DK1957461T3 - Bisamidhæmmere af hedgehog-signalering - Google Patents
Bisamidhæmmere af hedgehog-signalering Download PDFInfo
- Publication number
- DK1957461T3 DK1957461T3 DK06844364.7T DK06844364T DK1957461T3 DK 1957461 T3 DK1957461 T3 DK 1957461T3 DK 06844364 T DK06844364 T DK 06844364T DK 1957461 T3 DK1957461 T3 DK 1957461T3
- Authority
- DK
- Denmark
- Prior art keywords
- chloro
- phenyl
- nicotinamide
- methyl
- alkyl
- Prior art date
Links
- -1 acylamine Chemical group 0.000 claims description 303
- 125000000217 alkyl group Chemical group 0.000 claims description 105
- 150000001875 compounds Chemical class 0.000 claims description 96
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 90
- 125000000623 heterocyclic group Chemical group 0.000 claims description 67
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 125000002252 acyl group Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 51
- 239000011570 nicotinamide Substances 0.000 claims description 51
- 229960003966 nicotinamide Drugs 0.000 claims description 51
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 51
- 235000005152 nicotinamide Nutrition 0.000 claims description 45
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 41
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 39
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 229940124530 sulfonamide Drugs 0.000 claims description 19
- 150000003456 sulfonamides Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- NHIBDGLYFWBTSK-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-6-chloropyridine-3-carboxamide Chemical compound C1=NC(Cl)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=CC=CC=2)=C1 NHIBDGLYFWBTSK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- ZAIGVERZTSUEJI-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC(NC(=O)C=2C=NC(Cl)=CC=2)=CC=C1Cl ZAIGVERZTSUEJI-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 230000001404 mediated effect Effects 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- DLAVOYHAYUBYBH-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound ClC1=CC=CC(C(=O)NC=2C(=CC=C(NC(=O)C=3C=NC(Cl)=CC=3)C=2)Cl)=C1 DLAVOYHAYUBYBH-UHFFFAOYSA-N 0.000 claims description 10
- 230000033115 angiogenesis Effects 0.000 claims description 10
- BUMIPXWMQKBXQR-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)pyridine-3-carboxamide Chemical compound C1=C(NC(=O)C=2C=CC=CC=2)C(Cl)=CC=C1NC(=O)C1=CC=C(CBr)N=C1 BUMIPXWMQKBXQR-UHFFFAOYSA-N 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 125000006413 ring segment Chemical group 0.000 claims description 10
- SJDJALYZTVCQFF-UHFFFAOYSA-N 6-(bromomethyl)-n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound ClC1=CC=CC(C(=O)NC=2C(=CC=C(NC(=O)C=3C=NC(CBr)=CC=3)C=2)Cl)=C1 SJDJALYZTVCQFF-UHFFFAOYSA-N 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- CFOBDVARPHSHCM-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]-2-methylpyridine-3-carboxamide Chemical compound CC1=NC(Cl)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=C(Cl)C=CC=2)=C1 CFOBDVARPHSHCM-UHFFFAOYSA-N 0.000 claims description 8
- KGHAIQYAUKVPSR-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(4-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NC1=CC(NC(=O)C=2C=NC(Cl)=CC=2)=CC=C1Cl KGHAIQYAUKVPSR-UHFFFAOYSA-N 0.000 claims description 8
- IRVGEFOZMIQFPH-UHFFFAOYSA-N n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC(NC(=O)C=2C=NC(=CC=2)N2CCNCC2)=CC=C1Cl IRVGEFOZMIQFPH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- WRUIXGRWYAORRV-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(2-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound C1=NC(Cl)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C(=CC=CC=2)Cl)=C1 WRUIXGRWYAORRV-UHFFFAOYSA-N 0.000 claims description 7
- BKXOMLCZOBVEAG-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(3-fluorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound FC1=CC=CC(C(=O)NC=2C(=CC=C(NC(=O)C=3C=NC(Cl)=CC=3)C=2)Cl)=C1 BKXOMLCZOBVEAG-UHFFFAOYSA-N 0.000 claims description 7
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 208000026278 immune system disease Diseases 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000565 sulfonamide group Chemical group 0.000 claims description 7
- KGYYDBVEOJFKON-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(2-fluorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound FC1=CC=CC=C1C(=O)NC1=CC(NC(=O)C=2C=NC(Cl)=CC=2)=CC=C1Cl KGYYDBVEOJFKON-UHFFFAOYSA-N 0.000 claims description 6
- LKXZBHKMXDZFEY-UHFFFAOYSA-N 6-chloro-n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]-2-methylpyridine-3-carboxamide Chemical compound CC1=NC(Cl)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=CC(F)=CC=2)=C1 LKXZBHKMXDZFEY-UHFFFAOYSA-N 0.000 claims description 6
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 5
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- 206010052779 Transplant rejections Diseases 0.000 claims description 5
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- 201000008275 breast carcinoma Diseases 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- MDHDXACOTZFIHY-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-6-chloro-2-methylpyridine-3-carboxamide Chemical compound CC1=NC(Cl)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=CC=CC=2)=C1 MDHDXACOTZFIHY-UHFFFAOYSA-N 0.000 claims description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 5
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 4
- WABQKRNJMBSQMB-UHFFFAOYSA-N 6-(4-acetylpiperazin-1-yl)-n-[4-chloro-3-[(4-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound C1CN(C(=O)C)CCN1C1=CC=C(C(=O)NC=2C=C(NC(=O)C=3C=CC(Cl)=CC=3)C(Cl)=CC=2)C=N1 WABQKRNJMBSQMB-UHFFFAOYSA-N 0.000 claims description 4
- KUFHOIZRNPQYLI-UHFFFAOYSA-N 6-(4-acetylpiperazin-1-yl)-n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]-2-methylpyridine-3-carboxamide Chemical compound C1CN(C(=O)C)CCN1C(N=C1C)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=CC(F)=CC=2)=C1 KUFHOIZRNPQYLI-UHFFFAOYSA-N 0.000 claims description 4
- SCXOPJLGWZCMOL-UHFFFAOYSA-N 6-[(4-acetylpiperazin-1-yl)methyl]-n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound C1CN(C(=O)C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC(=O)C=3C=C(Cl)C=CC=3)C(Cl)=CC=2)C=N1 SCXOPJLGWZCMOL-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
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- BGMXZZNMUQEDLF-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-2-methyl-4-phenylpyrimidine-5-carboxamide Chemical compound C=1C=CC=CC=1C1=NC(C)=NC=C1C(=O)NC(C=1)=CC=C(Cl)C=1NC(=O)C1=CC=CC=C1 BGMXZZNMUQEDLF-UHFFFAOYSA-N 0.000 claims description 4
- INHZYOWKDGYIMC-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-2-phenyl-1,3-thiazole-4-carboxamide Chemical compound C1=C(NC(=O)C=2C=CC=CC=2)C(Cl)=CC=C1NC(=O)C(N=1)=CSC=1C1=CC=CC=C1 INHZYOWKDGYIMC-UHFFFAOYSA-N 0.000 claims description 4
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- VURIHKMGNGBSFS-UHFFFAOYSA-N n-(3-benzamido-4-chlorophenyl)-6-morpholin-4-ylpyridine-3-carboxamide Chemical compound C1=C(NC(=O)C=2C=CC=CC=2)C(Cl)=CC=C1NC(=O)C(C=N1)=CC=C1N1CCOCC1 VURIHKMGNGBSFS-UHFFFAOYSA-N 0.000 claims description 4
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- CSFAEEBDMGKDKY-UHFFFAOYSA-N n-[4-chloro-3-[(2-morpholin-4-ylbenzoyl)amino]phenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide Chemical compound CC1=NC(C(F)(F)F)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C(=CC=CC=2)N2CCOCC2)=C1 CSFAEEBDMGKDKY-UHFFFAOYSA-N 0.000 claims description 4
- TZCSEURJEIFSFX-UHFFFAOYSA-N n-[4-chloro-3-[(3-chloro-4-fluorobenzoyl)amino]phenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide Chemical compound CC1=NC(C(F)(F)F)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=C(Cl)C(F)=CC=2)=C1 TZCSEURJEIFSFX-UHFFFAOYSA-N 0.000 claims description 4
- HHGGELGIWCMDQB-UHFFFAOYSA-N n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]-6-(4-hydroxypiperidin-1-yl)-2-methylpyridine-3-carboxamide Chemical compound CC1=NC(N2CCC(O)CC2)=CC=C1C(=O)NC(C=1)=CC=C(Cl)C=1NC(=O)C1=CC=CC(Cl)=C1 HHGGELGIWCMDQB-UHFFFAOYSA-N 0.000 claims description 4
- YZPHNIDWIKXVML-IYBDPMFKSA-N n-[4-chloro-3-[(3-chlorobenzoyl)amino]phenyl]-6-[(3r,5s)-3,5-dimethylpiperazin-1-yl]-2-methylpyridine-3-carboxamide Chemical compound C1[C@@H](C)N[C@@H](C)CN1C(N=C1C)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=C(Cl)C=CC=2)=C1 YZPHNIDWIKXVML-IYBDPMFKSA-N 0.000 claims description 4
- YVGZPZQXOQYOKL-UHFFFAOYSA-N n-[4-chloro-3-[(3-fluorobenzoyl)amino]phenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide Chemical compound CC1=NC(C(F)(F)F)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=C(F)C=CC=2)=C1 YVGZPZQXOQYOKL-UHFFFAOYSA-N 0.000 claims description 4
- VPPUAPPRJHCBQG-UHFFFAOYSA-N n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide Chemical compound CC1=NC(C(F)(F)F)=CC=C1C(=O)NC1=CC=C(Cl)C(NC(=O)C=2C=CC(F)=CC=2)=C1 VPPUAPPRJHCBQG-UHFFFAOYSA-N 0.000 claims description 4
- LOWXYZOZNHDYCY-UHFFFAOYSA-N n-[4-chloro-3-[(4-fluorobenzoyl)amino]phenyl]-6-(3-methylpiperazin-1-yl)pyridine-3-carboxamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC=2C=C(NC(=O)C=3C=CC(F)=CC=3)C(Cl)=CC=2)C=N1 LOWXYZOZNHDYCY-UHFFFAOYSA-N 0.000 claims description 4
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Claims (17)
1. Forbindelse med formlen I til anvendelse ved behandling af angiogenese-medierede sygdomme valgt blandt en solid tumor, makulade-generation og en inflammatorisk sygdom eller en immunsygdom, hvor den inflammatoriske sygdom eller immunsygdommen er Crohns sygdom, inflammatorisk tarmsygdom, Sjogrens syndrom, astma, organtransplantat-afstødning, systemisk lupus erythematosus, reumatoid arthritis, psoriasis-arthritis, psoriasis eller multipel sklerose:
Ϊ hvor ringen A er benzen; ringen B er pyridin; carbocyklen er en mono-, bi- eller tricyklisk alifatisk ring med 3 til 14 carbonatomer, som er mættet eller umættet, aromatisk eller ikke-aromatisk; heterocyklen er en mono-, bi- eller tricyklisk, mættet eller umættet, aromatisk eller ikke-aromatisk ring med fra 5 til ca. 14 ringatomer, hvor ringatomerne er 1 til 4 nitrogen-, svovl- eller oxygenheteroatomer, og resten er carbonatomer; Ri er hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl eller sulfonamid; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-og sulfonamidsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; eller Ri er en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl, sulfonamid, en carbocykel eller en heterocykel som defineret ovenfor; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-, sulfonamid-, carbocykel- og heterocykelsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; R2 er hydrogen; R3 er halogen, hydroxy, carboxy, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, en carbocykel eller en heterocykel som defineret ovenfor, hvor hver(t) alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, carbocykel og heterocykel eventuelt er substitueret med hydroxy, halogen, amino, nitro, alkyl, acyl, sulfonyl eller alkoxy; hvert R4 uafhængigt er H eller alkyl; R5 er chlor; m er 0 til 3; n er 0 til 4; eller et salt eller solvat deraf.
2. Forbindelse til anvendelse ved behandling af angiogenesemedierede sygdomme ifølge krav 1, hvor sygdommen med solid tumor er en colon-, lunge-, pankreas-, ovarie-, bryst- eller gliomsygdom med solid tumor, og makuladegenerationssygdommen er våd aldersrelateret makuladegeneration.
3. Anvendelse af en forbindelse med formlen I til fremstilling af et lægemiddel til anvendelse ved behandling af angiogenesemedierede sygdomme valgt blandt en solid tumor, makuladegeneration og en inflammatorisk sygdom/immunsygdom, hvor den inflammatoriske sygdom/immunsygdommen er Crohns sygdom, inflammatorisk tarmsygdom, Sjogrens syndrom, astma, organtransplantatafstødning, systemisk lupus erythematosus, reumatoid arthritis, psoriasisarthritis, psoriasis eller multipel sklerose:
I hvor ringen A er benzen; ringen B er pyridin; carbocyklen er en mono-, bi- eller tricyklisk alifatisk ring med 3 til 14 carbonatomer, som er mættet eller umættet, aromatisk eller ikke-aromatisk; heterocyklen er en mono-, bi- eller tricyklisk, mættet eller umættet, aromatisk eller ikke-aromatisk ring med fra 5 til ca. 14 ringatomer, hvor ringatomerne er 1 til 4 nitrogen-, svovl- eller oxygenheteroatomer, og resten er carbonatomer; Ri er hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl eller sulfonamid; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-og sulfonamidsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; eller Ri er en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl, sulfonamid, en carbocykel eller en heterocykel som defineret ovenfor; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-, sulfonamid-, carbocykel- og heterocykelsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel som defineret ovenfor, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; Fb er hydrogen; Fb er halogen, hydroxy, carboxy, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, en carbocykel eller en heterocykel som defineret ovenfor, hvor hver(t) alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, carbocykel og heterocykel eventuelt er substitueret med hydroxy, halogen, amino, nitro, alkyl, acyl, sulfonyl eller alkoxy; hvert FU uafhængigt er H eller alkyl; R5 er chlor; m er 0 til 3; n er 0 til 4; eller et salt eller solvat deraf.
4. Anvendelse af en forbindelse med formlen I ifølge krav 3, hvor sygdommen med solid tumor er en colon-, lunge-, pankreas-, ovarie-, bryst- eller gliomsygdom med solid tumor, og makuladegenerationssygdommen er våd aldersrelateret makuladegeneration.
5. Forbindelse til anvendelsen ifølge et hvilket som helst af kravene 1 til 4, hvor Ri er alkyl, halogenalkyl, aryl, en heterocykel eller heterocycloalkyl, hvor aryl-, heterocykel- og heterocycloalkylgruppen eventuelt er substitueret med hydroxy, halogen, alkyl, alkanoyl eller hydroxyalkyl.
6. Forbindelse til anvendelsen ifølge krav 5, hvor Ri er Me, CF3, Ph, 4-F-phenyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1 -yl, 3,5-dimethylpiperazin-1 -yl, 4-(2-hydroxyethyl)-piperazin-1 -yl, (4-methylpiperazin-1 -yl)methyl, (4-ethylpiperazin-1 -yl)methyl, (4-acetylpiperazin-1 -yl)methyl, (3,5-dimethylpiperazin-1 -yl)methyl, 4-hydroxypiperidin-1 -yl, (piperidin-1 -yl)methyl, (1 -methylpiperidin-4-ylamino)methyl, morpholino, (3,5-dimethyl)morpholino, morpholinomethyl eller 1/-/-1,2,4-triazol-1-yl.
7. Forbindelse til anvendelsen ifølge et hvilket som helst af kravene 1 til 3 eller 5 til 6, hvor R3 er halogen, alkyl, alkylsulfonyl, alkylsulfonylalkyl eller en heterocykel.
8. Forbindelse til anvendelsen ifølge krav 7, hvor R3 er Me, F, Cl, -CH2-S02-Me, -SC>2-Me, 1H-1,2,4-triazol-1-yl, 1 /-/-imidazol-1 -yl, morpholino, thiomorpholino-methyl (hvor S er i den oxiderede form SO2), 1,2,3-thiadiazol-4-yl eller N-methyl-piperizinyl.
9. Forbindelse til anvendelsen ifølge et hvilket som helst af kravene 1 til 3 eller 5 til 8, hvor begge R4-grupper er H.
10. Forbindelse til anvendelsen ifølge et hvilket som helst af kravene 1 til 3 eller 5 til 9, hvor sygdommen er cancer, hvor canceren er en cancer med solid tumor.
11. Forbindelse til anvendelsen ifølge krav 10, hvor sygdommen er basalcellekarcinom, medullablastom, meningiom, hæmangiom, glioblastom, pancreas-adenokarcinom, pianocellulært lungekarcinom, småcellet lungekarcinom, ikke-småcellet lungekarcinom, chondrosarkom, mammakarcinom, rhabdomyosarkom, øsofaguscancer, mavecancer, galdevejscancer, nyrekarcinom eller thyroideakarcinom.
12. Forbindelse med formlen II:
11 hvor: X er CRi; Yer CRi; Ri er hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl eller sulfonamid; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-og sulfonamidsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; eller Ri er en carbocykel eller en heterocykel, der eventuelt er substitueret med hydroxy, halogen, amino, nitro, cyano, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamin, sulfamoyl, sulfonamid, en carbocykel eller en heterocykel; hvor amino-, alkyl-, acyl-, sulfonyl-, sulfinyl-, alkoxy-, carbamoyl-, acylamin-, sulfamoyl-, sulfonamid-, carbocykel- og heterocykelsubstituenten eventuelt er substitueret med amino, halogen, hydroxy, oxo eller er substitueret med en carbocykel eller en heterocykel, der eventuelt er substitueret med hydroxy, amino, halogen, halogenalkyl, alkyl, alkoxy eller acyl; carbocyklen er en mono-, bi- eller tricyklisk alifatisk ring med 3 til 14 carbonatomer, som er mættet eller umættet, aromatisk eller ikke-aromatisk; heterocyklen er en mono-, bi- eller tricyklisk, mættet eller umættet, aromatisk eller ikke-aromatisk ring med fra 5 til ca. 14 ringatomer, hvor ringatomerne er 1 til 4 nitrogen-, svovl- eller oxygenheteroatomer, og resten er carbonatomer; R2 er hydrogen; R3 er halogen, hydroxy, carboxy, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, en carbocykel eller en heterocykel som defineret ovenfor, hvor hver(t) alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, sulfid, sulfinyl, sulfonyl, carbocykel og heterocykel eventuelt er substitueret med hydroxy, halogen, amino, nitro, alkyl, acyl, sulfonyl eller alkoxy; R4 er H eller alkyl; R5 er chlor; m er 0 til 3; n er 0 til 4; eller et salt eller solvat deraf.
13. Forbindelse ifølge krav 12 til anvendelse ved behandling af cancer hos et pattedyr, hvor canceren er en cancer med solid tumor.
14. Forbindelse til anvendelse ifølge krav 13, hvor canceren er basalcellekarcinom, medullablastom, pancreas-adenokarcinom, småcellet lungekarcinom, mammakarcinom, rhabdomyosarkom, øsofaguscancer, mavecancer, galdevejscancer.
15. Forbindelse ifølge krav 12 til anvendelse ved behandling af angiogenesemedierede sygdomme valgt blandt en solid tumor, makuladegeneration, og følgende inflammatoriske sygdomme eller immunsygdomme: Crohns sygdom, inflammatorisk tarmsygdom, Sjogrens syndrom, astma, organtransplantatafstødning, systemisk lupus erythematosus, reumatoid arthritis, psoriasisarthritis, psoriasis eller multipel sklerose hos et pattedyr.
16. Anvendelse af forbindelsen ifølge krav 12 til fremstilling af et lægemiddel til behandling af angiogenesemedierede sygdomme valgt blandt en solid tumor, makuladegeneration, og følgende inflammatoriske sygdomme eller immunsygdomme: Crohns sygdom, inflammatorisk tarmsygdom, Sjogrens syndrom, astma, organtransplantatafstødning, systemisk lupus erythematosus, reumatoid arthritis, psoriasisarthritis, psoriasis eller multipel sklerose.
17. Forbindelse valgt fra gruppen bestående af: N-(3-benzamido-4-chlorphenyl)-4-methyl-6-(trifluormethyl)nicotinamid; N-(4-chlor-3-(2-chlorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(4-chlorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(2-fluorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(3-fluorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(3,4-difluorbenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(4-chlor-3-(3-chlor-4-fluorbenzamido)phenyl)-2-methyl-6- (trifluormethyl)-nicotinamid; N-(4-chlor-3-(2-morpholinobenzamido)phenyl)-2-methyl-6- (trifluormethyl)-nicotinamid; N-(4-chlor-3-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)-2-methyl-6- (trifluormethyl)nicotinamid; N-(4-chlor-3-(4-methoxybenzamido)phenyl)-2-methyl-6-(trifluormethyl)- nicotinamid; N-(3-(4-(1,2,3-thiadiazol-4-yl)benzamido)-4-chlorphenyl)-2-methyl-6- (trifluormethyl)nicotinamid; N-(3-(4-(1H-imidazol-1-yl)benzamido)-4-chlorphenyl)-2-methyl-6- (trifluormethyl)nicotinamid; N-(3-(4-(1 H-1,2,4-triazol-1 -yl)benzamido)-4-chlorphenyl)-2-methyl-6-(trifluormethyl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-morpholinonicotinamid; N-(3-benzamido-4-chlorphenyl)-2-methyl-4-phenylpyrimidin-5- carboxamid; N-(3-benzamido-4-chlorphenyl)-1-(4-fluorphenyl)-4-methyl-1H-pyrazol-3- carboxamid; N-(3-benzamido-4-chlorphenyl)-4-methyl-2-phenylpyrimidin-5- carboxamid; N-(3-benzamido-4-chlorphenyl)-6-chlornicotinamid; N-(3-benzamido-4-chlorphenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)- nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(4-ethylpiperazin-1-yl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)- nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(2,6-dimethylmorpholino)nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(3-benzamido-4-chlorphenyl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(3-methylpiperazin-1-yl)nicotinamid; (R) -N-(3-benzamido-4-chlorphenyl)-6-(3-methylpiperazin-1-yl)nicotinamid; (S) -N-(3-benzamido-4-chlorphenyl)-6-(3-methylpiperazin-1-yl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(piperazin-1-yl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-chlor-2-methylnicotinamid; N-(3-benzamido-4-chlorphenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2- methyl-nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(brommethyl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(morpholinomethyl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-(piperidin-1-ylmethyl)nicotinamid; N-(3-benzamido-4-chlorphenyl)-6-((4-methylpiperazin-1-yl)methyl)- nicotinamid; N-(3-benzamido-4-chlorphenyl)-2-phenylthiazol-4-carboxamid; 6-chlor-N-(4-chlor-3-(4-fluorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(4-hydroxypiperidin-1- yl)nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(4-fluorbenzamido)- phenyl)nicotinamid; 6-(4-methylsulfonylpiperazin-1-yl-N-(4-chlor-3-(4-fluorbenzamido)phenyl- nicotinamid; N-(3-(4-fluorbenzamido)-4-chlorphenyl)-6-(4-propionylpiperazin-1- yl)pyridin-3-carboxamid; 6-(4-(3-methylbutanoyl)piperazin-1-yl)-N-(3-(4-fluorbenzamido)-4- chlorphenyl)pyridin-3-carboxamid; N-(3-(4-fluorbenzamido)-4-chlorphenyl)-6-(4- cyclopropylcarbonylpiperazin-1-yl)pyridin-3-carboxamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(4-ethylpiperazin-1- yl)nicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(piperazin-1-yl)nicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(3-methylpiperazin-1 -yl)nicotinamid; (R) -N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(3-methylpiperazin-1-yl)-nicotinamid; (S) -N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(3-methylpiperazin-1-yl)-nicotinamid; 6-chlor-N-(4-chlor-3-(4-fluorbenzamido)phenyl)-2-methylnicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2- methylnicotinamid; N-(4-chlor-3-(4-fluorbenzamido)phenyl)-6-(3,5-dimethylpiperazin-1-yl)-2- methylnicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(4-fluorbenzamido)phenyl)-2- methylnicotinamid; 6-chlor-N-(4-chlor-3-(3-chlorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpjperazin-1-yl)nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(3-chlorbenzamido)phenyl)- nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(4-ethylpiperazin-1- yl)nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(piperazin-1-yl)nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(4-(2-hydroxyethyl)piperazin- 1-yl)-nicotinamid; 6-(brommethyl)-N-(4-chlor-3-(3-chlorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((4-ethylpiperazin-1-yl)methyl)- nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((4-methylpiperazin-1- yl)methyl)-nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((1-methylpiperidin-4- ylamino)methyl)nicotinamid; 6-((4-acetylpiperazin-1-yl)methyl)-N-(4-chlor-3-(3- chlorbenzamido)phenyl)-nicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(((3S,5R)-3,5- dimethylpiperazin-1-yl)methyl)nicotinamid; 6-chlor-N-(4-chlor-3-(3-chlorbenzamido)phenyl)-2-methylnicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)-2-methylnicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2- methylnicotinamid; 6-chlor-N-(4-chlor-3-(3-chlorbenzamido)phenyl)-2-methylnicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)-2-methylnicotinamid; N-(4-chlor-3-(3-chlorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-2- methylnicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(3-chlorbenzamido)phenyl)-2- methyl-nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(2-chlorbenzamido)- phenyl)nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(2-fluorbenzamido)- phenyl)nicotinamid; 6-chlor-N-(4-chlor-3-(3-fluorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(3-fluorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)-nicotinamid; N-(4-chlor-3-(3-fluorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(3-fluorbenzamido)phenyl)- nicotinamid; 6-chlor-N-(4-chlor-3-(2-fluorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(2-fluorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(2-fluorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-chlor-N-(4-chlor-3-(4-chlorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(4-chlorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(4-chlorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(4-chlorbenzamido)phenyl)- nicotinamid; 6-chlor-N-(4-chlor-3-(2-chlorbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(2-chlorbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(2-chlorbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-chlor-N-(4-chlor-3-(4-methylbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(4-methylbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(4-methylbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(4-methylbenzamido)phenyl)- nicotinamid; 6-chlor-N-(4-chlor-3-(2-methylbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(2-methylbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(2-methylbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)- nicotinamid; 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(2-methylbenzamido)phenyl)- nicotinamid; 6-chlor-N-(4-chlor-3-(3-methylbenzamido)phenyl)nicotinamid; N-(4-chlor-3-(3-methylbenzamido)phenyl)-6-((3S,5R)-3,5- dimethylpiperazin-1-yl)nicotinamid; N-(4-chlor-3-(3-methylbenzamido)phenyl)-6-(4-hydroxypiperidin-1-yl)-nicotinamid; og 6-(4-acetylpiperazin-1-yl)-N-(4-chlor-3-(3-methylbenzamido)phenyl)- nicotinamid.
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DK06844364.7T DK1957461T3 (da) | 2005-11-14 | 2006-11-14 | Bisamidhæmmere af hedgehog-signalering |
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US (1) | US8101610B2 (da) |
EP (1) | EP1957461B1 (da) |
JP (2) | JP5225857B2 (da) |
AU (1) | AU2006315467B2 (da) |
CA (1) | CA2629814C (da) |
DK (1) | DK1957461T3 (da) |
ES (1) | ES2604539T3 (da) |
WO (1) | WO2007059157A1 (da) |
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AU2005293384A1 (en) | 2004-10-15 | 2006-04-20 | Astrazeneca Ab | Quinoxalines as B Raf inhibitors |
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- 2006-11-14 WO PCT/US2006/044240 patent/WO2007059157A1/en active Application Filing
- 2006-11-14 AU AU2006315467A patent/AU2006315467B2/en not_active Ceased
- 2006-11-14 EP EP06844364.7A patent/EP1957461B1/en active Active
- 2006-11-14 JP JP2008541289A patent/JP5225857B2/ja not_active Expired - Fee Related
- 2006-11-14 CA CA2629814A patent/CA2629814C/en not_active Expired - Fee Related
- 2006-11-14 DK DK06844364.7T patent/DK1957461T3/da active
- 2006-11-14 ES ES06844364.7T patent/ES2604539T3/es active Active
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Also Published As
Publication number | Publication date |
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CA2629814A1 (en) | 2007-05-24 |
WO2007059157A1 (en) | 2007-05-24 |
AU2006315467B2 (en) | 2013-02-07 |
EP1957461A1 (en) | 2008-08-20 |
AU2006315467A1 (en) | 2007-05-24 |
JP2013079283A (ja) | 2013-05-02 |
EP1957461B1 (en) | 2016-11-02 |
ES2604539T3 (es) | 2017-03-07 |
US8101610B2 (en) | 2012-01-24 |
US20080269215A1 (en) | 2008-10-30 |
JP5225857B2 (ja) | 2013-07-03 |
JP2009516685A (ja) | 2009-04-23 |
CA2629814C (en) | 2013-12-31 |
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