WO2012133802A1 - 新規フラノン誘導体 - Google Patents
新規フラノン誘導体 Download PDFInfo
- Publication number
- WO2012133802A1 WO2012133802A1 PCT/JP2012/058636 JP2012058636W WO2012133802A1 WO 2012133802 A1 WO2012133802 A1 WO 2012133802A1 JP 2012058636 W JP2012058636 W JP 2012058636W WO 2012133802 A1 WO2012133802 A1 WO 2012133802A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mmol
- oxo
- dihydrofuran
- yield
- carboxylate
- Prior art date
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- 150000002241 furanones Chemical class 0.000 title claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 125000003277 amino group Chemical group 0.000 claims abstract description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 4
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 abstract description 367
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 685
- 239000000243 solution Substances 0.000 description 441
- 239000007787 solid Substances 0.000 description 409
- 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 156
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 138
- 238000001914 filtration Methods 0.000 description 125
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 238000000034 method Methods 0.000 description 117
- 239000000203 mixture Substances 0.000 description 115
- -1 and specifically Chemical group 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 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 76
- 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 71
- 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 52
- 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 35
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 33
- 229930182821 L-proline Natural products 0.000 description 33
- 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
- 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
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 238000001816 cooling Methods 0.000 description 20
- 239000003999 initiator Substances 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 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
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 15
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 230000008569 process Effects 0.000 description 13
- 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
- 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
- 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
- 150000007942 carboxylates Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 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
- 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
- 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
- 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
- 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
- 238000002360 preparation method 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
- 238000003756 stirring Methods 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
- 0 *C(C1=O)=C(N(*)*)OC1=Cc1c[n]c2c1cccn2 Chemical compound *C(C1=O)=C(N(*)*)OC1=Cc1c[n]c2c1cccn2 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
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 5
- 125000005842 heteroatom Chemical group 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-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
- 150000001412 amines Chemical class 0.000 description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 4
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- 201000010099 disease Diseases 0.000 description 4
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- 239000007788 liquid Substances 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
- 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
- 239000000126 substance Substances 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
- 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
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
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- 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
- 125000005907 alkyl ester group Chemical group 0.000 description 3
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- 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
- 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
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- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
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- 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
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- 239000011550 stock solution Substances 0.000 description 3
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- 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
- 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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- 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
- 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
- GZVYDHQDGHNYKS-UHFFFAOYSA-N ethyl 2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]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(NC(=O)OC(C)(C)C)C=C1 GZVYDHQDGHNYKS-UHFFFAOYSA-N 0.000 description 1
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- 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
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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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- 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
- 238000006386 neutralization reaction Methods 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
- 125000001181 organosilyl group Chemical group [SiH3]* 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
- 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
-
- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—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
Definitions
- the present invention relates to a pharmaceutical, particularly a novel furanone derivative having Cdc7 inhibitory action or a pharmaceutically acceptable salt thereof.
- Cancer is a disease caused by the growth of cells in a living body without control. Since cancer cells usually grow faster than normal cells, it is considered that cancer can be treated by controlling DNA replication during cell division, particularly chromosome division. Actually, gemcitabine having a DNA replication inhibitory action is widely used for the treatment of non-small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, breast cancer, ovarian cancer and the like.
- Cdc7 is a kind of serine threonine protein kinase and is an essential enzyme for initiating DNA replication in the cell cycle. Specifically, Cdc7 forms a complex with a cofactor such as Dbf4 (ASK) and phosphorylates MCM (minichromosome maintenance) protein as a substrate. It is believed that this phosphorylation causes Cdc45 and DNA polymerase to gather on DNA to form an MCM complex, and DNA replication starts (see Non-Patent Document 1). More recent studies have shown that Cdc7 plays an important role not only in DNA replication but also in the DNA damage pathway (see Non-Patent Document 2).
- ASK Dbf4
- MCM minichromosome maintenance
- Cdc7 has attracted attention as a target for anticancer agents, and is actively researched.
- CDC7 was found to be overexpressed not only in general human tumor-derived cell lines but also in cells collected from living organisms such as breast cancer, colon cancer, and lung cancer (see Non-Patent Document 3).
- Non-Patent Document 4 it has been shown that CDC7 is overexpressed in breast cancer cells of p53 mutant triple negative (ER- / PR- / Her2-) (see Non-Patent Document 4), and triples that have been considered difficult to treat so far.
- Cdc7 is expected to be a promising target molecule for negative breast cancer.
- Cdc7 inhibition induces cell cycle arrest in Cdc7 expression suppression experiments using RNA interference technology. More importantly, Cdc7 inhibition by RNA interference technology inhibits the growth of human tumor cells such as HeLa and HCT116, but has only a limited effect on normal cells (normal human skin fibroblasts). There was no (refer nonpatent literature 5).
- a Cdc7 selective inhibitor is expected to have an effective therapeutic effect on various cancers.
- Various compounds having a Cdc7 inhibitory action have been reported so far, but it has not been reported that the novel furanone derivative of the present invention or a pharmaceutically acceptable salt thereof has a Cdc7 inhibitory action.
- An object of the present invention is to provide a pharmaceutical, particularly a novel furanone derivative having a Cdc7 inhibitory action, or a pharmaceutically acceptable salt thereof.
- the present invention is achieved by the following (1) to (3).
- A represents —COOR1 or a hydrogen atom
- R1 represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic ring which may have a substituent
- R2 and R3 are It may be the same or different and may have a hydrogen atom, a hydrocarbon group which may have a substituent, a phenyl group which may have a substituent, a heterocyclic ring which may have a substituent, or a substituent.
- a heterocyclic fused ring that may be present may be formed, and R4 represents a hydrogen atom or a halogen atom, provided that when A represents —COOR1, R2 and R3 have a substituent at the same time. R3 when R is not a good amino group and A represents a hydrogen atom It represents a hydrogen atom.)
- R4 represents a hydrogen atom or a halogen atom, provided that when A represents —COOR1, R2 and R3 have a substituent at the same time.
- R3 when R is not a good amino group and A represents a hydrogen atom It represents a hydrogen atom.
- the present inventors have found that the novel furanone derivative represented by the formula (I) and pharmaceutically acceptable salts thereof have an excellent Cdc7 inhibitory action.
- the present invention has been completed.
- Cell proliferation can be controlled by the compounds provided by the present invention. Therefore, the compound of the present invention having a Cdc7 inhibitory action is useful as a therapeutic agent for a drug, particularly a disease derived from abnormal cell proliferation such as cancer.
- novel furanone derivative of the present invention is a compound represented by the following formula (I).
- A represents —COOR1 or a hydrogen atom
- R1 represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic ring which may have a substituent
- R2 and R3 are It may be the same or different and may have a hydrogen atom, a hydrocarbon group which may have a substituent, a phenyl group which may have a substituent, a heterocyclic ring which may have a substituent, or a substituent.
- a heterocyclic fused ring that may be present may be formed, and R4 represents a hydrogen atom or a halogen atom, provided that when A represents —COOR1, R2 and R3 have a substituent at the same time.
- the hydrocarbon group which may have a substituent include: a) a linear or branched alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl, isopropyl, tert-butyl, hexyl, etc.) ), b) a linear or branched alkenyl group having 1 to 6 carbon atoms (for example, vinyl, allyl, isopropenyl, 2-butenyl, etc.), c) an alkynyl group having 2 to 6 carbon atoms (eg, ethynyl, propargyl, 2-buty
- the aryl part of the aralkyl group and the aryl part of the aralkyl group includes aryl having 6 to 14 carbon atoms (for example, phenyl, naphthyl, indenyl, etc.).
- the alkylene part of the aralkyl group includes 1 hydrogen atom from the alkyl group. It is synonymous with what is excluded.
- heterocyclic portion of the heterocyclic ring which may have a substituent examples include an alicyclic heterocyclic group and an aromatic heterocyclic group.
- the alicyclic heterocyclic group include a nitrogen atom, a sulfur atom and And a 3- to 8-membered heterocyclic group containing at least one heteroatom selected from oxygen atoms.
- Specific examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and the like.
- aromatic heterocyclic group examples include a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom.
- Specific examples include imidazolyl, pyrazolyl, thienyl, thiazolyl, pyridyl and the like.
- the heterocyclic condensed ring portion of the heterocyclic condensed ring which may have a substituent is, for example, a bicyclic condensed 3- to 8-membered ring and selected from a nitrogen atom, a sulfur atom and an oxygen atom
- a condensed heterocyclic group containing at least one hetero atom is exemplified. Specific examples include benzothiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoquinolyl, phthalimide and the like.
- Examples of the amino group which may have a substituent include a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an aryl group, a heteroaryl group, and the like.
- an alkyl group, an alkylamino group, an aryl group, a heteroaryl group, a heterocyclic group, a heterocyclic fused ring group or the like having one or more substituents or unsubstituted is bonded.
- the “one or more substituents” of these groups bonded to the amino group are one or two or more of the same or different arbitrary substituents.
- a halogen atom for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, Examples thereof include an amino group, a nitro group, a cyano group, a hydroxy group, a substituted or unsubstituted alkylamino group, a carbamoyl group, a carboxyl group, a formyl group, an acetyl group, and a benzoyl group.
- substituents may be present at any chemically possible position, and when there are two or more substituents, These substituents may be the same or different, for example, halogen atoms, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted amino groups, nitro groups, cyano groups, hydroxy groups, Examples thereof include a substituted or unsubstituted alkylamino group, carbamoyl group, carboxyl group, formyl group, acetyl group, and benzoyl group.
- examples thereof include a condensed alicyclic heterocyclic group containing at least one selected hetero atom, and specifically, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, azepinyl, diazepinyl, dihydroisoquinolyl, tetrahydroisoquinolyl , Tetrahydroquinolyl, isoindolinyl, indolinyl, te
- Compound (I) of the present invention may have an isomer depending on, for example, the type of substituent.
- the chemical structure of only one form of those isomers may be described, but the present invention includes all isomers (geometric isomers, optical isomers, tautomers) that can occur structurally. Etc.) and also includes isomers alone or a mixture thereof. Further, these stereoisomers specifically represented by the formulas (IZ) and (IE), which are the compounds of the present invention, and mixtures thereof are also included in the present invention.
- pharmaceutically acceptable salts of the compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, p Organic acid salts with toluenesulfonic acid and the like can be mentioned.
- ammonium salts and the like are also included in the present invention.
- Compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced, for example, by the following method.
- a method commonly used in organic synthetic chemistry such as functional group It can be easily produced by adding means such as protection and deprotection [TW Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc., 1999]. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
- Compound (Ia) in which A is —COOR1 can be produced, for example, according to Scheme 1. [Scheme 1]
- Compound (Ia) of the present invention comprises compound (III) and compound (IV) in an amount of 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents in a solvent in the conditions of Knefenergel condensation reaction, ie piperidine, etc. It can obtain by making it heat-react in presence of a catalyst base.
- the solvent may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- a lower alcohol preferably ethanol can be used.
- a catalytic amount to an equivalent amount of piperidine or proline can be used with respect to compound (III).
- the reaction can be carried out in the range of room temperature to reflux temperature for 3 hours to 2 weeks. Preferably, it can be synthesized by reacting in ethanol under reflux conditions for 1 to 3 days. This reaction can also be produced under other normal conditions used in the Knoevenager condensation reaction, for example, acidic conditions such as hydrochloric acid and acetic acid.
- Compound (IV) used as a raw material in Scheme 1 is a commercially available product (for example, a product of SIGMA-ALDRICH), or a known method [for example, Rajesh H. Bahekar et al. Bioorganic & Medicinal Chemistry, 15 (21), 6782-6795. (2007) and Seung-Jun Oh et al. Bioorganic & Medicinal Chemistry, 12 (21), 5505-5513 (2004)]. Further, the compound (III) used as the raw material of Scheme 1 can be produced by, for example, the method shown in Scheme 2 or 3. [Scheme 2]
- R1 ′ represents a substituted or unsubstituted lower alkyl group.
- Compound (VII) can be obtained by converting malonic acid diester (V) to enolate with a base such as sodium hydride in a solvent such as anhydrous tetrahydrofuran and then reacting with chloroacetyl chloride (VI).
- a base such as sodium hydride
- a solvent such as anhydrous tetrahydrofuran
- Compound (III) can be obtained by reacting compound (VII) obtained in the previous step with an equivalent to excess amount, preferably 1.2 to 3 molar equivalents of amine (VIII) in a solvent at room temperature or with heating. Can do.
- the solvent is not particularly limited as long as it is inert to the reaction, and for example, tetrahydrofuran, dimethylformamide, ethanol and the like can be used.
- the reaction varies depending on the reactivity of amine (VIII) used, but is generally completed in 1 hour to 1 day from room temperature to the reflux temperature of the solvent.
- a base such as sodium hydride, sodium hydroxide, triethylamine or the like in an equivalent amount to an excessive amount.
- compound (III) can be prepared by a known method [for example, see Sheng-Chu Kuo et al. Chem. Pharm. Bull., 36 (11), 4403-4407 (1988)] or a method analogous thereto. ) Can be produced by continuous reaction without isolation. That is, compound (III) is obtained by adding an equivalent to an excess amount, preferably 1.2 to 3 molar equivalents of amine (VIII) to the solution after the reaction in step 2-1, and reacting at room temperature or by heating. Can do.
- the malonic acid diester (V) and amine (VIII) used as raw materials of Scheme 2 can be obtained as a commercial product or by a known method. [Scheme 3]
- the compound (IIIa) in which R3 is a hydrogen atom is obtained by a known method [for example, Robert A. Mack et al. J J Med Med. 31 (10), 1910-1918 (1988) Reference] or a method according to it. That is, it can be obtained by cyclocondensing compound (IX) with 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents of isocyanate (X) in a solvent in the presence of a base such as triethylamine.
- the solvent is not particularly limited as long as it is inert to the reaction.
- diethyl ether, ethyl acetate, or a mixed solvent thereof can be used.
- reaction can be carried out in the range of ice cooling to reflux temperature for 30 minutes to 1 day, but it can be synthesized preferably by reacting at room temperature for 1 to 3 hours.
- Compound (IX) and isocyanate (X), which are raw materials of Scheme 3, can be obtained as commercially available products or by known methods.
- the compound (Ia) of the present invention can also be produced by a transesterification reaction of the compound (Ia ′) which is a lower alkyl ester shown in Scheme 4. [Scheme 4]
- R1 ′ represents a substituted or unsubstituted lower alkyl group.
- Compound (Ia) of the present invention can be obtained by known method [for example, see Takanori Iwasaki et al. J. Org. Chem., 73 (13), 5147-5150 (2008)] or a method analogous thereto. It can be produced by transesterification of '). That is, it can be obtained by subjecting compound (Ia ') and an excess amount, preferably 10 molar equivalents or more, of alcohol (XI) to a heating reaction in a solvent in the presence of a zinc tetranuclear cluster catalyst.
- the solvent is not particularly limited as long as it is inert to the reaction.
- dimethylacetamide, 1,4-dioxane, diisopropyl ether, or the like can be used.
- alcohol (XI) can be used as a solvent.
- ZnTAC24 a commercially available product (for example, manufactured by STREM CHEMICALS, product name: ZnTAC24) or one produced by the method described in the above-mentioned literature is used, and a catalyst amount, preferably 1 to 10% molar equivalent is added, Furthermore, in order to accelerate the reaction, a tertiary amount of tertiary amine such as dimethylaminopyridine or triethylamine can be added in a catalytic amount.
- the reaction can be carried out in the range of room temperature to reflux temperature for 1 hour to 1 week, but can be preferably synthesized by reacting for 1 to 3 days under reflux conditions. Alternatively, the synthesis can be performed by reacting for several minutes to several hours using a microwave synthesizer, for example, at a temperature of 60 to 150 ° C.
- This reaction can also be carried out under other ordinary conditions used in the transesterification reaction shown in Scheme 5, such as acid or base conditions, conditions using a catalyst such as tetravalent titanium, and the like.
- the compound (Ib) of the present invention is obtained by reacting a compound (Ia ′), which is a lower alkyl ester, with reaction conditions [TW Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. , 1999, pp. 377, etc., or a method analogous thereto]. That is, it can be obtained by reacting compound (Ia ′) with an equivalent to excess amount of base or acid in a solvent at a temperature between 0 ° C. and the boiling point of the solvent used.
- reaction conditions [TW Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. , 1999, pp. 377, etc., or a method analogous thereto]. That is, it can be obtained by reacting compound (Ia ′) with an equivalent to excess amount of base or acid in a solvent at a temperature between 0 ° C. and the boiling point of the solvent used.
- the solvent is not particularly limited as long as it is inert to the reaction.
- 1,4-dioxane, tetrahydrofuran, or various alcohols can be used.
- the base or acid for example, sodium hydroxide, potassium hydroxide, or hydrochloric acid can be used.
- reaction can be carried out at a temperature between 0 ° C. and the boiling point of the solvent used for 1 hour to 1 week, but can be preferably synthesized by reacting under reflux conditions for 1 hour to 1 day.
- compound (Ic) in which A and R3 are hydrogen atoms among compounds (I) of the present invention can be produced, for example, according to Scheme 6. [Scheme 6]
- R1 ′′ represents a hydrogen atom and a substituted or unsubstituted lower alkyl group.
- Compound (Ic) of the present invention is compound (Ia), wherein R1 is a substituted or unsubstituted lower alkyl ester and R3 is hydrogen by a known method [eg, Sheng-Chu Kuo et al. Chem. Pharm Bull. 38 (2) 340 -341 (1990)] or a method analogous thereto.
- the reaction involves heating a solution or suspension of compound (Ia ′′) in N, N-dimethylformamide or N, N-dimethylacetamide at a temperature between 100 ° C. and the boiling point of the solvent used for 1 to 24 hours. However, it can be synthesized by heating under reflux conditions for 1 to 12 hours.
- This reaction can also be carried out by heating and stirring in the presence of a base.
- a base for example, it can be synthesized by heating to reflux with an alcohol solvent such as ethanol in the presence of a high concentration aqueous potassium hydroxide solution.
- the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be used as a medicine, particularly as an antitumor agent, in the form of a conventional pharmaceutical preparation for oral administration or parenteral administration such as infusion. .
- Preparations for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as syrups. These formulations can be prepared by conventional methods. Solid preparations can be prepared by using conventional pharmaceutical carriers such as lactose, starch such as corn starch, crystalline cellulose such as microcrystalline cellulose, hydroxypropylcellulose, calcium carboxymethylcellulose, talc, magnesium stearate, etc. it can. Capsules can be prepared by wrapping the granules or powders thus prepared in capsules. A syrup can be prepared by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethylcellulose and the like.
- Preparations for parenteral administration include infusions such as instillation.
- Injectable formulations can also be prepared by conventional methods, including isotonic agents (eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (eg, sodium sulfite, Albumin) and preservatives (eg, benzyl alcohol, methyl p-oxybenzoate).
- isotonic agents eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose
- stabilizers eg, sodium sulfite, Albumin
- preservatives eg, benzyl alcohol, methyl p-oxybenzoate
- the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is effective for the treatment of drugs, particularly tumors.
- tumors include solid tumors such as breast cancer, colon cancer and lung cancer, and blood cancers such as leukemia, lymphoma and myeloma.
- the dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be varied according to the severity of the disease, the age and weight of the patient, the dosage form, etc., but is usually 1 mg per day in an adult. It is in the range of ⁇ 1,000 mg, which can be administered once or divided into two or three times by the oral or parenteral route.
- Hexamethylenetetramine (0.69 g, 4.9 mmol) was added to an acetic acid solution (5.0 mL) of 5-chloro-7-azaindole (0.50 g, 3.3 mmol) at room temperature, and the mixture was heated to reflux for 8 hours.
- the reaction solution was allowed to cool to room temperature, diluted with water, and extracted twice with ethyl acetate. The obtained organic layer was washed in turn with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
- Diethyl malonate (5.0 (mL, 0.033 mol) was added dropwise to an anhydrous tetrahydrofuran solution (50 mL) of sodium hydride (60% w / w ⁇ ⁇ ⁇ ⁇ in oil, 2.7 g, 0.066 mol) under ice cooling, and heated to reflux for 5 minutes. did.
- the reaction solution was ice-cooled, chloroacetyl chloride (2.8 mL, 0.035 mol) was added dropwise, and the mixture was stirred for 1 hr and then heated and stirred at 45 ° C. for 1 hr.
- reaction solution was ice-cooled again, piperidine (3.9 mL, 0.040 mol) was added dropwise, and the mixture was stirred at room temperature for 12 hours.
- the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (2 times), and further extracted with chloroform (1 time).
- the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Methyl 4-oxo-2- (phenylamino) -4,5-dihydrofuran-3- obtained in the same manner as described in the first step of Example 2 using methyl 4-chloroacetoacetate and phenyl isocyanate.
- Piperidine (0.022 mL, ⁇ ⁇ ⁇ ⁇ 0.22 mmol) was added to a 2-propanol solution (1.0 mL) of carboxylate (0.047 g, 0.20 mmol) and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) at room temperature, Heated to reflux for 5 days.
- Methyl 2-[(4-fluorophenyl) amino] -4-oxo-4 obtained in the same manner as described in the first step of Example 2 using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate , 5-Dihydrofuran-3-carboxylate (0.25 g, 1.0 mmol) and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol solution (5.0 mL) at room temperature with L-proline (0.023 g, 0.20 mmol) was added, and the mixture was heated to reflux for 2 days.
- Methyl 2-[(4-fluorophenyl) amino] -4-oxo-4 obtained in the same manner as described in the first step of Example 2 using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate , 5-dihydrofuran-3-carboxylate (0.13 g, 0.50 mmol) and zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0062 g, 0.0065 mmol) in 1-butanol (2.0 mL) under nitrogen atmosphere The mixture was heated and stirred at 80 ° C. for 3 days, and further stirred at room temperature for 3 days.
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M sodium hydroxide aqueous solution (0.13 mL, 0.26 mmol), ethanol (5.0 mL) was added, and the mixture was heated to reflux for 1.5 hr. The precipitate was quickly filtered and washed with heated ethanol. The obtained solid was washed with hexane and dried to give the title compound as a solid (yield 0.051 g, yield 44%).
- Example 63 Ethyl 5-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate In the same manner as in the method described in Example 56, the title compound (solid) was obtained.
- Example 51 compound 0.038 g, 0.10 mmol
- N- (2-hydroxyethyl) morpholine (0.20 mL, 1.6 mmol)
- zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O 0.0019 g, 0.0020 mmol
- N-dimethylacetamide solution 0.8 mL
- the reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration.
- the filtrate was purified by HPLC preparative chromatography to give the title compound as a solid (yield 0.0075 g, 15% yield).
- Example 79 Ethyl 5-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -2-morpholino-4-oxo-4,5-dihydrofuran-3-carboxylate In the same manner as in the method described in Example 76, the title compound (solid) was obtained.
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.015 mL, ⁇ 0.029 ⁇ mmol), ethanol (1.5 mL) was added, and the mixture was heated to reflux for 30 minutes. The precipitate was quickly filtered and washed with heated ethanol. The obtained solid was washed with hexane and dried to obtain the title compound as a solid (yield 0.0051 g, yield 32%).
- reaction solution was ice-cooled, neutralized with 2M sodium hydroxide aqueous solution (0.047 mL, 0.094 mL), ethanol (0.5 mL) was added, and the mixture was heated to reflux for 16 min. The precipitate was quickly filtered and washed with heated ethanol. The obtained solid was washed with hexane and dried to obtain the title compound as a solid (yield 0.014 g, yield 59%).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.041 mL, 0.082 mL), ethanol (0.5 mL) was added, and the mixture was heated to reflux for 16 min. The precipitate was quickly filtered and washed with heated ethanol. The obtained solid was washed with hexane and dried to obtain the title compound as a solid (yield 0.00079 g, yield 5%).
- Example 21 (0.039 g, 0.10 mmol), 4-dimethylaniline (0.0024 g, 0.020 mmol) and zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0012 g, 0.0013 mmol) in 2-propanol / N,
- the N-dimethylacetamide mixed solution (1.0 mL / 1.0 mL) was heated and stirred at 150 ° C. for 1.5 hours using a microwave synthesizer (Initiator TM manufactured by Biotage).
- the reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration.
- the filtrate was purified by HPLC preparative chromatography to give the title compound as a solid (Yield 0.011 g, Yield 27%).
- Methyl 2-[(2,4-difluorophenyl) amino] -4 obtained in the same manner as described in the first step of Example 2 using methyl 4-chloroacetoacetate and 2,4-difluorophenyl isocyanate -Oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 1.0 mmol) and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL) at room temperature L-proline (0.023 g, 0.20 mmol) was added and heated to reflux for 12 hours.
- 1,3-propanediol / N, N-dimethylacetamide mixed solution (0.5 mL) of the compound of Example 51 (0.038 g, 0.10 mmol) and the zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0019 g, 0.0020 mmol) /0.5 mL) was heated and stirred at 120 ° C. for 2 hours and further at 100 ° C. for 12 hours.
- the reaction solution was allowed to cool to room temperature, diluted with water, and the precipitated solid was collected by filtration. Further, ethyl acetate was added to the filtrate, and the precipitated solid was collected by filtration.
- These solids were combined and purified by HPLC preparative chromatography to give the title compound as a solid (yield 0.0067 g, 16% yield).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.047 mL, 0.094 mmol), and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0066 g, yield 28%).
- Methyl 2- (cyclopropylamino) -4-oxo-4,5-dihydroform obtained in the same manner as described in the first step of Example 4 using dimethyl malonate, chloroacetyl chloride and cyclopropylamine.
- L-proline (0.029 g, 0.25 mmol) in ethanol solution (6.0 mL) of furan-3-carboxylate (0.50 g, 2.5 mmol) and 7-azaindole-3-carboxyaldehyde (0.37 ⁇ ⁇ ⁇ ⁇ g, 2.5 mmol) at room temperature ) And heated to reflux for 16 hours.
- the reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration, washed with methanol, and dried to give the title compound as a solid (yield 0.012 g, yield 30%).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.49 mL, 0.97 mmol), ethanol (8.0 mL) was added, and the mixture was heated to reflux for 30 min. The precipitate was quickly collected by filtration and further washed with heated ethanol. The obtained solid was washed with hexane and dried to give the title compound as a solid (yield 0.027 g, yield 18%).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.46 mL, 0.92 ⁇ mmol), ethanol (11 mL) was added, and the mixture was heated to reflux for 40 minutes. The precipitate was quickly filtered and washed with heated ethanol. The obtained solid was washed with hexane and dried to obtain the title compound as a solid (yield 0.10 g, yield 70%).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M aqueous sodium hydroxide solution (0.30 mL, 0.60 mmol), and the solvent was evaporated under reduced pressure.
- the residue was suspended in chloroform, collected by filtration, washed successively with water, ethanol and hexane, and dried to give the title compound as a solid (yield 0.028 g, yield 12%).
- reaction solution was ice-cooled, neutralized by dropwise addition of 2M sodium hydroxide aqueous solution (0.57 mL, 1.1 mmol), and heated to reflux for 10 minutes. After the solvent was concentrated under reduced pressure, the precipitated solid was collected by filtration, washed successively with water and ethyl acetate, and dried to give the title compound as a solid (yield 0.010 g, yield 5%).
- Example 63 The compound of Example 63 (0.052 g, 0.14 mmol), 2- (dimethylamino) ethanol (0.14 mL, 1.4 mmol), zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0019 g, 0.0020 mmol) and 4-dimethyl
- a solution of aminopyridine (0.0049 g, 0.040 mmol) in N, N-dimethylacetamide (1.0 mL) was heated and stirred at 150 ° C. for 1 hour using a microwave synthesizer (Initiator TM manufactured by Biotage).
- the reaction solution was purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.018 g, yield 24%).
- 1-methyl-2-pyrrolidone solution (15 mL) of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol), N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6 mL, 0.012 (mol) The mixture was heated and stirred at 60 ° C. for 12 hours. After allowing to cool to room temperature, the reaction solution was added to ice water and extracted with ethyl acetate.
- reaction solution was allowed to cool to room temperature, hexamethyleneimine (0.071 mL, 0.63 mmol) was added dropwise, and the mixture was stirred for 1 hr.
- the reaction solution was diluted with water and extracted with chloroform.
- the obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform / methanol) to give 2-methoxyethyl 2-azepinyl-4-oxo-4,5- Dihydrofuran-3-carboxylate was obtained as an oil (yield 0.065 g, yield 43%).
- Example 141 The mixture obtained by the same method as in Example 141 was purified by HPLC preparative chromatography purification (aqueous ammonium acetate / acetonitrile) to obtain the title compound (solid).
- reaction solution was allowed to cool to room temperature and then purified by HPLC preparative chromatography (aqueous ammonium acetate / acetonitrile) to obtain the title compound as a solid (yield 0.010 g, yield 3%).
- N-butanol / N, N-dimethylacetamide mixed solution (0.5 mL / 0.5 mL) of the compound of Example 74 (0.032 g, 0.070 mmol) and the zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0033 g, 0.0035 mmol) ) was stirred with heating at 150 ° C. for 30 minutes using a microwave synthesizer (Initiator TM manufactured by Biotage). The reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration. The filtrate was purified by HPLC preparative chromatography to give the title compound as a solid (yield 0.015 g, yield 44%).
- N, -N-dimethylformamide solution of 4-nitro-m-cresol (0.25 g, 1.6 mmol), 2- (chloromethyl) pyrimidine hydrochloride (0.40 g, 2.4 mmol) and potassium carbonate (0.50 g, 4.0 mmol) ( 6.0 mL) was heated and stirred at 70 ° C. for 18 hours. After allowing to cool to room temperature, the reaction solution was added to ice water and extracted with ethyl acetate.
- Example 161 The mixture obtained by the same method as in Example 161 was purified by HPLC preparative chromatography purification (aqueous ammonium acetate / acetonitrile) to obtain the title compound (solid).
- Example 128 The compound of Example 128 (0.070 g, 0.14 mmol) and a saturated aqueous sodium hydrogen carbonate solution (0.80 mL) in a methanol / dichloromethane mixed solution (0.4 mL / 1.6 mL) were cooled to 3-chloroperbenzoic acid (0.050 g, 0.28 mmol) was added and stirred for 1 hour.
- the reaction solution was extracted with dichloromethane, and the obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution.
- the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.010 g, yield 13%).
- the reaction mixture was diluted with water and extracted twice with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the residue was purified by column chromatography (silica gel, ethyl acetate / methanol) and concentrated under reduced pressure. Hexamethyleneimine (0.046 ⁇ mL, 0.41 mmol) was added dropwise to an ethanol solution (3.0 mL) of the obtained residue (about 0.11 g) and stirred for 30 minutes. 7-azaindole-3-carboxaldehyde (0.043 g, 0.30 mmol) was added to the reaction solution, and the mixture was heated to reflux for 4 days. The reaction solution was allowed to cool to room temperature and purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.020 g, yield 3%).
- a microwave synthesizer Initiator TM manufactured by Biotage
- Example 108 The compound of Example 108 (0.050 g, 0.12 mmol), 1-butanol (0.50 mL, 5.5 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst Zn 4 (OCOCF 3 ) 6 O (0.0058 g, 0.0061 mmol) of N, N-dimethylacetamide solution (0.5 mL) was heated and stirred at 150 ° C. for 1.5 hours using a microwave synthesizer (Initiator TM manufactured by Biotage). The reaction solution was allowed to cool to room temperature and purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0044 g, yield 6%).
- Example 108 compound (0.10 g, 0.25 mmol), 2- (dimethylamino) ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.0060 g, 0.049 mmol) and zinc cluster catalyst Zn 4 (OCOCF 3 )
- a solution of 6 O (0.012 g, 0.012 mmol) in N, N-dimethylacetamide (0.5 mL) was stirred with heating at 150 ° C. for 30 minutes using a microwave synthesizer (Initiator TM manufactured by Biotage). The reaction solution was allowed to cool to room temperature and then purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0023 g, yield 2%).
- Diisopropyl azodicarboxylate (5.8 mL, 0.030 mmol) was added dropwise to a tetrahydrofuran solution (50 mL) of 4-nitro-m-cresol (3.0 g, 0.020 mmol) and triphenylphosphine (7.7 g, 0.029 mmol) with ice cooling. And stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, and a solution of 2-pyridineethanol (2.6 mL, 0.024 mmol) in tetrahydrofuran (5.0 mL) was added dropwise and stirred at room temperature for 16 hours.
- Example 15 compound (0.10 g, 0.24 mmol), 2- (dimethylamino) ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.010 g, 0.082 mmol) and zinc cluster catalyst Zn 4 (OCOCF 3 )
- a solution of 6 O (0.018 g, 0.019 mmol) in N, N-dimethylacetamide (2.0 mL) was heated and stirred at 130 ° C. for 24 hours.
- tert-butyl hypochlorite (4.7 mL, 0.038 mol) was added dropwise to a solution of cyclohexanone oxime (4.0 g, 0.035 mol) in dichloromethane / ethanol (40 mL / 5.0 mL) until -20 °C Cooled and stirred for 30 minutes.
- 1,3-Cyclohexadiene (5.0 mL, 0.052 mol) was added dropwise, the temperature was raised to 0 ° C., and the mixture was stirred for 4 days.
- Cis-4-aminocyclohexanol hydrochloride (0.051 g, 0.34 mmol) and ethyl -2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.073) obtained in the third step of Example 74
- ethanol solution 0. mL
- triethylamine (0.052 mL, 0.37 mmol) was added at room temperature and stirred for 1 hour.
- 7-azaindole-3-carboxaldehyde (0.044 g, 0.30 mmol) and piperidine (0.0067 mL, 0.067 mmol) were added, and the mixture was heated to reflux for 4 days.
- Example 15 A solution of the compound obtained in Example 15 (0.050 g, 0.12 mmol) in N, N-dimethylformamide (1.0 mL) was heated and stirred at 150 ° C. for 6 hours. The reaction solution was allowed to cool to room temperature and purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0050 g, yield 11%).
- Example 211 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5- (3-pyridinylamino) furan-3 (2H) -one Using the compound obtained in Example 27, the title compound (solid) was obtained in the same manner as described in Example 210.
- Example 212 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(4-carbamoylphenyl) amino] furan-3 (2H) -one Using the compound obtained in Example 25, the title compound (solid) was obtained in the same manner as in Example 210.
- Example 213 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(2,4-dimethylphenyl) amino] furan-3 (2H) -one Using the compound obtained in Example 26, the title compound (solid) was obtained in the same manner as in Example 210.
- Example 214 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5- (p-toluylamino) furan-3 (2H) -one Using the compound obtained in Example 20, the title compound (solid) was obtained in the same manner as in the method described in Example 210.
- Example 215 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(4-bromophenyl) amino] furan-3 (2H) -one Using the compound obtained in Example 19, the title compound (solid) was obtained in the same manner as in Example 210.
- Example 217 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(4-fluorophenyl) amino] furan-3 (2H) -one Using the compound obtained in Example 21, the title compound (solid) was obtained in the same manner as described in Example 216.
- Example 218 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(1,1'-biphenyl) -4-ylamino] furan-3 (2H) -one
- the title compound (solid) was obtained in the same manner as in the method described in Example 216, using the compound obtained in Example 39.
- Example 29 A solution of the compound obtained in Example 29 (0.015 g, 0.034 mmol) in N, N-dimethylformamide (0.50 mL) was heated to reflux for 4 hours. The reaction solution was allowed to cool to room temperature and then purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0013 g, yield 11%).
- Example 42 A solution of the compound obtained in Example 42 (0.080 g, 0.17 mmol) in N, N-dimethylacetamide (3.0 mL) was heated and stirred at 160 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, diluted with water, and the precipitated solid was collected by filtration. The obtained solid was washed with water, tetrahydrofuran and diethyl ether in this order and then dried to obtain the title compound as a solid (yield 0.015 g, yield 22%).
- Example 60 A solution of the compound obtained in Example 60 (0.10 g, 0.26 mmol) in N, N-dimethylformamide (0.80 mL) was heated to reflux for 16 hours. The reaction solution was allowed to cool to room temperature, diluted with chloroform, and the precipitated solid was collected by filtration. The obtained solid was washed with chloroform / methanol (10/1) and hexane in this order and then dried to obtain the title compound as a solid (yield 0.019 g, yield 22%).
- Example 56 A solution of the compound obtained in Example 56 (0.15 g, ⁇ 0.43 mmol) in N, N-dimethylacetamide (1.5 mL) was heated to reflux for 12 hours. The reaction solution was allowed to cool to room temperature, diluted with water, and the precipitated solid was collected by filtration. The obtained solid was washed with diethyl ether and dried to give the title compound as a solid (yield 0.015 g, yield 12%).
- Example 228 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(3-pyrazolyl) amino] furan-3 (2H) -one Using the compound obtained in Example 67, the title compound (solid) was obtained in the same manner as in the method described in Example 227.
- Example 94 To an ethanol solution (7.0 mL) of the compound obtained in Example 94 (0.25 g, 0.76 mmol) was added 50% aqueous potassium hydroxide solution (4.0 mL, 0.071 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was diluted with water, 1M hydrochloric acid was added to acidify the liquid, and the mixture was concentrated again under reduced pressure. The residue was purified by HPLC preparative chromatography to give the title compound as a solid (yield 0.0090 g, yield 4%).
- Example 98 To an ethanol solution (2.0 mL) of the compound obtained in Example 98 (0.070 g, 0.20 mmol) was added 50% aqueous potassium hydroxide solution (1.0 mL, 0.018 mol) at room temperature, and the mixture was heated to reflux for 1 hour. The reaction solution was allowed to cool to room temperature, acidified with 1M hydrochloric acid, and concentrated under reduced pressure. Ethanol / water mixed solution (2.0 mL / 2.0 mL) was added to the resulting residue, and the mixture was heated to reflux for 1 hour. The reaction solution was allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by HPLC preparative chromatography to give the title compound as a solid (yield 0.0060 g, yield 12%).
- Example 232 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(1-methyl-4-piperidinyl) amino] furan-3 (2H) -one
- the title compound (solid) was obtained in the same manner as in the method described in Example 231 using the compound obtained in Example 65.
- Example 97 To an ethanol solution (4.0 (mL) of the compound obtained in Example 97 (0.15 g, 0.37) mmol) was added 50% aqueous potassium hydroxide solution (2.0 mL, 0.036 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, washed with ethyl acetate, and 1M hydrochloric acid was added to acidify the liquid.
- Example 107 To an ethanol solution (4.0 mL) of the compound obtained in Example 107 (0.090 g, 0.20 mmol) was added 50% aqueous potassium hydroxide solution (2.0 mL, 0.036 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, washed with ethyl acetate, and 1M hydrochloric acid was added to acidify the liquid. The precipitated solid was collected by filtration, washed with water and diethyl ether in that order, and dried to give the title compound as a solid (yield 0.037 g, yield 50%).
- Example 112 To an ethanol solution (2.0 mL) of the compound obtained in Example 112 (0.060 g, 0.14 mmol) was added 50% aqueous potassium hydroxide solution (1.0 mL, 0.018 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was washed with ethyl acetate. The solution was acidified by adding 1M hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and diethyl ether in that order, and then dried. The title compound was obtained as a solid (yield 0.010 g, yield 20%).
- Example 237 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5- (2-adamantylamino) furan-3 (2H) -one Using the compound obtained in Example 113, the title compound (solid) was obtained in the same manner as in the method described in Example 236.
- Example 103 To an ethanol solution (4.0 mL) of the compound obtained in Example 103 (0.10 g, 0.27 mmol) was added 50% aqueous potassium hydroxide solution (2.0 mL, 0.036 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water was added to the resulting residue, and the mixture was washed with ethyl acetate. The solution was acidified with 1M hydrochloric acid, and concentrated under reduced pressure. The obtained residue was purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.0015 g, yield 5%).
- Example 118 To an ethanol solution (4.0 mL) of the compound obtained in Example 118 (0.14 g, 0.33 mmol) was added 50% aqueous potassium hydroxide solution (2.2 mL, 0.039 mol) at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was allowed to cool to room temperature, 1M hydrochloric acid was added to acidify the solution, and the solvent was evaporated under reduced pressure. The precipitated residue was purified by HPLC preparative chromatography to obtain the title compound as a solid (yield 0.010 g, yield 9%).
- Example 241 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(1-phenylethyl) amino] furan-3 (2H) -one Using the compound obtained in Example 106, the title compound (solid) was obtained in the same manner as in the method described in Example 240.
- Example 243 2-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -5-[(trans-4-hydroxycyclohexyl) amino] furan-3 (2H) -one Using the compound obtained in Example 116, the title compound (solid) was obtained in the same manner as in the method described in Example 240.
- Example 244 Ethyl 5-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -2- (7-methoxy-3,4-dihydroisoquinolin-2 (1H) -yl) -4-oxo- 4,5-dihydrofuran-3-carboxylate (First step) Triethylamine (3.48 mL, 25.0 mmol) was added to a tetrahydrofuran suspension of 7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.10 g, 10.5 mmol) at room temperature and stirred for 30 minutes. did.
- Example 245 Isopropyl 5-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -2- (morpholinoamino) -4-oxo-4,5-dihydrofuran-3-carboxylate (First step) Isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (12.2) obtained in the same manner as described in Step 3 of Example 74 using diisopropyl malonate and chloroacetyl chloride.
- Example 246 Ethyl 5-[(1H-pyrrolo [2,3-b] pyridin-3-yl) methylene] -4-oxo-2- ⁇ [4- (2,2,2-trifluoroethyl) piperazinyl] amino ⁇ - 4,5-dihydrofuran-3-carboxylate (First step) To an aqueous solution (4.9 mL) of 1- (2,2,2-trifluoroethyl) piperazine (4.88 g, 29.0 mmol), an aqueous solution (20 mL) of sodium nitrite (4.04 g, 58.6 mmol) under ice-cooling, Then, acetic acid (5.0 mL, 87.0 mmol) was slowly added dropwise, and then stirred for 1 hour.
- 1- (2,2,2-trifluoroethyl) piperazine 4.88 g, 29.0 mmol
- sodium nitrite 4.04 g, 58.6 mmol
- Tables 1-1 to 1-10 show the above-mentioned Examples using corresponding raw materials (commercially available products, or compounds derivatized from commercially available compounds by known methods or modifications thereof). According to this method, the methods usually used in organic synthetic chemistry were appropriately combined as necessary. The physicochemical data of each compound are shown in Tables 2-1 to 2-6 below.
- the biological activity of the compound of the present invention was measured according to the following method. [Preparation and storage of test compound solution] The test compound was dissolved or suspended in DMSO to a concentration of 10 mM or 1 mM to obtain a stock solution, and stored in a dark place at ⁇ 20 ° C. until testing.
- Test example 1 [Cdc7 protein kinase inhibitory action]
- the kinase activity was measured using an MSA assay kit (QuickScout Screening Assist TM Kit, manufactured by Carna Biosciences).
- Substrate for kinase reaction (FITC-labeled MCM2 peptide) 4 ⁇ M, 40 mM MgCl 2 , 20 ⁇ M ATP using assay buffer (20 mM HEPES, 0.01% Triton X-100 TM, 2 mM dithiothreitol, pH 7.5) The mixed solution was adjusted. An enzyme solution was prepared by diluting the enzyme attached to the kit (human Cdc7 / human ASK complex protein) with an assay buffer to 7 nM.
- kit human Cdc7 / human ASK complex protein
- test compound was diluted with DMSO in stock solution, and diluted in 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 0.00mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM)
- concentrations 0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 0.00mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM
- the kinase reaction was performed by mixing 5 ⁇ l of drug solution or solvent (assay buffer containing 4% DMSO), 5 ⁇ l of substrate mixture, and 10 ⁇ l of enzyme solution in wells of a polypropylene 384-well plate.
- an assay buffer was added to the blank well instead of the enzyme solution.
- 60 ⁇ l termination buffer attached to the kit was added to stop the reaction.
- the reaction inhibition rate was measured using a LabChip EZ Reader II system (Caliper Life Sciences) according to the assay kit protocol. At this time, the height of each peak of the separated substrate and phosphorylated substrate was defined as S and P, respectively, and the inhibition rate (%) of the test compound was calculated according to the following formula.
- Inhibition rate (%) (1-(C-A) / (B-A)) X 100
- IC 50 value was calculated by regression analysis of inhibition rate and test compound concentration (logarithm). As shown in Table 4 below, the IC 50 values of the compounds of the present invention for Cdc7 were all less than 1 ⁇ M.
- Test example 2 [Inhibition of phosphorylation using cells] Cultured cells
- COLO205 cells were seeded in a 6-well plate (FALCON, 35046) at 2.5 ⁇ 10 5 cells (1 ml) per well and cultured overnight in a 5% CO 2 incubator.
- a drug solution prepared by adding 1.5 ⁇ l of a 0.1 mM DMSO stock solution of a test compound to 500 ⁇ l of a medium was added to each well (final drug concentration was 0.1 ⁇ M), and further cultured for 24 hours.
- the cells were cultured for 24 hours in the presence of the test compound, and the cells were collected using the same method as described above, washed with PBS, pelleted and stored at -80 ° C. After thawing the cells, the cells were immediately suspended in 2 ⁇ SDS-PAGE running buffer (1 ⁇ 10 5 cells / 10 ⁇ l) and heated at 95 ° C. for 10 minutes to lyse and denature the protein. The obtained sample solution was subjected to SDS-PAGE using a 5-20% gradient acrylamide gel (e-PAGEL (5-20%): ATTO E-T520L).
- the gel After completion of electrophoresis, the gel is immersed in 20% methanol-added Tris-Glycine buffer, and then placed on a PVDF membrane (MILLIPORE Immobilon-P IPVH00010) using a semi-dry transfer device (BIO RAD TRNS-BLOT SD SEMI-DRY TRANSFER CELL). The protein was transcribed.
- Each band consists of HRP-labeled anti-goat IgG donkey antibody (Santa Cruz 2020 sc2020), anti-rabbit IgG sheep antibody (Roche, 12015218001), anti-mouse IgG donkey antibody (Jackson ImmunoResearch, 715-035-151) was detected by chemiluminescence.
- the combinations and dilution concentrations of the primary antibody and the secondary antibody are as follows.
- the obtained band was normalized based on the amount of endogenous ⁇ -tubulin, and the phosphorylation rate of MCM2 was calculated.
- the MCM2 phosphorylation inhibitory activity is ** if the phosphorylation rate of the obtained MCM2 is less than 20%, ** if it is 20% or more and less than 50%, or * if it is 50% or more and less than 70%. Shown with a mark. According to this test, as shown in Table 4, the compound of the present invention inhibited phosphorylation of MCM2 at a concentration of 0.1 ⁇ M.
- the compound provided by the present invention can control cell proliferation through Cdc7 inhibitory action. Therefore, the compound of the present invention having a Cdc7 inhibitory action is useful as a therapeutic agent for a drug, particularly a disease derived from abnormal cell proliferation such as cancer.
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Abstract
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
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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
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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
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(第2工程)
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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
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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
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(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
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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。
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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]+
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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。
Claims (3)
- 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。
(式中、Aは、-COOR1もしくは水素原子を表わし、R1は、水素原子、置換基を有してもよい炭化水素基、置換基を有してもよい複素環を表し、R2およびR3は同一または異なって、水素原子、置換基を有してもよい炭化水素基、置換基を有してもよいフェニル基、置換基を有してもよい複素環、置換基を有してもよい複素環式縮合環または置換基を有してもよいアミノ基を表す。あるいは、R2およびR3は、これらが結合している窒素原子と共に、置換基を有してもよい複素環あるいは置換基を有してもよい複素環式縮合環を形成してもよい。R4は、水素原子またはハロゲン原子を表す。ただし、Aが-COOR1を表す場合は、R2、R3は同時に置換基を有してもよいアミノ基にならず、Aが水素原子を表す場合は、R3は水素原子を表す。) - Aが-COOR1である請求項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。
- Aが水素原子である請求項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。
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