BR112014032745B1 - Novos derivados de piridina fundidas úteis como inibidores de tirosina-quinase c-met - Google Patents

Info

Publication number

BR112014032745B1

BR112014032745B1 BR112014032745-9A BR112014032745A BR112014032745B1 BR 112014032745 B1 BR112014032745 B1 BR 112014032745B1 BR 112014032745 A BR112014032745 A BR 112014032745A BR 112014032745 B1 BR112014032745 B1 BR 112014032745B1

Authority

BR

Brazil

Prior art keywords

phenyl

dihydro

yloxy

fluoro

oxo

Prior art date

2012-06-29

Links

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• 229940121358 tyrosine kinase inhibitor Drugs 0.000 title abstract 2
• 239000005483 tyrosine kinase inhibitor Substances 0.000 title abstract 2
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims description 129
• 239000001257 hydrogen Substances 0.000 claims description 97
• 229910052739 hydrogen Inorganic materials 0.000 claims description 97
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
• 150000002431 hydrogen Chemical group 0.000 claims description 58
• 229910052736 halogen Inorganic materials 0.000 claims description 50
• 150000002367 halogens Chemical group 0.000 claims description 50
• 206010028980 Neoplasm Diseases 0.000 claims description 46
• 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 31
• 201000011510 cancer Diseases 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
• 239000008194 pharmaceutical composition Substances 0.000 claims description 23
• 239000002253 acid Substances 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
• IZTVDTIADHKZNM-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CNC=C1C1=CC=C(F)C=C1 IZTVDTIADHKZNM-UHFFFAOYSA-N 0.000 claims description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
• 206010027476 Metastases Diseases 0.000 claims description 8
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• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 208000035475 disorder Diseases 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• 230000009401 metastasis Effects 0.000 claims description 7
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
• WLIZYVKCXBYABW-UHFFFAOYSA-N n-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazin-8-yloxy)phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1)=CC=C1OC1=CC=NC2=C1OCCN2 WLIZYVKCXBYABW-UHFFFAOYSA-N 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
• 206010017758 gastric cancer Diseases 0.000 claims description 5
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
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• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
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• 208000020816 lung neoplasm Diseases 0.000 claims description 4
• HMLAPEFIMHQHAK-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-oxo-n-[4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)phenyl]-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1)=CC=C1OC1=CC=NC2=C1OCCCN2 HMLAPEFIMHQHAK-UHFFFAOYSA-N 0.000 claims description 3
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• 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims description 3
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• NAQXSTWFIQVVRY-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1CC(=O)N2 NAQXSTWFIQVVRY-UHFFFAOYSA-N 0.000 claims description 3
• VGCVRWZIPZWDPL-UHFFFAOYSA-N n-[3-fluoro-4-[[3-(2-hydroxyethyl)-2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C=12C(CCO)CNC2=NC=CC=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 VGCVRWZIPZWDPL-UHFFFAOYSA-N 0.000 claims description 3
• DGMFNZXEGKFREH-UHFFFAOYSA-N n-[4-(2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1CCN2 DGMFNZXEGKFREH-UHFFFAOYSA-N 0.000 claims description 3
• OTCZXXKLOWXXFL-UHFFFAOYSA-N n-[4-[(2,2-difluoro-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1CC(F)(F)N2 OTCZXXKLOWXXFL-UHFFFAOYSA-N 0.000 claims description 3
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• UKYXBGZGMZUGHG-UHFFFAOYSA-N 5-(4-fluorophenyl)-4-oxo-n-[4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]thiazepin-9-yloxy)phenyl]-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1)=CC=C1OC1=CC=NC2=C1SCCCN2 UKYXBGZGMZUGHG-UHFFFAOYSA-N 0.000 claims description 2
• DZRJUGZZXNPYHY-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-[3-fluoro-4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)phenyl]-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1OCCCN2 DZRJUGZZXNPYHY-UHFFFAOYSA-N 0.000 claims description 2
• XVFFVRKZIUKGAX-UHFFFAOYSA-N 5-(4-fluorophenyl)-n-[3-fluoro-4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]thiazepin-9-yloxy)phenyl]-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1SCCCN2 XVFFVRKZIUKGAX-UHFFFAOYSA-N 0.000 claims description 2
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
• 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
• 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 2
• 208000027927 Hereditary papillary renal cell carcinoma Diseases 0.000 claims description 2
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
• 206010025538 Malignant ascites Diseases 0.000 claims description 2
• 206010029260 Neuroblastoma Diseases 0.000 claims description 2
• 201000000582 Retinoblastoma Diseases 0.000 claims description 2
• 206010039491 Sarcoma Diseases 0.000 claims description 2
• 208000005017 glioblastoma Diseases 0.000 claims description 2
• 230000009033 hematopoietic malignancy Effects 0.000 claims description 2
• 201000010982 kidney cancer Diseases 0.000 claims description 2
• 201000001441 melanoma Diseases 0.000 claims description 2
• LEHXYZCOHFNEIQ-UHFFFAOYSA-N n-[3-fluoro-4-[(3-oxo-4h-pyrido[3,2-b][1,4]oxazin-8-yl)oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1OCC(=O)N2 LEHXYZCOHFNEIQ-UHFFFAOYSA-N 0.000 claims description 2
• MMYWEXNODBDKCL-UHFFFAOYSA-N n-[3-fluoro-4-[[2-(hydroxymethyl)-3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazin-8-yl]oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C=12OC(CO)CNC2=NC=CC=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 MMYWEXNODBDKCL-UHFFFAOYSA-N 0.000 claims description 2
• BTPLOKSZZUQPOT-UHFFFAOYSA-N n-[4-[(3,3-dimethyl-2,4-dihydropyrido[3,2-b][1,4]thiazin-8-yl)oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CN=C2NC(C)(C)CSC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 BTPLOKSZZUQPOT-UHFFFAOYSA-N 0.000 claims description 2
• XGDZIDIBULRTBN-UHFFFAOYSA-N n-[4-[(3,4-dimethyl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CN=C2NC(C)C(C)COC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 XGDZIDIBULRTBN-UHFFFAOYSA-N 0.000 claims description 2
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• BXAOWYGNLKPHSL-UHFFFAOYSA-N 2-(4-fluoroanilino)-3-methyl-5-[5-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)pyridin-2-yl]pyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4OCCCNC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 BXAOWYGNLKPHSL-UHFFFAOYSA-N 0.000 claims 1
• JBZTXEHTQXPUHW-UHFFFAOYSA-N 2-(4-fluoroanilino)-3-methyl-5-[5-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]thiazepin-9-yloxy)pyridin-2-yl]pyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4SCCCNC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 JBZTXEHTQXPUHW-UHFFFAOYSA-N 0.000 claims 1
• ZJDWVOKEDWFBCQ-UHFFFAOYSA-N 5-[5-(3,4-dihydro-2h-pyrido[3,2-b][1,4]thiazin-8-yloxy)pyridin-2-yl]-2-(4-fluoroanilino)-3-methylpyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4SCCNC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 ZJDWVOKEDWFBCQ-UHFFFAOYSA-N 0.000 claims 1
• SIULNZPSBTZEPG-UHFFFAOYSA-N 5-[5-[(3,3-dimethyl-2,4-dihydropyrido[3,2-b][1,4]oxazin-8-yl)oxy]pyridin-2-yl]-2-(4-fluoroanilino)-3-methylpyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4OCC(C)(C)NC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 SIULNZPSBTZEPG-UHFFFAOYSA-N 0.000 claims 1
• RMIXTFLTXNXKKL-UHFFFAOYSA-N 5-[5-[(3,3-dimethyl-2,4-dihydropyrido[3,2-b][1,4]thiazin-8-yl)oxy]pyridin-2-yl]-2-(4-fluoroanilino)-3-methylpyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4SCC(C)(C)NC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 RMIXTFLTXNXKKL-UHFFFAOYSA-N 0.000 claims 1
• VPJGESSPJGADBC-UHFFFAOYSA-N 8-[6-[2-(4-fluoroanilino)-1-methyl-6-oxopyrimidin-5-yl]pyridin-3-yl]oxy-4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4OCC(=O)NC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 VPJGESSPJGADBC-UHFFFAOYSA-N 0.000 claims 1
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• ZYWWEIUYYFNZPL-UHFFFAOYSA-N n-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]thiazin-8-yloxy)-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1SCCN2 ZYWWEIUYYFNZPL-UHFFFAOYSA-N 0.000 claims 1
• JNPQWGVVQFLTKH-UHFFFAOYSA-N n-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]thiazin-8-yloxy)phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1)=CC=C1OC1=CC=NC2=C1SCCN2 JNPQWGVVQFLTKH-UHFFFAOYSA-N 0.000 claims 1
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• UUBMZBPHSSCCGT-UHFFFAOYSA-N n-[4-[(3,3-dimethyl-2,4-dihydropyrido[3,2-b][1,4]oxazin-8-yl)oxy]phenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CN=C2NC(C)(C)COC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 UUBMZBPHSSCCGT-UHFFFAOYSA-N 0.000 claims 1
• IEWKIQPDCLBITI-UHFFFAOYSA-N n-[4-[[2-(aziridin-1-ylmethyl)-3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazin-8-yl]oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1C(C1=O)=CNC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1OC(CN1CC1)CN2 IEWKIQPDCLBITI-UHFFFAOYSA-N 0.000 claims 1
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