ES2514325T3 - Morfolinopirimidinas y su uso en terapia - Google Patents
Morfolinopirimidinas y su uso en terapia Download PDFInfo
- Publication number
- ES2514325T3 ES2514325T3 ES11725494.6T ES11725494T ES2514325T3 ES 2514325 T3 ES2514325 T3 ES 2514325T3 ES 11725494 T ES11725494 T ES 11725494T ES 2514325 T3 ES2514325 T3 ES 2514325T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- pyrimidin
- methylmorpholin
- methylsulfonimidoyl
- hydrogen
- 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.)
- Active
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- 238000002560 therapeutic procedure Methods 0.000 title description 2
- DUIMWXDLDBNUFD-UHFFFAOYSA-N 4-pyrimidin-2-ylmorpholine Chemical class C1COCCN1C1=NC=CC=N1 DUIMWXDLDBNUFD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 78
- 239000001257 hydrogen Substances 0.000 claims abstract description 78
- -1 3-methylmorpholin-4-yl Chemical group 0.000 claims abstract description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 47
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000004429 atom Chemical group 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- OHUHVTCQTUDPIJ-JYCIKRDWSA-N ceralasertib Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-JYCIKRDWSA-N 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 5
- OOEYPUFPMHMEAP-ONSXPEOJSA-N imino-[1-[2-(1h-indol-4-yl)-6-[(3r)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]-methyl-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(C=2C=3C=CNC=3C=CC=2)=N1 OOEYPUFPMHMEAP-ONSXPEOJSA-N 0.000 claims description 4
- OOEYPUFPMHMEAP-IZPCHGGPSA-N imino-[1-[2-(1h-indol-4-yl)-6-[(3r)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]-methyl-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3C=CC=2)=N1 OOEYPUFPMHMEAP-IZPCHGGPSA-N 0.000 claims description 4
- OHUHVTCQTUDPIJ-MUWSIPGASA-N imino-methyl-[1-[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-MUWSIPGASA-N 0.000 claims description 4
- FEFZJKWFEQKDHO-KHXSAUHESA-N imino-methyl-[[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]methyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 FEFZJKWFEQKDHO-KHXSAUHESA-N 0.000 claims description 4
- WUJFVGIVMGNTPV-RZQXLCLMSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CC1 WUJFVGIVMGNTPV-RZQXLCLMSA-N 0.000 claims description 3
- DTTJKLNXNZAVSM-RNHBAAACSA-N imino-methyl-[1-[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)S(C)(=N)=O)=NC(C=2C=3C=CNC=3C=NC=2)=N1 DTTJKLNXNZAVSM-RNHBAAACSA-N 0.000 claims description 3
- JESNSKPPMWEWAT-JKGBWWFKSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CC1 JESNSKPPMWEWAT-JKGBWWFKSA-N 0.000 claims description 3
- LRIFUSYFLXZCKX-YSVRNHBLSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C LRIFUSYFLXZCKX-YSVRNHBLSA-N 0.000 claims description 3
- YXSYJGJKBNBZLQ-BRRNQIAESA-N 1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(N2C3=CC=CC=C3N=C2N)=N1 YXSYJGJKBNBZLQ-BRRNQIAESA-N 0.000 claims description 2
- YXSYJGJKBNBZLQ-OSXTUODASA-N 1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(N2C3=CC=CC=C3N=C2N)=N1 YXSYJGJKBNBZLQ-OSXTUODASA-N 0.000 claims description 2
- JESNSKPPMWEWAT-YSVRNHBLSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@@](C)(=N)=O)CC1 JESNSKPPMWEWAT-YSVRNHBLSA-N 0.000 claims description 2
- LRIFUSYFLXZCKX-JKGBWWFKSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C LRIFUSYFLXZCKX-JKGBWWFKSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 122
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 80
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
- 239000000203 mixture Substances 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- 239000000377 silicon dioxide Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 239000003480 eluent Substances 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 16
- 238000004296 chiral HPLC Methods 0.000 description 16
- 125000006239 protecting group Chemical group 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- ALBBQFWHUCTZFM-UHFFFAOYSA-N n-methyl-1h-benzimidazol-2-amine Chemical compound C1=CC=C2NC(NC)=NC2=C1 ALBBQFWHUCTZFM-UHFFFAOYSA-N 0.000 description 8
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000395 magnesium oxide Substances 0.000 description 7
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- QTQBSOLQWXAFRV-AVBQWDGQSA-N [1-[2-chloro-6-[(3r)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]-imino-methyl-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)S(C)(=N)=O)=NC(Cl)=N1 QTQBSOLQWXAFRV-AVBQWDGQSA-N 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 6
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 4
- HJXLHCKCNYDEBQ-UHFFFAOYSA-N 4-fluoro-n-methyl-1h-benzimidazol-2-amine Chemical compound C1=CC=C2NC(NC)=NC2=C1F HJXLHCKCNYDEBQ-UHFFFAOYSA-N 0.000 description 4
- FTMWWKJQYUELFV-UHFFFAOYSA-N 6-fluoro-n-methyl-1h-benzimidazol-2-amine Chemical compound C1=C(F)C=C2NC(NC)=NC2=C1 FTMWWKJQYUELFV-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 238000007080 aromatic substitution reaction Methods 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- FNSOTTSUNRRYRU-VCLORWJBSA-N (3r)-4-[2-chloro-6-(2-methylsulfinylpropan-2-yl)pyrimidin-4-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C(C)(C)S(C)=O)=NC(Cl)=N1 FNSOTTSUNRRYRU-VCLORWJBSA-N 0.000 description 3
- USJUQEVUEBCLLR-UHFFFAOYSA-N 1h-indol-4-ylboronic acid Chemical compound OB(O)C1=CC=CC2=C1C=CN2 USJUQEVUEBCLLR-UHFFFAOYSA-N 0.000 description 3
- HQFFRTPOWLGAIX-FZAOIFNZSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C HQFFRTPOWLGAIX-FZAOIFNZSA-N 0.000 description 3
- FGTJUHKILGGMAK-FZAOIFNZSA-N 5-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC(F)=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C FGTJUHKILGGMAK-FZAOIFNZSA-N 0.000 description 3
- FGTJUHKILGGMAK-RZQXLCLMSA-N 5-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC(F)=CC=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C FGTJUHKILGGMAK-RZQXLCLMSA-N 0.000 description 3
- PSIPSQLSHTYKJT-RZQXLCLMSA-N 6-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=C(F)C=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C PSIPSQLSHTYKJT-RZQXLCLMSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- YIASZZUGUQHGBB-JTJFVBHCSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[4-(methylsulfonimidoyl)oxan-4-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CCOCC1 YIASZZUGUQHGBB-JTJFVBHCSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 1
- ZHKSWKOYMANKCN-UHFFFAOYSA-N tert-butyl 4-bromopyrrolo[2,3-c]pyridine-1-carboxylate Chemical compound C1=NC=C2N(C(=O)OC(C)(C)C)C=CC2=C1Br ZHKSWKOYMANKCN-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35371310P | 2010-06-11 | 2010-06-11 | |
| US353713P | 2010-06-11 | ||
| PCT/GB2011/051074 WO2011154737A1 (en) | 2010-06-11 | 2011-06-09 | Morpholino pyrimidines and their use in therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2514325T3 true ES2514325T3 (es) | 2014-10-28 |
Family
ID=44168987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES11725494.6T Active ES2514325T3 (es) | 2010-06-11 | 2011-06-09 | Morfolinopirimidinas y su uso en terapia |
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| SA111320519B1 (ar) * | 2010-06-11 | 2014-07-02 | Astrazeneca Ab | مركبات بيريميدينيل للاستخدام كمثبطات atr |
| PT3157566T (pt) | 2014-06-17 | 2019-07-11 | Vertex Pharma | Método para tratamento de cancro utilizando uma combinação de inibidores chk1 e atr |
| TWI656121B (zh) | 2014-08-04 | 2019-04-11 | 德商拜耳製藥公司 | ２－（嗎啉－４－基）－１，７－萘啶 |
| RU2768621C1 (ru) | 2015-09-30 | 2022-03-24 | Вертекс Фармасьютикалз Инкорпорейтед | Способ лечения рака с использованием комбинации повреждающих днк средств и ингибиторов atr |
| WO2018029117A1 (en) * | 2016-08-10 | 2018-02-15 | Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) | New atr inhibitors for the use in cancer therapy |
| US11110108B2 (en) * | 2016-09-27 | 2021-09-07 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors |
| JOP20190197A1 (ar) | 2017-02-24 | 2019-08-22 | Bayer Pharma AG | مثبط كيناز ايه تي آر للاستخدام في طريقة لعلاج مرض فرط التكاثر |
| WO2018153972A1 (en) | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and antiandrogens |
| AR110995A1 (es) | 2017-02-24 | 2019-05-22 | Bayer Ag | Combinación de inhibidores de quinasa atr con sal de radio-223 |
| WO2018206547A1 (en) | 2017-05-12 | 2018-11-15 | Bayer Pharma Aktiengesellschaft | Combination of bub1 and atr inhibitors |
| US10421765B2 (en) | 2017-05-26 | 2019-09-24 | Board Of Regents, The University Of Texas System | Tetrahydropyrido[4,3-d]pyrimidine inhibitors of ATR kinase |
| EP3651768B1 (en) | 2017-07-13 | 2023-12-20 | Board of Regents, The University of Texas System | Heterocyclic inhibitors of atr kinase |
| CA3071760A1 (en) | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and pd-1/pd-l1 inhibitors |
| EP3668839B1 (en) * | 2017-08-17 | 2023-04-12 | Board of Regents, The University of Texas System | Heterocyclic inhibitors of atr kinase |
| CA3074719A1 (en) | 2017-09-08 | 2019-03-14 | Bluevalley Pharmaceutical Llc | Substituted pyrrolopyridines as atr inhibitors |
| EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
| EP3720973A1 (en) | 2017-12-08 | 2020-10-14 | Bayer Aktiengesellschaft | Predictive markers for atr kinase inhibitors |
| GB201720989D0 (en) * | 2017-12-15 | 2018-01-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| SMT202400055T1 (it) * | 2018-02-07 | 2024-03-13 | Wuxi Biocity Biopharmaceutics Co Ltd | Inibitore di atr e relativa applicazione |
| US10894052B2 (en) | 2018-03-16 | 2021-01-19 | Board Of Regents, The University Of Texas System | Heterocyclic inhibitors of ATR kinase |
| WO2019222272A1 (en) | 2018-05-14 | 2019-11-21 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| CA3116230A1 (en) | 2018-10-16 | 2020-04-23 | Bayer Aktiengesellschaft | Combination of atr kinase inhibitors with 2,3-dihydroimidazo[1,2-c]quinazoline compounds |
| EP3873905A4 (en) | 2018-10-30 | 2022-08-17 | Repare Therapeutics Inc. | COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, METHODS FOR PREPARING COMPOUNDS AND THEIR USE AS KINASE ATR INHIBITORS |
| JP7600116B2 (ja) * | 2018-12-18 | 2024-12-16 | アストラゼネカ・アクチエボラーグ | 製薬方法及び中間体 |
| WO2020232119A1 (en) | 2019-05-14 | 2020-11-19 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| GB201908536D0 (en) * | 2019-06-13 | 2019-07-31 | Glaxosmithkline Ip Dev Ltd | Compounds |
| CN112142744A (zh) * | 2019-06-28 | 2020-12-29 | 上海瑛派药业有限公司 | 取代的稠合杂芳双环化合物作为激酶抑制剂及其应用 |
| PL4011881T3 (pl) * | 2019-08-06 | 2025-04-07 | Wuxi Biocity Biopharmaceutics Co., Ltd. | Postacie krystaliczne inhibitora atr i ich zastosowanie |
| US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
| CA3159376A1 (en) * | 2019-11-21 | 2021-05-27 | Jiangsu Hengrui Medicine Co., Ltd. | Pyrazolo-heteroaryl derivative, preparation method therefor, and medical use thereof |
| CN112939966B (zh) * | 2019-12-10 | 2023-03-24 | 武汉光谷亚太医药研究院有限公司 | 嘧啶衍生物、其制备及应用 |
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