ZA200508372B - Quinazoline derivatives for treatment of cancer - Google Patents
Quinazoline derivatives for treatment of cancer Download PDFInfo
- Publication number
- ZA200508372B ZA200508372B ZA200508372A ZA200508372A ZA200508372B ZA 200508372 B ZA200508372 B ZA 200508372B ZA 200508372 A ZA200508372 A ZA 200508372A ZA 200508372 A ZA200508372 A ZA 200508372A ZA 200508372 B ZA200508372 B ZA 200508372B
- Authority
- ZA
- South Africa
- Prior art keywords
- amino
- pyrazol
- acetamide
- difluorophenyl
- quinazolin
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title description 20
- 201000011510 cancer Diseases 0.000 title description 11
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 2
- -1 cyano, nitro, amino Chemical group 0.000 claims description 197
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 169
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 74
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 23
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 125000006413 ring segment Chemical group 0.000 claims description 17
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000002950 monocyclic group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229940002612 prodrug Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 102000003989 Aurora kinases Human genes 0.000 claims description 8
- 108090000433 Aurora kinases Proteins 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000003545 alkoxy 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
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 102000004000 Aurora Kinase A Human genes 0.000 claims description 4
- 108090000461 Aurora Kinase A Proteins 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 230000003463 hyperproliferative effect Effects 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 108090000749 Aurora kinase B Proteins 0.000 claims description 2
- 102000004228 Aurora kinase B Human genes 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 162
- 150000002431 hydrogen Chemical class 0.000 claims 31
- 125000001475 halogen functional group Chemical group 0.000 claims 21
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 14
- 239000000126 substance Substances 0.000 claims 8
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 6
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 6
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 3
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims 2
- 230000009286 beneficial effect Effects 0.000 claims 2
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- VTZGLNKYHUFNBK-UHFFFAOYSA-N 2-[2-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-6-methoxyquinazolin-7-yl]oxyethyl-(oxan-4-yl)amino]ethyl dihydrogen phosphate Chemical compound N1=CN=C2C=C(OCCN(CCOP(O)(O)=O)C3CCOCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F VTZGLNKYHUFNBK-UHFFFAOYSA-N 0.000 claims 1
- VPYSHQDXFFYFBF-UHFFFAOYSA-N 2-[2-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxyethyl-(oxan-4-yl)amino]ethyl dihydrogen phosphate Chemical compound C1COCCC1N(CCOP(O)(=O)O)CCOC(C=C1N=CN=2)=CC=C1C=2NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F VPYSHQDXFFYFBF-UHFFFAOYSA-N 0.000 claims 1
- CZDUMXAUTAUYSZ-UHFFFAOYSA-N 2-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl-propylamino]ethyl dihydrogen phosphate Chemical compound N=1C=NC2=CC(OCCCN(CCC)CCOP(O)(O)=O)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F CZDUMXAUTAUYSZ-UHFFFAOYSA-N 0.000 claims 1
- LEZFRKYLKAYVTA-UHFFFAOYSA-N 2-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-6-methoxyquinazolin-7-yl]oxypropyl-(2-methoxyethyl)amino]ethyl dihydrogen phosphate Chemical compound C=12C=C(OC)C(OCCCN(CCOC)CCOP(O)(O)=O)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 LEZFRKYLKAYVTA-UHFFFAOYSA-N 0.000 claims 1
- PZWZEUCSMWMDAQ-UHFFFAOYSA-N 2-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl-(2-methoxyethyl)amino]ethyl dihydrogen phosphate Chemical compound N=1C=NC2=CC(OCCCN(CCOC)CCOP(O)(O)=O)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 PZWZEUCSMWMDAQ-UHFFFAOYSA-N 0.000 claims 1
- HBVJZGHCKAWHHL-UHFFFAOYSA-N 2-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl-propylamino]ethyl dihydrogen phosphate Chemical compound N=1C=NC2=CC(OCCCN(CCC)CCOP(O)(O)=O)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 HBVJZGHCKAWHHL-UHFFFAOYSA-N 0.000 claims 1
- JFHKKQBOUOQZNV-UHFFFAOYSA-N 2-[3-acetamido-4-[[7-(3-chloropropoxy)quinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound C1=C(NC=2C3=CC=C(OCCCCl)C=C3N=CN=2)C(NC(=O)C)=NN1CC(=O)NC1=CC=CC(F)=C1 JFHKKQBOUOQZNV-UHFFFAOYSA-N 0.000 claims 1
- NGBFROQDGZCMCE-UHFFFAOYSA-N 2-[4-[(6,7-dimethoxyquinazolin-4-yl)amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 NGBFROQDGZCMCE-UHFFFAOYSA-N 0.000 claims 1
- IPQFGCUEXBRFMF-UHFFFAOYSA-N 2-[4-[[7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCl)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F IPQFGCUEXBRFMF-UHFFFAOYSA-N 0.000 claims 1
- NYLLJQFJCBRRPY-UHFFFAOYSA-N 2-[4-[[7-(3-chloropropoxy)-6-fluoroquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound FC1=CC=CC(NC(=O)CN2N=CC(NC=3C4=CC(F)=C(OCCCCl)C=C4N=CN=3)=C2)=C1F NYLLJQFJCBRRPY-UHFFFAOYSA-N 0.000 claims 1
- OJCGFQJMOFKEHE-UHFFFAOYSA-N 2-[4-[[7-[2-(cyclopentylamino)ethoxy]quinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound FC1=CC=CC(NC(=O)CN2N=CC(NC=3C4=CC=C(OCCNC5CCCC5)C=C4N=CN=3)=C2)=C1F OJCGFQJMOFKEHE-UHFFFAOYSA-N 0.000 claims 1
- KHTRPIFYFWEWKC-UHFFFAOYSA-N 2-[4-[[7-[2-[cyclopentyl-(2-hydroxyacetyl)amino]ethoxy]quinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound C1CCCC1N(C(=O)CO)CCOC(C=C1N=CN=2)=CC=C1C=2NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F KHTRPIFYFWEWKC-UHFFFAOYSA-N 0.000 claims 1
- MQUAARDPYYBPKL-UHFFFAOYSA-N 2-[4-[[7-[3-(cyclopropylmethylamino)propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCNCC3CC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 MQUAARDPYYBPKL-UHFFFAOYSA-N 0.000 claims 1
- PVSJEQCEYQILIW-UHFFFAOYSA-N 2-[4-[[7-[3-[2,2-dimethylpropyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC(C)(C)C)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 PVSJEQCEYQILIW-UHFFFAOYSA-N 0.000 claims 1
- RPUVSYLHQXEHFL-UHFFFAOYSA-N 2-[4-[[7-[3-[2-(diethylamino)ethyl-ethylamino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound C=12C=C(OC)C(OCCCN(CC)CCN(CC)CC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 RPUVSYLHQXEHFL-UHFFFAOYSA-N 0.000 claims 1
- HFTXSGBBWJXIGF-UHFFFAOYSA-N 2-[4-[[7-[3-[2-cyanoethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CCC#N)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F HFTXSGBBWJXIGF-UHFFFAOYSA-N 0.000 claims 1
- CKTVIBHCQJSKKT-UHFFFAOYSA-N 2-[4-[[7-[3-[bis(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CCO)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F CKTVIBHCQJSKKT-UHFFFAOYSA-N 0.000 claims 1
- HAADPSXACHJIBW-UHFFFAOYSA-N 2-[4-[[7-[3-[cyclobutyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)C3CCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F HAADPSXACHJIBW-UHFFFAOYSA-N 0.000 claims 1
- NWBFRFOSWVOYKH-UHFFFAOYSA-N 2-[4-[[7-[3-[cyclobutylmethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC3CCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 NWBFRFOSWVOYKH-UHFFFAOYSA-N 0.000 claims 1
- HWIGLDAOPMCHPQ-UHFFFAOYSA-N 2-[4-[[7-[3-[cyclopropylmethyl(2-hydroxyethyl)amino]propoxy]-6-fluoroquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound C1CC1CN(CCO)CCCOC(C(=CC1=2)F)=CC1=NC=NC=2NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F HWIGLDAOPMCHPQ-UHFFFAOYSA-N 0.000 claims 1
- BUEWFSGUFWAHQF-UHFFFAOYSA-N 2-[4-[[7-[3-[cyclopropylmethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC3CC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F BUEWFSGUFWAHQF-UHFFFAOYSA-N 0.000 claims 1
- RDYUXBVAJCOFGV-UHFFFAOYSA-N 2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-6-fluoroquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound C=12C=C(F)C(OCCCN(CCO)CC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 RDYUXBVAJCOFGV-UHFFFAOYSA-N 0.000 claims 1
- QFNBIMZYKKIEQO-UHFFFAOYSA-N 2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 QFNBIMZYKKIEQO-UHFFFAOYSA-N 0.000 claims 1
- VSDDGQRRPZFYHV-UHFFFAOYSA-N 2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]-n-(3-fluorophenyl)acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 VSDDGQRRPZFYHV-UHFFFAOYSA-N 0.000 claims 1
- YBPZQSRSICTFMZ-UHFFFAOYSA-N 2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]-n-phenylacetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC=C1 YBPZQSRSICTFMZ-UHFFFAOYSA-N 0.000 claims 1
- ZAGRNUGDOZAVNY-UHFFFAOYSA-N 2-[cyclobutyl-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-6-methoxyquinazolin-7-yl]oxypropyl]amino]ethyl dihydrogen phosphate Chemical compound N1=CN=C2C=C(OCCCN(CCOP(O)(O)=O)C3CCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F ZAGRNUGDOZAVNY-UHFFFAOYSA-N 0.000 claims 1
- OJTNFZVICDSWPN-UHFFFAOYSA-N 2-[cyclobutyl-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-6-methoxyquinazolin-7-yl]oxypropyl]amino]ethyl dihydrogen phosphate Chemical compound N1=CN=C2C=C(OCCCN(CCOP(O)(O)=O)C3CCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 OJTNFZVICDSWPN-UHFFFAOYSA-N 0.000 claims 1
- BNVWDLHQBQOZML-UHFFFAOYSA-N 2-[ethyl-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-6-methoxyquinazolin-7-yl]oxypropyl]amino]ethyl dihydrogen phosphate Chemical compound C=12C=C(OC)C(OCCCN(CC)CCOP(O)(O)=O)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 BNVWDLHQBQOZML-UHFFFAOYSA-N 0.000 claims 1
- ALBTWBXFQKIWRG-UHFFFAOYSA-N 3-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl-ethylamino]propyl dihydrogen phosphate Chemical compound N=1C=NC2=CC(OCCCN(CC)CCCOP(O)(O)=O)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F ALBTWBXFQKIWRG-UHFFFAOYSA-N 0.000 claims 1
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 claims 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- ARLFDXBHTLTFSF-UHFFFAOYSA-N N-(3-fluorophenyl)-2-[4-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(O)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 ARLFDXBHTLTFSF-UHFFFAOYSA-N 0.000 claims 1
- XCIRZTHZACWKJP-UHFFFAOYSA-N N-(3-fluorophenyl)-2-[4-[(7-hydroxyquinazolin-4-yl)amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(O)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 XCIRZTHZACWKJP-UHFFFAOYSA-N 0.000 claims 1
- HZDJEZRJQXNYCP-LJQANCHMSA-N [(2r)-1-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-5-methoxyquinazolin-7-yl]oxypropyl]pyrrolidin-2-yl]methyl dihydrogen phosphate Chemical compound C=1C2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C(OC)=CC=1OCCCN1CCC[C@@H]1COP(O)(O)=O HZDJEZRJQXNYCP-LJQANCHMSA-N 0.000 claims 1
- MENXWSXYUOWBKZ-JOCHJYFZSA-N [(2r)-1-[3-[4-[[1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl]pyrrolidin-2-yl]methyl dihydrogen phosphate Chemical compound OP(O)(=O)OC[C@H]1CCCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C=C(F)C=CC=3)N=C2)=NC=N2)C2=C1 MENXWSXYUOWBKZ-JOCHJYFZSA-N 0.000 claims 1
- YKIYRFSTXDDTLB-UHFFFAOYSA-N [2-[4-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]-2-oxoethyl] dihydrogen phosphate Chemical compound C1CN(C(=O)COP(O)(=O)O)CCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 YKIYRFSTXDDTLB-UHFFFAOYSA-N 0.000 claims 1
- LLVGNGZPBCMOMP-UHFFFAOYSA-N [3-[3-[4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]quinazolin-7-yl]oxypropylamino]-3-methylbutyl] dihydrogen phosphate Chemical compound N=1C=NC2=CC(OCCCNC(C)(CCOP(O)(O)=O)C)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F LLVGNGZPBCMOMP-UHFFFAOYSA-N 0.000 claims 1
- KHSDIBDUQZKWRN-UHFFFAOYSA-N [4-[[1-[2-(2,3-difluoroanilino)-2-oxoethyl]pyrazol-4-yl]amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-6-yl] dihydrogen phosphate Chemical compound C1CN(C)CCC1COC1=CC2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C=C1OP(O)(O)=O KHSDIBDUQZKWRN-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000006011 chloroethoxy group Chemical group 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 125000004212 difluorophenyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- LVMPSVVYLYSPPD-JOCHJYFZSA-N ethyl 1-[2-(3-fluoroanilino)-2-oxoethyl]-4-[[7-[3-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazole-3-carboxylate Chemical compound C1=C(NC=2C3=CC=C(OCCCN4[C@H](CCC4)CO)C=C3N=CN=2)C(C(=O)OCC)=NN1CC(=O)NC1=CC=CC(F)=C1 LVMPSVVYLYSPPD-JOCHJYFZSA-N 0.000 claims 1
- BBRUYRPMFVYWQE-UHFFFAOYSA-N ethyl 4-[[7-(3-chloropropoxy)quinazolin-4-yl]amino]-1-[2-(3-fluoroanilino)-2-oxoethyl]pyrazole-3-carboxylate Chemical compound C1=C(NC=2C3=CC=C(OCCCCl)C=C3N=CN=2)C(C(=O)OCC)=NN1CC(=O)NC1=CC=CC(F)=C1 BBRUYRPMFVYWQE-UHFFFAOYSA-N 0.000 claims 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 claims 1
- MRWPHXHFTWDGQU-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-(quinazolin-4-ylamino)pyrazol-1-yl]acetamide Chemical compound FC1=CC=CC(NC(=O)CN2N=CC(NC=3C4=CC=CC=C4N=CN=3)=C2)=C1F MRWPHXHFTWDGQU-UHFFFAOYSA-N 0.000 claims 1
- XFLURXFMAHYNLN-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[6-hydroxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C1CN(C)CCC1COC1=CC2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C=C1O XFLURXFMAHYNLN-UHFFFAOYSA-N 0.000 claims 1
- DWJINKHLZZOBDG-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-(3-piperazin-1-ylpropoxy)-5-propan-2-yloxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=1C2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C(OC(C)C)=CC=1OCCCN1CCNCC1 DWJINKHLZZOBDG-UHFFFAOYSA-N 0.000 claims 1
- HBCQLMCEDOHZTN-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[2-[4-(2-hydroxyethyl)piperidin-1-yl]ethoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C1CC(CCO)CCN1CCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 HBCQLMCEDOHZTN-UHFFFAOYSA-N 0.000 claims 1
- QAXUPWYXPBVXCN-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[2-[4-(3-hydroxypropyl)piperazin-1-yl]ethoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCN3CCN(CCCO)CC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F QAXUPWYXPBVXCN-UHFFFAOYSA-N 0.000 claims 1
- OPUGXVFXFFXULH-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-(2-hydroxyethylamino)propoxy]-5-propan-2-yloxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C(OC(C)C)=CC(OCCCNCCO)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F OPUGXVFXFFXULH-UHFFFAOYSA-N 0.000 claims 1
- WICSYSFYNPLSKT-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-(oxan-4-ylamino)propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound FC1=CC=CC(NC(=O)CN2N=CC(NC=3C4=CC=C(OCCCNC5CCOCC5)C=C4N=CN=3)=C2)=C1F WICSYSFYNPLSKT-UHFFFAOYSA-N 0.000 claims 1
- NDLDMUZSANRXST-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-(oxolan-2-ylmethylamino)propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound FC1=CC=CC(NC(=O)CN2N=CC(NC=3C4=CC=C(OCCCNCC5OCCC5)C=C4N=CN=3)=C2)=C1F NDLDMUZSANRXST-UHFFFAOYSA-N 0.000 claims 1
- XBNBEIXZFVCDEC-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(1-hydroxy-2-methylpropan-2-yl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCNC(C)(CO)C)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F XBNBEIXZFVCDEC-UHFFFAOYSA-N 0.000 claims 1
- QXWRWFOJUDTQPF-OAQYLSRUSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2r)-2-(2-hydroxyethyl)piperidin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound OCC[C@H]1CCCCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 QXWRWFOJUDTQPF-OAQYLSRUSA-N 0.000 claims 1
- TVSKCEZDHBUHFX-HXUWFJFHSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2r)-2-(hydroxymethyl)morpholin-4-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C1CO[C@@H](CO)CN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 TVSKCEZDHBUHFX-HXUWFJFHSA-N 0.000 claims 1
- AQLCVHOQMKRAAH-OAQYLSRUSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy]-5-propan-2-yloxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=1C2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C(OC(C)C)=CC=1OCCCN1CCC[C@@H]1CO AQLCVHOQMKRAAH-OAQYLSRUSA-N 0.000 claims 1
- YFGMURZUSPAEJH-LJQANCHMSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3[C@H](CCC3)CO)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F YFGMURZUSPAEJH-LJQANCHMSA-N 0.000 claims 1
- BQSSHYNPAGSOBT-LJQANCHMSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound OC[C@H]1CCCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 BQSSHYNPAGSOBT-LJQANCHMSA-N 0.000 claims 1
- QXWRWFOJUDTQPF-NRFANRHFSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(2s)-2-(2-hydroxyethyl)piperidin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound OCC[C@@H]1CCCCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 QXWRWFOJUDTQPF-NRFANRHFSA-N 0.000 claims 1
- PEFODWGQRYVBPW-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCNCC(C)(CO)C)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F PEFODWGQRYVBPW-UHFFFAOYSA-N 0.000 claims 1
- RYAMIYBBGXRPKT-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[(5-methyl-1,2-oxazol-3-yl)methylamino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound O1C(C)=CC(CNCCCOC=2C=C3N=CN=C(NC4=CN(CC(=O)NC=5C(=C(F)C=CC=5)F)N=C4)C3=CC=2)=N1 RYAMIYBBGXRPKT-UHFFFAOYSA-N 0.000 claims 1
- QRRWYTVVTNNYRU-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(2-methoxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CCOC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F QRRWYTVVTNNYRU-UHFFFAOYSA-N 0.000 claims 1
- JJYJPSRFSCKDSO-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(2-methylpropyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC(C)C)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F JJYJPSRFSCKDSO-UHFFFAOYSA-N 0.000 claims 1
- KNAMPTUOMYAIAW-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(2-methylpropyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC(C)C)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F KNAMPTUOMYAIAW-UHFFFAOYSA-N 0.000 claims 1
- XIBFLLIGGNCQAR-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(propan-2-yl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)C(C)C)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F XIBFLLIGGNCQAR-UHFFFAOYSA-N 0.000 claims 1
- HKLUVMBDPRHAGD-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(propyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CCC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F HKLUVMBDPRHAGD-UHFFFAOYSA-N 0.000 claims 1
- DRTVRIDUQCBEFN-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[2-hydroxyethyl(propyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CCC)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F DRTVRIDUQCBEFN-UHFFFAOYSA-N 0.000 claims 1
- FGKKWXYHFGPSKP-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[3-hydroxypropyl(propyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCCO)CCC)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F FGKKWXYHFGPSKP-UHFFFAOYSA-N 0.000 claims 1
- KGFWEOJQDBKLNC-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[4-(2-hydroxyacetyl)piperazin-1-yl]propoxy]-5-propan-2-yloxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=1C2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C(OC(C)C)=CC=1OCCCN1CCN(C(=O)CO)CC1 KGFWEOJQDBKLNC-UHFFFAOYSA-N 0.000 claims 1
- MLBPGECXGBLYED-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[4-(2-hydroxyacetyl)piperazin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C1CN(C(=O)CO)CCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 MLBPGECXGBLYED-UHFFFAOYSA-N 0.000 claims 1
- BAWDGXGQGWGLBC-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy]-5-propan-2-yloxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=1C2=NC=NC(NC3=CN(CC(=O)NC=4C(=C(F)C=CC=4)F)N=C3)=C2C(OC(C)C)=CC=1OCCCN1CCN(CCO)CC1 BAWDGXGQGWGLBC-UHFFFAOYSA-N 0.000 claims 1
- PLUKBYVAAOYCAE-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCN(CCO)CC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F PLUKBYVAAOYCAE-UHFFFAOYSA-N 0.000 claims 1
- ZMNHTQBMAQSWBW-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[4-(hydroxymethyl)piperidin-1-yl]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C1CC(CO)CCN1CCCOC1=CC=C(C(NC2=CN(CC(=O)NC=3C(=C(F)C=CC=3)F)N=C2)=NC=N2)C2=C1 ZMNHTQBMAQSWBW-UHFFFAOYSA-N 0.000 claims 1
- NYOGIGBHKYKOEE-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F NYOGIGBHKYKOEE-UHFFFAOYSA-N 0.000 claims 1
- AIWNZNBAVKCNND-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC)=CC=C2C=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F AIWNZNBAVKCNND-UHFFFAOYSA-N 0.000 claims 1
- DOFVEHDSKNDDIE-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[4-[[7-[3-[ethyl(methyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(C)CC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1F DOFVEHDSKNDDIE-UHFFFAOYSA-N 0.000 claims 1
- PPYRJSYWJLMBGS-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[4-[(6-hydroxy-7-methoxyquinazolin-4-yl)amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(O)C(OC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 PPYRJSYWJLMBGS-UHFFFAOYSA-N 0.000 claims 1
- UZUPXZMGVPTXCE-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[4-[[6-methoxy-7-[3-(4-methyl-1,4-diazepan-1-yl)propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCN(C)CCC3)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 UZUPXZMGVPTXCE-UHFFFAOYSA-N 0.000 claims 1
- KVUWBXWBTLWMFX-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[4-[[6-methoxy-7-[3-[methyl(propyl)amino]propoxy]quinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(C)CCC)=CC2=NC=NC=1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 KVUWBXWBTLWMFX-UHFFFAOYSA-N 0.000 claims 1
- ACDXDLIQFJBPHN-JOCHJYFZSA-N n-(3-fluorophenyl)-2-[4-[[7-[3-[(2r)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]pyrazol-1-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3[C@H](CCC3)CO)C(OC)=CC2=C1NC(=C1)C=NN1CC(=O)NC1=CC=CC(F)=C1 ACDXDLIQFJBPHN-JOCHJYFZSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03290951 | 2003-04-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200508372B true ZA200508372B (en) | 2007-04-25 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| ZA200508372A ZA200508372B (en) | 2003-04-16 | 2005-10-14 | Quinazoline derivatives for treatment of cancer |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US7691867B2 (de) |
| EP (1) | EP1613619B1 (de) |
| JP (1) | JP4709139B2 (de) |
| KR (1) | KR20060003351A (de) |
| CN (1) | CN1809557B (de) |
| AR (1) | AR043875A1 (de) |
| AT (1) | ATE390422T1 (de) |
| AU (1) | AU2004232527A1 (de) |
| BR (1) | BRPI0409427A (de) |
| CA (1) | CA2522079A1 (de) |
| CL (1) | CL2004000797A1 (de) |
| CO (1) | CO5640037A2 (de) |
| DE (1) | DE602004012725T2 (de) |
| ES (1) | ES2301981T3 (de) |
| HK (1) | HK1086573A1 (de) |
| IS (1) | IS8125A (de) |
| MX (1) | MXPA05011076A (de) |
| NO (1) | NO20054842L (de) |
| RU (1) | RU2005135337A (de) |
| TW (1) | TW200510392A (de) |
| UY (1) | UY28271A1 (de) |
| WO (1) | WO2004094410A1 (de) |
| ZA (1) | ZA200508372B (de) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL211694B1 (pl) * | 2001-12-24 | 2012-06-29 | Astrazeneca Ab | Podstawiona pochodna chinazoliny, jej zastosowania oraz jej kompozycja farmaceutyczna |
| MY136174A (en) * | 2002-12-24 | 2008-08-29 | Astrazeneca Ab | Phosphonooxy quinazoline derivatives and their pharmaceutical use |
| EP1635837B1 (de) * | 2003-06-02 | 2008-07-16 | AstraZeneca AB | (3-((chinazolin-4-yl)amino)-1h-pyrazol-1-yl)acetamid derivate und verwandte verbindungen als aurora kinase inhibitoren zur behandlung von proliferativen erkrankungen wie krebs |
| ME01267B (me) | 2004-05-06 | 2013-06-20 | Warner Lambert Co | 4-fenilaminokinazolin-6-ilamidi |
| US20090036474A1 (en) * | 2004-10-12 | 2009-02-05 | Patrick Ple | Quinazoline derivatives for use against cancer |
| WO2006040522A1 (en) * | 2004-10-12 | 2006-04-20 | Astrazeneca Ab | Quinoline derivatives |
| MX2007004403A (es) | 2004-10-12 | 2007-04-27 | Astrazeneca Ab | Derivados de quinazolina. |
| EP1812439B2 (de) | 2004-10-15 | 2017-12-06 | Takeda Pharmaceutical Company Limited | Kinaseinhibitoren |
| JP6097946B2 (ja) * | 2004-11-17 | 2017-03-22 | レクサン ファーマシューティカルズ インコーポレイテッド | １−［（６，７−置換−アルコキシキノキサリニル）アミノカルボニル］−４−（ヘテロ）アリールピペラジン誘導体 |
| GB0510963D0 (en) * | 2005-05-28 | 2005-07-06 | Astrazeneca Ab | Chemical compounds |
| JP2008542345A (ja) * | 2005-05-28 | 2008-11-27 | アストラゼネカ アクチボラグ | キナゾリン類及びオーロラキナーゼ阻害剤としてのその使用 |
| US20080269500A1 (en) * | 2005-09-22 | 2008-10-30 | Astrazeneca Ab | Process for the Preparation of 4-Aminopyrazole Derivatives |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| GB0601215D0 (en) * | 2006-01-21 | 2006-03-01 | Astrazeneca Ab | Chemical compounds |
| EP1994023A1 (de) * | 2006-03-02 | 2008-11-26 | AstraZeneca AB | Chinazolinderivate |
| UY30183A1 (es) | 2006-03-02 | 2007-10-31 | Astrazeneca Ab | Derivados de quinolina |
| WO2007113565A1 (en) * | 2006-04-06 | 2007-10-11 | Astrazeneca Ab | Naphthyridine derivatives as anti-cancer agents |
| GB0609617D0 (en) | 2006-05-16 | 2006-06-21 | Astrazeneca Ab | Process & intermediate |
| JP2010505962A (ja) | 2006-10-09 | 2010-02-25 | 武田薬品工業株式会社 | キナーゼ阻害剤 |
| FR2908409B1 (fr) | 2006-11-10 | 2009-01-09 | Sanofi Aventis Sa | Pyrazoles substituees,compositions les contenant,procede de fabrication et utilisation |
| TWI577671B (zh) * | 2011-11-14 | 2017-04-11 | Sunshine Lake Pharma Co Ltd | Aminoquinazoline derivatives and salts thereof and methods of use thereof |
| CN103012428A (zh) * | 2013-01-08 | 2013-04-03 | 中国药科大学 | 4-(五元杂环并嘧啶/吡啶取代)氨基-1H-3-吡唑甲酰胺类CDK/Aurora双重抑制剂及其用途 |
| CN104098551B (zh) * | 2013-04-03 | 2019-03-22 | 广东东阳光药业有限公司 | 作为欧若拉激酶抑制剂的取代喹唑啉类衍生物 |
| CN103382158B (zh) * | 2013-07-29 | 2015-11-18 | 张家港市大伟助剂有限公司 | 一种2-环戊基氨基乙醇的制备方法 |
| JP6567505B2 (ja) * | 2013-09-19 | 2019-08-28 | ピエール、ファーブル、メディカマン | キナゾリン誘導体およびｄｎａメチルトランスフェラーゼ阻害剤としてのその使用 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
| TW321649B (de) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
| WO1997017329A1 (fr) * | 1995-11-07 | 1997-05-15 | Kirin Beer Kabushiki Kaisha | Derives de quinoline et derives de quinazoline inhibant l'autophosphorylation d'un recepteur de facteur de croissance originaire de plaquettes, et compositions pharmaceutiques les contenant |
| WO2001021596A1 (en) * | 1999-09-21 | 2001-03-29 | Astrazeneca Ab | Quinazoline derivatives and their use as pharmaceuticals |
| GB9922171D0 (en) | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Chemical compounds |
| NZ522696A (en) * | 2000-06-28 | 2004-08-27 | Astrazeneca Ab | Substituted quinazoline derivatives and their use as inhibitors |
| PL211694B1 (pl) | 2001-12-24 | 2012-06-29 | Astrazeneca Ab | Podstawiona pochodna chinazoliny, jej zastosowania oraz jej kompozycja farmaceutyczna |
| WO2004018430A1 (ja) * | 2002-08-23 | 2004-03-04 | Kirin Beer Kabushiki Kaisha | ＴＧＦβ阻害活性を有する化合物およびそれを含んでなる医薬組成物 |
| AU2003294142A1 (en) | 2002-12-24 | 2004-07-22 | Astrazeneca Ab | Therapeutic quinazoline derivatives |
| MY136174A (en) | 2002-12-24 | 2008-08-29 | Astrazeneca Ab | Phosphonooxy quinazoline derivatives and their pharmaceutical use |
| WO2004058752A1 (en) | 2002-12-24 | 2004-07-15 | Astrazeneca Ab | Quinazoline compounds |
| EP1635837B1 (de) * | 2003-06-02 | 2008-07-16 | AstraZeneca AB | (3-((chinazolin-4-yl)amino)-1h-pyrazol-1-yl)acetamid derivate und verwandte verbindungen als aurora kinase inhibitoren zur behandlung von proliferativen erkrankungen wie krebs |
| TW200505452A (en) * | 2003-06-17 | 2005-02-16 | Astrazeneca Ab | Chemical compounds |
-
2004
- 2004-04-14 KR KR1020057019633A patent/KR20060003351A/ko not_active Application Discontinuation
- 2004-04-14 DE DE602004012725T patent/DE602004012725T2/de not_active Expired - Lifetime
- 2004-04-14 RU RU2005135337/04A patent/RU2005135337A/ru not_active Application Discontinuation
- 2004-04-14 CL CL200400797A patent/CL2004000797A1/es unknown
- 2004-04-14 CN CN2004800165460A patent/CN1809557B/zh not_active Expired - Fee Related
- 2004-04-14 MX MXPA05011076A patent/MXPA05011076A/es unknown
- 2004-04-14 WO PCT/GB2004/001614 patent/WO2004094410A1/en active IP Right Grant
- 2004-04-14 US US10/552,425 patent/US7691867B2/en not_active Expired - Fee Related
- 2004-04-14 CA CA002522079A patent/CA2522079A1/en not_active Abandoned
- 2004-04-14 AT AT04727325T patent/ATE390422T1/de not_active IP Right Cessation
- 2004-04-14 BR BRPI0409427-1A patent/BRPI0409427A/pt not_active IP Right Cessation
- 2004-04-14 AU AU2004232527A patent/AU2004232527A1/en not_active Abandoned
- 2004-04-14 EP EP04727325A patent/EP1613619B1/de not_active Expired - Lifetime
- 2004-04-14 ES ES04727325T patent/ES2301981T3/es not_active Expired - Lifetime
- 2004-04-14 JP JP2006506123A patent/JP4709139B2/ja not_active Expired - Fee Related
- 2004-04-16 TW TW093110602A patent/TW200510392A/zh unknown
- 2004-04-16 UY UY28271A patent/UY28271A1/es not_active Application Discontinuation
- 2004-04-16 AR ARP040101300A patent/AR043875A1/es not_active Application Discontinuation
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2005
- 2005-10-14 ZA ZA200508372A patent/ZA200508372B/en unknown
- 2005-10-19 NO NO20054842A patent/NO20054842L/no not_active Application Discontinuation
- 2005-11-11 IS IS8125A patent/IS8125A/is unknown
- 2005-11-15 CO CO05115649A patent/CO5640037A2/es not_active Application Discontinuation
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| Publication number | Publication date |
|---|---|
| ES2301981T3 (es) | 2008-07-01 |
| CA2522079A1 (en) | 2004-11-04 |
| EP1613619B1 (de) | 2008-03-26 |
| WO2004094410A1 (en) | 2004-11-04 |
| DE602004012725D1 (de) | 2008-05-08 |
| AU2004232527A1 (en) | 2004-11-04 |
| NO20054842L (no) | 2005-11-08 |
| MXPA05011076A (es) | 2006-01-24 |
| DE602004012725T2 (de) | 2009-04-16 |
| TW200510392A (en) | 2005-03-16 |
| KR20060003351A (ko) | 2006-01-10 |
| HK1086573A1 (en) | 2006-09-22 |
| CO5640037A2 (es) | 2006-05-31 |
| ATE390422T1 (de) | 2008-04-15 |
| EP1613619A1 (de) | 2006-01-11 |
| BRPI0409427A (pt) | 2006-04-18 |
| CL2004000797A1 (es) | 2005-05-27 |
| RU2005135337A (ru) | 2006-06-10 |
| US7691867B2 (en) | 2010-04-06 |
| AR043875A1 (es) | 2005-08-17 |
| JP4709139B2 (ja) | 2011-06-22 |
| IS8125A (is) | 2005-11-11 |
| JP2006523660A (ja) | 2006-10-19 |
| CN1809557B (zh) | 2012-07-04 |
| CN1809557A (zh) | 2006-07-26 |
| UY28271A1 (es) | 2004-11-30 |
| US20060270692A1 (en) | 2006-11-30 |
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