CA2417050C - Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them - Google Patents
Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them Download PDFInfo
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- CA2417050C CA2417050C CA002417050A CA2417050A CA2417050C CA 2417050 C CA2417050 C CA 2417050C CA 002417050 A CA002417050 A CA 002417050A CA 2417050 A CA2417050 A CA 2417050A CA 2417050 C CA2417050 C CA 2417050C
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- amino
- oxo
- buten
- chloro
- fluorophenyl
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 title claims description 86
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 8
- 230000008569 process Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 201000010099 disease Diseases 0.000 claims abstract description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 36
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 210000004072 lung Anatomy 0.000 claims abstract description 7
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 3
- 150000007524 organic acids Chemical class 0.000 claims abstract description 3
- -1 2-oxo-morpholin-4-yl group Chemical group 0.000 claims description 101
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 93
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 19
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 9
- SMCDHGJQIQUNIM-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(2,2-dimethyl-6-oxomorpholin-4-yl)but-2-enamide Chemical compound C1C(=O)OC(C)(C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SMCDHGJQIQUNIM-UHFFFAOYSA-N 0.000 claims description 8
- ZOOUDMWPZJXWEZ-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ZOOUDMWPZJXWEZ-UHFFFAOYSA-N 0.000 claims description 8
- ONOWKYWJTZDNCT-MRXNPFEDSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[(3r)-3-methyl-2-oxomorpholin-4-yl]but-2-enamide Chemical compound C1COC(=O)[C@@H](C)N1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ONOWKYWJTZDNCT-MRXNPFEDSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 208000037062 Polyps Diseases 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- CCOKBACMAWRBJZ-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(2-methyl-6-oxomorpholin-4-yl)but-2-enamide Chemical compound C1C(=O)OC(C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 CCOKBACMAWRBJZ-UHFFFAOYSA-N 0.000 claims description 7
- KMIVCBCOKOZZRN-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(5-methyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 KMIVCBCOKOZZRN-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 210000000013 bile duct Anatomy 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- GOEZUUHXYGDNCD-GOSISDBHSA-N ethyl (2r)-2-[[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]-(2-hydroxyethyl)amino]propanoate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CCN(CCO)[C@H](C)C(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 GOEZUUHXYGDNCD-GOSISDBHSA-N 0.000 claims description 5
- XWSRRYNPCDAWKP-UHFFFAOYSA-N ethyl 2-[[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]-(2-hydroxy-2-methylpropyl)amino]acetate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CCN(CC(=O)OCC)CC(C)(C)O)=CC2=C1NC1=CC=C(F)C(Cl)=C1 XWSRRYNPCDAWKP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 210000000232 gallbladder Anatomy 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- CCOKBACMAWRBJZ-MRXNPFEDSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 CCOKBACMAWRBJZ-MRXNPFEDSA-N 0.000 claims description 5
- MTSNTESNMVUHHV-QGZVFWFLSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxan-4-yloxy)quinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCOCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 MTSNTESNMVUHHV-QGZVFWFLSA-N 0.000 claims description 5
- YDTSPMQRCGKWRK-CQSZACIVSA-N n-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC1=CC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=C1 YDTSPMQRCGKWRK-CQSZACIVSA-N 0.000 claims description 5
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- OQFKTDPRJBLWPS-UHFFFAOYSA-N ethyl 2-[[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]-(2-hydroxyethyl)amino]acetate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CCN(CCO)CC(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 OQFKTDPRJBLWPS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- ONOWKYWJTZDNCT-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(3-methyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound C1COC(=O)C(C)N1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ONOWKYWJTZDNCT-UHFFFAOYSA-N 0.000 claims description 4
- MQPOXBYCYDBMJH-UHFFFAOYSA-N 2-[[4-[[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]amino]-4-oxobut-2-enyl]-(2-hydroxyethyl)amino]acetic acid Chemical compound C=12C=C(NC(=O)C=CCN(CCO)CC(O)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 MQPOXBYCYDBMJH-UHFFFAOYSA-N 0.000 claims description 3
- HTWMYCGEXASIGG-GOSISDBHSA-N 4-(5,5-dimethyl-2-oxomorpholin-4-yl)-n-[4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]but-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=C2)=NC=NC1=CC=C2NC(=O)C=CCN1CC(=O)OCC1(C)C HTWMYCGEXASIGG-GOSISDBHSA-N 0.000 claims description 3
- WLCDWQKCHZPMLJ-ZWKOTPCHSA-N 4-[(2s)-2-methyl-6-oxomorpholin-4-yl]-n-[4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]but-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=C2)=NC=NC1=CC=C2NC(=O)C=CCN1C[C@H](C)OC(=O)C1 WLCDWQKCHZPMLJ-ZWKOTPCHSA-N 0.000 claims description 3
- YHDXPFVJAIHRAS-WMZOPIPTSA-N N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-[(2S)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YHDXPFVJAIHRAS-WMZOPIPTSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- SEOUETYTEUFQGQ-UHFFFAOYSA-N n-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]-4-(2-oxomorpholin-4-yl)but-2-enamide Chemical compound C=12C=C(NC(=O)C=CCN3CC(=O)OCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 SEOUETYTEUFQGQ-UHFFFAOYSA-N 0.000 claims description 3
- QDVZMCXFARFESQ-UHFFFAOYSA-N n-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]-4-[1,3-dioxolan-2-ylmethyl(methyl)amino]but-2-enamide Chemical compound C=12C=C(NC(=O)C=CCN(C)CC3OCCO3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 QDVZMCXFARFESQ-UHFFFAOYSA-N 0.000 claims description 3
- VMDRYOBNPDPEFY-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound C=12C=C(NC(=O)C=CCN3C(COC(=O)C3)(C)C)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 VMDRYOBNPDPEFY-UHFFFAOYSA-N 0.000 claims description 3
- ONOWKYWJTZDNCT-INIZCTEOSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[(3s)-3-methyl-2-oxomorpholin-4-yl]but-2-enamide Chemical compound C1COC(=O)[C@H](C)N1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ONOWKYWJTZDNCT-INIZCTEOSA-N 0.000 claims description 3
- PCJFYVJPOFXARK-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[1,3-dioxolan-2-ylmethyl(methyl)amino]but-2-enamide Chemical compound O1CCOC1CN(C)CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 PCJFYVJPOFXARK-UHFFFAOYSA-N 0.000 claims description 3
- MZZRGWDBGCKNCG-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxan-4-yloxy)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCOCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 MZZRGWDBGCKNCG-UHFFFAOYSA-N 0.000 claims description 3
- NCLFLVTUXADXQE-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxolan-2-ylmethoxy)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3OCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 NCLFLVTUXADXQE-UHFFFAOYSA-N 0.000 claims description 3
- YHDXPFVJAIHRAS-SJLPKXTDSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(3r)-oxolan-3-yl]oxyquinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YHDXPFVJAIHRAS-SJLPKXTDSA-N 0.000 claims description 3
- YHDXPFVJAIHRAS-FUHWJXTLSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(3r)-oxolan-3-yl]oxyquinazolin-6-yl]-4-[(2s)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YHDXPFVJAIHRAS-FUHWJXTLSA-N 0.000 claims description 3
- YWGCPWOZUWEHGA-SFHVURJKSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(3s)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YWGCPWOZUWEHGA-SFHVURJKSA-N 0.000 claims description 3
- YHDXPFVJAIHRAS-AEFFLSMTSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(3s)-oxolan-3-yl]oxyquinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YHDXPFVJAIHRAS-AEFFLSMTSA-N 0.000 claims description 3
- YATAUUBWSCHJNQ-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YATAUUBWSCHJNQ-UHFFFAOYSA-N 0.000 claims description 3
- WVKDOGWQTANXMX-MRXNPFEDSA-N n-[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]-4-[(2r)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 WVKDOGWQTANXMX-MRXNPFEDSA-N 0.000 claims description 3
- WVKDOGWQTANXMX-INIZCTEOSA-N n-[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]-4-[(2s)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 WVKDOGWQTANXMX-INIZCTEOSA-N 0.000 claims description 3
- RHQSWQLBVJZSIR-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-cyclopentyloxyquinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 RHQSWQLBVJZSIR-UHFFFAOYSA-N 0.000 claims description 3
- SJNPYHNHNFJXCY-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound C=12C=C(NC(=O)C=CCN3C(COC(=O)C3)(C)C)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 SJNPYHNHNFJXCY-UHFFFAOYSA-N 0.000 claims description 3
- WOWRAEPIBQSHBM-ZWKOTPCHSA-N n-[7-methoxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]-4-[(2s)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1([C@@H](C)NC=2N=CN=C3C=C(C(=CC3=2)NC(=O)C=CCN2CC(=O)O[C@@H](C)C2)OC)=CC=CC=C1 WOWRAEPIBQSHBM-ZWKOTPCHSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- PJUPDYXOPGQSMN-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(2-oxomorpholin-4-yl)but-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC(C1=C2)=NC=NC1=CC(OCC1CC1)=C2NC(=O)C=CCN1CC(=O)OCC1 PJUPDYXOPGQSMN-UHFFFAOYSA-N 0.000 claims description 2
- CCOKBACMAWRBJZ-INIZCTEOSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[(2s)-2-methyl-6-oxomorpholin-4-yl]but-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 CCOKBACMAWRBJZ-INIZCTEOSA-N 0.000 claims description 2
- HBJJUSHREJSZCK-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxan-4-yloxy)quinazolin-6-yl]-4-(2,2-dimethyl-6-oxomorpholin-4-yl)but-2-enamide Chemical compound C1C(=O)OC(C)(C)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCOCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 HBJJUSHREJSZCK-UHFFFAOYSA-N 0.000 claims description 2
- YWGCPWOZUWEHGA-GOSISDBHSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(3r)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)O[C@H]3COCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 YWGCPWOZUWEHGA-GOSISDBHSA-N 0.000 claims description 2
- COCKMRXZOILWAZ-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC1=CC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=C1 COCKMRXZOILWAZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- WGMSRVIBKPCHSA-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(2-ethyl-6-oxomorpholin-4-yl)but-2-enamide Chemical compound C1C(=O)OC(CC)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 WGMSRVIBKPCHSA-UHFFFAOYSA-N 0.000 claims 1
- ASFSCZPQJLOHJQ-HXUWFJFHSA-N n-[7-(cyclopropylmethoxy)-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2NC(=O)C=CCN3C(COC(=O)C3)(C)C)=NC=NC1=CC=2OCC1CC1 ASFSCZPQJLOHJQ-HXUWFJFHSA-N 0.000 claims 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 8
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 230000001404 mediated effect Effects 0.000 abstract description 4
- 230000019491 signal transduction Effects 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 235000005985 organic acids Nutrition 0.000 abstract description 2
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Classifications
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10042060A DE10042060A1 (de) | 2000-08-26 | 2000-08-26 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| DE10042060.5 | 2000-08-26 | ||
| PCT/EP2001/009537 WO2002018373A1 (de) | 2000-08-26 | 2001-08-18 | Chinazolin derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
Publications (2)
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| CA2417050A1 CA2417050A1 (en) | 2002-03-07 |
| CA2417050C true CA2417050C (en) | 2009-04-14 |
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| CA002417050A Expired - Fee Related CA2417050C (en) | 2000-08-26 | 2001-08-18 | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
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| EP (1) | EP1315717A1 (enExample) |
| JP (1) | JP2004517048A (enExample) |
| AU (1) | AU2001284021A1 (enExample) |
| CA (1) | CA2417050C (enExample) |
| DE (1) | DE10042060A1 (enExample) |
| MX (1) | MXPA03000873A (enExample) |
| WO (1) | WO2002018373A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| NZ516633A (en) | 1999-06-21 | 2004-09-24 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
| US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
| TW200813014A (en) | 2002-03-28 | 2008-03-16 | Astrazeneca Ab | Quinazoline derivatives |
| US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
| DE10221018A1 (de) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie |
| DE10307165A1 (de) * | 2003-02-20 | 2004-09-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung |
| US7223749B2 (en) | 2003-02-20 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
| GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
| WO2005026150A1 (en) | 2003-09-16 | 2005-03-24 | Astrazeneca Ab | Quinazoline derivatives as tyrosine kinase inhibitors |
| BRPI0414532B1 (pt) | 2003-09-19 | 2018-06-05 | Astrazeneca Ab | Composto derivado de quinazolina, processo para preparar 0 mesmo, composição farmaceutica, e, uso de um composto derivado de quinazolina |
| CA2557433C (en) * | 2004-02-19 | 2013-05-14 | Rexahn Corporation | Quinazoline derivatives and therapeutic use thereof |
| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
| AU2006217738A1 (en) | 2005-02-26 | 2006-08-31 | Astrazeneca Ab | Quinazoline derivatives as tyrosine kinase inhibitors |
| KR100832593B1 (ko) * | 2005-11-08 | 2008-05-27 | 한미약품 주식회사 | 신호전달 저해제로서의 퀴나졸린 유도체 및 이의 제조방법 |
| WO2007055513A1 (en) * | 2005-11-08 | 2007-05-18 | Hanmi Pharm. Co., Ltd. | Quinazoline derivatives as a signal transduction inhibitor and method for the preparation thereof |
| CA2833706C (en) | 2005-11-11 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Quinazoline derivatives for the treatment of cancer diseases |
| CA2663599A1 (en) | 2006-09-18 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Method for treating cancer harboring egfr mutations |
| EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
| JP5377332B2 (ja) | 2007-02-06 | 2013-12-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 二環式へテロ環、それらの化合物を含む薬剤、その使用及びその製法 |
| WO2009098061A1 (de) | 2008-02-07 | 2009-08-13 | Boehringer Ingelheim International Gmbh | Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
| MX2010012442A (es) | 2008-05-13 | 2011-10-11 | Astrazeneca Ab | Sal de fumarato de 4-(3-cloro-2-fluoroanilino)-7-metoxi-6-{[1-(n-m etilcarbamoilmetil) piperidin-4-il]oxi}quinazolina. |
| EP2313397B1 (de) | 2008-08-08 | 2016-04-20 | Boehringer Ingelheim International GmbH | Cyclohexyloxy-substituierte heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
| WO2010054285A2 (en) | 2008-11-10 | 2010-05-14 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
| SI2451445T1 (sl) | 2009-07-06 | 2019-07-31 | Boehringer Ingelheim International Gmbh | Postopek za sušenje BIBW2992, njegovih soli in trdnih farmacevtskih formulacij, ki obsegajo to aktivno sestavino |
| PH12012500097A1 (en) * | 2009-07-21 | 2011-01-27 | Shanghai Inst Organic Chem | Potent small molecule inhibitors of autophagy, and methods of use thereof |
| CN102382106A (zh) * | 2010-08-30 | 2012-03-21 | 黄振华 | 苯胺取代的喹唑啉衍生物 |
| WO2013135176A1 (zh) * | 2012-03-16 | 2013-09-19 | 苏州迈泰生物技术有限公司 | 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途 |
| US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
| CN108148071B (zh) * | 2016-11-25 | 2019-10-15 | 广东东阳光药业有限公司 | 氨基喹唑啉衍生物的盐及其用途 |
| CN115894455B (zh) * | 2021-09-30 | 2024-04-19 | 北京赛特明强医药科技有限公司 | 一种喹唑啉类化合物、组合物及其应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW436485B (en) * | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
| TR200102505T2 (tr) * | 1999-02-27 | 2003-01-21 | Boehringer Ingelheim Pharma Kg | 4-amino-kinazolin ve kinolin türevleri. |
| DE19911509A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| NZ516633A (en) * | 1999-06-21 | 2004-09-24 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
| DE19928281A1 (de) * | 1999-06-21 | 2000-12-28 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| DE10017539A1 (de) * | 2000-04-08 | 2001-10-11 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbingungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
-
2000
- 2000-08-26 DE DE10042060A patent/DE10042060A1/de not_active Withdrawn
-
2001
- 2001-08-18 WO PCT/EP2001/009537 patent/WO2002018373A1/de not_active Ceased
- 2001-08-18 JP JP2002523888A patent/JP2004517048A/ja active Pending
- 2001-08-18 CA CA002417050A patent/CA2417050C/en not_active Expired - Fee Related
- 2001-08-18 EP EP01962953A patent/EP1315717A1/de not_active Withdrawn
- 2001-08-18 MX MXPA03000873A patent/MXPA03000873A/es unknown
- 2001-08-18 AU AU2001284021A patent/AU2001284021A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004517048A (ja) | 2004-06-10 |
| WO2002018373A1 (de) | 2002-03-07 |
| AU2001284021A1 (en) | 2002-03-13 |
| MXPA03000873A (es) | 2003-06-06 |
| DE10042060A1 (de) | 2002-03-07 |
| CA2417050A1 (en) | 2002-03-07 |
| EP1315717A1 (de) | 2003-06-04 |
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