JP2013504537A

JP2013504537A - Ａｍｐｋ活性化因子としてのピロロピリジン誘導体

Ａｍｐｋ活性化因子としてのピロロピリジン誘導体 Download PDF

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Publication number: JP2013504537A
Authority: JP; Japan
Prior art keywords: hydroxy; dihydro; pyrrolo; oxo; pyridine
Prior art date: 2009-09-10
Legal status : Pending

Application number

JP2012528352A

Other languages

English (en)

Japanese (ja)

Other versions

JP2013504537A5 (enExample

Inventor

オリビエ、ミルゲ

Current Assignee

GlaxoSmithKline LLC

Original Assignee

GlaxoSmithKline LLC

Priority date

2009-09-10

Filing date

2010-09-08

Publication date

2013-02-07

2010-09-08 Application filed by GlaxoSmithKline LLC filed Critical GlaxoSmithKline LLC

2013-02-07 Publication of JP2013504537A publication Critical patent/JP2013504537A/ja

2013-10-24 Publication of JP2013504537A5 publication Critical patent/JP2013504537A5/ja

Status Pending legal-status Critical Current

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239000012190 activator Substances 0.000 title abstract description 6
102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 title abstract 2
101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 title abstract 2
150000001875 compounds Chemical class 0.000 claims abstract description 238
-1 pyrrolopyridone compound Chemical class 0.000 claims abstract description 94
150000003839 salts Chemical class 0.000 claims abstract description 93
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
239000003814 drug Substances 0.000 claims abstract description 23
125000000217 alkyl group Chemical group 0.000 claims description 184
238000000034 method Methods 0.000 claims description 120
125000004093 cyano group Chemical group *C#N 0.000 claims description 69
125000001153 fluoro group Chemical group F* 0.000 claims description 65
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
125000001309 chloro group Chemical group Cl* 0.000 claims description 62
229910052736 halogen Inorganic materials 0.000 claims description 62
150000002367 halogens Chemical class 0.000 claims description 61
125000002947 alkylene group Chemical group 0.000 claims description 60
125000003118 aryl group Chemical group 0.000 claims description 42
238000011282 treatment Methods 0.000 claims description 33
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208000017170 Lipid metabolism disease Diseases 0.000 claims description 29
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125000000623 heterocyclic group Chemical group 0.000 claims description 28
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OPWAKAHNFYSFPF-UHFFFAOYSA-N 1-(4-bromophenyl)-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C1=CC=C(Br)C=C1 OPWAKAHNFYSFPF-UHFFFAOYSA-N 0.000 claims description 14
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ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 claims description 7
MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 claims description 6
OWVRYRWMCLLPHJ-UHFFFAOYSA-N 1-(4-bromophenyl)-2-chloro-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=C(Cl)N1C1=CC=C(Br)C=C1 OWVRYRWMCLLPHJ-UHFFFAOYSA-N 0.000 claims description 5
YDXGVHCPIALQPW-UHFFFAOYSA-N 1-(4-bromophenyl)-7-hydroxy-6-(4-methoxyphenyl)-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound C1=CC(OC)=CC=C1C(C(N1)=O)=C(O)C2=C1C=CN2C1=CC=C(Br)C=C1 YDXGVHCPIALQPW-UHFFFAOYSA-N 0.000 claims description 5
DHKNCTZGBFIRHF-UHFFFAOYSA-N 1-[4-(6-fluoropyridin-3-yl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(F)N=C1 DHKNCTZGBFIRHF-UHFFFAOYSA-N 0.000 claims description 5
SPFGDGBQOVJWBA-UHFFFAOYSA-N 2-chloro-7-hydroxy-5-oxo-1-(4-thiophen-3-ylphenyl)-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=C(Cl)N1C(C=C1)=CC=C1C=1C=CSC=1 SPFGDGBQOVJWBA-UHFFFAOYSA-N 0.000 claims description 5
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
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LBVXXAWJAUZWJA-UHFFFAOYSA-N 7-hydroxy-5-oxo-1-(4-thiophen-3-ylphenyl)-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C=1C=CSC=1 LBVXXAWJAUZWJA-UHFFFAOYSA-N 0.000 claims description 5
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SMGBGXKCPRVWPU-UHFFFAOYSA-N ethyl 4-(6-cyano-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridin-1-yl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1N1C(C(O)=C(C#N)C(=O)N2)=C2C=C1 SMGBGXKCPRVWPU-UHFFFAOYSA-N 0.000 claims description 5
VYHYKFYJOXHZDP-UHFFFAOYSA-N ethyl 7-hydroxy-1-[4-(2-hydroxyphenyl)phenyl]-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carboxylate Chemical compound C1=CC=2NC(=O)C(C(=O)OCC)=C(O)C=2N1C(C=C1)=CC=C1C1=CC=CC=C1O VYHYKFYJOXHZDP-UHFFFAOYSA-N 0.000 claims description 5
GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 5
GGNBFPAPHVBNMS-UHFFFAOYSA-N 1-(4-bromophenyl)-7-hydroxy-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound C1=2C(O)=CC(=O)NC=2C=CN1C1=CC=C(Br)C=C1 GGNBFPAPHVBNMS-UHFFFAOYSA-N 0.000 claims description 4
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GPXHMPKRTGSMPG-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)phenyl]-7-hydroxy-4-methyl-5-oxopyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)N(C)C=2C=CN1C(C=C1)=CC=C1C1=CC=C(F)C=C1 GPXHMPKRTGSMPG-UHFFFAOYSA-N 0.000 claims description 4
PHXMQINEDUJDET-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(F)C=C1 PHXMQINEDUJDET-UHFFFAOYSA-N 0.000 claims description 4
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UMXKJRDKTRWKFL-UHFFFAOYSA-N 2-chloro-6-(2-fluorophenyl)-7-hydroxy-1-(4-methoxyphenyl)-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound C1=CC(OC)=CC=C1N1C(C(O)=C(C(=O)N2)C=3C(=CC=CC=3)F)=C2C=C1Cl UMXKJRDKTRWKFL-UHFFFAOYSA-N 0.000 claims description 4
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MXXBPTUMTQLSCV-UHFFFAOYSA-N 6-(4-fluorophenyl)-7-hydroxy-1-[4-(2-hydroxyphenyl)phenyl]-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound OC1=CC=CC=C1C1=CC=C(N2C=3C(O)=C(C(=O)NC=3C=C2)C=2C=CC(F)=CC=2)C=C1 MXXBPTUMTQLSCV-UHFFFAOYSA-N 0.000 claims description 4
125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 4
PDQVBRQVSAVMIE-UHFFFAOYSA-N 7-hydroxy-1-[4-(2-hydroxyphenyl)phenyl]-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound OC1=CC=CC=C1C1=CC=C(N2C=3C(O)=CC(=O)NC=3C=C2)C=C1 PDQVBRQVSAVMIE-UHFFFAOYSA-N 0.000 claims description 4
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125000000753 cycloalkyl group Chemical group 0.000 claims description 4
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LWBQKVJXMARBOW-UHFFFAOYSA-N 1-(4-bromophenyl)-6-(4-fluorophenyl)-7-hydroxy-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C=CN(C=3C=CC(Br)=CC=3)C=2C(O)=C1C1=CC=C(F)C=C1 LWBQKVJXMARBOW-UHFFFAOYSA-N 0.000 claims description 3
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HDXPALQWOKGQDK-UHFFFAOYSA-N 1-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound O1CCOC2=CC(C3=CC=C(C=C3)N3C=CC=4NC(=O)C(C#N)=C(C3=4)O)=CC=C21 HDXPALQWOKGQDK-UHFFFAOYSA-N 0.000 claims description 3
JZACVLHBVDTOKS-UHFFFAOYSA-N 1-[4-(2,4-dichlorophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(Cl)C=C1Cl JZACVLHBVDTOKS-UHFFFAOYSA-N 0.000 claims description 3
AKJWCZCDAPJZQR-UHFFFAOYSA-N 1-[4-(2,4-difluorophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(F)C=C1F AKJWCZCDAPJZQR-UHFFFAOYSA-N 0.000 claims description 3
ISZKOVZBYZGFOI-UHFFFAOYSA-N 1-[4-(2,4-dimethylphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound CC1=CC(C)=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 ISZKOVZBYZGFOI-UHFFFAOYSA-N 0.000 claims description 3
RHZMFNXCUKPEKI-UHFFFAOYSA-N 1-[4-(2-chloro-6-hydroxyphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound OC1=CC=CC(Cl)=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 RHZMFNXCUKPEKI-UHFFFAOYSA-N 0.000 claims description 3
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RWHJMHFIXDMCJC-UHFFFAOYSA-N 1-[4-(2-cyanophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=CC=C1C#N RWHJMHFIXDMCJC-UHFFFAOYSA-N 0.000 claims description 3
CGTQAVXGBSUIAB-UHFFFAOYSA-N 1-[4-(2-fluoro-4-methylphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound FC1=CC(C)=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 CGTQAVXGBSUIAB-UHFFFAOYSA-N 0.000 claims description 3
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LWPSMLAPKBLKSQ-UHFFFAOYSA-N 1-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound CC1=NOC(C)=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 LWPSMLAPKBLKSQ-UHFFFAOYSA-N 0.000 claims description 3
WNEYRUZRBQLDFP-UHFFFAOYSA-N 1-[4-(3-fluoro-2-hydroxyphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound OC1=C(F)C=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 WNEYRUZRBQLDFP-UHFFFAOYSA-N 0.000 claims description 3
VJEFMYKXXQWXAP-UHFFFAOYSA-N 1-[4-(3-fluorophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=CC(F)=C1 VJEFMYKXXQWXAP-UHFFFAOYSA-N 0.000 claims description 3
ASRCCDVHJPWBLY-UHFFFAOYSA-N 1-[4-(4-chloro-2-hydroxyphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound OC1=CC(Cl)=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 ASRCCDVHJPWBLY-UHFFFAOYSA-N 0.000 claims description 3
GUOXWXJRPBODNP-UHFFFAOYSA-N 1-[4-(4-chlorophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(Cl)C=C1 GUOXWXJRPBODNP-UHFFFAOYSA-N 0.000 claims description 3
XGAFRTYMPFNLFF-UHFFFAOYSA-N 1-[4-(4-cyanophenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 XGAFRTYMPFNLFF-UHFFFAOYSA-N 0.000 claims description 3
SFDHEXOFDQWSNB-UHFFFAOYSA-N 1-[4-(4-fluoro-2-hydroxyphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound OC1=CC(F)=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 SFDHEXOFDQWSNB-UHFFFAOYSA-N 0.000 claims description 3
YLVLCMUWAPBADG-UHFFFAOYSA-N 1-[4-(5-cyanopyridin-2-yl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound C1=2C(O)=C(C#N)C(=O)NC=2C=CN1C(C=C1)=CC=C1C1=CC=C(C#N)C=N1 YLVLCMUWAPBADG-UHFFFAOYSA-N 0.000 claims description 3
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125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
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OEHRFTBXDCMGLR-UHFFFAOYSA-N 2-chloro-1-[4-(5-fluoro-2-hydroxyphenyl)phenyl]-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound OC1=CC=C(F)C=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2Cl)C=C1 OEHRFTBXDCMGLR-UHFFFAOYSA-N 0.000 claims description 2
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PVELZJYPSHSTPP-UHFFFAOYSA-N 2-chloro-7-hydroxy-6-phenyl-1-[4-(trifluoromethyl)phenyl]-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound O=C1NC=2C=C(Cl)N(C=3C=CC(=CC=3)C(F)(F)F)C=2C(O)=C1C1=CC=CC=C1 PVELZJYPSHSTPP-UHFFFAOYSA-N 0.000 claims description 2
OCPHPGBAQNSHFH-UHFFFAOYSA-N 3-[2-chloro-7-hydroxy-1-(4-methylphenyl)-5-oxo-4h-pyrrolo[3,2-b]pyridin-6-yl]benzoic acid Chemical compound C1=CC(C)=CC=C1N1C(C(O)=C(C=2C=C(C=CC=2)C(O)=O)C(=O)N2)=C2C=C1Cl OCPHPGBAQNSHFH-UHFFFAOYSA-N 0.000 claims description 2
IBLFDOQPBPYTJB-UHFFFAOYSA-N 3-[2-chloro-7-hydroxy-1-(4-methylphenyl)-5-oxo-4h-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile Chemical compound C1=CC(C)=CC=C1N1C(C(O)=C(C=2C=C(C=CC=2)C#N)C(=O)N2)=C2C=C1Cl IBLFDOQPBPYTJB-UHFFFAOYSA-N 0.000 claims description 2
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KIERFPBJKUGMNO-UHFFFAOYSA-N 3-[2-chloro-7-hydroxy-5-oxo-1-(4-thiophen-3-ylphenyl)-4h-pyrrolo[3,2-b]pyridin-6-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C(NC=3C=C(Cl)N(C=3C=2O)C=2C=CC(=CC=2)C2=CSC=C2)=O)=C1 KIERFPBJKUGMNO-UHFFFAOYSA-N 0.000 claims description 2
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125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
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CQWYRICKVIKLCR-UHFFFAOYSA-N 4-[2-chloro-7-hydroxy-1-[4-(2-hydroxy-3-methoxyphenyl)phenyl]-5-oxo-4h-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile Chemical compound COC1=CC=CC(C=2C=CC(=CC=2)N2C=3C(O)=C(C(=O)NC=3C=C2Cl)C=2C=CC(=CC=2)C#N)=C1O CQWYRICKVIKLCR-UHFFFAOYSA-N 0.000 claims description 2
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YKYKUFCQOURZMO-UHFFFAOYSA-N 4-[4-(2-chloro-6-cyano-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridin-1-yl)phenyl]thiophene-3-carboxamide Chemical compound NC(=O)C1=CSC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2Cl)C=C1 YKYKUFCQOURZMO-UHFFFAOYSA-N 0.000 claims description 2
LCDMMZWWOPRAPX-UHFFFAOYSA-N 5-[4-(6-cyano-7-hydroxy-5-oxo-4h-pyrrolo[3,2-b]pyridin-1-yl)phenyl]thiophene-2-sulfonamide Chemical compound S1C(S(=O)(=O)N)=CC=C1C1=CC=C(N2C=3C(O)=C(C#N)C(=O)NC=3C=C2)C=C1 LCDMMZWWOPRAPX-UHFFFAOYSA-N 0.000 claims description 2
PJDGZHXIBGEOHW-UHFFFAOYSA-N 6-(2-fluorophenyl)-7-hydroxy-1-(4-methoxyphenyl)-4h-pyrrolo[3,2-b]pyridin-5-one Chemical compound C1=CC(OC)=CC=C1N1C(C(O)=C(C(=O)N2)C=3C(=CC=CC=3)F)=C2C=C1 PJDGZHXIBGEOHW-UHFFFAOYSA-N 0.000 claims description 2
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