JPWO2020178282A5 - - Google Patents
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- JPWO2020178282A5 JPWO2020178282A5 JP2021552640A JP2021552640A JPWO2020178282A5 JP WO2020178282 A5 JPWO2020178282 A5 JP WO2020178282A5 JP 2021552640 A JP2021552640 A JP 2021552640A JP 2021552640 A JP2021552640 A JP 2021552640A JP WO2020178282 A5 JPWO2020178282 A5 JP WO2020178282A5
- Authority
- JP
- Japan
- Prior art keywords
- prop
- chloro
- pyrazino
- hydroxyphenyl
- tetrahydro
- 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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- 150000001875 compounds Chemical class 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 4
- 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- QXNLXOROUHNHEK-MRXNPFEDSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-9-ethynyl-7-fluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1C#C)F QXNLXOROUHNHEK-MRXNPFEDSA-N 0.000 claims description 3
- 102100030708 GTPase KRas Human genes 0.000 claims description 3
- 102100039788 GTPase NRas Human genes 0.000 claims description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims description 3
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 230000035772 mutation Effects 0.000 claims description 3
- 102200006614 rs104894229 Human genes 0.000 claims description 3
- FDKSHORUCMDCBE-LLVKDONJSA-N (11R)-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-13-prop-2-enoyl-9-oxa-1,5,13-triazatricyclo[9.4.0.03,8]pentadeca-3(8),6-dien-4-one Chemical compound ClC1=C(NC(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)C1=C(C=CC=C1O)F FDKSHORUCMDCBE-LLVKDONJSA-N 0.000 claims description 2
- LBKFXNCTCJUAPJ-GFCCVEGCSA-N (11R)-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-5-methyl-13-prop-2-enoyl-9-oxa-1,5,13-triazatricyclo[9.4.0.03,8]pentadeca-3(8),6-dien-4-one Chemical compound ClC1=C(N(C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)C)C1=C(C=CC=C1O)F LBKFXNCTCJUAPJ-GFCCVEGCSA-N 0.000 claims description 2
- WTXRIZHWPYILPO-LLVKDONJSA-N (4aR)-7,9-dichloro-8-(2-fluoro-6-hydroxyphenyl)-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound ClC=1C(=C(C2=C(C(N3[C@@H](CO2)CN(CC3)C(C=C)=O)=O)C=1)Cl)C1=C(C=CC=C1O)F WTXRIZHWPYILPO-LLVKDONJSA-N 0.000 claims description 2
- WLRNPQLVIGZTHP-OAHLLOKOSA-N (4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-3-prop-2-enoyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepine-9-carbonitrile Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#N)C1=C(C=CC=C1O)Cl WLRNPQLVIGZTHP-OAHLLOKOSA-N 0.000 claims description 2
- HDZROUHWOKROFK-LLVKDONJSA-N (4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-10-hydroxy-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound ClC1=C(C=C(C=2C(N3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)O)C1=C(C=CC=C1O)F HDZROUHWOKROFK-LLVKDONJSA-N 0.000 claims description 2
- HXXMATDQQRYYQN-CQSZACIVSA-N (4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-3-prop-2-enoyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepine-10-carbonitrile Chemical compound ClC=1C(=CC(=C2CN3[C@@H](COC2=1)CN(CC3)C(C=C)=O)C#N)C1=C(C=CC=C1O)F HXXMATDQQRYYQN-CQSZACIVSA-N 0.000 claims description 2
- VQRNBOAUJWBBGH-OAHLLOKOSA-N (4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-3-prop-2-enoyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepine-9-carbonitrile Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#N)C1=C(C=CC=C1O)F VQRNBOAUJWBBGH-OAHLLOKOSA-N 0.000 claims description 2
- JYWPJYUDJOXMPA-CYBMUJFWSA-N (4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-9-methyl-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound ClC1=C(C(=CC=2C(N3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)C)C1=C(C=CC=C1O)F JYWPJYUDJOXMPA-CYBMUJFWSA-N 0.000 claims description 2
- QQLJPAAVIPYNJM-QGZVFWFLSA-N (4aR)-7-chloro-8-(2-hydroxy-6-methylphenyl)-3-prop-2-enoyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepine-9-carbonitrile Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#N)C1=C(C=CC=C1C)O QQLJPAAVIPYNJM-QGZVFWFLSA-N 0.000 claims description 2
- FWVAKNWCWBVPKK-CQSZACIVSA-N (4aR)-7-chloro-8-(5-methyl-1H-indazol-4-yl)-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound ClC1=C(C=CC=2C(N3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)C1=C2C=NNC2=CC=C1C FWVAKNWCWBVPKK-CQSZACIVSA-N 0.000 claims description 2
- BOJFNACUBIZYFZ-LLVKDONJSA-N (4aR)-7-chloro-9-fluoro-8-(2-fluoro-6-hydroxyphenyl)-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound ClC1=C(C(=CC=2C(N3[C@@H](COC=21)CN(CC3)C(C=C)=O)=O)F)C1=C(C=CC=C1O)F BOJFNACUBIZYFZ-LLVKDONJSA-N 0.000 claims description 2
- QOHRESGZAFPFTN-OAHLLOKOSA-N (4aR)-8-(2-chloro-6-hydroxyphenyl)-7-fluoro-3-prop-2-enoyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepine-9-carbonitrile Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1C#N)F QOHRESGZAFPFTN-OAHLLOKOSA-N 0.000 claims description 2
- JNYFZDGABROKLB-HNNXBMFYSA-N (4aS)-7-chloro-6-methyl-8-(5-methyl-1H-indazol-4-yl)-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzodiazepin-11-one Chemical compound ClC1=C(C=CC=2C(N3[C@@H](CN(C=21)C)CN(CC3)C(C=C)=O)=O)C1=C2C=NNC2=CC=C1C JNYFZDGABROKLB-HNNXBMFYSA-N 0.000 claims description 2
- LXRIKUVKYZTDOX-AWEZNQCLSA-N (4aS)-7-chloro-8-(5-methyl-1H-indazol-4-yl)-3-prop-2-enoyl-1,2,4,4a,5,6-hexahydropyrazino[2,1-c][1,4]benzodiazepin-11-one Chemical compound ClC1=C(C=CC=2C(N3[C@@H](CNC=21)CN(CC3)C(C=C)=O)=O)C1=C2C=NNC2=CC=C1C LXRIKUVKYZTDOX-AWEZNQCLSA-N 0.000 claims description 2
- FWVAKNWCWBVPKK-AWEZNQCLSA-N (4aS)-7-chloro-8-(5-methyl-1H-indazol-4-yl)-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-11-one Chemical compound C(C=C)(=O)N1C[C@H]2COC3=C(C(N2CC1)=O)C=CC(=C3Cl)C1=C2C=NNC2=CC=C1C FWVAKNWCWBVPKK-AWEZNQCLSA-N 0.000 claims description 2
- LTAWOYKJBOJKAK-LLVKDONJSA-N 1-[(11R)-4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)-9-oxa-1,5,13-triazatricyclo[9.4.0.03,8]pentadeca-3(8),4,6-trien-13-yl]prop-2-en-1-one Chemical compound ClC1=NC(=C(C2=C1CN1[C@@H](CO2)CN(CC1)C(C=C)=O)Cl)C1=C(C=CC=C1O)F LTAWOYKJBOJKAK-LLVKDONJSA-N 0.000 claims description 2
- FMNDGABXICBRRK-CQSZACIVSA-N 1-[(11R)-7-chloro-6-(2-chloro-6-hydroxyphenyl)-4-prop-1-ynyl-9-oxa-1,5,13-triazatricyclo[9.4.0.03,8]pentadeca-3,5,7-trien-13-yl]prop-2-en-1-one Chemical compound ClC1=C(N=C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#CC)C1=C(C=CC=C1O)Cl FMNDGABXICBRRK-CQSZACIVSA-N 0.000 claims description 2
- QSXKFUQZPCMAFG-IBIJPGRPSA-N 1-[(11R)-7-chloro-6-(2-chloro-6-hydroxyphenyl)-5-(trideuteriomethoxy)-9-oxa-1,4,13-triazatricyclo[9.4.0.03,8]pentadeca-3(8),4,6-trien-13-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=NC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)OC([2H])([2H])[2H])C1=C(C=CC=C1O)Cl QSXKFUQZPCMAFG-IBIJPGRPSA-N 0.000 claims description 2
- IEKIKHOMPSASFH-CYBMUJFWSA-N 1-[(11R)-7-chloro-6-(2-chloro-6-hydroxyphenyl)-5-ethynyl-9-oxa-1,4,13-triazatricyclo[9.4.0.03,8]pentadeca-3(8),4,6-trien-13-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=NC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#C)C1=C(C=CC=C1O)Cl IEKIKHOMPSASFH-CYBMUJFWSA-N 0.000 claims description 2
- CRXVWQJGHIYEHY-CYBMUJFWSA-N 1-[(4aR)-7,9-dichloro-8-(2-fluoro-6-hydroxyphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)Cl)C1=C(C=CC=C1O)F CRXVWQJGHIYEHY-CYBMUJFWSA-N 0.000 claims description 2
- ULYBFBYMMHFCBU-LLVKDONJSA-N 1-[(4aR)-7,9-dichloro-8-(2-fluoro-6-hydroxyphenyl)-10-hydroxy-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1O)Cl)C1=C(C=CC=C1O)F ULYBFBYMMHFCBU-LLVKDONJSA-N 0.000 claims description 2
- UIEKASIZRZVGHP-OAHLLOKOSA-N 1-[(4aR)-7,9-difluoro-8-(2-hydroxy-6-methylphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound FC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)F)C1=C(C=CC=C1C)O UIEKASIZRZVGHP-OAHLLOKOSA-N 0.000 claims description 2
- HKIMHZZLARGRGN-OAHLLOKOSA-N 1-[(4aR)-7,9-difluoro-8-[2-fluoro-6-(hydroxymethyl)phenyl]-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound FC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)F)C1=C(C=CC=C1CO)F HKIMHZZLARGRGN-OAHLLOKOSA-N 0.000 claims description 2
- HPHRWQRHJOIBFI-CYBMUJFWSA-N 1-[(4aR)-7,9-difluoro-8-[2-hydroxy-6-(trifluoromethyl)phenyl]-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound FC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)F)C1=C(C=CC=C1C(F)(F)F)O HPHRWQRHJOIBFI-CYBMUJFWSA-N 0.000 claims description 2
- BHCIYQSAUKPTNJ-GFCCVEGCSA-N 1-[(4aR)-7-chloro-8-(2,3-difluoro-6-hydroxyphenyl)-9-fluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)F)C1=C(C(=CC=C1O)F)F BHCIYQSAUKPTNJ-GFCCVEGCSA-N 0.000 claims description 2
- DDCOLYFWRBCEPK-LLVKDONJSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9,10-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)F)F)C1=C(C=CC=C1O)Cl DDCOLYFWRBCEPK-LLVKDONJSA-N 0.000 claims description 2
- QSWCVSXSKPKERJ-MRXNPFEDSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-(2-methoxyethoxy)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)OCCOC)C1=C(C=CC=C1O)Cl QSWCVSXSKPKERJ-MRXNPFEDSA-N 0.000 claims description 2
- NWZJRPBBZJDTLS-CYBMUJFWSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-(difluoromethoxy)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)OC(F)F)C1=C(C=CC=C1O)Cl NWZJRPBBZJDTLS-CYBMUJFWSA-N 0.000 claims description 2
- FPRHMVHSPSFFKE-MRXNPFEDSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-(methoxymethyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)COC)C1=C(C=CC=C1O)Cl FPRHMVHSPSFFKE-MRXNPFEDSA-N 0.000 claims description 2
- INAQRJCAPCGYHP-MRXNPFEDSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-ethynyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#C)C1=C(C=CC=C1O)Cl INAQRJCAPCGYHP-MRXNPFEDSA-N 0.000 claims description 2
- NZDYCPMSAGXVLE-CYBMUJFWSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-fluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)F)C1=C(C=CC=C1O)Cl NZDYCPMSAGXVLE-CYBMUJFWSA-N 0.000 claims description 2
- WACPCGDPHOOOFE-QGZVFWFLSA-N 1-[(4aR)-7-chloro-8-(2-chloro-6-hydroxyphenyl)-9-prop-1-ynyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#CC)C1=C(C=CC=C1O)Cl WACPCGDPHOOOFE-QGZVFWFLSA-N 0.000 claims description 2
- DMCYJIJCULHAMF-OAHLLOKOSA-N 1-[(4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-10-imidazol-1-yl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C=C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)N1C=NC=C1)C1=C(C=CC=C1O)F DMCYJIJCULHAMF-OAHLLOKOSA-N 0.000 claims description 2
- YXFXMMFKQJRVMS-CYBMUJFWSA-N 1-[(4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-10-methoxy-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C=C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)OC)C1=C(C=CC=C1O)F YXFXMMFKQJRVMS-CYBMUJFWSA-N 0.000 claims description 2
- JDIHBVOUGNFWHI-OAHLLOKOSA-N 1-[(4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-10-pyrazol-1-yl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C=C(C=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)N1N=CC=C1)C1=C(C=CC=C1O)F JDIHBVOUGNFWHI-OAHLLOKOSA-N 0.000 claims description 2
- AITRFIXHCLHORE-CQSZACIVSA-N 1-[(4aR)-7-chloro-8-(2-fluoro-6-hydroxyphenyl)-9-methoxy-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)OC)C1=C(C=CC=C1O)F AITRFIXHCLHORE-CQSZACIVSA-N 0.000 claims description 2
- HKCSRGQGNGOUGG-MRXNPFEDSA-N 1-[(4aR)-7-chloro-8-(5-methyl-1H-indazol-4-yl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C1=C2C=NNC2=CC=C1C HKCSRGQGNGOUGG-MRXNPFEDSA-N 0.000 claims description 2
- OYJJJJCLXMMCHM-MRXNPFEDSA-N 1-[(4aR)-7-chloro-9-ethynyl-8-(2-fluoro-6-hydroxyphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)C#C)C1=C(C=CC=C1O)F OYJJJJCLXMMCHM-MRXNPFEDSA-N 0.000 claims description 2
- RYCAFVGOTJZYEW-OAHLLOKOSA-N 1-[(4aR)-7-chloro-9-fluoro-8-(5-methyl-1H-benzimidazol-4-yl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)F)C1=C(C=CC=2NC=NC=21)C RYCAFVGOTJZYEW-OAHLLOKOSA-N 0.000 claims description 2
- UVRQRUSDXDUETH-QGZVFWFLSA-N 1-[(4aR)-7-ethynyl-9-fluoro-8-(2-hydroxy-6-methylphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound C(#C)C1=C(C(=CC=2CN3[C@@H](COC=21)CN(CC3)C(C=C)=O)F)C1=C(C=CC=C1C)O UVRQRUSDXDUETH-QGZVFWFLSA-N 0.000 claims description 2
- INISFAUXTYWNRF-CYBMUJFWSA-N 1-[(4aR)-8-(2-bromo-6-hydroxyphenyl)-7,9-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound BrC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1F)F INISFAUXTYWNRF-CYBMUJFWSA-N 0.000 claims description 2
- ODZXALUNVDIZLX-MRXNPFEDSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-10-[2-(dimethylamino)ethoxy]-7-fluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C(=C1)OCCN(C)C)F ODZXALUNVDIZLX-MRXNPFEDSA-N 0.000 claims description 2
- CUHVMVHSASDHBD-CYBMUJFWSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-7,9-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1F)F CUHVMVHSASDHBD-CYBMUJFWSA-N 0.000 claims description 2
- XYMCHFLTXXOQMK-HXUWFJFHSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-7-fluoro-9-(2-piperidin-1-ylethoxy)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1OCCN1CCCCC1)F XYMCHFLTXXOQMK-HXUWFJFHSA-N 0.000 claims description 2
- NUQPWYJTVLKFMX-LJQANCHMSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-7-fluoro-9-(pyridin-4-ylmethoxy)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1OCC1=CC=NC=C1)F NUQPWYJTVLKFMX-LJQANCHMSA-N 0.000 claims description 2
- CNQOLVBNICGIJB-QGZVFWFLSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-7-fluoro-9-prop-1-ynyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1C#CC)F CNQOLVBNICGIJB-QGZVFWFLSA-N 0.000 claims description 2
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- MHWYYXDJTOKBMG-LJQANCHMSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-9-[3-(dimethylamino)prop-1-ynyl]-7-fluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1C#CCN(C)C)F MHWYYXDJTOKBMG-LJQANCHMSA-N 0.000 claims description 2
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- SFXSKORCEGFOFT-CYBMUJFWSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-9-ethynyl-7,10-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C(=C1C#C)F)F SFXSKORCEGFOFT-CYBMUJFWSA-N 0.000 claims description 2
- NOPXJJMERVEVRZ-GOSISDBHSA-N 1-[(4aR)-8-(2-chloro-6-hydroxyphenyl)-9-ethynyl-7-methyl-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1C#C)C NOPXJJMERVEVRZ-GOSISDBHSA-N 0.000 claims description 2
- LZJHWHGSADWXSG-MRXNPFEDSA-N 1-[(4aR)-8-(2-ethyl-6-hydroxyphenyl)-7,9-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound C(C)C1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1F)F LZJHWHGSADWXSG-MRXNPFEDSA-N 0.000 claims description 2
- CWJDPRNPEJUPNS-CYBMUJFWSA-N 1-[(4aR)-8-[2-(difluoromethyl)-6-hydroxyphenyl]-7,9-difluoro-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound FC(C1=C(C(=CC=C1)O)C1=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=C1F)F)F CWJDPRNPEJUPNS-CYBMUJFWSA-N 0.000 claims description 2
- JBVHZQGOFXLOAS-QGZVFWFLSA-N 1-[(4aR)-9-chloro-7-ethynyl-8-(2-hydroxy-6-methylphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)C#C)C1=C(C=CC=C1C)O JBVHZQGOFXLOAS-QGZVFWFLSA-N 0.000 claims description 2
- VZVIPQOWUWWEID-OAHLLOKOSA-N 1-[(4aR)-9-chloro-7-fluoro-8-(2-hydroxy-6-methylphenyl)-1,2,4,4a,5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]prop-2-en-1-one Chemical compound ClC=1C(=C(C2=C(CN3[C@@H](CO2)CN(CC3)C(C=C)=O)C=1)F)C1=C(C=CC=C1C)O VZVIPQOWUWWEID-OAHLLOKOSA-N 0.000 claims description 2
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| US11453683B1 (en) | 2019-08-29 | 2022-09-27 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
| JP2022548791A (ja) | 2019-09-24 | 2022-11-21 | ミラティ セラピューティクス， インコーポレイテッド | 組み合わせ療法 |
| EP4051678A1 (en) | 2019-10-28 | 2022-09-07 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| CN114980976A (zh) | 2019-11-27 | 2022-08-30 | 锐新医药公司 | 共价ras抑制剂及其用途 |
| HUE060684T2 (hu) * | 2019-12-11 | 2023-04-28 | Lilly Co Eli | KRas G12C inhibitorok |
| WO2021127429A1 (en) | 2019-12-20 | 2021-06-24 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
| TWI799871B (zh) * | 2020-05-27 | 2023-04-21 | 大陸商勁方醫藥科技(上海)有限公司 | 三環并環類化合物，其製法與醫藥上的用途 |
| IL299131A (en) | 2020-06-18 | 2023-02-01 | Revolution Medicines Inc | Methods for delaying, preventing and treating acquired resistance to RAS inhibitors |
| EP4208261A1 (en) | 2020-09-03 | 2023-07-12 | Revolution Medicines, Inc. | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
| CN114539286B (zh) * | 2020-11-24 | 2024-02-02 | 成都百裕制药股份有限公司 | 哌嗪衍生物及其在医药上的应用 |
| TW202235082A (zh) | 2020-12-04 | 2022-09-16 | 美商美國禮來大藥廠 | Ｋｒａｓ ｇ１２ｃ抑制劑 |
| US20230107642A1 (en) | 2020-12-18 | 2023-04-06 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| CA3215949A1 (en) * | 2021-04-08 | 2022-10-13 | Genentech, Inc. | Oxazepine compounds and uses thereof in the treatment of cancer |
| KR20240055778A (ko) | 2021-09-01 | 2024-04-29 | 노파르티스 아게 | Tead 억제제를 포함하는 제약 조합물 및 암의 치료를 위한 이의 용도 |
| WO2023072297A1 (zh) * | 2021-11-01 | 2023-05-04 | 江苏恒瑞医药股份有限公司 | 含氮的四环化合物、其制备方法及其在医药上的应用 |
| TW202333800A (zh) | 2021-12-28 | 2023-09-01 | 英商阿斯特捷利康英國股份有限公司 | 抗體-藥物結合物及rasg12c抑制劑之組合 |
| WO2023168036A1 (en) | 2022-03-04 | 2023-09-07 | Eli Lilly And Company | Method of treatment including kras g12c inhibitors and shp2 inhibitors |
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| TW201906848A (zh) * | 2017-05-11 | 2019-02-16 | 瑞典商阿斯特捷利康公司 | 化學化合物 |
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