JP5891576B2 - 新規フラノン誘導体 - Google Patents
新規フラノン誘導体 Download PDFInfo
- Publication number
- JP5891576B2 JP5891576B2 JP2014219074A JP2014219074A JP5891576B2 JP 5891576 B2 JP5891576 B2 JP 5891576B2 JP 2014219074 A JP2014219074 A JP 2014219074A JP 2014219074 A JP2014219074 A JP 2014219074A JP 5891576 B2 JP5891576 B2 JP 5891576B2
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- JP
- Japan
- Prior art keywords
- mmol
- oxo
- dihydrofuran
- yield
- carboxylate
- 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.)
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- 150000002241 furanones Chemical class 0.000 title claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 685
- 239000000243 solution Substances 0.000 description 440
- 239000007787 solid Substances 0.000 description 409
- 150000001875 compounds Chemical class 0.000 description 365
- 238000005481 NMR spectroscopy Methods 0.000 description 293
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 282
- 238000006243 chemical reaction Methods 0.000 description 227
- 238000010992 reflux Methods 0.000 description 158
- 239000000203 mixture Substances 0.000 description 139
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 138
- 238000001914 filtration Methods 0.000 description 125
- 238000000034 method Methods 0.000 description 121
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- -1 and specifically Chemical group 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 87
- KAIWRKYDYWYFIT-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=N1 KAIWRKYDYWYFIT-UHFFFAOYSA-N 0.000 description 86
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 79
- 238000004128 high performance liquid chromatography Methods 0.000 description 76
- 238000004237 preparative chromatography Methods 0.000 description 76
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 62
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 59
- 239000011701 zinc Substances 0.000 description 56
- 239000002904 solvent Substances 0.000 description 54
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 229960002429 proline Drugs 0.000 description 34
- 239000000706 filtrate Substances 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- 239000003054 catalyst Substances 0.000 description 32
- 229930182821 L-proline Natural products 0.000 description 30
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 29
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 29
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 29
- 229910052725 zinc Inorganic materials 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 20
- 239000003999 initiator Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 238000001816 cooling Methods 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- PGMYNVMHWVMOPP-UHFFFAOYSA-N ethyl 2-ethoxy-4-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(OCC)OCC1=O PGMYNVMHWVMOPP-UHFFFAOYSA-N 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 14
- 239000011259 mixed solution Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 238000006386 neutralization reaction Methods 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 150000007942 carboxylates Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- 102100030960 DNA replication licensing factor MCM2 Human genes 0.000 description 7
- 101000583807 Homo sapiens DNA replication licensing factor MCM2 Proteins 0.000 description 7
- 101001018431 Homo sapiens DNA replication licensing factor MCM7 Proteins 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution 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
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 6
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 5
- IHCCAYCGZOLTEU-UHFFFAOYSA-M 3-furoate Chemical compound [O-]C(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-M 0.000 description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 230000004543 DNA replication Effects 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- BNNCZCRRYDVISK-UHFFFAOYSA-N propan-2-yl 4-oxo-2-propan-2-yloxyfuran-3-carboxylate Chemical compound CC(C)OC(=O)C1=C(OC(C)C)OCC1=O BNNCZCRRYDVISK-UHFFFAOYSA-N 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 4
- PIIZYNQECPTVEO-UHFFFAOYSA-N 4-nitro-m-cresol Chemical compound CC1=CC(O)=CC=C1[N+]([O-])=O PIIZYNQECPTVEO-UHFFFAOYSA-N 0.000 description 4
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 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 4
- 0 *C(C1=O)=C(N(*)*)OC1=Cc1c[n]c2c1cccn2 Chemical compound *C(C1=O)=C(N(*)*)OC1=Cc1c[n]c2c1cccn2 0.000 description 3
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 3
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000945740 Homo sapiens Cell division cycle 7-related protein kinase Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 2
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- ZSFOKJYVTQSSKV-UHFFFAOYSA-N 1-methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine Chemical compound C1CN(C)CCN1CCOC1=CC=C([N+]([O-])=O)C(C)=C1 ZSFOKJYVTQSSKV-UHFFFAOYSA-N 0.000 description 2
- SOKKPDGDBGAFCB-UHFFFAOYSA-N 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine Chemical compound FC(F)(F)CN1CCN(N=O)CC1 SOKKPDGDBGAFCB-UHFFFAOYSA-N 0.000 description 2
- NYFGIFSPRDNGBT-UHFFFAOYSA-N 1-o-ethyl 3-o-(2-hydroxyethyl) propanedioate Chemical compound CCOC(=O)CC(=O)OCCO NYFGIFSPRDNGBT-UHFFFAOYSA-N 0.000 description 2
- YWPHBESVUYOQNT-UHFFFAOYSA-N 1-o-ethyl 3-o-(2-methoxyethyl) propanedioate Chemical compound CCOC(=O)CC(=O)OCCOC YWPHBESVUYOQNT-UHFFFAOYSA-N 0.000 description 2
- BJBWVEANJVANKR-UHFFFAOYSA-N 1-o-ethyl 3-o-[2-[(2-methylpropan-2-yl)oxycarbonyloxy]ethyl] propanedioate Chemical compound CCOC(=O)CC(=O)OCCOC(=O)OC(C)(C)C BJBWVEANJVANKR-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
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- UAQBBDNWAFULDP-UHFFFAOYSA-N ethyl 2-(1,3-benzothiazol-6-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1=CC=C2C(C=C3OC(NC=4C=C5SC=NC5=CC=4)=C(C3=O)C(=O)OCC)=CNC2=N1 UAQBBDNWAFULDP-UHFFFAOYSA-N 0.000 description 1
- AHKMRZKWQKUBKC-UHFFFAOYSA-N ethyl 2-(1,3-benzothiazol-6-ylamino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(N=CS2)C2=C1 AHKMRZKWQKUBKC-UHFFFAOYSA-N 0.000 description 1
- QRLRBRNKSAOPJT-UHFFFAOYSA-N ethyl 2-(1h-indazol-5-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1=CC=C2C(C=C3OC(NC=4C=C5C=NNC5=CC=4)=C(C3=O)C(=O)OCC)=CNC2=N1 QRLRBRNKSAOPJT-UHFFFAOYSA-N 0.000 description 1
- FGZJDKNKPYRBKR-UHFFFAOYSA-N ethyl 2-(1h-indazol-6-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1=CC=C2C(C=C3OC(NC=4C=C5NN=CC5=CC=4)=C(C3=O)C(=O)OCC)=CNC2=N1 FGZJDKNKPYRBKR-UHFFFAOYSA-N 0.000 description 1
- VCQMQPFFAAZNKC-UHFFFAOYSA-N ethyl 2-(2,2-dimethylhydrazinyl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(NN(C)C)OC1=CC1=CNC2=NC=CC=C12 VCQMQPFFAAZNKC-UHFFFAOYSA-N 0.000 description 1
- GLXQRISHKNMOOK-UHFFFAOYSA-N ethyl 2-(2,3-dihydro-1h-isoindol-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound N1CC2=CC=CC=C2C1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 GLXQRISHKNMOOK-UHFFFAOYSA-N 0.000 description 1
- KGUZCQAMAQNYDP-UHFFFAOYSA-N ethyl 2-(2,3-dihydro-1h-isoindol-1-yl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1C1C2=CC=CC=C2CN1 KGUZCQAMAQNYDP-UHFFFAOYSA-N 0.000 description 1
- FDRVCSJVBKGQTR-UHFFFAOYSA-N ethyl 2-(2,3-dihydroindol-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1CC2=CC=CC=C2N1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 FDRVCSJVBKGQTR-UHFFFAOYSA-N 0.000 description 1
- PKGLAFBARMLJSK-UHFFFAOYSA-N ethyl 2-(2,4-difluoroanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C=C1F PKGLAFBARMLJSK-UHFFFAOYSA-N 0.000 description 1
- DQJSGBPOJBIVLV-UHFFFAOYSA-N ethyl 2-(2,4-difluoroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C=C1F DQJSGBPOJBIVLV-UHFFFAOYSA-N 0.000 description 1
- COXQEYRZLVIIBA-UHFFFAOYSA-N ethyl 2-(2,4-dimethoxyanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OC)C=C1OC COXQEYRZLVIIBA-UHFFFAOYSA-N 0.000 description 1
- JTTLLCLJQLSSCH-UHFFFAOYSA-N ethyl 2-(2,4-dimethoxyanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(OC)C=C1OC JTTLLCLJQLSSCH-UHFFFAOYSA-N 0.000 description 1
- JMXFTUQIOFNKPC-UHFFFAOYSA-N ethyl 2-(2-adamantylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1=CC=C2C(C=C3OC(NC4C5CC6CC(C5)CC4C6)=C(C3=O)C(=O)OCC)=CNC2=N1 JMXFTUQIOFNKPC-UHFFFAOYSA-N 0.000 description 1
- CUJJRMWKLNEBMD-UHFFFAOYSA-N ethyl 2-(2-chloroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1Cl CUJJRMWKLNEBMD-UHFFFAOYSA-N 0.000 description 1
- YMRSQFNEZHHTRL-UHFFFAOYSA-N ethyl 2-(2-fluoroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1F YMRSQFNEZHHTRL-UHFFFAOYSA-N 0.000 description 1
- NYAAABTZBKZPEI-UHFFFAOYSA-N ethyl 2-(2-hydroxy-4-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1O NYAAABTZBKZPEI-UHFFFAOYSA-N 0.000 description 1
- CUUAWUAJMBMYFI-UHFFFAOYSA-N ethyl 2-(2-hydroxy-4-methylanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1O CUUAWUAJMBMYFI-UHFFFAOYSA-N 0.000 description 1
- TWISMVUVDZVETA-UHFFFAOYSA-N ethyl 2-(2-methoxyanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1OC TWISMVUVDZVETA-UHFFFAOYSA-N 0.000 description 1
- MATMYAMSFWOBRE-UHFFFAOYSA-N ethyl 2-(2-methoxyethylamino)-4-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(NCCOC)OCC1=O MATMYAMSFWOBRE-UHFFFAOYSA-N 0.000 description 1
- GYVTUWIXUBJYGO-UHFFFAOYSA-N ethyl 2-(2-methyl-2-phenylhydrazinyl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NN(C)C1=CC=CC=C1 GYVTUWIXUBJYGO-UHFFFAOYSA-N 0.000 description 1
- MMSJOKQVKGSYES-UHFFFAOYSA-N ethyl 2-(2-methyl-2-phenylhydrazinyl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NN(C)C1=CC=CC=C1 MMSJOKQVKGSYES-UHFFFAOYSA-N 0.000 description 1
- UXHVHQZCEWWVGN-UHFFFAOYSA-N ethyl 2-(2-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1C UXHVHQZCEWWVGN-UHFFFAOYSA-N 0.000 description 1
- MGOZODDTHVNMDT-UHFFFAOYSA-N ethyl 2-(2-methylanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1C MGOZODDTHVNMDT-UHFFFAOYSA-N 0.000 description 1
- IIFIDQKGJZMMCY-UHFFFAOYSA-N ethyl 2-(3,4-difluoroanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C(F)=C1 IIFIDQKGJZMMCY-UHFFFAOYSA-N 0.000 description 1
- QOVMGLMSLQNKMO-UHFFFAOYSA-N ethyl 2-(3,4-difluoroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C(F)=C1 QOVMGLMSLQNKMO-UHFFFAOYSA-N 0.000 description 1
- INVQNWGZEHEYMW-UHFFFAOYSA-N ethyl 2-(3,4-dihydro-1h-isoquinolin-2-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1CC2=CC=CC=C2CN1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 INVQNWGZEHEYMW-UHFFFAOYSA-N 0.000 description 1
- WSLJGCJLTMKSCJ-UHFFFAOYSA-N ethyl 2-(3,4-dimethoxyanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OC)C(OC)=C1 WSLJGCJLTMKSCJ-UHFFFAOYSA-N 0.000 description 1
- YUYFSQWXJPLOEZ-UHFFFAOYSA-N ethyl 2-(3,5-dimethylpiperidin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CC(C)CC(C)C1 YUYFSQWXJPLOEZ-UHFFFAOYSA-N 0.000 description 1
- CZSOHNKWYXDPSI-UHFFFAOYSA-N ethyl 2-(3-carbamoylpiperidin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCCC(C(N)=O)C1 CZSOHNKWYXDPSI-UHFFFAOYSA-N 0.000 description 1
- TWNVMOLGWUZTTR-UHFFFAOYSA-N ethyl 2-(3-carbamoylpiperidin-1-yl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CC(C(N)=O)CCC1 TWNVMOLGWUZTTR-UHFFFAOYSA-N 0.000 description 1
- ODYZVGWYASXAFR-UHFFFAOYSA-N ethyl 2-(3-chloroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC(Cl)=C1 ODYZVGWYASXAFR-UHFFFAOYSA-N 0.000 description 1
- IMUYQEGREJCUGE-UHFFFAOYSA-N ethyl 2-(3-hydroxypiperidin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCCC(O)C1 IMUYQEGREJCUGE-UHFFFAOYSA-N 0.000 description 1
- FJRLVLJZASXGCA-UHFFFAOYSA-N ethyl 2-(3-methoxyanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC(OC)=C1 FJRLVLJZASXGCA-UHFFFAOYSA-N 0.000 description 1
- MQQCFVHPLYYBGW-UHFFFAOYSA-N ethyl 2-(3h-benzimidazol-5-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1=CC=C2C(C=C3OC(NC=4C=C5NC=NC5=CC=4)=C(C3=O)C(=O)OCC)=CNC2=N1 MQQCFVHPLYYBGW-UHFFFAOYSA-N 0.000 description 1
- UGRLALVSVBEJOQ-UHFFFAOYSA-N ethyl 2-(3h-benzimidazol-5-ylamino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(N=CN2)C2=C1 UGRLALVSVBEJOQ-UHFFFAOYSA-N 0.000 description 1
- VJGJCWJLDRNURJ-UHFFFAOYSA-N ethyl 2-(4-acetyl-1,4-diazepan-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCCN(C(C)=O)CC1 VJGJCWJLDRNURJ-UHFFFAOYSA-N 0.000 description 1
- AGTSYZAWOLJQLX-UHFFFAOYSA-N ethyl 2-(4-acetylpiperazin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCN(C(C)=O)CC1 AGTSYZAWOLJQLX-UHFFFAOYSA-N 0.000 description 1
- GUZAEXKIKUZYTO-UHFFFAOYSA-N ethyl 2-(4-bromoanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(Br)C=C1 GUZAEXKIKUZYTO-UHFFFAOYSA-N 0.000 description 1
- KRJWNHKSBHBACC-UHFFFAOYSA-N ethyl 2-(4-chloroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(Cl)C=C1 KRJWNHKSBHBACC-UHFFFAOYSA-N 0.000 description 1
- PTXJDYVVRIWBRL-UHFFFAOYSA-N ethyl 2-(4-fluoro-2-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C=C1C PTXJDYVVRIWBRL-UHFFFAOYSA-N 0.000 description 1
- PYGCIIBWCHANEQ-UHFFFAOYSA-N ethyl 2-(4-fluoro-2-methylanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C=C1C PYGCIIBWCHANEQ-UHFFFAOYSA-N 0.000 description 1
- DZWKAPDMVSPJEE-UHFFFAOYSA-N ethyl 2-(4-fluoro-n-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;hydrochloride Chemical compound Cl.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N(C)C1=CC=C(F)C=C1 DZWKAPDMVSPJEE-UHFFFAOYSA-N 0.000 description 1
- DRXQAADJYGEZIE-UHFFFAOYSA-N ethyl 2-(4-fluoroanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(F)C=C1 DRXQAADJYGEZIE-UHFFFAOYSA-N 0.000 description 1
- MJFWBGQAHYUTSS-UHFFFAOYSA-N ethyl 2-(4-hydroxy-2-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(O)C=C1C MJFWBGQAHYUTSS-UHFFFAOYSA-N 0.000 description 1
- RDIQGAYEJVIOBO-UHFFFAOYSA-N ethyl 2-(4-methoxyanilino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(OC)C=C1 RDIQGAYEJVIOBO-UHFFFAOYSA-N 0.000 description 1
- PPLFTIGHDVRREK-UHFFFAOYSA-N ethyl 2-(4-methylanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1 PPLFTIGHDVRREK-UHFFFAOYSA-N 0.000 description 1
- WQKGPKQRUSTVPE-UHFFFAOYSA-N ethyl 2-(4-methylpiperazin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;hydrochloride Chemical compound Cl.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCN(C)CC1 WQKGPKQRUSTVPE-UHFFFAOYSA-N 0.000 description 1
- IXSRYRNGPVTUSV-UHFFFAOYSA-N ethyl 2-(4-methylpiperazin-1-yl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CCN(C)CC1 IXSRYRNGPVTUSV-UHFFFAOYSA-N 0.000 description 1
- PCNKTIHZRTXCPA-UHFFFAOYSA-N ethyl 2-(4-morpholin-4-ylpiperidin-1-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N(CC1)CCC1N1CCOCC1 PCNKTIHZRTXCPA-UHFFFAOYSA-N 0.000 description 1
- YFDIEPQTDBUMBD-UHFFFAOYSA-N ethyl 2-(4-morpholin-4-ylpiperidin-1-yl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CCC(N2CCOCC2)CC1 YFDIEPQTDBUMBD-UHFFFAOYSA-N 0.000 description 1
- HXYKJEKKQIDIPL-UHFFFAOYSA-N ethyl 2-(6,8-dihydro-5h-1,7-naphthyridin-7-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;formic acid Chemical compound OC=O.C1CC2=CC=CN=C2CN1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 HXYKJEKKQIDIPL-UHFFFAOYSA-N 0.000 description 1
- DOUVXIVMJMSKLI-UHFFFAOYSA-N ethyl 2-(7,8-dihydro-5h-1,6-naphthyridin-6-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;formic acid Chemical compound OC=O.C1CC2=NC=CC=C2CN1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 DOUVXIVMJMSKLI-UHFFFAOYSA-N 0.000 description 1
- OUGAGADONJPCAI-UHFFFAOYSA-N ethyl 2-(7-methoxy-3,4-dihydro-1h-isoquinolin-2-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound C1CC2=CC=C(OC)C=C2CN1C(O1)=C(C(=O)OCC)C(=O)C1=CC1=CNC2=NC=CC=C12 OUGAGADONJPCAI-UHFFFAOYSA-N 0.000 description 1
- KULFEJDLDHDYPK-UHFFFAOYSA-N ethyl 2-(benzylamino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NCC1=CC=CC=C1 KULFEJDLDHDYPK-UHFFFAOYSA-N 0.000 description 1
- WUFTZTQNKCIDHC-UHFFFAOYSA-N ethyl 2-(cyclohexylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;hydrochloride Chemical compound Cl.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1CCCCC1 WUFTZTQNKCIDHC-UHFFFAOYSA-N 0.000 description 1
- OLUQUMJXISVXEM-UHFFFAOYSA-N ethyl 2-(cyclohexylamino)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1CCCCC1 OLUQUMJXISVXEM-UHFFFAOYSA-N 0.000 description 1
- LBQFWODCSAOWHK-UHFFFAOYSA-N ethyl 2-(cyclohexylmethylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NCC1CCCCC1 LBQFWODCSAOWHK-UHFFFAOYSA-N 0.000 description 1
- IAEVEJFIEJPGKG-UHFFFAOYSA-N ethyl 2-(cyclopentylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1CCCC1 IAEVEJFIEJPGKG-UHFFFAOYSA-N 0.000 description 1
- PBKVOMXAISHYCT-UHFFFAOYSA-N ethyl 2-(cyclopropylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1CC1 PBKVOMXAISHYCT-UHFFFAOYSA-N 0.000 description 1
- LBQVSTFEDLERAV-UHFFFAOYSA-N ethyl 2-(cyclopropylmethylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NCC1CC1 LBQVSTFEDLERAV-UHFFFAOYSA-N 0.000 description 1
- RSTPKMUCYICKMZ-UHFFFAOYSA-N ethyl 2-(diethylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;hydrochloride Chemical compound Cl.O=C1C(C(=O)OCC)=C(N(CC)CC)OC1=CC1=CNC2=NC=CC=C12 RSTPKMUCYICKMZ-UHFFFAOYSA-N 0.000 description 1
- RUDKITBNXPXJMI-UHFFFAOYSA-N ethyl 2-(diethylamino)-4-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(N(CC)CC)OCC1=O RUDKITBNXPXJMI-UHFFFAOYSA-N 0.000 description 1
- UMYWUSVBQMNKAM-UHFFFAOYSA-N ethyl 2-(ethylamino)-4-oxofuran-3-carboxylate Chemical compound CCNC1=C(C(=O)OCC)C(=O)CO1 UMYWUSVBQMNKAM-UHFFFAOYSA-N 0.000 description 1
- YBLJJUGWYINDEB-UHFFFAOYSA-N ethyl 2-(morpholin-4-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NN1CCOCC1 YBLJJUGWYINDEB-UHFFFAOYSA-N 0.000 description 1
- OPZWXHJMKMSTIS-UHFFFAOYSA-N ethyl 2-[(1-methylpiperidin-4-yl)amino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1CCN(C)CC1 OPZWXHJMKMSTIS-UHFFFAOYSA-N 0.000 description 1
- MJHOWPILRYPKJW-UHFFFAOYSA-N ethyl 2-[(4-methylpiperazin-1-yl)amino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NN1CCN(C)CC1 MJHOWPILRYPKJW-UHFFFAOYSA-N 0.000 description 1
- UZXPXIWNBUOWBK-UHFFFAOYSA-N ethyl 2-[(4-methylpiperazin-1-yl)amino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NN1CCN(C)CC1 UZXPXIWNBUOWBK-UHFFFAOYSA-N 0.000 description 1
- TXENGMPXDYPSBP-UHFFFAOYSA-N ethyl 2-[2-(2-hydroxyethoxy)-4-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1OCCO TXENGMPXDYPSBP-UHFFFAOYSA-N 0.000 description 1
- AZOKNCQXTZPXBI-UHFFFAOYSA-N ethyl 2-[2-(2-methoxyethoxy)-4-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1OCCOC AZOKNCQXTZPXBI-UHFFFAOYSA-N 0.000 description 1
- VCVGIIZTTFQNLD-UHFFFAOYSA-N ethyl 2-[2-(2-methoxyethoxymethoxy)ethyl-methylamino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(N(C)CCOCOCCOC)OC1=CC1=CNC2=NC=CC=C12 VCVGIIZTTFQNLD-UHFFFAOYSA-N 0.000 description 1
- BWXFUVGNCAJBSI-UHFFFAOYSA-N ethyl 2-[2-(2-morpholin-4-ylethoxy)anilino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1OCCN1CCOCC1 BWXFUVGNCAJBSI-UHFFFAOYSA-N 0.000 description 1
- LHRNVGZSUKQCSU-UHFFFAOYSA-N ethyl 2-[2-(dimethylamino)ethyl-methylamino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;formic acid Chemical compound OC=O.O=C1C(C(=O)OCC)=C(N(C)CCN(C)C)OC1=CC1=CNC2=NC=CC=C12 LHRNVGZSUKQCSU-UHFFFAOYSA-N 0.000 description 1
- FQQOQWUUMVOMEV-UHFFFAOYSA-N ethyl 2-[2-(dimethylamino)ethylamino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(NCCN(C)C)OC1=CC1=CNC2=NC=CC=C12 FQQOQWUUMVOMEV-UHFFFAOYSA-N 0.000 description 1
- MOVWZUYSFZLTQN-UHFFFAOYSA-N ethyl 2-[2-[2-(dimethylamino)ethoxy]-4-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(C)C=C1OCCN(C)C MOVWZUYSFZLTQN-UHFFFAOYSA-N 0.000 description 1
- QWGPRJZTEZEMID-UHFFFAOYSA-N ethyl 2-[2-[2-(dimethylamino)ethoxy]anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=CC=C1OCCN(C)C QWGPRJZTEZEMID-UHFFFAOYSA-N 0.000 description 1
- RDVGXIPTVFJNQP-UHFFFAOYSA-N ethyl 2-[2-fluoro-4-(2-hydroxyethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCO)C=C1F RDVGXIPTVFJNQP-UHFFFAOYSA-N 0.000 description 1
- AJAKPJCLCWVBFB-UHFFFAOYSA-N ethyl 2-[2-fluoro-4-(2-methoxyethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCOC)C=C1F AJAKPJCLCWVBFB-UHFFFAOYSA-N 0.000 description 1
- LVAJHQWZVYRGFJ-UHFFFAOYSA-N ethyl 2-[2-hydroxyethyl(methyl)amino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(N(C)CCO)OC1=CC1=CNC2=NC=CC=C12 LVAJHQWZVYRGFJ-UHFFFAOYSA-N 0.000 description 1
- SEBXZBBJQBOQGT-UHFFFAOYSA-N ethyl 2-[2-hydroxyethyl(methyl)amino]-4-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(N(C)CCO)OCC1=O SEBXZBBJQBOQGT-UHFFFAOYSA-N 0.000 description 1
- WBTGCMMZVNEXLR-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(2-methylsulfanylethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCSC)C=C1C WBTGCMMZVNEXLR-UHFFFAOYSA-N 0.000 description 1
- MQQZWKGEFCFBBX-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(2-methylsulfonylethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCS(C)(=O)=O)C=C1C MQQZWKGEFCFBBX-UHFFFAOYSA-N 0.000 description 1
- IXUHJJOTCNYTSF-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(2-pyridin-2-ylethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1OCCC1=CC=CC=N1 IXUHJJOTCNYTSF-UHFFFAOYSA-N 0.000 description 1
- IDVCPWSSMYLKMB-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(2-pyrrol-1-ylethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1OCCN1C=CC=C1 IDVCPWSSMYLKMB-UHFFFAOYSA-N 0.000 description 1
- PMLBRMAZXOJCMB-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(morpholin-4-ylmethyl)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1CN1CCOCC1 PMLBRMAZXOJCMB-UHFFFAOYSA-N 0.000 description 1
- SVNKUJXSMLAPNB-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(pyridin-2-ylmethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1OCC1=CC=CC=N1 SVNKUJXSMLAPNB-UHFFFAOYSA-N 0.000 description 1
- DHFQSDYDROYOAS-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(pyridin-3-ylmethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1OCC1=CC=CN=C1 DHFQSDYDROYOAS-UHFFFAOYSA-N 0.000 description 1
- QBWWTXZXJZXREP-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(pyrimidin-2-ylmethoxy)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1OCC1=NC=CC=N1 QBWWTXZXJZXREP-UHFFFAOYSA-N 0.000 description 1
- MOYLYCWMMDNEKC-UHFFFAOYSA-N ethyl 2-[2-methyl-4-(pyrrolidin-1-ylmethyl)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1CN1CCCC1 MOYLYCWMMDNEKC-UHFFFAOYSA-N 0.000 description 1
- PPJGPXWILAGSLJ-UHFFFAOYSA-N ethyl 2-[2-methyl-4-[(4-methylpiperazin-1-yl)methyl]anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC(C(=C1)C)=CC=C1CN1CCN(C)CC1 PPJGPXWILAGSLJ-UHFFFAOYSA-N 0.000 description 1
- TZKWVQGGJAUIDW-UHFFFAOYSA-N ethyl 2-[3-(hydroxymethyl)piperidin-1-yl]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CC(CO)CCC1 TZKWVQGGJAUIDW-UHFFFAOYSA-N 0.000 description 1
- YXUIWKJEAKYYCN-UHFFFAOYSA-N ethyl 2-[4-(2,3-dihydroxypropoxy)-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCC(O)CO)C=C1C YXUIWKJEAKYYCN-UHFFFAOYSA-N 0.000 description 1
- FUARRVBCBYKCIA-UHFFFAOYSA-N ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCC(C)(C)O)C=C1C FUARRVBCBYKCIA-UHFFFAOYSA-N 0.000 description 1
- JZJQKWVEYCTBTI-UHFFFAOYSA-N ethyl 2-[4-(2-hydroxyethoxy)-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCO)C=C1C JZJQKWVEYCTBTI-UHFFFAOYSA-N 0.000 description 1
- UBDHCGMWOVVKRM-UHFFFAOYSA-N ethyl 2-[4-(2-hydroxyethoxy)-2-methylanilino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCO)C=C1C UBDHCGMWOVVKRM-UHFFFAOYSA-N 0.000 description 1
- FWQRZBQNFLWDEY-UHFFFAOYSA-N ethyl 2-[4-(2-hydroxyethyl)piperazin-1-yl]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCN(CCO)CC1 FWQRZBQNFLWDEY-UHFFFAOYSA-N 0.000 description 1
- WMGUIGNAFUGGPU-UHFFFAOYSA-N ethyl 2-[4-(2-hydroxyethyl)piperazin-1-yl]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CCN(CCO)CC1 WMGUIGNAFUGGPU-UHFFFAOYSA-N 0.000 description 1
- YJQYFGUPIQMTTE-UHFFFAOYSA-N ethyl 2-[4-(2-methoxyethoxy)-2-methylanilino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCOC)C=C1C YJQYFGUPIQMTTE-UHFFFAOYSA-N 0.000 description 1
- FSWUCHGDPFIGOH-UHFFFAOYSA-N ethyl 2-[4-(diethylamino)piperidin-1-yl]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCC(N(CC)CC)CC1 FSWUCHGDPFIGOH-UHFFFAOYSA-N 0.000 description 1
- KHLMFPLDIHUMMI-UHFFFAOYSA-N ethyl 2-[4-(diethylamino)piperidin-1-yl]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1N1CCC(N(CC)CC)CC1 KHLMFPLDIHUMMI-UHFFFAOYSA-N 0.000 description 1
- GWFKJVKLZCOGPC-UHFFFAOYSA-N ethyl 2-[4-(dimethylamino)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;hydrochloride Chemical compound Cl.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(N(C)C)C=C1 GWFKJVKLZCOGPC-UHFFFAOYSA-N 0.000 description 1
- XNDILSHAOUCSJH-UHFFFAOYSA-N ethyl 2-[4-(dimethylamino)anilino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(N(C)C)C=C1 XNDILSHAOUCSJH-UHFFFAOYSA-N 0.000 description 1
- MLHUNANKDNMWQY-UHFFFAOYSA-N ethyl 2-[4-(hydroxymethyl)anilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(CO)C=C1 MLHUNANKDNMWQY-UHFFFAOYSA-N 0.000 description 1
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- HZRQNQAHLAFCBG-UHFFFAOYSA-N ethyl 2-[4-[(dimethylamino)methyl]-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(CN(C)C)C=C1C HZRQNQAHLAFCBG-UHFFFAOYSA-N 0.000 description 1
- JHBBFPBAVVWGAH-UHFFFAOYSA-N ethyl 2-[4-[(dimethylamino)methyl]-2-methylanilino]-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OCC)=C1NC1=CC=C(CN(C)C)C=C1C JHBBFPBAVVWGAH-UHFFFAOYSA-N 0.000 description 1
- JZHBMODROBRDLG-UHFFFAOYSA-N ethyl 2-[4-[2-(2-hydroxyethoxy)ethoxy]-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCOCCO)C=C1C JZHBMODROBRDLG-UHFFFAOYSA-N 0.000 description 1
- DNWPWINHGPOBEA-UHFFFAOYSA-N ethyl 2-[4-[2-(dimethylamino)ethoxy]-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;formic acid Chemical compound OC=O.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(OCCN(C)C)C=C1C DNWPWINHGPOBEA-UHFFFAOYSA-N 0.000 description 1
- NFWRFOAWBVTPLB-UHFFFAOYSA-N ethyl 2-[4-[2-(dimethylamino)ethylamino]-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate;formic acid Chemical compound OC=O.O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NC1=CC=C(NCCN(C)C)C=C1C NFWRFOAWBVTPLB-UHFFFAOYSA-N 0.000 description 1
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- LMXVZPYCHKDODF-UHFFFAOYSA-N ethyl 2-morpholin-4-yl-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1N1CCOCC1 LMXVZPYCHKDODF-UHFFFAOYSA-N 0.000 description 1
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- JQQKWMDUIVOUPG-UHFFFAOYSA-N ethyl 4-oxo-2-(2-piperidin-1-ylethylamino)-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OCC)=C1NCCN1CCCCC1 JQQKWMDUIVOUPG-UHFFFAOYSA-N 0.000 description 1
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- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- TTXJMSRLGMWEJZ-UHFFFAOYSA-N n-methyl-1-thiophen-2-ylmethanamine Chemical compound CNCC1=CC=CS1 TTXJMSRLGMWEJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000027405 negative regulation of phosphorylation Effects 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- HOCZNGGYDMAETH-UHFFFAOYSA-N propan-2-yl 2-(1h-azepin-2-yl)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1C1=CC=CC=CN1 HOCZNGGYDMAETH-UHFFFAOYSA-N 0.000 description 1
- MZOVVTUDWNNUJK-UHFFFAOYSA-N propan-2-yl 2-(1h-azepin-2-yl)-4-oxofuran-3-carboxylate Chemical compound O1CC(=O)C(C(=O)OC(C)C)=C1C1=CC=CC=CN1 MZOVVTUDWNNUJK-UHFFFAOYSA-N 0.000 description 1
- QDZJQSNYTZKIPW-UHFFFAOYSA-N propan-2-yl 2-(2,4-difluoroanilino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NC1=CC=C(F)C=C1F QDZJQSNYTZKIPW-UHFFFAOYSA-N 0.000 description 1
- HVOLDEWHMOJLTC-UHFFFAOYSA-N propan-2-yl 2-(cyclohexylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NC1CCCCC1 HVOLDEWHMOJLTC-UHFFFAOYSA-N 0.000 description 1
- ZCZBGTQHTNEIRM-UHFFFAOYSA-N propan-2-yl 2-(cyclohexylmethylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NCC1CCCCC1 ZCZBGTQHTNEIRM-UHFFFAOYSA-N 0.000 description 1
- AHWZPJUJQZBTJU-UHFFFAOYSA-N propan-2-yl 2-(cyclopropylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NC1CC1 AHWZPJUJQZBTJU-UHFFFAOYSA-N 0.000 description 1
- UNNTWJJPROLDQD-UHFFFAOYSA-N propan-2-yl 2-(morpholin-4-ylamino)-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NN1CCOCC1 UNNTWJJPROLDQD-UHFFFAOYSA-N 0.000 description 1
- KYECCRIGONTHGD-UHFFFAOYSA-N propan-2-yl 2-[4-(2-hydroxyethoxy)-2-methylanilino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1NC1=CC=C(OCCO)C=C1C KYECCRIGONTHGD-UHFFFAOYSA-N 0.000 description 1
- QLUMGICXACFOCQ-UHFFFAOYSA-N propan-2-yl 2-[methyl(thiophen-2-ylmethyl)amino]-4-oxo-5-(1h-pyrrolo[2,3-b]pyridin-3-ylmethylidene)furan-3-carboxylate Chemical compound O1C(=CC=2C3=CC=CN=C3NC=2)C(=O)C(C(=O)OC(C)C)=C1N(C)CC1=CC=CS1 QLUMGICXACFOCQ-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 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 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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- 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
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
(1)下式(I)で示されるフラノン誘導体またはその薬学的に許容される塩。
(2)Aが−COOR1である(1)に記載のフラノン誘導体またはその薬学的に許容される塩。
(3)Aが水素原子である(1)に記載のフラノン誘導体またはその薬学的に許容される塩。
本発明の新規なフラノン誘導体は、下式(I)で示される化合物である。
前記式(I)において、
置換基を有してもよい炭化水素基としては、例えば、a)炭素数1から6の直鎖状、あるいは分岐鎖状のアルキル基(例えば、メチル、エチル、イソプロピル、tert−ブチル、ヘキシルなど)、
b) 炭素数1から6の直鎖状、あるいは分岐鎖状のアルケニル基(例えば、ビニル、アリル、イソプロペニル、2−ブテニルなど)、
c) 炭素数2から6のアルキニル基(例えば、エチニル、プロパルギル、2−ブチニルなど)、
d) 炭素数3から8のシクロアルキル基(例えば、シクロプロピル、シクロペンチル、シクロヘキシル、シクロヘプチルなど)、
e) 炭素数3から8のシクロアルケニル基(例えば、シクロヘキセニル、シクロヘプテニルなど)、
ハロゲン原子としては、例えばフッ素、塩素、臭素などが挙げられる。
また、本発明の化合物である式(I−Z)および(I−E)で具体的に示されるこれら立体異性体およびこれらの混合物も本発明に包含される。
Aが−COOR1である化合物(Ia)は、例えばスキーム1によって製造することができる。
[スキーム1]
また、スキーム1の原料として用いられる化合物(III)は、例えばスキーム2もしくは3に示す方法によって製造することができる。
[スキーム2]
工程2−2
スキーム2の原料として用いられるマロン酸ジエステル(V)とアミン(VIII)は、市販品として、または公知の方法により得ることができる。
[スキーム3]
スキーム3の原料である化合物(IX)とイソシアネート(X)は、市販品として、または公知の方法により得ることができる。
[スキーム4]
[スキーム5]
塩基もしくは酸は、例えば水酸化ナトリウム、水酸化カリウム、もしくは塩酸などを用いることができる。
また、本発明の化合物(I)のうち、AおよびR3が水素原子である化合物(Ic)は、例えばスキーム6によって製造することができる。
[スキーム6]
HPLC分取クロマトグラフィーは、市販のODSカラムを用い、特に記載のない限りは水/メタノール(ギ酸を含む)を溶出液としてグラジェントモードにて分取した。
実施例1
実施例2
(第2工程)
実施例3
(第2工程)
(第3工程)
(第4工程)
(第5工程)
実施例4
エチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-4-オキソ-2-ピペリジノ-4,5-ジヒドロフラン-3-カルボキシレート
(第2工程)
実施例5
実施例6
実施例7
実施例8
実施例9
実施例10
実施例11
5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-4-オキソ-2-ピペリジノ-4,5-ジヒドロフラン-3-カルボン酸
実施例12
実施例13
実施例14
実施例15
実施例16
実施例17
実施例18
実施例19
実施例20
実施例21
実施例22
5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン)-4-オキソ-2-(フェニルアミノ)-4,5-ジヒドロフラン-3-カルボン酸
実施例23
実施例24
実施例25
実施例26
実施例27
実施例28
実施例29
(第2工程)
実施例30
実施例31
実施例32
実施例33
実施例34
メチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-4-オキソ-2-ピペリジノ-4,5-ジヒドロフラン-3-カルボキシレート
実施例35
実施例36
実施例37
実施例38
実施例39
実施例40
実施例41
(第2工程)
実施例42
実施例41の第1工程記載の方法と同様にして、表題化合物(固体)を得た。
実施例43
実施例41の第1工程記載の方法と同様にして、表題化合物(固体)を得た。
実施例44
実施例41の第1工程記載の方法と同様にして、表題化合物(固体)を得た。
実施例45
実施例41の第1工程記載の方法と同様にして、表題化合物(固体)を得た。
実施例46
実施例41の第1工程記載の方法と同様にして、表題化合物(固体)を得た。
実施例47
(第1工程)
(第2工程)
実施例48
実施例49
実施例48記載の方法と同様にして、表題化合物(固体)を得た。
実施例50
実施例48記載の方法と同様にして、表題化合物(固体)を得た。
実施例51
実施例52
(第2工程)
実施例53
実施例54
実施例55
実施例56
実施例57
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例58
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例59
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例60
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例61
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例62
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例63
エチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-2-アゼピニル-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例64
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例65
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例66
実施例56記載の方法と同様にして、表題化合物(固体)を得た。
実施例67
実施例68
実施例67記載の方法と同様にして、表題化合物(固体)を得た。
実施例69
実施例67記載の方法と同様にして、表題化合物(固体)を得た。
実施例70
1H NMR (DMSO-d6) δ (ppm) 10.22 (s, 1H), 7.43 - 7.56 (m, 2H), 7.27 (t, J = 8.78 Hz, 2H), 4.66 (s, 2H), 4.22 - 4.37 (m, 2H), 3.52 - 3.66 (m, 2H), 3.30 (s, 3H); LCMS (m/z): 295.8 [M+H]+
(第2工程)
実施例71
実施例72
実施例73
実施例74
(第1工程)
(第2工程)
(第3工程)
(第4工程)
(第5工程)
実施例75
実施例76
実施例77
実施例76記載の方法と同様にして、表題化合物(固体)を得た。
実施例78
実施例76記載の方法と同様にして、表題化合物(固体)を得た。
実施例79
エチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-2-モルホリノ-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート
実施例76記載の方法と同様にして、表題化合物(固体)を得た。
実施例80
実施例81
実施例82
実施例83
実施例84
実施例85
実施例86
実施例87
実施例88
実施例87記載の方法と同様にして、表題化合物(固体)を得た。
実施例89
実施例90
実施例91
実施例92
実施例93
実施例94
実施例95
実施例96
実施例97
実施例98
実施例97記載の方法と同様にして、表題化合物(固体)を得た。
実施例99
(第1工程)
(第2工程)
実施例100
実施例101
実施例102
実施例103
実施例102記載の方法と同様にして、表題化合物(固体)を得た。
実施例104
実施例105
実施例106
実施例107
実施例106記載の方法と同様にして、表題化合物(固体)を得た。
実施例108
実施例106記載の方法と同様にして、表題化合物(固体)を得た。
実施例109
実施例106記載の方法と同様にして、表題化合物(固体)を得た。
実施例110
実施例106記載の方法と同様にして、表題化合物(固体)を得た。
実施例111
実施例112
実施例113
実施例112記載の方法と同様にして、表題化合物(固体)を得た。
実施例114
実施例112記載の方法と同様にして、表題化合物(固体)を得た。
実施例115
実施例112記載の方法と同様にして、表題化合物(固体)を得た。
実施例116
実施例117
実施例116記載の方法と同様にして、表題化合物(固体)を得た。
実施例118
実施例116記載の方法と同様にして、表題化合物(固体)を得た。
実施例119
実施例120
(第2工程)
実施例121
実施例122
実施例123
実施例124
実施例125
(第1工程)
(第2工程)
(第3工程)
(第4工程)
実施例126
実施例125記載の方法と同様にして、表題化合物(固体)を得た。
実施例127
実施例128
実施例127記載の方法と同様にして、表題化合物(固体)を得た。
実施例129
(第1工程)
(第2工程)
(第3工程)
(第4工程)
実施例130
実施例131
実施例132
実施例131記載の方法と同様にして、表題化合物(固体)を得た。
実施例133
実施例131記載の方法と同様にして、表題化合物(固体)を得た。
実施例134
実施例135
実施例134記載の方法と同様にして、表題化合物(固体)を得た。
実施例136
実施例134記載の方法と同様にして、表題化合物(固体)を得た。
実施例137
実施例138
(第2工程)
(第3工程)
実施例139
実施例140
実施例141
実施例142
実施例143
実施例141記載の方法と同様にして、表題化合物(固体)を得た。
実施例144
実施例145
(第1工程)
(第2工程)
(第3工程)
(第4工程)
(第5工程)
実施例146
実施例141記載の方法と同様にして、表題化合物(固体)を得た。
実施例147
実施例148
実施例149
実施例150
実施例151
実施例152
実施例153
実施例154
実施例155
実施例156
実施例157
実施例158
実施例159
実施例160
実施例161
(第1工程)
(第2工程)
(第3工程)
(第4工程)
実施例162
実施例163
実施例164
実施例165
実施例166
(第1工程)
(第2工程)
(第3工程)
実施例167
実施例168
実施例169
実施例170
実施例171
(第1工程)
(第2工程)
(第3工程)
(第4工程)
実施例172
実施例173
実施例172と同様な方法により、表題化合物(固体)を得た。
実施例174
実施例172と同様な方法により、表題化合物(固体)を得た。
実施例175
実施例176
実施例175と同様な方法により、表題化合物(固体)を得た。
実施例177
実施例178
実施例177と同様な方法により、表題化合物(固体)を得た。
実施例179
実施例180
実施例181
実施例180記載の方法と同様にして、表題化合物(固体)を得た。
実施例182
実施例183
実施例184
実施例183記載の方法と同様にして、表題化合物(固体)を得た。
実施例185
実施例183記載の方法と同様にして、表題化合物(固体)を得た。
実施例186
実施例183記載の方法と同様にして、表題化合物(固体)を得た。
実施例187
実施例183記載の方法と同様にして、表題化合物(固体)を得た。
実施例188
実施例189
実施例190
実施例189記載の方法と同様にして、表題化合物(固体)を得た。
実施例191
実施例189記載の方法と同様にして、表題化合物(固体)を得た。
実施例192
実施例193
実施例194
(第2工程)
(第3工程)
(第4工程)
(第5工程)
実施例195
実施例196
実施例195記載の方法と同様にして、表題化合物(固体)を得た。
実施例197
実施例198
実施例199
(第2工程)
(第3工程)
実施例200
実施例194記載の方法と同様にして、表題化合物(固体)を得た。
実施例201
(第1工程)
(第2工程)
実施例202
実施例203
実施例194記載の方法と同様にして、表題化合物(固体)を得た。
実施例204
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(フェニルアミノ)フラン-3(2H)-オン
実施例205
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-メトキシフェニル)アミノ]フラン-3(2H)-オン
実施例206
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-クロロフェニル)アミノ]フラン-3(2H)-オン
実施例207
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(3-クロロフェニル)アミノ]フラン-3(2H)-オン
実施例208
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-クロロフェニル)アミノ]フラン-3(2H)-オン
実施例209
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2,4-ジメトキシフェニル)アミノ]フラン-3(2H)-オン
実施例210
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-イソプロピルフェニル)アミノ]フラン-3(2H)-オン
実施例211
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(3-ピリジニルアミノ)フラン-3(2H)-オン
実施例27で得られた化合物を用い、実施例210記載の方法と同様にして、表題化合物(固体)を得た。
実施例212
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-カルバモイルフェニル)アミノ]フラン-3(2H)-オン
実施例25で得られた化合物を用い、実施例210記載の方法と同様にして、表題化合物(固体)を得た。
実施例213
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2,4-ジメチルフェニル)アミノ]フラン-3(2H)-オン
実施例26で得られた化合物を用い、実施例210記載の方法と同様にして、表題化合物(固体)を得た。
実施例214
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(p-トルイルアミノ)フラン-3(2H)-オン
実施例20で得られた化合物を用い、実施例210記載の方法と同様にして、表題化合物(固体)を得た。
実施例215
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-ブロモフェニル)アミノ]フラン-3(2H)-オン
実施例19で得られた化合物を用い、実施例210記載の方法と同様にして、表題化合物(固体)を得た。
実施例216
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(3,4-ジメトキシフェニル)アミノ]フラン-3(2H)-オン
実施例217
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-フルオロフェニル)アミノ]フラン-3(2H)-オン
実施例21で得られた化合物を用い、実施例216記載の方法と同様にして、表題化合物(固体)を得た。
実施例218
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(1,1'-ビフェニル)-4-イルアミノ]フラン-3(2H)-オン
実施例39で得られた化合物を用い、実施例216記載の方法と同様にして、表題化合物(固体)を得た。
実施例219
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-{[2-(2-ヒドロキシエトキシ)フェニル]アミノ}フラン-3(2H)-オン
実施例220
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(6-キノリニルアミノ)フラン-3(2H)-オン
実施例221
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-メトキシフェニル)アミノ]フラン-3(2H)-オン
実施例222
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2,4-ジフルオロフェニル)アミノ]フラン-3(2H)-オン
実施例223
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-モルホリノフェニル)アミノ]フラン-3(2H)-オン
実施例224
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-フルオロベンジル)アミノ]フラン-3(2H)-オン
実施例225
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-チエニルメチル)アミノ]フラン-3(2H)-オン
実施例226
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(シクロヘプチルアミノ)フラン-3(2H)-オン
実施例227
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(イソプロピルアミノ)フラン-3(2H)-オン
実施例228
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(3-ピラゾリル)アミノ]フラン-3(2H)-オン
実施例67で得られた化合物を用い、実施例227記載の方法と同様にして、表題化合物(固体)を得た。
実施例229
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(3-フルオロベンジル)アミノ]フラン-3(2H)-オン
実施例230
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(シクロプロピルアミノ)フラン-3(2H)-オン
実施例231
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-メトキシエチル)アミノ]フラン-3(2H)-オン
実施例232
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(1-メチル-4-ピペリジニル)アミノ]フラン-3(2H)-オン
実施例65で得られた化合物を用い、実施例231記載の方法と同様にして、表題化合物(固体)を得た。
実施例233
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(4-フルオロ-2-メチルフェニル)アミノ]フラン-3(2H)-オン
実施例234
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2,6-ジメチル3-ピリジニル)アミノ]フラン-3(2H)-オン
実施例235
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-フルオロベンジル)アミノ]フラン-3(2H)-オン
実施例236
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(2-フェニル-2-プロパニル)アミノ]フラン-3(2H)-オン
実施例237
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(2-アダマンチルアミノ)フラン-3(2H)-オン
実施例113で得られた化合物を用い、実施例236記載の方法と同様にして、表題化合物(固体)を得た。
実施例238
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-(シクロペンチルアミノ)フラン-3(2H)-オン
実施例239
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]- 5-[(5-インダゾリル)アミノ]フラン-3(2H)-オン
実施例240
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]- 5-[(5-ベンゾイミダゾリル)アミノ]フラン-3(2H)-オン
実施例241
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(1-フェニルエチル)アミノ]フラン-3(2H)-オン
実施例106で得られた化合物を用い、実施例240記載の方法と同様にして、表題化合物(固体)を得た。
実施例242
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-{[(3-メチル-2-チエニル)メチル]アミノ}フラン-3(2H)-オン
実施例243
2-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-5-[(トランス-4-ヒドロキシシクロヘキシル)アミノ]フラン-3(2H)-オン
実施例244
エチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-2-(7-メトキシ-3,4-ジヒドロイソキノリン-2(1H)-イル)-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート
(第1工程)
7-メトキシ-1,2,3,4-テトラヒドロイソキノリン塩酸塩(2.10 g、10.5 mmol)のテトラヒドロフラン懸濁液に、室温にてトリエチルアミン(3. 48 mL, 25.0 mmol)を添加し、30分間攪拌した。次いで、実施例74の第3工程記載の方法と同様にして得られるエチル 2-エトキシ-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート(2.00 g、10.0 mmol)を添加し、室温のまま5日間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した。得られる有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー(シリカゲル、クロロホルム/メタノール)で精製し、エチル 2-[7-メトキシ-3,4-ジヒドロイソキノリン-2(1H)-イル]-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレートを油状物として得た(収量 2.85 g、収率 89%)。
1H NMR (CDCl3) δ (ppm) 7.09 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.6 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.78 (s, 2H), 4.54 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.89 (t, J = 5.9 Hz, 2H), 3.79 (d, J = 2.9 Hz, 3H), 2.86 - 3.04 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H); LCMS (m/z): 318.2 [M+H] +.
(第2工程)
エチル 2-[7-メトキシ-3,4-ジヒドロイソキノリン-2(1H)-イル]-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート(2.58 g, 8.98 mmol)および7-アザインドール-3-カルボキシアルデヒド(1.31 g, 8.98 mmol)のエタノール溶液(12 mL)に、室温でL-プロリンを加え、24時間加熱還流した。析出した固体をろ取し、エタノールついでジイソプロピルエーテルで洗浄、乾燥させて、表題化合物を固体として得た(収量 1.20 g、収率 30%)。
1H NMR (DMSO-d6) δ (ppm) 12.37 (s, 1H), 8.41 (dd, J = 7.9, 1.5 Hz, 1H), 8.33 (dd, J = 4.7, 1.5 Hz, 1H), 8.08 (s, 1H), 7.26 - 7.13 (m, 2H), 6.90 (s, 2H), 6.85 (dd, J = 8.3, 2.6 Hz, 1H), 4.95 (br. s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.85 - 4.05 (m, 2H), 3.76 (s, 3H), 3.00 (t, J = 5.8 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); LCMS (m/z): 446.2 [M+H] +.
イソプロピル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-2-(モルホリノアミノ)-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート
マロン酸ジイソプロピル及びクロロアセチルクロリドを用いて実施例74の第3工程記載の方法と同様にして得られたイソプロピル2-イソプロポキシ-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート(12.2 g, 53.6 mmo1)のエタノール溶液(45 mL)に、4-アミノモルホリン(5.7 ml, 59.2 mmol)を室温で滴下し,その後18時間攬件した。反応溶液を減圧濃縮し、得られる固体をメチルtert−ブチルエーテルで懸濁してろ取し、メチルtert−ブチルエーテルついでヘキサンで洗浄、乾燥させ、イソプロピル 2-(モルホリノアミノ)-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレートを固体として得た(収量11.2 g, 収率75%)。
1H NMR (DMSO-d6) δ (ppm) 9.60 (s, 1H), 4.95 - 5.05 (m, 1H), 4.57 (s, 2H), 3.60 - 3.68 (m, 4H), 2.87 - 2.95 (m, 4H), 1.22 (d, J = 6.40 Hz, 6H); LCMS (m/z): 271.0 [M+H] +
(第2工程)
イソプロピル 2-(モルホリノアミノ)-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート(5.00 g, 18.5 mmol)および7-アザインドール-3-カルボキシアルデヒド(2.49 g, 17.1 mmol)のエタノール溶液(25 mL)に、室温でL-プロリン(0.24 g, 2.04 mmol)を加え、3日間加熱還流した。析出した固体をすばやくろ取し、加熱したエタノール、ついでヘキサンで洗浄、乾燥させて、表題化合物を固体として得た(収量 4.22 g、収率 62%)。
1H NMR (DMSO-d6) δ (ppm) 12.34 (br. s, 1H), 10.07 (s, 1H), 8.94 (d, J = 7.78 Hz, 1H), 8.33 (dd, J = 1.38, 4.64 Hz, 1H), 8.12 (d, J = 2.76 Hz, 1H), 7.22 (dd, J = 4.52, 8.03 Hz, 1H), 6.84 (s, 1H), 4.99 - 5.12 (m, 1H), 3.75 - 3.86 (m, 4H), 3.03 - 3.13 (m, 4H), 1.27 (d, J = 6.27 Hz, 6H); LCMS (m/z): 399.1 [M+H] +.
エチル 5-[(1H-ピロロ[2,3-b]ピリジン-3-イル)メチレン]-4-オキソ-2-{[4-(2,2,2-トリフルオロエチル)ピペラジニル]アミノ}-4,5-ジヒドロフラン-3-カルボキシレート
1-(2,2,2-トリフルオロエチル)ピペラジン(4.88 g, 29.0 mmol)の水溶液(4.9 mL)に、氷冷下、亜硝酸ナトリウム(4.04 g, 58.6 mmol)の水溶液(20 mL)、ついで酢酸(5.0 mL, 87.0 mmol)をゆっくり滴下し、その後1時間攪拌した。室温に戻し、さらに2時間攪拌した。反応溶液に炭酸ナトリウムを加え、液性をpH 9に調整した後、酢酸エチルで希釈し、水、ついで飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、減圧濃縮し、1-ニトロソ-4-(2,2,2-トリフルオロエチル)ピペラジンを油状物として得た(収量 5.57 g、収率 97%)。
1H NMR (DMSO-d6) δ (ppm) 4.18 - 4.22 (m, 2H), 3.72 - 3.76 (m, 2H), 3.32 (q, J = 10.13 Hz, 2H), 2.84 - 2.89 (m, 2H), 2.59 - 2.64 (m, 2H).
(第2工程)
水素化アルミニウムリチウム(2.22 g, 58.5 mmol)のテトラヒドロフラン懸濁液(100 mL)に、氷冷下、1-ニトロソ-4-(2,2,2-トリフルオロエチル)ピペラジン(5.43 g, 27.5 mmol)のテトラヒドロフラン溶液(10 mL)を滴下し、室温に戻して5日間攪拌した。反応溶液を再び氷冷し、発泡がおさまるまで酢酸エチルを加え、次いで、水(2.1 mL)を加え、20分間攪拌した。15% w/v 水酸化ナトリウム水溶液(2.1 mL)、水(6.3 mL)を順次加え、得られる懸濁液を室温に戻して1時間激しく攪拌した。さらに、無水硫酸マグネシウムを加え、しばらく攪拌した後、懸濁液をろ過した。ろ液を減圧濃縮させ、4-(2,2,2-トリフルオロエチル)ピペラジン-1-アミンを油状物として得た(収量 4.72 g、収率 94%)。
1H NMR (DMSO-d6) δ (ppm) 3.12 (br. s, 1H), 2.98 (q, J = 9.6 Hz, 2H), 2.60 - 2.80 (m, 8H).
(第3工程)
4-(2,2,2-トリフルオロエチル)ピペラジン-1-アミン(4.72 g、25.8 mmol)のエタノール溶液(43 mL)に、実施例74の第3工程記載の方法と同様にして得られるエチル 2-エトキシ-4-オキソ-4,5-ジヒドロフラン-3-カルボキシレート(4.70 g、23.5 mmol)を室温で添加し、2時間攪拌した。析出した固体をろ取し、ジエチルエーテルついでヘキサンで洗浄、乾燥させ、エチル4-オキソ-2-{[4-(2,2,2-トリフルオロエチル)ピペラジニル]アミノ}-4,5-ジヒドロフラン-3-カルボキシレートを固体として得た(収量 5.64 g、収率 71%)。
1H NMR (DMSO-d6) δ (ppm) 8.94 (s, 1H), 4.61 (s, 2H), 4.32 (q, J = 7.07 Hz, 2H), 3.03 (q, J = 9.47 Hz, 2H), 2.95 - 2.99 (m, 4H), 2.85 - 2.90 (m, 4H), 1.37 (t, J = 7.20 Hz, 3H); LCMS (m/z): 338.1 [M+H] +.
(第4工程)
エチル4-オキソ-2-{[4-(2,2,2-トリフルオロエチル)ピペラジニル]アミノ}-4,5-ジヒドロフラン-3-カルボキシレート(3.01 g, 8.93 mmol)および7-アザインドール-3-カルボキシアルデヒド(1.25 g, 8.55 mmol)のエタノール溶液(25 mL)に、室温でL-プロリン(99 mg, 0.86 mmol)を加え、2日間加熱還流した。析出した固体をすばやくろ取し、加熱したエタノール、ついでヘキサンで洗浄、乾燥させて、表題化合物を固体として得た(収量 2.64 g、収率 66%)。
1H NMR (DMSO-d6) δ (ppm) 12.32 (s, 1H), 10.09 (s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 4.1 Hz, 1H), 8.09 (s, 1H), 7.30 - 7.16 (m, 1H), 6.80 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.31 - 3.41 (m, 2H), 3.06 (s, 4H), 2.88 (s, 4H), 1.25 (t, J = 7.0 Hz, 3H); LCMS (m/z): 466.0 [M+H] +.
[被験化合物溶液の調整および保存]
被験化合物は10 mMもしくは1 mMになるようにDMSOに溶解あるいは懸濁してストック溶液とし、試験するまで-20℃の暗所に保存した。
[Cdc7プロテインキナーゼ阻害作用]
キット付属の酵素(human Cdc7/human ASK複合体タンパク質)は7 nMとなるようアッセイバッファーで希釈して酵素溶液を調製した。
阻害率(%)=(1-(C - A)/(B - A))X 100
ただし、A:ブランクウェルのP/(P+S)、B:溶媒ウェルのP/(P+S)、C:化合物添加ウェルのP/(P+S)を示す。
また、IC50値は、阻害率と被験化合物濃度(対数)の回帰分析により算出した。
本発明化合物のCdc7に対するIC50値は、以下の表4に示すとおり、すべて1 μM未満であった。
[細胞を用いたリン酸化阻害作用]
培養細胞
培養細胞への薬剤添加
MCM2リン酸化阻害作用の測定
本試験により、表4のとおり本発明化合物は、0.1 μMの濃度でMCM2のリン酸化を阻害していた。
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