JP2012506876A - Fakの阻害剤としてのピラゾリルアミノピリジン - Google Patents
Fakの阻害剤としてのピラゾリルアミノピリジン Download PDFInfo
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- JP2012506876A JP2012506876A JP2011533421A JP2011533421A JP2012506876A JP 2012506876 A JP2012506876 A JP 2012506876A JP 2011533421 A JP2011533421 A JP 2011533421A JP 2011533421 A JP2011533421 A JP 2011533421A JP 2012506876 A JP2012506876 A JP 2012506876A
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- JP
- Japan
- Prior art keywords
- amino
- pyrazol
- pyridinyl
- chloro
- 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.)
- Granted
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- 239000003112 inhibitor Substances 0.000 title description 24
- RSLYEFKTNVKNFJ-UHFFFAOYSA-N n-(1h-pyrazol-5-yl)pyridin-2-amine Chemical compound C=1C=CC=NC=1NC=1C=CNN=1 RSLYEFKTNVKNFJ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims description 84
- -1 C 1 -C 6 -alkoxy Chemical group 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 46
- 206010028980 Neoplasm Diseases 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 201000011510 cancer Diseases 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- BVAHPPKGOOJSPU-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl BVAHPPKGOOJSPU-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- MKIAVTUJKXGIKQ-UHFFFAOYSA-N 2-[[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1Cl MKIAVTUJKXGIKQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- SCVNTDKWNCHHCM-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-hydroxy-n-methylbenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)N(C)O)=C(Cl)C=N1 SCVNTDKWNCHHCM-UHFFFAOYSA-N 0.000 claims description 5
- LTLWIMIXXZTOHI-UHFFFAOYSA-N 4-chloro-2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=C(Cl)C=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl LTLWIMIXXZTOHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 4
- GKPABKGPJRHDGP-UHFFFAOYSA-N 2-[[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-5-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC(F)=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1Cl GKPABKGPJRHDGP-UHFFFAOYSA-N 0.000 claims description 4
- CQSRXUOGFGQPTB-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NOC)=C(Cl)C=N1 CQSRXUOGFGQPTB-UHFFFAOYSA-N 0.000 claims description 4
- BDAPLGVMJPEBQP-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-3-fluoro-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl BDAPLGVMJPEBQP-UHFFFAOYSA-N 0.000 claims description 4
- VTLCPGJZDYIOHX-UHFFFAOYSA-N 2-[[5-chloro-2-[[2-ethyl-5-(methoxymethyl)pyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CCN1N=C(COC)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NC)=C(Cl)C=N1 VTLCPGJZDYIOHX-UHFFFAOYSA-N 0.000 claims description 4
- IKHCXUMPHRRXFR-UHFFFAOYSA-N 2-[[5-chloro-2-[[5-(ethoxymethyl)-2-ethylpyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CCN1N=C(COCC)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NC)=C(Cl)C=N1 IKHCXUMPHRRXFR-UHFFFAOYSA-N 0.000 claims description 4
- RRVNTZDCQGERQZ-UHFFFAOYSA-N 2-[[5-chloro-2-[[5-(ethoxymethyl)-2-propan-2-ylpyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CC(C)N1N=C(COCC)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NC)=C(Cl)C=N1 RRVNTZDCQGERQZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- ZFRODCLWULXQHU-UHFFFAOYSA-N 2-[[5-chloro-2-[(1,5-dimethylpyrazol-4-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC2=C(N(C)N=C2)C)=NC=C1Cl ZFRODCLWULXQHU-UHFFFAOYSA-N 0.000 claims description 3
- CDYOTEBXCVHSEX-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-4-fluoro-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=C(F)C=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl CDYOTEBXCVHSEX-UHFFFAOYSA-N 0.000 claims description 3
- YTZKERJOZUXUBP-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-5-fluoro-n-methoxybenzamide Chemical compound CONC(=O)C1=CC(F)=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl YTZKERJOZUXUBP-UHFFFAOYSA-N 0.000 claims description 3
- VRGZVTVYHQMJOB-UHFFFAOYSA-N 2-[[5-cyano-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1C#N VRGZVTVYHQMJOB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- PWJOVTFYIHNFLJ-UHFFFAOYSA-N 2-[[2-[(2,5-dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1C(F)(F)F PWJOVTFYIHNFLJ-UHFFFAOYSA-N 0.000 claims description 2
- PHWMONBBOQGSSH-UHFFFAOYSA-N 2-[[2-[(2,5-dimethylpyrazol-3-yl)amino]-5-propan-2-ylpyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1C(C)C PHWMONBBOQGSSH-UHFFFAOYSA-N 0.000 claims description 2
- JGUHFPRMVPQQGT-UHFFFAOYSA-N 2-[[2-[(2-ethyl-5-methylpyrazol-3-yl)amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(C(F)(F)F)C=N1 JGUHFPRMVPQQGT-UHFFFAOYSA-N 0.000 claims description 2
- XMMSMPGXLNJJOU-UHFFFAOYSA-N 2-[[2-[[2-ethyl-5-(2-hydroxyethyl)pyrazol-3-yl]amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CCN1N=C(CCO)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(C(F)(F)F)C=N1 XMMSMPGXLNJJOU-UHFFFAOYSA-N 0.000 claims description 2
- PASKSOABXRABRM-UHFFFAOYSA-N 2-[[2-[[2-ethyl-5-(hydroxymethyl)pyrazol-3-yl]amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CCN1N=C(CO)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(C(F)(F)F)C=N1 PASKSOABXRABRM-UHFFFAOYSA-N 0.000 claims description 2
- VCELSCAUUZYHJH-UHFFFAOYSA-N 2-[[2-[[5-[(dimethylamino)methyl]-2-methylpyrazol-3-yl]amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(CN(C)C)C=2)C)=NC=C1C(F)(F)F VCELSCAUUZYHJH-UHFFFAOYSA-N 0.000 claims description 2
- KTYCOOWCLAUUPX-UHFFFAOYSA-N 2-[[5-chloro-2-[(1,3-dimethylpyrazol-4-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2C(=NN(C)C=2)C)=NC=C1Cl KTYCOOWCLAUUPX-UHFFFAOYSA-N 0.000 claims description 2
- WTIAJEPPHUWKNS-UHFFFAOYSA-N 2-[[5-chloro-2-[(1,5-dimethylpyrazol-4-yl)amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC2=C(N(C)N=C2)C)=NC=C1Cl WTIAJEPPHUWKNS-UHFFFAOYSA-N 0.000 claims description 2
- CJUWDICOYDAZQU-UHFFFAOYSA-N 2-[[5-chloro-2-[(1,5-dimethylpyrazol-4-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC2=C(N(C)N=C2)C)=NC=C1Cl CJUWDICOYDAZQU-UHFFFAOYSA-N 0.000 claims description 2
- BPPXFIITOPDACD-UHFFFAOYSA-N 2-[[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-5-[4-(2-hydroxyethyl)piperazin-1-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC(N2CCN(CCO)CC2)=CC=C1NC(C(=CN=1)Cl)=CC=1NC1=CC(C)=NN1C BPPXFIITOPDACD-UHFFFAOYSA-N 0.000 claims description 2
- VNHICRPREQAOEF-UHFFFAOYSA-N 2-[[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1Cl VNHICRPREQAOEF-UHFFFAOYSA-N 0.000 claims description 2
- CGZYLYJVKOGRHM-UHFFFAOYSA-N 2-[[5-chloro-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]benzoic acid Chemical compound CN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2)C(O)=O)=C(Cl)C=N1 CGZYLYJVKOGRHM-UHFFFAOYSA-N 0.000 claims description 2
- PXXYYYZHOHZJMG-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethyl-4-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CCN1N=CC(C)=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NOC)=C(Cl)C=N1 PXXYYYZHOHZJMG-UHFFFAOYSA-N 0.000 claims description 2
- OBWNLLUFXMQJLV-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(Cl)C=N1 OBWNLLUFXMQJLV-UHFFFAOYSA-N 0.000 claims description 2
- LKRAQIOGOIRMCM-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-ethylbenzamide Chemical compound CCNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)CC)=NC=C1Cl LKRAQIOGOIRMCM-UHFFFAOYSA-N 0.000 claims description 2
- QXKHOUIIZIXZHJ-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-5-[4-(2-hydroxyethyl)piperazin-1-yl]-n-methylbenzamide Chemical compound CCN1N=CC=C1NC1=CC(NC=2C(=CC(=CC=2)N2CCN(CCO)CC2)C(=O)NC)=C(Cl)C=N1 QXKHOUIIZIXZHJ-UHFFFAOYSA-N 0.000 claims description 2
- APYOJVBVFQGTAL-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-ethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CCN1N=CC=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NC)=C(Cl)C=N1 APYOJVBVFQGTAL-UHFFFAOYSA-N 0.000 claims description 2
- COEVYNQBCQJNPD-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-methyl-5-phenylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C=2)C=2C=CC=CC=2)C)=NC=C1Cl COEVYNQBCQJNPD-UHFFFAOYSA-N 0.000 claims description 2
- DFSQVTQMLYMWRK-UHFFFAOYSA-N 2-[[5-chloro-2-[(2-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=CC=2)C)=NC=C1Cl DFSQVTQMLYMWRK-UHFFFAOYSA-N 0.000 claims description 2
- HLXGBPXCMARNLF-UHFFFAOYSA-N 2-[[5-chloro-2-[(4-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=CC=2C)C(C)C)=NC=C1Cl HLXGBPXCMARNLF-UHFFFAOYSA-N 0.000 claims description 2
- JVDMOPNPDZKYNK-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-cyclopropyl-2-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C=2)C2CC2)C)=NC=C1Cl JVDMOPNPDZKYNK-UHFFFAOYSA-N 0.000 claims description 2
- BTTBKLXVUMYRBW-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl BTTBKLXVUMYRBW-UHFFFAOYSA-N 0.000 claims description 2
- YYPFFKWDMCZDEA-UHFFFAOYSA-N 2-[[5-chloro-2-[[2-ethyl-5-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound C1=C(NC=2N=CC(Cl)=C(NC=3C(=CC=CC=3)C(=O)NC)C=2)N(CC)N=C1CCN1CCCC1 YYPFFKWDMCZDEA-UHFFFAOYSA-N 0.000 claims description 2
- UTLZIGDDOXHCIR-UHFFFAOYSA-N 2-[[5-chloro-2-[[2-ethyl-5-(hydroxymethyl)pyrazol-3-yl]amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CCN1N=C(CO)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(Cl)C=N1 UTLZIGDDOXHCIR-UHFFFAOYSA-N 0.000 claims description 2
- MRJXSKFDGGGXTE-UHFFFAOYSA-N 2-[[5-chloro-2-[[4-methyl-2-(2-methylpropyl)pyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=CC=2C)CC(C)C)=NC=C1Cl MRJXSKFDGGGXTE-UHFFFAOYSA-N 0.000 claims description 2
- XSEPUDGLDHDAHY-UHFFFAOYSA-N 2-[[5-chloro-2-[[5-(hydroxymethyl)-2-methylpyrazol-3-yl]amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(CO)C=2)C)=NC=C1Cl XSEPUDGLDHDAHY-UHFFFAOYSA-N 0.000 claims description 2
- LGFHUESOUCFEIA-UHFFFAOYSA-N 2-[[5-chloro-2-[[5-(hydroxymethyl)-2-propan-2-ylpyrazol-3-yl]amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(CO)C=2)C(C)C)=NC=C1Cl LGFHUESOUCFEIA-UHFFFAOYSA-N 0.000 claims description 2
- BELMYCSYHLANMJ-UHFFFAOYSA-N 2-[[5-chloro-2-[[5-[[ethyl(methyl)amino]methyl]-2-methylpyrazol-3-yl]amino]pyridin-4-yl]amino]-3-fluoro-n-methylbenzamide Chemical compound CN1N=C(CN(C)CC)C=C1NC1=CC(NC=2C(=CC=CC=2F)C(=O)NC)=C(Cl)C=N1 BELMYCSYHLANMJ-UHFFFAOYSA-N 0.000 claims description 2
- VYWRUIRAMWQHKE-UHFFFAOYSA-N 2-[[5-cyclopropyl-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1C1CC1 VYWRUIRAMWQHKE-UHFFFAOYSA-N 0.000 claims description 2
- GWGSOXZABRGOIL-UHFFFAOYSA-N 2-[[5-cyclopropyl-2-[(2,5-dimethylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C)=NC=C1C1CC1 GWGSOXZABRGOIL-UHFFFAOYSA-N 0.000 claims description 2
- GLLZQSHTUWLDCB-UHFFFAOYSA-N 2-[[5-cyclopropyl-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NOC)=C(C2CC2)C=N1 GLLZQSHTUWLDCB-UHFFFAOYSA-N 0.000 claims description 2
- BBMXUEJKYFFDSG-UHFFFAOYSA-N 2-[[5-cyclopropyl-2-[(2-ethyl-5-methylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CCN1N=C(C)C=C1NC1=CC(NC=2C(=CC=CC=2)C(=O)NC)=C(C2CC2)C=N1 BBMXUEJKYFFDSG-UHFFFAOYSA-N 0.000 claims description 2
- HYBBDSKOSPEJBO-UHFFFAOYSA-N 3-fluoro-2-[[2-[[5-(2-hydroxyethyl)-2-methylpyrazol-3-yl]amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(CCO)C=2)C)=NC=C1C(F)(F)F HYBBDSKOSPEJBO-UHFFFAOYSA-N 0.000 claims description 2
- NABGOJGWIGBJNI-UHFFFAOYSA-N 3-fluoro-2-[[2-[[5-(hydroxymethyl)-2-methylpyrazol-3-yl]amino]-5-(trifluoromethyl)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(F)=C1NC1=CC(NC=2N(N=C(CO)C=2)C)=NC=C1C(F)(F)F NABGOJGWIGBJNI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 4
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 230000009870 specific binding Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
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- 235000015523 tannic acid Nutrition 0.000 description 1
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- 229940120982 tarceva Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
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- 235000007586 terpenes Nutrition 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 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
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
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- Food Science & Technology (AREA)
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- Biotechnology (AREA)
- Cell Biology (AREA)
- Hospice & Palliative Care (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
R1は、ハロ、CF3、C1−C6−アルキル、イソプロペニル、(C2−C6−アルキレン)C3−C6−シクロアルキル、C1−C6−アルコキシ、またはシアノであり;
R2において、pが0でない場合、各R2は、独立に、F、Cl、CF3、メチル、メトキシ、CH2CF3、−(X)q−C1−C4−アルキレン−R4、−(X−C1−C4−アルキレン)q−NR5−C(O)−R6、−(X−C1−C4−アルキレン)q(NR5)qSOx−R7、−(X−C1−C4−アルキレン)q−Y−N(R8)2;五員から六員のヘテロシクロアルキル−(R9)q基、または五員から六員のヘテロアリール−(R10)r基であり;
R3は、独立に、H、C3−C6−シクロアルキル、C1−C6−アルキル、C1−C6アルコキシ、C1−C6−アルキレン−R4、O−C1−C6−アルキレン−R4であるか、またはR3基はZとともに、メチル、C1−C4−アルキレン−R4、もしくはC3−C6−シクロアルキルにより置換されていてもよい五員から六員の環を形成し;
R4は、H、−(Q)q−N(R8)2、OH、SH、C1−C6−アルコキシ、C1−C6−チオアルキル、または五員から六員のヘテロシクロアルキル−(R9)q基であり;
R5は、HまたはC1−C6−アルキルであり;
R6は、H、C1−C6−アルキル、C1−C6−アルコキシ、N(R8)2、または五員から六員のヘテロアリール−(R10)r基であり;
R7は、C1−C6−アルキル、フェニル−(R9)q、または五員から六員のヘテロアリール−(R10)rであり、
R8は、独立に、H、C1−C6−アルキル、−O−C1−C6−アルキルであるか、またはそれが結合している窒素原子とともに五員もしくは六員のヘテロシクロアルキル基を形成し;
R9は、H、C1−C6−アルキル、C1−C6−アルコキシ、−(Q)q−N(R8)2、−Q−C1−C6−アルキル、−C1−C6アルキルR4、または五員から六員のヘテロシクロアルキルであり;
R10は、H、C1−C6−アルキル、C1−C6−アルコキシ、または−Q−C2−C6−アルキルであり;
R11は、C1−C6−アルキル、CF3、−CH2CF3、−(Q)q−C1−C4−アルキレン−R4、−Q−N(R8)2、フェニル−(R5)s、五員から六員のヘテロシクロアルキル−(R9)q基、または五員から六員のヘテロアリール−(R10)r基であり;
R12は、H、C1−C6−アルキル、F、Cl、CF3、OH、CN、ニトロ、COOH、−COO−C1−C6−アルキル、−Y−N(R8)2、C3−C6−シクロアルキル−R14、−(X)q−C1−C6−アルキレン−R4、−(X−C1−C6−アルキレン)q−NR5−C(O)−R6、−(X−C1−C6−アルキレン)q−(NR5)q−SOx−R7、−(X−C1−C6−アルキレン)q−Y−N(R8)2、ヘテロシクロアルキル−(R9)q、ヘテロアリール−(R10)r、またはフェニル−(R15)sであり;
R13は、H、F、Cl、C1−C6−アルキル、もしくはC3−C6−シクロアルキルであり;またはR12とR13とが、それらが結合している炭素原子とともに、縮合した五員もしくは六員のカルボシクロアルキルもしくはヘテロシクロアルキル基を形成し;
R14は、独立に、H、C1−C6−アルキル、−NR5−SO2−R7、−Y−N(R8)2、または−(X)q−C1−C6−アルキレン−R4であり;
R15は、独立に、F、Cl、CF3、C1−C3−アルキル、またはC1−C3−アルコキシであり;
pは、0、1、2、または3であり;
qは、0または1であり;
rは、0、1、または2であり;
sは、0、1、2、または3であり;
xは、1または2であり;
Qは、−C(O)−、−S(O)−、または−SO2−であり;
Xは、NR5、O、S、−S(O)−、または−SO2−であり;
Yは、結合、SO2、またはC(O)であり;
Zは、NまたはCR5である]。
本発明の他の態様において、R1は、Cl、CF3、またはCNであり;
本発明の他の態様において、R2はFであり;
本発明の他の態様において、R3の1つはメチルであり、他のR3はHであり;
本発明の他の態様において、R3の1つはメトキシであり、他のR3はHであり;
本発明の他の態様において、R11はC1−C6−アルキルであり;
本発明の他の態様において、R12は、C1−C6−アルキル、ヒドロキシメチル、またはシクロプロピルであり;
本発明の他の態様において、R13はHであり;
本発明の他の態様において、pは、0または1である。
本発明の化合物および組成物は細胞増殖疾患の治療に使用される。本明細書に提供される方法および組成物により治療可能な病態には、癌、自己免疫疾患、真菌疾患、関節炎、移植片拒絶、炎症性腸疾患、限定されないが手術や血管形成等を含む医療処置後に誘起される増殖があるが、これらに限定されない。場合によっては、細胞が超増殖状態でも低増殖状態でも(異常状態)ないがそれでも治療が必要になることが認識される。例えば、傷の回復の間、細胞は「正常に」増殖しているだろうが、増殖の増大は望ましいことがある。したがって、一実施形態において、本発明は、本明細書において、冒された細胞もしくは個人またはこれらの疾患もしくは状態のいずれかによる切迫した苦痛への適用を含む。これらの化合物は、AMDなど血管新生に関連する黄斑変性の治療にも使用できる。
血液系:血液(骨髄性白血病(急性および慢性)、急性リンパ芽球性白血病、慢性リンパ性白血病、骨髄増多症、多発性骨髄腫、骨髄異形成症候群)、ホジキン病、非ホジキンリンパ腫(悪性リンパ腫);皮膚:悪性メラノーマ、基底細胞癌、扁平上皮癌、カポジ肉腫、異形成母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;および副腎:神経芽細胞腫。したがって、本明細書に与えられる「癌細胞」という用語は、上記で特定された病態のいずれかまたは関連する病態に冒された細胞を含む。
式(I)の化合物は、以下のスキーム1に概説される方法により製造することができる。式(II)および(III)の化合物は市販されているか、または当分野に従来ある技術を利用して合成できる。化合物(III)のL基は、FまたはClなどの脱離基を表す。式(II)および(III)の化合物を、還流下またはマイクロ波条件下で反応させると、中間体(IV)を得ることができる。付加反応は、典型的には、n−ブタノールまたはイソプロパノールなどの極性プロトン性溶媒を利用して実施される。別法としては、金属により触媒されるカップリング反応条件を利用できる。化合物(II)が、例えば、ヒドロキシルまたはアミノ基など保護の必要な官能基を含む場合、適切な保護基を利用すると好都合である。次いで、式(IV)の化合物を、市販されているか当分野に従来ある技術を利用して合成可能なアミノピラゾール(V)と反応させると、式(I)の化合物を与えることができる。反応は、典型的には、適切なホスフィンリガンドとともにパラジウム塩などの金属触媒の存在下で実施される。別法としては、塩化水素酸またはトリフルオロ酢酸などの触媒量の酸により、例えば、水、1,4−ジオキサン、もしくはイソプロパノール、またはこれらの組み合わせなどの好適な溶媒中で、反応を実施できる。高温、例えば還流条件下で、またはマイクロ波装置を使用して反応を実施するのが好都合である。酸触媒は、典型的には式(I)の化合物に対して10〜30モル%の量で存在する。
スキーム1
スキーム3
スキーム4
スキーム5
スキーム6
式(XXI)の化合物はスキーム7に概説されたとおり調製することもできる。式(XIV)のニトリルを加水分解して式(XX)のカルボン酸にし、次いでアミンとカップリングさせて式(XXI)の化合物を与えることができる。
FAK活性の生化学アッセイ
アッセイ1:GSTタグ付き(グルタチオンS−トランスフェラーゼタグ付き)FAKをInvitrogen(PV3832)(www.invitrogen.com)から購入した。FAKの活性は、ペプチド基質(Ac−RRRRRRSETDDYAEIID−NH2;(配列番号1)すなわち、Ac−Arg−Arg−Arg−Arg−Arg−Ser−Glu−Thr−Asp−Asp−Tyr−Ala−Glu−Ile−Ile−Asp−NH2)の放射標識ATPの存在下でのリン酸化をモニターして測定した。FAKの阻害剤を測定するために、最初に化合物を10%DMSO中の10倍ストックとして調製した。各溶液の少量(4μL)を、96ウェルプレート(Corning, 3884)に加えた。6nMのGST−FAK溶液を、44mMのHEPES、pH=7.2、11mMのMgCl2、2.2mMのMnCl2、1.1mMのDTT、および0.011%のTween−20を含む1.1倍反応バッファに調製した。次いで、20μLの6nMのGST FAK溶液を、化合物とともに室温で30分間プレインキュベートした。上述の反応バッファ中に調製した16μLの基質(62.5μMのペプチド、5μMのATP、および約0.02mCi/mLの33P−γ−ATP)を加えて反応を開始した。90分間反応を進行させ、40μLの1%H3PO4を加えて停止した。反応混合物の一部(60μL)をホスホ−セルロースフィルタープレート(Millipore; www.millipore.com, MAPHNOB50)に移し、20分間インキュベートした。プレートを濾過し、150μLの0.5%H3PO4を使用して3回洗浄し、50℃で30分間乾燥させた。60μLのMicroscint−20をプレートに加えた後、TopCount(PerkinElmer; www.PerkinElmer.com)を利用して放射能を測定した。
以下の化学実施例は例示目的のみであり、本発明の範囲を限定しないものとする。ACD Nameソフトウェア(Advanced Chemistry Development, www.acdlabs.com)を利用して化合物を名付けた。化合物は全て上述の生化学アッセイで6.5を超えるpIC50を有する。
最初に、実質的に中間体1の手順に従って2−アミノ−5−フルオロ−N−メチルベンズアミドを2,5−ジクロロ−4−ヨードピリジンと反応させて2−[(2,5−ジクロロ−4−ピリジニル)アミノ]−5−フルオロ−N−メチルベンズアミドを形成し、次いで、実質的に実施例2の手順に従ってこの中間体を1,3−ジメチル−1H−ピラゾール−5−アミンと反応させることにより、標題化合物を白色固体として調製した。LC−MS(ES)m/z=389.1(M+H)+,1H NMR(CD3OD,400MHz)δ 8.01(s,1H),7.60(m,1H),7.51(m,1H),7.38(m,1H),6.39(s,1H),6.18(s,1H),3.69(s,3H),2.89(s,3H),2.24(s,3H)
2−アミノ−5−フルオロ−N−メチルベンズアミドの代わりに2−アミノ−3−フルオロ−N−メチルベンズアミドを使用する以外、実施例7の手順に従って、標題化合物を白色固体として調製した。LC−MS(ES)m/z=389.1(M+H)+,1H NMR(CD3OD,400MHz)δ 8.01(s,1H),7.50(m,3H),6.14(s,1H),5.87(m,1H),3.65(s,3H),2.89(s,3H),2.22(s,3H)
2−[(2,5−ジクロロ−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド(100mg、0.320ミリモル)、1−エチル−3−メチル−1H−ピラゾール−5−アミン(60.1mg、0.481ミリモル)、炭酸セシウム(313mg、0.961ミリモル)、1,4−ジオキサン(5.0mL)、およびTHF(1.0mL)を20mLのマイクロ波チューブに入れた。反応混合物を窒素により10分間脱気した。次いで、最低限の量の1,4−ジオキサン中の(±)−2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン(19.95mg、0.032ミリモル)および酢酸パラジウム(II)(3.60mg、0.016ミリモル)を加えた。チューブを密封し、反応混合物をマイクロ波加熱炉中で160℃で40分間加熱した。生じた懸濁液を室温に冷却し、セライトで濾過した。濾液を蒸発乾固し、粗反応混合物を逆相HPLCにより精製すると、標題化合物を固体として得た(16mg、収率24%)。MS:M(C19H21ClN6O2)=400.86,(M+H)+=401;1H NMR(400MHz,MeOD)δ ppm 7.92(s,1H)7.44−7.66(m,3H)7.11−7.25(m,1H)6.61(s,1H)5.99(s,1H)3.98(q,J=7.3Hz,2H)3.80(s,3H)2.21(s,3H)1.32(t,J=7.2Hz,3H).
LCMS(M+H)+=371.1;1H NMR(400MHz,MeOD)δ ppm 2.17(s,3H)2.91(s,3H)3.78(s,3H)6.47(s,1H)7.13−7.24(m,1H)7.40(s,1H)7.46−7.57(m,2H)7.67(dd,J=7.83,1.26Hz,1H)7.82(s,1H).
2−{[5−クロロ−2−({1−エチル−3−[(メチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド
60a)1−エチル−3−[(メチルオキシ)メチル]−1H−ピラゾール−5−アミン
2−[(5−クロロ−2−{[3−[(エチルオキシ)メチル]−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド
61a)3−[(エチルオキシ)メチル]−1−(1−メチルエチル)−1H−ピラゾール−5−アミン
2−{[5−クロロ−2−({1−エチル−3−[(エチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド
62a)1−エチル−3−[(エチルオキシ)メチル]−1H−ピラゾール−5−アミン
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−ヒドロキシ−N−メチルベンズアミド
63a)2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)ベンゾニトリル
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−5−[4−(2−ヒドロキシエチル)−1−ピペラジニル]−N−メチルベンズアミド 10
2,5−ジクロロ−4−ヨードピリジン(4.5g、16.43ミリモル)、2−アミノ−4−クロロベンゾニトリル(2.507g、16.43ミリモル)および三リン酸カリウム(10.46g、49.3ミリモル)を1,4−ジオキサン(60ml)に溶かし、室温において窒素下で攪拌し脱気した溶液に、DPEPhos(0.708g、1.314ミリモル)および酢酸パラジウム(0.148g、0.657ミリモル)を加えた。反応混合物を還流下で18時間攪拌した。反応混合物を濾過した。溶液を蒸発させた。エーテル(50ml)を加え、形成した固体を濾過した。4−クロロ−2−[(2,5−ジクロロ−4−ピリジニル)アミノ]ベンゾニトリル(2.8g、9.38ミリモル、収率57.1%)を橙色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 6.70(s,1H)7.53(dd,J=8.34,2.02Hz,1H)7.65(d,J=2.02Hz,1H)7.95(d,J=8.34Hz,1H)8.28(s,1H)9.12(br.s.,1H);HPLC Rt=3.50分,MS(ESI):298.0,300.0[M+H]+.
4−クロロ−2−[(2,5−ジクロロ−4−ピリジニル)アミノ]ベンゾニトリル(2.8g、9.38ミリモル)、3−メチル−1−(1−メチルエチル)−1H−ピラゾール−5−アミン(1.305g、9.38ミリモル)、および炭酸セシウム(9.17g、28.1ミリモル)を1,4−ジオキサン(40mL)に溶かした溶液を脱気した。DPEPhos(0.404g、0.750ミリモル)を加え、次いで酢酸パラジウム(0.084g、0.375ミリモル)を加え、懸濁液を一晩還流した。固体を濾過し、反応混合物を蒸発させた。黒色の油を、シリカゲルのフラッシュカラムクロマトグラフィー(5%EtOAc:DCM)により精製した。合わせたフラクションを蒸発させた。得られた油をジオキサン(20mL)に溶かし、水酸化ナトリウム(20mL、20.00ミリモル)を加え、反応混合物を一晩還流した。層を分離し、有機層を20mlの1MのNaOHで洗浄した。水層を合わせ、EtOAcで洗浄した。合わせた有機層を水、塩水で洗浄し、MgSO4で乾燥させ、濾過した。溶液を蒸発させ、アセトニトリルに懸濁し、濾過した。4−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]安息香酸(260mg、0.619ミリモル、収率6.60%)を黄色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.28(d,J=6.57Hz,6H)1.91(s,1H)2.13(s,3H)4.43(quin,J=6.57Hz,1H)5.97(s,1H)6.78(s,1H)7.05(dd,J=8.46,1.89Hz,1H)7.48(d,J=1.77Hz,1H)7.96(d,J=8.34Hz,1H)8.03(s,1H)8.61(s,1H);HPLC Rt=2.70分,MS(ESI):420.1,422.0[M+H]+.
4−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]安息香酸(260mg、0.619ミリモル)をN,N−ジメチルホルムアミド(DMF)(20mL)に溶かした溶液に、HOBT(114mg、0.742ミリモル)およびEDC(142mg、0.742ミリモル)を加え、反応混合物を30分間攪拌した。この溶液に、O−メトキシルアミン塩酸塩(62.0mg、0.742ミリモル)を加え、30分後反応を0℃に冷却し、DIEA(0.323mL、1.856ミリモル)を加えた。反応混合物を室温で週末の間攪拌した。水(100mL)を加え、次いで酢酸(1mL)を加え、反応混合物を2×50mlの酢酸エチルで抽出した。有機層を2×50mlの飽和KHCO3、塩水で洗浄し、MgSO4で乾燥し、蒸発させた。得られた黄色い油を、DCM:EtOAc(10%から100%)を使用するシリカゲルのフラッシュカラムクロマトグラフィーにより精製した。4−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド(85mg、0.180ミリモル、収率29.1%)を白色のフォームとして単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.27(d,J=6.57Hz,6H)2.12(s,3H)3.70(s,3H)4.41(quin,J=6.57Hz,1H)5.95(s,1H)6.66(s,1H)7.01−7.39(m,1H)7.55−7.88(m,2H)8.02(s,1H)8.60(s,1H)9.76(br.s.,1H)12.01(br.s.,1H);HPLC Rt=2.50分,MS(ESI):449.0,451.1[M+H]+.
2,5−ジクロロ−4−ヨードピリジン(4.5g、16.43ミリモル)、2−アミノ−5−クロロベンゾニトリル(2.507g、16.43ミリモル)、および三リン酸カリウム(10.46g、49.3ミリモル)を1,4−ジオキサン(60ml)に溶かし室温にて窒素下で攪拌して脱気した溶液に、DPEPhos(0.708g、1.314ミリモル)および酢酸パラジウム(0.148g、0.657ミリモル)を加えた。反応混合物を18時間還流下で攪拌した。反応混合物を濾過した。反応混合物を蒸発させた。エーテル(50ml)を加え、固体を濾過した。5−クロロ−2−[(2,5−ジクロロ−4−ピリジニル)アミノ]ベンゾニトリル(1.8g、5.43ミリモル、収率33.0%)を橙色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 6.63(s,1H)7.52(d,J=8.59Hz,1H)7.81(dd,J=8.59,2.53Hz,1H)8.09(d,J=2.53Hz,1H)8.24(s,1H)9.06(br.s.,1H);HPLC Rt=3.53分,MS(ESI):298.0,299.9[M+H]+.
5−クロロ−2−[(2,5−ジクロロ−4−ピリジニル)アミノ]ベンゾニトリル(1.8g、6.03ミリモル)および3−メチル−1−(1−メチルエチル)−1H−ピラゾール−5−アミン(0.839g、6.03ミリモル)を1,4−ジオキサン(40mL)に溶かした溶液に、炭酸セシウム(5.89g、18.09ミリモル)を加え、反応混合物を脱気した。DPEPhos(0.260g、0.482ミリモル)を加え、次いで酢酸パラジウム(0.054g、0.241ミリモル)を加え、反応混合物を一晩加熱還流した。次いで、懸濁液を濾過した。ジオキサンを蒸発させた。固体を、1MのHClと酢酸エチルとの間で分配した。層を分離し、有機層を廃棄した。HClを含む層を中和し、2×50mLの酢酸エチルで抽出した。有機層を合わせ、塩水で洗浄し、MgSO4で乾燥し、濾過し、蒸発させた。5−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]ベンゾニトリル(850mg、2.118ミリモル、収率35.1%)を黄色の固体とした単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.25(d,J=6.57Hz,6H)2.09(s,3H)4.35(quin,J=6.57Hz,1H)5.89(s,1H)6.03(s,1H)7.46(d,J=8.84Hz,1H)7.81(dd,J=8.72,2.65Hz,1H)7.96(s,1H)8.11(d,J=2.53Hz,1H)8.42(s,1H)8.54(s,1H)HPLC Rt=2.60分,MS(ESI):400.8,403.1[M+H]+.
5−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]ベンゾニトリル(850mg、2.118ミリモル)を水酸化ナトリウム−1M(20mL、20.00ミリモル)および1,4−ジオキサン(20mL)に溶かした溶液を一晩還流した。酢酸エチルを加え、層を分離した。有機層を1MのNaOH(40ml)で洗浄した。合わせた水層を酢酸エチルで洗浄した。有機層を合わせ、蒸発させ、MeOHに溶かし、再び蒸発させた。5−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]安息香酸(800mg、1.903ミリモル、収率90%)を黄色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.28(d,J=6.57Hz,6H)2.12(s,3H)4.40(quin,J=6.51Hz,1H)5.97(s,1H)6.79(s,1H)7.56−7.62(m,1H)7.62−7.69(m,1H)7.94(d,J=2.27Hz,1H)8.04(s,1H)8.58(s,1H)9.94(br.s.,1H)13.97(br.s.,1H);HPLC Rt=2.65分,MS(ESI):420.2,421.1[M+H]+.
5−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]安息香酸(830mg、1.975ミリモル)をN,N−ジメチルホルムアミド(20mL)に溶かした溶液に、HOBT(363mg、2.370ミリモル)およびEDC(454mg、2.370ミリモル)を加え、反応混合物を30分間攪拌した。この溶液に、o−メトキシルアミン塩酸塩(198mg、2.370ミリモル)を加え、30分後混合物を0℃に冷却した。DIEA(1.032mL、5.92ミリモル)を加えた。反応混合物を室温で週末の間攪拌した。水(100mL)を加え、次いで酢酸(1mL)を加え、溶液を2×50mlの酢酸エチルで抽出した。有機層を2×50mlの飽和KHCO3、塩水で洗浄し、MgSO4で乾燥し、蒸発させた。この生成物を、EtOAc:DCM(10%から100%)を使用するシリカゲルのフラッシュカラムクロマトグラフィーにより精製した。5−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド(250mg、0.529ミリモル、収率26.8%)を白色のフォームとして単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.27(d,J=6.57Hz,6H)2.11(s,3H)3.71(s,3H)4.20−4.55(m,1H)5.94(s,1H)6.63(s,1H)7.59(s,2H)7.67(s,1H)7.99(s,1H)8.50(s,1H)9.43(br.s.,1H)12.03(br.s.,1H);HPLC Rt=2.46分,MS(ESI):449.1,451.1[M+H]+.
2,5−ジクロロ−4−ヨードピリジン(8g、29.2ミリモル)、2−アミノ−5−フルオロベンゾニトリル(3.98g、29.2ミリモル)および三リン酸カリウム(18.60g、88ミリモル)を1,4−ジオキサン(100ml)に溶かし室温において窒素下で攪拌して脱気した溶液に、DPEPhos(1.258g、2.337ミリモル)および酢酸パラジウム(0.262g、1.168ミリモル)を加えた。反応混合物を還流下で18時間攪拌した。反応混合物を濾過した。溶媒を蒸発させた。エーテル(50ml)を加え、固体を濾過した。2−[(2,5−ジクロロ−4−ピリジニル)アミノ]−5−フルオロベンゾニトリル(7.09g、25.1ミリモル、収率86%)を橙色の固体として単離した。1H NMR(400MHz,methanol−d4)δ ppm 6.44(s,1H)7.46−7.58(m,2H)7.66(dd,J=8.08,2.78Hz,1H)8.08(s,1H);HPLC Rt=3.23分,MS(ESI):382.0,384.19[M+H]+.
2−[(2,5−ジクロロ−4−ピリジニル)アミノ]−5−フルオロベンゾニトリル(7.09g、25.1ミリモル)および3−メチル−1−(1−メチルエチル)−1H−ピラゾール−5−アミン(3.5g、25.1ミリモル)を1,4−ジオキサン(100mL)に溶かした溶液に、炭酸セシウム(24.58g、75ミリモル)を加え、反応混合物を脱気した。DPEPhos(1.083g、2.012ミリモル)を加え、次いで酢酸パラジウム(0.226g、1.006ミリモル)を加え、反応混合物を一晩加熱還流した。次いで懸濁液を濾過した。ジオキサンを留去した。固体を、シリカゲルのフラッシュカラムクロマトグラフィー(10%DCM:EtOAC)により精製した。フラクションを合わせ、蒸発させた。黄色い油をジエチルエーテルに溶かし、超音波処理し、濾過した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロベンゾニトリル(1.3g、3.21ミリモル、収率12.76%)を白色固体として単離した;1H NMR(400MHz,methanol−d4)δ ppm 1.35(d,J=6.82Hz,6H)2.20(s,3H)4.43(quin,J=6.69Hz,1H)5.82(s,1H)5.89(s,1H)7.47−7.57(m,2H)7.61−7.74(m,1H)7.88(s,1H);HPLC Rt=2.40分,MS(ESI):385.2[M+H]+.
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロベンゾニトリル(1.3g、3.38ミリモル)を水酸化ナトリウム−1M(10mL、10.00ミリモル)および1,4−ジオキサン(10mL)に溶かした溶液を一晩還流した。酢酸エチルを加え、層を分離した。有機層を1MのNaOH(40ml)で洗浄した。合わせた水層を酢酸エチルで洗浄し、酢酸で中和した。濾過により生成物を単離した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロ安息香酸(1.1g、2.72ミリモル、収率27.2%)を黄色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.27(d,J=6.57Hz,6H)2.11(s,3H)4.39(quin,J=6.57Hz,1H)5.95(s,1H)6.70(s,1H)7.51(td,J=8.40,3.16Hz,1H)7.61(dd,J=9.09,4.80Hz,1H)7.72(dd,J=9.22,3.16Hz,1H)8.00(s,1H)8.53(s,1H)9.66(br.s.,1H)13.88(br.s.,1H);HPLC Rt=2.44分,MS(ESI):404.3[M+H]+.
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロ安息香酸(1128mg、2.79ミリモル)をN,N−ジメチルホルムアミド(DMF)(20mL)に溶かした溶液に、HOBT(513mg、3.35ミリモル)を加え、次いでEDC(643mg、3.35ミリモル)を加え、反応混合物を30分間攪拌した。この溶液に、o−メトキシルアミン塩酸塩(280mg、3.35ミリモル)を加え、30分後に、0℃でDIEA(1.460mL、8.38ミリモル)を加えた。反応混合物を室温で24時間攪拌した。水(100mL)を加え、次いで酢酸(1mL)を加え、溶液を2×50mlの酢酸エチルで抽出した。有機層を分離し、2×50mlの飽和KHCO3、塩水で洗浄し、MgSO4で乾燥させ、蒸発させた。得られた油をジクロロメタンに懸濁し、濾過した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロ−N−(メチルオキシ)ベンズアミド(620mg、1.361ミリモル、収率48.7%)を白色固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.26(d,J=6.57Hz,6H)2.10(s,3H)3.69(s,3H)4.38(quin,J=6.57Hz,1H)5.92(s,1H)6.50(s,1H)7.41−7.52(m,2H)7.58(dd,J=8.72,4.67Hz,1H)7.96(s,1H)8.46(s,1H)9.10(s,1H)11.95(s,1H);HPLC Rt=2.24分,MS(ESI):433.4[M+H]+.
2,5−ジクロロ−4−ヨードピリジン(8g、29.2ミリモル)、2−アミノ−3−フルオロベンゾニトリル(3.98g、29.2ミリモル)および三リン酸カリウム(18.60g、88ミリモル)を1,4−ジオキサン(60ml)に溶かした室温において窒素下で攪拌して脱気した溶液に、DPEPhos(1.258g、2.337ミリモル)および酢酸パラジウム(0.262g、1.168ミリモル)を加えた。反応混合物を18時間還流下で攪拌した。反応混合物を濾過した。3−メチル−1−(1−メチルエチル)−1H−ピラゾール−5−アミン(4.07g、29.2ミリモル)および炭酸セシウム(28.6g、88ミリモル)を加えた。反応混合物を脱気し、酢酸パラジウム(0.262g、1.168ミリモル)およびDPEPhos(1.258g、2.337ミリモル)を加えた。反応混合物を一晩還流した。反応混合物を濾過し、固体を水に溶かし、50℃に加熱し、10分間攪拌し、次いで再び濾過した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロベンゾニトリル(6g、15.59ミリモル、収率53.4%)を橙色の固体として単離した。1H NMR(400MHz,DMSO−d6)d ppm 1.23(d,J=6.57Hz,6H)2.07(s,3H)4.32(quin,J=6.57Hz,1H)5.64(d,J=2.02Hz,1H)5.83(s,1H)7.39−7.58(m,1H)7.63−7.82(m,2H)7.88(s,1H)8.26(br.s.,1H)8.41(br.s.,1H);HPLC Rt=2.35分,MS(ESI):385.0[M+H]+.
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロベンゾニトリル(4.5g、11.69ミリモル)を水酸化ナトリウム−1M(10mL、10.00ミリモル)および1,4−ジオキサン(10mL)に溶かした溶液を一晩還流した。酢酸エチルを加え、層を分離した。有機層を1MのNaOH(40ml)で洗浄した。合わせた水層を酢酸エチルで洗浄し、酢酸で中和した。固体を濾過した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ安息香酸(3.2g、7.53ミリモル、収率75%)を黄色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.24(d,J=6.57Hz,6H)2.09(s,3H)4.34(quin,J=6.57Hz,1H)5.86(s,1H)5.91(d,J=5.81Hz,1H)7.35(td,J=8.02,4.93Hz,1H)7.54−7.65(m,1H)7.81(d,J=7.58Hz,1H)7.94(s,1H)8.45(s,1H)8.88(br.s.,1H)13.74(br.s.,1H);HPLC Rt=2.36分,MS(ESI):404.3[M+H]+.
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ安息香酸(3.2g、7.92ミリモル)をN,N−ジメチルホルムアミド(DMF)(50mL)に溶かした溶液に、HOBT(1.456g、9.51ミリモル)およびEDC(1.823g、9.51ミリモル)を加え、反応混合物を30分間攪拌した。この溶液に、O−メトキシルアミン塩酸塩(0.794g、9.51ミリモル)を加えた。30分後、反応混合物を0℃に冷却し、DIEA(4.14mL、23.77ミリモル)を加えた。反応混合物を室温で24時間攪拌した。水(100mL)を加え、その後酢酸(1mL)を加え、溶液を2×50mlの酢酸エチルで抽出した。合わせた有機層を2×50mlの飽和KHCO3、塩水で洗浄し、MgSO4で乾燥させ、蒸発させた。油をジクロロメタンに懸濁し、濾過した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ−N−(メチルオキシ)ベンズアミド(1.1g、2.414ミリモル、収率30.5%)を白色固体として単離した;1H NMR(400MHz,DMSO−d6)δ ppm 1.24(d,J=6.57Hz,6H)2.08(s,3H)3.68(s,3H)4.33(quin,J=6.57Hz,1H)5.83(d,J=5.05Hz,1H)5.84(s,1H)7.30−7.49(m,2H)7.49−7.63(m,1H)7.92(s,1H)8.41(d,J=4.29Hz,2H)11.85(s,1H);HPLC Rt=2.18分,MS(ESI):433.3[M+H]+.
2,5−ジクロロ−4−ヨードピリジン(5g、18.26ミリモル)、2−アミノ−4−フルオロベンゾニトリル(2.485g、18.26ミリモル)および三リン酸カリウム(11.63g、54.8ミリモル)を1,4−ジオキサン(60ml)に溶かし室温において窒素下で攪拌して脱気した溶液に、DPEPhos(0.787g、1.460ミリモル)および酢酸パラジウム(0.164g、0.730ミリモル)を加えた。反応混合物を還流下で18時間攪拌した。反応混合物を濾過した。3−メチル−1−(1−メチルエチル)−1H−ピラゾール−5−アミン(2.54g、18.26ミリモル)および炭酸セシウム(17.84g、54.8ミリモル)を加えた。反応混合物を脱気し、酢酸パラジウム(0.164g、0.730ミリモル)およびDPEPhos(0.787g、1.460ミリモル)を加えた。反応混合物を一晩還流した。反応混合物を濾過した。NaOH(60mL、60.0ミリモル)を加え、反応混合物を一晩還流した。酢酸エチルを加え、層を分離した。合わせた有機物を1MのNaOH(40ml)で洗浄した。合わせた水層を酢酸エチルで洗浄し、酢酸で中和した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ安息香酸(2.5g、6.19ミリモル、収率33.9%)を濾過により黄色の固体として単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.29(d,J=6.57Hz,6H)2.12(s,3H)4.43(quin,J=6.57Hz,1H)5.99(s,1H)6.86(s,1H)6.87−6.93(m,1H)7.34(dd,J=11.62,2.53Hz,1H)8.03−8.10(m,2H)8.62(s,1H)10.65(br.s.,1H);HPLC Rt=2.57分,MS(ESI):404.2[M+H]+.
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ安息香酸(2.5g、6.19ミリモル)をN,N−ジメチルホルムアミド(DMF)(50mL)に溶かした溶液に、HOBT(1.138g、7.43ミリモル)およびEDC(1.424g、7.43ミリモル)を加え、反応混合物を30分間攪拌した。この溶液に、O−メトキシルアミン塩酸塩(0.620g、7.43ミリモル)を加え、30分後混合物を0℃に冷却した。次いで、DIEA(3.23mL、18.57ミリモル)を加えた。反応混合物を室温で24時間攪拌した。水(100mL)を加え、次いで酢酸(1mL)を加え、溶液を2×50mlの酢酸エチルで抽出した。有機層を2×50mlの飽和KHCO3、塩水で洗浄し、MgSO4で乾燥させ、濃縮した。得られた油を、シリカゲルのフラッシュカラムクロマトグラフィー(2:1のDCM:EtOAc)により精製した。2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ−N−(メチルオキシ)ベンズアミド(1g、2.195ミリモル、収率35.5%)を黄色のフォームとして単離した。1H NMR(400MHz,DMSO−d6)δ ppm 1.28(d,J=6.57Hz,6H)2.11(s,3H)3.71(s,3H)4.41(quin,J=6.51Hz,1H)5.97(s,1H)6.74(s,1H)6.87−7.06(m,1H)7.39(dd,J=11.37,2.53Hz,1H)7.66(dd,J=8.46,6.69Hz,1H)8.03(s,1H)8.57(s,1H)9.96(br.s.,1H)11.98(br.s.,1H);HPLC Rt=2.36分,MS(ESI):433.3[M+H]+.
実質的に実施例8の手順に従い、以下の化合物を、2,5−ジクロロ−4−ヨードピリジンまたは2−クロロ−4−ヨード−5−(トリフルオロメチル)ピリジンのいずれかと適切に置換された5−アミノピラゾールで出発して調製できる。
以下の化合物は、実質的に実施例72の手順に従い、適切に置換された5−アミノピラゾールを使用して作ることができる。
以下の化合物は、実質的に実施例41aまたは41bの手順に従い、3−[(ジメチルアミノ)メチル]−1−エチル−1H−ピラゾール−5−アミンを使用して作ることができる。
以下の化合物は、実質的に実施例73の手順に従い、適切に置換された5−アミノピラゾールを使用して作ることができる。
77(a)2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−4−フルオロ−N−(メチルオキシ)ベンズアミド
Claims (13)
- 下記式(I):
R1は、ハロ、CF3、C1−C6−アルキル、イソプロペニル、(C2−C6−アルキレン)C3−C6−シクロアルキル、C1−C6−アルコキシ、またはシアノであり;
R2において、pが0でない場合、各2は、独立に、F、Cl、CF3、メチル、メトキシ、CH2CF3、−(X)q−C1−C4−アルキレン−R4、−(X−C1−C4−アルキレン)q−NR5−C(O)−R6、−(X−C1−C4−アルキレン)q(NR5)q−SOx−R7、−(X−C1−C4−アルキレン)q−Y−N(R8)2、五員から六員のヘテロシクロアルキル−(R9)q基、または五員から六員のヘテロアリール−(R10)r基であり;
R3は、H、C3−C6−シクロアルキル、C1−C6−アルキル、C1−C6アルコキシ、C1−C6−アルキレン−R4、O−C1−C6−アルキレン−R4であるか、またはR3基はZとともに、メチル、C1−C4−アルキレン−R4、もしくはC3−C6−シクロアルキルにより置換されていてもよい五員から六員の環を形成し;
R4は、H、−(Q)q−N(R8)2、OH、SH、C1−C6−アルコキシ、C1−C6−チオアルキル、または五員から六員のヘテロシクロアルキル−(R9)q基であり;
R5は、HまたはC1−C6−アルキルであり;
R6は、H、C1−C6−アルキル、C1−C6−アルコキシ、N(R8)2、または五員から六員のヘテロアリール−(R10)r基であり;
R7は、C1−C6−アルキル、フェニル−(R9)q、または五員から六員のヘテロアリール−(R10)rであり、
R8は、独立に、H、C1−C6−アルキル、−O−C1−C6−アルキルであるか、またはそれが結合している窒素原子とともに五員もしくは六員のヘテロシクロアルキル基を形成し;
R9は、H、C1−C6−アルキル、C1−C6−アルコキシ、−(Q)q−N(R8)2、−Q−C1−C6−アルキル、−C1−C6アルキルR4、または五員から六員のヘテロシクロアルキルであり;
R10は、H、C1−C6−アルキル、C1−C6−アルコキシ、または−Q−C2−C6−アルキルであり;
R11は、C1−C6−アルキル、CF3、−CH2CF3、−(Q)q−C1−C4−アルキレン−R4、−Q−N(R8)2、フェニル−(R5)s、五員から六員のヘテロシクロアルキル−(R9)q基、または五員から六員のヘテロアリール−(R10)r基であり;
R12は、H、C1−C6−アルキル、F、Cl、CF3、OH、CN、ニトロ、COOH、−COO−C1−C6−アルキル、−Y−N(R8)2、C3−C6−シクロアルキル−R14、−(X)q−C1−C6−アルキレン−R4、−(X−C1−C6−アルキレン)q−NR5−C(O)−R6、−(X−C1−C6−アルキレン)q−(NR5)q−SOx−R7、−(X−C1−C6−アルキレン)q−Y−N(R8)2、ヘテロシクロアルキル−(R9)q、ヘテロアリール−(R10)r、またはフェニル−(R15)sであり;
R13は、H、F、Cl、C1−C6−アルキル、もしくはC3−C6−シクロアルキルであり;またはR12とR13とが、それらが結合している炭素原子とともに、縮合した五員もしくは六員のカルボシクロアルキルもしくはヘテロシクロアルキル基を形成し;
R14は、独立に、H、C1−C6−アルキル、−NR5−SO2−R7、−Y−N(R8)2、または−(X)q−C1−C6−アルキレン−R4であり;
各15は、独立に、F、Cl、CF3、C1−C3−アルキル、またはC1−C3−アルコキシであり;
pは、0、1、2、または3であり;
qは、0または1であり;
rは、0、1、または2であり;
sは、0、1、2、または3であり;
xは、1または2であり;
Qは、−C(O)−、−S(O)−、または−SO2−であり;
Xは、NR5、O、S、−S(O)−、または−SO2−であり;
Yは、結合、SO2、またはC(O)であり;かつ
Zは、NまたはCR5である]
の化合物またはその塩。 - Qが、C(O)であり、Zが、Nである、請求項1または2に記載の化合物またはその塩。
- R3の1つが、メトキシであり、他のR3が、Hである、請求項1〜3のいずれか一項に記載の化合物またはその塩。
- R3の1つが、メチルであり、他のR3が、Hである、請求項1〜3のいずれか一項に記載の化合物またはその塩。
- R1が、Cl、CF3、またはCNである、請求項1〜5のいずれか一項に記載の化合物またはその塩。
- pが、0または1であり、R2が、Fである、請求項1〜6のいずれか一項に記載の化合物またはその塩。
- R11が、C1−C3−アルキルである、請求項1〜7のいずれか一項に記載の化合物またはその塩。
- R12が、C1−C4−アルキル、ヒドロキシメチル、またはシクロプロピルである、請求項1〜8のいずれか一項に記載の化合物またはその塩。
- R13が、Hである、請求項1〜9のいずれか一項に記載の化合物またはその塩。
- 下記:
2−[5−クロロ−2−(2−メチル−5−フェニル−2H−ピラゾル−3−イルアミノ)−ピリジン−4−イルアミノ]−N−メチル−ベンズアミド;
2−({5−クロロ−2−[(1−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(3−シクロプロピル−1−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−5−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−5−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−4,5−ジフルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−4,5−ジフルオロ−N−メチルベンズアミド;
5−クロロ−2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
5−クロロ−2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−[(5−クロロ−2−{[3−(1,1−ジメチルエチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−[(5−クロロ−2−{[1−エチル−3−(ヒドロキシメチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−[(5−クロロ−2−{[1−(2−ヒドロキシエチル)−3−メチル−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
エチル5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−1−エチル−1H−ピラゾール−3−カルボキシラート;
5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−1−エチル−1H−ピラゾール−3−カルボン酸;
5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−1−エチル−N−(メチルオキシ)−1H−ピラゾール−3−カルボキサミド;
5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−1−エチル−N−メチル−1H−ピラゾール−3−カルボキサミド;
2−[(5−クロロ−2−{[3−メチル−1−(2,2,2−トリフルオロエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−[(5−クロロ−2−{[1−(1−メチル−4−ピペリジニル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−{[5−クロロ−2−({1−[2−(ジメチルアミノ)エチル]−3−メチル−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−N−[2−(ジメチルアミノ)エチル]−1−エチル−1H−ピラゾール−3−カルボキサミド;
5−{[5−クロロ−4−({2−[(メチルアミノ)カルボニル]フェニル}アミノ)−2−ピリジニル]アミノ}−N−[2−(ジメチルアミノ)エチル]−1−エチル−N−メチル−1H−ピラゾール−3−カルボキサミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−{[2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
N−メチル−2−{[2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}ベンズアミド;
2−{[2−({1−[2−(ジメチルアミノ)エチル]−3−メチル−1H−ピラゾル−5−イル}アミノ)−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
N−メチル−2−{[2−[(3−メチル−1−フェニル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}ベンズアミド;
2−{[2−{[1−(2−ヒドロキシエチル)−3−メチル−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)安息香酸;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチル−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−{[2−(ジメチルアミノ)エチル]オキシ}ベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミドHCl;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミドギ酸塩;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−エチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−エチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−エチルベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−エチルベンズアミド;
2−{[5−クロロ−2−({1−エチル−3−[2−(1−ピロリジニル)エチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,5−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[4−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1−エチル−4−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[4−メチル−1−(2−メチルプロピル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−(ヒドロキシメチル)−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
2−[5−シクロプロピル−2−(2,5−ジメチル−2H−ピラゾル−3−イルアミノ)−ピリジン−4−イルアミノ]−N−メチル−ベンズアミド;
2−[5−シクロプロピル−2−(2−エチル−5−メチル−2H−ピラゾル−3−イルアミノ)−ピリジン−4−イルアミノ]−N−メチルベンズアミド;
2−[5−シクロプロピル−2−(2,5−ジメチル−2H−ピラゾル−3−イルアミノ)−ピリジン−4−イルアミノ]−N−メトキシ−ベンズアミド;
2−[5−シクロプロピル−2−(2−エチル−5−メチル−2H−ピラゾル−3−イルアミノ)−ピリジン−4−イルアミノ]−N−メトキシ−ベンズアミド;
2−[2−(2,5−ジメチル−2H−ピラゾル−3−イルアミノ)−5−イソプロペニル−ピリジン−4−イルアミノ]−N−メチル−ベンズアミド;
2−[2−(2,5−ジメチル−2H−ピラゾル−3−イルアミノ)−5−イソプロピル−ピリジン−4−イルアミノ]−N−メチル−ベンズアミド;
2−({5−クロロ−2−[(1,5−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−{[5−クロロ−2−({1−エチル−3−[(メチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[5−クロロ−2−({1−エチル−3−[(メチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−[(5−クロロ−2−{[3−[(エチルオキシ)メチル]−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−[(5−クロロ−2−{[3−[(エチルオキシ)メチル]−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−メチルベンズアミド;
2−{[5−クロロ−2−({1−エチル−3−[(エチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[5−クロロ−2−({1−エチル−3−[(エチルオキシ)メチル]−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−ヒドロキシ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−ヒドロキシ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−(エチルオキシ)ベンズアミド;
2−({5−シアノ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−5−[4−(2−ヒドロキシエチル)−1−ピペラジニル]−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−5−[4−(2−ヒドロキシエチル)−1−ピペラジニル]−N−メチルベンズアミド;
4−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
4−クロロ−2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−5−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−メチル−1−(1−メチルエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1,5−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−{[2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−{[2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−{[2−{[1−エチル−3−(ヒドロキシメチル)−1H−ピラゾル−5−イル]アミノ}−5−クロロ−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
3−フルオロ−2−{[2−{[3−(ヒドロキシメチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−5−クロロ−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−{[1−エチル−3−(2−ヒドロキシエチル)−1H−ピラゾル−5−イル]アミノ}−5−クロロ−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
3−フルオロ−2−{[2−{[3−(2−ヒドロキシエチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−5−クロロ−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−({3−[(ジメチルアミノ)メチル]−1−メチル−1H−ピラゾル−5−イル}アミノ)−5クロロ−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−{[2−({3−[(ジメチルアミノ)メチル]−1−エチル−1H−ピラゾル−5−イル}アミノ)−5クロロ−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(3−{[エチル(メチル)アミノ]メチル}−1−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−メチルベンズアミド;
2−{[5−クロロ−2−({3−[(ジエチルアミノ)メチル]−1−メチル−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−{[2−{[1−エチル−3−(ヒドロキシメチル)−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
3−フルオロ−2−{[2−{[3−(ヒドロキシメチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−{[1−エチル−3−(2−ヒドロキシエチル)−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
3−フルオロ−2−{[2−{[3−(2−ヒドロキシエチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−N−メチルベンズアミド;
2−{[2−({3−[(ジメチルアミノ)メチル]−1−メチル−1H−ピラゾル−5−イル}アミノ)−5−(トリフルオロメチル)−4−ピリジニル]アミノ}−3−フルオロ−N−メチルベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[1−エチル−3−(ヒドロキシメチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−(ヒドロキシメチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−{[5−クロロ−2−({3−[(ジメチルアミノ)メチル]−1−エチル−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,5−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−3−フルオロ−N−(メチルオキシ)ベンズアミド;
2−{[5−クロロ−2−({3−[(ジメチルアミノ)メチル]−1−エチル−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1−エチル−3−メチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,3−ジメチル−1H−ピラゾル−5−イル)アミノ]−4−ピリジニル}アミノ)−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[1−エチル−3−(ヒドロキシメチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[1−エチル−3−(2−ヒドロキシエチル)−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−[(5−クロロ−2−{[3−(ヒドロキシメチル)−1−メチル−1H−ピラゾル−5−イル]アミノ}−4−ピリジニル)アミノ]−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−{[5−クロロ−2−({3−[(ジメチルアミノ)メチル]−1−エチル−1H−ピラゾル−5−イル}アミノ)−4−ピリジニル]アミノ}−4−フルオロ−N−(メチルオキシ)ベンズアミド;
2−({5−クロロ−2−[(1,5−ジメチル−1H−ピラゾル−4−イル)アミノ]−4−ピリジニル}アミノ)−4−フルオロ−N−(メチルオキシ)ベンズアミド
である請求項1に記載の化合物またはその塩。 - 請求項1〜11のいずれか一項に記載の式(I)の化合物またはその薬学上許容される塩および薬学上許容される賦形剤を含んでなる、薬学上許容される組成物。
- 医薬として有効な量の、請求項1〜11のいずれか一項に記載の化合物またはその薬学上許容される塩を、その必要のある患者へ投与することを含んでなる、癌の治療方法。
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UY (1) | UY32200A (ja) |
WO (1) | WO2010062578A1 (ja) |
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KR20140011322A (ko) * | 2011-01-26 | 2014-01-28 | 글락소스미스클라인 인털렉츄얼 프로퍼티 리미티드 | 조합물 |
CN103534240B (zh) | 2011-02-17 | 2015-12-09 | 癌症疗法Crc私人有限公司 | 选择性fak抑制剂 |
DK2675793T3 (en) | 2011-02-17 | 2018-11-12 | Cancer Therapeutics Crc Pty Ltd | FAK INHIBITORS |
WO2013003575A1 (en) * | 2011-06-28 | 2013-01-03 | Glaxosmithkline Llc | Method of administration and treatment |
WO2015054477A1 (en) | 2013-10-09 | 2015-04-16 | The General Hospital Corporation | Methods of diagnosing and treating b cell acute lymphoblastic leukemia |
US10532056B2 (en) | 2015-06-29 | 2020-01-14 | Verastem, Inc. | Therapeutic compositions, combinations, and methods of use |
CN108948019B (zh) * | 2017-05-18 | 2022-07-08 | 广东东阳光药业有限公司 | 黏着斑激酶抑制剂及其用途 |
WO2019117813A1 (en) * | 2017-12-15 | 2019-06-20 | National University Of Singapore | Focal adhesion kinase targeted therapeutics for the treatment of glaucoma and fibrosis |
CA3093742A1 (en) | 2018-03-12 | 2019-09-19 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers |
CN108912095B (zh) * | 2018-08-09 | 2019-08-20 | 广州安岩仁医药科技有限公司 | 苯并咪唑类化合物及其制备方法和应用 |
CA3109617A1 (en) * | 2018-09-27 | 2020-04-02 | Dana-Farber Cancer Institute, Inc. | Degradation of fak or fak and alk by conjugation of fak and alk inhibitors with e3 ligase ligands and methods of use |
CN113387947B (zh) * | 2021-07-12 | 2022-07-01 | 中国科学院成都生物研究所 | 调节雌激素受体合成活性的吡唑并吡啶衍生物 |
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