JP2016519685A - Ras/raf/mek/erk経路およびpi3k/akt/pten/mtor経路の二重阻害剤としてのキナゾリンおよびアザキナゾリン - Google Patents
Ras/raf/mek/erk経路およびpi3k/akt/pten/mtor経路の二重阻害剤としてのキナゾリンおよびアザキナゾリン Download PDFInfo
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- JP2016519685A JP2016519685A JP2016507671A JP2016507671A JP2016519685A JP 2016519685 A JP2016519685 A JP 2016519685A JP 2016507671 A JP2016507671 A JP 2016507671A JP 2016507671 A JP2016507671 A JP 2016507671A JP 2016519685 A JP2016519685 A JP 2016519685A
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- Prior art keywords
- sulfonamide
- fluorophenyl
- morpholinoquinazolin
- fluoropropane
- methoxy
- 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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- HNNSHBLYLKUEKC-HNNXBMFYSA-N N-[3-[2-(2-amino-4-methylpyrimidin-5-yl)-4-[(3S)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@H]1COCCN1c1nc(nc2ccc(nc12)-c1cccc(NS(=O)(=O)CCCF)c1F)-c1cnc(N)nc1C HNNSHBLYLKUEKC-HNNXBMFYSA-N 0.000 claims 1
- GOYNWVKPYAPRGK-UHFFFAOYSA-N N-[3-[2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=NC=C(C(=N1)C)C=1N=C(C2=C(N=1)C=CC(=N2)C=1C(=C(C=CC=1)NS(=O)(=O)CCCF)F)N1CCOCC1 GOYNWVKPYAPRGK-UHFFFAOYSA-N 0.000 claims 1
- HWGPFCJQFPPBOD-QGZVFWFLSA-N N-[3-[2-(2-aminopyrimidin-5-yl)-8-(2-fluoroethoxy)-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=NC=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F)OCCF HWGPFCJQFPPBOD-QGZVFWFLSA-N 0.000 claims 1
- MTGTVPVITJOLCP-QGZVFWFLSA-N N-[3-[2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=NC=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F)OCC MTGTVPVITJOLCP-QGZVFWFLSA-N 0.000 claims 1
- MTGTVPVITJOLCP-KRWDZBQOSA-N N-[3-[2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-[(3S)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound CCOc1cc(cc2c(nc(nc12)-c1cnc(N)nc1)N1CCOC[C@@H]1C)-c1cccc(NS(=O)(=O)CCCF)c1F MTGTVPVITJOLCP-KRWDZBQOSA-N 0.000 claims 1
- SSZKHFIPLIWYMR-QGZVFWFLSA-N N-[3-[2-(2-aminopyrimidin-5-yl)-8-ethyl-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound CCc1cc(cc2c(nc(nc12)-c1cnc(N)nc1)N1CCOC[C@H]1C)-c1cccc(NS(=O)(=O)CCCF)c1F SSZKHFIPLIWYMR-QGZVFWFLSA-N 0.000 claims 1
- BLMATCSJUYYMEA-MRXNPFEDSA-N N-[3-[2-(5-aminopyrazin-2-yl)-8-methoxy-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC=1N=CC(=NC1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F)OC BLMATCSJUYYMEA-MRXNPFEDSA-N 0.000 claims 1
- SOMFDSKXOLISGB-QGZVFWFLSA-N N-[3-[2-(6-amino-4-cyanopyridin-3-yl)-8-methoxy-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=CC(=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F)OC)C#N SOMFDSKXOLISGB-QGZVFWFLSA-N 0.000 claims 1
- LFAONIZWKJTNQP-OAHLLOKOSA-N N-[3-[2-(6-amino-4-fluoropyridin-3-yl)-4-[(3R)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=CC(=C(C=N1)C=1N=C(C2=C(N=1)C=CC(=N2)C=1C(=C(C=CC=1)NS(=O)(=O)CCCF)F)N1[C@@H](COCC1)C)F LFAONIZWKJTNQP-OAHLLOKOSA-N 0.000 claims 1
- LFAONIZWKJTNQP-HNNXBMFYSA-N N-[3-[2-(6-amino-4-fluoropyridin-3-yl)-4-[(3S)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@H]1COCCN1c1nc(nc2ccc(nc12)-c1cccc(NS(=O)(=O)CCCF)c1F)-c1cnc(N)cc1F LFAONIZWKJTNQP-HNNXBMFYSA-N 0.000 claims 1
- VSYCXHPMCJAWEN-MRXNPFEDSA-N N-[3-[2-(6-amino-4-fluoropyridin-3-yl)-8-methoxy-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=CC(=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC=1)NS(=O)(=O)CCCF)F)OC)F VSYCXHPMCJAWEN-MRXNPFEDSA-N 0.000 claims 1
- SAEYUAYUMCLKCT-KRWDZBQOSA-N N-[3-[2-(6-amino-4-methylpyridin-3-yl)-4-[(3S)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=CC(=C(C=N1)C=1N=C(C2=C(N=1)C=CC(=N2)C=1C(=C(C=CC=1)NS(=O)(=O)CCCF)F)N1[C@H](COCC1)C)C SAEYUAYUMCLKCT-KRWDZBQOSA-N 0.000 claims 1
- IGHWXSSWNCXBBT-QGZVFWFLSA-N N-[3-[2-(6-amino-5-fluoropyridin-3-yl)-8-(2-fluoroethoxy)-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=C(C=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F)OCCF)F IGHWXSSWNCXBBT-QGZVFWFLSA-N 0.000 claims 1
- XPNSJZCJXAMCPP-MRXNPFEDSA-N N-[3-[2-(6-amino-5-fluoropyridin-3-yl)-8-methoxy-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound NC1=C(C=C(C=N1)C1=NC2=C(C=C(C=C2C(=N1)N1[C@@H](COCC1)C)C=1C(=C(C=CC=1)NS(=O)(=O)CCCF)F)OC)F XPNSJZCJXAMCPP-MRXNPFEDSA-N 0.000 claims 1
- HKHWEKMHOSDGTA-HXUWFJFHSA-N N-[3-[2-(6-aminopyridin-3-yl)-4-[(3R)-3-methylmorpholin-4-yl]-8-pyrrolidin-1-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@@H]1COCCN1c1nc(nc2c(cc(cc12)-c1cccc(NS(=O)(=O)CCCF)c1F)N1CCCC1)-c1ccc(N)nc1 HKHWEKMHOSDGTA-HXUWFJFHSA-N 0.000 claims 1
- IOPPHACWXKLSDE-INIZCTEOSA-N N-[3-[2-(6-aminopyridin-3-yl)-4-[(3S)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@H]1COCCN1c1nc(nc2ccc(nc12)-c1cccc(NS(=O)(=O)CCCF)c1F)-c1ccc(N)nc1 IOPPHACWXKLSDE-INIZCTEOSA-N 0.000 claims 1
- KWKYMTIODSCPKX-UHFFFAOYSA-N N-[3-[2-(6-aminopyridin-3-yl)-8-methyl-4-morpholin-4-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound Cc1cc(cc2c(nc(nc12)-c1ccc(N)nc1)N1CCOCC1)-c1cccc(NS(=O)(=O)CCCF)c1F KWKYMTIODSCPKX-UHFFFAOYSA-N 0.000 claims 1
- HNTNRJOWCSMYHF-GOSISDBHSA-N N-[3-[8-ethoxy-2-[2-(methylamino)pyrimidin-5-yl]-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C(C)OC=1C=C(C=C2C(=NC(=NC12)C=1C=NC(=NC1)NC)N1[C@@H](COCC1)C)C=1C(=C(C=CC1)NS(=O)(=O)CCCF)F HNTNRJOWCSMYHF-GOSISDBHSA-N 0.000 claims 1
- DVGGRJLRAMFKKA-UHFFFAOYSA-N N-[4-[6-[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]-8-methoxy-4-morpholin-4-ylquinazolin-2-yl]phenyl]acetamide Chemical compound FC1=C(C=CC=C1NS(=O)(=O)CCCF)C=1C=C2C(=NC(=NC2=C(C=1)OC)C1=CC=C(C=C1)NC(C)=O)N1CCOCC1 DVGGRJLRAMFKKA-UHFFFAOYSA-N 0.000 claims 1
- XWRHMVYXGFTVIT-UHFFFAOYSA-N N-[5-[6-[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]-8-methoxy-4-morpholin-4-ylquinazolin-2-yl]pyridin-2-yl]acetamide Chemical compound COc1cc(cc2c(nc(nc12)-c1ccc(NC(C)=O)nc1)N1CCOCC1)-c1cccc(NS(=O)(=O)CCCF)c1F XWRHMVYXGFTVIT-UHFFFAOYSA-N 0.000 claims 1
- RXCVUDCDCGBNDA-UHFFFAOYSA-N Nc1ccc(cn1)-c1nc(N2CCOCC2)c2cc(cc(OCCO)c2n1)-c1cccc(NS(=O)(=O)CCCF)c1F Chemical compound Nc1ccc(cn1)-c1nc(N2CCOCC2)c2cc(cc(OCCO)c2n1)-c1cccc(NS(=O)(=O)CCCF)c1F RXCVUDCDCGBNDA-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 claims 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-O dipropylazanium Chemical compound CCC[NH2+]CCC WEHWNAOGRSTTBQ-UHFFFAOYSA-O 0.000 claims 1
- 125000003709 fluoroalkyl group Chemical group 0.000 claims 1
- AHUXCWLFJLUIHB-UHFFFAOYSA-N n-[2,4-difluoro-3-[8-methoxy-4-morpholin-4-yl-2-(1h-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl]phenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C(C=2C=C3C=CNC3=NC=2)N=C2C(OC)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3F)F)=CC2=C1N1CCOCC1 AHUXCWLFJLUIHB-UHFFFAOYSA-N 0.000 claims 1
- YACWSBWESYZOLB-LJQANCHMSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-[(3r)-3-methylmorpholin-4-yl]-8-morpholin-4-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@@H]1COCCN1C1=NC(C=2C=NC(N)=NC=2)=NC2=C(N3CCOCC3)C=C(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)C=C12 YACWSBWESYZOLB-LJQANCHMSA-N 0.000 claims 1
- KZLDMKLFOBDXRC-GOSISDBHSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-[(3r)-3-methylmorpholin-4-yl]-8-propan-2-yloxyquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OC(C)C)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2[C@@H](COCC2)C)N=C1C1=CN=C(N)N=C1 KZLDMKLFOBDXRC-GOSISDBHSA-N 0.000 claims 1
- HVSPLUAKXSNPDJ-OAHLLOKOSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-[(3r)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@@H]1COCCN1C1=NC(C=2C=NC(N)=NC=2)=NC2=CC=C(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)N=C12 HVSPLUAKXSNPDJ-OAHLLOKOSA-N 0.000 claims 1
- PSFCWWMIWHOTFC-UHFFFAOYSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-2,5-difluorobenzenesulfonamide Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)C=4C(=CC=C(F)C=4)F)C=CC=3)F)C2=N1 PSFCWWMIWHOTFC-UHFFFAOYSA-N 0.000 claims 1
- ZLWYTUNMJHQFBQ-UHFFFAOYSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)C=4C(=CC=CC=4F)F)C=CC=3)F)C2=N1 ZLWYTUNMJHQFBQ-UHFFFAOYSA-N 0.000 claims 1
- LPMZZHSJRQXVDE-UHFFFAOYSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)C2=N1 LPMZZHSJRQXVDE-UHFFFAOYSA-N 0.000 claims 1
- FJAFBKXIUIVOFD-UHFFFAOYSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-morpholin-4-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OCC)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2CCOCC2)N=C1C1=CN=C(N)N=C1 FJAFBKXIUIVOFD-UHFFFAOYSA-N 0.000 claims 1
- ACQKHLTVQZCRMC-MRXNPFEDSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-8-methoxy-4-[(3r)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OC)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2[C@@H](COCC2)C)N=C1C1=CN=C(N)N=C1 ACQKHLTVQZCRMC-MRXNPFEDSA-N 0.000 claims 1
- ACQKHLTVQZCRMC-INIZCTEOSA-N n-[3-[2-(2-aminopyrimidin-5-yl)-8-methoxy-4-[(3s)-3-methylmorpholin-4-yl]quinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OC)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2[C@H](COCC2)C)N=C1C1=CN=C(N)N=C1 ACQKHLTVQZCRMC-INIZCTEOSA-N 0.000 claims 1
- PGOQLDYCVFCOIQ-HXUWFJFHSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-[(3r)-3-methylmorpholin-4-yl]-8-morpholin-4-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@@H]1COCCN1C1=NC(C=2C=NC(N)=CC=2)=NC2=C(N3CCOCC3)C=C(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)C=C12 PGOQLDYCVFCOIQ-HXUWFJFHSA-N 0.000 claims 1
- IEHHNERSWWKFMA-LJQANCHMSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-[(3r)-3-methylmorpholin-4-yl]-8-propan-2-yloxyquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OC(C)C)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2[C@@H](COCC2)C)N=C1C1=CC=C(N)N=C1 IEHHNERSWWKFMA-LJQANCHMSA-N 0.000 claims 1
- IOPPHACWXKLSDE-MRXNPFEDSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-[(3r)-3-methylmorpholin-4-yl]pyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C[C@@H]1COCCN1C1=NC(C=2C=NC(N)=CC=2)=NC2=CC=C(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)N=C12 IOPPHACWXKLSDE-MRXNPFEDSA-N 0.000 claims 1
- JZBIKMAGUGEITA-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-yl-8-propan-2-yloxyquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OC(C)C)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2CCOCC2)N=C1C1=CC=C(N)N=C1 JZBIKMAGUGEITA-UHFFFAOYSA-N 0.000 claims 1
- JULZXZPLIIQFRU-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-yl-8-pyrrolidin-1-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C1=NC(N)=CC=C1C1=NC(N2CCOCC2)=C(C=C(C=C2N3CCCC3)C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)C2=N1 JULZXZPLIIQFRU-UHFFFAOYSA-N 0.000 claims 1
- ZAOUBHISQLGCCN-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-2,5-difluorobenzenesulfonamide Chemical compound C1=NC(N)=CC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)C=4C(=CC=C(F)C=4)F)C=CC=3)F)C2=N1 ZAOUBHISQLGCCN-UHFFFAOYSA-N 0.000 claims 1
- YBYHVBPIMGMRRM-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound C1=NC(N)=CC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)C=4C(=CC=CC=4F)F)C=CC=3)F)C2=N1 YBYHVBPIMGMRRM-UHFFFAOYSA-N 0.000 claims 1
- GZXPIRAVIANAFR-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound C1=NC(N)=CC=C1C1=NC(N2CCOCC2)=C(N=C(C=C2)C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)C2=N1 GZXPIRAVIANAFR-UHFFFAOYSA-N 0.000 claims 1
- LKQRACJFAPDYAG-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-4-morpholin-4-ylpyrido[3,2-d]pyrimidin-6-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C=2N=C3C(N4CCOCC4)=NC(=NC3=CC=2)C=2C=NC(N)=CC=2)=C1F LKQRACJFAPDYAG-UHFFFAOYSA-N 0.000 claims 1
- HORGZGMOHDXHCW-UHFFFAOYSA-N n-[3-[2-(6-aminopyridin-3-yl)-8-(2-methoxyethoxy)-4-morpholin-4-ylquinazolin-6-yl]-2-fluorophenyl]-3-fluoropropane-1-sulfonamide Chemical compound N1=C2C(OCCOC)=CC(C=3C(=C(NS(=O)(=O)CCCF)C=CC=3)F)=CC2=C(N2CCOCC2)N=C1C1=CC=C(N)N=C1 HORGZGMOHDXHCW-UHFFFAOYSA-N 0.000 claims 1
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- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
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- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57496—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving intracellular compounds
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
さらなる別の実施の形態では、R7は場合により置換したC1〜C6アルキルである。またさらなる実施の形態では、R7は1個または複数のFで場合により置換したC1〜C6アルキルである。別の実施の形態では、R7はi−プロピル、i−ブチル、n−プロピル、エチル、n−ブチル、CH2CH2CH2F、またはCH2CH2CF3である。またさらなる実施の形態では、R7は場合により置換したヘテロアリールである。別の実施の形態では、R7はチオフェンである。
2,6−ジフルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(4−(3−メチルウレイド)フェニル)−4−モルホリノキナゾリン−6−イル)フェニル)ベンゼンスルホンアミド
N−(3−(2−(1H−インダゾール−4−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(6−((2−アミノエチル)アミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(6−アミノピリジン−3−イル)−8−(2−ヒドロキシエトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(6−アミノピリジン−3−イル)−4,8−ジモルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(6−アミノピリジン−3−イル)−8−メチル−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
N−(3−(2−(2−(ジフルオロメチル)−1H−ベンゾ[d]イミダゾール−1−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド
(TBDMS脱保護):N−(2−フルオロ−3−(2−(2−(ヒドロキシメチル)−1H−ベンゾ[d]イミダゾール−1−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド
N−(3−(2−(2−アミノピリミジン−5−イル)−7−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド
<A.B−RAFV600E放射分析アッセイ>
BRAF酵素(カタログNo.14−557、Millipore、USA)および基質としてMEK−K97Mタンパク質(カタログNo.0785−0000−1、ProqQinase GmbH、Germany)を使用して、放射分析アッセイを介してB−RAFV600Eに対する化合物阻害(compound inhibition)を判定した。B−RAFキナーゼは、ガンマATP(PLC−101、Jonaki、CCMB、Hyderabad)、非標識ATPおよびMg2+の存在下でMEKタンパク質のリン酸化を触媒する(catalyze)。
基質としてULight−p70S6K(Thr389)ペプチドを使用して、均質なTR−FRETアッセイによりmTORキナーゼに対する化合物阻害を判定した。mTOR酵素(Millipore、US;5μg)をアッセイに使用した。反応物緩衝液はHEPES(50mM、pH7.5)、EGTA(1mM)、およびMnCl2(3mM)であった。試験化合物を、mTORと共に30min予備インキュベートし、これに続いて50nM ULight−p70S6K(Thr389)ペプチドをATP(20μM)と共に予備インキュベートした。
PI3Kαアッセイキット(Millipore、US、カタログ#33−016)を使用して、均質なTR−FRETアッセイにてPI3Kαに対する化合物阻害を判定した。PI3キナーゼは、ATPおよびMg2+の存在下で、ホスファチジルイノシトール、5−ビスホスフェート(PIP2)のホスファチジルイノシトール3,4,5−トリスリン酸(PIP3)へのリン酸化を触媒するものである。PIP3生成物は、ユウロピウム標識した抗GSTモノクローナル抗体、GSTタグを付けたプレクストリン相同性(PH)ドメイン、ビオチン化PIP3およびストレプトアビジン−アロフィコシアニン(APC)からなるエネルギー移動複合体からのビオチン−PIP3の置き換えにより検出する。複合体内のユウロピウムの励起はAPCへのエネルギー移動および665nmでの蛍光発光をもたらす。
約80%の密集度を1度達成した細胞株(A375 ATCC No.CRL−1619、A2058 ATCC No.CRL−11147およびRKO ATCC No.CRL−2577、American Type Culture Collection(ATCC)、ManassasVA)をトリプシン処理し、遠心分離し、新鮮な培地内に再懸濁させた。細胞(1000〜2000個/ウェル)を96−ウェルプレート内に播種し、5%CO2インキュベーター内で、37℃で一晩インキュベートした。化合物希釈物を100%DMSO中で調製し、これに続いてそれぞれの培地内で希釈した。細胞を、5%CO2インキュベーター内で、37℃で72h、NCEで処理した。72h後、調製したばかりのXTT(1mg/ml)/PMS(25μM)溶液を添加し、37℃で2〜3hインキュベートし、ELISAプレートリーダーを使用して450nmで吸光度を測定した。DMSO対照を100%に保ちながら、細胞増殖に対する化合物の阻害効果を計算し、GraphPad Prism(登録商標)v5ソフトウエアでシグモイドの用量反応曲線フィットを使用してGI50値を判定した。
上記に提供されているようなATCCから得た細胞株A375、A2058およびRKOを増殖させ、約80%の密集度を達成した後、トリプシン処理し、遠心分離し、新鮮な培地内に再懸濁させた。細胞を96−ウェルフォーマットの黒色ウェルの底が透明なプレート(Corning)に特定された密度(20,000〜50,000)で播種し、5%CO2インキュベーター内で、37℃で一晩インキュベートした。その翌日、試験化合物の化合物希釈物を100%DMSO中に調製し、これに続いてそれぞれの培地中で希釈した。5%CO2インキュベーター内で、37℃で3h、試験化合物の処置を実施した。3hの薬物処置後、条件付き培地を廃棄し、細胞を1度cPBS(0.1%塩化マグネシウム六水和物および0.1%無水の塩化カルシウムを含有するPBS)で洗浄し、rtで1h、cPBS中に4%パラホルムアルデヒドで固定した。固定後、cPBST(0.1%Triton(商標)X−100試薬を含有するcPBS)を使用して細胞を3回洗浄し、次いでブロッキング溶液(5%脱脂粉乳またはcPBST中で調製した5%BSA)を使用して、300rpmで振盪させながら、rtで2hブロッキングした。細胞をcPBSTで再び3回洗浄し、一次抗体ホスホ−p44/42MAPK(Erk1/2)(Thr202/204)抗体(Cell Signaling、Catalog#9101L)、ホスホS6リボソームタンパク質(Cell Signaling、Catalog#4858L)、ホスホAKT(Thr308)(Cell Signaling、Catalog#9275)またはホスホAKT(Ser473)(Cell Signaling、Catalog#4060L)と共に、それぞれのブロッキング溶液中で調製した、特定された希釈液(1:500〜1:2500)中、ラッカー内にて、4℃で一晩インキュベートした。翌日、細胞を1X Delfia(登録商標)洗浄緩衝液(4×1回洗浄)で洗浄し、二次抗体(Delfia(登録商標)−Eu−N1標識した抗ウサギ抗体;PerkinElmer、Catalog#AD0105;Delfia(登録商標)アッセイ緩衝液(PerkinElmer、Catalog#1244−111)中希釈物:1:2000〜1:6000)と共に暗所で、300rpmにて、rtで2hインキュベートした。次いで、細胞は、1x Delfia(登録商標)洗浄緩衝液で4回洗浄し、Wallac Delfia(登録商標)Enhancement溶液(100μL;PerkinElmer、Catalog#1244−105)と共に暗所で、300rpmにて、rtで20minインキュベートした。次いで、Victor V5 Fluorometer(Perkin Elmer、US)を使用して、340nMの励起波長を用いて615nMで、蛍光発光を読み取った。次いで、細胞を1X cPBSで1度洗浄し、cPBS中で調製した、100μLの0.5mg/mLのHoechst33258色素と共にインキュベートし、355nm励起を用いて460nmにて読み取ることによって、補正率を評価した。
<RAS/RAF/MEK/ERKおよびPI3K/AKT/PTEN/mTOR経路の阻害をモニタリングするためのタンパク質バイオマーカー>
本明細書に記載する化合物を、培養細胞中、さらに腫瘍試料から作製した溶解物中で、インビトロでの様々なバイオマーカー(pERK、pS6RP、pS6K、pAKT−S473およびpAKT−T308)の組合せを阻害するこれらの能力について試験した。図1に代表的な結果を示す。ここでは、マウス由来の腫瘍細胞溶解物中の様々なバイオマーカーのリン酸化の低減をウエスタンブロット法により評価した。実施例89Eにて詳細に記載するように、抗体プロバイダーにより提供されたプロトコルに従って生化学物質分析を行った。図1に示す実験に対して、結腸がん細胞株RKO由来の腫瘍を持つマウスを、本発明に係る化合物にて4時間(pERK1/2およびpS6RP分析物に対して)または8時間(pAKT−S473およびpAKT−T308分析物に対して)処置した。次いで腫瘍を切除し、溶解し、ウエスタンブロット法で全レベルおよびホスホタンパク質レベルについて分析した。各レーンは単一の動物由来の腫瘍からの溶解物を表し、各処置グループ当たり4匹の動物が存在した。ホスホ−タンパク質信号のパーセント阻害を上の各レーンに示す。パネルA)ERKタンパク質の全レベルおよびホスホ−タンパク質レベル。パネルB)S6タンパク質の全レベルおよびホスホ−タンパク質レベル。パネルC)AKTの全レベルおよびホスホ−タンパク質(S473)レベル。パネルD)AKTの全レベルおよびホスホ−タンパク質(T308)レベル。所与のホスホ−タンパク質に対応するバンドの信号の低減は、標的タンパク質に対する化合物の阻害作用を示す。
Claims (64)
- 下記式(I):
Xは、CHまたはNであり、
Yは、H、場合により置換したC1〜C6アルキル、OR1またはNR2R3であり、
Tは、HまたはC1〜C6アルコキシであり、
R1は、場合により置換したC1〜C6アルキル、場合により置換した(C1〜C6アルキル)OH、場合により置換した(C1〜C6アルキル)OC1〜C6アルキル、場合により置換したC3〜C8シクロアルキル、場合により置換した(C1〜C6アルキル)NH2、場合により置換した(C1〜C6アルキル)CO2H、または場合により置換した(C1〜C6アルキル)CONH2であり、
R2およびR3は連結して、場合により置換したヘテロ環を形成し、
R4は、場合により置換したモルホリンであり、
R6は、場合により置換したアリールまたは場合により置換したヘテロアリールであり、
R7は、場合により置換したアリール、場合により置換したC1〜C6アルキル、または場合により置換したヘテロアリールであり、
R8は、Hまたはハロゲンであり、
R8’は、ハロゲンである。)
で表される化合物。 - R4が、モルホリンである、請求項1に記載の化合物。
- R4が、C1〜C6アルキルで置換したモルホリンである、請求項1に記載の化合物。
- R4が、
- R7が、場合により置換したアリールである、請求項1に記載の化合物。
- R7が、1つまたは複数のハロゲンで置換したフェニルである、請求項5に記載の化合物。
- R7が、
- R7が、場合により置換したC1〜C6アルキルである、請求項1に記載の化合物。
- R7が、1種または複数のFで場合により置換したC1〜C6アルキルである、請求項8に記載の化合物。
- R7が、i−プロピル、i−ブチル、n−プロピル、エチル、n−ブチル、CH2CH2CH2F、またはCH2CH2CF3である、請求項8に記載の化合物。
- R7が、場合により置換したヘテロアリールである、請求項1に記載の化合物。
- R7が、チオフェンである、請求項11に記載の化合物。
- R6が、
Mは、NまたはCR10であり、
Qは、NまたはCR13であり、
Zは、NまたはCR14であり、
R10は、H、C1〜C6アルキル、ハロゲン、CNまたはCF3であり、
R12〜R14は、独立して、H、ハロゲン、C1〜C6アルキル、またはCF3であり、
R17は、NHC(O)NHNR9、H、C1〜C6アルキル、(C1〜C6アルキル)−NH2もしくは(C1〜C6アルキル)−OH、(C1〜C6アルキル)−O−(C1〜C6アルキル)、CO(C1〜C6アルキル)またはSO2(C1〜C6アルキル)であるか、または
R13とR17もしくはR14とR17は連結して、場合により不飽和の環を形成し、
R9は、C1〜C6アルキル、C1〜C6ヒドロキシアルキル、またはヘテロアリールである。)である、請求項1に記載の化合物。 - R6が、
Zは、CHまたはNであり、
R9は、C1〜C6アルキル、C1〜C6ヒドロキシアルキル、またはヘテロアリールである)である、請求項13に記載の化合物。 - R9が、CH3、CH2CH2OH、またはピリジン−4−イルである、請求項13に記載の化合物。
- R6が、場合により置換したピリミジン、場合により置換したピリジン、場合により置換したピロール[2,3−b]ピリジン、場合により置換したインダゾール、または場合により置換したベンゾイミダゾールである、請求項13に記載の化合物。
- R6が、
R10は、H、C1〜C6アルキルまたはCF3であり、
R17は、H、C1〜C6アルキル、(C1〜C6アルキル)−NH2または(C1〜C6アルキル)−OHである。)である、請求項13に記載の化合物。 - R6が、
R10、R12およびR13は、独立して、H、ハロゲン、C1〜C6アルキル、CNまたはCF3であり、
R17は、H、C1〜C6アルキル、(C1〜C6アルキル)−NH2もしくは(C1〜C6アルキル)−OHであるか、または
R13とR17は連結して、場合により不飽和の5員環を形成する。)である、請求項13に記載の化合物。 - R6が、
R10は、H、C1〜C6アルキル、ハロゲン、CNまたはCF3であり、
R12は、Hまたはハロゲンであり、
R13は、H、ハロゲンまたはC1〜C6アルキルであり、
R17は、H、C1〜C6アルキル、(C1〜C6アルキル)−NH2もしくは(C1〜C6アルキル)−OHであるか、または
R13とR17は連結して、場合により不飽和の5員環を形成する。)である、請求項18に記載の化合物。 - R6が、
- R6が、
- R6が、
- R6が、
- R6が、
- 前記化合物が、以下の化合物:
2,6−ジフルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(4−(3−メチルウレイド)フェニル)−4−モルホリノキナゾリン−6−イル)フェニル)ベンゼンスルホンアミド;
N−(3−(2−(1H−インダゾール−4−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−((2−アミノエチル)アミノ)ピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−(2−ヒドロキシエトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4,8−ジモルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メチル−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−(ジフルオロメチル)−1H−ベンゾ[d]イミダゾール−1−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(2−フルオロ−3−(2−(2−(ヒドロキシメチル)−1H−ベンゾ[d]イミダゾール−1−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−7−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
2,6−ジフルオロ−N−(2−フルオロ−3−(2−(4−(3−(2−ヒドロキシエチル)ウレイド)フェニル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)フェニル)ベンゼンスルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
N−(2−フルオロ−3−(8−メトキシ−2−(4−(3−メチルウレイド)フェニル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
2,6−ジフルオロ−N−(2−フルオロ−3−(8−メトキシ−4−モルホリノ−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)キナゾリン−6−イル)フェニル)ベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−2−フルオロピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2−メチルプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)エタンスルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)ブタン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2,4−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−5−メチルピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2−フルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3,3,3−トリフルオロプロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(4−(3−メチルウレイド)フェニル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−2−スルホンアミド;
N−(2−フルオロ−3−(8−メトキシ−4−モルホリノ−2−(4−(3−(ピリジン−4−イル)ウレイド)フェニル)キナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノ−4−メチルピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(1H−インダゾール−4−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)チオフェン−2−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(6−(3−メチルウレイド)ピリジン−3−イル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−4−モルホリノ−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)キナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−4−(3−メチルモルホリノ)−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)キナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
(S)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−2−フルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノ−5−クロロピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−4−モルホリノ−2−(6−(プロピルアミノ)ピリジン−3−イル)キナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(6−(メチルアミノ)ピリジン−3−イル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(2−(メチルアミノ)ピリミジン−5−イル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−エトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−(シクロペンチルオキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−エトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−イソプロポキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(8−(2−アミノエトキシ)−2−(6−アミノピリジン−3−イル)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−(シクロプロピルメトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−(2−ヒドロキシエトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
2−((2−(6−アミノピリジン−3−イル)−6−(2−フルオロ−3−(3−フルオロプロピルスルホンアミド)フェニル)−4−モルホリノキナゾリン−8−イル)オキシ)酢酸2,2,2−トリフルオロアセテート;
2−((2−(6−アミノピリジン−3−イル)−6−(2−フルオロ−3−(3−フルオロプロピルスルホンアミド)フェニル)−4−モルホリノキナゾリン−8−イル)オキシ)アセトアミド;
(R)−N−(3−(8−エトキシ−4−(3−メチルモルホリノ)−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−8−(シクロペンチルオキシ)−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−8−イソプロポキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−イソプロポキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノピリジン−3−イル)−8−エトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−エトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−(2−メトキシエトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−(2−メトキシエトキシ)−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4,8−ジモルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノ−8−(ピロリジン−1−イル)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノ−8−(ピロリジン−1−イル)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−4−(3−メチルモルホリノ)−8−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−4−(3−メチルモルホリノ)−8−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−4−(3−メチルモルホリノ)−8−(ピロリジン−1−イル)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−4−クロロ−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(1H−インダゾール−4−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(2,4−ジフルオロ−3−(8−メトキシ−4−モルホリノ−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)キナゾリン−6−イル)フェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−2,4−ジフルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メトキシ−4−モルホリノキナゾリン−6−イル)−4−クロロ−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(1H−インダゾール−4−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−5−メチルピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(4−モルホリノ−2−(1H−ピロロ[2,3−b]ピリジン−5−イル)ピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
(R)−N−(3−(2−(6−アミノピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(6−((2−ヒドロキシエチル)アミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノ−4−(トリフルオロメチル)ピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−メチルピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−フルオロピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−5−クロロピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
N−(3−(2−(6−アミノ−5−フルオロピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,6−ジフルオロベンゼンスルホンアミド;
(R)−N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(2−アミノ−4−メチルピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(2−((3−ヒドロキシプロピル)アミノ)ピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(6−((3−ヒドロキシプロピル)アミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(4−モルホリノ−2−(2−(プロピルアミノ)ピリミジン−5−イル)ピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(6−(メチルアミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(6−(イソプロピルアミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(4−モルホリノ−2−(6−(プロピルアミノ)ピリジン−3−イル)ピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−アミノピリミジン−5−イル)−8−メチル−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−8−メチル−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(1H−インダゾール−4−イル)−8−メチル−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−エチル−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−アミノピリジン−3−イル)−7−メトキシ−4−モルホリノキナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(2−(メチルアミノ)ピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
N−(3−(2−(2−(エチルアミノ)ピリミジン−5−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(3−(2−(6−(エチルアミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
N−(5−(6−(2−フルオロ−3−(3−フルオロプロピルスルホンアミド)フェニル)−8−メトキシ−4−モルホリノキナゾリン−2−イル)ピリジン−2−イル)アセトアミド;
N−(4−(6−(2−フルオロ−3−(3−フルオロプロピルスルホンアミド)フェニル)−8−メトキシ−4−モルホリノキナゾリン−2−イル)フェニル)アセトアミド;
3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(4−(メチルスルホンアミド)フェニル)−4−モルホリノキナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(2−アミノピリミジン−5−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノ−4−フルオロピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(6−アミノ−4−メチルピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(2−アミノ−4−メチルピリミジン−5−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(S)−N−(3−(2−(2−アミノ−4−メチルピリミジン−5−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−2,5−ジフルオロベンゼンスルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(6−((2−メトキシエチル)アミノ)ピリジン−3−イル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノ−5−フルオロピリジン−3−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノ−4−フルオロピリジン−3−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−3−フルオロ−N−(2−フルオロ−3−(8−メトキシ−2−(2−(メチルアミノ)ピリミジン−5−イル)−4−(3−メチルモルホリノ)キナゾリン−6−イル)フェニル)プロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−エトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(8−エトキシ−2−(2−(メチルアミノ)ピリミジン−5−イル)−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
3−フルオロ−N−(2−フルオロ−3−(2−(4−(3−メチルウレイド)フェニル)−4−モルホリノピリド[3,2−d]ピリミジン−6−イル)フェニル)プロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノ−4−フルオロピリジン−3−イル)−4−(3−メチルモルホリノ)ピリド[3,2−d]ピリミジン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(2−アミノピリミジン−5−イル)−8−(2−フルオロエトキシ)−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(6−アミノ−5−フルオロピリジン−3−イル)−8−(2−フルオロエトキシ)−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
(R)−N−(3−(2−(5−アミノピラジン−2−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド;
および
(R)−N−(3−(2−(6−アミノ−4−シアノピリジン−3−イル)−8−メトキシ−4−(3−メチルモルホリノ)キナゾリン−6−イル)−2−フルオロフェニル)−3−フルオロプロパン−1−スルホンアミド
からなる群から選択される請求項1に記載の化合物。 - 前記化合物が、酸または塩基の塩である、請求項1〜25のいずれか一項に記載の化合物。
- 前記酸の塩が、酢酸、プロピオン酸、乳酸、クエン酸、酒石酸、コハク酸、フマル酸、マレイン酸、マロン酸、マンデル酸、リンゴ酸、フタル酸、塩酸、臭水素酸、リン酸、硝酸、硫酸、メタンスルホン酸、ナフタレンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、トリフルオロ酢酸、およびカンファースルホン酸の各塩からなる群から選択される、請求項26に記載の化合物。
- 前記塩基の塩が、ナトリウム、リチウム、カリウム、モノメチルアンモニウム、ジメチルアモニウム、トリメチルアンモニウム、モノエチルアンモニウム、ジエチルアンモニウム、トリエチルアンモニウム、モノプロピルアンモニウム、ジプロピルアンモニウム、トリプロピルアンモニウム、エチルジメチルアンモニウム、ベンジルジメチルアンモニウム、シクロヘキシルアンモニウム、ベンジルアンモニウム、ジベンジルアンモニウム、ピペリジニウム、モルホリニウム、ピロリジニウム、ピペラジニウム、1−メチルピペリジニウム、4−エチルモルホリニウム、1−イソプロピルピロリジニウム、1,4−ジメチルピペラジニウム、1−n−ブチルピペリジニウム、2−メチルピペリジニウム、1−エチル−2−メチルピペリジニウム、モノ−、ジ−およびトリエタノールアンモニウム、エチルジエタノールアンモニウム、n−ブチルモノエタノールアンモニウム、トリス(ヒドロキシメチル)メチルアンモニウム、およびフェニルモノエタノールアンモニウムの各塩からなる群から選択される、請求項26に記載の化合物。
- 請求項1〜28のいずれか一項に記載の化合物と、薬学的に許容される担体とを含む組成物。
- 請求項1〜28のいずれか一項に記載の化合物を含むキット。
- 化学療法剤をさらに含む、請求項30に記載のキット。
- RAS/RAF/MEK/ERKおよびPI3K/AKT/PTEN/mTORを共調節するための方法であって、請求項1〜28のいずれか一項に記載の化合物を治療有効量で、それを必要とする患者に投与することを含む、方法。
- 前記共調節が、前記RAS/RAF/MEK/ERKの経路の阻害を含む、請求項32に記載の方法。
- 前記共調節が、前記PI3K/AKT/PTEN/mTORの経路の阻害を含む、請求項32に記載の方法。
- 前記共調節が、前記RAS/RAF/MEK/ERKの経路と前記PI3K/AKT/PTEN/mTORの経路の阻害を含む、請求項32に記載の方法。
- RAS/RAF/MEK/ERK経路およびPI3K/AKT/PTEN/mTOR経路を阻害することによって処置可能な症状を処置するための方法であって、請求項1〜28のいずれか一項に記載の化合物を治療有効量でそれを必要とする患者に投与することを含む、方法。
- RAS/RAF/MEK/ERK経路およびPI3K/AKT/PTEN/mTOR経路の調節不全から生じる異常な細胞増殖によって特徴付けられる疾患を処置するための方法であって、請求項1〜28のいずれか一項に記載の化合物を治療有効量でそれを必要とする患者に投与することを含む、方法。
- 前記疾患が、がんである、請求項37に記載の方法。
- 前記がんが、前立腺、頭部、頚部、眼、口、喉、食道、気管支、喉頭、咽頭、胸、骨、肺、結腸、直腸、胃、膀胱、子宮、子宮頚部、乳房、卵巣、膣、睾丸、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、腸、膵臓、脳、中枢神経系、副腎のがんまたは白血病もしくはリンパ腫である、請求項38に記載の方法。
- 前記患者が、少なくとも1種の固形腫瘍を有する、請求項39に記載の方法。
- 請求項1〜28のいずれか一項に記載の化合物の効力をモニタリングする方法であって、
請求項1〜28のいずれか一項に記載の化合物の少なくとも1種を初回投薬量で患者に投与するステップと、
前記化合物の投与後、前記患者からの試料をアッセイして、(a)pERK、(b)pS6RPもしくはpS6Kまたは(c)pAKT、またはこれらの組合せの活性レベルが、未処置の患者の活性と比較して、既定の活性レベルだけ減少しているかどうか判定するステップと、
前記化合物を第2回目の投薬量で投与するステップと
を含む、方法。 - 前記アッセイするステップが、(a)pERKおよび(b)pS6RPまたはpS6Kの活性を測定する、請求項41に記載の方法。
- 前記アッセイするステップが、(a)pERKおよび(c)pAKTの活性を測定する、請求項41に記載の方法。
- 前記アッセイするステップが、(a)pERK、(b)pS6RPまたはpS6Kおよび(c)pAKTの活性を測定する、請求項41に記載の方法。
- (a)pERKが減少する前記既定の活性レベルが、少なくとも約80%である、請求項41に記載の方法。
- (b)pS6RPまたはpS6Kが減少する前記既定の活性レベルが、少なくとも約50%である、請求項41に記載の方法。
- (c)pAKTが減少する前記既定の活性レベルが、少なくとも約50%である、請求項41に記載の方法。
- RAS/RAF/MEK/ERK経路およびPI3K/AKT/PTEN/mTOR経路を阻害することにより処置可能な症状を処置するための方法であって、
請求項1〜28のいずれか一項に記載の化合物を初回投薬量で患者に投与するステップと、
前記化合物の投与後に患者からの試料をアッセイして、(a)pERK、(b)pS6RPもしくはpS6Kまたは(c)pAKT、またはこれらの組合せの活性レベルが、未処置の患者の活性と比較して、既定の活性レベルだけ減少しているかどうか判定するステップと、
請求項1〜28のいずれか一項に記載の化合物を第2回目の投薬量で前記患者に投与するステップと
を含む、方法。 - 前記アッセイするステップが、(a)pERKおよび(b)pS6RPまたはpS6Kの活性を測定する、請求項48に記載の方法。
- 前記アッセイするステップが、(a)pERKおよび(c)pAKTの活性を測定する、請求項48に記載の方法。
- 前記アッセイするステップが、(a)pERK、(b)pS6RPまたはpS6Kおよび(c)pAKTの活性を測定する、請求項48に記載の方法。
- (a)pERKが減少する前記既定の活性レベルが、少なくとも約80%である、請求項48に記載の方法。
- (b)pS6RPまたはpS6Kが減少する前記既定の活性レベルが、少なくとも約50%である、請求項48に記載の方法。
- (c)pAKTが減少する前記既定の活性レベルが、少なくとも約50%である、請求項47に記載の方法。
- 前記症状が、がんである、請求項48に記載の方法。
- 前記がんが、前立腺、頭部、頚部、眼、口、喉、食道、気管支、喉頭、咽頭、胸、骨、肺、結腸、直腸、胃、膀胱、子宮、子宮頚部、乳房、卵巣、膣、睾丸、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、腸、膵臓、脳、中枢神経系、副腎のがん、または白血病もしくはリンパ腫である、請求項55に記載の方法。
- 前記患者が、少なくとも1種の固形腫瘍を有する、請求項55に記載の方法。
- RAS/RAF/MEK/ERK経路およびPI3K/AKT/PTEN/mTOR経路を阻害することにより、それを必要とする患者の処置可能な症状を処置するための方法であって、
患者からの試料をアッセイして、B−RAF、PI3KまたはPTEN突然変異またはこれらの組合せの存在を検出するステップと、
前記アッセイするステップで判定したB−RAF、PI3K、またはPTEN突然変異を有する患者に、請求項1〜28のいずれか一項に記載の化合物を治療有効量で投与するステップと
を含む、方法。 - 前記疾患が、がんである、請求項58に記載の方法。
- 前記がんが、前立腺、頭部、頚部、眼、口、喉、食道、気管支、喉頭、咽頭、胸、骨、肺、結腸、直腸、胃、膀胱、子宮、子宮頚部、乳房、卵巣、膣、睾丸、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、腸、膵臓、脳、中枢神経系、副腎のがんまたは白血病もしくはリンパ腫である、請求項59に記載の方法。
- 前記患者が、少なくとも1種の固形腫瘍を有する、請求項60に記載の方法。
- 前記患者が、B−RAFおよびmTOR突然変異を有する、請求項58に記載の方法。
- 前記患者が、B−RAFおよびPI3K突然変異を有する、請求項58に記載の方法。
- 前記患者が、B−RAF突然変異、mTORおよびPI3K突然変異を有する、請求項58に記載の方法。
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US10919877B2 (en) * | 2016-07-06 | 2021-02-16 | The Regents Of The University Of Michigan | Multifunctional inhibitors of MEK/PI3K and mTOR/MEK/PI3K biological pathways and therapeutic methods using the same |
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CN108239075B (zh) * | 2016-12-26 | 2021-07-02 | 中国医学科学院药物研究所 | 喹唑啉类化合物及其制备方法、用途和药物组合物 |
WO2018212774A1 (en) * | 2017-05-17 | 2018-11-22 | Vanderbilt University | Quinazoline compounds as modulators of ras signaling |
AU2018288841B2 (en) | 2017-06-21 | 2022-09-29 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease |
US10695296B2 (en) * | 2017-07-14 | 2020-06-30 | Asana Biosciences, Llc | Formulations, methods, kit, and dosage forms for improved stability of an active pharmaceutical ingredient |
CN108623582A (zh) * | 2017-10-10 | 2018-10-09 | 河南省锐达医药科技有限公司 | 一类新型含取代基吡啶并嘧啶化合物的制备方法 |
CN111499634B (zh) * | 2019-01-31 | 2023-05-12 | 贝达药业股份有限公司 | 一种喹唑啉化合物及其在医药上的应用 |
CN112341434B (zh) * | 2019-08-08 | 2021-11-26 | 恩瑞生物医药科技(上海)有限公司 | PI3K/mTOR蛋白降解靶向嵌合体类化合物及其制备方法和医药用途 |
AU2020372895A1 (en) | 2019-11-01 | 2022-05-26 | Fmc Agro Singapore Pte. Ltd. | An efficient new process for synthesis of 2-amino-5-chloro-N-,3-dimethylbenzamide |
CN113416181B (zh) * | 2021-08-02 | 2022-05-03 | 四川大学 | 喹唑啉类衍生物及其用途 |
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HK1215810A1 (zh) | 2016-09-15 |
US9757382B2 (en) | 2017-09-12 |
AU2014250836C1 (en) | 2019-01-17 |
CN105283454B (zh) | 2019-10-29 |
IL242020B (en) | 2019-08-29 |
US10226468B2 (en) | 2019-03-12 |
US9499495B2 (en) | 2016-11-22 |
US20210113578A1 (en) | 2021-04-22 |
KR20150143672A (ko) | 2015-12-23 |
EP2984088A1 (en) | 2016-02-17 |
IL262314A (en) | 2018-11-29 |
RU2015148359A (ru) | 2017-05-15 |
WO2014169167A1 (en) | 2014-10-16 |
MX2015014387A (es) | 2017-04-10 |
US20170027953A1 (en) | 2017-02-02 |
US20160068496A1 (en) | 2016-03-10 |
JP6496301B2 (ja) | 2019-04-03 |
US10912779B2 (en) | 2021-02-09 |
AU2014250836B2 (en) | 2018-07-12 |
US20170290838A1 (en) | 2017-10-12 |
BR112015025901A8 (pt) | 2020-01-14 |
CN105283454A (zh) | 2016-01-27 |
ZA201507750B (en) | 2017-08-30 |
CA2909310A1 (en) | 2014-10-16 |
US20190151327A1 (en) | 2019-05-23 |
EP2984088B1 (en) | 2019-03-20 |
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