CA2878049C - Fused pyridine derivatives useful as c-met tyrosine kinase inhibitors - Google Patents
Fused pyridine derivatives useful as c-met tyrosine kinase inhibitors Download PDFInfo
- Publication number
- CA2878049C CA2878049C CA2878049A CA2878049A CA2878049C CA 2878049 C CA2878049 C CA 2878049C CA 2878049 A CA2878049 A CA 2878049A CA 2878049 A CA2878049 A CA 2878049A CA 2878049 C CA2878049 C CA 2878049C
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- Prior art keywords
- phenyl
- fluoro
- dihydro
- yloxy
- oxo
- Prior art date
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- 150000003222 pyridines Chemical class 0.000 title description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 2
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims description 111
- 239000001257 hydrogen Substances 0.000 claims description 110
- 229910052736 halogen Inorganic materials 0.000 claims description 91
- 150000002431 hydrogen Chemical group 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
- 206010028980 Neoplasm Diseases 0.000 claims description 63
- 150000002367 halogens Chemical group 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 201000011510 cancer Diseases 0.000 claims description 43
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 42
- -1 hydroxy, amino, carboxy Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 39
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- FEHLGOYZDFFMND-UHFFFAOYSA-N cyclopropane-1,1-dicarboxamide Chemical compound NC(=O)C1(C(N)=O)CC1 FEHLGOYZDFFMND-UHFFFAOYSA-N 0.000 claims description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 11
- 208000026278 immune system disease Diseases 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 206010027476 Metastases Diseases 0.000 claims description 10
- 208000022873 Ocular disease Diseases 0.000 claims description 10
- 102000001253 Protein Kinase Human genes 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 230000009401 metastasis Effects 0.000 claims description 10
- 108060006633 protein kinase Proteins 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 208000027927 Hereditary papillary renal cell carcinoma Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 201000002689 pediatric hepatocellular carcinoma Diseases 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 5
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010025538 Malignant ascites Diseases 0.000 claims description 5
- 206010029260 Neuroblastoma Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 201000000582 Retinoblastoma Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 230000009033 hematopoietic malignancy Effects 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
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- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 5
- 208000001608 teratocarcinoma Diseases 0.000 claims description 5
- 102100021435 Macrophage-stimulating protein receptor Human genes 0.000 claims description 4
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- ZMDHKMBAJZASIH-UHFFFAOYSA-N 1-n-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]thiazin-8-yloxy)phenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(OC=3C=4SCCNC=4N=CC=3)=CC=2)CC1 ZMDHKMBAJZASIH-UHFFFAOYSA-N 0.000 claims description 3
- 101100481408 Danio rerio tie2 gene Proteins 0.000 claims description 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims description 3
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims description 3
- 101001106413 Homo sapiens Macrophage-stimulating protein receptor Proteins 0.000 claims description 3
- 101000987310 Homo sapiens Serine/threonine-protein kinase PAK 2 Proteins 0.000 claims description 3
- 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 claims description 3
- 101100481410 Mus musculus Tek gene Proteins 0.000 claims description 3
- 101700056750 PAK1 Proteins 0.000 claims description 3
- 102000001332 SRC Human genes 0.000 claims description 3
- 108060006706 SRC Proteins 0.000 claims description 3
- 102100027910 Serine/threonine-protein kinase PAK 1 Human genes 0.000 claims description 3
- 102100027939 Serine/threonine-protein kinase PAK 2 Human genes 0.000 claims description 3
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 108091008743 testicular receptors 4 Proteins 0.000 claims description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- 239000013522 chelant Substances 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 101100268648 Mus musculus Abl1 gene Proteins 0.000 claims 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 claims 2
- 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 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- FRKYTXQYFMZKNZ-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxo-n-[4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)phenyl]pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=CC(OC=3C=4OCCCNC=4N=CC=3)=CC=2)=CC=C1 FRKYTXQYFMZKNZ-UHFFFAOYSA-N 0.000 claims 1
- OFYUXXBJSFCKRK-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxo-n-[4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]thiazepin-9-yloxy)phenyl]pyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=CC(OC=3C=4SCCCNC=4N=CC=3)=CC=2)=CC=C1 OFYUXXBJSFCKRK-UHFFFAOYSA-N 0.000 claims 1
- WPJGHIVGAOVUAT-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=C(F)C=C1 WPJGHIVGAOVUAT-UHFFFAOYSA-N 0.000 claims 1
- MJGODWYRMWCVJP-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-[3-fluoro-4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)phenyl]-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4OCCCNC=4N=CC=3)=CC=2)=CC=C1 MJGODWYRMWCVJP-UHFFFAOYSA-N 0.000 claims 1
- ZBJUBBZDANWDTM-UHFFFAOYSA-N 1-n'-[3-fluoro-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C=1C=C(F)C=CC=1N(C=1C=C(F)C(OC=2C=3CC(=O)NC=3N=CC=2)=CC=1)C(=O)C1(C(=O)N)CC1 ZBJUBBZDANWDTM-UHFFFAOYSA-N 0.000 claims 1
- HEGQLRSJOYHPJC-UHFFFAOYSA-N 1-n'-[3-fluoro-4-[(3-oxo-4h-pyrido[3,2-b][1,4]oxazin-8-yl)oxy]phenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C=1C=C(F)C=CC=1N(C=1C=C(F)C(OC=2C=3OCC(=O)NC=3N=CC=2)=CC=1)C(=O)C1(C(=O)N)CC1 HEGQLRSJOYHPJC-UHFFFAOYSA-N 0.000 claims 1
- UGAYQTUPHGUJTQ-UHFFFAOYSA-N 1-n'-[3-fluoro-5-methyl-4-[(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C=1C(F)=C(OC=2C=3CC(=O)NC=3N=CC=2)C(C)=CC=1N(C=1C=CC(F)=CC=1)C(=O)C1(C(N)=O)CC1 UGAYQTUPHGUJTQ-UHFFFAOYSA-N 0.000 claims 1
- QWQXKABHQCATCB-UHFFFAOYSA-N 1-n'-[4-(2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C=1C=C(F)C=CC=1N(C=1C=C(F)C(OC=2C=3CCNC=3N=CC=2)=CC=1)C(=O)C1(C(=O)N)CC1 QWQXKABHQCATCB-UHFFFAOYSA-N 0.000 claims 1
- RGNVUEGYBZTTDB-UHFFFAOYSA-N 1-n'-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazin-8-yloxy)-3-fluorophenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C=1C=C(F)C=CC=1N(C=1C=C(F)C(OC=2C=3OCCNC=3N=CC=2)=CC=1)C(=O)C1(C(=O)N)CC1 RGNVUEGYBZTTDB-UHFFFAOYSA-N 0.000 claims 1
- IRCMORRLEYDMBU-UHFFFAOYSA-N 1-n'-[4-(3,4-dihydro-2h-pyrido[3,2-b][1,4]thiazin-8-yloxy)-3-fluorophenyl]-1-n-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1(C(=O)NC=2C=C(F)C(OC=3C=4SCCNC=4N=CC=3)=CC=2)CC1 IRCMORRLEYDMBU-UHFFFAOYSA-N 0.000 claims 1
- SNFMFGKVRUTWHA-UHFFFAOYSA-N 1-n-[4-[(3,3-dimethyl-2,4-dihydropyrido[3,2-b][1,4]oxazin-8-yl)oxy]phenyl]-1-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound N1C(C)(C)COC2=C1N=CC=C2OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 SNFMFGKVRUTWHA-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
- WIKUBKNCIIIRKR-UHFFFAOYSA-N 3-(4-fluorophenyl)-n-[3-fluoro-4-(2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yloxy)phenyl]-2-oxoimidazolidine-1-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)N(C(=O)NC=2C=C(F)C(OC=3C=4OCCCNC=4N=CC=3)=CC=2)CC1 WIKUBKNCIIIRKR-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
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- 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 1
- 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 1
- DAMCSNDKULLWBA-UHFFFAOYSA-N 5-[5-(2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-4-yloxy)pyridin-2-yl]-2-(4-fluoroanilino)-3-methylpyrimidin-4-one Chemical compound N=1C=C(C=2N=CC(OC=3C=4CCNC=4N=CC=3)=CC=2)C(=O)N(C)C=1NC1=CC=C(F)C=C1 DAMCSNDKULLWBA-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
- PWMWSMAJODTXQE-UHFFFAOYSA-N 8-[2-fluoro-4-[[5-(4-fluorophenyl)-4-oxo-1h-pyridine-3-carbonyl]amino]phenoxy]-3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazine-2-carboxamide Chemical compound C=12OC(C(=O)N)CNC2=NC=CC=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CNC=C1C1=CC=C(F)C=C1 PWMWSMAJODTXQE-UHFFFAOYSA-N 0.000 claims 1
- KNGBPRKOLWEKLF-UHFFFAOYSA-N C1(CC1)(C(=O)O)C(=O)O.CC1(NC2=C(SC1)C(=CC=N2)OC2=CC=C(C=C2)NC(=O)C=2C(N(C=CC2)C2=CC=C(C=C2)F)=O)C Chemical compound C1(CC1)(C(=O)O)C(=O)O.CC1(NC2=C(SC1)C(=CC=N2)OC2=CC=C(C=C2)NC(=O)C=2C(N(C=CC2)C2=CC=C(C=C2)F)=O)C KNGBPRKOLWEKLF-UHFFFAOYSA-N 0.000 claims 1
- VPZMLTLMYLZSOR-UHFFFAOYSA-N Fc1ccc(cc1)-n1cccc(C(=O)Nc2ccc(Oc3ccnc4NCCCSc34)c(F)c2)c1=O Chemical compound Fc1ccc(cc1)-n1cccc(C(=O)Nc2ccc(Oc3ccnc4NCCCSc34)c(F)c2)c1=O VPZMLTLMYLZSOR-UHFFFAOYSA-N 0.000 claims 1
- CHPOUHYRQQAQKO-UHFFFAOYSA-N Nc1ccc(F)cc1.CC1(C)CSc2c(N1)nccc2Oc1ccc(N)cc1 Chemical compound Nc1ccc(F)cc1.CC1(C)CSc2c(N1)nccc2Oc1ccc(N)cc1 CHPOUHYRQQAQKO-UHFFFAOYSA-N 0.000 claims 1
- UWRZHNJKLRWYON-UHFFFAOYSA-N n-[3-fluoro-4-(2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-4-yl)oxyphenyl]-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=C1C1(CC1)C(=O)N2 UWRZHNJKLRWYON-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- KOOWZDQYWTWBHU-UHFFFAOYSA-N n-[3-fluoro-4-[(3-oxo-4h-pyrido[3,2-b][1,4]oxazin-8-yl)oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4OCC(=O)NC=4N=CC=3)=CC=2)=CC=C1 KOOWZDQYWTWBHU-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
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- JQEXXZKPEDSLNT-UHFFFAOYSA-N n-[4-(2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C=4CCNC=4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 JQEXXZKPEDSLNT-UHFFFAOYSA-N 0.000 claims 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 150000003212 purines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- 230000006340 racemization Effects 0.000 description 1
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- 201000010174 renal carcinoma Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003345 scintillation counting Methods 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
- 238000007493 shaping process Methods 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 238000000547 structure data Methods 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLTRPTRRNKYFGY-UHFFFAOYSA-N tert-butyl 4-chloro-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound N1=CC=C(Cl)C2=C1N(C(=O)OC(C)(C)C)CC2 YLTRPTRRNKYFGY-UHFFFAOYSA-N 0.000 description 1
- LPNLSGOSKOBZIR-UHFFFAOYSA-N tert-butyl n-[4-chloro-3-(2-hydroxyethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=NC=CC(Cl)=C1CCO LPNLSGOSKOBZIR-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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Classifications
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- 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
-
- 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
-
- 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
- A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012077924 | 2012-06-29 | ||
| CNPCT/CN2012/077924 | 2012-06-29 | ||
| PCT/CN2013/078592 WO2014000713A1 (en) | 2012-06-29 | 2013-07-01 | NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2878049A1 CA2878049A1 (en) | 2014-01-03 |
| CA2878049C true CA2878049C (en) | 2016-12-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2878049A Expired - Fee Related CA2878049C (en) | 2012-06-29 | 2013-07-01 | Fused pyridine derivatives useful as c-met tyrosine kinase inhibitors |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US9617257B2 (en:Method) |
| EP (1) | EP2867223B1 (en:Method) |
| JP (1) | JP6059342B2 (en:Method) |
| KR (3) | KR101726555B1 (en:Method) |
| AU (1) | AU2013283993B2 (en:Method) |
| BR (1) | BR112014032745B1 (en:Method) |
| CA (1) | CA2878049C (en:Method) |
| ES (1) | ES2698511T3 (en:Method) |
| IN (1) | IN2015DN00372A (en:Method) |
| RU (1) | RU2619130C2 (en:Method) |
| SG (1) | SG11201408750VA (en:Method) |
| TW (1) | TWI520962B (en:Method) |
| WO (1) | WO2014000713A1 (en:Method) |
| ZA (1) | ZA201500344B (en:Method) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279147A (zh) * | 2015-05-21 | 2017-01-04 | 中国科学院上海药物研究所 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
| AU2016297395B2 (en) * | 2015-07-20 | 2019-01-17 | Betta Pharmaceuticals Co., Ltd | Crystalline form of fused pyridine derivative's maleate and uses thereof |
| CN108853108A (zh) * | 2015-12-31 | 2018-11-23 | 北京浦润奥生物科技有限责任公司 | 化合物在制备用于治疗脑胶质瘤的药物中的用途 |
| CA3012832A1 (en) | 2016-02-05 | 2017-08-10 | Denali Therapeutics Inc. | N-azepinyl-carboxamide inhibitors of receptor-interacting protein kinase1 |
| RS63203B1 (sr) | 2016-12-09 | 2022-06-30 | Denali Therapeutics Inc | Jedinjenja korisna kao inhibitori ripk1 |
| KR20200011965A (ko) * | 2017-05-26 | 2020-02-04 | 아이크노스 사이언스 에스. 아. | Map4k1의 신규한 억제제 |
| EP3643715A4 (en) * | 2017-06-19 | 2020-10-28 | Abbisko Therapeutics Co., Ltd. | HETERARYLE DERIVATIVE OF NITROGEN HAVING AN INHIBITORING ACTIVITY OF CSF1R, ITS PREPARATION PROCESS AND ITS APPLICATION |
| CN109988108B (zh) * | 2017-12-29 | 2022-04-29 | 江苏豪森药业集团有限公司 | 一种卡博替尼的制备方法 |
| AU2019395282A1 (en) | 2018-12-14 | 2021-07-08 | Beta Pharma, Inc. | Organophosphorus-substituted compounds as c-MET inhibitors and therapeutic uses thereof |
| MX2021009863A (es) | 2019-03-21 | 2021-11-12 | Onxeo | Una molecula dbait en combinacion con inhibidor de quinasa para el tratamiento del cancer. |
| CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| TWI812302B (zh) * | 2021-06-24 | 2023-08-11 | 南韓商Ｌｇ化學股份有限公司 | 作為ｒｏｎ抑制劑之新穎尿素衍生物化合物 |
| EP4463229A1 (en) | 2022-01-12 | 2024-11-20 | Denali Therapeutics Inc. | Crystalline forms of (s)-5-benzyl-n-(5-methyl-4-oxo-2, 3,4,5- tetrahydropyrido [3,2-b] [l,4]oxazepin-3-yl)-4h-l,2,4-triazole-3-carboxamide |
| EP4289427A1 (en) * | 2022-06-10 | 2023-12-13 | Anagenesis Biotechnologies | Dihydro[1,8]naphthyridin-7-one and pyrido[3,2-b][1,4]oxazin-3-one for use in treating cancer, and metastases in particular. |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2531485C (en) * | 2003-07-07 | 2013-03-26 | Merck Patent Gmbh | Malonamide derivatives |
| DE10357510A1 (de) * | 2003-12-09 | 2005-07-07 | Bayer Healthcare Ag | Heteroarylsubstituierte Benzole |
| US7173031B2 (en) * | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| WO2006014325A2 (en) * | 2004-07-02 | 2006-02-09 | Exelixis, Inc. | C-met modulators and method of use |
| BRPI0513982A (pt) * | 2004-07-30 | 2007-11-27 | Methylgene Inc | inibidores de sinalização de receptor de vegf e receptor de hgf |
| JP2008521900A (ja) * | 2004-11-30 | 2008-06-26 | アムジエン・インコーポレーテツド | キノリン及びキナゾリン類似体並びにがん治療のための医薬としてのその使用 |
| JO2787B1 (en) * | 2005-04-27 | 2014-03-15 | امجين إنك, | Alternative amide derivatives and methods of use |
| EP1904504B1 (en) | 2005-05-20 | 2014-03-19 | MethylGene Inc. | Inhibitors of vegf receptor and hgf receptor signaling |
| US20100016307A1 (en) * | 2006-10-27 | 2010-01-21 | Toshihiro Hamajima | Novel compounds |
| US7960567B2 (en) | 2007-05-02 | 2011-06-14 | Amgen Inc. | Compounds and methods useful for treating asthma and allergic inflammation |
| RU2011119478A (ru) * | 2008-10-14 | 2012-11-27 | Нин Си | Соединения и способы применения |
| KR100961410B1 (ko) * | 2008-10-14 | 2010-06-09 | (주)네오팜 | 단백질 키나제 억제제로서 헤테로사이클릭 화합물 |
| CN102086211B (zh) * | 2009-12-08 | 2013-09-11 | 广东东阳光药业有限公司 | 作为蛋白激酶抑制剂的芳杂环化合物 |
| JP5770281B2 (ja) * | 2010-07-14 | 2015-08-26 | ベータ ファーマシューティカルズ カンパニー リミテッド | ｃ−ＭＥＴチロシンキナーゼ阻害薬として有用な新規な縮合複素環式誘導体 |
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2013
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Also Published As
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|---|---|
| US9617257B2 (en) | 2017-04-11 |
| EP2867223A4 (en) | 2016-01-06 |
| KR101726522B1 (ko) | 2017-04-12 |
| HK1207642A1 (en) | 2016-02-05 |
| CA2878049A1 (en) | 2014-01-03 |
| AU2013283993B2 (en) | 2016-07-07 |
| KR101726555B1 (ko) | 2017-04-12 |
| KR20150031320A (ko) | 2015-03-23 |
| KR101770545B1 (ko) | 2017-08-22 |
| BR112014032745B1 (pt) | 2022-01-04 |
| US20150315210A1 (en) | 2015-11-05 |
| KR20170017015A (ko) | 2017-02-14 |
| TW201418254A (zh) | 2014-05-16 |
| JP6059342B2 (ja) | 2017-01-11 |
| RU2619130C2 (ru) | 2017-05-12 |
| ZA201500344B (en) | 2016-08-31 |
| IN2015DN00372A (en:Method) | 2015-06-12 |
| AU2013283993A1 (en) | 2015-02-05 |
| WO2014000713A1 (en) | 2014-01-03 |
| TWI520962B (zh) | 2016-02-11 |
| BR112014032745A2 (pt) | 2017-06-27 |
| RU2015102057A (ru) | 2016-08-20 |
| SG11201408750VA (en) | 2015-01-29 |
| ES2698511T3 (es) | 2019-02-05 |
| KR20170017014A (ko) | 2017-02-14 |
| EP2867223A1 (en) | 2015-05-06 |
| JP2015521634A (ja) | 2015-07-30 |
| EP2867223B1 (en) | 2018-09-05 |
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