RU2016139690A - Новые соединения в качестве ингибиторов гистондеацетилазы 6 и содержащие их фармацевтические композиции - Google Patents
Новые соединения в качестве ингибиторов гистондеацетилазы 6 и содержащие их фармацевтические композиции Download PDFInfo
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- RU2016139690A RU2016139690A RU2016139690A RU2016139690A RU2016139690A RU 2016139690 A RU2016139690 A RU 2016139690A RU 2016139690 A RU2016139690 A RU 2016139690A RU 2016139690 A RU2016139690 A RU 2016139690A RU 2016139690 A RU2016139690 A RU 2016139690A
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- RU
- Russia
- Prior art keywords
- methyl
- hydroxybenzamide
- benzyl
- dimethylpiperazin
- dimethyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims 19
- 239000008194 pharmaceutical composition Substances 0.000 title claims 3
- 239000003112 inhibitor Substances 0.000 title 1
- -1 atoms halogen Chemical class 0.000 claims 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 63
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 21
- 150000003839 salts Chemical class 0.000 claims 14
- 239000004305 biphenyl Substances 0.000 claims 12
- 125000000217 alkyl group Chemical group 0.000 claims 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 10
- 229910052739 hydrogen Inorganic materials 0.000 claims 10
- 239000001257 hydrogen Substances 0.000 claims 10
- 125000005843 halogen group Chemical group 0.000 claims 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 4
- WSTPEHQLWFLDFZ-OKILXGFUSA-N 4-[[(3S,5R)-3,5-dimethyl-4-(thiophene-2-carbonyl)piperazin-1-yl]methyl]-N-hydroxybenzamide Chemical compound C[C@@H]1CN(C[C@@H](N1C(=O)C=1SC=CC1)C)CC1=CC=C(C(=O)NO)C=C1 WSTPEHQLWFLDFZ-OKILXGFUSA-N 0.000 claims 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 3
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- UWMWCMUSYUISMV-IYBDPMFKSA-N ONC(=O)C1=CC=C(CN2[C@@H](CN(C[C@@H]2C)C(=O)NC2=CC=CC=C2)C)C=C1 Chemical compound ONC(=O)C1=CC=C(CN2[C@@H](CN(C[C@@H]2C)C(=O)NC2=CC=CC=C2)C)C=C1 UWMWCMUSYUISMV-IYBDPMFKSA-N 0.000 claims 1
- HXBOCEHDKKEVJJ-CALCHBBNSA-N ONC(=O)C1=CC=C(CN2[C@@H](CN(C[C@@H]2C)C(=O)NCC2=CC(=CC=C2)OC)C)C=C1 Chemical compound ONC(=O)C1=CC=C(CN2[C@@H](CN(C[C@@H]2C)C(=O)NCC2=CC(=CC=C2)OC)C)C=C1 HXBOCEHDKKEVJJ-CALCHBBNSA-N 0.000 claims 1
- 229960001171 acetohydroxamic acid Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
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Claims (72)
1. Соединение, представленное следующей формулой I, его изомер или его фармацевтически приемлемая соль:
Формула I
где
R1 представляет собой водород или -CH3,
R2 представляет собой водород или -CH3, при условии, что R2 представляет собой -CH3, когда R1 представляет собой водород, и R2 представляет собой водород, когда R1 представляет собой -CH3
L представляет собой -(C4-C5 алкил)-; -(C1-C3 алкил)-L1-; -C(=O)-L1- или -S(=O)2-L1-,
где -(C4-C5 алкил)- и -(C1-C3 алкил)- могут быть незамещенными или замещены -CH3,
A1 и A2, каждый, независимо, представляют собой -N- или -CR3-, при условии, что оба, A1 и A2, не могут представлять собой -N-,
R3 представляет собой водород; -F, -Cl, -Br, -I или -OH, и
A3 представляет собой -NH- или -O-,
где -(C1-C6)алкил- и -(C2-C6)алкенил- могут быть незамещенными, или каждый, независимо друг от друга, может быть замещен от 1 до 3 группами -CH3 или атомами галогена,
Q1 представляет собой водород; -F, -Cl, -Br или -I,
X может быть выбран из группы, включающей -C1-C6 алкил; -C3-C6 циклоалкил; -C2-C6 алкенил; -C3-C6 циклоалкенил; -(C0-C2 алкил)Ar; -OAr; -(C0-C2 алкил)Het; нафтил и следующие группы:
где R4 представляет собой H или -C1-C4 алкил,
-C0-C2 алкил, -C2-C6 алкенил и -C1-C6 алкил могут быть незамещенными или замещены от 1 до 2 группами -CH3; от 1 до 3 группами -F или их комбинацией,
Ar представляет собой C6 моноциклическую ароматическую группу, которая может быть незамещенной или замещена одним или несколькими атомами галогена; группами -OH; -NH2; -C1-C6 алкил; -O(C1-C6)алкил; -C3-C6 циклоалкенил; -NH(C1-C6 алкил); -N(C1-C3 алкил)2; -CH2N(C1-C3 алкил)2; -S(=O)2-(C1-C3 алкил) или фенил, где -C1-C3 алкил; -C1-C6 алкил и -C3-C6 циклоалкенил, каждый, могут быть независимо замещены от 1 до 5 группами -F или -CH3, и
Het представляет собой 4-6-членное гетероароматическую или неароматическую кольцевую группу, содержащую от 1 до 3 элементов, выбранных из группы, включающей N, O и S, содержащую от 0 до 3 двойных связей, и может быть незамещенной или замещена одним или несколькими атомами галогена; группами -C1-C6 алкил; -C(=O)(C1-C3 алкил); -S(=O)2(C1-C3 алкил) или бензил, где -C1-C3 алкил и -C1-C6 алкил, каждый, могут быть необязательно замещены -OH; от 1 до 5 группами -F или -CH3.
2. Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.1, где соединение, представленное формулой I является соединением, представленным следующей формулой II или формула III:
Формула II
Формула III
где
L представляет собой -(C5 алкил)-; -(C1-C2 алкил)-L1-; -C(=O)-L1- или -S(=O)2-L1-,
где -(C5 алкил)- и -(C1-C2 алкил)- имеют прямую цепь и могут быть незамещенными или замещены -CH3,
A1 и A2, каждый, независимо, представляют собой -N- или -CR3-, при условии, что оба, A1 и A2, не могут представлять собой -N-,
R3 представляет собой водород, -F или -OH, и
A3 представляет собой -NH- или -O-,
где -(C1-C3)алкил- может быть незамещенным или замещен от 1 до 3 группами -CH3 или атомами галогена,
Q1 представляет собой водород; -F или -Cl,
X может быть выбран из группы, включающей -C1-C6 алкил; -C3-C6 циклоалкил; -C2-C6 алкенил; -C3-C6 циклоалкенил; -(C0-C2 алкил)Ar; -OAr; -(C0-C2 алкил)Het; нафтил; и следующие группы:
где R4 представляет собой H или -C1-C4 алкил,
-C0-C2 алкил; -C2-C6 алкенил и -C1-C6 алкил могут быть незамещенными или замещены 1 или 2 группами -CH3 или от 1 до 3 группами -F,
Ar представляет собой C6 моноциклическую ароматическую группу, которая может быть незамещенной или замещена одним или несколькими атомами галогена; группами -OH; -NH2; -C1-C6 алкил; -O(C1-C6)алкил; -C3-C6 циклоалкенил; -NH(C1-C6 алкил); -N(C1-C3 алкил)2; -CH2N(C1-C3 алкил)2; -S(=O)2-(C1-C3 алкил) или фенил, где -C1-C3 алкил; -C1-C6 алкил и -C3-C6 циклоалкенил, каждый, могут быть независимо замещены от 1 до 5 группами -F или -CH3, и
Het представляет собой 4-6-членное гетероароматическую или неароматическую кольцевую группу, содержащую от 1 до 3 элементов, выбранных из группы, включающей N; O и S, содержащую от 0 до 3 двойных связей, и может быть незамещенной или замещена одним или несколькими атомами галогена; группами -C1-C6 алкил; -C(=O)(C1-C3 алкил); -S(=O)2(C1-C3 алкил) или бензил, где -C1-C3 алкил и -C1-C6 алкил, каждый, могут быть необязательно замещены -OH; или от 1 до 5 группами -F или -CH3.
3.Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.1, где Het выбран из следующих групп:
где R5, каждый, независимо, представляет собой водород; -F; -Cl; -C1-C6 алкил; -C(=O)(C1-C3 алкил); -S(=O)2(C1-C3 алкил) или бензил, где -C1-C3 алкил и -C1-C6 алкил, каждый, могут быть необязательно замещены -OH; от 1 до 5 группами -F или -CH3,
m обозначает целое число 0, 1, 2 или 3, и
Het является незамещенным, когда m обозначает 0, и Het может быть независимо замещен R5, когда m обозначает 1, 2 или 3.
4. Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.1, где L, L1, A1, A2, A3, R3, R4, Q и X имеют следующие значения:
L представляет собой -CH2-L1-,
где
A1 и A2, каждый, независимо, представляют собой -N- или -CR3-, при условии, что оба, A1 и A2, не могут представлять собой -N-,
R3 представляет собой водород, -F или -OH, и
A3 представляет собой -NH- или -O-,
Q представляет собой -CH2-, -C(=O)- или -S(=O)2-, и
X может быть выбран из группы, включающей -C1-C6 алкил; -(C0-C2 алкил)Ar; -(C0-C2 алкил)Het; -OAr; или следующие группы:
где R4 представляет собой H или -C1-C4 алкил,
-C0-C2 алкил и -C1-C6 алкил могут быть незамещенными или замещены 1 или 2 группами -CH3 и/или от 1 до 3 группами -F, и
Ar и Het, каждый, независимо, имеют значения, определенные при описании формул от I до III.
5. Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.1, где соединение, представленное формулой I, является одним из соединений, указанных в следующей таблице:
6. Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.5, где соединение, представленное формулой I является одним из соединений, указанных в следующей таблице:
7. Соединение, представленное формулой I, его изомер или его фармацевтически приемлемая соль по п.6, где соединение, представленное формулой I является одним из соединений, указанных в следующей таблице:
8. Фармацевтическая композиция, содержащая соединение, представленное формулой I, его изомер или его фармацевтически приемлемую соль в соответствии с любым из пп.1-7.
9. Фармацевтическая композиция по п.8, которая используется для предупреждения или лечения злокачественного новообразования, воспалительных заболеваний, аутоиммунных заболеваний, неврологических заболеваний или нейродегенеративных заболеваний.
10. Способ предупреждения или лечения злокачественного новообразования, воспалительных заболеваний, аутоиммунных заболеваний, неврологических заболеваний или нейродегенеративных заболеваний, включающий введение млекопитающим, включая людей, нуждающимся в этом, композиций, содержащих в качестве активных ингредиентов соединения формулы I, их изомеры их или фармацевтически приемлемые соли в соответствии с любым из пп.1-7.
11. Применение композиций, содержащих в качестве активных ингредиентов соединения формулы I, их изомеры их или фармацевтически приемлемые соли в соответствии с любым из пп.1-7, при получении лекарственных средств для предупреждения или лечения злокачественного новообразования, воспалительных заболеваний, аутоиммунных заболеваний, неврологических заболеваний или нейродегенеративных заболеваний.
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| US9499479B2 (en) | 2011-10-03 | 2016-11-22 | The Trustees Of Columbia University In The City Of New York | Molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase 1 |
| WO2013134467A1 (en) | 2012-03-07 | 2013-09-12 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Selective histone deactylase 6 inhibitors |
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2015
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| AU2015230127A1 (en) | 2016-09-22 |
| JP6392888B2 (ja) | 2018-09-19 |
| EP3116859B1 (en) | 2018-08-01 |
| NZ724030A (en) | 2017-09-29 |
| US10287255B2 (en) | 2019-05-14 |
| JP2017507976A (ja) | 2017-03-23 |
| WO2015137750A1 (en) | 2015-09-17 |
| PH12016501735B1 (en) | 2019-05-31 |
| EP3116859A4 (en) | 2017-02-08 |
| CA2941581A1 (en) | 2015-09-17 |
| EP3116859A1 (en) | 2017-01-18 |
| ES2694053T3 (es) | 2018-12-17 |
| HRP20181534T1 (hr) | 2019-01-11 |
| CA2941581C (en) | 2018-07-24 |
| RU2660897C2 (ru) | 2018-07-11 |
| PT3116859T (pt) | 2018-11-15 |
| PH12016501735A1 (en) | 2017-02-06 |
| PL3116859T3 (pl) | 2019-04-30 |
| MX2016011833A (es) | 2017-03-29 |
| MY177631A (en) | 2020-09-23 |
| CN106232584A (zh) | 2016-12-14 |
| KR20150106857A (ko) | 2015-09-22 |
| US20170096405A1 (en) | 2017-04-06 |
| TR201816176T4 (tr) | 2018-11-21 |
| KR101697518B1 (ko) | 2017-01-19 |
| AU2015230127B2 (en) | 2017-04-20 |
| DK3116859T3 (en) | 2018-11-26 |
| CN106232584B (zh) | 2019-06-28 |
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