JP2009543798A - タンパク質キナーゼ阻害剤としての［４，５’］ビピリミジニル−６，４’−ジアミン誘導体 - Google Patents
タンパク質キナーゼ阻害剤としての［４，５’］ビピリミジニル−６，４’−ジアミン誘導体 Download PDFInfo
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- JP2009543798A JP2009543798A JP2009519623A JP2009519623A JP2009543798A JP 2009543798 A JP2009543798 A JP 2009543798A JP 2009519623 A JP2009519623 A JP 2009519623A JP 2009519623 A JP2009519623 A JP 2009519623A JP 2009543798 A JP2009543798 A JP 2009543798A
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- JP
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- Prior art keywords
- pyridin
- dimethoxy
- bipyrimidinyl
- phenyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
- 239000003909 protein kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 195
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 51
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 47
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 47
- 201000010099 disease Diseases 0.000 claims abstract description 40
- 230000000694 effects Effects 0.000 claims abstract description 40
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims abstract description 34
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 pyrrolidino, piperidino, piperazino Chemical group 0.000 claims description 170
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 239000001257 hydrogen Substances 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 229920006395 saturated elastomer Polymers 0.000 claims description 32
- 125000002950 monocyclic group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 20
- 230000005764 inhibitory process Effects 0.000 claims description 20
- 150000001204 N-oxides Chemical class 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- 150000004985 diamines Chemical class 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 8
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 7
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 6
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- DEQWECAWVNDIHY-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCOCC4)=CC=3)C=2)=C1Cl DEQWECAWVNDIHY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- TYOCSGNRWAHCPK-UHFFFAOYSA-N 1-[3-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1Cl TYOCSGNRWAHCPK-UHFFFAOYSA-N 0.000 claims description 2
- WIGBPFMLSVEBSH-UHFFFAOYSA-N 1-[3-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1F WIGBPFMLSVEBSH-UHFFFAOYSA-N 0.000 claims description 2
- ZXOGVOGAINUMFX-UHFFFAOYSA-N 1-[3-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1F ZXOGVOGAINUMFX-UHFFFAOYSA-N 0.000 claims description 2
- KDHDEIZNVKDEEH-UHFFFAOYSA-N 1-[4-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)N3CCN(CC3)C(=O)CO)C=2)=C1Cl KDHDEIZNVKDEEH-UHFFFAOYSA-N 0.000 claims description 2
- FIJKNTZDZYOAGB-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(=O)CO)=CC=3)C=2)=C1Cl FIJKNTZDZYOAGB-UHFFFAOYSA-N 0.000 claims description 2
- NMMBKQUZGJYFKU-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(C)=O)=CC=3)C=2)=C1Cl NMMBKQUZGJYFKU-UHFFFAOYSA-N 0.000 claims description 2
- PNCFUDLLXJUXSH-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(C)=O)=CC=3)C=2)=C1F PNCFUDLLXJUXSH-UHFFFAOYSA-N 0.000 claims description 2
- AYJYBVQKLXRDQJ-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(=O)CO)=CC=3)C=2)=C1F AYJYBVQKLXRDQJ-UHFFFAOYSA-N 0.000 claims description 2
- GSQTWFXIKOAEQF-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(C)=O)=CC=3)C=2)=C1F GSQTWFXIKOAEQF-UHFFFAOYSA-N 0.000 claims description 2
- FFHPXSVUVZJSNL-UHFFFAOYSA-N 1-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1Cl FFHPXSVUVZJSNL-UHFFFAOYSA-N 0.000 claims description 2
- LFWDKYXONJPXLV-UHFFFAOYSA-N 1-[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1Cl LFWDKYXONJPXLV-UHFFFAOYSA-N 0.000 claims description 2
- YWENEVBVNPLSKO-UHFFFAOYSA-N 1-[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F YWENEVBVNPLSKO-UHFFFAOYSA-N 0.000 claims description 2
- STNPCJBTHDGVDG-UHFFFAOYSA-N 1-[6-[[6-[4-(2-chloro-3,5-dimethoxy-6-methylanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1C STNPCJBTHDGVDG-UHFFFAOYSA-N 0.000 claims description 2
- WXASKJZNTGILEK-UHFFFAOYSA-N 1-[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F WXASKJZNTGILEK-UHFFFAOYSA-N 0.000 claims description 2
- OQKZUTMDCSLCLS-UHFFFAOYSA-N 1-[6-[[6-[4-(2-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=CC(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F OQKZUTMDCSLCLS-UHFFFAOYSA-N 0.000 claims description 2
- RMCRWRACPLILML-UHFFFAOYSA-N 2-[4-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)N3CCN(CCO)CC3)C=2)=C1Cl RMCRWRACPLILML-UHFFFAOYSA-N 0.000 claims description 2
- MWXFVCCQBSSGDD-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1Cl MWXFVCCQBSSGDD-UHFFFAOYSA-N 0.000 claims description 2
- HBJDUPZNFBWSNF-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F HBJDUPZNFBWSNF-UHFFFAOYSA-N 0.000 claims description 2
- XUPGEWMUHRNEHO-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-chloro-3,5-dimethoxy-6-methylanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1C XUPGEWMUHRNEHO-UHFFFAOYSA-N 0.000 claims description 2
- SWQLRHRBOQUCSW-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F SWQLRHRBOQUCSW-UHFFFAOYSA-N 0.000 claims description 2
- XYIBIKYKRKQRGW-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=CC(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F XYIBIKYKRKQRGW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- YUCPGZSYMDFVJE-UHFFFAOYSA-N 3-(6-aminopyrimidin-4-yl)-n-(2,6-dichlorophenyl)pyrazin-2-amine Chemical compound C1=NC(N)=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=N1 YUCPGZSYMDFVJE-UHFFFAOYSA-N 0.000 claims description 2
- FHVWPPCTAIQSHC-UHFFFAOYSA-N 3-(6-aminopyrimidin-4-yl)-n-(2,6-difluoro-3-methoxyphenyl)pyrazin-2-amine Chemical compound COC1=CC=C(F)C(NC=2C(=NC=CN=2)C=2N=CN=C(N)C=2)=C1F FHVWPPCTAIQSHC-UHFFFAOYSA-N 0.000 claims description 2
- INTJAFCJKRIGGB-UHFFFAOYSA-N 4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]-n,n-dimethylpiperazine-1-carboxamide Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(=O)N(C)C)=CC=3)C=2)=C1Cl INTJAFCJKRIGGB-UHFFFAOYSA-N 0.000 claims description 2
- BQCMYVJTMQXVKS-UHFFFAOYSA-N 4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]-n-methylpiperazine-1-carboxamide Chemical compound C1CN(C(=O)NC)CCN1CC(C=N1)=CC=C1NC1=CC(C=2C(=NC=NC=2)NC=2C(=C(OC)C=C(OC)C=2Cl)Cl)=NC=N1 BQCMYVJTMQXVKS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- VHTOEAQTTZXCOA-UHFFFAOYSA-N 6-[4-(2-chloro-3,5-dimethoxy-6-methylanilino)pyrimidin-5-yl]-n-[5-(morpholin-4-ylmethyl)pyridin-2-yl]pyrimidin-4-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCOCC4)=CC=3)C=2)=C1C VHTOEAQTTZXCOA-UHFFFAOYSA-N 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- IMLBLNTWKDEHCS-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[6-[[4-(2-morpholin-4-ylethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC=C(CCN4CCOCC4)C=3)C=2)=C1Cl IMLBLNTWKDEHCS-UHFFFAOYSA-N 0.000 claims description 2
- DTGFLQCDFNOWSG-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[6-[[4-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC=C(CN4CCOCC4)C=3)C=2)=C1Cl DTGFLQCDFNOWSG-UHFFFAOYSA-N 0.000 claims description 2
- XTBHWTYTNGOVJE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=NC=N1 XTBHWTYTNGOVJE-UHFFFAOYSA-N 0.000 claims description 2
- CXTQRJIXPYUUSY-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[4-[2-(diethylamino)ethoxy]anilino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=NC=N1 CXTQRJIXPYUUSY-UHFFFAOYSA-N 0.000 claims description 2
- RWKOJOJGEWDVNF-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[[5-(2-morpholin-4-ylethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NC=CN=C1C1=CC(NC=2N=CC(CCN3CCOCC3)=CC=2)=NC=N1 RWKOJOJGEWDVNF-UHFFFAOYSA-N 0.000 claims description 2
- CQYCMUYFDNMOFE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NC=CN=C1C1=CC(NC=2N=CC(CN3CCOCC3)=CC=2)=NC=N1 CQYCMUYFDNMOFE-UHFFFAOYSA-N 0.000 claims description 2
- YKLFRTKTQNBSNA-UHFFFAOYSA-N n-(2,6-difluoro-3-methoxyphenyl)-3-[6-[[4-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC=C(F)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC=C(CN4CCOCC4)C=3)C=2)=C1F YKLFRTKTQNBSNA-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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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
- C07D401/14—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 three or more hetero rings
-
- 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83049206P | 2006-07-12 | 2006-07-12 | |
| PCT/US2007/073111 WO2008008747A1 (en) | 2006-07-12 | 2007-07-10 | [4,5']bipyrimidinyl-6,4'-diamine derivatives as protein kinase inhbitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009543798A true JP2009543798A (ja) | 2009-12-10 |
| JP2009543798A5 JP2009543798A5 (https=) | 2010-08-26 |
Family
ID=38617203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009519623A Pending JP2009543798A (ja) | 2006-07-12 | 2007-07-10 | タンパク質キナーゼ阻害剤としての［４，５’］ビピリミジニル−６，４’−ジアミン誘導体 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US8026243B2 (https=) |
| EP (1) | EP2044036B1 (https=) |
| JP (1) | JP2009543798A (https=) |
| KR (1) | KR20090029832A (https=) |
| CN (1) | CN101511798B (https=) |
| AR (1) | AR061867A1 (https=) |
| AT (1) | ATE508119T1 (https=) |
| AU (1) | AU2007272646A1 (https=) |
| BR (1) | BRPI0714291A2 (https=) |
| CA (1) | CA2657381A1 (https=) |
| CL (1) | CL2007002017A1 (https=) |
| DE (1) | DE602007014374D1 (https=) |
| ES (1) | ES2367666T3 (https=) |
| MX (1) | MX2009000429A (https=) |
| PE (1) | PE20080548A1 (https=) |
| PL (1) | PL2044036T3 (https=) |
| PT (1) | PT2044036E (https=) |
| RU (1) | RU2009104340A (https=) |
| TW (1) | TW200811134A (https=) |
| UY (1) | UY30477A1 (https=) |
| WO (1) | WO2008008747A1 (https=) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008078091A1 (en) | 2006-12-22 | 2008-07-03 | Astex Therapeutics Limited | Bicyclic heterocyclic compounds as fgfr inhibitors |
| US8131527B1 (en) | 2006-12-22 | 2012-03-06 | Astex Therapeutics Ltd. | FGFR pharmacophore compounds |
| CN101679409B (zh) | 2006-12-22 | 2014-11-26 | Astex治疗学有限公司 | 双环杂环衍生化合物、其医药组合物和其用途 |
| GB0720041D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New Compounds |
| GB0720038D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New compounds |
| GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
| GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
| GB0906470D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
| EP2308866A1 (de) | 2009-10-09 | 2011-04-13 | Bayer CropScience AG | Phenylpyri(mi)dinylpyrazole und ihre Verwendung als Fungizide |
| AR079545A1 (es) | 2009-12-21 | 2012-02-01 | Bayer Cropscience Ag | Tienilpiri(mi)dinilazol |
| US8754114B2 (en) | 2010-12-22 | 2014-06-17 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
| WO2012175513A1 (en) | 2011-06-20 | 2012-12-27 | Bayer Intellectual Property Gmbh | Thienylpyri(mi)dinylpyrazole |
| RU2627272C2 (ru) | 2011-10-06 | 2017-08-04 | Байер Интеллектчуал Проперти Гмбх | Гетероциклилпиридинилпиразолы |
| CN104039785A (zh) | 2011-10-06 | 2014-09-10 | 拜耳知识产权有限责任公司 | 作为杀真菌剂的杂环基吡(嘧)啶基吡唑 |
| JP6378171B2 (ja) | 2012-04-24 | 2018-08-22 | バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ | Ｄｎａ−ｐｋ阻害剤 |
| ES2704744T3 (es) | 2012-06-13 | 2019-03-19 | Incyte Holdings Corp | Compuestos tricíclicos sustituidos como inhibidores de FGFR |
| US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
| CA2886002C (en) * | 2012-09-27 | 2020-06-09 | Chugai Seiyaku Kabushiki Kaisha | Fgfr3 fusion gene and pharmaceutical drug targeting same |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| AR094812A1 (es) | 2013-02-20 | 2015-08-26 | Eisai R&D Man Co Ltd | Derivado de piridina monocíclico como inhibidor del fgfr |
| SI3527563T1 (sl) | 2013-03-12 | 2022-01-31 | Vertex Pharmaceuticals Incorporated | Inhibitorji DNA-PK |
| EA035095B1 (ru) | 2013-04-19 | 2020-04-27 | Инсайт Холдингс Корпорейшн | Бициклические гетероциклы в качестве ингибиторов fgfr |
| RU2675270C2 (ru) | 2013-10-17 | 2018-12-18 | Вертекс Фармасьютикалз Инкорпорейтед | Сокристаллы и содержащие их фармацевтические композиции |
| KR102344105B1 (ko) | 2014-08-18 | 2021-12-29 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 모노시클릭 피리딘 유도체의 염 및 이의 결정 |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
| MX373169B (es) | 2015-02-20 | 2020-04-24 | Incyte Holdings Corp | Heterociclos bicíclicos como inhibidores de receptores del factor de crecimiento fibroblástico (fgfr). |
| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| ES2887148T3 (es) | 2015-03-25 | 2021-12-21 | Nat Cancer Ct | Agente terapéutico contra el cáncer de vías biliares |
| US12414945B2 (en) | 2015-12-17 | 2025-09-16 | Eisai R&D Management Co., Ltd. | Therapeutic agent for breast cancer |
| RU2758669C2 (ru) | 2016-09-27 | 2021-11-01 | Вертекс Фармасьютикалз Инкорпорейтед | Способ лечения рака с применением сочетания днк-поражающих агентов и ингибиторов днк-пк |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
| KR102613433B1 (ko) * | 2017-10-11 | 2023-12-13 | 주식회사 대웅제약 | 신규한 페닐피리딘 유도체 및 이를 포함하는 약학 조성물 |
| SG11202007591RA (en) | 2018-03-28 | 2020-09-29 | Eisai R&D Man Co Ltd | Therapeutic agent for hepatocellular carcinoma |
| CR20200590A (es) | 2018-05-04 | 2021-04-26 | Incyte Corp | Formas sólidas de un inhibidor de fgfr y procesos para prepararlas |
| MA52493A (fr) | 2018-05-04 | 2021-03-10 | Incyte Corp | Sels d'un inhibiteur de fgfr |
| WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
| KR102133595B1 (ko) | 2019-05-31 | 2020-07-13 | 에이치케이이노엔 주식회사 | 단백질 키나제 억제제로서의 헤테로고리 화합물 |
| WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| KR102112336B1 (ko) | 2019-08-12 | 2020-05-18 | 에이치케이이노엔 주식회사 | 단백질 키나제 억제제로서의 헤테로고리 화합물 |
| WO2021067374A1 (en) | 2019-10-01 | 2021-04-08 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| TWI891666B (zh) | 2019-10-14 | 2025-08-01 | 美商英塞特公司 | 作為ｆｇｆｒ抑制劑之雙環雜環 |
| WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
| EP4069696A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| WO2021146424A1 (en) | 2020-01-15 | 2021-07-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| TW202304459A (zh) | 2021-04-12 | 2023-02-01 | 美商英塞特公司 | 包含ｆｇｆｒ抑制劑及ｎｅｃｔｉｎ－４靶向劑之組合療法 |
| WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| EP4352059A1 (en) | 2021-06-09 | 2024-04-17 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033086A1 (en) * | 2003-09-30 | 2005-04-14 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
| WO2005113494A2 (en) * | 2004-05-07 | 2005-12-01 | Amgen Inc. | Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9924862D0 (en) | 1999-10-20 | 1999-12-22 | Celltech Therapeutics Ltd | Chemical compounds |
| JP4847868B2 (ja) | 2003-05-14 | 2011-12-28 | ニューロジェネティック ファーマシューティカルズ、 インコーポレイテッド | 化合物、及び、アミロイドベータの調節におけるその使用 |
| JP2009525978A (ja) | 2006-02-06 | 2009-07-16 | アイアールエム・リミテッド・ライアビリティ・カンパニー | プロテインキナーゼ阻害剤としての化合物および組成物 |
-
2007
- 2007-07-04 TW TW096124311A patent/TW200811134A/zh unknown
- 2007-07-10 AR ARP070103061A patent/AR061867A1/es unknown
- 2007-07-10 PL PL07812739T patent/PL2044036T3/pl unknown
- 2007-07-10 KR KR1020097002815A patent/KR20090029832A/ko not_active Withdrawn
- 2007-07-10 WO PCT/US2007/073111 patent/WO2008008747A1/en not_active Ceased
- 2007-07-10 MX MX2009000429A patent/MX2009000429A/es not_active Application Discontinuation
- 2007-07-10 CN CN2007800337140A patent/CN101511798B/zh not_active Expired - Fee Related
- 2007-07-10 BR BRPI0714291-9A2A patent/BRPI0714291A2/pt not_active Application Discontinuation
- 2007-07-10 RU RU2009104340/04A patent/RU2009104340A/ru not_active Application Discontinuation
- 2007-07-10 JP JP2009519623A patent/JP2009543798A/ja active Pending
- 2007-07-10 EP EP07812739A patent/EP2044036B1/en not_active Not-in-force
- 2007-07-10 DE DE602007014374T patent/DE602007014374D1/de active Active
- 2007-07-10 CA CA002657381A patent/CA2657381A1/en not_active Abandoned
- 2007-07-10 ES ES07812739T patent/ES2367666T3/es active Active
- 2007-07-10 AT AT07812739T patent/ATE508119T1/de active
- 2007-07-10 PE PE2007000885A patent/PE20080548A1/es not_active Application Discontinuation
- 2007-07-10 AU AU2007272646A patent/AU2007272646A1/en not_active Abandoned
- 2007-07-10 US US12/373,441 patent/US8026243B2/en not_active Expired - Fee Related
- 2007-07-10 PT PT07812739T patent/PT2044036E/pt unknown
- 2007-07-11 UY UY30477A patent/UY30477A1/es not_active Application Discontinuation
- 2007-07-11 CL CL200702017A patent/CL2007002017A1/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033086A1 (en) * | 2003-09-30 | 2005-04-14 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
| WO2005113494A2 (en) * | 2004-05-07 | 2005-12-01 | Amgen Inc. | Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| US20100234376A1 (en) | 2010-09-16 |
| PE20080548A1 (es) | 2008-06-24 |
| CN101511798B (zh) | 2011-11-02 |
| AR061867A1 (es) | 2008-09-24 |
| RU2009104340A (ru) | 2010-08-20 |
| MX2009000429A (es) | 2009-01-29 |
| CA2657381A1 (en) | 2008-01-17 |
| DE602007014374D1 (de) | 2011-06-16 |
| CL2007002017A1 (es) | 2008-06-13 |
| TW200811134A (en) | 2008-03-01 |
| WO2008008747A1 (en) | 2008-01-17 |
| ATE508119T1 (de) | 2011-05-15 |
| CN101511798A (zh) | 2009-08-19 |
| PL2044036T3 (pl) | 2011-09-30 |
| EP2044036B1 (en) | 2011-05-04 |
| US8026243B2 (en) | 2011-09-27 |
| KR20090029832A (ko) | 2009-03-23 |
| PT2044036E (pt) | 2011-08-23 |
| AU2007272646A1 (en) | 2008-01-17 |
| UY30477A1 (es) | 2009-04-30 |
| EP2044036A1 (en) | 2009-04-08 |
| BRPI0714291A2 (pt) | 2014-10-21 |
| ES2367666T3 (es) | 2011-11-07 |
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