JP6505131B2 - イミダゾ［４，５−ｃ］キノリン−２−オン化合物および癌の処置におけるそれらの使用 - Google Patents
イミダゾ［４，５−ｃ］キノリン−２−オン化合物および癌の処置におけるそれらの使用 Download PDFInfo
- Publication number
- JP6505131B2 JP6505131B2 JP2016567002A JP2016567002A JP6505131B2 JP 6505131 B2 JP6505131 B2 JP 6505131B2 JP 2016567002 A JP2016567002 A JP 2016567002A JP 2016567002 A JP2016567002 A JP 2016567002A JP 6505131 B2 JP6505131 B2 JP 6505131B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- imidazo
- quinolin
- pyridin
- fluoro
- 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
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 144
- 201000011510 cancer Diseases 0.000 title claims description 124
- 238000011282 treatment Methods 0.000 title claims description 64
- NSHFLKZNBPJNPA-UHFFFAOYSA-N imidazo[4,5-c]quinolin-2-one Chemical class C1=CC=C2C3=NC(=O)N=C3C=NC2=C1 NSHFLKZNBPJNPA-UHFFFAOYSA-N 0.000 title claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 631
- 150000001875 compounds Chemical class 0.000 claims description 216
- -1 1-methoxy-cyclobut-3-yl Chemical group 0.000 claims description 178
- 150000003839 salts Chemical class 0.000 claims description 153
- 239000001257 hydrogen Substances 0.000 claims description 61
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 210000004027 cell Anatomy 0.000 claims description 44
- 239000002246 antineoplastic agent Substances 0.000 claims description 41
- 125000001153 fluoro group Chemical group F* 0.000 claims description 37
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 27
- 208000005017 glioblastoma Diseases 0.000 claims description 24
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 22
- 206010009944 Colon cancer Diseases 0.000 claims description 22
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 22
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
- 229960004768 irinotecan Drugs 0.000 claims description 20
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 20
- AOTRIQLYUAFVSC-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C)C AOTRIQLYUAFVSC-UHFFFAOYSA-N 0.000 claims description 18
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 18
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 18
- 238000001959 radiotherapy Methods 0.000 claims description 18
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 16
- 206010017758 gastric cancer Diseases 0.000 claims description 16
- 201000011549 stomach cancer Diseases 0.000 claims description 16
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 15
- 206010006187 Breast cancer Diseases 0.000 claims description 15
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 15
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 15
- 206010033128 Ovarian cancer Diseases 0.000 claims description 15
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 15
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 15
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 229960000572 olaparib Drugs 0.000 claims description 14
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims description 14
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 14
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 13
- 229960004679 doxorubicin Drugs 0.000 claims description 13
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 13
- 125000003566 oxetanyl group Chemical group 0.000 claims description 13
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 12
- 229960000303 topotecan Drugs 0.000 claims description 12
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 12
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 12
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 11
- 125000002393 azetidinyl group Chemical group 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 229960005420 etoposide Drugs 0.000 claims description 11
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 11
- 125000003386 piperidinyl group Chemical group 0.000 claims description 11
- 108010006654 Bleomycin Proteins 0.000 claims description 10
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 10
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 10
- 229960002707 bendamustine Drugs 0.000 claims description 10
- 229960001561 bleomycin Drugs 0.000 claims description 10
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 10
- 229960005243 carmustine Drugs 0.000 claims description 10
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 10
- 229960004630 chlorambucil Drugs 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 10
- 229960001924 melphalan Drugs 0.000 claims description 10
- 229960004857 mitomycin Drugs 0.000 claims description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 9
- 229930192392 Mitomycin Natural products 0.000 claims description 9
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 9
- DWICJHMMZLNUEB-UHFFFAOYSA-N COC1CC(C1)n1c2c(cnc3ccc(cc23)-c2ccc(OCCCN(C)C)nc2)n(C)c1=O Chemical compound COC1CC(C1)n1c2c(cnc3ccc(cc23)-c2ccc(OCCCN(C)C)nc2)n(C)c1=O DWICJHMMZLNUEB-UHFFFAOYSA-N 0.000 claims description 8
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 8
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 8
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 claims description 7
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 7
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 7
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 7
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 7
- 229950009557 adavosertib Drugs 0.000 claims description 7
- 229960002550 amrubicin Drugs 0.000 claims description 7
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 claims description 7
- 229960004397 cyclophosphamide Drugs 0.000 claims description 7
- 229960001904 epirubicin Drugs 0.000 claims description 7
- 229960001101 ifosfamide Drugs 0.000 claims description 7
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 7
- 229960001221 pirarubicin Drugs 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 6
- 229960004562 carboplatin Drugs 0.000 claims description 6
- 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 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 6
- 229960004316 cisplatin Drugs 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 229950009791 durvalumab Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229960001756 oxaliplatin Drugs 0.000 claims description 6
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 6
- ZPOCWOPPQUMNCW-NHCUHLMSSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C)C ZPOCWOPPQUMNCW-NHCUHLMSSA-N 0.000 claims description 5
- ALMNQGLNZWNMGU-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3(CCOCC3)C)=O)C)C ALMNQGLNZWNMGU-UHFFFAOYSA-N 0.000 claims description 5
- IJNIRMWVECLJOY-FQEVSTJZSA-N FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3COCCC3)=O)C)C=3C=NC(=CC3)OCCCN3CCCC3 Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3COCCC3)=O)C)C=3C=NC(=CC3)OCCCN3CCCC3 IJNIRMWVECLJOY-FQEVSTJZSA-N 0.000 claims description 5
- 229960000653 valrubicin Drugs 0.000 claims description 5
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 5
- SMWBKQZPBQNELS-DNQXCXABSA-N 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CO[C@H]1C[C@@H](CC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCCC2)C)=O SMWBKQZPBQNELS-DNQXCXABSA-N 0.000 claims description 4
- SMWBKQZPBQNELS-ZEQRLZLVSA-N 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CO[C@@H]1C[C@H](CC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCCC2)C)=O SMWBKQZPBQNELS-ZEQRLZLVSA-N 0.000 claims description 4
- QSVMUHYIHOFSRB-HSZRJFAPSA-N 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)[C@H]2COCCC2)=O QSVMUHYIHOFSRB-HSZRJFAPSA-N 0.000 claims description 4
- BHZJNQALHTWTBX-UHFFFAOYSA-N 3-methyl-8-[6-[3-(methylamino)propoxy]pyridin-3-yl]-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCNC)C2CCOCC2)=O BHZJNQALHTWTBX-UHFFFAOYSA-N 0.000 claims description 4
- ARZGDKFYXFLWNZ-IBGZPJMESA-N 3-methyl-8-[6-[3-(methylamino)propoxy]pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCNC)[C@@H]2COCCC2)=O ARZGDKFYXFLWNZ-IBGZPJMESA-N 0.000 claims description 4
- QHRPXFUAYFWEPQ-UHFFFAOYSA-N 7-fluoro-3-methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3C3CCOCC3)=O)C)C=3C=NC(=CC3)OCCCN3CCCCC3 QHRPXFUAYFWEPQ-UHFFFAOYSA-N 0.000 claims description 4
- DCYIRFHUZMQEJE-OAQYLSRUSA-N 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3COCCC3)=O)C DCYIRFHUZMQEJE-OAQYLSRUSA-N 0.000 claims description 4
- QNJITDREARMZMY-RTBURBONSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C)C QNJITDREARMZMY-RTBURBONSA-N 0.000 claims description 4
- QNJITDREARMZMY-OALUTQOASA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C)C QNJITDREARMZMY-OALUTQOASA-N 0.000 claims description 4
- NDSGFLSESAHGIW-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C)C NDSGFLSESAHGIW-UHFFFAOYSA-N 0.000 claims description 4
- SBWOIJRPFUUCGS-GOSISDBHSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3COCCC3)=O)C)C SBWOIJRPFUUCGS-GOSISDBHSA-N 0.000 claims description 4
- SBWOIJRPFUUCGS-SFHVURJKSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)C SBWOIJRPFUUCGS-SFHVURJKSA-N 0.000 claims description 4
- GHXGFAYAOFHWSA-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)NC(N3C3CCOCC3)=O)C GHXGFAYAOFHWSA-UHFFFAOYSA-N 0.000 claims description 4
- ZPOCWOPPQUMNCW-SFTDATJTSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C)C ZPOCWOPPQUMNCW-SFTDATJTSA-N 0.000 claims description 4
- ABKGTFFKSJEJIQ-HXUWFJFHSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3COCCC3)=O)C)C ABKGTFFKSJEJIQ-HXUWFJFHSA-N 0.000 claims description 4
- NJZBNLVCEXZHPD-LJQANCHMSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxolan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3COCC3)=O)C)C NJZBNLVCEXZHPD-LJQANCHMSA-N 0.000 claims description 4
- UAWYNAAMALKRLO-RTBURBONSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C)C UAWYNAAMALKRLO-RTBURBONSA-N 0.000 claims description 4
- UAWYNAAMALKRLO-OALUTQOASA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C)C UAWYNAAMALKRLO-OALUTQOASA-N 0.000 claims description 4
- YHUHZZWORFKBEO-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3COC3)=O)C)C YHUHZZWORFKBEO-UHFFFAOYSA-N 0.000 claims description 4
- MIWJHOLSRSWLAK-GOSISDBHSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@H]3COCCC3)=O)C)C MIWJHOLSRSWLAK-GOSISDBHSA-N 0.000 claims description 4
- UIARIXNNMVEXGS-HDICACEKSA-N CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C UIARIXNNMVEXGS-HDICACEKSA-N 0.000 claims description 4
- GCCDCEIIJOUYDQ-IYBDPMFKSA-N CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C GCCDCEIIJOUYDQ-IYBDPMFKSA-N 0.000 claims description 4
- WGCDXRFFSPQJBW-UHFFFAOYSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3COC3)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3COC3)=O)C)C WGCDXRFFSPQJBW-UHFFFAOYSA-N 0.000 claims description 4
- ABKGTFFKSJEJIQ-FQEVSTJZSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)C ABKGTFFKSJEJIQ-FQEVSTJZSA-N 0.000 claims description 4
- FDRMGIUKKYTDRK-KDURUIRLSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)O)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)O)=O)C)C FDRMGIUKKYTDRK-KDURUIRLSA-N 0.000 claims description 4
- JDAPKZUDSPQCGU-KDURUIRLSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)NC(N3[C@@H]3C[C@@H](C3)OC)=O)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)NC(N3[C@@H]3C[C@@H](C3)OC)=O)C JDAPKZUDSPQCGU-KDURUIRLSA-N 0.000 claims description 4
- OYVAXJFYSDAHQN-UHFFFAOYSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3CCOCC3)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3CCOCC3)=O)C)C OYVAXJFYSDAHQN-UHFFFAOYSA-N 0.000 claims description 4
- MIWJHOLSRSWLAK-SFHVURJKSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3COCCC3)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3COCCC3)=O)C)C MIWJHOLSRSWLAK-SFHVURJKSA-N 0.000 claims description 4
- ZOFXOZXMDBPIQF-HDICACEKSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C ZOFXOZXMDBPIQF-HDICACEKSA-N 0.000 claims description 4
- YEATVEYMKOCGIR-UHFFFAOYSA-N CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCC2)C2CCOCC2)=O Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCC2)C2CCOCC2)=O YEATVEYMKOCGIR-UHFFFAOYSA-N 0.000 claims description 4
- QPPQIPKYKRIZGK-UHFFFAOYSA-N CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)C2CCOCC2)=O Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)C2CCOCC2)=O QPPQIPKYKRIZGK-UHFFFAOYSA-N 0.000 claims description 4
- QSVMUHYIHOFSRB-QHCPKHFHSA-N CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)[C@@H]2COCCC2)=O Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)[C@@H]2COCCC2)=O QSVMUHYIHOFSRB-QHCPKHFHSA-N 0.000 claims description 4
- OPNZWUZVFPAJIO-SZPZYZBQSA-N CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O Chemical compound CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O OPNZWUZVFPAJIO-SZPZYZBQSA-N 0.000 claims description 4
- QBXNJMCSVGEQDI-ZRZAMGCNSA-N CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCCC2)C)=O Chemical compound CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCCC2)C)=O QBXNJMCSVGEQDI-ZRZAMGCNSA-N 0.000 claims description 4
- NLDJVYUQOPIMNA-KDURUIRLSA-N CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCNC)C)=O Chemical compound CO[C@H]1C[C@H](C1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCNC)C)=O NLDJVYUQOPIMNA-KDURUIRLSA-N 0.000 claims description 4
- OPVXIIKFNBQKCN-OYRHEFFESA-N CO[C@H]1C[C@H](C1)N1C(NC=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)=O Chemical compound CO[C@H]1C[C@H](C1)N1C(NC=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)=O OPVXIIKFNBQKCN-OYRHEFFESA-N 0.000 claims description 4
- UZJSWYAKTSRJGA-BGYRXZFFSA-N FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C=3C=NC(=CC3)OCCCN3CCCC3 Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C=3C=NC(=CC3)OCCCN3CCCC3 UZJSWYAKTSRJGA-BGYRXZFFSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 4
- QEJSKPORGMNWPI-UHFFFAOYSA-N N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C Chemical compound N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C QEJSKPORGMNWPI-UHFFFAOYSA-N 0.000 claims description 4
- PIGDKCHEKYYPIG-BGYRXZFFSA-N N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)O)=O)C Chemical compound N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)O)=O)C PIGDKCHEKYYPIG-BGYRXZFFSA-N 0.000 claims description 4
- HVCFZONVQJFMNR-OYRHEFFESA-N N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C Chemical compound N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C HVCFZONVQJFMNR-OYRHEFFESA-N 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 229960000908 idarubicin Drugs 0.000 claims description 4
- QEOJMXMERFKIIJ-DHIUTWEWSA-N 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CO[C@H]1C[C@@H](CC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O QEOJMXMERFKIIJ-DHIUTWEWSA-N 0.000 claims description 3
- QEOJMXMERFKIIJ-GOTSBHOMSA-N 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CO[C@@H]1C[C@H](CC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O QEOJMXMERFKIIJ-GOTSBHOMSA-N 0.000 claims description 3
- XBNPBSGEEQCUDU-UHFFFAOYSA-N 1-cyclobutyl-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound C1(CCC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCCC2)C)=O XBNPBSGEEQCUDU-UHFFFAOYSA-N 0.000 claims description 3
- VZIXHCCDQGAFCF-UHFFFAOYSA-N 1-cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound C1(CCC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C(=NC(=CC2)OCCCN(C)C)F)C)=O VZIXHCCDQGAFCF-UHFFFAOYSA-N 0.000 claims description 3
- QKORYAJYXMUUGT-UHFFFAOYSA-N 1-cyclobutyl-8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound C1(CCC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN(C)C)C)=O QKORYAJYXMUUGT-UHFFFAOYSA-N 0.000 claims description 3
- ZFNJITCOJTUEJF-UHFFFAOYSA-N 3-methyl-1-(oxetan-3-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)C2COC2)=O ZFNJITCOJTUEJF-UHFFFAOYSA-N 0.000 claims description 3
- DAFNHYUSSJGHDH-QFIPXVFZSA-N 3-methyl-1-[(3S)-oxolan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)[C@@H]2COCC2)=O DAFNHYUSSJGHDH-QFIPXVFZSA-N 0.000 claims description 3
- ARZGDKFYXFLWNZ-LJQANCHMSA-N 3-methyl-8-[6-[3-(methylamino)propoxy]pyridin-3-yl]-1-[(3R)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCNC)[C@H]2COCCC2)=O ARZGDKFYXFLWNZ-LJQANCHMSA-N 0.000 claims description 3
- XATUJGCUKAYZDO-NRFANRHFSA-N 7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3COCCC3)=O)C)C=3C=NC(=CC3)OCCCN3CCCCC3 XATUJGCUKAYZDO-NRFANRHFSA-N 0.000 claims description 3
- HXYXATRUGWSHIJ-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3COC3)=O)C)C HXYXATRUGWSHIJ-UHFFFAOYSA-N 0.000 claims description 3
- YEFCFNFQLXFZGI-QGZVFWFLSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxolan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3COCC3)=O)C)C YEFCFNFQLXFZGI-QGZVFWFLSA-N 0.000 claims description 3
- YEFCFNFQLXFZGI-KRWDZBQOSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxolan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCC3)=O)C)C YEFCFNFQLXFZGI-KRWDZBQOSA-N 0.000 claims description 3
- PMMBGQNKBPHEEE-INIZCTEOSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C(=N1)F)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3COCCC3)=O)C)C PMMBGQNKBPHEEE-INIZCTEOSA-N 0.000 claims description 3
- NJZBNLVCEXZHPD-IBGZPJMESA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-[(3S)-oxolan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCC3)=O)C)C NJZBNLVCEXZHPD-IBGZPJMESA-N 0.000 claims description 3
- ZUTMTQGPKVQWPJ-UHFFFAOYSA-N C1(CCC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O Chemical compound C1(CCC1)N1C(N(C=2C=NC=3C=CC(=CC3C21)C=2C=NC(=CC2)OCCCN2CCCC2)C)=O ZUTMTQGPKVQWPJ-UHFFFAOYSA-N 0.000 claims description 3
- MQEUUOSLBCMAPQ-FQEVSTJZSA-N FC1=NC(=CC=C1C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)OCCCN3CCCC3 Chemical compound FC1=NC(=CC=C1C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)OCCCN3CCCC3 MQEUUOSLBCMAPQ-FQEVSTJZSA-N 0.000 claims description 3
- DCYIRFHUZMQEJE-NRFANRHFSA-N N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C Chemical compound N1(CCC1)CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C DCYIRFHUZMQEJE-NRFANRHFSA-N 0.000 claims description 3
- DAFNHYUSSJGHDH-JOCHJYFZSA-N 3-methyl-1-[(3R)-oxolan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCCC2)[C@H]2COCC2)=O DAFNHYUSSJGHDH-JOCHJYFZSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 226
- 238000005481 NMR spectroscopy Methods 0.000 description 186
- 239000000203 mixture Substances 0.000 description 185
- 238000001819 mass spectrum Methods 0.000 description 180
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 177
- 239000000543 intermediate Substances 0.000 description 157
- 239000007787 solid Substances 0.000 description 133
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 125
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- 239000000463 material Substances 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 83
- 238000006243 chemical reaction Methods 0.000 description 79
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000001914 filtration Methods 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- XRKYMMUGXMWDAO-UHFFFAOYSA-N 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone Chemical compound O1C(C=2C=3SC4=CC=CC=C4SC=3C=CC=2)=CC(=O)C=C1N1CCOCC1 XRKYMMUGXMWDAO-UHFFFAOYSA-N 0.000 description 39
- 206010027476 Metastases Diseases 0.000 description 39
- 230000009401 metastasis Effects 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 239000012043 crude product Substances 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 34
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 32
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- 239000002953 phosphate buffered saline Substances 0.000 description 27
- 238000003556 assay Methods 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 238000007792 addition Methods 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 229940034982 antineoplastic agent Drugs 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 210000003169 central nervous system Anatomy 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- 201000010099 disease Diseases 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 208000037819 metastatic cancer Diseases 0.000 description 17
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 17
- 229960005419 nitrogen Drugs 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 14
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 239000012458 free base Substances 0.000 description 11
- 229910052738 indium Inorganic materials 0.000 description 11
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 102000020233 phosphotransferase Human genes 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000003643 water by type Substances 0.000 description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- 102000000872 ATM Human genes 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 8
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 8
- 125000001246 bromo group Chemical group Br* 0.000 description 8
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- YGMLKBFPHVLHGT-UHFFFAOYSA-N ethyl 6-bromo-4-chloroquinoline-3-carboxylate Chemical compound C1=CC(Br)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 YGMLKBFPHVLHGT-UHFFFAOYSA-N 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 8
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 229920000136 polysorbate Polymers 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- IQYPSFAWXDKDBA-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-c]quinolin-2-one Chemical compound C1=CC=CC2=C(NC(=O)N3)C3=CN=C21 IQYPSFAWXDKDBA-UHFFFAOYSA-N 0.000 description 7
- QKSSHCVHJAEALR-VXGBXAGGSA-N 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C QKSSHCVHJAEALR-VXGBXAGGSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 102000038030 PI3Ks Human genes 0.000 description 7
- 108091007960 PI3Ks Proteins 0.000 description 7
- 108091008611 Protein Kinase B Proteins 0.000 description 7
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 230000005782 double-strand break Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 229940098779 methanesulfonic acid Drugs 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 6
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 6
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 6
- 102100024148 [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Human genes 0.000 description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 6
- 229960004853 betadex Drugs 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- KGXQUPKOFCIFDQ-UHFFFAOYSA-N ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate Chemical compound C1=C(F)C(Br)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 KGXQUPKOFCIFDQ-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 6
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 5
- 238000004296 chiral HPLC Methods 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical group CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- QWJUJXPYTLOKRL-UHFFFAOYSA-N n,n-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine Chemical compound C1=NC(OCCCN(C)C)=CC=C1B1OC(C)(C)C(C)(C)O1 QWJUJXPYTLOKRL-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- DJXNJVFEFSWHLY-UHFFFAOYSA-M quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)[O-])=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-M 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 230000003442 weekly effect Effects 0.000 description 5
- 238000012447 xenograft mouse model Methods 0.000 description 5
- OJBYZWHAPXIJID-UHFFFAOYSA-N (6-fluoropyridin-3-yl)boronic acid Chemical compound OB(O)C1=CC=C(F)N=C1 OJBYZWHAPXIJID-UHFFFAOYSA-N 0.000 description 4
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 4
- YXJGKECEJNCEIH-JOCHJYFZSA-N 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCC2)[C@H]2COCCC2)=O YXJGKECEJNCEIH-JOCHJYFZSA-N 0.000 description 4
- CQLKKOGGXXBDFU-UHFFFAOYSA-N 6-bromo-4-chloroquinoline-3-carboxamide Chemical compound C1=CC(Br)=CC2=C(Cl)C(C(=O)N)=CN=C21 CQLKKOGGXXBDFU-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- BKZLJPUSHWSZEO-HZPDHXFCSA-N 8-(6-fluoropyridin-3-yl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound FC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C BKZLJPUSHWSZEO-HZPDHXFCSA-N 0.000 description 4
- KWVUSDFWDAXLLD-UHFFFAOYSA-N 8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound FC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C KWVUSDFWDAXLLD-UHFFFAOYSA-N 0.000 description 4
- QKSSHCVHJAEALR-RYUDHWBXSA-N 8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C QKSSHCVHJAEALR-RYUDHWBXSA-N 0.000 description 4
- OVSVYVIWPLAWJT-UHFFFAOYSA-N 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C OVSVYVIWPLAWJT-UHFFFAOYSA-N 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 206010014733 Endometrial cancer Diseases 0.000 description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 201000004101 esophageal cancer Diseases 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- NMQNMWRHFDSXBF-UHFFFAOYSA-N ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate Chemical compound BrC=1C=C2C(C(=CN(C2=CC1)CC1=CC=C(C=C1)OC)C(=O)OCC)=O NMQNMWRHFDSXBF-UHFFFAOYSA-N 0.000 description 4
- LMQDIXWMOUCVKZ-UHFFFAOYSA-N ethyl 6-bromo-7-fluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(F)C(Br)=CC2=C(O)C(C(=O)OCC)=CN=C21 LMQDIXWMOUCVKZ-UHFFFAOYSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000011368 organic material Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- BLTDCIWCFCUQCB-UHFFFAOYSA-N quinoline-3-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- NPVRFSSTNGPBEB-UHFFFAOYSA-N 3-methoxycyclobutan-1-amine;hydrochloride Chemical compound Cl.COC1CC(N)C1 NPVRFSSTNGPBEB-UHFFFAOYSA-N 0.000 description 3
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 3
- NIIITMUQTUBBKD-UHFFFAOYSA-N 4-methyl-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one Chemical compound CC1=NC=2C=CC=CC=2C2=C1NC(N2C1CCOCC1)=O NIIITMUQTUBBKD-UHFFFAOYSA-N 0.000 description 3
- LEGBISULKASFCD-UHFFFAOYSA-N 5-bromo-2-fluorobenzoyl chloride Chemical compound FC1=CC=C(Br)C=C1C(Cl)=O LEGBISULKASFCD-UHFFFAOYSA-N 0.000 description 3
- MYUQKYGWKHTRPG-UHFFFAOYSA-N 5-bromo-2-fluoropyridine Chemical compound FC1=CC=C(Br)C=N1 MYUQKYGWKHTRPG-UHFFFAOYSA-N 0.000 description 3
- QDDDNHBIMCLMHJ-GHMZBOCLSA-N 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)N[C@H]1C[C@@H](CC1)OC QDDDNHBIMCLMHJ-GHMZBOCLSA-N 0.000 description 3
- BKZLJPUSHWSZEO-HOTGVXAUSA-N 8-(6-fluoropyridin-3-yl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound FC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C BKZLJPUSHWSZEO-HOTGVXAUSA-N 0.000 description 3
- FYCCWDWJZSCVHF-UHFFFAOYSA-N 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3C3CCOCC3)=O FYCCWDWJZSCVHF-UHFFFAOYSA-N 0.000 description 3
- IRMRZEHRHZQHGZ-ZJUUUORDSA-N 8-bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@H]3C[C@H](CC3)OC)=O)C IRMRZEHRHZQHGZ-ZJUUUORDSA-N 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 3
- SGHUNIAWARINMU-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)NC1CCOCC1 Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)NC1CCOCC1 SGHUNIAWARINMU-UHFFFAOYSA-N 0.000 description 3
- GUKAOHNCEOKUBL-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)N)Cl Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)N)Cl GUKAOHNCEOKUBL-UHFFFAOYSA-N 0.000 description 3
- YXJGKECEJNCEIH-QFIPXVFZSA-N CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCC2)[C@@H]2COCCC2)=O Chemical compound CN1C(N(C2=C1C=NC=1C=CC(=CC21)C=2C=NC(=CC2)OCCCN2CCCC2)[C@@H]2COCCC2)=O YXJGKECEJNCEIH-QFIPXVFZSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 239000012391 XPhos Pd G2 Substances 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 101150113535 chek1 gene Proteins 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 239000008098 formaldehyde solution Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 210000002418 meninge Anatomy 0.000 description 3
- 239000003068 molecular probe Substances 0.000 description 3
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 229950008882 polysorbate Drugs 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 229940107700 pyruvic acid Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- PLRXAFVBCHEMGD-UHFFFAOYSA-N 3-piperidin-1-ylpropan-1-ol Chemical compound OCCCN1CCCCC1 PLRXAFVBCHEMGD-UHFFFAOYSA-N 0.000 description 2
- ZMJQROKRSPSLFH-UHFFFAOYSA-N 3-pyrrolidin-1-ylpropan-1-ol Chemical compound OCCCN1CCCC1 ZMJQROKRSPSLFH-UHFFFAOYSA-N 0.000 description 2
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 2
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- JBTIPAKRVUCURY-UHFFFAOYSA-N 4-methyloxan-4-amine;hydrochloride Chemical compound Cl.CC1(N)CCOCC1 JBTIPAKRVUCURY-UHFFFAOYSA-N 0.000 description 2
- PEXAZYDITWXYNJ-UHFFFAOYSA-N 5-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1F PEXAZYDITWXYNJ-UHFFFAOYSA-N 0.000 description 2
- SJXWFNBZBXZDCL-UHFFFAOYSA-N 5-bromo-6-fluoropyridin-2-amine Chemical compound NC1=CC=C(Br)C(F)=N1 SJXWFNBZBXZDCL-UHFFFAOYSA-N 0.000 description 2
- QDDDNHBIMCLMHJ-QWRGUYRKSA-N 6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound CO[C@H]1CC[C@@H](C1)NC1=C(C=NC2=CC=C(Br)C=C12)C(O)=O QDDDNHBIMCLMHJ-QWRGUYRKSA-N 0.000 description 2
- GIUZUAUCCUFVKW-UHFFFAOYSA-N 6-bromo-4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(=O)C(C(=O)O)=CNC2=C1 GIUZUAUCCUFVKW-UHFFFAOYSA-N 0.000 description 2
- RSHWETDVKCTHJA-RKDXNWHRSA-N 6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)O)N[C@H]1C[C@@H](CC1)OC RSHWETDVKCTHJA-RKDXNWHRSA-N 0.000 description 2
- XPDHCUKRZHVEJX-SFYZADRCSA-N 6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)O)N[C@H]1C[C@H](CC1)O XPDHCUKRZHVEJX-SFYZADRCSA-N 0.000 description 2
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- BUTWMVGTJQJKGT-ZDUSSCGKSA-N 8-(2,6-difluoropyridin-3-yl)-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound FC1=NC(=CC=C1C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C)F BUTWMVGTJQJKGT-ZDUSSCGKSA-N 0.000 description 2
- IRMRZEHRHZQHGZ-NXEZZACHSA-N 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@H]3C[C@@H](CC3)OC)=O)C IRMRZEHRHZQHGZ-NXEZZACHSA-N 0.000 description 2
- VGYFLWUPQAVKAZ-RKDXNWHRSA-N 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)NC(N3[C@H]3C[C@@H](CC3)OC)=O VGYFLWUPQAVKAZ-RKDXNWHRSA-N 0.000 description 2
- GZWMCKNWHDOXEX-JGVFFNPUSA-N 8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)NC(N3[C@@H]3C[C@@H](CC3)O)=O GZWMCKNWHDOXEX-JGVFFNPUSA-N 0.000 description 2
- IRMRZEHRHZQHGZ-VHSXEESVSA-N 8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](CC3)OC)=O)C IRMRZEHRHZQHGZ-VHSXEESVSA-N 0.000 description 2
- IRMRZEHRHZQHGZ-UWVGGRQHSA-N 8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@H](CC3)OC)=O)C IRMRZEHRHZQHGZ-UWVGGRQHSA-N 0.000 description 2
- 239000012827 ATM inhibitor Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- LZCCUGNCFSFVKS-NSHDSACASA-N BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3COCCC3)=O)C LZCCUGNCFSFVKS-NSHDSACASA-N 0.000 description 2
- SKFUTCCEGKGWHH-PHIMTYICSA-N BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C SKFUTCCEGKGWHH-PHIMTYICSA-N 0.000 description 2
- XXUOBAQBJJLVLY-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1)C(=O)Cl)Cl Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)Cl)Cl XXUOBAQBJJLVLY-UHFFFAOYSA-N 0.000 description 2
- TVLIRODQLQEDQC-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1)C(=O)N)NC1CCOCC1 Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)N)NC1CCOCC1 TVLIRODQLQEDQC-UHFFFAOYSA-N 0.000 description 2
- YETQBECFGDMUGT-UHFFFAOYSA-N BrC=1C=CC(=NC1F)OCCCN(C)C Chemical compound BrC=1C=CC(=NC1F)OCCCN(C)C YETQBECFGDMUGT-UHFFFAOYSA-N 0.000 description 2
- DWICJHMMZLNUEB-BGYRXZFFSA-N CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C DWICJHMMZLNUEB-BGYRXZFFSA-N 0.000 description 2
- IDDZARAHPKZZBW-UHFFFAOYSA-N CN1C2=CN=C3C=CC(=CC3=C2N(C1=O)C4=CC=CC5=C4OC6=CC=CC=C6C5)C7=CN=C(C=C7)OCCCN(C)C Chemical compound CN1C2=CN=C3C=CC(=CC3=C2N(C1=O)C4=CC=CC5=C4OC6=CC=CC=C6C5)C7=CN=C(C=C7)OCCCN(C)C IDDZARAHPKZZBW-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 230000012746 DNA damage checkpoint Effects 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011394 anticancer treatment Methods 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 125000005620 boronic acid group Chemical group 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- YIUXAFBVVPAGSH-UHFFFAOYSA-N diethyl 2-[(4-bromo-3-fluoroanilino)methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC=C(Br)C(F)=C1 YIUXAFBVVPAGSH-UHFFFAOYSA-N 0.000 description 2
- CZRWKFPNRGCSND-UHFFFAOYSA-N diethyl 2-[(4-bromoanilino)methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC=C(Br)C=C1 CZRWKFPNRGCSND-UHFFFAOYSA-N 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000005670 electromagnetic radiation Effects 0.000 description 2
- MVUMJYQUKKUOHO-AATRIKPKSA-N ethyl (e)-3-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)\C=C\N(C)C MVUMJYQUKKUOHO-AATRIKPKSA-N 0.000 description 2
- VWBVYAGWTIBFKX-UHFFFAOYSA-N ethyl 6-bromo-4-[(3-methoxycyclobutyl)amino]quinoline-3-carboxylate Chemical compound CCOC(=O)c1cnc2ccc(Br)cc2c1NC1CC(C1)OC VWBVYAGWTIBFKX-UHFFFAOYSA-N 0.000 description 2
- GEIVRQFUMMHZPQ-CHWSQXEVSA-N ethyl 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)OCC)N[C@H]1C[C@@H](CC1)OC GEIVRQFUMMHZPQ-CHWSQXEVSA-N 0.000 description 2
- CQYPUVDNHVYWMX-LLVKDONJSA-N ethyl 6-bromo-4-[[(3R)-oxolan-3-yl]amino]quinoline-3-carboxylate Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)OCC)N[C@H]1COCC1 CQYPUVDNHVYWMX-LLVKDONJSA-N 0.000 description 2
- IVZIOBTVAJBBAS-UHFFFAOYSA-N ethyl 6-bromo-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(Br)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 IVZIOBTVAJBBAS-UHFFFAOYSA-N 0.000 description 2
- UIILZOONRMHJFL-GHMZBOCLSA-N ethyl 6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)OCC)N[C@H]1C[C@@H](CC1)OC UIILZOONRMHJFL-GHMZBOCLSA-N 0.000 description 2
- DXKQPUSAHIKZSJ-ZJUUUORDSA-N ethyl 6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate Chemical compound CCOC(=O)C1=C(N[C@@H]2CC[C@H](O)C2)C2=CC(Br)=C(F)C=C2N=C1 DXKQPUSAHIKZSJ-ZJUUUORDSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 150000003840 hydrochlorides Chemical group 0.000 description 2
- 239000002596 immunotoxin Substances 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- RDELIYPIRSMXOH-UHFFFAOYSA-N methyl 3-(azetidin-1-yl)propanoate Chemical compound COC(=O)CCN1CCC1 RDELIYPIRSMXOH-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 229910021421 monocrystalline silicon Inorganic materials 0.000 description 2
- 230000000683 nonmetastatic effect Effects 0.000 description 2
- 238000012758 nuclear staining Methods 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 229920002113 octoxynol Polymers 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940076788 pyruvate Drugs 0.000 description 2
- UTOMICFLROGMAE-UHFFFAOYSA-N quinoline-3,4-diamine Chemical compound C1=CC=CC2=C(N)C(N)=CN=C21 UTOMICFLROGMAE-UHFFFAOYSA-N 0.000 description 2
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000028617 response to DNA damage stimulus Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RPXMEBXMNZWQAN-UHFFFAOYSA-N tert-butyl 8-bromo-1-(oxan-4-yl)-2-oxoimidazo[4,5-c]quinoline-3-carboxylate Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C(=O)OC(C)(C)C RPXMEBXMNZWQAN-UHFFFAOYSA-N 0.000 description 2
- GJGLBUZZTLPCOT-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)-n-methylcarbamate Chemical compound OCCCN(C)C(=O)OC(C)(C)C GJGLBUZZTLPCOT-UHFFFAOYSA-N 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- SGKRJNWIEGYWGE-UYXJWNHNSA-N (1r,3s)-3-aminocyclopentan-1-ol;hydrochloride Chemical compound Cl.N[C@H]1CC[C@@H](O)C1 SGKRJNWIEGYWGE-UYXJWNHNSA-N 0.000 description 1
- BVILPGWUKJERFN-WDSKDSINSA-N (1s,3s)-3-methoxycyclopentan-1-amine Chemical compound CO[C@H]1CC[C@H](N)C1 BVILPGWUKJERFN-WDSKDSINSA-N 0.000 description 1
- MIPHRQMEIYLZFZ-SCSAIBSYSA-N (3r)-oxolan-3-amine Chemical compound N[C@@H]1CCOC1 MIPHRQMEIYLZFZ-SCSAIBSYSA-N 0.000 description 1
- FRXOYYBDUSFAGK-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane Chemical compound ClN1CN(Cl)CN(Cl)C1 FRXOYYBDUSFAGK-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- OQOWSXVZUCZHFN-UHFFFAOYSA-N 2-[3-(azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound N1(CCC1)CCCOC1=NC=C(C=C1)B1OC(C(O1)(C)C)(C)C OQOWSXVZUCZHFN-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- DERAACKMMNJAFU-UHFFFAOYSA-N 2-ethoxy-1,3-dioxane-4,6-dione Chemical compound CCOC1OC(=O)CC(=O)O1 DERAACKMMNJAFU-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- NDZCQLBVBUYBKW-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)oxy-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCOC1=CC=C(Br)C=N1 NDZCQLBVBUYBKW-UHFFFAOYSA-N 0.000 description 1
- FUEPSWDWSHCZHJ-UHFFFAOYSA-N 3-(azetidin-1-yl)propan-1-ol Chemical compound OCCCN1CCC1 FUEPSWDWSHCZHJ-UHFFFAOYSA-N 0.000 description 1
- CGWOEOXQHIMZEQ-UHFFFAOYSA-N 3-[1-[[4-(2-phenylquinolin-3-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound OC1=NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=CC2=CC=CC=C2N=C1C1=CC=CC=C1 CGWOEOXQHIMZEQ-UHFFFAOYSA-N 0.000 description 1
- JPNPRWMRUCIEMN-UHFFFAOYSA-N 3-ditert-butylphosphaniumylpropane-1-sulfonate Chemical compound CC(C)(C)P(C(C)(C)C)CCCS(O)(=O)=O JPNPRWMRUCIEMN-UHFFFAOYSA-N 0.000 description 1
- RUGQXUQYHJUGMD-UHFFFAOYSA-N 3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(N(C2=C1C=NC=1C=CC=CC2=1)C1CCOCC1)=O RUGQXUQYHJUGMD-UHFFFAOYSA-N 0.000 description 1
- GANLNLJAWMPXIT-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propoxy-1,3,2-dioxaborolane Chemical compound CCCOB1OC(C)(C)C(C)(C)O1 GANLNLJAWMPXIT-UHFFFAOYSA-N 0.000 description 1
- YTMVYYAKOPIJCZ-UHFFFAOYSA-N 4-bromo-3-fluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1 YTMVYYAKOPIJCZ-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- YHQDZJICGQWFHK-UHFFFAOYSA-N 4-nitroquinoline N-oxide Chemical compound C1=CC=C2C([N+](=O)[O-])=CC=[N+]([O-])C2=C1 YHQDZJICGQWFHK-UHFFFAOYSA-N 0.000 description 1
- UHBDJKZMWZAFTC-SECBINFHSA-N 6-bromo-4-[[(3R)-oxolan-3-yl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)N[C@H]1COCC1 UHBDJKZMWZAFTC-SECBINFHSA-N 0.000 description 1
- KHKPVEMMXJCWGP-UHFFFAOYSA-N 6-bromo-4-chloro-3-nitroquinoline Chemical compound C1=CC(Br)=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 KHKPVEMMXJCWGP-UHFFFAOYSA-N 0.000 description 1
- IAWVWGGVXZPWRQ-UHFFFAOYSA-N 6-bromo-4-chloro-7-fluoro-3-nitroquinoline Chemical compound C1=C(F)C(Br)=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 IAWVWGGVXZPWRQ-UHFFFAOYSA-N 0.000 description 1
- XPDHCUKRZHVEJX-JGVFFNPUSA-N 6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)O)N[C@@H]1C[C@@H](CC1)O XPDHCUKRZHVEJX-JGVFFNPUSA-N 0.000 description 1
- RSHWETDVKCTHJA-IUCAKERBSA-N 6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)O)N[C@@H]1C[C@H](CC1)OC RSHWETDVKCTHJA-IUCAKERBSA-N 0.000 description 1
- DKEBKYIGCXIPCG-RYUDHWBXSA-N 6-bromo-N-[(1S,3S)-3-methoxycyclopentyl]quinolin-4-amine Chemical compound BrC=1C=C2C(=CC=NC2=CC=1)N[C@@H]1C[C@H](CC1)OC DKEBKYIGCXIPCG-RYUDHWBXSA-N 0.000 description 1
- UZALKVXCOUSWSL-UHFFFAOYSA-N 6-fluoropyridin-2-amine Chemical compound NC1=CC=CC(F)=N1 UZALKVXCOUSWSL-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- IJNIRMWVECLJOY-HXUWFJFHSA-N 7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@H]3COCCC3)=O)C)C=3C=NC(=CC3)OCCCN3CCCC3 IJNIRMWVECLJOY-HXUWFJFHSA-N 0.000 description 1
- UDEKZUNTEBAJOV-ZDUSSCGKSA-N 7-fluoro-8-(6-fluoropyridin-3-yl)-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3COCCC3)=O)C)C=3C=NC(=CC3)F UDEKZUNTEBAJOV-ZDUSSCGKSA-N 0.000 description 1
- SKTWHGGZPLFIOO-NTISSMGPSA-N 8-[6-[3-(dimethylamino)propoxy]-2-fluoropyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one methanesulfonic acid Chemical compound CS(O)(=O)=O.CN(C)CCCOc1ccc(c(F)n1)-c1cc2c3n([C@H]4CCCOC4)c(=O)n(C)c3cnc2cc1F SKTWHGGZPLFIOO-NTISSMGPSA-N 0.000 description 1
- UAWYNAAMALKRLO-MOPGFXCFSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@H]3C[C@H](CC3)OC)=O)C)C UAWYNAAMALKRLO-MOPGFXCFSA-N 0.000 description 1
- UAWYNAAMALKRLO-RBUKOAKNSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3C[C@@H](CC3)OC)=O)C)C UAWYNAAMALKRLO-RBUKOAKNSA-N 0.000 description 1
- BGRYKXFVNMBRKQ-UHFFFAOYSA-N 8-bromo-1-(4-methyloxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3C3(CCOCC3)C)=O BGRYKXFVNMBRKQ-UHFFFAOYSA-N 0.000 description 1
- UWKKMAJFOUCTIO-UHFFFAOYSA-N 8-bromo-1-(oxetan-3-yl)-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3C3COC3)=O UWKKMAJFOUCTIO-UHFFFAOYSA-N 0.000 description 1
- ISEXRHWDQIZQJJ-GHMZBOCLSA-N 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3[C@H]3C[C@@H](CC3)OC)=O ISEXRHWDQIZQJJ-GHMZBOCLSA-N 0.000 description 1
- ISEXRHWDQIZQJJ-QWRGUYRKSA-N 8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3[C@@H]3C[C@H](CC3)OC)=O ISEXRHWDQIZQJJ-QWRGUYRKSA-N 0.000 description 1
- SCNYRYYANZOKBI-SECBINFHSA-N 8-bromo-1-[(3R)-oxolan-3-yl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3[C@H]3COCC3)=O SCNYRYYANZOKBI-SECBINFHSA-N 0.000 description 1
- LRYQHJDNCVRJKE-UHFFFAOYSA-N 8-bromo-3-methyl-1-(4-methyloxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)N(C(N3C3(CCOCC3)C)=O)C LRYQHJDNCVRJKE-UHFFFAOYSA-N 0.000 description 1
- CCGMZEHMTXFVGN-SNVBAGLBSA-N 8-bromo-3-methyl-1-[(3R)-oxolan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound CN1C(=O)N([C@@H]2CCOC2)C2=C1C=NC1=CC=C(Br)C=C21 CCGMZEHMTXFVGN-SNVBAGLBSA-N 0.000 description 1
- IGTMGMLDBXYHFS-GHMZBOCLSA-N 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-2H-imidazo[4,5-c]quinoline Chemical compound BrC1=CC=2C3=C(C=NC=2C=C1F)N(CN3[C@H]1C[C@@H](CC1)OC)C IGTMGMLDBXYHFS-GHMZBOCLSA-N 0.000 description 1
- GZWMCKNWHDOXEX-SFYZADRCSA-N 8-bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)NC(N3[C@H]3C[C@H](CC3)O)=O GZWMCKNWHDOXEX-SFYZADRCSA-N 0.000 description 1
- VGYFLWUPQAVKAZ-IUCAKERBSA-N 8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)NC(N3[C@@H]3C[C@H](CC3)OC)=O VGYFLWUPQAVKAZ-IUCAKERBSA-N 0.000 description 1
- BQDPPVHJMJEOBU-UHFFFAOYSA-N 8-bromo-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3(CCOCC3)C)=O)C BQDPPVHJMJEOBU-UHFFFAOYSA-N 0.000 description 1
- DLMXCRMQPUPMDG-VIFPVBQESA-N 8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[4,5-c]quinolin-2-one Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3[C@@H]3COCCC3)=O)C DLMXCRMQPUPMDG-VIFPVBQESA-N 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 102000009840 Angiopoietins Human genes 0.000 description 1
- 108010009906 Angiopoietins Proteins 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 101100297694 Arabidopsis thaliana PIP2-7 gene Proteins 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- RDWSKHOSKGCRJD-AOOOYVTPSA-N BrC1=CC=2C3=C(C=NC2C=C1)NC(N3[C@@H]3C[C@@H](C3)OC)=O Chemical compound BrC1=CC=2C3=C(C=NC2C=C1)NC(N3[C@@H]3C[C@@H](C3)OC)=O RDWSKHOSKGCRJD-AOOOYVTPSA-N 0.000 description 1
- LKGZXIKRWHYSQL-UHFFFAOYSA-N BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3CCOCC3)=O)C Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)N(C(N3C3CCOCC3)=O)C LKGZXIKRWHYSQL-UHFFFAOYSA-N 0.000 description 1
- JOIWOVRBFLCDPM-BDAKNGLRSA-N BrC1=CC=2C3=C(C=NC2C=C1F)NCN3[C@H]3C[C@H](CC3)O Chemical compound BrC1=CC=2C3=C(C=NC2C=C1F)NCN3[C@H]3C[C@H](CC3)O JOIWOVRBFLCDPM-BDAKNGLRSA-N 0.000 description 1
- TWUOMAYLSCLNLO-AOOOYVTPSA-N BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)N[C@@H]1C[C@@H](C1)OC Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)O)N[C@@H]1C[C@@H](C1)OC TWUOMAYLSCLNLO-AOOOYVTPSA-N 0.000 description 1
- GHQANGDJRQTHKF-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1)C(=O)OCC)NC1CCOCC1 Chemical compound BrC=1C=C2C(=C(C=NC2=CC1)C(=O)OCC)NC1CCOCC1 GHQANGDJRQTHKF-UHFFFAOYSA-N 0.000 description 1
- OBUSEQKWCMKBTR-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC1F)[N+](=O)[O-])NC1(CCOCC1)C Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)[N+](=O)[O-])NC1(CCOCC1)C OBUSEQKWCMKBTR-UHFFFAOYSA-N 0.000 description 1
- KTVIAHKRBVIUKU-UHFFFAOYSA-N BrC=1C=C2C(C(=CNC2=CC1F)C(=O)O)=O Chemical compound BrC=1C=C2C(C(=CNC2=CC1F)C(=O)O)=O KTVIAHKRBVIUKU-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- LBQHZEWQZXNZIL-UHFFFAOYSA-N C(C)(C)(C)P(C(C)(C)C)C(CC)S(=O)(=O)O Chemical compound C(C)(C)(C)P(C(C)(C)C)C(CC)S(=O)(=O)O LBQHZEWQZXNZIL-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 102100031065 Choline kinase alpha Human genes 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- CETDGUOMNOLFGB-UHFFFAOYSA-N Cl.COC1(CCCC1)N Chemical compound Cl.COC1(CCCC1)N CETDGUOMNOLFGB-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000008265 DNA repair mechanism Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 1
- 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 101100481404 Danio rerio tie1 gene Proteins 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- ICXMATZTKVIKBW-GASCZTMLSA-N FC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C Chemical compound FC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C ICXMATZTKVIKBW-GASCZTMLSA-N 0.000 description 1
- GIILAJNJVXXLPI-BETUJISGSA-N FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C=3C=NC(=CC3)F Chemical compound FC=1C(=CC=2C3=C(C=NC2C1)N(C(N3[C@@H]3C[C@@H](C3)OC)=O)C)C=3C=NC(=CC3)F GIILAJNJVXXLPI-BETUJISGSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000621390 Homo sapiens Wee1-like protein kinase Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 240000008415 Lactuca sativa Species 0.000 description 1
- 235000003228 Lactuca sativa Nutrition 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 101100481406 Mus musculus Tie1 gene Proteins 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 101150062285 PGF gene Proteins 0.000 description 1
- 229940125520 PI3Kβ inhibitor Drugs 0.000 description 1
- 101150037263 PIP2 gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102100035194 Placenta growth factor Human genes 0.000 description 1
- 108030005449 Polo kinases Proteins 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102000046941 Rapamycin-Insensitive Companion of mTOR Human genes 0.000 description 1
- 108700019586 Rapamycin-Insensitive Companion of mTOR Proteins 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 101100456541 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MEC3 gene Proteins 0.000 description 1
- 101100262439 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UBA2 gene Proteins 0.000 description 1
- 101100483663 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UFD1 gene Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100023921 Serine/threonine-protein kinase ATR Human genes 0.000 description 1
- 101710178061 Serine/threonine-protein kinase ATR Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 108010060825 Toll-Like Receptor 7 Proteins 0.000 description 1
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 102100023037 Wee1-like protein kinase Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- VOCGXOGLPNJLKT-UHFFFAOYSA-N [In+2] Chemical compound [In+2] VOCGXOGLPNJLKT-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 101150045355 akt1 gene Proteins 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical compound C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000011243 body radiation therapy Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 208000014581 breast ductal adenocarcinoma Diseases 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 238000013481 data capture Methods 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 108700020302 erbB-2 Genes Proteins 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- DWXQUAHMZWZXHP-UHFFFAOYSA-N ethyl 4-chloroquinoline-3-carboxylate Chemical compound C1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 DWXQUAHMZWZXHP-UHFFFAOYSA-N 0.000 description 1
- UIILZOONRMHJFL-QWRGUYRKSA-N ethyl 6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate Chemical compound BrC=1C=C2C(=C(C=NC2=CC1F)C(=O)OCC)N[C@@H]1C[C@H](CC1)OC UIILZOONRMHJFL-QWRGUYRKSA-N 0.000 description 1
- OTTDACPMYLDVTL-UHFFFAOYSA-N ethyl quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)OCC)=CN=C21 OTTDACPMYLDVTL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000011347 external beam therapy Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- ODLHGICHYURWBS-FOSILIAISA-N molport-023-220-444 Chemical compound CC(O)COC[C@@H]([C@@H]([C@H]([C@@H]1O)O)O[C@@H]2O[C@H]([C@H](O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O3)[C@@H](O)[C@@H]2O)COCC(O)C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@H]3O[C@H]1COCC(C)O ODLHGICHYURWBS-FOSILIAISA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- ABKQFSYGIHQQLS-UHFFFAOYSA-J sodium tetrachloropalladate Chemical compound [Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl ABKQFSYGIHQQLS-UHFFFAOYSA-J 0.000 description 1
- GFWRVVCDTLRWPK-KPKJPENVSA-N sofalcone Chemical compound C1=CC(OCC=C(C)C)=CC=C1\C=C\C(=O)C1=CC=C(OCC=C(C)C)C=C1OCC(O)=O GFWRVVCDTLRWPK-KPKJPENVSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- 229940006509 strontium-89 Drugs 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461990232P | 2014-05-08 | 2014-05-08 | |
| US61/990,232 | 2014-05-08 | ||
| PCT/GB2015/051312 WO2015170081A1 (en) | 2014-05-08 | 2015-05-05 | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017514877A JP2017514877A (ja) | 2017-06-08 |
| JP2017514877A5 JP2017514877A5 (enExample) | 2018-06-14 |
| JP6505131B2 true JP6505131B2 (ja) | 2019-04-24 |
Family
ID=53264681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016567002A Active JP6505131B2 (ja) | 2014-05-08 | 2015-05-05 | イミダゾ［４，５−ｃ］キノリン−２−オン化合物および癌の処置におけるそれらの使用 |
Country Status (39)
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE045477T2 (hu) * | 2015-04-02 | 2019-12-30 | Merck Patent Gmbh | Imidazolonilkinolinok és ezek alkalmazása ATM kináz inhibitorként |
| GB201516504D0 (en) * | 2015-09-17 | 2015-11-04 | Astrazeneca Ab | Imadazo(4,5-c)quinolin-2-one Compounds and their use in treating cancer |
| GB201519406D0 (en) * | 2015-11-03 | 2015-12-16 | Astrazeneca Ab | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
| GB201519568D0 (en) * | 2015-11-05 | 2015-12-23 | Astrazeneca Ab | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
| KR102830910B1 (ko) * | 2016-02-15 | 2025-07-04 | 아스트라제네카 에이비이 | 세디라닙의 고정된 간헐적 투약을 포함하는 방법 |
| PE20181895A1 (es) * | 2016-03-21 | 2018-12-11 | Astrazeneca Ab | Compuestos de cinnolin-4-amina y su uso en el tratamiento del cancer |
| US20190119270A1 (en) * | 2016-04-07 | 2019-04-25 | Astrazeneca Ab | N-Oxide Compound and Its Use in Treating Cancer |
| GB201608227D0 (en) * | 2016-05-11 | 2016-06-22 | Astrazeneca Ab | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
| JOP20190151B1 (ar) | 2016-12-20 | 2023-09-17 | Astrazeneca Ab | مركبات أمينو - ترايازولو بيريدين واستخدامها في علاج سرطان |
| JP7247092B2 (ja) * | 2017-01-09 | 2023-03-28 | 上海瑛派▲薬▼▲業▼有限公司 | キナーゼ阻害剤としての置換された縮合ヘテロアリール化合物及びその用途 |
| CN106798741A (zh) * | 2017-02-07 | 2017-06-06 | 宫英 | 一种治疗抑郁症的药物组合物 |
| CN106692147A (zh) * | 2017-02-07 | 2017-05-24 | 李明英 | 一种治疗男性不育的药物组合物 |
| CN106822123A (zh) * | 2017-02-09 | 2017-06-13 | 王艳苓 | 一种治疗心脑血管疾病的药物组合物 |
| US11547703B2 (en) | 2017-02-27 | 2023-01-10 | Impact Therapeutics (Shanghai), Inc | Substituted fused heteroaromatic tricyclic compounds as kinase inhibitors and the use thereof |
| JOP20190209A1 (ar) * | 2017-03-16 | 2019-09-12 | Astrazeneca Ab | مركبات إيميدازو [ 4، 5-c ] كينولين-2-أون ديوترومية واستخدامها في علاج السرطان |
| WO2019057757A1 (en) | 2017-09-20 | 2019-03-28 | Astrazeneca Ab | 1,3-DIHYDROIMIDAZO [4,5-C] CINNOLIN-2-ONE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CANCER |
| CN110386932A (zh) | 2018-04-20 | 2019-10-29 | 艾科思莱德制药公司 | 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂 |
| WO2019201283A1 (en) * | 2018-04-20 | 2019-10-24 | Xrad Therapeutics, Inc. | Dual atm and dna-pk inhibitors for use in anti-tumor therapy |
| CA3111994A1 (en) * | 2018-09-14 | 2020-03-19 | Suzhou Zanrong Pharma Limited | 1-isopropyl-3-methyl-8-(pyridin-3-yl)-1,3-dihydro-2h-imidazo[4,5-c]cinnolin-2-one as selective modulators of ataxia telangiectasia mutated (atm) kinase and uses thereof |
| CN113164447A (zh) * | 2018-10-15 | 2021-07-23 | 默克专利股份公司 | 利用dna烷化剂和atr抑制剂的组合疗法 |
| JP7453989B2 (ja) * | 2019-03-05 | 2024-03-21 | アストラゼネカ・アクチエボラーグ | 抗癌剤として有用な縮合三環式化合物 |
| TW202102497A (zh) * | 2019-03-29 | 2021-01-16 | 瑞典商阿斯特捷利康公司 | 化合物及它們在治療癌症中之用途 |
| CN111909147B (zh) * | 2019-05-10 | 2021-07-20 | 山东轩竹医药科技有限公司 | Dna-pk抑制剂 |
| CN114026097B (zh) * | 2019-07-10 | 2024-02-23 | 上海瑛派药业有限公司 | 取代的吡唑并喹唑啉酮化合物及其应用 |
| KR20220062003A (ko) * | 2019-09-12 | 2022-05-13 | 임팩트 테라퓨틱스 (상하이), 인코포레이티드 | 치환된 이미다조퀴녹살린 화합물 및 이의 용도 |
| CN115003672A (zh) * | 2020-01-09 | 2022-09-02 | 南京明德新药研发有限公司 | 喹啉并咪唑类化合物及其应用 |
| US20230087844A1 (en) * | 2020-01-13 | 2023-03-23 | Shanghai Huayu Biotechnology Co., Ltd. | Use of n2-quincline or isoquinoline substituted purine derivatives in cancer treatment |
| JP2023539715A (ja) * | 2020-06-24 | 2023-09-19 | アストラゼネカ ユーケー リミテッド | 抗体－薬物コンジュゲートとａｔｍ阻害剤との組合わせ |
| EP3992191A1 (en) | 2020-11-03 | 2022-05-04 | Deutsches Krebsforschungszentrum | Imidazo[4,5-c]quinoline compounds and their use as atm kinase inhibitors |
| CN117015534A (zh) * | 2021-02-03 | 2023-11-07 | 艾科思莱德制药公司 | 用于癌症疗法的双重atm和dna-pk抑制剂以及免疫治疗剂的组合 |
| WO2022193166A1 (en) * | 2021-03-17 | 2022-09-22 | Suzhou Zanrong Pharma Limited | Selective modulators of ataxia telangiectasia mutated (atm) kinase and uses thereof |
| TW202340189A (zh) * | 2022-01-26 | 2023-10-16 | 大陸商正大天晴藥業集團股份有限公司 | 含有肼基的化合物 |
| CN121038817A (zh) | 2023-04-10 | 2025-11-28 | 第一三共株式会社 | 抗-b7-h3抗体-药物缀合物和atr抑制剂或atm抑制剂的组合 |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0211649D0 (en) * | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
| BRPI0416801A (pt) | 2003-11-21 | 2007-01-09 | Novartis Ag | derivados de 1h-imidazoquinolina como inibidores de proteìna sinase |
| GB0510390D0 (en) * | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| PE20090717A1 (es) * | 2007-05-18 | 2009-07-18 | Smithkline Beecham Corp | Derivados de quinolina como inhibidores de la pi3 quinasa |
| MX2010014559A (es) | 2008-07-01 | 2011-03-04 | Genentech Inc | Heterociclos bicíclicos sustituidos y metodos de uso. |
| EP2356120B1 (en) | 2008-09-30 | 2016-10-12 | Pfizer Inc. | Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions |
| TW201041888A (en) * | 2009-05-06 | 2010-12-01 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| WO2010139747A1 (en) * | 2009-06-04 | 2010-12-09 | Novartis Ag | 1H-IMIDAZO[4, 5-c]QUINOLINONE COMPOUNDS, USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
| EP2438064A1 (en) | 2009-06-04 | 2012-04-11 | Novartis AG | 1H-IMIDAZO[4,5-c]QUINOLINONE DERIVATIVES |
| JP5546636B2 (ja) * | 2009-09-28 | 2014-07-09 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | ベンゾキセピンｐｉ３ｋ阻害剤化合物及び使用方法 |
| GB0919423D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
| CN102199152A (zh) | 2010-03-25 | 2011-09-28 | 高大新 | 杂环咪唑类磷脂激酶抑制剂 |
| CN102372711B (zh) * | 2010-08-18 | 2014-09-17 | 山东轩竹医药科技有限公司 | 咪唑并喹啉类PI3K和mTOR双重抑制剂 |
| WO2012026233A1 (ja) | 2010-08-26 | 2012-03-01 | 日立建機株式会社 | 建設機械 |
| DE102010035744A1 (de) | 2010-08-28 | 2012-03-01 | Merck Patent Gmbh | Imidazolonylchinoline |
| CN102399218A (zh) * | 2010-09-16 | 2012-04-04 | 和记黄埔医药（上海）有限公司 | 一类并合三杂环及其作为pi3k抑制剂的用途 |
| TW201307340A (zh) | 2010-12-06 | 2013-02-16 | Piramal Life Sciences Ltd | 取代咪唑并喹啉衍生物 |
| WO2012138789A2 (en) | 2011-04-04 | 2012-10-11 | Netherlands Cancer Institute | Methods and compositions for predicting resistance to anticancer treatment |
| JP6042060B2 (ja) * | 2011-09-26 | 2016-12-14 | サノフイ | ピラゾロキノリノン誘導体、その調製および治療上の使用 |
-
2012
- 2012-05-25 NO NO12793015A patent/NO2714752T3/no unknown
-
2015
- 2015-05-05 CR CR20160523A patent/CR20160523A/es unknown
- 2015-05-05 KR KR1020167034005A patent/KR102013021B1/ko active Active
- 2015-05-05 WO PCT/GB2015/051312 patent/WO2015170081A1/en not_active Ceased
- 2015-05-05 SI SI201530247T patent/SI3140303T1/en unknown
- 2015-05-05 SG SG11201609164VA patent/SG11201609164VA/en unknown
- 2015-05-05 TN TN2016000458A patent/TN2016000458A1/en unknown
- 2015-05-05 AU AU2015257456A patent/AU2015257456B2/en active Active
- 2015-05-05 MX MX2016014639A patent/MX374401B/es active IP Right Grant
- 2015-05-05 HU HUE15724351A patent/HUE037558T2/hu unknown
- 2015-05-05 CA CA2946459A patent/CA2946459C/en active Active
- 2015-05-05 EA EA201692095A patent/EA031674B1/ru not_active IP Right Cessation
- 2015-05-05 SM SM20180259T patent/SMT201800259T1/it unknown
- 2015-05-05 PE PE2016002124A patent/PE20170403A1/es unknown
- 2015-05-05 LT LTEP15724351.0T patent/LT3140303T/lt unknown
- 2015-05-05 NZ NZ726042A patent/NZ726042A/en not_active IP Right Cessation
- 2015-05-05 PT PT157243510T patent/PT3140303T/pt unknown
- 2015-05-05 ES ES15724351.0T patent/ES2670416T3/es active Active
- 2015-05-05 TR TR2018/07101T patent/TR201807101T4/tr unknown
- 2015-05-05 HR HRP20180697TT patent/HRP20180697T1/hr unknown
- 2015-05-05 CN CN201580022454.1A patent/CN106255692B/zh active Active
- 2015-05-05 US US14/704,031 patent/US9428503B2/en active Active
- 2015-05-05 JP JP2016567002A patent/JP6505131B2/ja active Active
- 2015-05-05 RS RS20180593A patent/RS57223B1/sr unknown
- 2015-05-05 EP EP15724351.0A patent/EP3140303B1/en active Active
- 2015-05-05 DK DK15724351.0T patent/DK3140303T3/en active
- 2015-05-05 PL PL15724351T patent/PL3140303T3/pl unknown
- 2015-05-05 MA MA039960A patent/MA39960A/fr unknown
- 2015-05-05 AP AP2016009532A patent/AP2016009532A0/en unknown
- 2015-05-06 UY UY0001036112A patent/UY36112A/es not_active Application Discontinuation
- 2015-05-07 AR ARP150101395A patent/AR100340A1/es not_active Application Discontinuation
- 2015-05-08 TW TW104114814A patent/TWI662034B/zh active
-
2016
- 2016-07-22 US US15/217,079 patent/US9822111B2/en active Active
- 2016-10-19 IL IL248397A patent/IL248397B/en active IP Right Grant
- 2016-10-19 DO DO2016000281A patent/DOP2016000281A/es unknown
- 2016-10-27 CL CL2016002735A patent/CL2016002735A1/es unknown
- 2016-11-02 PH PH12016502168A patent/PH12016502168A1/en unknown
- 2016-11-04 NI NI201600166A patent/NI201600166A/es unknown
- 2016-11-08 SV SV2016005312A patent/SV2016005312A/es unknown
-
2017
- 2017-10-17 US US15/785,974 patent/US10189834B2/en active Active
-
2018
- 2018-05-22 CY CY20181100532T patent/CY1120248T1/el unknown
- 2018-12-12 US US16/217,190 patent/US20190185468A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6505131B2 (ja) | イミダゾ［４，５−ｃ］キノリン−２−オン化合物および癌の処置におけるそれらの使用 | |
| US11613539B2 (en) | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer | |
| AU2016348620B2 (en) | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer | |
| KR20180070703A (ko) | 이미다조[4,5-c]퀴놀린-2-온 화합물 및 암 치료에서의 이의 용도 | |
| JP2018531226A6 (ja) | 癌の治療のための血管拡張性失調症変異（ａｔｍ）キナーゼの選択的モジュレーターとしての８−［６−［３−（アミノ）プロポキシ］−３−ピリジル］−１−イソプロピル−イミダゾ［４，５−ｃ］キノリン−２−オン誘導体 | |
| BR112016025153B1 (pt) | "compostos de imidazo[4,5-c]quinolin-2-ona, composição farmaceutica e seu uso no tratamento de câncer | |
| HK1232528B (en) | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer | |
| HK1232528A1 (en) | Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180502 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180502 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190117 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190205 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190225 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190312 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190326 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6505131 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |