物可以以无菌可注射的水性或油性悬浮液或溶液的形式制备、包装或出售。该悬浮液或溶液可以根据已知技术配制,并且除了活性成分外还可以包含另外的成分,比如本文所述的分散剂、润湿剂或悬浮剂。可以使用无毒的肠胃外可接受的稀释剂或溶剂,诸如例如水或1,3-丁二醇来制备这种无菌可注射制剂。其他可接受的稀释剂和溶剂包括但不限于林格氏溶液、等渗氯化钠溶液和不挥发性油比如合成的甘油单酯或甘油二酯。有用的其他可肠胃外施用的制剂包括包含活性成分的那些,该活性成分为重组人白蛋白、流化明胶、脂质体制剂或生物可降解的聚合物体系的组分中的微晶形式。用于持续释放或植入的组合物可以包括药学上可接受的聚合物或疏水材料,比如乳剂、离子交换树脂、微溶聚合物或微溶盐。
局部施用
局部施用药物制剂的障碍是表皮的角质层。角质层是由蛋白质、胆固醇、鞘脂、游离脂肪酸和各种其他脂质组成的高抗蚀层,并且包括角质化细胞和活细胞。限制化合物穿过角质层的渗透率(通量)的因素之一是可以负载或施加到皮肤表面上的活性物质的量。每单位皮肤面积施加的活性物质的量越大,皮肤表面与皮肤下层之间的浓度梯度越大,进而活性物质穿过皮肤的扩散力越大。因此,与其他浓度较低的制剂相比,含有较高浓度的活性物质的制剂更可能导致更多的活性物质以更一致的速率渗透穿过皮肤,所有其他内容都是一样的。
适用于局部施用的制剂包括但不限于液体或半液体制剂,比如擦剂、洗剂、水包油或油包水乳剂,比如乳膏、药膏或糊剂,以及溶液或悬浮液。尽管活性成分的浓度可以与活性成分在溶剂中的溶解度极限相同,但是可局部施用的制剂可以例如包括约1%至约10%(w/w)的活性成分。用于局部施用的制剂可以进一步包括一种或多种本文所述的另外的成分。
可以使用渗透促进剂。这些材料增加了药物穿过皮肤的渗透率。本领域中典型的促进剂包括乙醇、单月桂酸甘油酯、PGML(聚乙二醇单月桂酸酯)、二甲基亚砜等。其他促进剂包括油酸、油醇、乙氧基乙二醇、月桂氮酮、链烷羧酸、二甲基亚砜、极性脂质或N-甲基-2-吡咯烷酮。
用于局部递送本公开内容的一些组合物的一种可接受的媒介物可以包含脂质体。脂质体的组成及其用途是本领域已知的(即,美国专利号6,323,219)。
在可选的实施方式中,局部活性药物组合物可以任选地与其他成分比如佐剂、抗氧化剂、螯合剂、表面活性剂、发泡剂、润湿剂、乳化剂、增粘剂、缓冲剂、防腐剂等组合。在其他实施方式中,渗透或渗透促进剂包括在组合物中,并且相对于缺乏渗透促进剂的组合物,对于改善活性成分渗透到皮肤中和穿过角质层是有效的。各种渗透促进剂,包括油酸、油醇、乙氧基乙二醇、月桂氮酮、链烷羧酸、二甲基亚砜、极性脂质或N-甲基-2-吡咯烷酮是本领域技术人员已知的。在另一方面,所述组合物可以进一步包含水溶助剂,其起到增加角质层结构的紊乱的作用,并因此允许增加穿过角质层的运输。各种水溶助剂比如异丙醇、丙二醇或二甲苯磺酸钠是本领域技术人员已知的。
局部活性药物组合物应以有效影响所需变化的量施用。如本文所使用的“有效量”是指足以覆盖需要改变的皮肤表面区域的量。活性化合物应该以按组合物的重量体积计约0.0001%至约15%的量存在。例如,它应该以组合物的约0.0005%至约5%的量存在;例如,它应该以组合物的约0.001%至约1%的量存在。这样的化合物可以源自合成的或天然的。
含服施用
本公开内容的药物组合物可以适合于含服施用的制剂来制备、包装或出售。这样的制剂可以例如为使用常规方法制备的片剂或锭剂的形式,并且可以包含例如0.1至20%(w/w)的活性成分,余量包括口腔可溶解的或可降解的组合物,以及任选地本文所述的一种或多种另外的成分。可选地,适合含服施用的制剂可以包括包含活性成分的粉末状或气雾化(aerosolized)或喷雾化(atomized)溶液或悬浮液。当分散时,这种粉末状、气雾化或喷雾化的制剂可具有在约0.1至约200纳米范围内的平均颗粒或液滴尺寸,并且可以进一步包括一种或多种本文所述的另外的成分。本文描述的制剂的实例不是穷举的,并且应当理解,本公开内容包括本文未描述但本领域技术人员已知的这些和其他制剂的另外的修改。
直肠施用
本公开内容的药物组合物可以以适于直肠施用的制剂制备、包装或出售。这样的组合物可以是例如栓剂、保留灌肠制剂和用于直肠或结肠灌洗的溶液的形式。
栓剂制剂可通过将活性成分与无刺激性的药学上可接受的赋形剂混合来制备,该赋形剂在正常室温(即,约20℃)下呈固体,并且在受试者的直肠温度(即,在健康人体内约37℃)下呈液体。合适的药学上可接受的赋形剂包括但不限于可可脂、聚乙二醇和各种甘油酯。栓剂制剂可以进一步包含各种另外的成分,包括但不限于抗氧化剂和防腐剂。
用于直肠或结肠灌洗的保留灌肠制剂或溶液可通过将活性成分与药学上可接受的液体载体混合来制备。如本领域中众所周知的,可以使用适合于受试者的直肠解剖结构的递送装置来施用灌肠制剂,并且可以将灌肠制剂包装在递送装置中。灌肠制剂可以进一步包含各种另外的成分,包括但不限于抗氧化剂和防腐剂。
另外施用形式
本公开内容的另外的剂型包括如在美国专利号6,340,475、6,488,962、6,451,808、5,972,389、5,582,837和5,007,790中描述的剂型。本公开内容的另外的剂型还包括如在美国专利申请号20030147952、20030104062、20030104053、20030044466、20030039688和20020051820中描述的剂型。本公开内容的另外的剂型还包括如在PCT申请号WO 03/35041、WO 03/35040、WO 03/35029、WO 03/35177、WO 03/35039、WO 02/96404、WO 02/32416、WO01/97783、WO 01/56544、WO 01/32217、WO 98/55107、WO 98/11879、WO 97/47285、WO 93/18755和WO 90/11757中描述的剂型。
控释制剂和药物递送系统:
在某些实施方式中,本公开内容的组合物和/或制剂可以是但不限于短期、起效快(rapid-onset)和/或快速补偿以及受控的例如持续释放、延迟释放和脉冲释放制剂。
术语持续释放在其常规意义上是指可在延长的时间段内逐渐释放药物的药物制剂,尽管不一定,但在延长的时间段内可导致药物的血液水平基本恒定。该时间段可以长达一个月或更长时间,并且应该是长于以推注形式施用相同量的释放。
为了持续释放,可以将化合物与合适的聚合物或疏水材料一起配制,所述聚合物或疏水材料为化合物提供持续释放特性。这样,用于本公开内容方法的化合物可以以微粒形式通过例如注射施用,或者以晶片或圆盘形式通过植入施用。
在本公开内容的某些实施方式中,使用缓释制剂将本公开内容中有用的化合物单独或与另一种药物制剂组合施用至受试者。
术语延迟释放在本文中在其常规意义上是指在药物施用后的一定延迟之后提供药物的初始释放的药物制剂,并且尽管不是必须的,但是可以包括从约10分钟直至大约12个小时。
术语脉冲释放在本文中在其常规意义上是指以药物施用后产生脉冲血浆分布的方式提供药物释放的药物制剂。
术语立即释放在其常规意义上是指在药物施用后立即提供释放药物的药物制剂。
如本文所使用的,短期指在药物施用之后的任何时间段,至多并且包括在药物施用之后约8小时、约7小时、约6小时、约5小时、约4小时、约3小时、约2小时、约1小时、约40分钟、约20分钟或约10分钟和其任何或所有完整增量或部分增量。
如本文所使用的,快速补偿指在药物施用之后的任何时间段,至多并且包括约8小时、约7小时、约6小时、约5小时、约4小时、约3小时、约2小时、约1小时、约40分钟、约20分钟或约10分钟,以及其任何完整增量和部分增量。
仅使用常规实验,本领域技术人员将认识到或能够确定本文所述的具体程序、实施方式、权利要求和实施例的许多等同方案。这样的等同方案被认为在本公开内容的范围内,并由所附权利要求书涵盖。例如,应当理解,利用本领域公认的替代方案并且仅使用常规实验,包括但不限于反应时间、反应规格(size)/规模(volume)和实验试剂比如溶剂、催化剂、压力、大气条件例如氮气气氛、以及还原剂/氧化剂的反应条件的改进均在本申请的范围内。
应当理解,无论在本文何处提供数值和范围,范围格式的描述仅是为了方便和简洁,而不应被解释为对本公开内容范围的僵化限制。因此,这些值和范围所涵盖的所有值和范围意在被涵盖在本公开内容的范围内。此外,本申请还考虑了落入这些范围内的所有值以及该值的范围的上限或下限。范围的描述应被认为已明确公开了所有可能的子范围以及该范围内的单个数值,以及在合适时该范围内的数值的部分整数。例如,对范围从1到6的描述应被视为已明确公开了从1到3、从1到4、从1到5、从2到4、从2到6、从3到6等的子范围,以及该范围内的单个数值,例如1、2、2.7、3、4、5、5.3和6。无论该范围的广度如何,这都适用。
以下实施例进一步阐释了本公开内容的方面。然而,它们决不是对本文所述的本公开内容的教导或公开内容的限制。
实施例
现在参考以下实施例描述本公开内容。提供这些实施例仅出于说明的目的,并且本公开内容不限于这些实施例,而是涵盖由于本文提供的教导而显而易见的所有变型。
材料&方法
以下程序可用于评估和选择可抑制乙型肝炎病毒感染的化合物。
利用HBV rcDNA的bDNA定量的HepDE19测定:
HepDE19细胞培养系统是一种HepG2(人类肝癌)衍生的细胞系,它以四环素(Tet)调控方式支持HBV DNA复制和cccDNA形成,并产生HBV rcDNA和依赖于cccDNA产生和维持的可检测报告分子(Guo等人,2007,J.Virol.81:12472-12484)。
将HepDE19(50,000个细胞/孔)铺在DMEM/F12培养基中的96孔胶原蛋白包被的组织培养处理的微量滴定板中,该培养基补充有10%的胎牛血清、1%的青霉素-链霉素和1μg/mL的四环素,并在加湿培养箱中在37℃和5%CO2下过夜。第二天,将细胞转移至不含四环素的新鲜培养基中,并在37℃和5%CO2下温育4小时。用新鲜的不含Tet的培养基处理细胞,该化合物的浓度从25μM开始,并且连续的1/2log,8点滴定系列,一式两份。测定中的最终DMSO浓度为0.5%。将板在37℃和5%CO2下在加湿培养箱中温育7天。在温育7天后,使用Quantigene 2.0bDNA测定试剂盒(Affymetrix,Santa Clara,CA),结合HBV特有的定制探针组和制造商的说明书,测量抑制剂处理过的孔中存在的rcDNA的水平。同时,使用复制板评估化合物对细胞活力的影响,将板以5,000个细胞/孔的密度铺板并温育4天,以按照制造商的说明书使用细胞滴度glo试剂(CTG;Promega Corporation,Madison,WI)确定作为细胞活力的量度的ATP含量。使用Victor发光板读数器(PerkinElmer Model 1420Multilabel计数器)读取板,并将每个孔生成的相对发光单位(RLU)数据计算为未处理的对照孔的抑制百分比,并使用Microsoft Excel中的XL-Fit模块进行分析以使用4参数曲线拟合算法确定EC50和EC90(bDNA)和CC50(CTG)的值。
LCMS方法:
LCMS方法A:Waters Acquity UPLC系统,采用Waters Acquity UPLC BEH C18,1.7μm,50×2.1mm柱,其中基于水性乙腈的溶剂梯度为2-98%CH3CN/H2O(0.05%TFA),历时9.5min。流速=0.8mL/min。
LCMS方法B:Waters Acquity UPLC系统,采用Waters Acquity UPLC BEH C18,1.7μm,50×2.1mm柱,其中基于水性乙腈的溶剂梯度为2-98%CH3CN/H2O(0.05%TFA),历时1.0min。流速=0.8mL/min。
LCMS方法C:Shimadzu UFLC系统,采用ACE UltraCore Super PhenylHexyl,2.5μm,50×2.1mm柱,其中基于水性乙腈的溶剂梯度为5-100%CH3CN/H2O(0.05%甲酸),历时5.0min。流速=1.0mL/min。
LCMS方法D:Waters Acquity UPLC系统,采用Waters Acquity UPLC C18,1.7μm,50×2.1mm柱,其中基于水性乙腈的溶剂梯度为5-95%CH3CN/H2O(0.05%甲酸),历时4.0min。流速=0.5mL/min。
LCMS方法E:X Bridge BEH C18,2.5μm,50×2.1mm柱,其中基于水性乙腈的溶剂梯度为5-95%CH3CN/(10mM乙酸铵的水溶液),历时4.0min。流速=0.5mL/min。
如在本文中所描述的,“对映异构体I”或“非对映异构体I”是指在针对本文其他地方提供的实例详述的特定手性分析条件下从手性柱上逸出的第一对映异构体或非对映异构体;“对映异构体II”或“非对映异构体II”是指在针对本文其他地方提供的实例详述的特定手性分析条件下从手性柱上逸出的第二对映异构体或非对映异构体。对于这些化合物,这种命名法并不暗示或赋予任何具体的相对和/或绝对的构型。
实施例1:化合物
2,3,4,5-四氢菲啶-1,6-二酮(IVa)
步骤i:将2-碘苯甲酸(IIIa,2.00g,8.06mmol)、环己烷-1,3-二酮(IIa,1.09g,9.68mmol)、碘化铜(I)(0.15g,0.81mmol)和磷酸钾(2.39g,11.29mmol)在氮气气氛中在密封管中在干燥的1,4-二噁烷(12mL)中合并。将混合物在室温下搅拌30min,并且然后在110℃下搅拌3小时。将反应混合物用乙酸乙酯(10mL)稀释并通过过滤,并将垫用乙酸乙酯(3×10mL)洗涤。将溶剂在高真空下蒸发并通过快速色谱法(硅胶,乙酸乙酯/己烷0-90%梯度)进一步纯化产物,得到中间体3,4-二氢-2H-苯并[c]色烯-1,6-二酮(1.09g,63%)。1H NMR(400MHz,CDCl3):δ9.05(ddd,1H),8.28(ddd,1H),7.83–7.74(m,1H),7.52(ddd,1H),2.94(t,2H),2.70–2.62(m,2H),2.17(tt,2H)。
步骤ii:将步骤i中获得的3,4-二氢-2H-苯并[c]色烯-1,6-二酮(1.09g,5.11mmol)和乙酸铵(2.36g,30.67mmol)在140℃下在密封管中在1,2-二氯乙烷(24mL)中搅拌10小时。使反应混合物冷却至室温,用二氯甲烷(100mL)稀释并将有机相用饱和氯化铵(50mL)洗涤。将水相用二氯甲烷(各50mL)萃取三次并将合并的有机萃取物经硫酸钠干燥,然后过滤。蒸发溶剂,并通过快速色谱法(硅胶,甲醇/二氯甲烷0-5%梯度)分离产物,得到784mg(产率72%)2,3,4,5-四氢菲啶-1,6-二酮(IVa)。LCMS:m/z实测值214.1[M+H]+;1H NMR(400MHz,CDCl3):δ11.32(s,1H),9.32(ddd,1H),8.41(ddd,1H),7.83–7.74(m,1H),7.52(ddd,1H),3.05(t,2H),2.70(dd,2H),2.28–2.11(m,2H)。
1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Va)
将四异丙氧基钛(0.28mL,0.94mmol)加入2,3,4,5-四氢菲啶-1,6-二酮(50mg,0.23mmol)在1,4-二噁烷(1mL)中的溶液和2M甲胺的THF溶液(1.17mL,2.34mmol)的混合物中。然后将混合物在95℃下在氮气气氛中在密封管中加热16小时。将反应混合物用1mL无水甲醇稀释并在冰浴中冷却。一次性加入硼氢化钠(17.75mg,0.47mmol)并在5分钟之后除去冰浴。在另外20min之后,通过加入盐水(1mL)将反应物淬灭,用20mL乙酸乙酯稀释,并搅拌另外15min。通过过滤混合物,并将滤饼用另外25mL乙酸乙酯洗涤。将合并的有机溶液经硫酸钠干燥,过滤并蒸发溶剂,得到45mg(产率84%)1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Va),其无需进一步纯化即可用于下一步。LCMS:m/z实测值216[M-(MeNH2)+H2O+H]+;1H NMR(400MHz,CDCl3):δ9.67–9.59(m,1H),8.39(ddd,1H),7.85–7.61(m,2H),7.44(ddd,1H),3.87(d,1H),2.73–2.52(m,5H),2.28–2.15(m,1H),2.17–1.96(m,1H),1.89–1.80(m,1H),1.63–1.49(m,1H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物6/化合物16/化合物17)
在0℃下将2-氯-1-氟-4-异氰氧基(isocyanato)-苯(21uL,0.16mmol)在0.5mL二氯甲烷中的溶液缓慢加入粗1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Va,45mg,0.20mmol)在1mL二氯甲烷中的搅拌混合物。在10min后,加入甲醇(0.1mL)并将反应混合物蒸发至初始体积的一半,然后直接加载到预处理的硅胶柱上。通过快速色谱法(硅胶,乙酸乙酯/己烷20-100%)纯化产物,得到外消旋3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物6,38mg,48%)。LCMS:m/z实测值400.2/402.2[M+H]+;RT=4.31min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.46(s,1H),8.20(dd,J=8.0,1.4Hz,1H),7.90(dd,1H),7.70(ddd,1H),7.53(ddd,1H),7.48–7.37(m,2H),7.32(t,1H),5.59(br。s,1H),2.73–2.60(m,4H),2.57(t,1H),1.89(s,1H),1.95–1.69(m,1H)。
随后通过SFC(Waters)分离对映异构体,柱:IG-semiprep(10mMX 250mm)5μ,35%IPA的CO2溶液,流速为9ml/min,得到9.5mg和7.2mg解析的对映异构体。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲:对映异构体I(化合物16)。LCMS:m/z实测值400.1/402.1[M+H]+;RT=4.38min,(方法A);1H NMR(400MHz,CDCl3)δ11.12(s,1H),8.44(dd,1H),7.74–7.61(m,2H),7.54(d,1H),7.51–7.42(m,1H),7.31–7.22(m,1H),7.08(td,1H),6.41(s,1H),5.81(s,1H),2.92–2.74(m,2H),2.73(s,3H),2.13–2.02(m,2H),1.91(dt,2H);手性分析SFC:RT=6.23min,柱:IG-分析;35%IPA的CO2溶液;流速=3.0g/min。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲:对映异构体II(化合物17)。LCMS:m/z实测值400.1/402.2[M+H]+;RT=4.38min,(方法A);1H NMR(400MHz,CDCl3)δ11.02(s,1H),8.44(dd,1H),7.74–7.62(m,2H),7.54(dd,1H),7.47(ddd,1H),7.31–7.22(m,1H),7.08(t,1H),6.40(s,1H),5.81(s,1H),2.91–2.74(m,2H),2.73(s,3H),2.13–2.02(m,2H),1.91(dt,2H);手性分析SFC:RT=11.47min,柱:IG-分析;35%IPA的CO2溶液;流速=3.0g/min。
化合物17也根据方案2如下文步骤中所述独立地制备。
6-甲氧基-3,4-二氢-2H-菲啶-1-酮(VII-A)和5-甲基-3,4-二氢-2H-菲啶-1,6-二酮(IV-B)
在室温下在密封管中将2,3,4,5-四氢菲啶-1,6-二酮(IVa,0.22g,1.03mmol)、碘代甲烷(321uL,5.16mmol)和碳酸银(0.17g,0.62mmol)在氯仿(4mL)中搅拌48小时。LCMS分析指示~60%转化。将反应混合物在50℃下搅拌2小时,当LCMS分析指示完全转化时,区域选择性没有显著变化。将反应混合物冷却至室温,用二氯甲烷稀释,并通过过滤。在减压下蒸发溶剂并通过快速色谱法(硅胶,乙酸乙酯/己烷0-30%)分离产物,得到:6-甲氧基-3,4-二氢-2H-菲啶-1-酮(VII-A,192mg,产率82%);LCMS:m/z实测值228.1[M+H]+;RT=1.31min,(方法B);1H NMR(400MHz,CDCl3)δ9.37(dt,1H),8.23(ddq,1H),7.80–7.70(m,1H),7.55–7.46(m,1H),4.16(s,3H),3.17–3.09(m,2H),2.72(ddd,2H),2.17(pd,2H);和5-甲基-3,4-二氢-2H-菲啶-1,6-二酮(IV-B,29mg,12%);LCMS:m/z实测值228.2[M+H]+;RT=0.96min,(方法B);1H NMR(400MHz,CDCl3)δ9.22(dt,1H),8.42(ddd,1H),7.72(ddd,1H),7.49(ddd,1H),3.69(s,3H),3.03(t,2H),2.69–2.61(m,2H),2.26–2.14(m,2H)。
方案2
(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-2-甲基-丙烷-2-亚磺酰胺(VIII)
将(R)-2-甲基丙烷-2-亚磺酰胺(0.21g,1.76mmol)和工业级四乙氧基钛(0.28mL,1.32mmol)的混合物在90℃下在密封小瓶中搅拌48小时。然后加入6-甲氧基-3,4-二氢-2H-菲啶-1-酮(VII-A,50.00mg,0.22mmol)在无水二噁烷(0.2mL)中的溶液并继续搅拌24小时。加入另一份(R)-2-甲基丙烷-2-亚磺酰胺(0.21g,1.76mmol)并继续搅拌另外24小时。使反应混合物冷却至室温并用3mL无水2-甲基四氢呋喃稀释,然后进一步冷却至-40℃。一次性加入硼氢化钠(25mg,0.66mmol)。将反应物温度保持在-40和-20℃之间,持续50min,然后在-10℃下持续1小时。然后在30min内将反应缓慢升温至0℃。在0℃下用0.5mL盐水淬灭反应物并用乙酸乙酯(25mL)稀释,通过过滤,并用乙酸乙酯(3×20mL)洗涤滤饼。蒸发溶剂并通过快速色谱法(硅胶,EtOAc/己烷0–25%)分离产物,得到(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-2-甲基-丙烷-2-亚磺酰胺(VIII,18.7mg,26%)。LCMS m/z实测值333.3[M+H]+;RT=4.45min(方法B);1H NMR(400MHz,CDCl3)δ8.27–8.15(m,2H),7.75(ddd,1H),7.49(ddd,1H),5.07(s,1H),4.10(s,3H),3.29(s,1H),3.00–2.79(m,2H),2.31–2.21(m,1H),2.14(dddd,1H),1.91–1.69(m,1H),1.45(s,9H),1.37–1.21(m,1H)。
(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-N,2-二甲基-丙烷-2-亚磺酰胺(IX)
将(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-2-甲基-丙烷-2-亚磺酰胺(VIII,18.0mg,0.05mmol)在1mL无水DMF中的溶液在氮气气氛中在冰浴中冷却,并一次性加入60%w/w氢化钠的矿物油溶液(4.33mg,0.11mmol)。在0℃下20分钟之后,加入碘代甲烷(6.7uL,0.11mmol)。然后将反应物在0℃下搅拌90分钟。通过缓慢加入1mL水淬灭反应混合物,用二乙醚萃取,并将合并的有机萃取物用水,然后用盐水洗涤2次,经硫酸钠干燥,倾析,并在真空下蒸发溶剂。粗产物无需进一步纯化即可用于下一步:(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-N,2-二甲基-丙烷-2-亚磺酰胺(IX,16mg,85%)。LCMS m/z实测值347.3[M+H]+;RT=4.49min(方法B);1H NMR(400MHz,CDCl3)δ8.21(ddd,1H),7.90(dt,1H),7.69(ddd,1H),7.46(ddd,1H),4.86(dd,1H),4.11(s,3H),3.13–2.99(m,1H),2.86(ddd,1H),2.58(s,3H),2.35–2.19(m,1H),2.00–1.80(m,1H),1.63(s,1H),1.01(s,8H),0.92–0.80(m,1H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲:对映异构体II(化合物17)。
步骤i:将1.25M氯化氢在甲醇中的溶液(1.85mL,2.31mmol)加入(R)-N-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-N,2-二甲基-丙烷-2-亚磺酰胺(IX,16.0mg,0.05mmol)中,并将混合物在室温下搅拌1小时,并且然后在55℃下搅拌16小时。真空除去挥发物并将残余物与甲苯共沸2次,然后在高真空下进一步干燥并且无需进一步纯化即可用于接下来的反应。
步骤ii:在先前步骤中获得的粗的富对映异构体的1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(10.54mg,0.05mmol)悬浮在0.5mL二氯甲烷中并在0℃下用二异丙基乙胺(20uL,0.12mmol)处理。缓慢加入2-氯-1-氟-4-异氰氧基-苯(5.2uL,0.04mmol)在0.5mL二氯甲烷中的溶液并继续搅拌1小时。将反应物用0.5mL MeOH淬灭,并在5min之后,将混合物吸附到硅胶上并通过快速色谱法(硅胶,乙酸乙酯/己烷10-95%)分离产物并在高真空下干燥,得到3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲:对映异构体II(化合物17,10.5mg,57%)。LCMS:m/z实测值400.1/402.2[M+H]+;RT=4.38min,(方法A);1H NMR(400MHz,甲醇-d4)δ8.32(ddd,1H),7.76–7.66(m,2H),7.58–7.44(m,2H),7.39(ddd,1H),7.17(t,1H),5.72(s,1H),2.83–2.60(m,2H),2.69(s,3H),2.14–1.81(m,4H);手性分析SFC:RT=11.62min,柱:IG-分析;35%IPA的溶液CO2;流速=3.0g/min。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物31)
由5-甲基-3,4-二氢-2H-菲啶-1,6-二酮(IV-B)以与上述化合物6类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲。LCMS:m/z实测值414.3/416.3[M+H]+;RT=4.59min,(方法A);1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.27(ddd,1H),7.91(dd,1H),7.71(ddd,1H),7.54(ddd,1H),7.51–7.39(m,2H),7.32(t,1H),5.64(s,1H),3.56(s,3H),2.91(d,1H),2.81–2.70(m,1H),2.63(s,3H),1.87(m,4H)。
3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲(化合物34)
由6-甲氧基-3,4-二氢-2H-菲啶-1-酮(VII-A)以与上述化合物6类似的方式合成3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值414.3/416.3[M+H]+;RT=5.60min,(方法A);1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.22–8.14(m,1H),7.91(dd,1H),7.76(ddd,1H),7.70–7.63(m,1H),7.60–7.50(m,2H),7.32(t,1H),5.87(s,1H),4.06(s,3H),3.04–2.93(m,1H),2.81(dt,1H),2.51(s,3H),2.05–1.90(m,3H),1.85–1.69(m,1H)。
1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vb)
由2,3,4,5-四氢菲啶-1,6-二酮(IVa)和3-氨基丙-1-醇以与上述类似的方式合成1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。1H NMR(400MHz,CDCl3)δ8.46–8.36(m,1H),7.70(ddd,1H),7.59(d,1H),7.44(ddd,1H),3.95(t,1H),2.71–2.58(m,2H),2.27–2.17(m,1H),2.08–1.91(m,1H),1.87(td,1H),1.74(tt,2H),1.70–1.64(m,3H),1.59(tt,1H),1.29–1.20(m,1H)。
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物7)
由外消旋1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vb)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲。LCMS:m/z实测值444.1/446.2[M+H]+;RT=4.21min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.68(s,1H),8.19(dd,1H),7.85(dd,1H),7.69(ddd,1H),7.51–7.38(m,3H),7.33(t,1H),5.62(s,1H),4.94(s,1H),3.15(tt,4H),2.68(m,1H),2.56(q,1H),2.01–1.82(m,3H),1.74(s,1H),1.31–1.22(m,1H),1.14(s,1H)。
1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vc)
由2,3,4,5-四氢菲啶-1,6-二酮(IVa)和2-甲基丙-1-胺以与上述类似的方式合成1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值198.1[M-(Me2CHCH2NH)]+;RT=0.66min,(方法B);1H NMR(400MHz,CDCl3)δ10.45(s,1H),8.41(dt,1H),7.76–7.63(m,2H),7.52–7.39(m,1H),3.93(t,1H),2.71–2.60(m,3H),2.54(dd,1H),2.23–2.13(m,1H),2.08(tdd,1H),1.80(ddd,1H),1.70(dp,1H),1.54(tt,1H),1.25(s,1H),1.08–0.79(m,6H)。
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物8)
由外消旋1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vc)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲。LCMS:m/z实测值442.2/444.3[M+H]+;RT=1.08min,(方法B);1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.49(s,1H),8.17(dd,1H),7.81(dd,1H),7.69(ddd,1H),7.55(d,1H),7.48(ddd,1H),7.46–7.37(m,1H),7.30(t,1H),5.62(s,1H),3.00(dd,1H),2.83(dd,1H),2.72–2.65(m,1H),2.54(q,1H),2.00(m,1H),1.89–1.80(m,2H),1.70(m,1H),1.34(dt,1H),0.61(d,J=6.7Hz,3H),0.43(d,3H)。
8-氟-2,3,4,5-四氢菲啶-1,6-二酮(IVb)
步骤i:将5-氟-2-碘-苯甲酸(IIIb,543.7mg,2.04mmol)、环己烷-1,3-二酮(IIa,275.02mg,2.45mmol)、碘化铜(I)(38.93mg,0.20mmol)和磷酸钾(606.64mg,2.86mmol)在氮气气氛中在管中合并。加入无水1,4-二噁烷(1.5mL)并将反应物管用氮气吹扫并在室温下搅拌30min,并且然后加热在110℃下搅拌4小时。使反应混合物冷却至室温,用乙酸乙酯(10mL)稀释,通过过滤,并将垫用乙酸乙酯(3×25mL)洗涤。将合并的有机萃取物经硫酸钠干燥,过滤并将溶剂在高真空下蒸发,得到434mg(产率91%)8-氟-3,4-二氢-2H-苯并[c]色烯-1,6-二酮,其纯度是令人满意的。1H NMR(400MHz,CDCl3)δ9.11(ddd,1H),7.91(ddd,1H),7.49(ddd,1H),2.93(t,2H),2.69–2.58(m,2H),2.23–2.11(m,2H)。
步骤ii:将来自步骤i的8-氟-3,4-二氢-2H-苯并[c]色烯-1,6-二酮(434.00mg,1.87mmol)和乙酸铵(1.44g,18.69mmol)在140℃下在密封管中在1,2-二氯乙烷(2mL)中搅拌10小时。将反应混合物冷却并用二氯甲烷稀释,并用饱和氯化铵洗涤。将水相用二氯甲烷萃取三次并将合并的有机萃取物经硫酸钠干燥,然后过滤。蒸发溶剂,并通过快速色谱法(硅胶,甲醇/二氯甲烷0-5%梯度)分离产物,得到225mg(产率52%)8-氟-2,3,4,5-四氢菲啶-1,6-二酮(IVb)。LCMS:m/z实测值232.1[M+H]+;RT=0.82min,(方法B);1H NMR(400MHz,CDCl3)δ9.21(dd,1H),7.87(ddd,1H),7.38(dddd,1H),2.83(t,2H),2.57(dd,2H),2.09(dt,2H)。
8-氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vd)
由8-氟-2,3,4,5-四氢菲啶-1,6-二酮(IVb)和甲胺以与上述类似的方式合成8-氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值216.1[M-MeNH)]+;RT=0.60min,(方法B);1H NMR(400MHz,CDCl3)δ10.49(s,1H),8.12–7.97(m,1H),7.69(dd,1H),7.43(ddd,1H),3.86–3.82(m,1H),2.65(dd,1H),2.58(s,3H),2.24(dd,1H),2.08–1.91(m,1H),1.85(dt,1H),1.56(tt,1H),1.25(m,1H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物9)
由外消旋8-氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vd)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值418.1/420.1[M+H]+;RT=4.56min,(方法A);1HNMR(400MHz,DMSO-d6)δ11.45(s,1H),8.47(s,1H),8.02–7.78(m,2H),7.65(td,1H),7.59–7.40(m,2H),7.32(t,1H),5.59(s,1H),2.74–2.52(m,2H),2.62(s,3H),1.98–1.65(m,4H)。
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物32)
由外消旋8-氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vd)和1,2-二氟-4-异氰氧基-苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值402.3[M+H]+;RT=4.23min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.48(s,1H),7.85(dd,1H),7.77(ddd,1H),7.65(td,1H),7.47(dd,1H),7.40–7.26(m,2H),5.59(s,1H),2.67(dd,1H),2.62(s,3H),2.56(t,1H),1.97–1.61(m,4H)。
1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲(化合物33)
由外消旋8-氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vd)和1,2,3-三氟-5-异氰氧基-苯以与上述类似的方式合成1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲。LCMS:m/z实测值420.2[M+H]+;RT=4.58min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.62(s,1H),7.85(dd,1H),7.70–7.56(m,2H),7.60–7.51(m,1H),7.44(dd,1H),5.58(s,1H),2.67(dd,1H),2.62(s,3H),2.56(t,1H),2.05–1.57(m,4H)。
8-氟-1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Ve)
由8-氟-2,3,4,5-四氢菲啶-1,6-二酮(IVb)和2-甲基丙-1-胺以与上述类似的方式合成8-氟-1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。通过快速色谱法(硅胶,MeOH/DCM 0-10%)纯化产物。LCMS:m/z实测值216.1[M-(Me2CHCH2NH)]+;RT=0.70min,(方法B);1H NMR(400MHz,CDCl3)δ10.86(s,1H),8.04(dd,1H),7.73(dd,1H),7.41(ddd,1H),3.90(t,1H),2.72–2.58(m,3H),2.50(dd,1H),2.25–2.14(m,1H),2.08–1.94(m,1H),1.83(dt,1H),1.70(dq,1H),1.54(tt,1H),0.94(dd,6H)。
8-氟-1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vf)
由8-氟-2,3,4,5-四氢菲啶-1,6-二酮(IVb)和3-氨基丙-1-醇以与上述类似的方式合成8-氟-1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值216.1[M-(HO(CH2)3NH)]+;RT=0.62min,(方法B);1H NMR(400MHz,CDCl3)δ10.96(s,1H),8.03(dd,1H),7.63(dd,1H),7.43(dddd,1H),3.94(d,1H),3.82(td,2H),3.11(dt,1H),3.01(dt,1H),2.89(s,1H),2.66(dd,2H),2.28–2.18(m,1H),2.07–1.83(m,1H),1.75(hept,2H),1.66–1.53(m,1H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲(化合物10)
由外消旋8-氟-1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Ve)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲。LCMS:m/z实测值460.2/462.2[M+H]+;RT=5.28min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),8.52(s,1H),7.84(ddd,2H),7.66(dd,2H),7.49(ddd,1H),7.32(t,1H),5.65(s,1H),3.05(dd,1H),2.82(dd,1H),2.69(dt,1H),2.57(t,1H),2.04–1.95(m,1H),1.86(m,2H),1.72(m,1H),1.32(dq,1H),0.63(d,3H),0.44(d,3H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲(化合物11)
由外消旋8-氟-1-(3-羟基丙氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vf)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲。LCMS:m/z实测值462.2[M+H]+;RT=4.43min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.68(s,1H),7.85(ddd,2H),7.65(td,1H),7.58–7.42(m,2H),7.33(td,1H),5.62(s,1H),4.94(s,1H),3.24–2.96(m,4H),2.80–2.62(m,1H),2.57(t,1H),2.05–1.79(m,3H),1.74(s,1H),1.25(d,1H),1.11(s,1H)。
3,4-二氢-2H-环戊二烯并[c]异喹啉-1,5-二酮(IVc)
步骤i:由2-碘苯甲酸(IIIa)和环戊烷-1,3-二酮(IIb)以与上述类似的方式合成2,3-二氢环戊二烯并[c]异色烯-1,5-二酮。1H NMR(400MHz,CDCl3):δ8.51(ddd,1H),8.29(ddd,1H),7.82(ddd,1H),7.58(ddd,1H),3.08–3.00(m,2H),2.80–2.72(m,2H)。
步骤ii:由2,3-二氢环戊二烯并[c]异色烯-1,5-二酮和乙酸铵以与上述类似的方式合成3,4-二氢-2H-环戊二烯并[c]异喹啉-1,5-二酮。LCMS:m/z实测值200.1[M+H]+;RT=0.75min(方法B);1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.56(ddd,1H),8.19(ddd,1H),7.88–7.75(m,1H),7.54(ddd,1H),2.98–2.91(m,2H),2.64–2.54(m,2H)。
1-(甲氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vg)
由3,4-二氢-2H-环戊二烯并[c]异喹啉-1,5-二酮(IVc)和甲胺以与上述类似的方式合成1-(甲氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮。LCMS:m/z实测值184.1[M-MeNH)]+;RT=0.58min,(方法B);1H NMR(400MHz,CDCl3)δ11.17(s,1H),8.38(ddd,1H),7.76(dt,1H),7.66(ddd,1H),7.41(ddd,1H),4.48(dt,1H),3.22–3.04(m,1H),2.83(ddd,1H),2.47(s,3H),2.39(ddt,1H),2.13(ddt,1H)。
1-(异丁基氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vh)
由3,4-二氢-2H-环戊二烯并[c]异喹啉-1,5-二酮(IVc)和2-甲基丙-1-胺以与上述类似的方式合成1-(异丁基氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮。LCMS:m/z实测值184.1[M-(Me2CHCH2NH)]+;RT=0.69min,(方法B);1H NMR(400MHz,CDCl3)δ11.41(s,1H),8.40(dp,1H),7.82(dt,1H),7.77–7.61(m,1H),7.46–7.37(m,1H),4.52–4.44(m,1H),3.16–3.02(m,1H),2.82(ddd,1H),2.58–2.41(m,2H),2.45–2.32(m,1H),2.11–1.97(m,2H),1.79–1.61(m,1H),0.91(ddd,6H)。
1-(3-羟基丙氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vi)
由3,4-二氢-2H-环戊二烯并[c]异喹啉-1,5-二酮(IVc)和3-氨基丙-1-醇以与上述类似的方式合成1-(3-羟基丙氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮。LCMS:m/z实测值184.1[M-(HO(CH2)3NH)]+;RT=0.59min,(方法B);1H NMR(400MHz,CDCl3)δ8.43–8.34(m,1H),7.73–7.57(m,2H),7.42(ddd,1H),4.49(dt,1H),3.88–3.70(m,2H),3.08(dddd,1H),2.97(ddd,1H),2.90(ddd,1H),2.82(ddd,1H),2.36(ddt,1H),2.21–2.06(m,1H),1.82–1.61(m,2H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲(化合物12)
由外消旋1-(甲氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vg)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲。LCMS:m/z实测值386.2/388.2[M+H]+;RT=4.23min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.56(s,1H),8.19(dq,1H),7.87(ddd,1H),7.73–7.64(m,1H),7.52(dddd,1H),7.47–7.38(m,2H),7.32(td,1H),6.06(d,1H),2.98(dt,1H),2.73(ddd,1H),2.59(s,3H),2.56–2.43(m,1H),1.96–1.83(m,1H)。
3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲(化合物13)
由外消旋1-(异丁基氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vh)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲。LCMS:m/z实测值428.1/430.3[M+H]+;RT=1.05min,(方法B);1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.54(s,1H),8.18(ddd,1H),7.78(dd,1H),7.70(ddd,1H),7.56–7.49(m,1H),7.49–7.37(m,2H),7.30(t,1H),5.85(s,1H),3.10–2.84(m,3H),2.72(ddd,1H),2.66–2.53(m,1H),1.99(s,1H),1.50(s,1H),0.64(dd,6H)。
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲(化合物14)
由外消旋1-(3-羟基丙氨基)-1,2,3,4-四氢环戊二烯并[c]异喹啉-5-酮(Vi)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲。LCMS:m/z实测值430.2[M+H]+;RT=4.11min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.73(s,1H),8.18(dd,1H),7.81(dd,1H),7.73–7.64(m,1H),7.49–7.37(m,3H),7.32(t,1H),6.04(d,1H),4.92(t,1H),3.23(d,1H),3.24–3.10(m,1H),3.06(td,2H),2.73(ddd,1H),2.57(dt,1H),2.01–1.86(m,1H),1.32(d,2H)。
8,9-二氟-2,3,4,5-四氢菲啶-1,6-二酮(IVd)
步骤i:由4,5-二氟-2-碘-苯甲酸(IIIc)和环己烷-1,3-二酮(IIa)以与上述类似的方式合成8,9-二氟-3,4-二氢-2H-苯并[c]色烯-1,6-二酮。1H NMR(400MHz,CDCl3)δ8.99(dd,1H),8.04(dd,1H),2.94(t,2H),2.73–2.58(m,2H),2.24–2.12(m,2H)。
步骤ii:由8,9-二氟-3,4-二氢-2H-苯并[c]色烯-1,6-二酮和乙酸铵以与上述类似的方式合成8,9-二氟-2,3,4,5-四氢菲啶-1,6-二酮。LCMS:m/z实测值250.1[M+H]+;RT=0.90min(方法B);1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),9.14(dd,1H),8.06(dd,1H),2.88(t,2H),2.54(dd,2H),2.02(h,2H)。
8,9-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vj)
将四异丙氧基钛(0.48mL,1.58mmol)加入8,9-二氟-2,3,4,5-四氢菲啶-1,6-二酮(0.1g,0.40mmol)和2M甲胺的THF溶液(0.36mL,0.71mmol)在1,4-二噁烷(5mL)中的混合物。将混合物在氮气气氛中在室温下搅拌2小时。将另外0.1mL 2M甲胺溶液和0.2mL四异丙氧基钛加入反应物中并在室温下继续搅拌2小时,并且然后在45℃下再搅拌1小时。将反应混合物用2mL无水甲醇稀释并在冰浴中冷却。一次性加入硼氢化钠(30mg,0.79mmol),将反应混合物搅拌5分钟并除去冰浴。在另外15min之后,通过加入盐水(1.5mL)淬灭反应物,用20mL乙酸乙酯稀释,并再搅拌15min。通过过滤混合物并将滤饼用25mL乙酸乙酯洗涤。通过快速色谱法(硅胶,MeOH/DCM 0-10%)分离产物,得到84mg(产率80%)8,9-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值265.2[M+H]+,234.1[M-MeNH]+;RT=0.70min,(方法B);1H NMR(400MHz,CDCl3)δ8.02(dd,1H),7.33(dd,1H),3.65(dd,1H),3.59–3.37(bs,可交换质子),2.59–2.45(m,5H),2.21–2.11(m,1H),1.96–1.79(m,1H),1.78(tt,1H),1.49(tt,1H)。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物15/化合物38/化合物39)
由外消旋8,9-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vj)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(外消旋)。LCMS:m/z实测值436.1/438.1[M+H]+;RT=4.76min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.50(s,1H),8.07(dd,1H),7.85(dd,1H),7.52(ddd,1H),7.38–7.26(m,2H),5.56(s,1H),2.71-2.63(m,2H),2.63(s,3H),2.56(t,1H),2.01–1.89(m,1H),1.84(q,1H),1.74(m,1H)。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:CHIRALPAK IC(30×150mM)5μm;40%甲醇;总流量:90g/min分离对映异构体。
对映异构体I(化合物38)。LCMS:m/z实测值436.1/438.1[M+H]+;RT=4.51min,(方法A);手性分析SFC:RT=1.40min,柱:CHIRALPAK IC-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
对映异构体II(化合物39)。LCMS:m/z实测值436.2/438.1[M+H]+;RT=4.51min,(方法A);手性分析SFC:RT=2.16min,柱:CHIRALPAK IC-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲(化合物19)
由外消旋8,9-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vj)和1-氟-4-异氰氧基-苯以与上述类似的方式合成1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲。LCMS:m/z实测值402.2[M+H]+;RT=4.21min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.35(s,1H),8.07(dd,1H),7.60–7.49(m,2H),7.35(dd,1H),7.17–7.06(m,2H),5.58(d,1H),2.72–2.62(m,1H),2.62(s,3H),2.55(m,1H),2.01–1.88(m,1H),1.83(m,2H),1.77–1.70(m,1H)。
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲(化合物144)
将三乙胺(47uL,0.34mmol)加入外消旋8,9-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vj,23.0mg,0.09mmol)和N-[1-(三氟甲基)环丙基]氨基甲酸苯酯(VIf–与VIb类似地制备–21.3mg,0.09mmol)在1mL无水THF中的混合物中,并将反应混合物在室温下搅拌5min,然后在50℃下过夜。将反应混合物用30mL EtOAc稀释,并用0.2N HCl(10mL),然后用5%NaHCO3水溶液(15mL),然后用水和盐水洗涤,并经硫酸钠干燥。过滤有机溶液,并蒸发溶剂,并将残余物吸附到硅胶上。通过快速色谱法(硅胶,EtOAc/己烷20-95%)纯化产物并在高真空下干燥过夜,得到19.9mg(产率55%)1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲。LCMS m/z实测值416.2[M+H]+;RT=3.30min(方法A);1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.05(dd,1H),7.56–7.04(m,2H),5.50(s,1H),2.72–2.58(m,1H),2.46(d,2H),1.97–1.60(m,3H),1.35–1.18(m,2H),1.18–0.96(m,2H)。
4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVe)
步骤i:2-碘苯甲酸(IIIa,0.99g,4.0mmol)、四氢吡喃-3,5-二酮(IIc,0.55g,4.8mmol)、碘化铜(I)(76mg,0.4mmol)和磷酸钾(1.19g,5.6mmol)在氮气气氛中在管中合并。加入无水1,4-二噁烷(10mL)并将反应物管用氮气吹扫并在室温下搅拌30min,并且然后在110℃下再搅拌3小时。将反应混合物用乙酸乙酯(10mL)稀释,通过过滤并将垫用乙酸乙酯(3×10mL)洗涤。在高真空下蒸发滤液并通过快速色谱法(硅胶,乙酸乙酯/己烷0-90%)纯化残余物,得到0.41g(产率47%)4H-吡喃并[3,4-c]异色烯-1,6-二酮。LCMS m/z实测值217.1[M+H]+;RT=0.94min(方法B);1H NMR(400MHz,CDCl3)δ8.92(ddd,1H),8.30(ddd,1H),7.84(ddd,1H),7.59(ddd,1H),4.74(d,J=0.9Hz,2H),4.36–4.30(m,2H)。
步骤ii:将4H-吡喃并[3,4-c]异色烯-1,6-二酮(80mg,0.37mmol)和乙酸铵(0.17g,2.22mmol)在1,2-二氯乙烷(4mL)中在140℃下在密封管中搅拌7小时。使反应混合物冷却至室温,用二氯甲烷/甲醇稀释,并吸附到硅胶上。通过快速色谱法(硅胶,干燥装载的,MeOH/DCM 0-4%)分离产物,得到60mg(产率75%)4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮。LCMS:m/z实测值216.1[M+H]+;RT=0.87min(方法B);1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),9.02(dq,1H),8.23(ddd,1H),7.82(ddd,1H),7.56(ddd,1H),4.79(d,2H),4.27(d,2H)。
1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vk)
将四异丙氧基钛(0.56mL,1.86mmol)加入4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVe,0.10g,0.46mmol)和2M甲胺的THF溶液(0.46mL,0.93mmol)和1,4-二噁烷(5mL)的混合物。将混合物在氮气气氛中在80℃下搅拌3小时。将反应混合物用2mL无水MeOH稀释,冷却至0℃,用硼氢化钠(35.2mg,0.93mmol)处理并允许搅拌1小时。通过加入盐水(1.5mL)将反应物淬灭,用20mL乙酸乙酯稀释,并再搅拌15min。通过过滤混合物,并将滤饼用另外25mL乙酸乙酯洗涤。将合并的滤液经硫酸钠干燥,过滤,并在减压下蒸发溶剂。通过快速色谱法(硅胶,MeOH/DCM 0-10%)分离产物,得到86mg(产率80%)1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值200.1[M-(MeNH)]+;RT=0.59min,(方法B);1H NMR(400MHz,CDCl3)δ11.61(s,1H),8.46–8.39(m,1H),7.79–7.68(m,2H),7.49(ddd,1H),4.72(d,1H),4.60(dd,1H),4.42(d,1H),3.69–3.60(m,2H),2.62(s,3H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物18/化合物36/化合物37)
在0℃下将2-氯-1-氟-4-异氰氧基-苯(24.3μL,0.19mmmol)在0.5mL二氯甲烷中的溶液缓慢加入1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vk,61mg,0.26mmol)在2mL二氯甲烷中的搅拌混合物。将反应物搅拌1.5小时,使冷却浴升温至室温。加入MeOH(0.1mL)并在5min之后将粗反应混合物直接吸附到硅胶上。通过快速色谱法(4g硅胶,20%-80%乙酸乙酯/己烷梯度)分离产物,随后与乙酸盐/己烷一起研制,并在高真空下干燥,得到外消旋3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物18,49mg,46.0%)。LCMS:m/z实测值402.1/404.1[M+H]+;RT=4.17min,(方法A);1H NMR(400MHz,甲醇-d4)δ8.34(ddd,1H),7.80–7.66(m,2H),7.62(d,1H),7.53(ddd,1H),7.39(ddd,1H),7.18(t,1H),5.55(s,1H),4.67(d,1H),4.54(dd,1H),4.21(dd,1H),4.01(dd,1H),2.89(s,3H)。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:CHIRALPAK AD(30×150mM)5μm;总流量:90g/min分离对映异构体。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲:对映异构体I(化合物36)。LCMS:m/z实测值402.2/404.1[M+H]+;RT=3.80min,(方法A);手性分析SFC:RT=1.77min,柱:CHIRALPAK AD-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲:对映异构体II(化合物37)。LCMS:m/z实测值402.2/404.1[M+H]+;RT=3.79min,(方法A);手性分析SFC:RT=4.30min,柱:CHIRALPAK AD-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vel)
由4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVe)和2-甲基丙-1-胺以与上述类似的方式合成1-(异丁基氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值200.1[M-(Me2CHCH2NH)]+;RT=0.77min,(方法B);1H NMR(400MHz,CDCl3)δ11.76(s,1H),8.45–8.31(m,1H),7.81–7.62(m,2H),7.48(ddd,1H),4.72(d,1H),4.59(dd,1H),4.37(dd,1H),3.70–3.55(m,2H),2.77(dd,1H),2.50(dd,1H),1.76(dq,1H),0.95(t,6H)。
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物30)
在0℃下将2-氯-1-氟-4-异氰氧基-苯(10μL,0.07mmol)在0.5mL二氯甲烷中的溶液缓慢加入1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vel,28mg,0.10mmol)在1.5mL二氯甲烷中的搅拌溶液中。将反应物搅拌1.5小时,使冷却浴升温至室温。加入MeOH(~1.5mL)并在15min之后将溶剂在真空下蒸发至接近干燥。将产物与甲醇一起研制并通过过滤收集产物,用甲醇、然后用~1:1的甲醇/二氯甲烷、然后用己烷洗涤,并高真空干燥,得到3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(33.3mg,73.0%)。LCMS m/z实测值444.2/446.2[M+H]+;RT=4.67min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.53(s,1H),8.25–8.18(m,1H),7.82(dd,1H),7.75(ddd,1H),7.57–7.44(m,3H),7.33(t,1H),5.42(s,1H),4.57(d,1H),4.44(dd,1H),4.14–4.05(m,1H),3.93(dd,1H),3.33–3.20(m,1H),2.96(dd,1H),1.64(p,1H),0.67(d,3H),0.60(d,3H)。
8,10-二氟-2,3,4,5-四氢菲啶-1,6-二酮(IVf)
由环己烷-1,3-二酮(IIa)和2-溴-3,5-二氟-苯甲酸(IIId)以与上述类似的方式合成8,10-二氟-2,3,4,5-四氢菲啶-1,6-二酮。LCMS:m/z实测值250.1[M+H]+;RT=0.85min,(方法B);1H NMR(400MHz,CDCl3)δ7.75(dddd,1H),7.21–7.05(m,1H),2.83–2.70(m,2H),2.60(td,2H),2.17–2.05(m,2H)。
8,10-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vm)
由8,10-二氟-2,3,4,5-四氢菲啶-1,6-二酮(IVf)和甲胺以与上述类似的方式合成8,10-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值234.1[M-MeNH]+;RT=0.71min,(方法B);1H NMR(400MHz,甲醇-d4)δ7.85(dd,1H),7.36–7.25(m,1H),4.29(s,1H),2.70–2.60(m,2H),2.54(s,3H),2.28–2.17(m,1H),2.02(dddd,1H),1.83(dt,1H),1.68(tt,1H)。
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物20)
由外消旋8,10-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vm)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值438.1/440.1[M+H]+;RT=4.21min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.51(s,1H),7.88–7.76(m,2H),7.79–7.66(m,1H),7.48(ddd,1H),7.30(t,1H),5.37(s,1H),4.59(d,1H),4.52–4.42(m,1H),4.04(dd,1H),3.85(dd,1H),2.80(s,3H)。
7,8,9,10-四氢-6H-环庚三烯并[c]异喹啉-5,11-二酮(IVg)
步骤i:由环庚烷-1,3-二酮(IId)和2-碘苯甲酸(IIIa)以与上述类似的方式合成7,8,9,10-四氢环庚三烯并[c]异色烯-5,11-二酮。LCMS:m/z实测值229.1[M+H]+;RT=1.03min,(方法B);1H NMR(400MHz,CDCl3)δ8.29(ddd,1H),8.11(ddd,1H),7.79–7.68(m,1H),7.51(ddd,1H),3.00–2.88(m,2H),2.87–2.75(m,2H),2.04–1.90(m,4H)。
步骤ii:由7,8,9,10-四氢环庚三烯并[c]异色烯-5,11-二酮和乙酸铵以与上述类似的方式合成7,8,9,10-四氢-6H-环庚三烯并[c]异喹啉-5,11-二酮。LCMS:m/z实测值228.1[M+H]+;RT=0.87min,(方法B);1H NMR(400MHz,CDCl3)δ11.81(s,1H),8.43(ddd,1H),8.30(dt,1H),7.71(ddd,1H),7.50(ddd,1H),3.09–3.01(m,2H),2.82–2.74(m,2H),2.05–1.98(m,2H),1.98–1.85(m,2H)。
11-(甲氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮(Vn)
由7,8,9,10-四氢-6H-环庚三烯并[c]异喹啉-5,11-二酮(IVg)和甲胺以与上述类似的方式合成11-(甲氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮。LCMS:m/z实测值212.1[M-MeNH]+;RT=0.71min,(方法B);1H NMR(400MHz,甲醇-d4)δ8.34(ddd,1H),7.97(dd,1H),7.77(ddd,1H),7.48(ddd,1H),4.60(dd,1H),3.32–3.20(m,1H),2.70–2.59(m,1H),2.42(s,3H),2.30–2.18(m,1H),2.09–1.91(m,2H),1.95–1.73(m,2H),1.68–1.52(m,1H)。
11-(3-羟基丙氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮(Vo)
由7,8,9,10-四氢-6H-环庚三烯并[c]异喹啉-5,11-二酮(IVg)和3-氨基丙-1-醇以与上述类似的方式合成11-(3-羟基丙氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮。LCMS:m/z实测值212.1[M-(HO(CH2)3NH)]+;RT=0.71min,(方法B);1H NMR(400MHz,甲醇-d4)δ8.34(dd,1H),7.90–7.83(m,1H),7.71(ddd,1H),7.44(ddd,1H),4.52(dd,1H),3.71–3.54(m,2H),3.22(ddd,1H),2.81(dt,1H),2.70–2.51(m,2H),2.25–2.13(m,1H),2.07–1.89(m,2H),1.82–1.64(m,4H),1.68–1.51(m,1H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲(化合物21)
由外消旋11-(甲氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮(Vn)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲。LCMS:m/z实测值414.2/416.2[M+H]+;RT=4.61min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.47(s,1H),8.24–8.17(m,1H),7.87(ddd,1H),7.73–7.63(m,1H),7.59(d,1H),7.56–7.47(m,1H),7.42(ddd,1H),7.32(td,1H),5.73(t,1H),3.25–3.12(m,1H),2.71(s,3H),2.61(d,1H),2.13–1.87(m,2H),1.76(d,3H),1.28(dd,1H)。
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲(化合物22)
由外消旋11-(3-羟基丙氨基)-6,7,8,9,10,11-六氢环庚三烯并[c]异喹啉-5-酮(Vo)和2-氯-1-氟-4-异氰氧基-苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲。LCMS:m/z实测值458.2/460.2[M+H]+;RT=4.50min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.73(s,1H),8.19(dd,1H),7.81(dd,1H),7.73–7.64(m,1H),7.57(d,1H),7.48–7.37(m,2H),7.33(t,1H),5.73(t,1H),5.06(s,1H),3.33–3.15(m,2H),3.15(d,2H),2.59(d,1H),2.15–2.06(m,1H),1.92(q,1H),1.77(m,3H),1.21(m,4H)。
8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)
步骤i:将5-氟-2-碘-苯甲酸(IIIb,2.51g,9.44mmol)、四氢吡喃-3,5-二酮(IIc,3.23g,28.31mmol)、碘化铜(I)(0.18g,0.94mmol)、L-脯氨酸(0.22g,1.89mmol)和碳酸氢钾(8.69g,37.74mmol)在管中合并抽真空并充满氮气。加入干燥DMSO(30mL)并将反应混合物用氮气吹扫,密封,并在室温下搅拌10min,并且然后在90℃下搅拌2.5小时。使反应混合物冷却,用8mL水稀释,用2M HCl酸化至pH<2,并用乙酸乙酯(3×100mL)萃取。将合并的有机萃取物用水洗涤3次并用盐水洗涤1次,经硫酸钠干燥,并过滤。将溶剂在高真空下蒸发,得到粗产物,将其在高真空下进一步干燥过夜(当发生完全固化时)并且无需进一步纯化即可用于下一步。
步骤ii:将上一步获得的粗5-氟-2-(3-羟基-5-氧-2H-吡喃-4-基)苯甲酸(2.38g,9.44mmol)和乙酸铵(7.27g,94.37mmol)在120℃下在1,2-二氯乙烷(100mL)中在密封管中搅拌5小时。将反应混合物用二氯甲烷/甲醇稀释并吸附到硅胶上,然后进行快速色谱法(硅胶,MeOH/DCM 0-10%)。将所需产物与EtOAc/己烷一起进一步研制,得到8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(1.15g,52.3%)。LCMS m/z实测值234.1[M+H]+;RT=0.77min,(方法B);1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.06(dd,1H),7.86(dd,1H),7.70(ddd,1H),4.76(s,2H),4.25(s,2H)。
8-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vp)
由8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)和甲胺以与上述类似的方式合成8-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值249.2[M+H]+;RT=0.49min,(方法B);1H NMR(400MHz,CDCl3)δ8.00–7.92(m,1H),7.68(dd,1H),7.42(dddd,1H),4.60(d,1H),4.53–4.44(m,1H),4.36(dd,1H),3.60(dd,1H),3.55(dt,1H),2.55(d,3H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物23/化合物40/化合物41)
在0℃下将2-氯-1-氟-4-异氰氧基-苯(23μL,0.17mmol)在0.5mL二氯甲烷中的溶液逐滴加入外消旋8-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vp,54mg,0.22mmol)在2mL二氯甲烷中的搅拌混合物。将反应物搅拌1.5小时,同时使其升温至室温。加入甲醇(1.5mL)并在15min之后通过过滤收集产物,用甲醇,随后用1:1的甲醇/二氯甲烷,并且然后用己烷洗涤,并在50℃下在高真空下干燥,得到外消旋3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物23,75.0mg,82%)。LCMS:m/z实测值420.2/422.1[M+H]+;RT=4.28min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.57(s,1H),7.92–7.84(m,2H),7.69(td,1H),7.61–7.48(m,2H),7.32(t,1H),5.44(s,1H),4.58(d,1H),4.47–4.38(m,1H),4.05(d,1H),3.93(dd,1H),2.80(s,3H)。
随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:CHIRALPAK AD(30×150mM)5μm;总流量:90g/min分离对映异构体。
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体I(化合物40)。LCMS:m/z实测值420.1/422.1[M+H]+;RT=4.03min,(方法A);手性分析SFC:RT=1.37min,柱:CHIRALPAK AD-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II(化合物41)。LCMS:m/z实测值420.1/422.1[M+H]+;RT=4.02,(方法A);1H NMR(400MHz,CDCl3)δ11.25(s,1H),8.08(dd,1H),7.69(td,2H),7.46(td,1H),7.24(d,1H),7.10(t,1H),6.42(s,1H),5.71(d,1H),4.78(d,1H),4.62(d,1H),4.30(d,1H),3.99(dd,1H),2.93(s,3H);手性分析SFC:RT=7.15min,柱:CHIRALPAK AD-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
化合物41也如下面所述并根据通用方案3独立地制备。
方案3
(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xa)
将四异丙氧基钛(1.95mL,6.43mmol)加入8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh,500mg,2.14mmol)和(1R)-1-(4-甲氧基苯基)乙胺(400uL,2.65mmol)在1,4-二噁烷(5mL)中合并的混合物。将混合物在80℃下在氮气气氛中搅拌3小时。将反应混合物用5mL二噁烷稀释,然后冷却至-12℃并用硼氢化钠(162mg,4.29mmol)在10mL无水MeOH中的溶液处理。将反应混合物搅拌1小时,使冷却浴升温至0℃。当LCMS指示初始材料完全转化时,在0℃下继续搅拌30min。在0℃下通过加入3mL盐水和15mL EtOAc淬灭反应物。将混合物倒入10mL盐水和40mL EtOAc的搅拌混合物中并保持在室温下。在15min之后通过过滤混合物,并用另外40mL EtOAc洗涤滤饼。将合并的滤液经硫酸钠干燥,过滤,并在减压下蒸发溶剂,得到粗材料,为非对映异构体的混合物(d.r.~5:1,通过LCMS DAD积分)。通过快速色谱法(硅胶,MeOH/DCM 0-2%15min梯度,然后等度,然后3%以洗脱次要异构体)分离主要非对映异构体,得到(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xa,522.0mg,6产率6%;d.r.=49:1,通过LCMS DAD积分)。LCMS:m/z实测值369.3[M+H]+;RT=0.59,(方法B);1H NMR(400MHz,CDCl3)δ11.12(s,1H),8.04(dd,1H),7.87(dd,1H),7.47(dddd,1H),7.34–7.23(m,2H),6.92–6.80(m,2H),4.63(d,1H),4.56–4.47(m,1H),4.17–4.03(m,2H),3.87(t,1H),3.78(d,3H),3.52(dd,1H),1.45(dd,3H)。
(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIa)
在室温下将非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xa,120mg,0.33mmol)、甲醛的水溶液(37%)(70uL,0.85mmol)、三乙酰氧基硼氢化钠(124mg,0.59mmol)和乙酸(34uL,0.59mmol)的混合物在1,2-二氯乙烷(1.5mL)中搅拌过夜。将反应混合物用5mL二氯甲烷稀释并用1M水性NaOH中和。将水相再用二氯甲烷萃取两次,并将合并的有机萃取物用盐水(1.5mL)洗涤,干燥(硫酸钠)并在减压下蒸发溶剂。通过快速色谱法(硅胶,EtOAc/己烷)进一步纯化产物,得到非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIa,80.6mg,65%)。LCMS:m/z实测值383.3[M+H]+;RT=2.09,(方法A);1H NMR(400MHz,CDCl3)δ11.05(s,1H),8.23(dd,1H),8.05(dd,1H),7.48(ddd,1H),7.19–7.11(m,2H),6.83–6.74(m,2H),4.67(d,1H),4.57–4.48(m,1H),4.46(d,1H),4.20(s,1H),3.92(q,1H),3.77(s,3H),3.63(dd,1H),2.16(s,3H),1.50(d,3H)。
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II(化合物41)。
步骤i:将非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIa,11mg,0.03mmol)与三氟乙酸(0.12mL,1.05mmol)在二氯甲烷(0.12mL)中在室温下搅拌过夜。当深紫色混合物几乎瞬间转变为无色透明溶液时,用0.2mL MeOH处理反应混合物。蒸发挥发物并将残余物与甲苯共沸2次并在高真空下进一步干燥,得到粗的对映异构体纯的(S)-8-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vp),其无需进一步纯化即可用于下一步。LCMS:m/z实测值249.3[M+H]+;RT=0.45,(方法B)。
步骤ii:在0℃下将二异丙基乙胺(13uL,0.07mmol)加入上述步骤中获得的残余物悬浮在0.5mL二氯甲烷中的溶液。缓慢加入2-氯-1-氟-4-异氰氧基-苯(3uL,0.03mmol)在0.5mL二氯甲烷中的溶液,并继续搅拌1小时。将反应物用0.5mL MeOH淬灭,并在5min之后将混合物直接吸附到硅胶上。通过快速色谱法(硅胶,EtOAc/己烷10-95%)分离产物并在高真空下干燥,得到(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II(化合物41,10mg,82.2%)。LCMS m/z 420.2/422.2[M+H]+;RT=4.02,(方法A);1H NMR(400MHz,CDCl3)δ12.06(s,1H),8.08(ddd,1H),7.74–7.63(m,2H),7.45(tdd,1H),7.33–7.20(m,1H),7.10(td,1H),6.46(s,1H),5.70(d,1H),4.83(d,1H),4.64(dt,1H),4.34–4.26(m,1H),3.99(dd,1H),2.93(d,3H);手性分析SFC:RT=4.83min,柱:OD-10分析;35%甲醇;总流量:3g/min;ee=98%。
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物64)
由非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIa)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯(VIa)以对于化合物41和70所描述的类似的方式合成(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z 411.3[M+H]+;RT=0.80min(方法B);1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),8.75(s,1H),8.09(dd,1H),7.93–7.84(m,2H),7.70(td,1H),7.57(dd,1H),7.46(t,1H),5.45(s,1H),4.58(d,1H),4.48–4.38(m,1H),4.06(d,1H),3.94(dd,1H),2.81(s,3H)。
(S)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物67)
由非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xa)以与上述化合物41类似的方式合成(S)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z 406.1/408.2[M+H]+;RT=3.91min(方法A);1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.57(s,1H),7.91–7.66(m,4H),7.28(t,1H),7.20(ddd,1H),6.76(d,1H),4.91(d,1H),4.55–4.40(m,2H),4.00(dd,1H),3.83(dd,1H)。
8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vq)
由8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)和2-甲基丙-1-胺以与上述类似的方式合成8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值291.2.2[M+H]+;RT=0.52min,(方法B);1H NMR(400MHz,CDCl3)δ11.52(s,1H),8.06–7.98(m,1H),7.82(dd,1H),7.44(dddd,1H),4.69(d,1H),4.57(d,1H),4.39(d,1H),3.69–3.58(m,2H),2.82–2.72(m,1H),2.47(dd,1H),1.74(hept,1H),1.10–0.91(m,6H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲(化合物43)
由外消旋8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vq)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲。LCMS:m/z实测值462.3/464.3[M+H]+;RT=4.83,(方法A);1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.53(s,1H),7.92–7.78(m,2H),7.71(td,1H),7.62(dd,1H),7.49(ddd,1H),7.33(t,1H),5.44(s,1H),4.57(d,1H),4.43(d,1H),4.09(d,1H),3.93(dd,1H),3.33–3.20(m,1H),3.00(dd,1H),1.61(dt,1H),0.67(d,3H),0.58(d,3H)。
3-(3,4-二氟苯基)-1-(8-氟-6-氧-2,4,5,6-四氢-1H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲(化合物99和100)
由8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vq)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-(8-氟-6-氧-2,4,5,6-四氢-1H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–20:80.柱:(R,R)Whelk-01(30×250mm),5μm,流速:100g/min分离对映异构体。
对映异构体I(化合物99):LCMS:m/z实测值446.3[M+H]+,RT=4.48min,(方法A);1HNMR(400MHz,DMSO-d6)δ11.57(br s,1H),8.53(br s,1H),7.89-7.85(m,1H),7.73-7.64(m,2H),7.62-7.58(m,1H),7.36-7.26(m,2H),5.44-5.43(m,1H),4.56(d,1H),4.43(d,1H),4.8(d,1H),3.95-3.90(m,1H),3.31-3.22(m,1H),3.03-2.97(m,1H),1.66-1.58(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=6.35min;柱((R,R)Whelk-01(4.6×250mm)3.5μ,15%甲醇,流速:3.0g/min。
对映异构体II(化合物100):LCMS:m/z实测值446.3[M+H]+,RT=4.48,(方法A);1HNMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.53(br s,1H),7.89-7.85(m,1H),7.73-7.64(m,2H),7.62-7.58(m,1H),7.36-7.26(m,2H),5.44-5.43(m,1H),4.56(d,1H),4.43(d,1H),4.8(d,1H),3.95-3.90(m,1H),3.31-3.22(m,1H),3.03-2.97(m,1H),1.66-1.58(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=7.24min;柱((R,R)Whelk-01(4.6×250mm)3.5μ,15%甲醇,流速:3.0g/min。
1-(8-氟-6-氧-2,4,5,6-四氢-1H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲(化合物113和114)
由8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vq)和1,2,3-三氟-5-异氰氧基苯以与上述类似的方式合成1-(8-氟-6-氧-2,4,5,6-四氢-1H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–15:85.柱:Chiralpak IC(30×250mm),5μm,流速:90g/min分离对映异构体。
对映异构体I(化合物113):LCMS:m/z实测值464.3[M+H]+,RT=4.88min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.57(br s,1H),8.66(br s,1H),7.88-7.85(m,1H),7.71-7.66(m,1H),7.59-7.48(m,3H),5.42-5.41(m,1H),4.56(d,1H),4.43(d,1H),4.09(d,1H),3.94-3.90(m,1H),3.31-3.22(m,1H),3.02-2.96(m,1H),1.65-1.58(m,1H),0.66(d,3H),0.58(d,3H);手性分析SFC:RT=3.01min,柱CHIRALPAK IC-3(4.6×150mm)3μm,25%甲醇,流速:3.0g/min。
对映异构体II(化合物114):LCMS:m/z实测值464.3[M+H]+,RT=4.88min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.57(br s,1H),8.68(br s,1H),7.88-7.85(m,1H),7.71-7.66(m,1H),7.59-7.48(m,3H),5.42-5.41(m,1H),4.56(d,1H),4.43(d,1H),4.09(d,1H),3.94-3.90(m,1H),3.31-3.22(m,1H),3.02-2.96(m,1H),1.65-1.58(m,1H),0.66(d,3H),0.58(d,3H);手性分析SFC:RT=3.91min,柱CHIRALPAK IC-3(4.6×150mm)3μm,25%甲醇,流速:3.0g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲(化合物115和116)
在室温下向100mg(0.34mmol)8-氟-1-(异丁基氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vq)在5mL DMF中的搅拌溶液加入0.13mL(1.03mmol)DIPEA,随后加入105.9mg(0.43mmol)(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)。将反应混合物加热至80℃并搅拌4小时。将混合物用水(20mL)稀释并在室温下再搅拌30min。通过过滤收集由反应形成的固体并在真空下干燥。在室温下将获得的粗产物与Et2O(10mL)和MTBE(10mL)一起研制,将固体过滤并在真空下干燥,得到130mg(0.28mmol,84%)3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–45:55.柱:Chiralpak IG(30×250)mm,5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物115):LCMS:m/z实测值453.3[M+H]+,RT=4.20min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.57(br s,1H),8.69(br s,1H),8.05-8.02(m,1H),7.89-7.83(m,2H),7.72-7.66(m,1H),7.62-7.58(m,1H),7.46(t,1H),5.44(s,1H),4.57(d,1H),4.43(d,1H),4.10(d,1H),3.95-3.91(m,1H),3.30-3.23(m,1H),3.03-2.97(m,1H),1.64-1.58(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=4.42min;柱CHIRALPAK IC-3(4.6×150mm)3um,20%甲醇,流速:3.0g/min。
对映异构体II(化合物116):LCMS:m/z实测值453.3[M+H]+,RT=4.20min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.69(br s,1H),8.05-8.02(m,1H),7.89-7.83(m,2H),7.72-7.66(m,1H),7.62-7.58(m,1H),7.46(t,1H),5.44(s,1H),4.57(d,1H),4.43(d,1H),4.10(d,1H),3.95-3.91(m,1H),3.30-3.23(m,1H),3.03-2.97(m,1H),1.64-1.58(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=5.85min;柱CHIRALPAK IC-3(4.6×150mM)3um,20%甲醇,流速:3.0g/min。
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲(化合物131和132)
由8-氟-1-(异丁基氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vq)和1-氟-4-异氰氧基-2-甲基苯以与上述类似的方式合成3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–20:80.柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物131):LCMS:m/z实测值442.3[M+H]+,RT=4.50min,(方法A);1H NMR(400MHz,DMSO-d6δ11.52(br s,1H),8.28(br s,1H),7.89-7.86(m,1H),7.72-7.62(m,2H),7.42-7.39(m,1H),7.34-7.30(m,1H),7.03(t,1H),5.45-5.44(m,1H),4.57(d,1H),4.43(d,1H),4.07(d,1H),3.94-3.90(m,1H),3.31-3.21(m,1H),3.02-2.96(m,1H),2.21(s,3H),1.64-1.59(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=3.49min,柱:CHIRALPAK IC-3(4.6×150mm),3μm,20%甲醇,流速:3.0g/min。
对映异构体II(化合物132):LCMS:m/z实测值442.3[M+H]+,RT=4.51min,(方法A);1H NMR(400MHz,DMSO-d6δ11.52(br s,1H),8.28(br s,1H),7.89-7.86(m,1H),7.72-7.62(m,2H),7.42-7.39(m,1H),7.34-7.30(m,1H),7.03(t,1H),5.45-5.44(m,1H),4.57(d,1H),4.43(d,1H),4.07(d,1H),3.94-3.90(m,1H),3.31-3.21(m,1H),3.02-2.96(m,1H),2.21(s,3H),1.64-1.59(m,1H),0.67(d,3H),0.58(d,3H);手性分析SFC:RT=4.84min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3.0g/min。
1-(乙氨基)-8-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vr)
由8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)和乙胺以与上述类似的方式合成1-(乙氨基)-8-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值263.2[M+H]+;RT=0.44min,(方法B);1H NMR(400MHz,CDCl3)δ7.96–7.81(m,1H),7.68(dd,1H),7.41(td,1H),4.60–4.32(m,2H),4.30(d,1H),3.65(dd,1H),3.63–3.54(m,1H),3.08(br s,exch。质子),2.89(dq,1H),2.73(dq,1H),1.14(td,3H)。
3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物44)
由外消旋1-(乙氨基)-8-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vr)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS:m/z实测值434.2/436.1[M+H]+;RT=4.22min(方法A);1HNMR(400MHz,DMSO-d6)δ11.58(s,1H),8.47(s,1H),7.95–7.82(m,2H),7.75–7.63(m,1H),7.59–7.50(m,2H),7.33(td1H),5.46(s,1H),4.59(d,1H),4.48–4.39(m,1H),4.03(d,1H),3.91(dd,1H),3.48–3.34(m,1H),3.23(ddd,1H),0.84(t,3H)。
(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIb)
由非对映异构体纯的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xa)和乙醛开始以与上述XIa类似的方式合成非对映异构体纯的(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,产率为86%。LCMS m/z实测值397.4[M+H]+;RT=0.64min(方法B);1H NMR(400MHz,CDCl3)δ12.03(s,1H),8.11(dd,1H),8.02(dd,1H),7.39(ddd,1H),7.03(d,2H),6.74–6.65(m,2H),4.77(d,1H),4.64–4.49(m,2H),4.19–4.06(m,2H),3.74(s,3H),3.66(dd,1H),2.83(dq,1H),2.72(dq,1H),1.48(d,3H),0.90(t,3H)。
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物87)
由非对映异构体纯的(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIb)以与上述化合物41类似的方式合成光学纯的(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z 434.3/436.3[M+H]+;RT=6.73min(方法A);1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.47(s,1H),7.93–7.84(m,2H),7.70(td,1H),7.55(dddd,2H),7.33(td,1H),5.46(s,1H),4.59(d,1H),4.44(dd,1H),4.03(d1H),3.91(dd,1H),3.41(dd,1H),3.33–3.15(m,1H),0.84(t,3H);手性分析SFC:RT=7.74min,柱:AD-分析;35%甲醇;总流量:3g/min;ee=98.5%。
8-氟-1-((3-羟丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vpa)
由8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)和3-氨基丙-1-醇以与上述类似的方式合成8-氟-1-((3-羟丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值293.1[M+H]+;RT=1.70min,(方法A);1H NMR(300MHz,DMSO-d6)δ7.91-7.79(m,2H),7.65-7.58(m,1H),4.46-4.31(m,2H),4.21(d,1H),3.67(s,1H),3.58-3.53(m,1H),3.48-3.40(m,3H),2.87-2.78(m,1H),2.73-2.67(m,1H),1.63-1.48(m,4H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲(化合物109和110)
由8-氟-1-((3-羟丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vpa)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲,不同之处在于使用DMF作为溶剂。随后通过制备型SFC:等度方法,流动相甲醇:CO2–25:75.柱:Chiralpak IG(30×250mM),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物109):LCMS:m/z实测值464.3/466.3[M+H]+,RT=3.94min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(br s,1H),8.82(br s,1H),7.89-7.86(m,1H),7.84-7.81(m,1H),7.72-7.66(m,1H),7.56-7.53(m,1H),7.46-7.42(m,1H),7.33(t,1H),5.47-5.46(m,1H),5.02(br s,1H),4.58(d,1H),4.44(d,1H),4.04(d,1H),3.93-3.89(m,1H),3.50-3.42(m,1H),3.25-3.17(m,3H),1.41-1.31(m,2H);手性分析SFC:RT=2.04min,柱CHIRALPAK IG-3(4.6×150mM)3μm,25%甲醇,流速:3.0g/min。
对映异构体II(化合物110):LCMS:m/z实测值464.2/466.2[M+H]+,RT=3.93min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(br s,1H),8.82(br s,1H),7.89-7.86(m,1H),7.84-7.81(m,1H),7.72-7.66(m,1H),7.56-7.53(m,1H),7.46-7.42(m,1H),7.33(t,1H),5.47-5.46(m,1H),5.02(br s,1H),4.58(d,1H),4.44(d,1H),4.04(d,1H),3.93-3.89(m,1H),3.50-3.42(m,1H),3.25-3.17(m,3H),1.41-1.31(m,2H);手性分析SFC:RT=3.0min,柱CHIRALPAK IG-3(4.6×150mM)3μm,25%甲醇,流速:3.0g/min。
8-氟-1-((2-羟基-2-甲基丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vpb)
由8-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVh)和1-氨基-2-甲基丙-2-醇以与上述类似的方式合成8-氟-1-((2-羟基-2-甲基丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值307.22[M+H]+;RT=1.42min,(方法A);1H NMR(300MHz,DMSO-d6)δ7.91-7.79(m,2H),7.65-7.58(m,1H),4.46-4.31(m,2H),4.21(d,1H),3.67(s,1H),3.58-3.53(m,1H),3.48-3.40(m,3H),2.87-2.78(m,1H),2.73-2.67(m,1H),1.63-1.48(m,4H)。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲(化合物111和112)
由8-氟-1-((2-羟基-2-甲基丙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vpb)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲。通过制备型HPLC纯化产物(柱:SYMMETRY C18(300×19)mm 7u;流动相A:10mM碳酸氢铵(Aq);流动相B:乙腈;方法T/%B=0.1/40,11/70,11.1/100,13/100,13.1/40,15/40流速:19mL/min。随后通过制备型SFC:等度方法,流动相甲醇:CO2–15:85.柱:CHIRALPAK-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物111):LCMS:m/z实测值478.3/480.2[M+H]+,RT=4.36min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(br s,1H),10.70(br s,1H),7.88-7.84(m,1H),7.80-7.77(m,1H),7.71-7.61(m,2H),7.34(t,1H),7.28-7.23(m,1H),6.16(br s,1H),5.65-5.64(m,1H),4.58(d,1H),4.42(d,1H),4.10(d,1H),3.95-3.91(m,1H),3.44(d,1H),3.34-3.31(m,1H),1.12(s,3H),0.57(s,3H);手性分析SFC:RT=2.66min,柱CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3.0g/min。
对映异构体II(化合物112):LCMS:m/z实测值478.3/480.2[M+H]+,RT=4.36min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(br s,1H),10.70(br s,1H),7.88-7.84(m,1H),7.80-7.77(m,1H),7.71-7.61(m,2H),7.34(t,1H),7.28-7.23(m,1H),6.16(br s,1H),5.65-5.64(m,1H),4.58(d,1H),4.42(d,1H),4.10(d,1H),3.95-3.91(m,1H),3.44(d,1H),3.34-3.31(m,1H),1.12(s,3H),0.57(s,3H);手性分析SFC:RT=3.94min,柱CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3.0g/min。
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物57)
由8-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮三氟乙酸盐盐(Vp)和1-氟-4-异氰氧基-2-甲基-苯以与上述化合物41类似的方式合成3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值400.3[M+H]+;RT=3.69min(方法A);1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.34(s,1H),7.88(dd,1H),7.74–7.64(m,1H),7.59(dd,1H),7.51–7.43(m,1H),7.36(ddd,1H),7.03(t,1H),6.77(s,3H),5.45(s,1H),4.58(d,1H),4.47–4.38(m,1H),4.03(d,1H),3.92(dd,1H),2.81–2.76(m,3H),2.21(d,3H)。
3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物97和98)
在0℃下向8-氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vp,0.18g,0.72mmol)在5mL THF中的搅拌溶液加入0.22g(2.17mmol)三乙胺,随后加入0.22g(0.72mmol)(3,5-二氯-4-氟苯基)氨基甲酸苯酯(VIc,与VIb类似地制备)并在室温下继续搅拌16小时。将混合物倒入冰冷的水(50mL)中并通过过滤收集沉淀的固体,用水(10mL)和正戊烷(10mL)洗涤并在真空下干燥,得到105mg(0.23mmol,32%)3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralcel OD-H(30×250mm),5μ,流速:70g/min分离对映异构体。
对映异构体I(化合物97):LCMS:m/z实测值454.2/456.2[M+H]+,RT=4.70min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.69(br s,1H)7.89-7.83(m,3H),7.72-7.65(m,1H),7.55-7.51(m,1H),5.43-5.42(m,1H),4.57(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.79(s,3H);手性分析SFC:RT=1.31min,柱CHIRALCEL OD-3(4.6×150mm)3μm;40%甲醇,流速:3.0g/min。
对映异构体II(化合物98):LCMS:m/z实测值454.3/456.2[M+H]+,RT=4.70min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.69(br s,1H)7.89-7.83(m,3H),7.72-7.65(m,1H),7.55-7.51(m,1H),5.43-5.42(m,1H),4.57(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.79(s,3H);UPLC:99.66%,RT=3.43min;手性分析SFC:RT=2.03min柱:Chiralcel OD-H(30×250mm),5μ,流速:70g/min。
3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物107和108)
由8-氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vp)和(3-氯-4,5-二氟苯基)氨基甲酸苯酯(VId)以与上述类似的方式合成3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相2-丙醇:CO2–40:60.柱:Chiralpak IA 30×250mm,5μ,流速:60g/min分离对映异构体。
对映异构体I(化合物107):LCMS:m/z实测值438.2/440.2[M+H]+,RT=4.40min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.70(s,1H),7.90-7.87(m,1H),7.75-7.66(m,3H),7.56-7.52(m,1H),5.43-5.42(m,1H),4.58(d,1H),4.43(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.80(s,3H);手性分析SFC:RT=3.84min,柱:Chiralpak IA(250×4.6mm),5μ,25%2-丙醇,流速:3.0ml/min。
对映异构体II(化合物108):LCMS:m/z实测值438.2/440.2[M+H]+,RT=4.40min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.70(s,1H),7.90-7.87(m,1H),7.75-7.66(m,3H),7.56-7.52(m,1H),5.43-5.42(m,1H),4.58(d,1H),4.43(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.80(s,3H);手性分析SFC:RT=8.02min,柱:Chiralpak IA(250×4.6mm),5μ,25%2-丙醇,流速:3.0ml/min。
3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物123和124)
由8-氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vp)和(3-氯-4,5-二氟苯基)氨基甲酸苯酯(VIe)以与上述类似的方式合成3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相2-丙醇:CO2–50:50.柱:Chiralpak IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物123):LCMS:m/z实测值436.3[M+H]+,RT=3.77min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.59(br s,1H),8.62(br s,1H),7.92-7.87(m,2H),7.77-7.65(m,2H),7.59-7.56(m,1H),7.34-7.06(m,2H),5.45-5.44(m,1H),4.58(d,1H),4.43(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.81(s,3H);手性分析SFC:RT=0.98min,柱CHIRALPAK IG-3(4.6×150mm)3μm,40%甲醇,流速:3.0g/min。
对映异构体II(化合物124):LCMS:m/z实测值436.2[M+H]+,RT=3.77min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.59(br s,1H),8.62(br s,1H),7.92-7.87(m,2H),7.77-7.65(m,2H),7.59-7.56(m,1H),7.34-7.06(m,2H),5.45-5.44(m,1H),4.58(d,1H),4.43(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.81(s,3H);手性分析SFC:RT=7.09min,柱CHIRALPAKIG-3(4.6×150mm)3μm,40%甲醇,流速:3.0g/min。
8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)
步骤i:将4,5-二氟-2-碘-苯甲酸(IIIc,7.50g,26.4mmol)、四氢吡喃-3,5-二酮(IIc,7.53g,66.0mmol)、碘化铜(I)(0.50g,2.64mmol)、L-脯氨酸(0.61g,5.28mmol)和碳酸氢钾(21.3g,92.43mmol)在250mL圆底烧瓶中合并,然后将其抽真空并用氮气回填。加入无水DMSO(90mL)并将反应混合物用氮气吹扫,并在氮气气氛中在室温下搅拌10min,然后在90℃(预热浴温度)下搅拌4小时。LCMS分析指示初始材料酸几乎完全转化为产物(剩余<4%,DAD积分)。将反应混合物冷却至室温,用水缓慢稀释直到均匀,并且然后在0℃下用2M HCl水溶液酸化至pH<2,并用乙酸乙酯(3×400mL)萃取。将合并的有机萃取物用5%盐水洗涤3次并用饱和盐水洗涤1次,经硫酸钠干燥,并在真空下将溶剂蒸发至残余物,通过与甲苯(50mL)共沸蒸发将其进一步干燥,并且然后在高真空下过夜,得到粗8,9-二氟-4H-吡喃并[3,4-c]异色烯-1,6-二酮,其无需进一步纯化即可用于下一步。1H NMR(400MHz,DMSO-d6)δ8.72(ddd,1H),8.25(ddd,1H),4.82(s,2H),4.35(d,2H)。
步骤ii:将上述步骤中获得的粗8,9-二氟-4H-吡喃并[3,4-c]异色烯-1,6-二酮和乙酸铵(10.2g,132.1mmol)在120℃下在1,2-二氯乙烷(150mL)中在密封管中搅拌5小时。在真空下蒸发挥发物,并将残余物悬浮在水中并搅拌15min,然后通过过滤收集产物,用水,随后用甲醇,并且然后用二乙醚洗涤,并在高真空下干燥过夜,得到8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(4.53g,68%)。252.2[M+H]+;RT=0.74min(方法B);1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.90(dd,1H),8.08(dd,1H),4.77(s,2H),4.27(s,2H)。
8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)和甲胺以与上述Vp类似的方式合成8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮,产率为87%。LCMS m/z实测值267.1[M+H]+;RT=0.45min(方法B);1H NMR(400MHz,CDCl3)δ11.40(s,1H),8.16(dd,1H),7.54(dd,1H),4.66(d,1H),4.56(d,1H),4.43(d,1H),3.63(dd,1H),3.49(d,1H),2.61(s,3H)。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物24/化合物71/化合物72)
在0℃下将2-氯-1-氟-4-异氰氧基-苯(32.8μL,0.25mmol)在0.5mL二氯甲烷中的溶液缓慢加入8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs,83.4mg,0.31mmol)在5mL二氯甲烷中的搅拌混合物。将反应物搅拌1.5小时,同时使其升温至室温。加入MeOH(1.5mL)并在15min之后将溶剂在真空下蒸发至接近干燥。将产物与甲醇一起研制并通过过滤收集,用甲醇,随后用1:1的甲醇/二氯甲烷,并且然后用己烷洗涤,并在高真空下干燥,得到外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(118.0mg,86.0%)。LCMS:m/z实测值438.1/440.2[M+H]+;RT=4.24min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.60(s,1H),8.11(dd,1H),7.84(dd,1H),7.56–7.43(m,2H),7.34(t,1H),5.41(s,1H),4.59(d,1H),4.47–4.37(m,1H),4.10–4.02(m,1H),3.93(dd,1H),2.82(s,3H)。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:CHIRALPAK AD(30×150mM)5μm;总流量:90g/min分离对映异构体。
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体I(化合物71)。LCMS m/z实测值438.2/440.2[M+H]+;RT=4.26min(方法A);手性分析SFC:RT=4.06min,柱:CHIRALPAK IC-3(4.6×150mM)3μm;40%甲醇;总流量:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II(化合物72)。LCMS m/z实测值438.2/440.2[M+H]+;RT=4.26min(方法A);手性分析SFC:RT=6.55min,柱:CHIRALPAK IC-3(4.6×150mM)3μm;20%甲醇;总流量:3g/min。
化合物72也如下面所述并根据通用方案3独立地制备。
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xb)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)开始以与上述Xa类似的方式合成非对映异构体纯的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,产率为69%。LCMS m/z实测值387.27[M+H]+;RT=0.60min(方法B);1H NMR(400MHz,CDCl3)δ11.29(s,1H),8.14(dd,1H),7.67(dd,1H),7.31–7.27(m,2H),6.90–6.79(m,2H),4.61(d,1H),4.55–4.46(m,1H),4.23–4.15(m,1H),4.08(q,1H),3.84–3.76(m,1H),3.78(s,3H),3.54(dd,1H),1.47(d,3H)。
基于化合物72的X射线晶体学分析,新生成的手性α-中心的立体化学显示为(S)(参见本文中其他地方)。
(S)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物68)
由光学纯的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xb)以与上述化合物41类似的方式合成对映异构体纯的(S)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z 424.2[M+H]+;RT=4.20min(方法A);1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.62(s,1H),8.09(dd,1H),7.78(dd,1H),7.68(dd,1H),7.29(t,1H),7.22(ddd,1H),6.80(d,1H),4.88(d,1H),4.55–4.40(m,2H),4.00(dd,1H),3.84(dd,1H)。
(S)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物135)
由光学纯的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xb)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯(VIa)以对于化合物41和70所描述的类似的方式合成对映异构体纯的(S)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z 415.3[M+H]+;RT=3.67min(方法A);1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.76(s,1H),8.09(dd,1H),7.94(dd,1H),7.73–7.62(m,2H),7.43(t,1H),6.91(d,1H),4.88(d,1H),4.55–4.41(m,2H),4.01(d,1H),3.84(dd,1H)。
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIc)
由(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xb)开始以与上述XIa类似的方式合成非对映异构体纯的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,产率为82%。LCMS m/z实测值401.3[M+H]+;RT=2.24min(方法A);1H NMR(400MHz,CDCl3)δ12.01(s,1H),8.14(dd,1H),8.03(dd,1H),7.22–7.10(m,2H),6.85–6.74(m,2H),4.70(d,1H),4.53(dd,1H),4.45(d,1H),4.19–4.06(m,1H),3.90(q,1H),3.78(s,3H),3.63(dd,1H),2.14(s,3H),1.51(d,3H)。
(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs);对映异构体纯的
在室温下在氮气气氛中将(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIc,1.93g,4.82mmol)与三氟乙酸(20mL,175.4mmol)在二氯甲烷(20.0mL)中搅拌过夜。当深紫色不透明的混合物转变为黄色透明溶液时,然后将反应混合物用40mL MeOH处理并将混合物搅拌20min。蒸发挥发物,并通过与1:1v/v甲醇/甲苯混合物共沸蒸发进一步干燥残余物,然后与甲苯共沸蒸发一次。与二乙醚一起研制15min,生成沉淀,通过过滤收集沉淀,用二乙醚洗涤,并在高真空下干燥,得到(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,为单一对映异构体,单-TFA盐(1.67g,91%)。LCMS实测值m/z 267.2[M+H]+;RT=0.47min(方法B);1HNMR(400MHz,甲醇-d4)δ8.17(dd,1H),7.83(dd,1H),4.89(s,1H),4.76–4.60(m,2H),4.58(s,1H),4.51(dd,1H),3.98(dd,1H),2.86(s,3H)。将如上所述获得的一部分TFA盐(S)-Vs在乙酸乙酯和饱和碳酸氢钠之间分配。将水相用乙酸乙酯进一步萃取,确保在最终萃取之后pH>8.5,并将合并的有机萃取物经硫酸钠干燥,过滤,在减压下蒸发溶剂并将固体残余物在高真空下进一步干燥,得到对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs),为游离碱。1H NMR(400MHz,DMSO-d6)δ11.40(br s,1H),8.03(dd,1H),7.73(dd,1H),4.41(d,1H),4.34(d,1H),4.22(dd,1H),3.59–3.51(m,1H),3.33(s,1H),2.39(s,3H),1.90(br s,1H)。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II(化合物72)
由对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)开始以与上述化合物41类似的方式合成对映异构体纯的(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲:对映异构体II,产率为75%。LCMS m/z实测值438.2/440.2[M+H]+;RT=4.26min(方法A);1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.60(s,1H),8.10(dd,1H),7.84(dt,1H),7.57–7.42(m,2H),7.34(t,1H),5.41(d,1H),4.59(d,1H),4.42(dd,1H),4.06(dd,1H),3.93(dd,1H),2.82(s,3H);手性分析SFC:RT=4.83min,柱:OD-10分析;20%甲醇;总流量:3g/min;ee=99.5%。
化合物72的X射线结构测定
化合物72的晶体通过蒸气扩散生长,使用1:3v/v的甲醇:二氯甲烷作为溶剂和1:2v/v的二乙醚:己烷作为抗溶剂。化合物72(分子式:C20H15ClF3N3O3),以四方空间群P212121(系统消光h00:h=奇数,0k0:k=奇数,和00l:l=奇数)结晶,其中 Z=4,和dcalc=1.627g/cm3。在配备HPC区域探测器(HyPix-6000HE)的Rigaku XtaLAB Synergy-S衍射仪上收集X射线强度数据,并且探测器采用在100K温度下的共焦多层光学单色Cu-Kα辐射初步索引是由一系列60个0.5°旋转帧进行,对于θ=±47.2°曝光0.25秒,并且对于θ=107.75°曝光1秒。采用ω扫描收集了总计4658帧(41次运行),其中晶体与探测器的距离为34.0mm,旋转宽度为0.5°,并且对于θ=±47.2°曝光0.05秒,和对于θ=107.75°曝光0.1秒。
旋转帧使用CrysAlisPro(CrysAlisPro 1.171.40.53:Rigaku OxfordDiffraction,Rigaku Corporation,Oxford,UK,2019)整合,产生一列非平均的F2和σ(F2)值。在6.406≤2θ≤148.832°、-9≤h≤9、-10≤k≤10、-27≤l≤34的范围内测量总共30097次反射,产生3668独特反射(Rint=0.0517)。使用SCALE3 ABSPACK(SCALE3 ABSPACKv1.0.7:an Oxford Diffraction program;Oxford Diffraction Ltd:Abingdon,UK,2005)(最小和最大透射率为0.6358,1.0000)校正Lorentz和极化效果以及吸收的强度数据。结构是通过直接方法-SHELXT(SHELXT v2014/4:Sheldrick,G.M.,Acta Cryst.,A,71,3-8(2015))求解的。精炼是通过使用SHELXL-2018(SHELXL-2018/3:Sheldrick,G.M.,ActaCryst.,A,71,3-8(2015))基于F2的全矩阵最小二乘法。在精炼过程中使用所有的反射。使用的加权方案是w=1/[σ2(Fo 2)+(0.0398P)2+0.4843P],其中P=(Fo 2+2Fc 2)/3。非氢原子各向异性地精炼,并使用骑行(riding)模型精炼氢原子。对于3642个观察到的反射,精炼收敛到R1=0.0255和wR2=0.0666,并且对于所有3668个独特的非零反射和272个变量,F>4σ(F)和R1=0.0257和wR2=0.0667和GOF=1.028。最小二乘法的最终循环中的最大Δ/σ是0.001,并且最终差分傅立叶中的两个最突出的峰是+0.18和
表1列出了化合物72的晶胞信息、数据收集参数和精炼数据。
表1.化合物72的结构测定的总结
表2中给出了化合物72的最终位置和等效各向同性热参数。
表2.化合物72的精炼位置参数
原子 | x | y | z | U(eq) |
Cl1 | 0.54718(6) | 0.99723(6) | 0.31799(2) | 0.02003(12) |
F1 | 0.19703(17) | 1.17189(13) | 0.65035(4) | 0.0237(3) |
F2 | 0.28355(18) | 1.09655(14) | 0.55966(4) | 0.0219(3) |
F3 | 0.37770(18) | 0.77377(15) | 0.25306(4) | 0.0241(3) |
O1 | 0.41654(19) | 0.71994(18) | 0.75288(5) | 0.0206(3) |
O2 | 0.6208(2) | 0.29469(16) | 0.59308(5) | 0.0177(3) |
O3 | 0.58862(19) | 0.73504(17) | 0.47876(5) | 0.0177(3) |
N1 | 0.5005(2) | 0.54255(19) | 0.69614(5) | 0.0141(3) |
N2 | 0.4538(2) | 0.54977(18) | 0.52504(5) | 0.0137(3) |
N3 | 0.3861(2) | 0.5726(2) | 0.44343(5) | 0.0152(3) |
C1 | 0.4381(2) | 0.6860(2) | 0.70974(6) | 0.0147(4) |
C2 | 0.3979(2) | 0.7924(2) | 0.66959(7) | 0.0139(4) |
C3 | 0.3156(2) | 0.9352(2) | 0.67993(7) | 0.0162(4) |
C4 | 0.2793(3) | 1.0346(2) | 0.64268(7) | 0.0169(4) |
C5 | 0.3271(3) | 0.9962(2) | 0.59535(6) | 0.0161(4) |
C6 | 0.4094(3) | 0.8599(2) | 0.58428(7) | 0.0144(4) |
C7 | 0.4438(2) | 0.7523(2) | 0.62163(6) | 0.0125(3) |
C8 | 0.5214(2) | 0.6022(2) | 0.61194(6) | 0.0126(4) |
C9 | 0.5417(2) | 0.5004(2) | 0.64896(6) | 0.0132(3) |
C10 | 0.6132(3) | 0.3387(2) | 0.64287(7) | 0.0158(4) |
C11 | 0.7055(3) | 0.4140(2) | 0.56535(7) | 0.0175(4) |
C12 | 0.5926(3) | 0.5614(2) | 0.56234(6) | 0.0133(4) |
C13 | 0.3115(3) | 0.4371(2) | 0.53117(7) | 0.0180(4) |
C14 | 0.4833(3) | 0.6258(2) | 0.48232(7) | 0.0137(4) |
C15 | 0.3941(3) | 0.6286(2) | 0.39528(6) | 0.0134(4) |
C16 | 0.4676(3) | 0.7715(2) | 0.38255(7) | 0.0145(3) |
C17 | 0.4601(3) | 0.8183(2) | 0.33442(7) | 0.0155(4) |
C18 | 0.3847(3) | 0.7238(2) | 0.29946(7) | 0.0172(4) |
C19 | 0.3166(3) | 0.5803(3) | 0.31153(7) | 0.0177(4) |
C20 | 0.3204(3) | 0.5332(2) | 0.35951(7) | 0.0158(4) |
化合物72的ORTEP表示将化合物72的绝对构型定义为(S)-(并且因此将XIc的主要非对映异构体的α-甲基取代基的绝对构型定义为如图1所示的(S)-)。
8,9-二氟-6-甲氧基-N-((R)-1-(4-甲氧基苯基)乙基)-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(XIe)和8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-5-甲基-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIf)
在室温下向1g(2.4mmol,1.0eq)非对映异构体纯的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIc)在10mL甲苯中的搅拌溶液加入1.3g(4.9mmol,2.0eq)碳酸银和0.2mL(4.9mmol,2.0eq)甲基碘。将反应混合物在60℃下搅拌16小时。在冷却之后,将反应混合物通过Celite垫过滤并用EtOAc(100mL)洗涤Celite床。将合并的滤液在减压下浓缩并通过柱色谱法(使用10%-20%的乙酸乙酯的石油醚溶液作为线性梯度)纯化粗产物混合物,得到400mg(S)-8,9-二氟-6-甲氧基-N-((R)-1-(4-甲氧基苯基)乙基)-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(XIe,0.96mmol,38%)和300mg(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-5-甲基-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIf,0.72mmol,30%),为浅黄色固体。XIe:LCMS:m/z实测值415.31[M+H]+;RT=1.76min,(方法D);1HNMR(400MHz,DMSO-d6):δ8.23(m,1H),8.05(m,1H),7.16(d,2H),6.83(d,2H),4.69(d,1H),4.55(d,1H),4.37(d,2H),4.01(s,3H),3.94(m,1H),3.70(s,3H),3.64(m,1H),1.94(s,3H),1.46(d,3H)。XIf:LCMS:m/z实测值415.31[M+H]+;RT=1.42min,(方法D);1HNMR(400MHz,DMSO-d6):δ8.12-7.99(m,2H),7.14(d,2H),6.81(d,2H),4.84(d,1H),4.51(d,1H),4.29(d,1H),4.16(s,1H),3.98(m,1H),3.75(s,3H),3.53(m,1H),3.40(s,3H),2.25(s,3H),1.46(d,3H)。
8,9-二氟-5-甲基-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vaaa)
在0℃下向300mg(0.18mmol,1.0eq)(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-5-甲基-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIf)在5mL DCM中的搅拌溶液加入0.5mL TFA。使混合物升温至室温并搅拌12小时。将混合物用饱和碳酸氢钠水溶液淬灭并用EtOAc(2×50mL)萃取。将合并的有机物用冰水洗涤,经硫酸钠干燥并蒸发,得到120mg粗(S)-8,9-二氟-5-甲基-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,将其直接用于下一步。
LCMS:m/z实测值281.2[M+H]+;RT=0.84min,(方法D)。
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物233)
在室温下在惰性气氛中向80mg(0.28mmol,1.0eq)粗(S)-8,9-二氟-5-甲基-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vaaa)在2mL DMF中的搅拌溶液加入0.12mL(0.86mmol,3.0eq)DIPEA,随后加入80mg(0.28mmol,1.0eq)(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)。将反应混合物加热至70℃,伴随搅拌1小时。在反应完成之后,将反应混合物用冰冷的水(40mL)稀释。过滤所得沉淀,用水(10mL)洗涤并在真空下干燥。通过快速色谱法(硅胶,MeOH/DCM 5–10%)纯化获得的粗固体产物,得到30mg(0.06mmol,22%)(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲,为灰白色固体。LCMS m/z实测值468.1[M+H]+;RT=4.35min,(方法A);1H(400MHz,DMSO-d6):δ8.64(s,1H),8.20(m,1H),7.88-7.87(m,1H),7.74-7.66(m,1H),7.52-7.50(m,1H),7.34-7.07(m,2H),5.47(s,1H),4.96(d,1H),4.64(d,1H),4.08(d,1H),3.90(m,1H),3.44(s,3H),2.82(s,3H)。手性分析SFC:RT=3.29min,柱:ChiralPakl AD-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物243)
由粗(S)-8,9-二氟-5-甲基-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vaaa)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。
LCMS m/z实测值452.1/454.0[M+H]+;RT=5.89min,(方法A);1H(400MHz,DMSO-d6):δ8.59(s,1H),8.20(m,1H),7.88-7.87(m,1H),7.56-7.45(m,2H),7.36(t,1H),5.46(s,1H),4.96(d,1H),4.64(d,1H),4.08(d,1H),3.90(m,1H),3.45(s,3H),2.82(s,3H)。手性分析SFC:RT=2.34min,柱:ChiralPak AD-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
8,9-二氟-6-甲氧基-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(V-Bc)
在0℃下向400mg(0.18mmol,1.0eq)(S)-8,9-二氟-6-甲氧基-N-((R)-1-(4-甲氧基苯基)乙基)-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(XIe)在5mL DCM中的搅拌溶液加入0.5mL TFA。使混合物升温至室温并搅拌12小时。用饱和碳酸氢钠水溶液淬灭反应混合物并用EtOAc(2×50mL)萃取。将合并的有机物用冰水洗涤,经硫酸钠干燥并蒸发至干燥,得到200mg粗(S)-8,9-二氟-6-甲氧基-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺,将其直接用于下一步。LCMS:m/z实测值281.23[M+H]+。
(S)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物234)
在室温下在惰性气氛中向80mg(0.28mmol,1.0eq)8,9-二氟-6-甲氧基-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(V-Bc)在2mL DMF中的搅拌溶液加入0.12mL(0.86mmol,3.0eq)DIPEA,随后加入80mg(0.28mmol,1.0eq)(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)。将反应混合物加热至70℃,伴随搅拌1小时。在冷却之后,将反应混合物用冰冷的水(40mL)稀释。过滤沉淀的固体,用水(10mL)洗涤并在真空下干燥。通过快速色谱法(硅胶,MeOH/DCM 5–10%)纯化获得的粗固体产物,得到30mg(0.06mmol,22%)(S)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲,为灰白色固体。LCMS m/z实测值468.1[M+H]+;RT=5.63min,(方法A);1H(400MHz,DMSO-d6):δ8.66(s,1H),8.17(m,1H),7.88-7.83(m,1H),7.75-7.70(m,2H),7.35-7.05(m,2H),5.69(s,1H),4.82(d,1H),4.67(d,1H),4.17(d,1H),4.06(s,3H),3.99(m,1H),2.77(s,3H)。手性分析SFC:RT=1.22min,柱:ChiralPak IC-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物244)
由粗(S)-8,9-二氟-6-甲氧基-N-甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-胺(V-Bc)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值452.1/454.0[M+H]+;RT=5.89min,(方法A);1H(400MHz,DMSO-d6):δ8.61(s,1H),8.17(m,1H),7.86(m,1H),7.72(m,1H),7.35-7.55(m,1H),7.37(m,1H),5.68(s,1H),4.82(d,1H),4.67(d,1H),4.16(d,1H),4.02(s,3H),3.99(m,1H),2.76(s,3H)。手性分析SFC:RT=2.057min,柱:ChiralPakl AD-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙酸乙酯(XIg)和2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(XIh)
在0℃下向2.0g(5.0mmol,1.0eq.)8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIc)在20mL DMF中的搅拌溶液加入180mg NaH(7.5mmol,1.5eq.)并将反应混合物搅拌15min。加入2.44g 2-碘代乙酸乙酯(10.0mmol,2.0eq.)并将反应混合物在80℃下加热3小时。在反应完成之后,将混合物冷却至室温,用冰冷的水淬灭,并用乙酸乙酯(2×200mL)萃取。将合并的有机层用冰冷的水(100mL)洗涤,经无水硫酸钠干燥,过滤,并蒸发挥发物.柱色谱法(硅胶100-200目,20%的乙酸乙酯的石油醚溶液作为线性梯度)得到410mg(产率17%)2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(XIg)和430mg(产率18%)2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(XIh),为灰白色固体。XIg:LCMS:m/z实测值487.32[M+H]+,RT=1.71min,(方法D);XIh:LCMS:m/z实测值487.32[M+H]+,RT=1.55min,(方法D)。
(2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(XIi)和(2-((8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(XIj)
以与上述类似的方式将8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XIc)转化为(2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(XIi)和(2-((8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(XIj)。XIi:LCMS:m/z实测值578.70[M+H]+,RT=1.62min,(方法D);XIj:LCMS:m/z实测值578.70[M+H]+,RT=1.77min,(方法D)。
2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙酸乙酯(V-Be)
在0℃下向350mg(0.72mmol,1.0eq.)2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(XIg)在3.5mL二氯甲烷中的搅拌溶液加入1.72mL三氟乙酸并将混合物搅拌12小时。在反应完成之后,将混合物用饱和碳酸氢钠淬灭并用乙酸乙酯(2×50mL)萃取。将合并的有机层用冰冷的水洗涤,经无水Na2SO4干燥并蒸发,以获得280mg 2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙酸乙酯。LCMS:m/z实测值352.9[M+H]+,RT=1.26min,(方法D)。
(S)-(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(V-Bf)
由(2-((8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(XIj)以与上述类似的方式合成(S)-(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯。LCMS:m/z实测值444.32[M+H]+,RT=2.02min,(方法D)。
2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(Vaab)
由2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(XIh)以与上述类似的方式合成2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(Vaab)。LCMS m/z实测值352.9[M+H]+;RT=1.01min,(方法D)。
(2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(Vaac)
由(2-(8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(XIi)以与上述类似的方式合成(2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(Vaac)。LCMS m/z实测值444.32[M+H]+;RT=1.35min,(方法D)。
(S)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物256)
步骤1.在室温下向50mg(0.14mmol,1.0eq.)2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(V-Be)和39mg(0.14mmol,1.0eq.)(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)在1mL DMF中的搅拌溶液加入0.07mL(0.42mmol,2.0eq.)DIPEA。将所得混合物在80℃下搅拌1小时。在反应完成之后,将混合物冷却并倒入冰冷的水(20mL)中并搅拌30min。通过过滤收集所得固体,用Et2O(2×10mL)洗涤并在真空下干燥,得到55mg粗(S)-2-((1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙酸乙酯,其无需进一步纯化即可用于下一步。LCMS:m/z实测值539.1[M-1]-,RT=2.21min,(方法D)。步骤2.在0℃下向50mg(0.092mmol,1.0eq.)(S)-2-((1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙酸乙酯在1mL MeOH中的搅拌溶液加入24mg K2CO3(0.18mmol,2.0eq.)并将反应混合物在室温下搅拌2小时。在反应完成之后,将混合物用10ml MeOH稀释并过滤并蒸发滤液。通过柱色谱法(硅胶(60-120目,60%的乙酸乙酯的石油醚溶液作为线性梯度)纯化产物,得到26mg(S)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(单一对映异构体),为灰白色固体。LCMS m/z实测值498.17[M+H]+;RT=1.94min,(方法D);1H(400MHz,DMSO-d6):δ8.64(s,1H),8.32(t,1H),7.89(d,1H),7.74(m,2H),7.35-7.05(m,2H),5.69(s,1H),5.01(t,1H),4.79-4.61(m,2H),4.46(t,2H),4.17-4.02(m,2H),3.84(t,2H),2.76(s,3H)。手性分析SFC:RT=2.15min,柱:Chiralcel IC-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物255)
由2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(V-Be)和(3-氯-4-氟苯基)氨基甲酸酯(VIj)以与上述类似的方式合成(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值482.10[M+H]+;RT=2.02min,(方法D);1H(400MHz,DMSO-d6):δ8.61(s,1H),8.32(t,1H),7.86(d,1H),7.73(1,2H),7.55(1,2H),7.37(t,1H),5.68(s,1H),5.01(t,1H),4.79-4.61(m,2H),4.46(t,2H),4.16-4.01(m,2H),3.84(t,2H),2.75(s,3H)。手性分析SFC:RT=4.41min,柱:Chiralcel IC-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物251)
由2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(Vaab)和(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)以与上述类似的方式合成(S)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲。LCMS m/z实测值496.35[M-H]-;RT=1.82min,(方法D);1H(400MHz,DMSO-d6):δ8.64(s,1H),8.19(t,1H),7.88(d,1H),7.74(d,1H),7.52(m,1H),7.34-7.07(m,2H),5.46(s,1H),5.14-5.02(m,2H),4.70(d,1H),4.07-3.84(m,6H),2.82(s,3H)。手性分析SFC:RT=1.36min,柱:Chiralcel OX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物254)
由2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙酸乙酯(Vaab)和(3-氯-4-氟苯基)氨基甲酸酯(VIj)以与上述类似的方式合成(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值482.41[M-H]-;RT=1.87min,(方法D);1H(400MHz,DMSO-d6):δ8.59(s,1H),8.19(t,1H),7.86(m,1H),7.54-7.32(m,3H),5.45(s,1H),5.14-5.02(m,2H),4.69(d,1H),4.06-3.84(m,6H),2.81(s,3H)。手性分析SFC:RT=1.92min,柱:Chiralcel OX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物252)
步骤1.由(S)-(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(V-Bf)和(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)以与上述类似的方式合成(S)-(2-((1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯。LCMS m/z实测值631.2[M-H]-;RT=2.10min,(方法D)。步骤2.在氢气(气囊)气氛中向150mg(0.23mmol,1.0eq.)(S)-(2-((1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(来自步骤1)在10mL EtOH中的搅拌溶液加入80mg(0.11mmol,0.6eq.)Pd/C并将混合物搅拌6小时。在反应完成之后,将混合物通过Celite垫过滤并用10%DMF/MeOH(20mL)洗涤。将合并的滤液在减压下浓缩并通过制备型HPLC纯化粗材料,得到12mg(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(单一对映异构体),为灰白色固体。LCMS m/z实测值495.42[M-H]-;RT=5.26min,(方法:流动相-A:10mM乙酸铵的水溶液,流动相-B:ACN.,柱–Ascentis R Express C18,2.7μm,50×2.1mm,流量-0.5mL/min,温度:40℃,时间(min)和%B:0-3;0.3-3;2.5-97;3.7-97;4-3;4.6-3);1H(400MHz,DMSO-d6):δ8.67(s,1H),8.35(t,1H),7.88(d,1H),7.73-7.07(m,4H),5.68(s,1H),4.79(d,1H),4.65(d,1H),4.37(bs,2H),4.16-4.02(m,2H),2.97(bs,2H),2.76(s,3H)。手性分析SFC:RT=3.68min,柱:Chiralcel IC-3(4.6×150mm)3μm,25%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-1-(5-(2-氨基乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物253)
由(2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(Vaac)和(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)以与上述类似的方式合成(S)-1-(5-(2-氨基乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲。LCMS m/z实测值497.45[M+H]+,RT=1.52min,(方法:流动相-A:10mM乙酸铵的水溶液,流动相-B:ACN,柱–Ascentis RExpress C18,2.7μm,50×2.1mm,流量-0.5mL/min,温度:40℃,时间(min)和%B:0-3;0.3-3;2.5-97;3.7-97;4-3;4.6-3);1H(400MHz,DMSO-d6):δ8.65(s,1H),8.18(t,1H),7.88(d,1H),7.73(d,1H),7.51(m,1H),7.34-7.07(m,2H),5.45(s,1H),5.12(d,1H),4.71(d,1H),4.07-3.74(m,4H),2.82(s,5H),1.23(bs,2H)。手性分析SFC:RT=2.98min,柱:ChiralcelOX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-1-(5-(2-氨基乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲(化合物257)
由(2-(8,9-二氟-1-(甲氨基)-6-氧-1,2,4,6-四氢-5H-吡喃并[3,4-c]异喹啉-5-基)乙基)氨基甲酸苄酯(Vaac)和(3-氯-4-氟苯基)氨基甲酸酯(VIj)以与上述类似的方式合成(S)-1-(5-(2-氨基乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲。LCMS m/z实测值481.11[M+H]+,RT=1.54min,(方法:流动相-A:10mM乙酸铵的水溶液,流动相-B:ACN.,柱–Ascentis R Express C18,2.7μm,50×2.1mm,流量-0.5mL/min,温度:40℃,时间(min)和%B:0-3;0.3-3;2.5-97;3.7-97;4-3;4.6-3);1H(400MHz,DMSO-d6):δ8.59(s,1H),8.18(t,1H),7.86-7.83(m,1H),7.54-7.32(m,3H),5.44(s,1H),5.11(d,1H),4.70(d,1H),4.07-3.82(m,4H),2.82(s,5H),1.23(bs,2H)。手性分析SFC:RT=3.59min,柱:Chiralcel OX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲(化合物258)
由(S)-(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氧基)乙基)氨基甲酸苄酯(V-Bf)和(3-氯-4-氟苯基)氨基甲酸酯(VIj)以与上述类似的方式合成(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲。LCMS m/z实测值481.41[M+H]+,RT=1.51min,(方法:流动相-A:10mM乙酸铵的水溶液,流动相-B:ACN.,柱–Ascentis R Express C18,2.7μm,50×2.1mm,流量-0.5mL/min,温度:40℃,时间(min)和%B:0-3;0.3-3;2.5-97;3.7-97;4-3;4.6-3);1H(400MHz,DMSO-d6):δ8.62(s,1H),8.34(t,1H),7.86(m,1H),7.72(m,1H),7.55(m,1H)7.37(t,1H),5.68(s,1H),4.79(d,1H),4.65(d,1H),4.37(bs,2H),4.16-4.02(m,2H),2.97(bs,2H),2.75(s,3H),1.98(bs,2H)。手性分析SFC:RT=4.25min,柱:ChiralcelIC-3(4.6×150mm)3μm,25%(0.5%DEA的甲醇溶液),流速:3g/min。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲:对映异构体II(化合物146)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)开始,通过与上述化合物72类似的手性合成顺序合成(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲:对映异构体II,不同之处在于使用氘标记的试剂:NaBD4,CD2O,和CD3CO2D。LCMS m/z实测值442.2/444.2[M+H]+;RT=4.25min(方法A);1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.59(s,1H),8.10(dd,1H),7.84(dd,1H),7.59–7.41(m,2H),7.34(t,1H),4.59(d,1H),4.42(d,1H),4.10–4.04(m,1H),3.93(d,1H)。
方案4
8,9-二氟-6-甲氧基-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VII-B)
将8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi,1g,4.0mmol)、碘代甲烷(3.25mL,52.2mmol)和碳酸银(2.74g,10mmol)在55℃下在氮气气氛中在氯仿(150mL)中搅拌48小时。将反应混合物冷却至室温,用二氯甲烷稀释,并通过过滤。在减压下蒸发溶剂并通过快速色谱法(硅胶,EtOAc/己烷0-30%)分离区域异构产物,得到8,9-二氟-6-甲氧基-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(方案4中的VII-B;497mg,产率47%)作为主要区域异构体:1H NMR(400MHz,氯仿-d)δ9.16(dd,1H),8.00(dd,1H),4.94(d,2H),4.39(dd,2H),4.16(s,3H)和8,9-二氟-5-甲基-4H-吡喃并[3,4-c]异喹啉-1,6-二酮作为次要异构体:1H NMR(400MHz,氯仿-d)δ9.05(dd,1H),8.18(dd,1H),4.93(s,2H),4.45–4.22(m,2H),3.58(s,3H)。
N-(8,9-二氟-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XII)
步骤i.将四异丙氧基钛(915L,3.0mmol)加入合并在1,4-二噁烷(10mL)中的8,9-二氟-6-甲氧基-4H-吡喃并[3,4-c]异喹啉-1-酮(VII-B,200mg,0.75mmol)和2M甲胺溶液(1.13mL,2.26mmol)在THF中的混合物。将混合物在65℃下在氮气气氛中搅拌2小时。然后将反应混合物用4mL无水甲醇稀释,并允许在冰浴中冷却。一次性加入硼氢化钠(57mg,1.5mmol)。将反应混合物搅拌5分钟,并除去冰浴。在另外1小时之后,通过加入盐水(2mL)淬灭反应物,用20mL乙酸乙酯稀释,并再搅拌15min。通过过滤混合物,并将滤饼用另外25mL乙酸乙酯洗涤。将合并的有机滤液经硫酸钠干燥,再次过滤,并蒸发溶剂。粗产物无需进一步纯化即可用于下一步。1H NMR(400MHz,甲醇-d4)δ8.13–7.97(m,1H),7.79(dd,1H),4.76(d,1H),4.65(d,1H),4.42(dd,1H),4.07(s,3H),3.85(dt,1H),3.70(dd,1H),2.55(s,3H)。
步骤ii.在0℃下将如上所述获得的8,9-二氟-6-甲氧基-N-甲基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-胺(210mg,0.75mmol)在5mL二氯甲烷中的溶液用三乙胺(0.21mL,1.5mmol)处理,随后用叔丁氧基羰基碳酸叔丁酯(180mg,0.82mmol)在二氯甲烷(5mL)中的溶液。在添加完成之后,将反应物继续过夜,使其升温至室温。将反应混合物用30mL二氯甲烷稀释,用0.5%HCl(20mL),然后用5%碳酸氢钠(20mL)、水(20mL)和盐水(20mL)洗涤。将有机萃取物经硫酸钠干燥,过滤,浓缩并通过快速色谱法(硅胶,EtOAc/己烷0-15%)纯化产物,得到外消旋N-(8,9-二氟-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(方案4中的XII,在两个步骤中226mg,产率78%)。LCMS m/z 381.3[M+H]+,RT=1.18min(方法B);1H NMR(400MHz,氯仿-d)δ7.96(ddd,1H),7.56(ddd,1H),5.49(p,1H),5.25(s)*,4.81(d,1H),4.65(dd,1H),4.30–4.18(m,1H),4.07(s,3H),3.96(ddd,1H),2.64(d,3H),1.61(s)*,1.53(s,6H)。“*”表示次要氨基甲酸酯旋转异构体的信号。
N-(8,9-二氟-4-羟基-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XIIIa)
在80℃下将N-(8,9-二氟-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XII,100mg,0.26mmol)在5mL四氯化碳中的溶液用1-溴吡咯烷-2,5-二酮(47mg,0.26mmol)和苯甲酰基苯碳过氧酸酯(3mg,0.01mmol)处理1小时。将反应混合物过滤,并蒸发溶剂。将残余物重新溶解在THF/水1:1v/v的混合物(12mL)中并用1mL 1MNaOH溶液处理并在75℃下搅拌1小时。将反应混合物冷却至室温并用2M HCl,随后用饱和碳酸氢钠处理至pH~6,并用EtOAc萃取。将有机萃取物经硫酸钠干燥,过滤并蒸发溶剂。通过快速色谱法(硅胶,EtOAc/己烷0-55%)分离产物,得到N-(8,9-二氟-4-羟基-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯作为端基异构体(方案4中的XIIIa,66mg,产率63%)的混合物。LCMS m/z 397.3[M+H]+,RT=1.02min(次要端基异构体:RT=1.01min)(方法B)。1H NMR(400MHz,氯仿-d)δ8.14–7.90(m,1H),7.78–7.65(m,1H),5.99(s,1H),5.49(d,1H),4.61(td,1H),4.15(s,3H),4.06(d,1H),2.67–2.51(m,3H),1.53(s,9H)。注意:报告了主要端基异构体的信号。
N-(8,9-二氟-6-甲氧基-4-氧-1,2-二氢吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XIIIb)
将N-(8,9-二氟-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XII,95mg,0.25mmol)在5mL二氯甲烷中的溶液用氯铬酸吡啶嗡盐(323mg,1.5mmol)处理,并将反应物在55℃下搅拌48小时。将反应混合物直接吸附到硅胶上并通过快速色谱法纯化产物,以提供N-(8,9-二氟-6-甲氧基-4-氧-1,2-二氢吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(方案4中的XIIIb,38mg,产率39%)。LCMS m/z 395.2[M+H]+,RT=1.01min(方法B)。1H NMR(400MHz,氯仿-d)δ8.12(dd,1H),7.98(dd,1H),5.98(d,1H),4.82(dd,1H),4.72(dd,1H),4.26(s,3H),2.69(s,3H),1.55(s,9H)。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物151)
步骤i.在室温下将N-(8,9-二氟-4-羟基-6-甲氧基-2,4-二氢-1H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XIIIa,26mg,0.07mmol)用4M氯化氢(2mL,8.00mmol)的二噁烷溶液处理1小时。逐滴加入水(0.4mL,22.2mmol)并继续反应16小时。蒸发挥发物,并将残余物与甲苯共沸,然后在高真空下干燥1小时,然后无需进一步纯化即可用于下一步。LCMS m/z 283.1[M+H]+,RT=0.45min(次要端基异构体:RT=0.50min)(方法B)。
步骤ii.将二异丙基乙胺(29L,0.16mmol)加入如上所述获得的8,9-二氟-4-羟基-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮盐酸盐(18.5mg,0.07mmol)和2-氯-1-氟-4-异氰氧基-苯(8L,0.06mmol)在1mL二氯甲烷中的溶液的预冷的(冰浴)混合物中,并将反应混合物搅拌1小时,使浴升温至室温。将反应混合物用10mL EtOAc稀释并用0.2M HCl(5mL)和5%碳酸钠(5mL),然后用水和用盐水洗涤,并经硫酸钠干燥。过滤有机溶液,并蒸发溶剂。将产物与乙酸乙酯一起研制,过滤并在高真空下干燥过夜,得到3-(3-氯-4-氟苯基)-1-(8,9-二氟-4-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,为非对映异构体的混合物(13.4mg,3产率6%)。LCMS m/z实测值454.1/456.1[M+H]+;RT=4.00min(方法A);1H NMR(400MHz,乙腈-d3)δ9.75(s,1H),8.19–8.07(m,1H),7.76(dd,1H),7.66–7.50(m,1H),7.43(dddd,1H),7.29(d,1H),7.19(t,1H),5.75–5.70(m,1H),5.56–5.45(m,2H),5.14(s,1H),4.40(ddd,1H),4.20–4.03(m,1H),4.03–3.84(m,1H),3.84–3.67(m,1H),2.87(s,1H),2.81(s,2H)。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物152)
由外消旋N-(8,9-二氟-6-甲氧基-4-氧-1,2-二氢吡喃并[3,4-c]异喹啉-1-基)-N-甲基-氨基甲酸叔丁酯(XIIIb)开始,以与上述化合物151类似的方式通过两步程序合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值452.1/454.1[M+H]+;RT=0.90min(方法B);1H NMR(400MHz,乙腈-d3;D2O/CD3OD)δ8.23(dd,1H),7.92(dd,1H),7.70(dd,1H),7.39(ddd,1H),7.18(t,1H),6.04(d,1H),4.86(dd,1H),4.70(dd,1H),2.80(s,3H)。
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲(化合物69)
由对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和1-氟-4-异氰氧基-2-甲基-苯开始,以与上述化合物41类似的方式合成对映异构体纯的(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲。LCMS m/z实测值418[M+H]+;RT=3.24min(方法C);1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),8.11(dd,1H),7.50(dd,1H),7.44(dd,1H),7.39–7.30(m,1H),7.05(t,1H),5.42(s,1H),4.58(d,1H),4.47–4.37(m,1H),4.04(d,1H),3.93(dd,1H),2.80(s,3H),2.21(d,3H)。
(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物147)
由对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和2-氯-4-异氰氧基-1-甲氧基苯开始,以与上述化合物41类似的方式合成对映异构体纯的(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值450.2/452.2[M+H]+;RT=3.81min(方法A);1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.40(s,1H),8.10(dd,1H),7.69(dd,1H),7.60–7.33(m,2H),7.09(d,1H),5.42(s,1H),4.58(d,1H),4.51–4.31(m,1H),4.09–4.02(m,1H),3.93(dd,1H),3.82(s,3H),2.80(s,3H)。
(S)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物148)
将三溴硼烷(25μL,0.27mmol)加入在冰浴中预冷的对映异构体纯的(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物147,48mg,0.11mmol)在2.0mL二氯甲烷中的混合物,并将反应混合物搅拌1小时,然后通过缓慢加入1mL甲醇,随后5%的碳酸氢钠溶液淬灭。将反应混合物用30mL EtOAc萃取并用0.2m HCl(10mL)和5%的碳酸氢钠溶液(15mL),然后用水和用盐水(各10mL)洗涤并经硫酸钠干燥。过滤有机溶液,并蒸发溶剂。将产物与乙酸乙酯一起研制,过滤并在高真空下干燥过夜,得到(S)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(28mg,6产率0%)。LCMS m/z实测值436.2/438.1[M+H]+;RT=2.97min(方法A);1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.76(s,1H),8.29(s,1H),8.10(dd,1H),7.59–7.45(m,2H),7.26(dd,1H),6.92–6.78(m,1H),5.41(s,1H),4.58(d,1H),4.46–4.37(m,1H),4.12–3.99(m,1H),3.92(dd,1H),2.78(s,3H)。
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物70)
将三乙胺(26uL,0.19mmol)加入对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)(29mg,0.08mmol)在1mL无水THF中的溶液。加入N-(3-氰基-4-氟-苯基)氨基甲酸苯酯(VIa,19mg,0.08mmol),并将反应混合物在室温下搅拌5min,然后在50℃下搅拌2小时。将反应混合物用30mL EtOAc稀释并用0.2MHCl(10mL),然后用5%的NaHCO3水溶液(15mL),并且然后用盐水洗涤,并经硫酸钠干燥。过滤有机溶液并将溶剂蒸发至白色固体,将其与甲醇一起研制并通过过滤收集产物,用甲醇,然后用1:1的甲醇/二氯甲烷,然后用己烷洗涤,并在50℃下在高真空下干燥过夜,得到对映异构体纯的(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(25.0mg,77.7%)。LCMS m/z实测值429.2[M+H]+;RT=3.68min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.77(s,1H),8.10(dd,1H),8.04(dd,1H),7.89(ddd,1H),7.52–7.40(m,2H),5.41(d,1H),4.59(d,1H),4.47–4.38(m,1H),4.12–4.05(m,1H),3.93(dd,1H),2.83(s,3H)。手性分析SFC:RT=4.83min,柱:OD-10分析;30%甲醇;总流量:3g/min。
(S)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物141)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和N-(4-氯-3-氟-苯基)氨基甲酸苯酯(VIg)开始,以与上述类似的方式合成对映异构体纯的(S)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值438.1[M+H]+;RT=4.41min(方法A);1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.72(s,1H),8.11(dd,1H),7.74(dd,1H),7.52–7.37(m,3H),5.41(s,1H),4.59(d,1H),4.47–4.38(m,1H),4.11–4.03(m,1H),3.93(dd,1H),2.83(s,3H)。
(S)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物142)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和N-(4-氯-3-氰基-苯基)氨基甲酸苯酯(VIh)开始,以与上述类似的方式合成对映异构体纯的(S)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值445.2/447.2[M+H]+;RT=4.08min(方法A);1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.86(s,1H),8.18–8.06(m,2H),7.90(dt,1H),7.66(d,1H),7.45(dd,1H),5.41(s,1H),4.59(d,1H),4.48–4.38(m,1H),4.12–4.04(m,1H),3.94(dd,1H),2.84(s,3H)。
(S)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物143)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和1,2-二氯-4-异氰氧基-苯(VIi)开始,以与上述类似的方式合成对映异构体纯的(S)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值454.1/456.2[M+H]+;RT=4.71min(方法A);1HNMR(400MHz,DMSO-d6)δ11.67(s,1H),8.69(s,1H),8.11(dd,1H),7.94(d,1H),7.61–7.49(m,2H),7.46(dd,1H),5.41(s,1H),4.59(d,1H),4.47–4.38(m,1H),4.11–4.01(m,1H),3.93(dd,1H),2.82(s,3H)。
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲(化合物145)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮单-TFA盐(Vs)和N-[1-(三氟甲基)环丙基]氨基甲酸苯酯(VIf)开始,以与上述类似的方式合成对映异构体纯的(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲。LCMS m/z实测值418.35[M+H]+;RT=3.10min(方法A);1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),7.95(dd,1H),7.34(dd,1H),7.25–7.20(m,1H),5.23(s,1H),4.41(d,1H),4.30–4.21(m,1H),3.86–3.71(m,2H),2.50(s,3H),1.19–1.06(m,2H),1.02(d,1H),0.92(s,1H)。
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物218)
在0℃下向30mg(0.113mmol,1eq)(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(S)-Vs在1mL THF中的搅拌溶液加入0.04ml DIPEA(0.28mmol,2.5eq)和20mg(0.068mmol,0.6eq)三光气并将反应混合物在相同温度下搅拌30min。加入异二氢吲哚(13.4mg,0.113mmol,1eq)并继续反应4小时。将反应混合物倒入水(20mL)中并用乙酸乙酯(2×10mL)萃取。将合并的有机层用水(10mL)洗涤,经无水硫酸钠干燥并在减压下浓缩。通过柱色谱法(硅胶,等度60%的乙酸乙酯的石油醚溶液)纯化产物,得到10mg(产率22%)(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺,为灰白色固体。LCMS m/z实测值412.3[M+H]+;RT=7.24min(方法A);1HNMR(400MHz,DMSO-d6)δ11.64(s,1H),8.13-8.08(m,1H),7.77-7.72(q,1H),7.34-7.27(m,4H)5.14(s,1H),4.82(d,2H),4.71(d,2H),4.58(d,1H),4.42(d,1H),4.23(d,1H),3.96-3.92(m,1H),2.79(s,3H)。
(S)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物219)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs)和5-氯异二氢吲哚开始,以与上述类似的方式合成对映异构体纯的(S)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺。LCMS m/z实测值446.3/448.3[M+H]+;RT=7.54min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.1(t,1H),7.76-7.71(q,1H),7.43(s,1H),7.37-7.32(m,2H),5.13(s,1H),4.83-4.66(m,4H),4.57(d,1H),4.42(d,1H),4.22(d,1H),3.95-3.91(m,1H),2.77(s,3H)。
(S)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物220)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs)和5-溴异二氢吲哚开始,以与上述类似的方式合成对映异构体纯的(S)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺。LCMS m/z实测值490.2[M+H]+;RT=7.57min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.1(t,1H),7.77-7.72(q,1H),7.56(s,1H),7.46(d,1H),7.30(d,1H),5.13(s,1H),4.83-4.55(m,5H),4.42(d,1H),4.22(d,1H),3.95-3.91(m,1H),2.77(s,3H)。
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺(化合物221)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs)和5-氟异二氢吲哚开始,以与上述类似的方式合成对映异构体纯的(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺。LCMS m/z实测值430.2[M+H]+;RT=6.39min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.1(t,1H),7.76-7.71(q,1H),7.36(t,1H),7.18(d,1H),7.08(t,1H),5.13(s,1H),4.83-4.66(m,4H),4.57(d,1H),4.42(d,1H),4.22(d,1H),3.95-3.91(m,1H),2.77(s,3H)。
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺(化合物230)
由对映异构体(S)-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vs)和5-(三氟甲基)异二氢吲哚盐酸盐开始,以与上述类似的方式合成对映异构体纯的(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺,不同之处在于采用二甲基甲酰胺作为溶剂。LCMS m/z实测值480.2[M+H]+;RT=4.72min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.13(t,1H),7.78-7.73(m,2H),7.66(d,1H),7.57(d,1H),5.14(s,1H),4.90-4.76(q,4H),4.60(d,1H),4.44(d,1H),4.25(d,1H),3.95(d,1H),2.79(s,3H)。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物106)
由外消旋8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)开始,以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值429.3[M+H]+;RT=3.68min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.77(s,1H),8.11(dd,1H),8.04(dd,1H),7.89(ddd,1H),7.52–7.41(m,2H),5.41(d,1H),4.59(d,1H),4.43(dd,1H),4.12–3.97(m,1H),3.93(dd,1H),2.83(s,3H)。
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物125和126)
由8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和3-(二氟甲基)-4-氟苯基氨基甲酸酯(VIe)开始,以与上述类似的方式合成1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak IG(30×250mm),5μ,流速:90g/min分离对映异构体。
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲:对映异构体I(化合物125):LCMS:m/z实测值454.3[M+H]+,RT=4.00min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.64(s,1H),8.11-8.06(m,1H),7.89-7.86(m,1H),7.75-7.71(m,1H),7.46-7.41(m,1H),7.32-7.27(m,1H),7.21(t,1H),5.41(s,1H),4.57(d,1H),4.41(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.82(s,3H);手性分析SFC:RT=0.96min,柱CHIRALPAK IG-3(4.6×150mm)3um,35%甲醇,流速:3.0g/min。
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲:对映异构体II(化合物126):LCMS:m/z实测值454.3[M+H]+,RT=4.00min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.64(s,1H),8.11-8.06(m,1H),7.89-7.86(m,1H),7.75-7.71(m,1H),7.46-7.41(m,1H),7.32-7.27(m,1H),7.21(t,1H),5.41(s,1H),4.57(d,1H),4.41(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.82(s,3H);手性分析SFC:RT=7.24min,柱CHIRALPAK IG-3(4.6×150mm)3um,35%甲醇,流速:3.0g/min。由对映异构体纯的(S)-8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮((S)-Vs)和3-(二氟甲基)-4-氟苯基氨基甲酸酯(VIe)开始,对映异构体II(化合物126)也以与上述类似的方式独立地制备,在由乙酸乙酯重结晶之后产率为62%。
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲(化合物101和102)
由外消旋8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和异氰氧基苯以与上述化合物24类似的方式合成1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物101):LCMS:m/z实测值386.2[M+H]+,RT=3.46min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.61(br s,1H),8.38(br s,1H),8.12-8.07(m,1H),7.55-7.49(m,3H),7.29-7.25(m,2H),7.00-6.96(m,1H),5.43(s,1H),4.58(d,1H),4.41(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.82(s,3H);手性分析SFC:RT=3.55min,柱:CHIRALPAK IC-3(4.6×150mm)3um,25%甲醇,流速:3g/min。
对映异构体II(化合物102):LCMS:m/z实测值386.2[M+H]+,RT=3.44min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.61(br s,1H),8.38(br s,1H),8.12-8.07(m,1H),7.55-7.49(m,3H),7.29-7.25(m,2H),7.00-6.96(m,1H),5.43(s,1H),4.58(d,1H),4.41(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.82(s,3H);手性分析SFC:RT=5.79min,柱:CHIRALPAKIC-3(4.6×150mm)3um,25%甲醇,流速:3g/min。
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲(化合物103和104)
由8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和1-氟-4-异氰氧基苯以与上述类似的方式合成1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物103):LCMS:m/z实测值404.2[M+H]+,RT=3.59min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.61(br s,1H),8.43(br s,1H),8.13-8.08(m,1H),7.56-7.48(m,3H),7.14-7.09(m,2H),5.43(s,1H),4.58(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.81(s,3H);手性分析SFC:RT=3.60min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
对映异构体II(化合物104):LCMS:m/z实测值404.2[M+H]+,RT=3.60min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.61(br s,1H),8.43(br s,1H),8.13-8.08(m,1H),7.56-7.48(m,3H),7.14-7.09(m,2H),5.43(s,1H),4.58(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.81(s,3H);手性分析SFC:RT=5.55min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲(化合物117和118)
由8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–20:80.柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物117):LCMS:m/z实测值422.2[M+H]+,RT=3.95min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.61(br s,1H),8.60(br s,1H),8.13-8.08(m,1H),7.74-7.68(m,1H),7.50-7.44(m,1H),7.36-7.31(m,2H),5.41(s,1H),4.58(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.82(s,3H);手性分析SFC:RT=3.03min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
对映异构体II(化合物118):LCMS:m/z实测值422.3[M+H]+,RT=4.95min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.61(br s,1H),8.60(br s,1H),8.13-8.08(m,1H),7.74-7.68(m,1H),7.50-7.45(m,1H),7.36-7.31(m,2H),5.41(s,1H),4.58(d,1H),4.42(d,1H),4.05(d,1H),3.95-3.91(m,1H),2.82(s,3H);HPLC:98.95%,RT=10.65min;手性分析SFC:RT=4.49min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物119和120)
由8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和1-氯-3-异氰氧基苯以与上述类似的方式合成3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–35:65,柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物119):LCMS:m/z实测值420.2/422.2[M+H]+,RT=4.16min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.65(br s,1H),8.57(br s,1H),8.13-8.08(m,1H),7.75-7.74(m,1H),7.51-7.45(m,2H),7.32-7.28(m,1H),7.04-7.02(m,1H),5.42(s,1H),4.58(d,1H),4.42(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.82(s,3H);Chiral SFC:RT=2.25min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,30%甲醇,流速:3g/min。
对映异构体II(化合物120):LCMS:m/z实测值420.2/422.2[M+H]+,RT=4.16min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.65(br s,1H),8.57(br s,1H),8.13-8.08(m,1H),7.75-7.74(m,1H),7.51-7.45(m,2H),7.32-7.28(m,1H),7.04-7.02(m,1H),5.42(s,1H),4.58(d,1H),4.42(d,1H),4.06(d,1H),3.95-3.91(m,1H),2.82(s,3H);Chiral SFC:RT=3.44min,柱:CHIRALPAK IC-3(4.6×150mm)3μm,30%甲醇,流速:3g/min。
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲(化合物133和134)
由8,9-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vs)和1,2,3-三氟-5-异氰氧基苯以与上述类似的方式合成1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–15:85,柱:(R,R)WHELK-01(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物133):LCMS:m/z实测值440.2[M+H]+,RT=4.37min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.74(br s,1H),8.13-8.07(m,1H),7.57-7.52(m,2H),7.44-7.39(m,1H),5.40(s,1H),4.58(d,1H),4.42(d,1H),4.06(d,1H),3.94-3.90(m,1H),2.82(s,3H);手性分析SFC:RT=3.88min,柱:(R,R)WHELK-01(4.6×150mm)3.5μm,20%甲醇,流速:3g/min。
对映异构体II(化合物134):LCMS:m/z实测值440.3[M+H]+,RT=4.37min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.74(br s,1H),8.13-8.07(m,1H),7.57-7.52(m,2H),7.44-7.39(m,1H),5.40(s,1H),4.58(d,1H),4.42(d,1H),4.06(d,1H),3.94-3.90(m,1H),2.82(s,3H);手性分析SFC:RT=4.56min,柱:(R,R)WHELK-01(4.6×150mm)3.5μm,20%甲醇,流速:3g/min。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲(化合物45)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)以与上述化合物44类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲。LCMS:m/z实测值452.1/454.2[M+H]+;RT=4.46min,(方法A);1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.50(s,1H),8.11(dd,1H),7.84(dd,1H),7.53(ddd,1H),7.44(dd,1H),7.34(t,1H),5.42(d,1H),4.60(d,1H),4.44(d,1H),4.04(d,1H),3.92(dd,1H),3.43(dq 1H),3.28(dd,1H),0.85(t,3H)。
(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8,9-二氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XId)
由(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Xb)和乙醛开始以与上述XIa类似的方式合成(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8,9-二氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮,产率为79%。LCMS m/z实测值415.4[M+H]+;RT=0.67min(方法B);1H NMR(400MHz,CDCl3)δ12.10(s,1H),8.11(dd,1H),7.88(dd,1H),7.08(d,2H),6.79–6.70(m,2H),4.74(d,1H),4.61–4.48(m,2H),4.17–4.05(m,2H),3.75(s,3H),3.66(dd,1H),2.84(dq,1H),2.72(dq,1H),1.48(d,3H),0.90(t,3H)。
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲(化合物88)。
由(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8,9-二氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XId),以与上述化合物41类似的方式合成光学纯的(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲。LCMS m/z452.2/454.3[M+H]+;RT=4.49min(方法A);1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.50(s,1H),8.11(dd,1H),7.84(ddd,1H),7.53(dddd,1H),7.44(dd,1H),7.34(td,1H),5.42(s,1H),4.60(d,1H),4.44(d,1H),4.04(d,1H),3.92(dd,1H),3.50–3.36(m,1H),3.28(dd,1H),0.85(t,3H);手性分析SFC:RT=6.32min,柱:OD-10-分析;25%甲醇;总流量:3g/min;ee=99.99%。
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲(化合物138)
由(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)氨基)-8,9-二氟-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(XId)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述化合物70所描述的类似的方式合成光学纯的(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲。LCMS实测值m/z 443.15[M+H]+,RT=2.88min(方法C);1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.66(s,1H),8.11(dd,1H),8.05(dd,1H),7.91(ddd,1H),7.53–7.37(m,2H),5.42(s,1H),4.60(d,1H),4.49–4.40(m,1H),4.09–3.99(m,1H),3.92(dd,1H),3.43(dt,1H),3.34–3.23(m,1H),0.86(t,3H)。
8,9-二氟-1-(异丁基氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vx)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)和2-甲基丙-1-胺,以与上述Vs类似的方式合成外消旋8,9-二氟-1-(异丁基氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值309.19[M+H]+,RT=1.23min(方法A)。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲(化合物121和122)
在室温下向150mg(0.48mmol)8,9-二氟-1-(异丁基氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vx)在4mL DMF中的溶液加入0.26mL(1.46mmol)DIPEA,随后加入125mg(0.48mmol)(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa),并将混合物在70℃下搅拌3小时。将反应混合物冷却至室温并用冰冷的水(30mL)稀释。通过过滤收集所得沉淀,用水(10mL)、正戊烷(10mL)洗涤并在真空下干燥,得到190mg(0.40mmol,84%)3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–15:85,柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物121):LCMS:m/z实测值471.3[M+H]+,RT=4.41min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.74(br s,1H),8.13-8.08(m,1H),8.00-7.97(m,1H),7.87-7.83(m,1H),7.55-7.45(m,2H),5.39(s,1H),4.58(d,1H),4.43(d,1H),4.11(d,1H),3.95-3.91(m,1H),3.32-3.24(m,1H),3.11-3.04(m,1H),1.64-1.58(m,1H),0.68(d,3H),0.57(d,3H);手性分析SFC RT=3.12min,柱:Chiralpak IC(4.6×150mm)3μ,20%甲醇,流速:3.0g/min。
对映异构体II(化合物122):LCMS:m/z实测值471.3[M+H]+,RT=4.42min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.74(br s,1H),8.13-8.08(m,1H),8.00-7.97(m,1H),7.87-7.83(m,1H),7.55-7.45(m,2H),5.39(s,1H),4.58(d,1H),4.43(d,1H),4.11(d,1H),3.95-3.91(m,1H),3.32-3.24(m,1H),3.11-3.04(m,1H),1.64-1.58(m,1H),0.68(d,3H),0.57(d,3H);手性分析SFC RT=3。90min,柱:Chiralpak IC(4.6×150mm)3μ,20%甲醇,流速:3.0g/min。
2-((8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)氨基)乙烷-1-磺酰胺(Vsa)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)和2-氨基乙烷-1-磺酰胺以与上述类似的方式合成2-((8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)氨基)乙烷-1-磺酰胺。通过逆相色谱法(C-18-12g柱:0.1%的甲酸的水溶液的10-30%的线性梯度与MeOH+THF(1:1))纯化粗产物。LCMS:m/z实测值360.13[M+H]+,RT=1.05min,(方法A);1H NMR(300MHz,DMSO-d6):δ11.40(br s,1H),8.07-8.00(m,1H),7.85-7.78(m,1H),6.76(br s,2H),4.47-4.33(m,2H),4.20(d,1H),3.73(s,1H),3.61-3.57(m,1H),3.22-3.03(m,5H)。
2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺(化合物136和137)
在0℃下向0.2g(0.55mmol)2-((8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)氨基)乙烷-1-磺酰胺(Vsa)在5mL DMF中的溶液加入95mg(0.55mmol)2-氯-1-氟-4-异氰氧基苯并将混合物搅拌1小时。将混合物用水(20mL)稀释并通过过滤收集所得固体,用乙醇(5mL)洗涤并在真空下干燥,得到110mg(0.20mmol,37%)2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺。随后通过制备型SFC:等度方法,流动相MeOH:CO2–45:55,柱:Chiralpak IC(30×250mm),5μ,流速:60g/min分离对映异构体。
对映异构体I(化合物136):LCMS:m/z实测值531.2/533.2[M+H]+,RT=3.99min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.69(br s,1H),8.76(br s,1H),8.16-8.11(m,1H),7.78-7.75(m,1H),7.49-7.44(m,1H),7.39-7.30(m,2H),6.84(br s,2H),5.30(s,1H),4.62(d,1H),4.45(d,1H),4.12(d,1H),3.92-3.88(m,1H),3.77-3.69(m,1H),3.45-3.38(m,1H),3.32-3.26(m,1H),3.08-3.03(m,1H);手性分析SFC:RT=1.45min,柱:Chiralpak IC-3(4.6×150mm)3μ,40%甲醇,流速:3.0g/min。
对映异构体II(化合物137):LCMS:m/z实测值531.2/533.2[M+H]+,RT=3.99min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.69(br s,1H),8.76(br s,1H),8.16-8.11(m,1H),7.78-7.75(m,1H),7.49-7.44(m,1H),7.39-7.30(m,2H),6.84(br s,2H),5.30(s,1H),4.62(d,1H),4.45(d,1H),4.12(d,1H),3.92-3.88(m,1H),3.77-3.69(m,1H),3.45-3.38(m,1H),3.32-3.26(m,1H),3.08-3.03(m,1H);手性分析SFC:RT=2.90min,柱:Chiralpak IC-3(4.6×150mm)3μ,40%甲醇,流速:3.0g/min。
8,9-二氟-1-((2-(甲基磺酰基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vsb)
由8,9-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVi)和2-(甲基磺酰基)乙-1-胺以与上述类似的方式合成8,9-二氟-1-((2-(甲基磺酰基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值359.17[M+H]+,RT=1.46,(方法A);1HNMR(400MHz,CDCl3):δ10.01(br s,1H),7.29-7.23(m,1H),7.18-7.12(m,1H),2.84-2.79(m,2H),2.61-2.56(m,2H),2.34(s,3H),2.19-2.14(m,1H),2.05-1.94(m,5H)。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲(化合物139和140)
由8,9-二氟-1-((2-(甲基磺酰基)乙基)氨基)-1,5-二氢-2H-吡喃并[3,4-c]异喹啉-6(4H)-酮(Vsb)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–35:65,柱:Chiralcel OD-H(30×250mm),5μ,流速:60g/min分离对映异构体。
对映异构体I(化合物139):LCMS:m/z实测值530.2/532.2[M+H]+,RT=4.19min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.68(br s,1H),8.78(br s,1H),8.14-8.09(m,1H),7.79-7.77(m,1H),7.49-7.45(m,1H),7.39-7.31(m,2H),5.34(s,1H),4.58(d,1H),4.46(d,1H),4.13(d,1H),3.93-3.89(m,1H),3.83-3.76(m,1H),3.47-3.36(m,2H),3.17-3.11(m,1H),2.88(s,3H);手性分析SFC:RT=2.87min,柱:Chiralcel OD-3(4.6×150mm),3μ,25%甲醇,流速:3.0g/min。
对映异构体II(化合物140):LCMS:m/z实测值530.2/532.2[M+H]+,RT=4.19min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.68(br s,1H),8.78(br s,1H),8.14-8.09(m,1H),7.79-7.77(m,1H),7.49-7.45(m,1H),7.39-7.31(m,2H),5.34(s,1H),4.58(d,1H),4.46(d,1H),4.13(d,1H),3.93-3.89(m,1H),3.83-3.76(m,1H),3.47-3.36(m,2H),3.17-3.11(m,1H),2.88(s,3H);手性分析SFC:RT=4.52min,柱:Chiralcel OD-3(4.6×150mm),3μ,25%甲醇,流速:3.0g/min。
6-氯-8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIa)
在惰性气氛中向圆底烧瓶中装入3g(11.9mmol,1eq.)8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(VIi)在15mL甲苯中的溶液并加入3.3mL(35.8mmol,0.2eq.)POCl3。将反应混合物在110℃下搅拌4小时。在反应完成之后,将混合物用饱和碳酸氢钠溶液(50mL)碱化。过滤生成的固体,并用乙酸乙酯(3×200mL)萃取滤液。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥,过滤并在减压下浓缩,得到1.6g 6-氯-8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIa),为浅黄色固体,其无需纯化即可进行下一步。LCMS:m/z实测值270.13[M]-。
8,9-二氟-6-(甲氨基)-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIb)
向密封管中400mg(1.48mmol,1eq.)6-氯-8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIa)在4mL二甲基亚砜中的溶液加入2.2mL(4.4mmol,3eq.)甲胺的THF溶液(2M)和二异丙基乙胺(0.5mL),并将反应混合物在50℃下搅拌16小时。在反应完成之后,将混合物冷却至室温并倒入冰冷的水(20mL)中,然后用乙酸乙酯(2×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,并在减压下浓缩。将所得粗产物与二乙醚一起研制,得到320mg(产率81%)8,9-二氟-6-(甲氨基)-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIb),为棕色固体。LCMS:m/z实测值265.34[M]-。
(2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(VIIc)
向密封管中600mg(2.22mmol,1eq.)6-氯-8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIa)在4mL DMSO中的溶液加入469mg(2.6mmol,1.2eq.)(2-氨乙基)氨基甲酸苄酯和0.77mL(4.45mmol,3.0eq.)二异丙基乙胺,并将混合物在室温下搅拌16小时。在反应完成之后,将混合物倒入冰冷的水(20mL)中,然后用乙酸乙酯(2×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,并在减压下浓缩。将所得产物与二乙醚一起研制,得到650mg(产率68%)(2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(VIIc),为棕色固体。LCMS:m/z实测值265.34[M]-。
2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙酸乙酯(VIId)
向密封管中500mg(1.85mmol,1.0eq)6-氯-8,9-二氟-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIa)在5mL DMSO中的溶液加入309mg(2.22mmol,1.2eq)2-氨基乙酸乙酯盐酸盐和DIPEA(0.09mL,3.0eq)。将管加盖并在50℃下搅拌16小时。在冷却之后,将混合物倒入冰冷的水(20mL)中并用EtOAC(2×50mL)萃取。将合并的有机物用盐水(50mL)洗涤,经硫酸钠干燥,过滤,并在减压下浓缩。将所得粗产物与二乙醚一起研制,得到420mg(1.2mmol,67%)2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙酸乙酯,为棕色固体。LCMS:m/z实测值335.17[M+H]+;RT=1.83min,(方法D)。
8,9-二氟-N1,N6-二甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1,6-二胺(V-Ba)
在室温下在惰性气氛中向239mg(0.9mmol,1eq.)8,9-二氟-6-(甲氨基)-2H-吡喃并[3,4-c]异喹啉-1(4H)-酮(VIIb)在2.5mL THF中的搅拌溶液加入0.1mL(2mmol,2.2eq.)2M甲胺的THF溶液,随后加入0.72mL异丙氧基钛并将混合物在80℃下搅拌24小时。在亚胺形成之后,将反应冷却至0℃并用无水甲醇(2mL)稀释。在0℃下向该混合物分批加入85mg(2.2mmol,2.5eq.)NaBH4并将反应混合物在室温下搅拌4小时。在反应完成之后,将混合物用水(50mL)稀释,通过Celite过滤,并用乙酸乙酯(50ml)洗涤滤饼。分离有机层,并用乙酸乙酯(3×100mL)萃取水性层。将合并的有机层经无水硫酸钠干燥,过滤,并在减压下浓缩。将所得粗产物与二乙醚(10mL)一起研制,通过过滤收集所得固体,并在真空下干燥,得到200mg外消旋8,9-二氟-N1,N6-二甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1,6-二胺(V-Ba),为浅棕色固体,将其进行下一步。
LCMS:m/z实测值251.19[M+H]+。
(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(V-Bb)
由(2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(VIIc)以与上述类似的方式合成外消旋(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯。LCMS:m/z实测值443.29[M+H]+。
2-((9-氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙-1-醇(V-Bd)
在室温下在惰性气氛中向240mg(0.9mmol,1.0eq)2-((8,9-二氟-1-氧-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙酸乙酯(VIId)在3mL THF中的搅拌溶液加入1.07mL(1.96mmol,2.2eq)2M甲胺的THF溶液,随后加入1.5mL(5vol)异丙氧基钛。将容器加盖并在50℃下搅拌24小时。将反应冷却至0℃并用甲醇(2mL)稀释。在0℃下向该混合物分批加入84mg(2.2mmol,2.5eq)NaBH4并在室温下搅拌4小时。将反应混合物用水(50mL)稀释,过滤并将滤液用乙酸乙酯(50ml)洗涤。分离有机层,并用乙酸乙酯(3×100mL)萃取水性层。将合并的有机层经无水硫酸钠干燥并在减压下浓缩。将所得粗产物与二乙醚(10mL)一起研制。收集所得沉淀并在真空下干燥,得到250mg 2-((9-氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙-1-醇,为浅棕色固体,其被原样用于下一步LCMS:m/z实测值310.26[M+H]+;RT=0.86min,(方法D)。
1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物235和236)
在室温下在惰性气氛中向200mg(0.71mmol,1eq.)外消旋8,9-二氟-N1,N6-二甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1,6-二胺(V-Ba)在2mL DMF中的搅拌溶液加入0.24mL(0.86mmol,2eq.)二异丙基乙胺,随后加入241mg(0.86mmol,1eq.)(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)。将反应混合物在70℃下搅拌1小时。在反应完成之后,将混合物用冰冷的水(40mL)稀释。过滤沉淀的固体,用水(10mL)洗涤并在真空下干燥。通过MPLC(Grace系统,硅胶-40g柱;用5-10%的甲醇的二氯甲烷溶液的线性梯度洗脱)纯化产物,得到140mg(产率42%)外消旋1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲,为灰白色固体。LCMS:m/z实测值467.30[M+H]+。随后通过制备型SFC:等度方法,流动相MeOH:CO2–17:83,柱:Chiralpak IG(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物235):LCMS:m/z实测值467.1[M+H]+,RT=3.31min,(方法A);1H NMR(400MHz,DMSO-d6):δ8.61(br s,1H),8.35-8.30(m,1H),7.88-7.87(m,1H),7.74-7.66(m,2H),7.55-7.50(m,1H),7.34-7.07(m,2H),5.54(s,1H),4.68(d,1H),4.55(d,1H),4.11(d,1H),3.96(d,1H),2.95(d,3H),2.75(s,3H);手性分析SFC:RT=1.89min,柱:Chiralpak IG-3(4.6×150mm),3μ,20%甲醇,流速:3.0g/min。
对映异构体II(化合物236):LCMS:m/z实测值467.1[M+H]+,RT=3.31min,(方法A);1H NMR(400MHz,DMSO-d6):δ8.61(br s,1H),8.35-8.30(m,1H),7.88-7.87(m,1H),7.74-7.66(m,2H),7.55-7.50(m,1H),7.34-7.07(m,2H),5.54(s,1H),4.68(d,1H),4.55(d,1H),4.11(d,1H),3.96(d,1H),2.95(d,3H),2.75(s,3H);手性分析SFC:RT=2.86min,柱:Chiralpak IG-3(4.6×150mm),3μ,20%甲醇,流速:3.0g/min。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物241和242)
由8,9-二氟-N1,N6-二甲基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1,6-二胺(V-Ba)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–20:80,柱:Chiralpak IG(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物241):LCMS:m/z实测值451.1[M+H]+,RT=3.57min,(方法A);1H NMR(400MHz,DMSO-d6):δ8.56(br s,1H),8.35-8.32(m,1H),7.88-7.87(m,1H),7.68(d,1H),7.54-7.49(m,2H),7.35-7.31(t,1H),5.52(s,1H),4.68(d,1H),4.55(d,1H),4.10(d,1H),3.96(d,1H),3.17(d,3H),2.74(s,3H);手性分析SFC:RT=3.0min,柱:Chiralpak IG-3(4.6×150mm),3μ,20%甲醇,流速:3.0g/min。
对映异构体II(化合物242):LCMS:m/z实测值451.1[M+H]+,RT=3.57min,(方法A);1H NMR(400MHz,DMSO-d6):δ8.56(br s,1H),8.35-8.32(m,1H),7.88-7.87(m,1H),7.68(d,1H),7.54-7.49(m,2H),7.35-7.31(t,1H),5.52(s,1H),4.68(d,1H),4.55(d,1H),4.10(d,1H),3.96(d,1H),3.17(d,3H),2.74(s,3H);手性分析SFC:RT=5.74min,柱:ChiralpakIG-3(4.6×150mm),3μ,20%甲醇,流速:3.0g/min。
1-(6-((2-氨基乙基)氨基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物239、247和248)
步骤1.由(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(V-Bb)和(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(VIe)以与上述类似的方式合成外消旋(2-((1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯。LCMS:m/z实测值614.35。
步骤2.向200mg(0.35mmol,1eq.)如上所述获得的粗(2-((1-(5,6-二氟-N-甲基-1H-吲哚-2-甲酰胺基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯在10mL乙酸乙酯中的搅拌溶液加入80mg(0.195mmol,0.6eq.)Pd/C。反应容器配备有氢气囊并继续反应16小时。在反应完成之后,将混合物通过Celite垫过滤,将其用甲醇和四氢呋喃(30mL)进一步洗涤。将合并的滤液在减压下浓缩,得到180mg粗品,将其通过非手性SFC纯化,得到80mg(产率51%)外消旋1-(6-((2-氨乙基)氨基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物239),为灰白色固体。LCMS:m/z实测值496.1[M+H]+,RT=3.33min,(方法A)。
随后通过制备型SFC分离对映异构体。
对映异构体I(化合物247):LCMS:m/z实测值496.29[M+H]+,RT=1.55min,(方法D);1H NMR(400MHz,DMSO-d6):δ8.61(br s,1H),8.47-8.30(m,1H),7.88-7.86(m,1H),7.74-7.72(m,1H),7.61-7.49(m,2H),7.37-7.07(m,2H),5.53(s,1H),4.65(d,1H),4.49(d,1H),4.10(d,1H),3.96(d,1H),3.48-3.45(m,2H),2.82-2.79(m,2H),2.75(s,3H);手性分析SFC:RT=4.1min,柱:Lux Cellulose-2(4.6×150mm),3μ,30%(0.2%7N甲醇胺的乙腈溶液:甲醇;1:1),流速:3.0g/min。
对映异构体II(化合物248):LCMS:m/z实测值496.29[M+H]+,RT=1.55min,(方法D);1H NMR(400MHz,DMSO-d6):δ8.61(br s,1H),8.47-8.30(m,1H),7.88-7.86(m,1H),7.74-7.72(m,1H),7.61-7.49(m,2H),7.37-7.07(m,2H),5.53(s,1H),4.65(d,1H),4.49(d,1H),4.10(d,1H),3.96(d,1H),3.48-3.45(m,2H),2.82-2.79(m,2H),2.75(s,3H);手性分析SFC:RT=6.58min,柱:Lux Cellulose-2(4.6×150mm),3μ,30%(0.2%7N甲醇胺的乙腈溶液:甲醇;1:1),流速:3.0g/min。
N-(6-((2-氨基乙基)氨基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲酰胺(化合物240、249和250)
由(2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙基)氨基甲酸苄酯(V-Bb)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成外消旋N-(6-((2-氨乙基)氨基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲酰胺(化合物240)。LCMS:m/z实测值480.1[M+H]+,RT=2.35min,(方法E);随后通过制备型SFC分离对映异构体。
对映异构体I(化合物249):LCMS:m/z实测值480.29/482.26[M+H]+,RT=1.58min,(方法D);1H NMR(400MHz,DMSO-d6):δ8.57(br s,1H),8.42-8.30(m,1H),7.86-7.83(m,1H),7.54-7.30(m,3H),5.53(s,1H),4.92(bs,1H),4.61(t,1H),4.52(d,1H),4.08(d,1H),3.95(d,1H),3.57-3.54(m,2H),3.17(m,2H),2.76(bs,2H),2.73(s,3H);手性分析SFC:RT=2.14min,柱:Chiralpak IC-3(4.6×150mm),3μ,30%(0.5%DEA的甲醇溶液),流速:3.0g/min。
对映异构体II(化合物250):LCMS:m/z实测值480.29/482.26[M+H]+,RT=1.58min,(方法D);1H NMR(400MHz,DMSO-d6):δ8.57(br s,1H),8.42-8.30(m,1H),7.86-7.83(m,1H),7.54-7.30(m,3H),5.53(s,1H),4.92(bs,1H),4.61(t,1H),4.52(d,1H),4.08(d,1H),3.95(d,1H),3.57-3.54(m,2H),3.17(m,2H),2.76(bs,2H),2.73(s,3H);手性分析SFC:RT=3.22min,柱:Chiralpak IC-3(4.6×150mm),3μ,30%(0.5%DEA的甲醇溶液),流速:3.0g/min。
1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物237和238)
在室温下向200mg(0.64mmol,1.0eq)2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙-1-醇(V-Bd)在2mL DMF中的搅拌溶液加入0.24mL(0.86mmol,2.0eq)DIPEA,随后加入145mg(0.51mmol,0.8eq)(3-(二氟甲基)-4-氟苯基)氨基甲酸苯酯(1)。将混合物加热至70℃,伴随搅拌1小时。将反应混合物用冰冷的水(40mL)稀释。收集沉淀的固体,用水(10mL)洗涤并在真空下干燥。通过MPLC(Grace系统,硅胶-40g柱;用5-10%的甲醇的二氯甲烷溶液的线性梯度洗脱)纯化获得的粗固体产物,得到80mg(0.16mmol,25%)1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–20:80.柱:Chiralpak-IG-3(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物237):LCMS m/z实测值497.1[M+H]+;RT=3.31min,(方法A);1HNMR(400MHz,DMSO-d6):δ8.61(s,1H),8.45-8.40(m,1H),7.88-7.86(m,1H),7.75-7.72(m,1H),7.62-7.60(m,1H),7.54-7.49(m,1H),7.34-7.07(m,2H),5.53(s,1H),4.76(t,1H),4.65(d,1H),4.53(d,1H),4.10(d,1H),3.96(m,1H),3.64-3.31(m,4H),2.75(s,3H)。手性分析SFC:RT=2.08min,柱:ChiralPak IG-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
对映异构体II(化合物238):LCMS m/z实测值497.1[M+H]+;RT=3.29min,(方法A);1HNMR(400MHz,DMSO-d6):δ8.61(s,1H),8.45-8.40(m,1H),7.88-7.86(m,1H),7.75-7.72(m,1H),7.62-7.60(m,1H),7.54-7.49(m,1H),7.34-7.07(m,2H),5.53(s,1H),4.76(t,1H),4.65(d,1H),4.53(d,1H),4.10(d,1H),3.96(m,1H),3.64-3.31(m,4H),2.75(s,3H)。手性分析SFC:RT=3.01min,柱:ChiralPak IG-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物245和246)
由外消旋2-((8,9-二氟-1-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-6-基)氨基)乙-1-醇(V-Bd)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–25:75.柱:Chiralpak-IG-3(30×250mm),5μ,流速:110g/min分离对映异构体。
对映异构体I(化合物245):LCMS m/z实测值481.0/483.0[M+H]+;RT=3.48min,(方法A);1HNMR(400MHz,DMSO-d6):δ8.56(s,1H),8.45-8.40(m,1H),7.86-7.83(m,1H),7.63-7.60(m,1H),7.54-7.48(m,2H),7.36(t,1H),5.52(s,1H),4.76(t,1H),4.65(d,1H),4.53(d,1H),4.10(d,1H),3.96(m,1H),3.64-3.31(m,4H),2.74(s,3H)。手性分析SFC:RT=3.01min,柱:ChiralPak IG-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
对映异构体II(化合物246):LCMS m/z实测值481.0/483.1[M+H]+;RT=3.48min,(方法A);1HNMR(400MHz,DMSO-d6):δ8.56(s,1H),8.45-8.40(m,1H),7.86-7.83(m,1H),7.63-7.60(m,1H),7.54-7.48(m,2H),7.36(t,1H),5.52(s,1H),4.76(t,1H),4.65(d,1H),4.53(d,1H),4.10(d,1H),3.96(m,1H),3.64-3.31(m,4H),2.74(s,3H)。手性分析SFC:RT=5.82min,柱:ChiralPak IG-3(4.6×150mm)3μm,20%甲醇,流速:3g/min。
8,10-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVj)
由四氢吡喃-3,5-二酮(IIc)和2-溴-3,5-二氟-苯甲酸(IIId)以与上述类似的方式合成8,10-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮。LCMS:m/z实测值252.1[M+H]+;RT=0.87min,(方法B);1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),7.83–7.71(m,2H),4.71(s,2H),4.29(s,2H)。
8,10-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vt)
由8,10-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVj)以与上述类似的方式合成8,10-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS m/z实测值236.1[M-MeNH]+;RT=0.70min(方法B);1H NMR(400MHz,CDCl3)δ7.98–7.89(m,1H),7.25–7.14(m,1H),4.69(d,1H),4.59(d,1H),4.34(d,1H),3.88(s,1H),3.65(dd,1H),3.49(s,1H),2.58(s,3H)。
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物25)
由8,10-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vt)以与上述24类似的方式合成3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,产率为60%。LCMS:m/z实测值438.1/440.1[M+H]+;RT=4.21min(方法A);1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.51(s,1H),7.88–7.76(m,2H),7.79–7.66(m,1H),7.48(ddd,1H),7.30(t,1H),5.37(s,1H),4.59(d,1H),4.52–4.42(m,1H),4.04(dd,1H),3.85(dd,1H),2.80(s,3H)。
3-甲基-2,3,4,5-四氢菲啶-1,6-二酮(IVk)
由5-甲基环己烷-1,3-二酮(IIe)和2-碘苯甲酸(IIIa)以与上述IVa类似的方式合成外消旋3-甲基-2,3,4,5-四氢菲啶-1,6-二酮。LCMS:m/z实测值228.1[M+H]+;RT=0.92min(方法B);。1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.19(dt,1H),8.19(ddd,1H),7.75(ddd,1H),7.49(ddd,1H),2.87(ddd,1H),2.70–2.60(m,1H),2.64–2.45(m,1H),2.39–2.23(m,2H),1.05(d,3H)。
3-甲基-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vu,外消旋顺式/反式异构体的混合物)
由外消旋3-甲基-2,3,4,5-四氢菲啶-1,6-二酮(IVk)以与上述类似的方式合成3-甲基-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(外消旋顺式/反式异构体的混合物)。1HNMR(400MHz,CDCl3)δ11.59(s,1H),8.63–8.29(m,1H),7.84(dd,1H),7.76–7.56(m,1H),7.44(ddd,1H),4.09(t,1H),3.86(dd,1H)*,2.85–2.73(m,1H)*,2.67(ddd,1H),2.59(s,1H),2.51–2.35(m,5H),2.35–2.09(m,1H),1.89(tdd,1H),1.40(ddd,1H),1.35–1.23(m,1H)*,1.15(d,3H)[“*”表示次要外消旋非对映异构体的可区分信号]。
3-(3-氯-4-氟苯基)-1-甲基-1-(3-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲(化合物26,外消旋顺式/反式异构体的混合物)
由3-甲基-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vu)以与上述24类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(3-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲,产率为81%,为85%外消旋反式和15%外消旋顺式异构体的混合物。LCMS:m/z实测值414.2/416.2[M+H]+;RT=4.56min(主要异构体);m/z实测值414.2/416.2[M+H]+;RT=4.59min(次要异构体)(方法A);1H NMR(400MHz,DMSO-d6)δ11.33(s,1H)*,11.28(s,1H),8.19(ddt,1H),7.91(dd,1H)*,7.88(dd,1H),7.74–7.69(m,1H)*,7.69–7.62(m,1H),7.53(dtd,1H),7.49–7.40(m,2H),7.38(d,1H)*,7.32(td,1H),5.75(s,1H),5.57(s,1H)*,2.75(dd,1H)*,2.66(s,1H),2.45(s,3H),2.33(dd,1H),2.25–2.16(m,1H)*,2.12(d,1H),1.94(d,1H)*,1.82(s,1H),1.59(td,1H)*,1.33(q,1H),1.03(dd,3H),1.03(dd,3H,重叠)*[“*”表示次要异构体的可区分信号]。
3,3-二甲基-4,5-二氢-2H-菲啶-1,6-二酮(IVm)
由5,5-二甲基环己烷-1,3-二酮(IIf)和2-碘苯甲酸(IIIa)以与上述IVa类似的方式合成3,3-二甲基-4,5-二氢-2H-菲啶-1,6-二酮。LCMS:m/z实测值242.1[M+H]+;RT=0.97min(方法B);1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.20(ddd,1H),8.20(ddd,1H),7.76(ddd,1H),7.50(ddd,1H),2.79(s,2H),2.45(s,2H),1.06(s,6H)。
3,3-二甲基-1-(甲氨基)-1,2,4,5-四氢菲啶-6-酮(Vv)
由3,3-二甲基-4,5-二氢-2H-菲啶-1,6-二酮(IVm)以与上述类似的方式合成3,3-二甲基-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。1H NMR(400MHz,CDCl3)δ11.01(s,1H),8.45(dd,1H),7.82(dt,1H),7.70(ddd,1H),7.45(ddd,1H),3.95(t,1H),2.62(d,1H),2.50(s,3H),2.43(d,1H),1.99–1.89(m,1H),1.74(dd,1H),1.20(s,3H),1.01(s,3H)。
3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物27)
由3,3-二甲基-1-(甲氨基)-1,2,4,5-四氢菲啶-6-酮(Vv)以与上述24类似的方式合成3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值428.2/430.2[M+H]+;RT=4.74min(方法A);1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.44(s,1H),8.24–8.16(m,1H),7.89(dd,1H),7.67(ddd,1H),7.56–7.38(m,3H),7.32(t,1H),5.68(s,1H),2.62(d,1H),2.47(s,3H),2.22(dd,1H),1.84(d,1H),1.51(dd,1H),1.08(s,3H),0.90(s,3H)。
7,8-二氟-2,3,4,5-四氢菲啶-1,6-二酮(IVn)
由环己烷-1,3-二酮(IIa)和2-溴-3,4-二氟-苯甲酸(IIIe)以对于IVa所描述的类似的方式合成7,8-二氟-2,3,4,5-四氢菲啶-1,6-二酮。LCMS:m/z实测值250.1[M+H]+;RT=0.87min(方法B);1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.05(ddd,1H),7.59(ddd,1H),2.80(t,2H),2.53(d,2H),2.07–1.96(m,2H)。
7,8-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vw)
由7,8-二氟-2,3,4,5-四氢菲啶-1,6-二酮(IVn)以与上述类似的方式合成7,8-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮。LCMS:m/z实测值265.28[M+H]+;RT=0.71min(方法B);1H NMR(400MHz,CDCl3)δ8.22(ddd,1H),7.23(td,1H),4.17(s,1H),2.74–2.61(m,2H),2.55(s,3H),2.25–2.16(m,1H),2.07(s,1H),1.78(d,1H),1.56(t,1H)。
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲(化合物28)
由7,8-二氟-1-(甲氨基)-2,3,4,5-四氢-1H-菲啶-6-酮(Vw)以与上述24类似的方式合成3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲。LCMS:m/z实测值436.1[M+H]+;RT=4.36min(方法A);1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.39(s,1H),8.11(ddd,1H),7.86(dd,1H),7.57–7.45(m,2H),7.30(t,1H),5.57(s,1H),2.69(s,3H),2.59(dt,1H),2.02–1.94(m,1H),1.91–1.59(m,4H)。
7,8-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVo)
由四氢吡喃-3,5-二酮(IIc)和2-溴-3,4-二氟-苯甲酸(IIIe)以与上述类似的方式合成7,8-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮。LCMS:m/z实测值252.1[M+H]+;RT=0.65min(方法B);1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),8.10(ddd,1H),7.67(ddd,1H),4.72(s,2H),4.31(s,2H)。
7,8-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vy)
由7,8-二氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVo)以与上述类似的方式合成7,8-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值267.2[M+H]+;RT=0.46min(方法B);1H NMR(400MHz,CDCl3)δ8.23(ddd,1H),7.28(td,1H),4.71(d,1H),4.65–4.55(m,1H),4.35(dd,1H),3.89(s,1H),3.65(dd,1H),2.58(s,3H)。
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物35)
由外消旋7,8-二氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vy)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS:m/z实测值438.1/440.2[M+H]+;RT=3.88min(方法A);1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.13(dd,1H),7.84(dd,1H),7.56(td,1H),7.49(ddd,1H),7.30(t,1H),5.38(s,1H),4.60(d,1H),4.48(d,1H),4.06(d,1H),3.86(dd,1H),2.82(s,3H)。
N-(3-氯-5-氟-苯基)氨基甲酸苯酯(VIb)
在氮气气氛中将3-氯-5-氟-苯胺(1.0g,6.87mmol)和吡啶(2.2mL,27.48mmol)在10mL无水THF中的混合物冷却至0℃。缓慢加入氯甲酸苯酯(0.95mL,7.56mmol),除去冰浴并将混合物在室温下搅拌16小时。将反应混合物用30mL水稀释,并用EtOAc(2×35mL)萃取。将合并的有机萃取物用盐水(10mL)洗涤,经硫酸钠干燥,过滤并蒸发至干燥。通过快速色谱法(硅胶,EtOAc/己烷0-20%)分离产物并在高真空下干燥,得到N-(3-氯-5-氟-苯基)氨基甲酸苯酯(1.39g,76.2%),为白色固体。LCMS:m/z实测值266.2[M+H]+;RT=1.29min(方法B);1H NMR(400MHz,CDCl3)δ7.44–7.37(m,2H),7.30–7.24(m,1H),7.24–7.20(m,2H),7.20–7.15(m,2H),7.05(s,1H),6.83(ddd,1H)。
3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物29)
将三乙胺(45uL,0.33mmol)加入1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Va,30mg,0.13mmol)在1.5mL无水THF中的溶液。加入N-(3-氯-5-氟-苯基)氨基甲酸苯酯(VIb,31.2mg,0.12mmol)在0.5mL无水THF中的溶液,并将反应混合物在室温下搅拌45min,然后在50℃下搅拌2小时。将反应混合物用30mL EtOAc稀释并用0.2M HCl(10mL),溶解的NaHCO3(15mL),然后用盐水洗涤,并经硫酸钠干燥。过滤有机溶液,并将溶剂蒸发至白色固体,将其与甲醇一起研制。通过过滤收集产物,用甲醇、然后用1:1v/v的甲醇/二氯甲烷、然后用己烷洗涤,并在50℃下在高真空下干燥过夜,得到3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(28.1mg,54%)。LCMS:m/z实测值402.2/404.2[M+H]+;RT=4.33min(方法A);1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.72(s,1H),8.22(ddd,1H),7.79–7.70(m,1H),7.59(td,1H),7.58–7.44(m,3H),6.99(ddd,1H),5.43(s,1H),4.58(d,1H),4.44(dd,1H),4.13–4.02(m,1H),3.94(dd,1H),2.81(s,3H)。
8-氯-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVp)
由四氢吡喃-3,5-二酮(IIc)和5-氯-2-碘-苯甲酸(IIIf)以与上述IVi类似的方式合成8-氯-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮。LCMS:m/z实测值250.2[M+H]+;RT=0.76min(方法B);1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),9.04(dd,1H),8.15(dd,1H),7.88(ddd,1H),4.81–4.76(m,2H),4.30–4.25(m,2H)。
8-氯-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vz)
由8-氯-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVp)以与上述类似的方式合成8-氯-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值234.1[M-MeNH]+;RT=0.49min(方法B);1H NMR(400MHz,CDCl3)δ11.84(s,1H),8.31(d,1H),7.69–7.58(m,2H),4.69(d,1H),4.58(d,1H),4.42(d,1H),3.64(dd,1H),3.56(s,1H),2.60(s,3H)。
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物55)
由8-氯-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vz)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值436.1/438.2[M+H]+;RT=4.36min(方法A);1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.57(s,1H),8.15(dd,1H),7.86(ddd,2H),7.56–7.47(m,2H),7.32(td,1H),5.43(s,1H),4.58(d,1H),4.43(dd,1H),4.05(d,1H),3.93(dd,1H),2.82–2.77(s,3H)。
8-氯-1-(乙氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vaa)
由8-氯-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVp)以与上述类似的方式合成8-氯-1-(乙氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。LCMS:m/z实测值279.3[M+H]+;RT=0.52min(方法B);1H NMR(400MHz,CDCl3)δ8.20(t,1H),7.56(d,2H),4.46(d,1H),4.36(dd,1H),4.23(dd,1H),3.83(br s,可交换Hs),3.63–3.49(m,2H),2.81(dq,1H),2.67(dq,1H),1.07(t,3H)。
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲(化合物56)
由8-氯-1-(乙氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vaa)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲。LCMS m/z实测值450.2/452.1[M+H]+;RT=4.60min(方法A);1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.47(s,1H),8.15(d,1H),7.86(ddd,2H),7.59–7.47(m,2H),7.33(t,1H),5.44(d,1H),4.59(d,1H),4.44(dd,1H),4.03(d,1H),3.91(dd,1H),3.40(dq,1H),3.33–3.13(m,1H),0.84(t,3H)。
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲(化合物58)
由8-氯-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vz)以与上述类似的方式合成1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲。LCMS m/z实测值416.2/418.2[M+H]+;RT=4.07min(方法A);1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.33(s,1H),8.15(d,1H),7.83(dd,1H),7.55(d,1H),7.47(dd,1H),7.40–7.31(m,1H),7.03(t,1H),5.44(s,1H),4.58(d,1H),4.42(d,1H),4.03(d,1H),3.92(dd,1H),2.81–2.75(m,3H),2.21(d,3H)。
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲(化合物59)
由8-氯-1-(乙氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vaa)以与上述类似的方式合成1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲。LCMS m/z实测值430.2/432.3[M+H]+;RT=4.31min(方法A);1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.24(s,1H),8.15(d,1H),7.83(dd,1H),7.53(d,1H),7.46(dd,1H),7.37(dt,1H),7.03(t,1H),5.45(s,1H),4.59(d,1H),4.48–4.39(m,1H),4.01(d,1H),3.90(dd,1H),3.45–3.36(m,1H),3.32–3.16(m,1H),2.22(d,3H),0.84(t,3H)。
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲(化合物65)
由8-氯-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vz)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯(VIa)以与上述化合物29类似的方式合成1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲。LCMS m/z实测值427.2/429.2[M+H]+;RT=3.82min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.74(s,1H),8.15(d,1H),8.08(d,1H),7.91–7.80(m,2H),7.52(d,1H),7.46(t,1H),5.43(s,1H),4.58(d,1H),4.43(d,1H),4.06(d,1H),3.93(dd,1H),2.80(s,3H)。
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲(化合物66)
由8-氯-1-(乙氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vaa)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲。LCMS m/z实测值441.2/443.2[M+H]+;RT=4.03min(方法A);1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.67–8.61(m,1H),8.12(dd,2H),7.94–7.87(m,1H),7.84(d,1H),7.54–7.42(m,2H),5.45(s,1H),4.60(d,1H),4.44(d,1H),4.04(d,1H),3.92(dd,1H),3.41(dd,1H),3.32–3.19(m,1H),2.50(t,3H),0.84(t,3H)。
3,4,7,8,9,10-六氢菲啶-1,6(2H,5H)-二酮(IVq)
步骤i:在室温下在氮气气氛中向2.5g(22.3mmol)环己烷-1,3-二酮(IIa)在7.5mL吡啶中的搅拌溶液加入5.69g(33.48mmol)2-氧代环己烷-1-羧酸乙酯(IIIg),随后加入54mg(0.44mmol)4-二甲基氨基吡啶(DMAP)。然后将混合物在140℃下加热6小时。注意:反应以4X 2.5g规模平行进行。使所有反应混合物冷却至室温,合并,用水(500mL)稀释并用乙酸乙酯(2×500mL)萃取。将合并的有机萃取物用1M HCl水溶液(200mL)、盐水(200mL)洗涤,经无水硫酸钠干燥并在减压下浓缩。通过硅胶柱色谱法(洗脱用10-20%的乙酸乙酯和石油醚的线性梯度)纯化获得的粗产物。在减压下浓缩纯级分,得到3.1g(14.2mmol,总产率16%)3,4,7,8,9,10-六氢-1H-苯并[c]色烯-1,6(2H)-二酮。LCMS:m/z实测值219.08[M+H]+,RT=1.73min,(方法A);1H NMR(400MHz,CDCl3):δ2.97-2.95(m,2H),2.86-2.82(m,2H),2.55-2.45(m,4H),2.11-2.05(m,2H),1.71-1.68(m,4H)。
步骤ii:将1.1g(5.04mmol)步骤i中获得的3,4,7,8,9,10-六氢-1H-苯并[c]色烯-1,6(2H)-二酮在25mL 7M甲醇胺中的搅拌溶液在高压釜中加热至140℃,持续4小时。使反应混合物冷却至室温并在减压下浓缩。将获得的残余物与戊烷(10mL)一起研制,过滤,并在真空下干燥固体,得到0.7g(3.22mmol,63%)3,4,7,8,9,10-六氢菲啶-1,6(2H,5H)-二酮。LCMS:m/z实测值218.11[M+H]+,RT=1.41min,(方法:D);1H NMR(300MHz,DMSO-d6):11.80(br s,1H),2.92-2.88(m,2H),2.77-2.73(m,2H),2.42-2.37(m,2H),2.34-2.30(m,2H),1.96-1.87(m,2H),1.60-1.56(m,4H)。
1-(甲氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮(Vab)
在室温下在惰性气氛中向0.3g(1.38mmol)3,4,7,8,9,10-六氢菲啶-1,6(2H,5H)-二酮(IVq)在3mL THF中的溶液加入1.3mL(2.60mmol)2M甲胺的THF溶液,随后加入1.5mL异丙氧基钛。然后将混合物在80℃下加热6小时。将反应冷却至0℃,用甲醇(1.5mL)稀释并用0.14g(4.14mmol)硼氢化钠分批处理,并且然后在室温下搅拌2小时。然后将混合物用水(30mL)和乙酸乙酯(30mL)稀释。将非均相混合物过滤并用乙酸乙酯(10mL)洗涤。分离有机层并用乙酸乙酯(2×40mL)萃取水性层。将合并的有机萃取物用盐水(50mL)洗涤,经无水硫酸钠干燥并在减压下浓缩,得到250mg 1-(甲氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮,其被直接进行下一步。LCMS:m/z实测值233.19[M+H]+。
1-(乙氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮(Vac)
以与上述类似的方式合成1-(乙氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮。LCMS:m/z实测值247.15[M+H]+,RT=1.04min,(方法A);1H NMR(300MHz,DMSO-d6):10.90(brs,1H),3.46-3.44(m,1H),2.89-2.81(m,1H),2.72-2.63(m,1H),2.51-2.26(m,5H),2.00-1.92(m,1H),1.87-1.73(m,1H),1.68-1.52(m,5H),1.30-11.19(m,3H),1.01(t,3H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲(化合物46和47)
在0℃下向0.16g的1-(甲氨基)-1,2,3,4,7,8,9,10-八氢菲啶-6(5H)-酮(Vab)在4mL二氯甲烷中的搅拌溶液加入0.21g(2.06mmol)三乙胺,随后加入70mg(0.41mmol)2-氯-1-氟-4-异氰氧基苯并在室温下继续搅拌2小时。然后将反应混合物用水(50mL)稀释,通过过滤收集沉淀的固体。用戊烷(10mL)洗涤固体并在真空下干燥,得到0.20g(在两个步骤中0.48mmol,总产率54%)外消旋3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralpak IG(30x250mm)5μm,流速:90g/min分离对映异构体。
对映异构体I(化合物46):LCMS:m/z实测值404.3/406.2[M+H]+,RT=3.88min(方法A);1H NMR(400MHz,DMSO-d6)δ11.27(br s,1H),8.38(br s,1H),7.85-7.82(m,1H),7.50-7.46(m,1H),7.28(t,1H),5.18-5.17(m,1H),2.67(s,3H),2.51-2.09(m,6H),1.79-1.53(m,6H),1.53-1.48(m,2H);手性分析SFC:RT=2.16min,柱:Chiralpak IG(250×4.6mm,5μm),50%甲醇,流速:4.0ml/min。
对映异构体II(化合物47):LCMS:m/z实测值404.2/406.2[M+H]+,RT=3.88min;(方法A);1H NMR(400MHz,DMSO-d6):δ11.27(br s,1H),8.39(br s,1H),7.85-7.82(m,1H),7.50-7.46(m,1H),7.28(t,1H),5.18-5.17(m,1H),2.67(s,3H),2.51-2.09(m,6H),1.79-1.53(m,6H),1.53-1.48(m,2H);手性分析SFC:RT=7.76min,柱:Chiralpak IG(250×4.6mm)5μm,50%甲醇,流速:4.0ml/min。
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲(化合物48和49)
由1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–55:45.柱:Chiralpak IG(30x 250mm)5μm,流速:90g/min分离对映异构体。
对映异构体I(化合物48):LCMS:m/z实测值388.3[M+H]+,RT=3.55min;(方法A);1HNMR(400MHz,DMSO-d6):δ11.26(br s,1H),8.39(br s,1H),7.73-7.67(m,1H),7.33-7.27(m,2H),5.19-5.18(m,1H),2.67(s,3H),2.60-2.34(m,4H),2.28-2.07(m,2H),1.79-1.64(m,6H),1.52-1.46(m,2H);手性分析SFC:RT=3.62min;(柱:Chiralpak IG-3(4.6×150mM)3μm,0.5%异丙胺,30%异丙醇,流速:3.0g/min。
对映异构体II(化合物49):LCMS:m/z实测值388.3[M+H]+,RT=3.55min(方法A);1HNMR(400MHz,DMSO-d6):δ11.26(br s,1H),8.39(br s,1H),7.73-7.67(m,1H),7.33-7.27(m,2H),5.19-5.18(m,1H),2.67(s,3H),2.60-2.34(m,4H),2.28-2.07(m,2H),1.79-1.64(m,6H),1.52-1.46(m,2H);手性分析SFC:RT=7.45min;(柱:Chiralpak IG-3(4.6×150mM)3μm,0.5%异丙胺,30%异丙醇,流速:3.0g/min。
3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲(化合物50和51)
由1-(乙氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮(Vac)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:LuxCellulose-2(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物50):LCMS:m/z实测值402.3[M+H]+,RT=3.78min(方法A);1HNMR(400MHz,DMSO-d6):δ11.27(br s,1H),8.32(br s,1H),7.77-7.67(m,1H),7.32-7.25(m,2H),5.19-5.18(m,1H),3.23-3.06(m,2H),2.61-2.25(m,6H),1.79-1.52(m,8H),0.91(t,3H);手性分析SFC:RT=3.23min;柱Lux Cellulose-2(4.6x 250mm),5μ,40%甲醇,流速:3.0g/min。
对映异构体II(化合物51):LCMS:m/z实测值402.3[M+H]+,RT=3.78min(方法A);1HNMR(400MHz,DMSO-d6):δ11.27(br s,1H),8.32(br s,1H),7.77-7.67(m,1H),7.32-7.25(m,2H),5.19-5.18(m,1H),3.23-3.06(m,2H),2.61-2.25(m,6H),1.79-1.52(m,8H),0.91(t,3H);手性分析SFC:RT=4.76min;柱Lux Cellulose-2(4.6x 250mm),5μ,40%甲醇,流速:3.0g/min。
3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲(化合物53和54)
由1-(乙氨基)-1,3,4,5,7,8,9,10-八氢菲啶-6(2H)-酮(Vac)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–45:55.柱:Chiralpak IG(30×250)mm,5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物53):LCMS:m/z实测值418.3/420.3[M+H]+,RT=4.10min(方法A);1H NMR(400MHz,DMSO-d6):δ11.27(br s,1H),8.32(br s,1H),7.84-7.81(m,1H),7.52-7.48(m,1H),7.29(t,1H),5.19-5.17(m,1H),3.28-3.04(m,2H),2.61-2.24(m,6H),1.78-1.51(m,8H),0.91(t,3H);手性分析SFC:RT=1.94min;柱CHIRALPAK IG-3(4.6×150mM)3μm,45%甲醇,流速:3.0g/min。
对映异构体II(化合物54):LCMS:m/z实测值418.3/420.3[M+H]+,RT=4.09min(方法A);1H NMR(400MHz,DMSO-d6):δ11.27(br s,1H),8.32(br s,1H),7.84-7.81(m,1H),7.52-7.48(m,1H),7.29(t,1H),5.19-5.17(m,1H),3.28-3.04(m,2H),2.61-2.24(m,6H),1.78-1.51(m,8H),0.91(t,3H);手性分析SFC:RT=4.02min;柱CHIRALPAK IG-3(4.6×150mm)3μm,45%甲醇,流速:3.0g/min。
4-溴-5,6-二氢-2H-吡喃-3-羧酸(IIIh)
在0℃下向2.9g(15.18mmol)4-溴-5,6-二氢-2H-吡喃-3-甲醛在29mL 1:1(v/v)的乙腈:水中的搅拌溶液加入0.55g(4.60mmol)磷酸二氢钠(NaH2PO4)和5.8mL 30%H2O2水溶液,随后加入1.94g(21.48mmol)亚氯酸钠(NaClO2)。将反应在室温下搅拌4小时。在减压下蒸发溶剂并将剩余的溶液用1M HCl水溶液酸化(至pH~4-5)并用10%甲醇的二氯甲烷溶液(3×100mL)萃取。将合并的有机萃取物经无水硫酸钠干燥并在减压下浓缩,得到2.5g(12.07mmol,79%)4-溴-5,6-二氢-2H-吡喃-3-羧酸。1H NMR(300MHz,DMSO-d6):δ13.10(brs,1H),4.24(t,2H),3.73(t,2H),2.67-2.61(m,2H)。
1,2,4,7,8,9-六氢-5H-吡喃并[3,4-c]喹啉-5,10(6H)-二酮(IVr)
步骤i:向微波管装入1.0g(4.85mmol)4-溴-5,6-二氢-2H-吡喃-3-羧酸(IIIh)在10mL DMF、0.82g(7.28mmol)环己烷-1,3-二酮(IIa)和2.06g(9.70mmol)K3PO4中溶液并将混合物用氮气脱气5min。加入碘化铜(I)(0.37g,1.94mmol),密封容器并对混合物进行微波照射,保持150℃的反应温度1小时。注意:反应以1.0g规模一式三份进行。将一式三份反应混合物合并并通过硅胶塞(用40-50%的乙酸乙酯和石油醚的线性梯度洗脱)。将滤液在减压下浓缩并通过硅胶柱色谱法(用25-35%的乙酸乙酯和石油醚的线性梯度洗脱)纯化产物,得到0.85g(3.86mmol,26%)1,2,4,7,8,9-六氢-5H,10H-吡喃并[3,4-c]色烯-5,10-二酮。LCMS:m/z实测值221.04[M+H]+,RT=1.39min(方法A);1H NMR(400,CDCl3)δ4.49-4.48(m,2H),3.84(t,2H),3.09-3.06(m,2H),2.89-2.86(m,2H),2.57-2.54(m,2H),2.15-2.08(m,2H)。
步骤ii:向高压釜装入1.1g(4.31mmol)步骤i中获得的1,2,4,7,8,9-六氢-5H,10H-吡喃并[3,4-c]色烯-5,10-二酮和15mL 7M甲醇胺,并将反应混合物在140℃下搅拌4小时。将混合物冷却至室温并在减压下浓缩。将残余物与戊烷(10mL)一起研制,将固体过滤并在真空下干燥,得到0.81g(3.69mmol,85%)1,2,4,7,8,9-六氢-5H-吡喃并[3,4-c]喹啉-5,10(6H)-二酮。LCMS:m/z实测值220.07[M+H]+,RT=1.17min,(方法A);1H NMR(300MHz,DMSO-d6):δ9.28(br s,1H),4.34-4.32(m,2H),3.73-3.69(m,2H),2.97-2.93(m,2H),2.81-2.77(m,2H),2.44-2.39(m,2H),1.98-1.92(m,2H)。
10-(甲氨基)-1,2,4,6,7,8,9,10-八氢-5H-吡喃并[3,4-c]喹啉-5-酮(Vad)
由1,2,4,7,8,9-六氢-5H-吡喃并[3,4-c]喹啉-5,10(6H)-二酮(IVr)和甲胺以与上述类似的方式合成10-(甲氨基)-1,2,4,6,7,8,9,10-八氢-5H-吡喃并[3,4-c]喹啉-5-酮。LCMS:m/z实测值235.14[M+H]+,RT=0.32min(方法A)。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲(化合物60和61)
由10-(甲氨基)-1,2,4,6,7,8,9,10-八氢-5H-吡喃并[3,4-c]喹啉-5-酮(Vad)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralpak IC(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物60):LCMS:m/z实测值406.2/408.2[M+H]+,RT=3.24min(方法A);1H NMR(400MHz,DMSO-d6):δ11.47(br s,1H),8.40(br s,1H),7.83-7.81(m,1H),7.49-7.45(m,1H),7.29(t,1H),5.23-5.21(m,1H),4.40(d,1H),4.27(d,1H),3.90-3.85(m,1H),3.59-3.53(m,1H),2.65-2.56(m,4H),2.49-2.31(m,3H),1.78-7.65(m,4H);手性分析SFC:RT=2.74min,柱:Chiralpak IC-3(4.6×150mM)3.5μm,40%甲醇,流速:3g/min。
对映异构体II(化合物61):LCMS:m/z实测值406.3/408.3[M+H]+,RT=3.24min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.47(br s,1H),8.40(br s,1H),7.83-7.81(m,1H),7.49-7.45(m,1H),7.29(t,1H),5.23-5.21(m,1H),4.40(d,1H),4.27(d,1H),3.90-3.85(m,1H),3.59-3.53(m,1H),2.65-2.56(m,4H),2.49-2.31(m,3H),1.78-7.65(m,4H);手性分析SFC:RT=5.19min,柱:Chiralpak IC-3(4.6×150mM)3.5μm,40%甲醇,流速:3g/min。
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲(化合物62和63)
由10-(甲氨基)-1,2,4,6,7,8,9,10-八氢-5H-吡喃并[3,4-c]喹啉-5-酮(Vad)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralpak IC(30x250 mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物62):LCMS:m/z实测值390.3[M+H]+,RT=2.89min,(方法A);1HNMR(400MHz,DMSO-d6):δ11.47(br s,1H),8.41(br s,1H),7.72-7.66(m,1H),7.33-7.27(m,2H),5.23-5.21(m,1H),4.40(d,1H),4.27(d,1H),3.89-3.85(m,1H),3.57-3.54(m,1H),2.66-2.56(m,4H),2.50-2.32(m,3H),1.82-1.65(m,4H);手性分析SFC:RT=2.21min,柱:Chiralpak IC-3(4.6×150mM)3.5μm,40%甲醇,流速:3g/min。
对映异构体II(化合物63):LCMS:m/z实测值390.3[M+H]+,RT=2.89min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.47(br s,1H),8.41(br s,1H),7.72-7.66(m,1H),7.33-7.27(m,2H),5.23-5.21(m,1H),4.40(d,1H),4.27(d,1H),3.89-3.85(m,1H),3.57-3.54(m,1H),2.66-2.56(m,4H),2.50-2.32(m,3H),1.82-1.65(m,4H);手性分析SFC:RT=3.96min,柱:Chiralpak IC-3(4.6×150mM)3.5μm,40%甲醇,流速:3g/min。
3,4,8,9-四氢-1H-吡喃并[4,3-c]喹啉-5,10(6H,7H)-二酮(IVs)
由3-氧代四氢-2H-吡喃-4-羧酸甲酯/3-氧代四氢-2H-吡喃-4-羧酸乙酯(IIIi)和环己烷-1,3-二酮(IIa)的~1:1的混合物以与上述IVq类似的方式合成3,4,8,9-四氢-1H-吡喃并[4,3-c]喹啉-5,10(6H,7H)-二酮。LCMS:m/z实测值220.13[M+H]+;1H NMR(400MHz,DMSO-d6):δ11.98(br s,1H),4.78(s,2H),3.74(t,2H),2.80-2.76(m,2H),2.45-2.38(m,4H),1.97-1.91(m,2H)。
10-(甲氨基)-3,4,7,8,9,10-六氢-1H-吡喃并[4,3-c]喹啉-5(6H)-酮(Vae)
由3,4,8,9-四氢-1H-吡喃并[4,3-c]喹啉-5,10(6H,7H)-二酮(IVs)和甲胺以与上述类似的方式合成10-(甲氨基)-3,4,7,8,9,10-六氢-1H-吡喃并[4,3-c]喹啉-5(6H)-酮。LCMS:m/z实测值235.14[M+H]+,RT=0.29min(方法A);1H NMR(400MHz,DMSO-d6):δ11.23(brs,1H),4.81(d,1H),4.51(d,1H),3.76(t,2H),2.43-2.31(m,8H),2.03-1.97(m,1H),1.86-1.62(m,2H),1.63-1.54(m,1H),1.40-1.29(m,1H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲(化合物79和80)
在0℃下向100mg(0.51mmol)10-(甲氨基)-3,4,7,8,9,10-六氢-1H-吡喃并[4,3-c]喹啉-5(6H)-酮(Vae)在10mL二氯甲烷中的搅拌溶液加入43mg(0.25mmol)1-氟-2-氯-4-异氰氧基苯并允许在室温下搅拌1小时。将反应混合物用水(50mL)稀释并用10%甲醇的二氯甲烷溶液(2×100mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并在减压下浓缩。在室温下将残余物与二乙醚(20mL)一起研制,将固体过滤并在真空下干燥,得到120mg(0.29mmol,69%)3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–60:40.柱:Chiralpak IG(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物79):LCMS:m/z实测值406.3/408.3[M+H]+,RT=3.23min(方法A);1H NMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.42(br s,1H),7.83-7.81(m,1H),7.50-7.46(m,1H),7.30(t,1H),5.17-5.16(m,1H),4.36(d,1H),4.10(d,1H),3.95-3.89(m,1H),3.64-3.58(m,1H),2.67-2.50(m,5H),2.49-2.37(m,2H),1.84-1.61(m,4H);手性分析SFC:RT=3.69min;柱:Chiralpak IG-3(4.6×150mM)3μm,40%甲醇,流速:3.0g/min。
对映异构体II(化合物80):LCMS:m/z实测值406.3/408.3[M+H]+,RT=3.23min(方法A);1H NMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.42(br s,1H),7.83-7.81(m,1H),7.50-7.46(m,1H),7.30(t,1H),5.17-5.16(m,1H),4.36(d,1H),4.10(d,1H),3.95-3.89(m,1H),3.64-3.58(m,1H),2.67-2.50(m,5H),2.49-2.37(m,2H),1.84-1.61(m,4H);手性分析SFC:RT=5.47min;柱:Chiralpak IG-3(4.6×150mM)3μm,40%甲醇,流速:3.0g/min。
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲(化合物81和82)
由10-(甲氨基)-3,4,7,8,9,10-六氢-1H-吡喃并[4,3-c]喹啉-5(6H)-酮(Vae)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralpak IG(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物81):LCMS:m/z实测值390.3[M+H]+,RT=2.89min,(方法A);1HNMR(400MHz,DMSO-d6):δ11.44(br s,1H),8.43(br s,1H),7.72-7.66(m,1H),7.34-7.26(m,2H),5.17-5.16(m,1H),4.36(d,1H),4.10(d,1H),3.95-3.89(m,1H),3.64-3.58(m,1H),2.66-2.51(m,5H),2.49-2.37(m,2H),1.82-1.61(m,4H);手性分析SFC:RT=2.93min,柱:Chiralpak IG-3(4.6×150mM)3μm,40%甲醇,流速:3.0g/min。
对映异构体II(化合物82):LCMS:m/z实测值390.3[M+H]+,RT=2.88min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.44(br s,1H),8.43(br s,1H),7.72-7.66(m,1H),7.34-7.26(m,2H),5.17-5.16(m,1H),4.36(d,1H),4.10(d,1H),3.95-3.89(m,1H),3.64-3.58(m,1H),2.66-2.51(m,5H),2.49-2.37(m,2H),1.82-1.61(m,4H);手性分析SFC:RT=6.21min,柱:Chiralpak IG-3(4.6×150mM)3μm,40%甲醇,流速:3.0g/min。
4,7-二氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5,10(6H,9H)-二酮(IVt)
由3-氧代四氢-2H-吡喃-4-羧酸甲酯/3-氧代四氢-2H-吡喃-4-羧酸乙酯(IIIi)和四氢吡喃-3,5-二酮(IIc)的~1:1的混合物以与上述类似的方式合成4,7-二氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5,10(6H,9H)-二酮。LCMS:m/z实测值222.12[M+H]+,RT=1.12min,(方法A);1H NMR(300MHz,DMSO-d6):δ11.02(br s,1H),4.78-4.68(m,4H),4.16-4.12(m,2H),3.80-3.76(m,2H),2.43-2.39(m,2H)。
10-(甲氨基)-4,7,9,10-四氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5(6H)-酮(Vaf)
由4,7-二氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5,10(6H,9H)-二酮(IVt)和甲胺以与上述类似的方式合成10-(甲氨基)-4,7,9,10-四氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5(6H)-酮。LCMS:m/z实测值237.13[M+H]+。
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲(化合物83和84)
由10-(甲氨基)-4,7,9,10-四氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5(6H)-酮(Vaf)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak IG(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物83):LCMS:m/z实测值408.3/410.3[M+H]+,RT=2.96min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.52(br s,1H),7.82-7.79(m,1H),7.49-7.45(m,1H),7.30(t,1H),5.03-5.02(m,1H),4.50(d,1H),4.45(d,1H),4.33(d,1H),4.15(d,1H),3.94-3.85(m,2H),3.81-3.76(m,1H),3.71-3.65(m,2H),2.79(s,3H),2.41-2.37(br m,2H);手性分析SFC:RT=2.94min,柱:Chiralpak IG-3(4.6×150mm)3μm,35%甲醇,流速:3.0g/min。
对映异构体II(化合物84):LCMS:m/z实测值408.3/410.2[M+H]+,RT=2.96min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.52(br s,1H),7.82-7.79(m,1H),7.49-7.45(m,1H),7.30(t,1H),5.03-5.02(m,1H),4.50(d,1H),4.45(d,1H),4.33(d,1H),4.15(d,1H),3.94-3.85(m,2H),3.81-3.76(m,1H),3.71-3.65(m,2H),2.79(s,3H),2.41-2.37(br m,2H);手性分析SFC:RT=5.93min,柱:Chiralpak IG-3(4.6×150mm)3μm,35%甲醇,流速:3.0g/min。
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,3,4,5,6,7,9,10-八氢二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲(化合物85和86)
由10-(甲氨基)-4,7,9,10-四氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-5(6H)-酮(Vaf)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,3,4,5,6,7,9,10-八氢二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–35:65.柱:(R,R)WHELK-01(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物85):LCMS:m/z实测值392.3[M+H]+,RT=2.60min,(方法A);1HNMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.53(br s,1H),7.70-7.65(m,1H),7.35-7.29(m,2H),5.03-5.01(m,1H),4.50(d,1H),4.44(d,1H),4.33(d,1H),4.15(d,1H),3.94-3.85(m,2H),3.81-3.77(m,1H),3.71-3.66(m,1H),2.79(s,3H),2.39-2.37(m,2H);手性分析SFC:RT=2.04min;柱:(R,R)WHELK-01(4.6×150mm)3.5μm,35%甲醇,流速:3.0g/min。
对映异构体II(化合物86):LCMS:m/z实测值392.3[M+H]+,RT=2.60min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.50(br s,1H),8.53(br s,1H),7.70-7.65(m,1H),7.35-7.29(m,2H),5.03-5.01(m,1H),4.50(d,1H),4.44(d,1H),4.33(d,1H),4.15(d,1H),3.94-3.85(m,2H),3.81-3.77(m,1H),3.71-3.66(m,1H),2.79(s,3H),2.39-2.37(m,2H);手性分析SFC:RT=2.75min;柱:(R,R)WHELK-01(4.6×150mM)3.5μm,35%甲醇,流速:3.0g/min。
5,7,9,10-四氢二吡喃并[3,4-b:4',3'-d]吡啶-1,6(2H,4H)-二酮(IVu)
步骤i:向0.5g(2.42mmol)4-溴-5,6-二氢-2H-吡喃-3-羧酸(IIIIh)在5mL干燥DMSO中的搅拌溶液加入0.83g(7.28mmol)2H-吡喃-3,5(4H,6H)-二酮(IIc)、1.34g(9.70mmol)碳酸钾、46mg(0.29mmol)碘化铜(I)和56mg(0.48mmol)L-脯氨酸。将反应混合物用氩气吹扫5min并在90℃下在预热油浴中搅拌2.5小时。注意:上述详细反应均以0.5g规模一式两份进行。将反应混合物合并并用2M HCl水溶液(30mL)酸化。将所得溶液用乙酸乙酯(3×50mL)萃取,将合并的有机萃取物用盐水(50mL)洗涤,经无水硫酸钠干燥并在减压下浓缩。通过硅胶柱色谱法(用40-45%的乙酸乙酯和石油醚的线性梯度洗脱)分离化合物,得到0.65g 4,7,9,10-四氢-6H-二吡喃并[3,4-b:4',3'-d]吡喃-1,6(2H)-二酮,将其用于下一步。LCMS:m/z实测值223.13[M+H]+,RT=1.31min,(方法A)。
步骤ii:向高压釜装入0.65g步骤i中获得的4,7,9,10-四氢-6H-二吡喃并[3,4-b:4',3'-d]吡喃-1,6(2H)-二酮和20mL 7M甲醇胺。然后将反应混合物在140℃下搅拌4小时。将混合物冷却至室温并在减压下浓缩。将获得的残余物与1:1(v/v)的乙醇:正戊烷(15mL)一起研制,过滤固体并且然后在真空下干燥,得到0.4g(在两个步骤中1.80mmol,37%)5,7,9,10-四氢二吡喃并[3,4-b:4',3'-d]吡啶-1,6(2H,4H)-二酮(IVu)。LCMS:m/z实测值222.11[M+H]+,RT=1.48min,(方法A);1H NMR(300MHz,DMSO-d6):δ11.47(br s,1H),4.69(s,2H),4.36(s,2H),4.16(s,2H),3.77-3.73(m,2H),2.98-2.94(m,2H)。
1-(甲氨基)-1,2,5,7,9,10-六氢二吡喃并[3,4-b:4',3'-d]吡啶-6(4H)-酮(Vag)
由5,7,9,10-四氢二吡喃并[3,4-b:4',3'-d]吡啶-1,6(2H,4H)-二酮(IVu)和甲胺以与上述类似的方式合成1-(甲氨基)-1,2,5,7,9,10-六氢二吡喃并[3,4-b:4',3'-d]吡啶-6(4H)-酮。LCMS:m/z实测值237.13[M+H]+。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲(化合物91和92)
由1-(甲氨基)-1,2,5,7,9,10-六氢二吡喃并[3,4-b:4',3'-d]吡吡啶啶-6(4H)-酮(VVag)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–60:40.柱:Chiralpak IG(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物91):LCMS:m/z实测值408.2/410.2[M+H]+,RT=2.95min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.51(br s,1H),8.51(s,1H),7.82-7.80(m,1H),7.48-7.44(m,1H),7.29(t,1H),5.08-5.06(m,1H),4.50(d,1H),4.37-4.28(m,3H),3.96(d,1H),3.88-3.83(m,2H),3.67-3.62(m,1H),2.78(s,3H),2.49-2.39(m,1H),2.33-2.28(m,1H);手性分析SFC:RT=1.79min,柱:Chiralpak IG-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物92):LCMS:m/z实测值408.2/410.3[M+H]+,RT=2.95min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.51(br s,1H),8.51(s,1H),7.82-7.80(m,1H),7.48-7.44(m,1H),7.29(t,1H),5.08-5.06(m,1H),4.50(d,1H),4.37-4.28(m,3H),3.96(d,1H),3.88-3.83(m,2H),3.67-3.62(m,1H),2.78(s,3H),2.49-2.39(m,1H),2.33-2.28(m,1H);手性分析SFC:RT=4.90min,柱:Chiralpak IG-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲(化合物93和94)
由1-(甲氨基)-1,2,5,7,9,10-六氢二吡喃并[3,4-b:4',3'-d]吡啶-6(4H)-酮(Vag)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成外消旋3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak AD-H(30×250mm),5μ,流速:90g/min分离对映异构体。
对映异构体I(化合物93):LCMS:m/z实测值392.3[M+H]+,RT=2.58min,(方法A);1HNMR(400MHz,DMSO-d6):δ11.51(br s,1H),8.52(br s,1H),7.71-7.65(m,1H),7.34-7.28(m,2H),5.08-5.06(m,1H),4.50(d,1H),4.41-4.27(m,3H),3.96(d,1H),3.87-3.78(m,2H),3.67-3.62(m,1H),2.78(s,3H),2.49-2.37(m,1H),2.34-2.22(m,1H);手性分析SFC:RT=1.61min,柱:Chiralpak AD-3(4.6×150mm)3μm,30%甲醇,流速:3g/min。
对映异构体II(化合物94):LCMS:m/z实测值392.3[M+H]+,RT=2.58min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.51(br s,1H),8.52(br s,1H),7.71-7.65(m,1H),7.34-7.28(m,2H),5.08-5.06(m,1H),4.50(d,1H),4.41-4.27(m,3H),3.96(d,1H),3.87-3.78(m,2H),3.67-3.62(m,1H),2.78(s,3H),2.49-2.37(m,1H),2.34-2.22(m,1H);手性分析SFC:RT=3.85min,柱:Chiralpak AD-3(4.6×150mm)3μm,30%甲醇,流速:3g/min。
9-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVv)
由4-氟-2-碘-苯甲酸(IIIj)和四氢吡喃-3,5-二酮(IIc)以与上述IVh类似的方式合成9-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮。LCMS m/z实测值234;RT=0.69min,(方法B);1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.72(dd,1H),8.28(dd,1H),7.42(td,1H),4.79(s,2H),4.27(s,2H)。
9-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vah)
由9-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVv)和甲胺以与上述类似的方式合成9-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。1H NMR(400MHz,CDCl3)δ11.78(s,1H),8.41(dd,1H),7.36(dd,1H),7.17(td,1H),4.70(d,1H),4.62–4.53(m,1H),4.42(dd,1H),3.62(dd,1H),3.50(d,1H),2.61(s,3H)。
3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物73)
由9-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vah)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值420.2[M+H]+;RT=3.24min(方法C,Shimadzu);1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.59(s,1H),8.28(dd,1H),7.84(dd,1H),7.51(ddd,1H),7.39–7.29(m,2H),7.23(dd,1H),5.41(s,1H),4.59(d,1H),4.43(dd,1H),4.10–4.02(m,1H),3.94(dd,1H),2.82(s,3H)。
1-(乙氨基)-9-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vai)
由9-氟-4,5-二氢吡喃并[3,4-c]异喹啉-1,6-二酮(IVv)和乙胺以与上述类似的方式合成1-(乙氨基)-9-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮。1H NMR(400MHz,CDCl3)δ11.91(s,1H),8.39(dd,1H),7.38(dd,1H),7.21–7.07(m,1H),4.71(d,1H),4.57(d1H),4.42–4.34(m,1H),3.63(m,2H),2.97(dq,1H),2.78(dq,1H),1.20(t,3H)。
3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物74)
由1-(乙氨基)-9-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vai)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z实测值434.2[M+H]+;RT=3.33min(方法C,Shimadzu);1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.50(s,1H),8.32–8.23(m,1H),7.84(ddd,1H),7.53(dddd,1H),7.34(ddt,2H),7.21(dd,1H),5.42(s,1H),4.60(d,1H),4.49–4.40(m,1H),4.04(d,1H),3.92(dd,1H),3.44(dt,1H),3.33–3.22(m,1H),0.85(t,3H)。
3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物75)
由9-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vah)和1-氟-4-异氰氧基-2-甲基-苯以与上述类似的方式合成3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值400.2[M+H]+;RT=3.15min(方法C,Shimadzu);1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.36(s,1H),8.28(dd,1H),7.44(dd,1H),7.39–7.29(m,2H),7.26(dd,1H),7.04(t,1H),5.42(d,1H),4.59(d,1H),4.42(dd,1H),4.08–4.00(m,1H),3.93(dd,1H),2.80(s,3H),2.21(d,3H)。
1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物76)
由1-(乙氨基)-9-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vai)和1-氟-4-异氰氧基-2-甲基-苯以与上述类似的方式合成1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z实测值414.2[M+H]+;RT=3.21min(方法C,Shimadzu);1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.32–8.23(m,2H),7.47–7.39(m,1H),7.40–7.28(m,2H),7.24(dd,1H),7.05(t,1H),5.42(s,1H),4.59(d,1H),4.48–4.39(m,1H),4.02(d,1H),3.92(dd,1H),3.42(dd,1H),3.33–3.13(m,1H),2.22(d,3H),0.85(t,3H)。
3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物77)
由9-氟-1-(甲氨基)-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vah)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯以与上述类似的方式合成3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值411.2[M+H]+;RT=3.07min(方法C,Shimadzu);1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.77(s,1H),8.28(dd,1H),8.05(dd,1H),7.94–7.84(m,1H),7.47(t,1H),7.34(td,1H),7.22(dd,1H),5.40(s,1H),4.59(d,J=16.2Hz,1H),4.43(dd,1H),4.07(d,1H),3.94(dd,1H),2.83(s,3H)。
3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲(化合物78)
由1-(乙氨基)-9-氟-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-6-酮(Vai)和N-(3-氰基-4-氟-苯基)氨基甲酸苯酯以与上述类似的方式合成3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲。LCMS m/z实测值425.2[M+H]+;RT=3.17min(方法C);1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.66(s,1H),8.28(dd,1H),8.05(dd,1H),7.96–7.87(m,1H),7.48(t,1H),7.34(td,1H),7.19(dd,1H),5.42(d,1H),4.60(d,1H),4.44(dd,1H),4.05(d,1H),3.93(dd,1H),3.44(dq,1H),3.29(dt,1H),0.86(t,3H)。
1,6-二氧代-4,5-二氢吡喃并[3,4-c]异喹啉-8-腈(IVw)
由5-氰基-2-碘-苯甲酸(IIIk)和四氢吡喃-3,5-二酮(IIc)以与上述类似的方式合成1,6-二氧代-4,5-二氢吡喃并[3,4-c]异喹啉-8-腈。LCMS m/z实测值241.2[M+H]+,RT=2.17min(方法C);1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),9.11(d,1H),8.53(d,1H),8.16(dd,1H),4.80(s,2H),4.29(s,2H)。
1-(甲氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈(Vaj)
由1,6-二氧-4,5-二氢吡喃并[3,4-c]异喹啉-8-腈(IVw)和甲胺以与上述类似的方式合成1-(甲氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈。LCMS m/z实测值256.2[M+H]+,RT=0.44min(方法B);1H NMR(400MHz,甲醇-d4)δ8.63–8.58(m,1H),7.93(dd,1H),7.84(d,1H),4.59(d,1H),4.48(dd,1H),4.42–4.33(m,1H),3.70–3.55(m,2H),2.55(s,3H)。
1-(乙氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈(Vak)
由1,6-二氧-4,5-二氢吡喃并[3,4-c]异喹啉-8-腈(IVw)和乙胺以与上述类似的方式合成1-(乙氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈。LCMS m/z实测值270.2[M+H]+,RT=0.45min(方法B);1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.49(dt,1H),8.08(ddd,1H),8.00–7.92(m,1H),4.46(d,1H),4.39(d,1H),4.22(d,1H),3.72(s,1H),3.57(dd,1H),2.79(dq,1H),2.74–2.61(m,1H),1.04(td,3H)。
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物89)
由1-(甲氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈(Vaj)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS m/z实测值427.25[M+H]+;RT=3.25min(方法C);1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.61–8.52(m,2H),8.14(ddd,1H),7.88(ddd,1H),7.67–7.59(m,1H),7.52(dddd,1H),7.33(td,1H),5.46(d,1H),4.62(d,1H),4.46(dd,1H),4.07(d,1H),3.94(dd,1H),2.80(s,3H)。
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲(化合物90)
由1-(乙氨基)-6-氧-1,2,4,5-四氢吡喃并[3,4-c]异喹啉-8-腈(Vak)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲。LCMS m/z实测值441.25[M+H]+;RT=3.33min(方法C);1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.55(dd,1H),8.48(s,1H),8.14(dd,1H),7.88(dd,1H),7.64–7.57(m,1H),7.54(ddd,1H),7.33(t,1H),5.47(s,1H),4.63(d,1H),4.47(dd,1H),4.04(d,1H),3.92(dd,1H),3.47–3.35(m,1H),3.33–3.18(m,1H),0.84(t,3H)。
2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1,6(4H,5H)-二酮(IVx)
由3-溴噻吩-2-羧酸(IIIm)和四氢吡喃-3,5-二酮(IIc)以与上述类似的方式合成2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1,6(4H,5H)-二酮。LCMS m/z实测值222.1[M+H]+;RT=0.59min(方法B);1H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.21(d,1H),8.11(d,1H),4.81(s,2H),4.28(s,2H)。
1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-6(4H)-酮(Val)
由2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1,6(4H,5H)-二酮(IVx)和甲胺以与上述类似的方式合成1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-6(4H)-酮。LCMS m/z实测值237.1[M+H]+;RT=0.36min(方法B);1H NMR(400MHz,CDCl3)δ7.78(d,1H),7.38(d,1H),4.78(d,1H),4.61(d,1H),4.35(d,1H),3.70–3.57(m,2H),2.58(s,3H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲(化合物95)
由1-(甲氨基)-1,5-二氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-6(4H)-酮(Val)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲。LCMS m/z实测值408.2/410.2[M+H]+;RT=3.46min(方法A);1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.58(s,1H),8.08(dd,1H),7.87(dd,1H),7.52(dddd,1H),7.32(t,1H),7.17(dd,1H),5.47(s,1H),4.61(d,1H),4.43(dd,1H),4.02(dd,1H),3.94(dd,1H),2.80(s,3H)。
5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4,9(6H,8H)-二酮(IVy)
由2-溴噻吩-3-羧酸(IIIn)和四氢吡喃-3,5-二酮(IIc)以与上述类似的方式合成5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4,9(6H,8H)-二酮。LCMS m/z实测值222.1[M+H]+;RT=0.58min(方法B);1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),7.71(d,1H),7.51(d,1H),4.83(s,2H),4.35(s,2H)。
9-(甲氨基)-8,9-二氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4(6H)-酮(Vam)
由5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4,9(6H,8H)-二酮(IVy)和甲胺以与上述类似的方式合成9-(甲氨基)-8,9-二氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4(6H)-酮。LCMS m/z实测值237.1[M+H]+;RT=0.36min(方法B);1H NMR(400MHz,CDCl3)δ7.61(d,1H),7.30(d,1H),4.74(d,1H),4.63–4.57(m,1H),4.25(dd,1H),3.82–3.74(m,1H),3.60(s,1H),2.59(s,3H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲(化合物96)
由9-(甲氨基)-8,9-二氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-4(6H)-酮(Vam)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲。LCMS m/z实测值408.2/410.2[M+H]+;RT=3.37min(方法A);1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.64(s,1H),7.86(ddd,1H),7.58–7.55(m,1H),7.55–7.49(m,1H),7.47(dd,1H),7.33(td,1H),5.36(s,1H),4.60(d,1H),4.44(d,1H),4.04–3.90(m,2H),2.77(s,3H)。
6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮(IVz)
由4-溴噻吩-3-羧酸(IIIo)和四氢吡喃-3,5-二酮(IIc)以与上述类似的方式合成6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮。LCMS m/z实测值222.1[M+H]+;RT=0.58min(方法B);1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),7.71(d,1H),7.51(d,1H),4.83(s,2H),4.35(s,2H)。
9-(甲氨基)-8,9-二氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮(Van)
由6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮(IVz)和甲胺以与上述类似的方式合成9-(甲氨基)-8,9-二氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮。LCMS m/z实测值237.1[M+H]+;RT=0.40min(方法B);1H NMR(400MHz,CDCl3)δ10.72(s,1H),8.37(dd,1H),7.45–7.38(m,1H),4.58(d,1H),4.47(dd,1H),4.29(dd,1H),3.64(dd,1H),3.52(p,1H),2.58(s,3H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲(化合物105)
由9-(甲氨基)-8,9-二氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮(Van)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲。LCMS m/z实测值408.2/410.2[M+H]+;RT=3.64min(方法A);1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.56(s,1H),8.46(dd,1H),7.88(dd,1H),7.52(ddd,1H),7.40–7.27(m,2H),5.36(s,1H),4.47(d,1H),4.32(dd,1H),4.02–3.87(m,2H),2.83(s,3H)。
5-(异丁基氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vao)
在氮气气氛中将四异丙氧基钛(0.25g,0.87mmol)加入4-(三氟甲基)-1,6,7,8-四氢喹啉-2,5-二酮(IVaa,50mg,0.22mmol)和2-甲基丙-1-胺(65uL,0.65mmol)在THF(2mL)中的混合物并将混合物在室温下搅拌16小时。将反应混合物用3mL无水甲醇稀释并在冰浴中冷却。一次性加入硼氢化钠(16mg,0.43mmol)并将反应混合物搅拌5分钟,并除去冰浴。在另外1小时之后,通过加入盐水(1mL)淬灭反应物,用20mL EtOAc稀释,并搅拌15min。通过过滤混合物,并用另外15mL EtOAc洗涤滤饼。将合并的滤液经硫酸钠干燥,过滤并蒸发溶剂。材料无需进一步纯化即可用于下一步:5-(异丁基氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(40.0mg,64.1%)。1H NMR(400MHz,甲醇-d4)δ6.66(s,1H),3.77(s,1H),2.82–2.57(m,2H),2.51(dd,1H),2.35(dd,1H),2.15(dd,2H),1.66(hept,2H),1.46(t,1H),0.92(q,6H)。
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲(化合物1)
由5-(异丁基氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vao)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲。LCMS m/z实测值460.1/462.1[M+H]+;RT=4.70min(方法A);1H NMR(400MHz,甲醇-d4)δ7.50(dd,1H),7.28–7.19(m,1H),7.12(t,1H),6.71(s,1H),3.30(p,2H),3.08(d,1H),2.82(dt,1H),2.75–2.64(m,1H),2.12(s,1H),2.06–1.98(m,3H),1.81(t,2H),0.88(dd,6H)。
5-(甲氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vap)
由4-(三氟甲基)-1,6,7,8-四氢喹啉-2,5-二酮(IVaa)和甲胺以与上述类似的方式合成5-(甲氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮。1H NMR(400MHz,CDCl3)δ13.83(s,1H),6.73(s,1H),3.69(d,1H),2.94–2.76(m,1H),2.67(ddd,1H),2.40(d,3H),2.22–2.03(m,2H),1.79–1.67(m,1H),1.48–1.34(m,1H)。
3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲(化合物2)
由5-(甲氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vap)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲。LCMS m/z实测值418.1/420.2[M+H]+;RT=3.87min(方法A);1H NMR(400MHz,甲醇-d4)δ7.60(dd,1H),7.32(ddd,1H),7.14(t,1H),6.74(d,1H),5.49(s,1H),2.83–2.65(m,2H),2.78(s,3H),2.03(dt,1H),1.89(m,3H)。
5-(3-羟基丙氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vaq)
由4-(三氟甲基)-1,6,7,8-四氢喹啉-2,5-二酮(IVaa)和3-氨基丙-1-醇以与上述类似的方式合成5-(3-羟基丙氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮。LCMS m/z实测值291.2[M+H]+;RT=0.49min(方法B)。
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲(化合物3)
由5-(3-羟基丙氨基)-4-(三氟甲基)-5,6,7,8-四氢-1H-喹啉-2-酮(Vaq)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲。LCMS m/z实测值462.1/464.1[M+H]+;RT=3.80min(方法A);1H NMR(400MHz,甲醇-d4)δ7.61(dd,1H),7.31(ddd,1H),7.13(t,1H),6.73(s,1H),5.48(s,1H),3.52(hept,2H),3.27(d,2H),2.97–2.55(m,3H),2.06(td,1H),2.02–1.79(m,4H),1.78–1.54(m,2H)。
5-(异丁基氨基)-4-(三氟甲基)-1,5,6,7-四氢环戊二烯并[b]吡啶-2-酮(Var)
由4-(三氟甲基)-6,7-二氢-1H-环戊二烯并[b]吡啶-2,5-二酮(IVab)和2-甲基丙-1-胺以与上述类似的方式合成5-(异丁基氨基)-4-(三氟甲基)-1,5,6,7-四氢环戊二烯并[b]吡啶-2-酮。LCMS m/z实测值275.2[M+H]+;RT=0.61min(方法B);1H NMR(400MHz,CDCl3)δ6.68(d,1H),4.30(d,1H),3.14(dt,1H),2.85–2.73(m,1H),2.39(dd,2H),2.33(dd,1H),2.31–2.16(m,1H),2.17–2.01(m,1H),1.67(dq,1H),0.89(d,6H)。
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲(化合物4)
由5-(异丁基氨基)-4-(三氟甲基)-1,5,6,7-四氢环戊二烯并[b]吡啶-2-酮(Var)和2-氯-1-氟-4-异氰氧基苯以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲。LCMS m/z实测值446.1/448.1[M+H]+;RT=4.64min(方法A);1H NMR(400MHz,甲醇-d4)δ7.45(dd,1H),7.19(d,1H),7.10(t,1H),6.60(s,1H),3.35(s,1H),3.26–3.01(m,3H),2.82(ddd,1H),2.66(dtd,1H),2.33(s,1H),2.09–1.81(m,1H),0.97(dd,6H)。
3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲(化合物5)
由5-(异丁基氨基)-4-(三氟甲基)-1,5,6,7-四氢环戊二烯并[b]吡啶-2-酮(Var)和1,2-二氟-4-异氰氧基-苯以与上述类似的方式合成3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲。LCMS m/z实测值430.2[M+H]+;RT=4.37min(方法A);1H NMR(400MHz,甲醇-d4)δ7.29(t,1H),7.11(dt,1H),7.02(s,1H),6.60(s,1H),3.35(s,1H),3.26–2.94(m,2H),2.82(ddd,1H),2.66(dtd,1H),2.33(s,1H),2.13–1.82(m,1H),0.96(dd,6H)。
8-氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVac)
步骤i:将3.0g(10.56mmol,1.0eq)4-氟-2-溴苯甲酸(IIIp)、2.7g(12.68,1.2eq.)3,5-二氧代哌啶-1-羧酸叔丁酯(IIg)、5.8g(42.2mmol,4.0eq.)碳酸钾、0.25g(2.11mmol,0.2eq.)L-脯氨酸和0.2g(1.05mmol,0.1eq.)碘化铜(I)在15mL干燥DMSO中的混合物在110℃下在氮气气氛中搅拌16小时(注意:反应以3×3g规模平行进行)。在冷却至室温后,将一式三份的反应混合物合并并用冷水(100mL)稀释。然后将混合物用饱和柠檬酸溶液(100mL)酸化。过滤所得悬浮液,并用乙酸乙酯(3×200mL)萃取滤液。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥,过滤并在减压下浓缩,得到12.2g 8-氟-1,6-二氧-1,2,4,6-四氢-3H-异色烯并[3,4-c]吡啶-3-羧酸叔丁酯和2-(1-(叔丁氧基羰基)-5-羟基-3-氧-1,2,3,6-四氢吡啶-4-基)-4-氟苯甲酸的混合物,其无需纯化即可用于下一步。
步骤ii:向密封管中6g上述制备的8-氟-1,6-二氧-1,2,4,6-四氢-3H-异色烯并[3,4-c]吡啶-3-羧酸叔丁酯和2-(1-(叔丁氧基羰基)-5-羟基-3-氧-1,2,3,6-四氢吡啶-4-基)-4-氟苯甲酸的粗混合物在30mL 1,2-二氯乙烷中的混合物加入3.4g(4.54mmol,2.5eq.)乙酸铵并将混合物在120℃下加热16小时。(注意:反应以2×6g规模平行进行)。在冷却至室温之后,将一式两份的反应混合物合并,倒入冰冷的水(200mL)中并用乙酸乙酯(2×25mL)萃取。将合并的有机萃取物用盐水(50mL)洗涤,经无水硫酸钠干燥,过滤并在减压下浓缩。将所得粗产物与丙酮(50mL)一起研制,得到3.8g(在两个步骤中1.14mmol,28%)8-氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVac)。LCMS:m/z实测值349.5[M-H]-;1H NMR(400MHz,DMSO-d6):δ12.45(br s,1H),9.03-8.97(m,1H),8.12(dd,1H),7.9(dd,1H),4.71(br s,2H),4.18(br s,2H),1.42(s,9H)。
8-氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vas)
在室温下在氮气气氛中向密封管中2.0g(6.02mmol,1.0eq.)8-氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVac)在10mL THF中的搅拌溶液加入3.6mL(7.2mmol,1.2eq.)2M甲胺的THF溶液,随后加入10mL(5vol)异丙氧基钛,并将反应混合物在70℃下加热3小时。将混合物冷却至室温,进一步冷却至0℃,并且然后用甲醇(2mL)稀释。在0℃下向该混合物分批加入0.69mg(18.64mmol,3.0eq)NaBH4,并且然后使反应在室温下继续2小时。然后将混合物用饱和盐水(15mL)和10%MeOH的二氯甲烷溶液(200mL)稀释。在搅拌30min之后,过滤非均相混合物并用10%MeOH的二氯甲烷溶液(50mL)洗涤。将滤液经无水硫酸钠干燥并在减压下浓缩。将所得粗产物与正戊烷(50mL)一起研制,通过过滤收集沉淀的固体并在真空下干燥,得到1.3g 8-氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vas)。LCMS:m/z实测值348.3[M+H]+。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物153和154)
步骤i.在0℃下向280mg(0.81mmol,1.0eq)8-氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vas)在5mL二氯甲烷中的搅拌溶液加入0.8mL(0.645mmol,1.0eq)2-氯-1-氟-4-异氰氧基苯并将所得混合物在室温下搅拌1小时。然后将混合物用水(20mL)稀释并用乙酸乙酯(2×50mL)萃取。将合并的有机萃取物用盐水(30mL)洗涤,经无水Na2SO4干燥并在减压下浓缩。将所得粗产物与二乙醚(10mL)一起研制,得到200mg(0.386mmol,47%)1-(3-(3-氯-4-氟苯基)-1-甲基脲基)-8-氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯,为无色液体。LCMS:m/z实测值517.3[M-H]-;1HNMR(400MHz,DMSO-d6)at 90℃:δ11.57(br s,1H),8.57(s,1H),8.11-8.06(m,1H)7.83(dd,1H),7.52-7.48(m,1H),7.37-7.26(m,2H),5.46(s,1H),3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.75-2.66(m,1H),1.4(s,9H)。
步骤ii.在0℃下向200mg(0.386mmol,1.0eq)步骤i中获得的1-(3-(3-氯-4-氟苯基)-1-甲基脲基)-8-氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯在5mL二氯甲烷中的搅拌溶液加入171mg(0.77mmol,2.0eq)三甲基甲硅烷基三氟甲烷磺酸盐,并将所得混合物在室温下搅拌1小时。然后在减压下除去挥发物。将所得残余物用饱和NaHCO3溶液(20mL)稀释并通过过滤收集沉淀的固体,并在真空下干燥;将粗品与二氯甲烷(2ml)和正戊烷(10mL)一起研制,得到130mg(0.317mmol,75%)3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲,为白色固体。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralcel OD-H(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物153):LCMS:m/z实测值419.2/421.2[M+H]+,RT=3.04min,(方法A);1H NMR(400MHz,DMSO-d6)at 90℃:δ11.58(br s,1H),8.58(br s,1H),8.11-8.06(m,1H)7.83(dd,1H),7.51-7.47(m,1H),7.37-7.30(m,2H),5.33(s,1H),3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=2.42min,柱:Chiralcel OD-H(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物154):LCMS:m/z实测值419.2/421.2[M+H]+,RT=3.04min,(方法A);1H NMR(400MHz,DMSO-d6)at 90℃:δ11.57(br s,1H),8.57(br s,1H),8.11-8.06(m,1H)7.83(dd,1H),7.52-7.48(m,1H),7.37-7.26(m,2H),5.46(s,1H),3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=3.2min,柱:Chiralcel OD-H(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物161和162)
步骤i.在室温下向8-氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vas,250mg,0.97mmol,1.0eq)在5mL DMF中的搅拌溶液加入0.52mL(4.1mmol,2.91eq)DIPEA和338mg(0.97mmol,1.0eq)(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa),并将所得反应混合物在70℃下搅拌3小时。然后将混合物用冷水(15mL)稀释并搅拌30分钟。过滤沉淀的固体,得到200mg(0.37mmol,产率54%)1-(3-(3-氰基-4-氟苯基)-1-甲基脲基)-8-氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯,为灰白色固体。LCMS:m/z实测值508.3[M-H]-。
步骤ii.在0℃下向1-(3-(3-氯-4-氟苯基)-1-甲基脲基)-8-氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(200mg,0.392mmol,1.0eq)在4mL二氯甲烷中的搅拌溶液加入三甲基甲硅烷基三氟甲烷磺酸盐(0.145mL,0.78mmol,2eq),并将所得反应混合物在室温下搅拌1小时。然后在减压下除去挥发物。将所得残余物用饱和NaHCO3溶液(15mL)稀释,通过过滤收集沉淀的固体并在真空下干燥,得到120mg(0.293mmol,产率72%)3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v):CO2–45:55.柱:Chiralpak-IE(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物161):LCMS:m/z实测值410.2[M+H]+,RT=2.61min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.65(br s,1H),8.96(br s,1H),8.11-8.04(m,1H)7.91-7.84(m,1H),7.86(t,1H),7.65-7.60(t,2H),7.4(d,1H),5.42(s,1H),4.9(d,1H),4.3(d,1H),3.70(s,1H),3.07(d,2H),2.61(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=1.89min,柱:Chiralpak IE-3(4.6×150mm)3μm,40%(0.2%7M甲醇胺的ACN溶液:MeOH(1:1)),流速:3g/min。
对映异构体II(化合物162):LCMS:m/z实测值410.2[M+H]+,RT=2.61min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.65(br s,1H),8.96(br s,1H),8.11-8.04(m,1H)7.91-7.84(m,1H),7.86(t,1H),7.65-7.60(t,2H),7.4(d,1H),5.42(s,1H),4.9(d,1H),4.3(d,1H),3.70(s,1H),3.07(d,2H),2.61(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=2.92min,柱:Chiralcel OD-H(4.6×150mm)3μm,40%(0.2%7M甲醇胺的ACN溶液:MeOH(1:1)),流速:3g/min。
3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVad)
步骤i:在0℃下向2.0g(6.024mmol,1.0eq)8-氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVac)在20mL二氯甲烷中的搅拌溶液加入1.6mL(9.03mmol,1.5eq)三甲基甲硅烷基三氟甲烷磺酸盐,并将所得反应混合物在室温下搅拌1小时。在减压下除去挥发物并将残余物与饱和碳酸氢钠溶液(20mL)一起研制。通过过滤收集固体并在真空下干燥,得到1.3g(5.85mmol,93%)8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6-(2H,5H)-二酮,为棕色固体。LCMS:m/z实测值233.4[M-H]-。
步骤ii:向1.75g(7.54mmol,1.0eq.)8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮在17.5mL甲醇中的搅拌溶液加入1.96g(11.31,1.5eq.)2-((叔丁基二甲基甲硅烷基)氧基)乙醛、0.87mL乙酸和0.95g(15.08mmol,2.0eq.)氰基硼氢化钠,并将所得反应混合物在室温下搅拌16小时。然后将反应混合物浓缩,并将残余物用水(50mL)稀释并搅拌30min。通过过滤收集沉淀的固体并在真空下干燥,得到1.3g(3.3mmol,45%)3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVad)。LCMS:m/z实测值391.17[M+H]-。
3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vat)
由甲胺和3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVad)通过与上述Vas类似的步骤制备3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。LCMS:m/z实测值406.5[M-H]-。
3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物171和172)
步骤i.在室温下向3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vat,350mg,0.86mmol,1.0eq)在7mLDMF中的搅拌溶液加入0.46mL(2.58mmol,3.0eq)DIPEA、155mg(0.60mmol,0.7eq)(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa),并将所得反应混合物在70℃下搅拌3小时。然后将反应混合物用冷水(25mL)稀释并搅拌30分钟。过滤沉淀的固体并干燥,得到450mg(0.81mmol,产率55%)1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲,为浅棕色固体。LCMS:m/z实测值568.50[M+H]-。
步骤ii.在0℃下向1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲(450mg,0.811mmol,1.0eq)在9mL THF中的搅拌溶液加入TBAF(1.62mL,1.62mmol,2.0eq),并使反应在室温下继续2小时。在反应完成之后(通过TLC监测),将反应物用MeOH(1mL)淬灭并且然后在减压下蒸发有机挥发物。将残余物用水(20mL)稀释并搅拌30分钟。通过过滤收集沉淀的固体并干燥,得到3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(180mg,85%)。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralcel-OX-H(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物171):LCMS:m/z实测值454.3[M+H]+,RT=2.87min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.52(br s,1H),8.6(br s,1H),8.09(s,1H),7.86-7.80(d,2H)7.64(t,1H),7.58-7.48(d,2H),5.5(s,1H),4.53(t,1H),3.88(d,1H),3.53-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=2.51min,柱:Chiralcel OX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物172):LCMS:m/z实测值454.3[M+H]+,RT=2.87min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.52(br s,1H),8.6(br s,1H),8.09(s,1H),7.86-7.80(d,2H)7.64(t,1H),7.58-7.48(d,2H),5.5(s,1H),4.53(t,1H),3.88(d,1H),3.53-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=3.49min,柱:Chiralcel OX-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
8-氟-3-甲基-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVae)
向1.0g(4.31mmol,1.0eq.)8,9-二氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(如上所述对于IVad获得的,步骤i)在10mL甲醇中的搅拌溶液加入5mL 37%的甲醛水溶液和0.54g(8.62mmol,2.0eq)氰基硼氢化钠,并将所得混合物在室温下搅拌16小时。然后将混合物用水(150mL)稀释并用乙酸乙酯(3×150mL)萃取。将合并的有机萃取物经无水硫酸钠干燥并在减压下浓缩,得到粗0.75g(3.17mmol,78%)8-氟-3-甲基-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVae)。LCMS:m/z实测值247.19[M+H]+。
8-氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vau)
由8-氟-3-甲基-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVae)和甲胺以与上述Vas类似的方式合成外消旋8-氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。LCMS:m/z实测值262.29[M+H]+。
3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物155和156)
由8-氟-3-甲基-1-(-甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vau)以与上述化合物153和154类似的方式(步骤i)合成外消旋3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralcel OD-H(30×250mm),5μ,流速:60g/min分离对映异构体。
对映异构体I(化合物155):LCMS:m/z实测值433.2/435.2[M+H]+,RT=3.02min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.51(br s,1H),7.88-7.85(m,2H),7.70-7.65(m,1H),7.51-7.47(m,2H),7.31(t,1H),5.52(br s,1H),3.66(d,1H),3.01(d,1H),2.91(d,1H),2.77(s,3H),2.61-2.57(m,1H),2.33(s,3H);手性分析SFC:RT=1.10min,柱:Chiralcel OD-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物156):LCMS:m/z实测值433.2/435.2[M+H]+,RT=3.02min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(br s,1H),8.51(br s,1H),7.89-7.85(m,2H),7.69-7.64(m,1H),7.50-7.47(m,2H),7.31(t,1H),5.52(br s,1H),3.66(d,1H),3.01(d,1H),2.91(d,1H),2.77(s,3H),2.61-2.57(m,1H),2.33(s,3H);手性分析SFC:RT=1.55min,柱:Chiralcel OD-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物163和164)
由8-氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vau)以与上述化合物161和162类似的方式(步骤i)合成外消旋3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–35:65.柱:Chiralpak IC(30×250mm),5μ,流速:60g/min分离对映异构体。
对映异构体I(化合物163):LCMS:m/z实测值424.2[M+H]+,RT=2.58min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.58(br s,1H),8.69(brs,1H),8.09(brs,1H),7.88-7.82(m,2H),7.70-7.64(m,1H),7.51-7.43(m,2H),5.52(brs,1H),3.66(d,1H),3.01(d,1H),2.92(d,1H),2.78(s,3H),2.61-2.58(m,1H),2.32(s,3H);手性分析SFC:RT=2.45min,柱:Chiralpak IC-3(4.6×150mm)3μm,30%(0.5DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物164):LCMS:m/z实测值424.2[M+H]+,RT=2.58min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.58(br s,1H),8.69(brs,1H),8.09(brs,1H),7.88-7.82(m,2H),7.70-7.64(m,1H),7.51-7.43(m,2H),5.52(brs,1H),3.66(d,1H),3.01(d,1H),2.92(d,1H),2.78(s,3H),2.61-2.58(m,1H),2.32(s,3H);手性分析SFC:RT=3.23min,柱:Chiralpak IC-3(4.6×150mm)3μm,30%(0.5DEA的甲醇溶液),流速:3g/min。
3-乙酰基-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVaf)
向0.5g(2.16mmol,3.0eq.)氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(如上所述对于IVad获得的,步骤i)在5mL二氯甲烷中的搅拌溶液加入0.6mL(4.31mmol,2.0eq.)三乙胺和0.20mL(2.16mmol,1.0eq.)乙酸酐,并将混合物在室温下搅拌4小时。将反应混合物浓缩并用水(20mL)洗涤,得到0.4g 3-乙酰基-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVaf),为浅黄色固体。LCMS:m/z实测值275.3[M+H]+。1H NMR(400MHz,DMSO-d6):δ9.13-9.09(m,1H),7.89-7.86(m,1H),7.73-7.68(1H),4.80-479(d,2H),4.34-4.28(d 2H),2.13-2.10(d,3H)。
3-乙酰基-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vav)
由3-乙酰基-8-氟-3,4-二氢苯并[c][1,7]二氮杂萘-1,6(2H,5H)-二酮(IVaf)和甲胺以与上述Vas类似的方式合成外消旋3-乙酰基-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。LCMS:m/z实测值288.4[M-H]+。
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲(化合物157和158)
由3-乙酰基-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vav)以与上述类似的方式合成外消旋1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak OJ(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物157):LCMS:m/z实测值461.2[M+H]+,RT=3.85min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.7(br s,1H),8.609-8.50(d,1H),7.90-7.87(m,2H),7.71-7.68(m,1H),7.57-7.48(m 2H),7.35-7.31(t,1H),5.61-5.5(d,1H),5.11-4.71(m,1H),4.59-4.3(m,1H)4.10-3.9(m,1H),3.61-3.5(m,1H),2.61(s 3H),2.11(s,3H);手性分析SFC:RT=2.56min,柱:Chiralpak OJ-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物158):LCMS:m/z m/z实测值461.2[M+H]+,RT=3.85min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.7(br s,1H),8.60-8.50(d,1H),7.91-7.87(m,2H),7.72-7.67(m,1H),7.57-7.49(m 2H),7.35-7.31(t,1H),5.61-5.5(d,1H),5.11-4.71(m,1H),4.59-4.3(m,1H)4.10-3.9(m,1H),3.61-3.5(m,1H),2.61(s 3H),2.11(s,3H);手性分析SFC:RT=3.60min,柱:Chiralpak OJ-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲(化合物165和166)
由3-乙酰基-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vav)以与上述类似的方式合成外消旋1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物165):LCMS:m/z实测值452.2[M+H]+,RT=3.36min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.01-7.98(m,1H),7.92-7.85(m,2H),7.636-7.559(m,2H),7.41-7.37(t,1H),8.79-8.70(m,1H),8.14-8.06(m,2H)7.92-7.89(m,1H),7.50-7.34(m,2H),7.37-7.30(m,2H),5.58(s,1H),5.04-3.62(m,4H)2.61(s 3H)2.09(s3H);手性分析SFC:RT=3.96min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物166):LCMS:m/z m/z实测值452.2[M+H]+,RT=3.36min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.01-7.98(m,1H),7.92-7.85(m,2H),7.636-7.559(m,2H),7.41-7.37(t,1H),8.79-8.70(m,1H),8.14-8.06(m,2H)7.92-7.89(m,1H),7.50-7.34(m,2H),7.37-7.30(m,2H),5.58(s,1H),5.04-3.62(m,4H)2.61(s 3H)2.09(s 3H);手性分析SFC:RT=5.40min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVag)
由3,5-二氧代哌啶-1-羧酸叔丁酯(IIg)和4,5-二氟-2-碘-苯甲酸(IIIc)以与上述IVac类似的方式合成8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯。1H NMR(400MHz,DMSO-d6):δ12.45(br s,1H),9.03-8.97(m,1H),8.12(dd,1H),4.71(br s,2H),4.18(br s,2H),1.42(s,9H)。
8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)
由8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVag)和甲胺以与上述Vas类似的方式合成外消旋8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯。LCMS:m/z实测值366.3[M+H]+。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物149和150)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v):CO2–45:55.柱:Chiralpak-IE(30×250mm),5μ,流速:110g/min分离对映异构体。
对映异构体I(化合物149):LCMS:m/z实测值437.2/439.2[M+H]+,RT=3.19min,(方法A);1H NMR(400MHz,DMSO-d6)at 90℃:δ11.58(br s,1H),8.58(br s,1H),8.11-8.06(m,1H)7.83(dd,1H),7.51-7.47(m,1H),7.37-7.30(m,2H),5.33(s,1H),3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=2.92min,柱:Chiralpak IE-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物150):LCMS:m/z实测值437.2/439.2[M+H]+,RT=3.19min,(方法A);1H NMR(400MHz,DMSO-d6)at 90℃:δ11.57(br s,1H),8.57(br s,1H),8.11-8.06(m,1H)7.83(dd,1H),7.52-7.48(m,1H),7.37-7.26(m,2H),5.46(s,1H),3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=5.18min,柱:Chiralpak IE-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲(化合物191和192)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和1,2-二氟-4-异氰氧基苯以与上述类似的方式合成外消旋1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v):CO2–50:50.柱:Chiralcel-IE(30×250mm),5μ,流速:120g/min分离对映异构体。
对映异构体I(化合物191):LCMS:m/z实测值421.2[M+H]+,RT=4.47min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.5(brs,1H),8.59(brs,1H),8.11-8.06(t,1H),7.73-7.68(m,1H),7.37-7.32(m,3H),5.33(s,1H),3.73(d,1H),3.58(d,1H),3.06(s,2H),),2.80-2.66(m,4H);手性分析SFC:RT=1.22min,柱:Chiralcel IE-3(4.6×150mm)3μm,50%(0.2%7M甲醇胺的ACN溶液:MeOH(1:1)),流速:3g/min。
对映异构体II(化合物192):LCMS:m/z实测值421.2[M+H]+,RT=4.47min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.5(brs,1H),8.59(brs,1H),8.11-8.06(t,1H),7.73-7.68(m,1H),7.37-7.32(m,3H),5.33(s,1H),3.73(d,1H),3.58(d,1H),3.06(s,2H),),2.80-2.66(m,4H);手性分析SFC:RT=2.37min,柱:Chiralcel IE-3(4.6×150mm)3μm,50%(0.2%7M甲醇胺的ACN溶液:MeOH(1:1)),流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物175和176)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)以与上述类似的方式制备外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v):CO2–45:55.柱:Chiralpak-IE(30×250mm),5μ,流速:120g/min分离对映异构体。
对映异构体I(化合物175):LCMS:m/z实测值428.2[M+H]+,RT=3.19min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(br s,1H),8.76(br s,1H),8.11-8.04(m,2H)7.91-7.84(m,1H),7.46(t,1H),7.35-7.30(m,2H),5.32(s,1H),3.76(d,1H),3.60(d,1H),3.12-3.07(m,2H),2.81(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=2.84min,柱:Chiralpak IE-3(4.6×150mm)3μm,40%(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v),流速:3g/min。
对映异构体II(化合物176):LCMS:m/z实测值428.2[M+H]+,RT=3.19min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(br s,1H),8.76(br s,1H),8.11-8.04(m,2H)7.91-7.84(m,1H),7.46(t,1H),7.35-7.30(m,2H),5.32(s,1H),3.76(d,1H),3.60(d,1H),3.12-3.07(m,2H),2.81(s,3H),2.75-2.66(m,1H);手性分析SFC:RT=6.65min,柱:ChiralpakIE-3(4.6×150mm)3μm,40%(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v),流速:3g/min。
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲(化合物216和217)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和3-(二氟甲基)-4-氟苯基氨基甲酸酯(VIe)以与上述类似的方式制备外消旋1-(3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲基)-8,9-二氟-6-氧-1,2,5,6-四氢苯并[c][1,7]二氮杂萘-3(4H)-羧酸叔丁酯。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak-OX-3(30×250mm),5μ,流速:100g/min分离对映异构体。每种对映异构体均以与上述类似的方式转化为单一对映异构体1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲。
对映异构体I(化合物216):LCMS:m/z实测值453.3[M+H]+,RT=7.20min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(s,1H),8.63(br s,1H),8.09(t,1H),7.87(d,1H),7.73-7.71(m,1H),7.38-7.06(m,3H),5.34(br s,1H)3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.73(br s,1H);手性分析SFC:RT=5.00min,柱:Chiralpak OX-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物217):LCMS:m/z实测值453.3[M+H]+,RT=7.20min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.57(s,1H),8.63(br s,1H),8.09(t,1H),7.87(d,1H),7.73-7.71(m,1H),7.38-7.06(m,3H),5.34(br s,1H)3.75(d,1H),3.60(d,1H),3.09-3.02(m,2H),2.80(s,3H),2.73(br s,1H);手性分析SFC:RT=5.58min,柱:Chiralpak OX-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物222和223)
在0℃下向150mg(0.136mmol,1eq)外消旋8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)在2mL THF中的搅拌溶液加入0.17mlDIPEA(0.96mmol,2.3eq)和74mg(0.82mmol,0.6eq)三光气并将反应混合物在相同温度下搅拌30min。加入异二氢吲哚(50mg,0.136mmol,1eq)并使反应在相同温度下继续4小时。将反应混合物倒入水(20mL)中并用乙酸乙酯(2×10mL)萃取。将合并的有机层用水(10mL)洗涤,经无水硫酸钠干燥,并在减压下浓缩。纯化产物通过柱色谱法(硅胶,等度(isochratic)60%的乙酸乙酯的石油醚溶液),得到90mg(0.17mmol,产率42%)外消旋8,9-二氟-1-(N-甲基异二氢吲哚-2-甲酰胺基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯,为灰白色固体。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:ChiralcelOD-3(30×250mm),5μ,流速:110g/min分离对映异构体。通过以与上述类似的方式用三甲基甲硅烷基三氟甲烷磺酸盐处理将每种对映异构体单独转化为最终产物。
对映异构体I(化合物223):LCMS:m/z实测值411.2[M+H]+,RT=2.96min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.63-7.58(m,1H),7.33-7.26(m,4H),5.11(s,1H),4.79(d,2H),4.68(d,2H),3.75(d,1H),3.60(d,1H),3.20(d,1H),3.10-3.06(m,1H),2.79-2.67(m,4H);手性分析SFC:RT=4.62min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物222):LCMS:m/z实测值411.2[M+H]+,RT=2.96min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.63-7.58(m,1H),7.33-7.26(m,4H),5.11(s,1H),4.79(d,2H),4.68(d,2H),3.75(d,1H),3.60(d,1H),3.20(d,1H),3.10-3.06(m,1H),2.79-2.63(m,4H);手性分析SFC:RT=5.71min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%(0.5%DEA的甲醇溶液),流速:3g/min。
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺(化合物224和225)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和5-氟异二氢吲哚以与上述类似的方式制备N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺。通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralcel OD-3(30×250mm),5μ,流速:110g/min分离中间体8,9-二氟-1-(5-氟-N-甲基异二氢吲哚-2-甲酰胺基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯的对映异构体。
对映异构体I(化合物225):LCMS:m/z实测值429.2[M+H]+,RT=3.10min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.57(m,1H),7.36-7.33(m,1H),7.19-7.08(m,2H),5.10(s,1H),4.80-4.61(m,4H),3.74(d,1H),3.59(d,1H),3.20(d,1H),3.09(d,1H),2.77(m,3H);手性分析SFC:RT=3.88min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物224):LCMS:m/z实测值429.2[M+H]+,RT=3.10min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.57(m,1H),7.36-7.33(m,1H),7.19-7.08(m,2H),5.10(s,1H),4.80-4.61(m,4H),3.74(d,1H),3.59(d,1H),3.20(d,1H),3.09(d,1H),2.77(m,3H);手性分析SFC:RT=4.85min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%(0.5%DEA的甲醇溶液),流速:3g/min。
5-氯-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物226和227)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和5-氯-异二氢吲哚以与上述类似的方式制备5-氯-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺。通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralcel OJ-3(30×250mm),5μ,流速:110g/min分离中间体1-(5-氯-N-甲基异二氢吲哚-2-甲酰胺基)-8,9-二氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯的对映异构体。
对映异构体I(化合物226):LCMS:m/z实测值445.2/447.2[M+H]+,RT=3.43min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.57(m,1H),7.42(m,1H),7.34(t,2H),5.10(s,1H),4.80-4.64(m,4H),3.74(d,1H),3.59(d,1H),3.18-3.06(m,2H),2.77(m,3H);手性分析SFC:RT=3.88min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物227):LCMS:m/z实测值445.2/447.2[M+H]+,RT=3.43min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.57(m,1H),7.42(m,1H),7.34(t,2H),5.10(s,1H),4.80-4.64(m,4H),3.74(d,1H),3.59(d,1H),3.18-3.06(m,2H),2.77(m,3H);手性分析SFC:RT=4.85min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
5-溴-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺(化合物228和229)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和5-溴-异二氢吲哚以与上述类似的方式制备5-溴-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺。通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralcel OJ-3(30×250mm),5μ,流速:110g/min分离中间体1-(5-溴-N-甲基异二氢吲哚-2-甲酰胺基)-8,9-二氟-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯的对映异构体。
对映异构体I(化合物228):LCMS:m/z实测值491.1[M+H]+,RT=3.55min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.56(m,2H),7.46(d,1H),7.29(d,1H),5.10(s,1H),4.80-4.62(m,4H),3.74(d,1H),3.59(d,1H),3.21-3.08(m,2H),2.77(m,3H),2.61(s,1H);手性分析SFC:RT=3.46min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物229):LCMS:m/z实测值491.1[M+H]+,RT=3.55min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.55(bs,1H),8.08(t,1H),7.62-7.56(m,2H),7.46(d,1H),7.29(d,1H),5.10(s,1H),4.80-4.62(m,4H),3.74(d,1H),3.59(d,1H),3.21-3.08(m,2H),2.77(m,3H),2.61(s,1H);手性分析SFC:RT=5.42min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺(化合物231和232)
由8,9-二氟-1-(甲氨基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(Vaw)和5-(三氟甲基)异二氢吲哚盐酸盐以与上述类似的方式制备N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺。通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralcel OJ-3(30×250mm),5μ,流速:110g/min分离中间体8,9-二氟-1-(N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺基)-6-氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯的对映异构体。
对映异构体I(化合物231):LCMS:m/z实测值479.1[M+H]+,RT=3.64min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(bs,1H),8.09(t,1H),7.73(s,1H),7.65-7.54(m,3H),5.11(s,1H),4.86(d,2H),4.76(d,2H),3.75(d,1H),3.60(d,1H),3.23-3.16(m,1H),3.1-3.06(m,1H),2.79-2.63(m,4H);手性分析SFC:RT=1.30min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物232):LCMS:m/z实测值479.1[M+H]+,RT=3.64min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.56(bs,1H),8.09(t,1H),7.73(s,1H),7.65-7.54(m,3H),5.11(s,1H),4.86(d,2H),4.76(d,2H),3.75(d,1H),3.60(d,1H),3.23-3.16(m,1H),3.1-3.06(m,1H),2.79-2.63(m,4H);手性分析SFC:RT=1.69min,柱:Chiralcel OJ-3(4.6×150mm)3μm,20%(0.5%DEA的甲醇溶液),流速:3g/min。
3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vax)
由8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVag)、2-((叔丁基二甲基甲硅烷基)氧基)乙醛和甲胺通过与上述Vat类似的步骤制备外消旋3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。LCMS:m/z实测值422.5[M-H]-。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物179和180)
步骤i.在0℃下向粗3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vax,271mg,0.64mmol,1.0eq)在5mL二氯甲烷中的搅拌溶液加入2-氯-1-氟-4-异氰氧基苯(35L,0.288mmol,0.45eq,基于Vax的纯度),并将所得反应混合物在室温下搅拌1小时。然后将混合物用水(15mL)稀释并用10%MeOH的二氯甲烷溶液(2×30mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥并在减压下浓缩。纯化粗产物通过快速色谱法(硅胶,4%MeOH的二氯甲烷溶液,等度),得到113mg(0.19mmol,69%)1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲,为棕色树脂。LCMS m/z实测值595.5[M+H]+。
步骤ii.在0℃下向113mg(0.19mmol,1.0eq)1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲在3mL THF中的搅拌溶液加入TBAF(380μL,0.38mmol,2.0eq),并使反应在室温下继续12小时。然后用MeOH(0.6mL)淬灭反应物并在减压下蒸发有机挥发物。将残余物用水(15mL)稀释并用乙酸乙酯(2×30mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥并在减压下浓缩。通过快速色谱法(硅胶,使用4.8%MeOH的二氯甲烷溶液,等度)纯化所得产物,得到3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(31mg,0.064mmol,33%)。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物179):LCMS:m/z实测值481.1/483.2[M+H]+,RT=4.03min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.55(br s,1H),8.11-8.06(m,1H)7.84(dd,1H),7.58-7.48(m,1H),7.41-7.30(m,2H),5.47(s,1H),4.53(t,1H),3.78(d,1H),3.51-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=1.25min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物180):LCMS:m/z实测值481.1/483.2[M+H]+,RT=4.03min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.62(br s,1H),8.55(br s,1H),8.11-8.06(m,1H)7.84(dd,1H),7.58-7.48(m,1H),7.41-7.30(m,2H),5.47(s,1H),4.53(t,1H),3.78(d,1H),3.51-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=1.83min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物169和170)
由3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8-氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vat)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物169):LCMS:m/z实测值463.2/465.2[M+H]+,RT=3.30min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.52(br s,1H),8.55(br s,1H),7.88-7.86(m,2H)7.64(dd,1H),7.58-7.48(m,2H),7.41-7.30(t,1H),5.5(s,1H),4.53(t,1H),3.88(d,1H),3.53-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=2.50min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物170):LCMS:m/z实测值463.2/465.2[M+H]+,RT=3.30min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.52(br s,1H),8.55(br s,1H),7.88-7.86(m,2H)7.64(dd,1H),7.58-7.48(m,2H),7.41-7.30(t,1H),5.5(s,1H),4.53(t,1H),3.88(d,1H),3.53-3.58(m,2H),3.17(d,1H),3.02(d,1H),2.83(s,3H),2.73-2.67(m,1H),2.59-2.51(m,2H);手性分析SFC:RT=3.65min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物181和182)
由3-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vax)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物181):LCMS:m/z实测值472.2[M+H]+,RT=3.63min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.63(br s,1H),8.74(br s,1H),8.11-8.06(m,2H)7.86-7.83(m,1H),7.46(t,1H),7.39-7.34(m,1H),5.47(s,1H),4.53(s,1H),3.78(d,1H),3.56(br s,2H),3.20(d,1H),3.03(dd,1H),2.84(s,3H),2.73-2.67(m,1H),2.56-2.49(m,2H);手性分析SFC:RT=2.50min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物182):LCMS:m/z实测值472.2[M+H]+,RT=3.63min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.63(br s,1H),8.74(br s,1H),8.11-8.06(m,2H)7.86-7.83(m,1H),7.46(t,1H),7.39-7.34(m,1H),5.47(s,1H),4.53(s,1H),3.78(d,1H),3.56(br s,2H),3.20(d,1H),3.03(dd,1H),2.84(s,3H),2.73-2.67(m,1H),2.56-2.49(m,2H);手性分析SFC:RT=3.34min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
8,9-二氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vay)
由8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVag)、甲醛和甲胺以与上述Vau类似的方式合成外消旋8,9-二氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物167和168)
由8,9-二氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vay)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物167):LCMS:m/z实测值451.2/453.2[M+H]+,RT=3.27min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.54(br s,1H),8.09(dd,1H)7.83(dd,1H),7.51-7.47(m,1H),7.38-7.30(m,2H),5.49(br s,1H),3.66(d,1H),3.00(d,1H),2.90(d,1H),2.799(s,3H),2.61(dd,1H),2.33(s,3H);手性分析SFC:RT=1.71min,柱:Chiralpak IC-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物168):LCMS:m/z实测值451.2/453.2[M+H]+,RT=3.27min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.54(br s,1H),8.09(dd,1H)7.83(dd,1H),7.51-7.47(m,1H),7.38-7.30(m,2H),5.49(br s,1H),3.66(d,1H),3.00(d,1H),2.90(d,1H),2.799(s,3H),2.61(dd,1H),2.33(s,3H);手性分析SFC:RT=3.02min,柱:Chiralpak IC-3(4.6×150mm)3μm,30%(0.5%DEA的甲醇溶液),流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲(化合物173和174)
由8,9-二氟-3-甲基-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vay)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相(0.2%7M甲醇胺的乙腈溶液:MeOH(1:1)v/v):CO2–25:75.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物173):LCMS:m/z实测值442.2[M+H]+,RT=3.18min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.72(br s,1H),8.12-8.04(m,2H)7.92-7.85(m,1H),7.46(t,1H),7.35(dd,1H),5.49(s,1H),3.67(d,1H),3.00(d,1H),2.95(d,1H),2.81(s,3H),2.62-2.58(m,1H),2.33(s,3H);手性分析SFC:RT=3.09min,柱:ChiralpakIC-3(4.6×150mm)3μm,25%(0.2%DEA的甲醇溶液),流速:3g/min。
对映异构体II(化合物174):LCMS:m/z实测值442.2[M+H]+,RT=3.18min,min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.66(br s,1H),8.72(br s,1H),8.12-8.04(m,2H)7.92-7.85(m,1H),7.46(t,1H),7.35(dd,1H),5.49(s,1H),3.67(d,1H),3.00(d,1H),2.95(d,1H),2.81(s,3H),2.62-2.58(m,1H),2.33(s,3H);手性分析SFC:RT=4.41min,柱:Chiralpak IC-3(4.6×150mm)3μm,25%(0.2%DEA的甲醇溶液),流速:3g/min。
3-乙酰基-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vaz)
由8,9-二氟-1,6-二氧-1,4,5,6-四氢苯并[c][1,7]二氮杂萘-3(2H)-羧酸叔丁酯(IVag)、乙酸酐和甲胺以与上述Vav类似的方式合成外消旋3-乙酰基-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮。LCMS:m/z实测值308.29[M-H]+。
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲(化合物159和160)
由3-乙酰基-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vaz)以与上述类似的方式合成外消旋1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物159):LCMS:m/z实测值479.2[M+H]+,RT=4.09min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.58(br s,1H),8.13-8.07(m,1H)7.87-7.85(m,1H),7.54-7.51(m,1H),7.44-7.32(m,2H),5.53(s,1H),5.10(d,1H),4.78(d,1H),4.60-4.37(m,1H),3.64(dd,1H),2.61(s,3H),2.11(m,1H);手性分析SFC:RT=2.13min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物160):LCMS:m/z实测值479.2[M+H]+,RT=4.09min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.58(br s,1H),8.13-8.07(m,1H)7.87-7.85(m,1H),7.54-7.51(m,1H),7.44-7.32(m,2H),5.53(s,1H),5.10(d,1H),4.78(d,1H),4.60-4.37(m,1H),3.64(dd,1H),2.61(s,3H),2.11(m,1H);手性分析SFC:RT=3.41min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲(化合物177和178)
由3-乙酰基-8,9-二氟-1-(甲氨基)-1,3,4,5-四氢苯并[c][1,7]二氮杂萘-6(2H)-酮(Vaz)以与上述类似的方式合成外消旋1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物177):LCMS:m/z实测值470.2[M+H]+,RT=4.53min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.79-8.70(m,1H),8.14-8.06(m,2H)7.92-7.89(m,1H),7.50-7.34(m,2H),7.37-7.30(m,2H),5.58(s,1H),5.06(d,1H),4.73(d,1H),4.35(d,1H),3.59(d,1H),2.63(s,3H),2.11(s,3H);手性分析SFC:RT=2.47min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物178):LCMS:m/z实测值470.2[M+H]+,RT=4.53min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.79-8.70(m,1H),8.14-8.06(m,2H)7.92-7.89(m,1H),7.50-7.34(m,2H),7.37-7.30(m,2H),5.58(s,1H),5.06(d,1H),4.73(d,1H),4.35(d,1H),3.59(d,1H),2.63(s,3H),2.11(s,3H);手性分析SFC:RT=3.66min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
8,9-二氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(IVah)
步骤i:在氮气气氛中将5.0g(17.6mmol,1.0eq)4,5-二氟-2-碘苯甲酸(IIIc)、2.74g(21.12mmol,1.2eq)2H-硫代吡喃-3,5(4H,6H)-二酮(IIh)、9.7g(70.4mmol,4.0eq)碳酸钾、0.41g(3.5mmol,0.2eq)L-脯氨酸和0.33g(1.17mmol,0.1eq)碘化铜(I)在30mL干燥DMSO中的混合物在110℃下搅拌16小时(注意:反应以4×5g规模平行进行)。在冷却至室温之后,将反应混合物合并并用冷水(100mL)稀释并用2M HCl溶液(30mL)酸化。过滤所得悬浮液,并用乙酸乙酯(3×500mL)萃取滤液。将合并的有机萃取物用盐水(150mL)洗涤,经无水Na2SO4干燥,过滤并在减压下浓缩,得到15.2g 8,9-二氟硫吡喃并[3,4-c]异色烯-1,6(2H,4H)-二酮和4,5-二氟-2-(5-羟基-3-氧-3,6-二氢-2H-硫代吡喃-4-基)苯甲酸,其原样用于下一步。
步骤ii:在-35℃下向钢制反应釜中5g(1.86mmol,1.0eq)上述制备的8,9-二氟硫吡喃并[3,4-c]异色烯-1,6(2H,4H)-二酮和4,5-二氟-2-(5-羟基-3-氧-3,6-二氢-2H-硫代吡喃-4-基)苯甲酸的粗混合物的混合物加入100mL 7M甲醇胺。密封容器并将混合物在120℃下加热1小时。然后将混合物冷却至室温并在减压下浓缩。将残余物用10vol的DMSO:水(1:9)搅拌30min以获得固体,将其过滤并用水洗涤,得到1.3g(4.8mmol,26%)8,9-二氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(IVah)。LCMS:m/z实测值266.2[M-H]-。
8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vba)
由8,9-二氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(IVah)和甲胺以与上述类似的方式合成外消旋8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值283.3[M+H]+。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物187和188)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vba)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物187):LCMS:m/z实测值454.1/456.1[M+H]+,RT=5.42min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.56(s,1H),8.11-8.06(t,1H)7.83-7.80(dd,1H),7.54-7.50(m,1H),7.37-7.26(m,2H),5.6(s,1H),3.75(d,1H),3.60(d,1H),2.9(d,1H),2.87(d,1H),2.80(s,3H);手性分析SFC:RT=1.80min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物188):LCMS:m/z实测值454.1/456.1[M+H]+,RT=5.42(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.56(s,1H),8.11-8.06(t,1H)7.83-7.80(dd,1H),7.54-7.50(m,1H),7.37-7.26(m,2H),5.6(s,1H),3.75(d,1H),3.60(d,1H),2.9(d,1H),2.87(d,1H),2.80(s,3H);手性分析SFC:RT=4.94min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物189和190)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vba)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–35:65.柱:Chiralpak-IC(30×250mm),5μ,流速:70g/min分离对映异构体。
对映异构体I(化合物189):LCMS:m/z实测值445.2[M+H]+,RT=5.21min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.72(s,1H),8.12-8.04(m,2H)7.92-7.85(m,1H),7.54-7.44(t,1H),7.35-7.22(dd,1H),5.64(s,1H),3.8-3.7(d,1H),3.6-3.5(d,1H),3.18-3.15(dd,1H),3.0-2.9(dd,1H),2.81(s,3H);手性分析SFC:RT=2.21min,柱:Chiralpak IC-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
对映异构体II(化合物190):LCMS:m/z实测值445.2[M+H]+,RT=5.21min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.72(s,1H),8.12-8.04(m,2H)7.92-7.85(m,1H),7.54-7.44(t,1H),7.35-7.22(dd,1H),5.64(s,1H),3.8-3.7(d,1H),3.6-3.5(d,1H),3.18-3.15(dd,1H),3.0-2.9(dd,1H),2.81(s,3H);手性分析SFC:RT=2.66min,柱:Chiralpak IC-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
8-氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(IVai)
由2H-硫代吡喃-3,5(4H,6H)-二酮(IIh)和5-氟-2-溴-苯甲酸(IIIp)以与上述IVah类似的方式合成8-氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮。1H NMR(400MHz,DMSO-d6):δ12.45(br s,1H),9.03-8.97(m,1H),8.12(dd,1H),4.71(br s,2H),4.18(br s,2H),1.42(s,9H)。LCMS:m/z实测值250.17[M+H]+。注意:反应以5g规模重复多次,结果一致。
8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vbb)
由8-氟-2H-硫吡喃并[3,4-c]异喹啉-1,6(4H,5H)-二酮(IVai)和甲胺以与上述类似的方式合成外消旋8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮。LCMS:m/z实测值263.29[M-H]-。注意:反应以0.5g规模重复多次,结果一致。
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物183和184)
由8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vbb)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,不同之处在于用二氯甲烷和DMF的1:1v/v的混合物作为溶剂进行反应。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IC(30×250mm),5μ,流速:100g/min分离对映异构体。
对映异构体I(化合物183):LCMS:m/z实测值436.1/438.1[M+H]+,RT=5.15min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.53(s,1H),7.91-7.86(m,2H)7.71-7.68(m,1H),7.54-7.45(m,2H),7.34-7.30(t,1H),5.68(s,1H),3.82(d,1H),3.56(d,1H),3.12(d,1H),2.96(d,1H),2.79(s,3H);手性分析SFC:RT=1.90min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物184):LCMS:m/z实测值436.1/438.1[M+H]+,RT=5.15min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.67(br s,1H),8.53(s,1H),7.91-7.86(m,2H)7.71-7.68(m,1H),7.54-7.45(m,2H),7.34-7.30(t,1H),5.68(s,1H),3.82(d,1H),3.56(d,1H),3.12(d,1H),2.96(d,1H),2.79(s,3H);手性分析SFC:RT=2.56min,柱:Chiralpak IC-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物185和186)
由8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vbb)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–30:70.柱:Chiralpak-OX-H(30×250mm),5μ,流速:70g/min分离对映异构体。
对映异构体I(化合物185):LCMS:m/z实测值427.2[M+H]+,RT=4.73min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.58(br s,1H),8.71(s,1H),8.11-8.09(m,1H)7.91-7.86(m,2H),7.71-7.66(m,1H),7.49-7.44(m,2H),5.68(s,1H),3.78(d,1H),3.56(d,1H),3.17(d,1H),3.13(d,1H),2.81(s,3H);手性分析SFC:RT=2.10min,柱:Chiralpak OX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
对映异构体II(化合物186):LCMS:m/z实测值427.2[M+H]+,RT=4.73min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.58(br s,1H),8.71(s,1H),8.11-8.09(m,1H)7.91-7.86(m,2H),7.71-7.66(m,1H),7.49-7.44(m,2H),5.68(s,1H),3.78(d,1H),3.56(d,1H),3.17(d,1H),3.13(d,1H),2.81(s,3H);手性分析SFC:RT=2.60min,柱:Chiralpak OX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbc)
在室温下向500mg(1.89mmol,1.0eq)8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vbb)在5mL乙腈:水(1:1,v/v)中的搅拌溶液加入523mg(1.7mmol,0.9eq)过硫酸氢钾制剂,并将所得反应混合物搅拌4小时。然后将混合物浓缩并用甲醇(10mL)稀释。在过滤悬浮液之后,将滤液在减压下浓缩,得到粗8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbc,800mg),其无需进一步纯化即可用于下一步。LCMS:m/z实测值281.18[M-H]-。
3-(3-氯-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物193、194、195和196)
在室温下向400mg(1.43mmol,1eq.)8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbc)在3mL DMF中的搅拌溶液加入0.76mL(4.28mmol,3eq.)DIPEA、378mg(1.43mmol,1eq.)(3-氯-4-氟苯基)氨基甲酸苯酯(VIj),并将所得反应混合物搅拌16小时。然后将反应混合物用冷水(15mL)稀释并搅拌30分钟。过滤所得悬浮液并将固体用5mL水洗涤。将粗固体(150mg)与乙酸乙酯(5mL)一起研制,得到110mg(在两个步骤中0.24mmol,产率26%)3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。对110mg该产物进行手性制备型SFC:等度方法,流动相MeOH:CO2–35:75.柱:DCPAK-P4VP(21×250)mm,5μ,流速:65g/min,得到75mg一种外消旋非对映异构体和65mg另一种外消旋非对映异构体。对这些两个外消旋体中的每一个进行手性制备型SFC:柱:Chiralcel OX-H(21×250)mm,5μ,等度方法,分别为流动相MeOH:CO2–40:60,流速:60g/min,以及流动相MeOH:CO2–45:55,流速:110g/min,分别得到20mg化合物193和22mg化合物194,以及13mg化合物195和12.8mg化合物196。
立体异构体I(化合物193):LCMS:m/z实测值452.2/454.2[M+H]+,RT=5.16min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.58(brs,1H),7.91-7.88(m,2H)7.74-7.69(m,1H),7.54-7.49(m,2H),7.33(t,1H),6.02(t,1H),4.12(s,2H),3.57-3.52(m,1H),3.27-3.24(m,1H),2.61(s,3H);手性分析SFC:RT=2.63min,柱:Chiralcel OX-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体II(化合物194,193的对映异构体):LCMS:m/z实测值452.2/454.2[M+H]+,RT=5.16min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.58(brs,1H),7.91-7.88(m,2H)7.74-7.69(m,1H),7.54-7.49(m,2H),7.33(t,1H),6.02(t,1H),4.12(s,2H),3.57-3.52(m,1H),3.27-3.24(m,1H),2.61(s,3H);手性分析SFC:RT=4.18min,柱:Chiralcel OX-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体III(化合物195):LCMS:m/z实测值452.2/454.2[M+H]+,RT=5.10min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.62(brs,1H),7.89-7.86(m,2H)7.69-7.64(m,1H),7.54-7.47(m,2H),7.33(t,1H),6.08(t,1H),4.30(d,1H),3.84(d,1H),3.50-3.45(m,1H),3.19-3.14(m,1H),2.57(s,3H);手性分析SFC:RT=2.81min,柱:Chiralcel OX-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体IV(化合物196,196的对映异构体):LCMS:m/z实测值452.2/454.2[M+H]+,RT=5.10min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.62(brs,1H),7.89-7.86(m,2H)7.69-7.64(m,1H),7.54-7.47(m,2H),7.33(t,1H),6.08(t,1H),4.30(d,1H),3.84(d,1H),3.50-3.45(m,1H),3.19-3.14(m,1H),2.57(s,3H);手性分析SFC:RT=4.59min,柱:Chiralcel OX-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物199、200、201和202)
由8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbc)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成3-(3-氰基-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,为立体异构体的混合物。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60,柱:DCPAK-P4VP(21×250)mm,5μ,流速:60g/min来分离化合物201和202中的每一种,随后对剩余的混合物进行第二制备型SFC:等度方法,流动相MeOH:CO2–40:60,柱:Chiralcel OD-H(30×250)mm,5μ,流速:100g/min来分离化合物199和200中的每一种,来分离立体异构体。
立体异构体I(化合物199):LCMS:m/z实测值443.2[M+H]+,RT=5.33min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.82(brs,1H),8.10-8.08(m,1H)7.91-7.87(m,2H),7.73-7.68(m,1H),7.54-7.45(m,2H),6.09(t,1H),4.32(d,1H),3.86(d,1H),3.58-3.48(m,1H),3.20-3.15(m,1H),2.59(s,3H);手性分析SFC:RT=7.68min,柱:ChiralcelOX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
立体异构体II(化合物200,199的对映异构体):LCMS:m/z实测值443.2[M+H]+,RT=5.33min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.83(brs,1H),8.10-8.08(m,1H)7.92-7.87(m,2H),7.74-7.67(m,1H),7.54-7.45(m,2H),6.09(t,1H),4.32(d,1H),3.86(d,1H),3.53-3.51(m,1H),3.20-3.15(m,1H),2.59(s,3H);手性分析SFC:RT=13.59min,柱:Chiralcel OX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
立体异构体III(化合物201):LCMS:m/z实测值443.1[M+H]+,RT=5.37min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.75(brs,1H),8.10-8.08(m,1H)7.89-7.87(m,2H),7.72-7.66(m,1H),7.51-7.44(m,2H),6.02(t,1H),4.10(s,2H),3.58-3.53(m,1H),3.31-3.25(m,1H),2.61(s,3H);手性分析SFC:RT=7.09min,柱:Chiralcel OX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
立体异构体IV(化合物202,201的对映异构体):LCMS:m/z实测值443.1[M+H]+,RT=5.37min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.76(brs,1H),8.10-8.08(m,1H)7.91-7.86(m,2H),7.75-7.70(m,1H),7.52-7.44(m,2H),6.03(t,1H),4.12(s,2H),3.57-3.52(m,1H),3.31-3.25(m,1H),2.62(s,3H);手性分析SFC:RT=10.05min,柱:Chiralcel OX-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbf)
在室温下向850mg(282mmol,1eq)8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vba)在10mL乙腈:水(1:1)中的搅拌溶液加入740mg(2.44mmol,0.8eq)过硫酸氢钾制剂并将所得反应混合物搅拌6小时。然后将混合物浓缩并用甲醇(20mL)稀释。在过滤悬浮液之后,将滤液在减压下浓缩,得到粗(700mg)8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbf)。该材料无需进一步纯化即可用于下一步。LCMS:m/z实测值299.24[M+H]+。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物207、208、209和210)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbf)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,为立体异构体的混合物。通过反相制备型HPLC将粗材料分离为非对映异构外消旋体。方法10min梯度(碳酸氢铵的水溶液)/乙腈,柱:X-bridge C18(30×150)mm,5μ,流速:18mL/min。通过制备型SFC:等度方法,流动相MeOH:CO2–40:60,柱:Chiralcel OX-H(21×250)mm,5μ,流速:70g/min将这些外消旋体中的每一种进一步分离为相应的对映异构体。
立体异构体I(化合物207):LCMS:m/z实测值470.2/472.2[M+H]+,RT=6.23min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.31(br s,1H),8.67(brs,1H),8.16-8.11(m,1H),7.84-7.82(m,1H),7.53-7.49(m,1H),7.43-7.33(m,2H),6.03(t,1H),4.31(d,1H),3.86(d,1H),3.52-3.51(m,1H),3.16-3.11(m,1H),2.61(s,3H);手性分析SFC:RT=1.21min,柱:Chiralpak AS-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体II(化合物208,207的对映异构体):LCMS:m/z实测值470.2/472.2[M+H]+,RT=6.23min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.31(br s,1H),8.67(brs,1H),8.16-8.11(m,1H),7.84-7.82(m,1H),7.53-7.49(m,1H),7.43-7.33(m,2H),6.03(t,1H),4.31(d,1H),3.86(d,1H),3.52-3.51(m,1H),3.16-3.11(m,1H),2.61(s,3H);手性分析SFC:RT=1.62min,柱:Chiralpak AS-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体III(化合物209):LCMS:m/z实测值470.1/472.1[M+H]+,RT=6.33min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.11(br s,1H),8.62(brs,1H),8.15-8.10(m,1H),7.84-7.82(m,1H),7.53-7.49(m,1H),7.43-7.32(m,2H),6.01(t,1H),4.18-4.10(m,2H),3.59-3.56(m,1H),3.32-3.25(m,1H),2.64(s,3H);手性分析SFC:RT=1.03min,柱:Chiralpak AS-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
立体异构体IV(化合物210,209的对映异构体):LCMS:m/z实测值470.1/472.1[M+H]+,RT=6.33min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.11(br s,1H),8.62(brs,1H),8.15-8.10(m,1H),7.84-7.82(m,1H),7.53-7.49(m,1H),7.43-7.32(m,2H),6.01(t,1H),4.18-4.10(m,2H),3.59-3.56(m,1H),3.32-3.25(m,1H),2.64(s,3H);手性分析SFC:RT=1.35min,柱:Chiralpak AS-3(4.6×150mm)3μm,50%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物211、212、213和214)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3-氧化物(Vbf)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲,为立体异构体的混合物。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60,柱:Chiralcel OX(30×250)mm,5μ,流速:70g/min分离化合物213和214中的每一种,随后对剩余的混合物进行第二制备型SFC:等度方法,流动相MeOH:CO2–40:60,柱:DCPAK-P4VP(21×250)mm,5μ,流速:60g/min分离化合物211和212中的每一种,分离立体异构体。
立体异构体I(化合物211):LCMS:m/z实测值461.2[M+H]+,RT=6.00min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.83(brs,1H),8.16-8.11(m,1H)8.04-8.02(m,1H),7.91-7.87(m,1H),7.49(t,1H),7.41-7.36(m,1H),6.03(t,1H),4.33(d,1H),3.87(d,1H),3.53-3.48(m,1H),3.18-3.13(m,1H),2.62(s,3H);手性分析SFC:RT=4.12min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
立体异构体II(化合物212,211的对映异构体):LCMS:m/z实测值461.2[M+H]+,RT=6.00min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.83(brs,1H),8.16-8.11(m,1H)8.04-8.02(m,1H),7.91-7.87(m,1H),7.49(t,1H),7.41-7.36(m,1H),6.03(t,1H),4.33(d,1H),3.87(d,1H),3.53-3.48(m,1H),3.18-3.13(m,1H),2.62(s,3H);手性分析SFC:RT=6.84min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
立体异构体III(化合物213):LCMS:m/z实测值461.3[M+H]+,RT=6.00min(方法A);1H NMR(400MHz,DMSO-d6):δ11.71(s,1H),8.78(brs,1H),8.15-8.10(m,1H)8.05-8.03(m,1H),7.90-7.86(m,1H),7.48(t,1H),7.38-7.33(m,1H),6.01(t,1H),4.14(s,2H),3.58-3.54(m,1H),3.33-3.25(m,1H),2.65(s,3H);手性分析SFC:RT=4.65min,柱:ChiralcelOX-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
立体异构体IV(化合物214,213的对映异构体):LCMS:m/z实测值461.3[M+H]+,RT=6.00min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.71(s,1H),8.78(brs,1H),8.15-8.10(m,1H)8.05-8.03(m,1H),7.90-7.86(m,1H),7.48(t,1H),7.38-7.33(m,1H),6.01(t,1H),4.14(s,2H),3.58-3.54(m,1H),3.33-3.25(m,1H),2.65(s,3H);手性分析SFC:RT=10.05min,柱:Chiralcel OX-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbd)
在室温下向600mg(2.26mmol,1eq)8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vbb)在12mL乙腈:水(1:1,v/v)中的搅拌溶液加入2.1g(6.8mmol,3eq)过硫酸氢钾制剂并将所得反应混合物搅拌16小时。然后将混合物浓缩,并将残余物用甲醇(15mL)稀释。在过滤悬浮液之后,将滤液在减压下浓缩,得到800mg粗产物。将该产物与20%甲醇的DCM溶液(10mL)一起研制,以获得8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbd),其无需进一步纯化即可用于下一步。LCMS:m/z实测值297.24[M+H]+。
3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物197和198)
由8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbd)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralcel OD(30×250mm),5μ,流速:120g/min分离对映异构体。
对映异构体I(化合物197):LCMS:m/z实测值468.2/470.2[M+H]+,RT=5.41min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.64(brs,1H),7.93-7.88(m,2H)7.77-7.72(m,1H),7.54-7.50(m,2H),7.34(t,1H),6.09(t,1H),4.73(d,1H),4.21-4.16(m,1H),3.84-3.79(m,1H),3.62-3.57(m,1H),2.62(s,3H);手性分析SFC:RT=2.01min,柱:Chiralcel OD-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
对映异构体II(化合物198):LCMS:m/z实测值468.2/470.2[M+H]+,RT=5.41(方法A);1H NMR(400MHz,DMSO-d6):δ11.60(br s,1H),8.63(brs,1H),7.92-7.89(m,2H)7.73-7.69(m,1H),7.53-7.49(m,2H),7.34(t,1H),6.08(t,1H),4.70(d,1H),4.20-4.15(m,1H),3.82-3.78(m,1H),3.61-3.55(m,1H),2.61(s,3H);手性分析SFC:RT=3.37min,柱:Chiralcel OD-3(4.6×150mm)3μm,35%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物215)
由8-氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbd)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。LCMS:m/z实测值459.2[M+H]+,RT=6.10min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.61(br s,1H),8.82(brs,1H),8.11-8.09(m,1H)7.94-7.86(m,2H),7.77-7.72(m,1H),7.53-7.45(m,2H),6.09(t,1H),4.72(d,1H),4.22-4.17(m,1H),3.84-3.80(m,1H),3.64-3.58(m,1H),2.63(s,3H)。
8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbe)
由8-8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮(Vba)和过硫酸氢钾制剂以与上述类似的方式合成外消旋8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物。LCMS:m/z实测值315.24[M+H]+。
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物203和204)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbe)和(3-氯-4-氟苯基)氨基甲酸苯酯(VIj)以与上述类似的方式合成外消旋3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–40:60.柱:Chiralpak-IA(30×250mm),5μ,流速:110g/min分离对映异构体。
对映异构体I(化合物203):LCMS:m/z实测值486.1/488.1[M+H]+,RT=6.09min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.67(s,1H),8.17-8.12(m,1H)7.85-7.83(m,1H),7.53-7.49(m,1H),7.41-7.33(m,2H),6.09-6.02(m,1H),4.79(d,1H),4.15(dd,1H),3.85-3.81(m,1H),3.64-3.58(m,1H),2.64(s,3H);手性分析SFC:RT=1.64min,柱:Chiralpak IA-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物204):LCMS:m/z实测值486.1/488.1[M+H]+,RT=6.09(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.67(s,1H),8.17-8.12(m,1H)7.85-7.83(m,1H),7.53-7.49(m,1H),7.41-7.33(m,2H),6.09-6.02(m,1H),4.79(d,1H),4.15(dd,1H),3.85-3.81(m,1H),3.64-3.58(m,1H),2.64(s,3H);手性分析SFC:RT=3.56min,柱:Chiralpak IA-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲(化合物205和206)
由8,9-二氟-1-(甲氨基)-1,5-二氢-2H-硫吡喃并[3,4-c]异喹啉-6(4H)-酮3,3-二氧化物(Vbe)和(3-氰基-4-氟苯基)氨基甲酸苯酯(VIa)以与上述类似的方式合成外消旋3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲。随后通过制备型SFC:等度方法,流动相MeOH:CO2–50:50.柱:Chiralpak-IA(30×250mm),5μ,流速:110g/min分离对映异构体。
对映异构体I(化合物205):LCMS:m/z实测值477.1[M+H]+,RT=5.68min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.85(s,1H),8.17-8.12(m,1H)8.05-8.03(m,1H),7.90-7.86(m,1H),7.49(t,1H),7.39-7.34(m,1H),6.03(t,1H),4.78(d,1H),4.16(dd,1H),3.86-3.82(m,1H),3.65-3.60(m,1H),2.65(s,3H);手性分析SFC:RT=1.12min,柱:Chiralpak IA-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
对映异构体II(化合物206):LCMS:m/z实测值477.1[M+H]+,RT=5.68min,(方法A);1H NMR(400MHz,DMSO-d6):δ11.78(br s,1H),8.84(s,1H),8.15-8.11(m,1H)8.05-8.03(m,1H),7.91-7.86(m,1H),7.49(t,1H),7.37-7.32(m,1H),6.03(t,1H),4.75(d,1H),4.16(dd,1H),3.83-3.80(m,1H),3.64-3.59(m,1H),2.65(s,3H);手性分析SFC:RT=3.90min,柱:Chiralpak IA-3(4.6×150mm)3μm,40%甲醇,流速:3g/min。
实施例2:生物学结果
如本文其他地方所描述,在HepDE19测定中测试了本公开内容的代表性化合物抑制松环DNA(rcDNA)形成的能力。结果列于表3中。
表3
列举的实施方式
提供以下示例性实施方式,其编号不应解释为指定重要程度:
实施方式1提供了一种式(I)的化合物或其盐、溶剂化物、前药、立体异构体、互变异构体或同位素标记的衍生物,或其任何混合物:
X、Y以及X与Y之间的键是这样的:
X是NR7,Y是C(=O),并且X与Y之间的键是单键,或
X是N,Y是CR10,并且X与Y之间的键是双键,
其中:
在(Ai)中,R8a和R8b任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aii)中,R8a和R8b、或R8c和R8d任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiii)中,R8c和R8d、或R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiv)中,R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
或者,A环不存在,吡啶-2-酮环的3位被R8a取代,并且吡啶-2-酮环的4位被R8b取代;
R1是-NR2R3或任选地取代的异二氢吲哚-2-基;
R2选自任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的苄基、任选地取代的杂芳基和-(CH2)(任选地取代的杂芳基);
R3选自H和C1-C6烷基;
R4选自H、C1-C6烷基和C3-C8环烷基,其中烷基或环烷基被选自C1-C6烷基、C3-C8环烷基、卤素、氰基、-OH、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷氧基、C3-C8卤代环烷氧基、任选地取代的苯基、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)OR9、-OC(=O)R9、-SR9、-S(=O)R9、-S(=O)2R9、-S(=O)2NR9R9、-N(R9)S(=O)2R9、-N(R9)C(=O)R9、-C(=O)NR9R9和-NR9R9的至少一个任选地取代;
R5选自H和任选地取代的C1-C6烷基;
R6是–(CH2)p-Q-(CH2)q-,
其中p和q独立地为0、1、2或3,和
Q是键(不存在)、-O-、-OCH(OH)-、-CH(OH)O-、-S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-、-C(=O)-、-C(=O)O-或-OC(=O)-,
其中选择p和q,使得:
如果Q是键,则2≤(p+q)≤4,
如果Q是-O-、S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-或-C(=O)-,则1≤(p+q)≤3,
如果Q是-C(=O)O-、-OC(=O)-、-OCH(OH)-或-CH(OH)O-,则0≤(p+q)≤2,和
其中每个CH2任选地独立地被一个或两个甲基取代;
R7选自H、任选地取代的C1-C6烷基和任选地取代的C3-C8环烷基;
R8a、R8b、R8c、R8d、R8e、R8f、R8g和R8h的每次出现独立地选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷氧基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基;
R9的每次出现独立地选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基和任选地取代的杂芳基;
R10选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基;
R11选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的杂芳基和任选地取代的C1-C6酰基。
实施方式2提供了实施方式1所述的化合物,其为:
实施方式3提供了实施方式1-2中任一项所述的化合物,其中R5选自H和CH3。
实施方式4提供了实施方式1-3中任一项所述的化合物,其中芳基或杂芳基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、苯基、C1-C6羟烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、酰基和C1-C6烷氧基羰基的至少一个取代基任选地取代,其中Rb的每次出现独立地为H、C1-C6烷基或C3-C8环烷基,其中在Rb中,烷基或环烷基被选自卤素、-OH、C1-C6烷氧基和杂芳基的至少一个任选地取代;或两个相邻碳原子上的取代基结合以形成-O(CH2)1-3O-。
实施方式5提供了实施方式1-4中任一项所述的化合物,其中烷基、烯基、炔基或环烷基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、卤素、氰基(-CN)、-ORa、任选地取代的苯基、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa和-N(Ra)(Ra)的至少一个取代基任选地取代,其中Ra的每次出现独立地为H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的芳基或任选地取代的杂芳基或两个Ra基团与它们所键连的N结合以形成杂环。
实施方式6提供了实施方式1-5中任一项所述的化合物,其中R2是被选自C1-C6烷基、卤素、C1-C3卤代烷基和-CN的至少一个任选地取代的苯基。
实施方式7提供了实施方式1-6中任一项所述的化合物,其中R2选自苯基、3-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3,5-二氟苯基、2,4,5-三氟苯基、3,4,5-三氟苯基、3,4-二氯苯基、3-氯-4-氟苯基、4-氯-3-氟苯基、4-氯-3-甲基苯基、3-氯-4-甲基苯基、4-氟-3-甲基苯基、3-氟-4-甲基苯基、4-氯-3-甲氧基苯基、3-氯-4-甲氧基苯基、4-氟-3-甲氧基苯基、3-氟-4-甲氧基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3-三氟甲基-4-氟苯基、4-三氟甲基-3-氟苯基、3-氰基苯基、4-氰基苯基、3-氰基-4-氟苯基、4-氰基-3-氟苯基、3-二氟甲基-4-氟苯基和4-二氟甲基-3-氟苯基。
实施方式8提供了实施方式1-7中任一项所述的化合物,其中R3选自H和甲基。
实施方式9提供了实施方式1-8中任一项所述的化合物,其中R6是选自-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2OCH(OH)-、-CH(OH)OCH2-、-CH2OC(=O)-、-C(=O)OCH2-、-CH2SCH2-、-CH2S(=O)CH2-、-CH2S(=O)2CH2-、-CH2NHCH2-、-CH2N(CH3)CH2-、-CH2N[C(=O)CH3]CH2-、-CH2N[CH2CH2OH]CH2-、-CH2CH2CH2CH2-、-CH2OCH2CH2-和-CH2CH2OCH2-的二价基团,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。
实施方式10提供了实施方式1-9中任一项所述的化合物,其选自:
实施方式11提供了实施方式1-10中任一项所述的化合物,其选自:
实施方式12提供了实施方式1-11中任一项所述的化合物,其选自:
实施方式13提供了实施方式1-11中任一项所述的化合物,其选自:
实施方式14提供了实施方式1-11中任一项所述的化合物,其选自:
实施方式15提供了实施方式1-11中任一项所述的化合物,其选自:
实施方式16提供了实施方式1-11和14-15中任一项所述的化合物,其为选自下列的至少一种:
实施方式18提供了实施方式1-17中任一项所述的化合物,其为选自下列的至少一种:
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(3-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的衍生物、立体异构体或互变异构体,或其任何混合物。
实施方式19提供了实施方式1-18中任一项所述的化合物,其为选自下列的至少一种:
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
R)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(R)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(R)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(R)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(R)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(S)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(R)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(R)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物,互变异构体和/或互变异构体的任何混合物。
实施方式20提供了一种药物组合物,其包括至少一种实施方式1-19中任一项所述的化合物和药学上可接受的载体。
实施方式21提供了实施方式20所述的药物组合物,进一步包括可用于治疗肝炎感染的至少一种另外的药剂。
实施方式22提供了实施方式21所述的药物组合物,其中至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
实施方式23提供了实施方式22所述的药物组合物,其中免疫刺激剂为检查点抑制剂。
实施方式24提供了实施方式23所述的药物组合物,其中检查点抑制剂为PD-L1抑制剂。
实施方式25提供了在受试者中治疗、减轻和/或预防乙型肝炎病毒(HBV)感染的方法,该方法包括向需要其的受试者施用治疗有效量的至少一种实施方式1-19中任一项所述的化合物和/或至少一种实施方式20-24中任一项所述的药物组合物。
实施方式26提供了实施方式25所述的方法,其中受试者进一步感染了丁型肝炎病毒(HDV)。
实施方式27提供了实施方式25-26中任一项所述的方法,其中至少一种化合物和/或组合物在药学上可接受的组合物中施用至受试者。
实施方式28提供了实施方式25-27中任一项所述的方法,其中进一步向受试者施用可用于治疗、减轻和/或预防乙型肝炎病毒感染的至少一种另外的药剂。
实施方式29提供了实施方式28所述的方法,其中至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
实施方式30提供了实施方式29所述的方法,其中免疫刺激剂为检查点抑制剂。
实施方式31提供了实施方式30所述的方法,其中检查点抑制剂为PD-L1抑制剂。
实施方式32提供了实施方式28-31中任一项所述的方法,其中向受试者共同施用至少一种化合物和/或组合物和至少一种另外的药剂。
实施方式33提供了实施方式28-32中任一项所述的方法,其中至少一种化合物和/或组合物和至少一种另外的药剂是共同配制的。
实施方式34提供了一种在感染乙型肝炎病毒的受试者中直接或间接抑制病毒衣壳蛋白的表达和/或功能的方法,方法包括向需要其的受试者施用治疗有效量的至少一种实施方式1-19中任一项所述的化合物和/或至少一种实施方式20-24中任一项所述的药物组合物。
实施方式35提供了实施方式34所述的方法,其中受试者进一步感染了丁型肝炎病毒(HDV)。
实施方式36提供了实施方式34-35中任一项所述的方法,其中至少一种化合物和/或组合物在药学上可接受的组合物中施用至受试者。
实施方式37提供了实施方式34-36中任一项所述的方法,其中进一步向受试者施用可用于治疗、减轻和/或预防乙型肝炎病毒感染的至少一种另外的药剂。
实施方式38提供了实施方式37所述的方法,其中至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
实施方式39提供了实施方式38所述的方法,其中免疫刺激剂为检查点抑制剂。
实施方式40提供了实施方式39所述的方法,其中检查点抑制剂为PD-L1抑制剂。
实施方式41提供了实施方式37-40中任一项所述的方法,其中向受试者共同施用至少一种化合物和/或组合物和至少一种另外的药剂。
实施方式42提供了实施方式37-41中任一项所述的方法,其中至少一种化合物和/或组合物和至少一种另外的药剂是共同配制的。
实施方式43提供了实施方式25-42中任一项所述的方法,其中受试者是哺乳动物。
实施方式44提供了实施方式43所述的方法,其中哺乳动物是人。
本文引用的每篇专利、专利申请和出版物的公开内容通过引用以其整体并入本文。尽管已经参考特定实施方式公开了本公开内容,但是显而易见,本领域的其他技术人员可以设计出本公开内容的其他实施方式和变型而不背离本公开内容的真实精神和范围。所附权利要求旨在被解释为包括所有这样的实施方式和等同变型。
Claims (44)
1.一种式(I)的化合物或其盐、溶剂化物、前药、立体异构体、互变异构体或同位素标记的衍生物,或其任何混合物:
其中:
X、Y以及X与Y之间的键是这样的:
X是NR7,Y是C(=O),并且X与Y之间的键是单键,或
X是N,Y是CR10,并且X与Y之间的键是双键,
其中:
在(Ai)中,R8a和R8b任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aii)中,R8a和R8b、或R8c和R8d任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiii)中,R8c和R8d、或R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
在(Aiv)中,R8e和R8f任选地与它们所连接的碳原子结合来形成羰基(-(C=O)-);
或者,所述A环不存在,吡啶-2-酮环的3位被R8a取代,并且所述吡啶-2-酮环的4位被R8b取代;
R1是-NR2R3或任选地取代的异二氢吲哚-2-基;
R2选自任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的苄基、任选地取代的杂芳基和-(CH2)(任选地取代的杂芳基);
R3选自H和C1-C6烷基;
R4选自H、C1-C6烷基和C3-C8环烷基,其中所述烷基或环烷基被选自C1-C6烷基、C3-C8环烷基、卤素、氰基、-OH、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷氧基、C3-C8卤代环烷氧基、任选地取代的苯基、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)OR9、-OC(=O)R9、-SR9、-S(=O)R9、-S(=O)2R9、-S(=O)2NR9R9、-N(R9)S(=O)2R9、-N(R9)C(=O)R9、-C(=O)NR9R9和-NR9R9的至少一个任选地取代;
R5选自H和任选地取代的C1-C6烷基;
R6是–(CH2)p-Q-(CH2)q-,
其中p和q独立地为0、1、2或3,和
Q是键(不存在)、-O-、-OCH(OH)-、-CH(OH)O-、-S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-、-C(=O)-、-C(=O)O-或-OC(=O)-,
其中选择p和q,使得:
如果Q是键,则2≤(p+q)≤4,
如果Q是-O-、S-、-S(=O)-、-S(=O)2-、-NR11、-CH(OH)-或-C(=O)-,则1≤(p+q)≤3,
如果Q是-C(=O)O-、-OC(=O)-、-OCH(OH)-或-CH(OH)O-,则0≤(p+q)≤2,
并且
其中每个CH2任选地独立地被一个或两个甲基取代;
R7选自H、任选地取代的C1-C6烷基和任选地取代的C3-C8环烷基;
R8a、R8b、R8c、R8d、R8e、R8f、R8g和R8h的每次出现独立地选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷氧基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基;
R9的每次出现独立地选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基和任选地取代的杂芳基;
R10选自H、卤素、-CN、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的C1-C6烷氧基、任选地取代的C3-C8环烷氧基、杂环基、杂芳基、-S(任选地取代的C1-C6烷基)、-SO(任选地取代的C1-C6烷基)、-SO2(任选地取代的C1-C6烷基)、-C(=O)OH、-C(=O)O(任选地取代的C1-C6烷基)、-C(=O)O(任选地取代的C3-C8环烷基)、-O(任选地取代的C1-C6烷基)、-O(任选地取代的C3-C8环烷基)、-NH2、-NH(任选地取代的C1-C6烷基)、-NH(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)、-N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基)、-C(=O)NH2、-C(=O)NH(任选地取代的C1-C6烷基)、-C(=O)NH(任选地取代的C3-C8环烷基)、-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C1-C6烷基)、-C(=O)N(任选地取代的C3-C8环烷基)(任选地取代的C3-C8环烷基)和-C(=O)N(任选地取代的C1-C6烷基)(任选地取代的C3-C8环烷基);
R11选自H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的苯基、任选地取代的杂芳基和任选地取代的C1-C6酰基。
3.根据权利要求1-2中任一项所述的化合物,其中R5选自H和CH3。
4.根据权利要求1-3中任一项所述的化合物,其中芳基或杂芳基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、苯基、C1-C6羟烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、酰基和C1-C6烷氧基羰基的至少一个取代基任选地取代,其中Rb的每次出现独立地为H、C1-C6烷基或C3-C8环烷基,其中在Rb中,所述烷基或环烷基被选自卤素、-OH、C1-C6烷氧基和杂芳基的至少一个任选地取代;或两个相邻碳原子上的取代基结合以形成-O(CH2)1-3O-。
5.根据权利要求1-4中任一项所述的化合物,其中烷基、烯基、炔基或环烷基的每次出现独立地被选自C1-C6烷基、C3-C8环烷基、卤素、氰基(-CN)、-ORa、任选地取代的苯基、任选地取代的杂芳基、任选地取代的杂环基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa和-N(Ra)(Ra)的至少一个取代基任选地取代,其中Ra的每次出现独立地为H、任选地取代的C1-C6烷基、任选地取代的C3-C8环烷基、任选地取代的芳基或任选地取代的杂芳基或两个Ra基团与它们所键连的N结合以形成杂环。
6.根据权利要求1-5中任一项所述的化合物,其中R2是被选自C1-C6烷基、卤素、C1-C3卤代烷基和-CN的至少一个任选地取代的苯基。
7.根据权利要求1-6中任一项所述的化合物,其中R2选自苯基、3-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3,5-二氟苯基、2,4,5-三氟苯基、3,4,5-三氟苯基、3,4-二氯苯基、3-氯-4-氟苯基、4-氯-3-氟苯基、4-氯-3-甲基苯基、3-氯-4-甲基苯基、4-氟-3-甲基苯基、3-氟-4-甲基苯基、4-氯-3-甲氧基苯基、3-氯-4-甲氧基苯基、4-氟-3-甲氧基苯基、3-氟-4-甲氧基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3-三氟甲基-4-氟苯基、4-三氟甲基-3-氟苯基、3-氰基苯基、4-氰基苯基、3-氰基-4-氟苯基、4-氰基-3-氟苯基、3-二氟甲基-4-氟苯基和4-二氟甲基-3-氟苯基。
8.根据权利要求1-7中任一项所述的化合物,其中R3选自H和甲基。
9.根据权利要求1-8中任一项所述的化合物,其中R6是选自-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2OCH(OH)-、-CH(OH)OCH2-、-CH2OC(=O)-、-C(=O)OCH2-、-CH2SCH2-、-CH2S(=O)CH2-、-CH2S(=O)2CH2-、-CH2NHCH2-、-CH2N(CH3)CH2-、-CH2N[C(=O)CH3]CH2-、-CH2N[CH2CH2OH]CH2-、-CH2CH2CH2CH2-、-CH2OCH2CH2-和-CH2CH2OCH2-的二价基团,其中每个CH2基团任选地被一个或两个CH3基团独立地取代。
18.根据权利要求1-17中任一项所述的化合物,其为选自下列的至少一种:
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(3-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的衍生物、立体异构体或互变异构体,或其任何混合物。
19.根据权利要求1-18中任一项所述的化合物,其为选自下列的至少一种:
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(2-氧-4-(三氟甲基)-1,2,5,6,7,8-六氢喹啉-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(S)-3-(3,4-二氟苯基)-1-异丁基-1-(2-氧-4-(三氟甲基)-2,5,6,7-四氢-1H-环戊二烯并[b]吡啶-5-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-2,3,4,5-四氢-1H-环戊二烯并[c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(3-羟丙基)-1-(5-氧-6,7,8,9,10,11-六氢-5H-环庚三烯并[c]异喹啉-11-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,10-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1R)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3R-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
3-(3-氯-4-氟苯基)-1-甲基-(1S)-(3S-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
R)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(3,3-二甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-5-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-异丁基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-甲基-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基脲;
(R)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(6-甲氧基-1,2,3,4-四氢菲啶-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(7,8-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(6-氧-1,2,3,4,5,6,7,8,9,10-十氢菲啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基-3-(4-氟-3-甲基苯基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-1,4,5,6,7,8,9,10-八氢-2H-吡喃并[3,4-c]喹啉-10-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(S)-1-(8-氯-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氰基-4-氟苯基)-1-乙基脲;
(R)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氯-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟-3-甲基苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-乙基-3-(4-氟-3-甲基苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-3-(3-氰基-4-氟苯基)-1-乙基-1-(9-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-3,4,5,6,7,8,9,10-八氢-1H-吡喃并[4,3-c]喹啉-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(5-氧-4,5,6,7,9,10-六氢-1H,3H-二吡喃并[3,4-b:3',4'-d]吡啶-10-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氰基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(S)-3-(3,4-二氟苯基)-1-甲基-1-(6-氧-1,2,4,5,6,7,9,10-八氢二吡喃并[3,4-b:4',3'-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-b]噻吩并[3,2-d]吡啶-1-基)脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,6,8,9-四氢-5H-吡喃并[3,4-b]噻吩并[2,3-d]吡啶-9-基)脲;
(R)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,5-二氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3,4-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-苯基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(S)-3-(3-氯-4-氟苯基)-1-甲基-1-(4-氧-4,5,8,9-四氢-6H-吡喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4,5-二氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(3-羟丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-羟基-2-甲基丙基)脲;
(R)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基-3-(3,4,5-三氟苯基)脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(R)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-(二氟甲基)-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(S)-3-(4-氟-3-甲基苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-异丁基脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(3,4,5-三氟苯基)脲;
(R)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(S)-1-(3-氰基-4-氟苯基)-3-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲;
(R)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(S)-2-(3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)脲基)乙烷-1-磺酰胺;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-乙基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-(2-(甲基磺酰基)乙基)脲;
(R)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(4-氯-3-氰基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3,4-二氯苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢菲啶-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(S)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基-3-(1-(三氟甲基)环丙基)脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基-1-d)-1-(甲基-d3)脲;
(R)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-甲氧基苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-羟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4R-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-4S-羟基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-4,6-二氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8-氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-甲基-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(S)-1-(3-乙酰基-8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-氰基-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3-(2-羟乙基)-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3,4-二氟苯基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8-氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8,9-二氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氯-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1R)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3R-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
3-(3-氰基-4-氟苯基)-(1S)-(8,9-二氟-3S-氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氰基-4-氟苯基)-1-(8-氟-3,3-二氧桥-6-氧-1,4,5,6-四氢-2H-硫吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氯-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-溴-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-5-氟-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氟-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-氯-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-5-溴-N-甲基异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(S)-N-(8,9-二氟-6-氧-1,2,3,4,5,6-六氢苯并[c][1,7]二氮杂萘-1-基)-N-甲基-5-(三氟甲基)异二氢吲哚-2-甲酰胺;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲
(S)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-氨乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(甲氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-甲基-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-甲氧基-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-((2-羟乙基)氨基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-5-(2-羟乙基)-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(S)-3-(3-氯-4-氟苯基)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-1-甲基脲;
(R)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(S)-1-(8,9-二氟-6-(2-羟基乙氧基)-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-(二氟甲基)-4-氟苯基)-1-甲基脲;
(R)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(5-(2-氨乙基)-8,9-二氟-6-氧-1,4,5,6-四氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(R)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
(S)-1-(6-(2-氨基乙氧基)-8,9-二氟-1,4-二氢-2H-吡喃并[3,4-c]异喹啉-1-基)-3-(3-氯-4-氟苯基)-1-甲基脲;
或其盐、溶剂化物、前药、同位素标记的、立体异构体、立体异构体的任何混合物、互变异构体和/或互变异构体的任何混合物。
20.一种药物组合物,其包括至少一种根据权利要求1-19中任一项所述的化合物和药学上可接受的载体。
21.根据权利要求20所述的药物组合物,进一步包括可用于治疗肝炎感染的至少一种另外的药剂。
22.根据权利要求21所述的药物组合物,其中所述至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
23.根据权利要求22所述的药物组合物,其中所述免疫刺激剂为检查点抑制剂。
24.根据权利要求23所述的药物组合物,其中所述检查点抑制剂为PD-L1抑制剂。
25.一种在受试者中治疗、减轻和/或预防乙型肝炎病毒(HBV)感染的方法,所述方法包括向需要其的受试者施用治疗有效量的至少一种权利要求1-19中任一项所述的化合物和/或至少一种权利要求20-24中任一项所述的药物组合物。
26.根据权利要求25所述的方法,其中所述受试者进一步感染了丁型肝炎病毒(HDV)。
27.根据权利要求25-26中任一项所述的方法,其中所述至少一种化合物和/或组合物在药学上可接受的组合物中施用至所述受试者。
28.根据权利要求25-27中任一项所述的方法,其中进一步向所述受试者施用可用于治疗、减轻和/或预防所述乙型肝炎病毒感染的至少一种另外的药剂。
29.根据权利要求28所述的方法,其中所述至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
30.根据权利要求29所述的方法,其中所述免疫刺激剂为检查点抑制剂。
31.根据权利要求30所述的方法,其中所述检查点抑制剂为PD-L1抑制剂。
32.根据权利要求28-31中任一项所述的方法,其中向所述受试者共同施用所述至少一种化合物和/或组合物和所述至少一种另外的药剂。
33.根据权利要求28-32中任一项所述的方法,其中所述至少一种化合物和/或组合物和所述至少一种另外的药剂是共同配制的。
34.一种在感染乙型肝炎病毒的受试者中直接或间接抑制病毒衣壳蛋白的表达和/或功能的方法,所述方法包括向需要其的受试者施用治疗有效量的至少一种权利要求1-19中任一项所述的化合物和/或至少一种权利要求20-24中任一项所述的药物组合物。
35.根据权利要求34所述的方法,其中所述受试者进一步感染了丁型肝炎病毒(HDV)。
36.根据权利要求34-35中任一项所述的方法,其中所述至少一种化合物和/或组合物在药学上可接受的组合物中施用至所述受试者。
37.根据权利要求34-36中任一项所述的方法,其中进一步向所述受试者施用可用于治疗、减轻和/或预防所述乙型肝炎病毒感染的至少一种另外的药剂。
38.根据权利要求37所述的方法,其中所述至少一种另外的药剂包括选自逆转录酶抑制剂;衣壳抑制剂;cccDNA形成抑制剂;RNA去稳定剂;靶向HBV基因组的寡聚核苷酸;免疫刺激剂;和靶向HBV基因转录体的GalNAc-siRNA缀合物中的至少一种。
39.根据权利要求38所述的方法,其中所述免疫刺激剂为检查点抑制剂。
40.根据权利要求39所述的方法,其中所述检查点抑制剂为PD-L1抑制剂。
41.根据权利要求37-40中任一项所述的方法,其中向所述受试者共同施用所述至少一种化合物和/或组合物和所述至少一种另外的药剂。
42.根据权利要求37-41中任一项所述的方法,其中所述至少一种化合物和/或组合物和所述至少一种另外的药剂是共同配制的。
43.根据权利要求25-42中任一项所述的方法,其中所述受试者是哺乳动物。
44.根据权利要求43所述的方法,其中所述哺乳动物是人。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962951299P | 2019-12-20 | 2019-12-20 | |
US62/951,299 | 2019-12-20 | ||
US202063036687P | 2020-06-09 | 2020-06-09 | |
US63/036,687 | 2020-06-09 | ||
PCT/US2020/065888 WO2021127356A1 (en) | 2019-12-20 | 2020-12-18 | Substituted Bicyclic and Tricyclic Ureas and Amides, Analogues Thereof, and Methods Using Same |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115087486A true CN115087486A (zh) | 2022-09-20 |
Family
ID=76478332
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080095887.0A Pending CN115087486A (zh) | 2019-12-20 | 2020-12-18 | 取代的双环和三环脲和酰胺、其类似物及其使用方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230108906A1 (zh) |
EP (1) | EP4076648A4 (zh) |
CN (1) | CN115087486A (zh) |
CA (1) | CA3162355A1 (zh) |
TW (1) | TW202138352A (zh) |
WO (1) | WO2021127356A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202208374A (zh) * | 2020-05-14 | 2022-03-01 | 加拿大商愛彼特生物製藥公司 | 經取代三環醯胺類、其類似物及使用其之方法 |
TW202321255A (zh) * | 2021-07-19 | 2023-06-01 | 加拿大商愛彼特生物製藥公司 | 經取代之三環醯胺及其類似物的合成 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003097586A1 (en) * | 2002-05-17 | 2003-11-27 | Janssen Pharmaceutica N.V. | Aminotetralin-derived urea modulators of vanilloid vr1 receptor |
WO2013096226A1 (en) * | 2011-12-19 | 2013-06-27 | Abbvie Inc. | Trpv1 antagonists |
WO2019137484A1 (zh) * | 2018-01-11 | 2019-07-18 | 南京明德新药研发股份有限公司 | Cxcr2拮抗剂 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4210941A1 (de) * | 1992-04-02 | 1993-10-07 | Bayer Ag | Neue 9-Fluor-7.oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxacin-6-carbonsäuren und -ester |
ATE552236T1 (de) * | 2003-01-14 | 2012-04-15 | Cytokinetics Inc | Verbindungen, zusammensetzungen und verfahren zur behandlung von herzinsuffizienz |
EP2770987B1 (en) * | 2011-10-27 | 2018-04-04 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
US8859584B2 (en) * | 2011-12-19 | 2014-10-14 | Abbvie, Inc. | TRPV1 antagonists |
US8796328B2 (en) * | 2012-06-20 | 2014-08-05 | Abbvie Inc. | TRPV1 antagonists |
MA41338B1 (fr) * | 2015-01-16 | 2019-07-31 | Hoffmann La Roche | Composés de pyrazine pour le traitement de maladies infectieuses |
CN113429341A (zh) * | 2016-09-18 | 2021-09-24 | 正大天晴药业集团股份有限公司 | 新型衣壳蛋白装配抑制剂 |
-
2020
- 2020-12-15 TW TW109144217A patent/TW202138352A/zh unknown
- 2020-12-18 CA CA3162355A patent/CA3162355A1/en active Pending
- 2020-12-18 US US17/784,596 patent/US20230108906A1/en active Pending
- 2020-12-18 EP EP20902216.9A patent/EP4076648A4/en active Pending
- 2020-12-18 CN CN202080095887.0A patent/CN115087486A/zh active Pending
- 2020-12-18 WO PCT/US2020/065888 patent/WO2021127356A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003097586A1 (en) * | 2002-05-17 | 2003-11-27 | Janssen Pharmaceutica N.V. | Aminotetralin-derived urea modulators of vanilloid vr1 receptor |
WO2013096226A1 (en) * | 2011-12-19 | 2013-06-27 | Abbvie Inc. | Trpv1 antagonists |
WO2019137484A1 (zh) * | 2018-01-11 | 2019-07-18 | 南京明德新药研发股份有限公司 | Cxcr2拮抗剂 |
Also Published As
Publication number | Publication date |
---|---|
CA3162355A1 (en) | 2021-06-24 |
EP4076648A1 (en) | 2022-10-26 |
WO2021127356A1 (en) | 2021-06-24 |
EP4076648A4 (en) | 2024-01-10 |
US20230108906A1 (en) | 2023-04-06 |
TW202138352A (zh) | 2021-10-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017353986B2 (en) | Substituted pyridinone-containing tricyclic compounds, and methods using same | |
TWI603972B (zh) | 用於治療及預防b型肝炎病毒感染之新穎6-稠合雜芳基二氫嘧啶 | |
KR102491125B1 (ko) | Sumo 활성화 효소의 억제제로서 유용한 헤테로아릴 화합물 | |
CN114025756B (zh) | 磷脂酰肌醇3-激酶抑制剂 | |
CN113825756A (zh) | 取代的多环羧酸、其类似物和其使用方法 | |
CN111163766A (zh) | Ahr抑制剂和其用途 | |
CN113923988A (zh) | 取代的芳甲基脲和杂芳甲基脲、其类似物和使用其的方法 | |
CN111655681A (zh) | 杂环基氨基取代的三唑类化合物作为Rho相关蛋白激酶的调节剂 | |
WO2023059581A1 (en) | Heterobifunctional compounds and their use in treating disease | |
CN115087486A (zh) | 取代的双环和三环脲和酰胺、其类似物及其使用方法 | |
US11858938B2 (en) | Imidazo-fused heterocycles and uses thereof | |
CN115667226A (zh) | 作为egfr抑制剂的三环化合物 | |
TWI815887B (zh) | 經取代的2,2'-雙嘧啶基化合物、其類似物及其使用方法 | |
CN112638376A (zh) | 取代的四氢环戊二烯并[c]吡咯、取代的二氢吡咯嗪、其类似物和其使用方法 | |
CA3110098A1 (en) | Tricyclic inhibitors of hepatitis b virus | |
CA3158731A1 (en) | Adenosine receptor antagonist compounds | |
CN107406414B (zh) | 作为用于治疗癌症的组蛋白脱甲基酶kdm2b的抑制剂的(哌啶-3-基)(萘-2-基)甲酮衍生物 | |
CN115551864A (zh) | 取代的三环酰胺、其类似物及使用其的方法 | |
JP2023532027A (ja) | 新規な化合物およびこれを含む耐性がんの予防または治療用薬学組成物 | |
TW202214574A (zh) | 經取代之(呔-1-基甲基)脲類、經取代之n-(呔-1-基甲基)醯胺類及其類似物 | |
TW202214585A (zh) | 經取代之異喹啉基甲基醯胺類、其類似物及使用其之方法 | |
CN115043836A (zh) | 一种咪唑并吡啶衍生物的p2x3受体选择性调节剂及其药物用途 | |
EP3741762A1 (en) | Oxalamido-substituted tricyclic inhibitors of hepatitis b virus |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40073314 Country of ref document: HK |