CN116874496A - 三环类化合物及其制备方法、药物组合物和应用 - Google Patents
三环类化合物及其制备方法、药物组合物和应用 Download PDFInfo
- Publication number
- CN116874496A CN116874496A CN202310837130.XA CN202310837130A CN116874496A CN 116874496 A CN116874496 A CN 116874496A CN 202310837130 A CN202310837130 A CN 202310837130A CN 116874496 A CN116874496 A CN 116874496A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- dmso
- preparation
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 143
- 238000002360 preparation method Methods 0.000 title claims abstract description 107
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 claims description 10
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 8
- 239000012661 PARP inhibitor Substances 0.000 claims description 8
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 claims description 5
- KTFKRVMXIVSARW-UHFFFAOYSA-N 4-acetylbenzaldehyde Chemical compound CC(=O)C1=CC=C(C=O)C=C1 KTFKRVMXIVSARW-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- QGKLPGKXAVVPOJ-UHFFFAOYSA-N pyrrolidin-3-one Chemical compound O=C1CCNC1 QGKLPGKXAVVPOJ-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 claims description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229940114124 ferulic acid Drugs 0.000 claims description 2
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 2
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 2
- 235000001785 ferulic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 34
- 210000004027 cell Anatomy 0.000 abstract description 22
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 abstract description 17
- 102000004190 Enzymes Human genes 0.000 abstract description 13
- 108090000790 Enzymes Proteins 0.000 abstract description 13
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 abstract description 13
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 abstract description 13
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000000857 drug effect Effects 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 110
- 239000007787 solid Substances 0.000 description 94
- 239000002994 raw material Substances 0.000 description 79
- 238000006243 chemical reaction Methods 0.000 description 78
- 238000001308 synthesis method Methods 0.000 description 64
- 239000000543 intermediate Substances 0.000 description 47
- 238000004896 high resolution mass spectrometry Methods 0.000 description 44
- 229940125904 compound 1 Drugs 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 230000005764 inhibitory process Effects 0.000 description 29
- IIGQLQZSWDUOBI-UHFFFAOYSA-N 1-amino-1-methylthiourea Chemical compound CN(N)C(N)=S IIGQLQZSWDUOBI-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 11
- 229960000572 olaparib Drugs 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 10
- UJTTUOLQLCQZEA-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(4-hydroxybutyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCCCCO)C3=CC=CC=C3C2=C1 UJTTUOLQLCQZEA-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 9
- NYMQJWVULPQXBK-UHFFFAOYSA-N [[amino(methylsulfanyl)methylidene]amino]azanium;iodide Chemical compound [I-].CSC(N)=[NH+]N NYMQJWVULPQXBK-UHFFFAOYSA-N 0.000 description 8
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- -1 benzofuran pyrimidinone Chemical compound 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- PXJJKVNIMAZHCB-UHFFFAOYSA-N 2,5-diformylfuran Chemical compound O=CC1=CC=C(C=O)O1 PXJJKVNIMAZHCB-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091007743 BRCA1/2 Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 230000007681 cardiovascular toxicity Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- WQUPOMUBXOPGSN-UHFFFAOYSA-N methyl n'-aminocarbamimidothioate Chemical compound CSC(N)=NN WQUPOMUBXOPGSN-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- DPSTYIOIVSHZRI-UHFFFAOYSA-N pyrrolidin-3-one;hydrochloride Chemical compound Cl.O=C1CCNC1 DPSTYIOIVSHZRI-UHFFFAOYSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- IOQORVDNYPOZPL-VQTJNVASSA-N (5S,6R)-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]-5,6-dihydro-2H-1,2,4-oxadiazine Chemical compound ClC1=CC=C(C=C1)[C@@H]1NC(=NO[C@@H]1C1CC1)C1=NC(=C(C=C1)N1C=NC(=C1)C)OC IOQORVDNYPOZPL-VQTJNVASSA-N 0.000 description 1
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- ZQEXIXXJFSQPNA-UHFFFAOYSA-N 1h-imidazole-5-carbaldehyde Chemical compound O=CC1=CNC=N1 ZQEXIXXJFSQPNA-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 1
- PRWBEMMIBAUUCY-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr.NC(=O)CBr PRWBEMMIBAUUCY-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- FCPHVJQWZFNNKD-UHFFFAOYSA-N 3-amino-1,1-dimethylthiourea Chemical compound CN(C)C(=S)NN FCPHVJQWZFNNKD-UHFFFAOYSA-N 0.000 description 1
- PTVZQOAHCSKAAS-UHFFFAOYSA-N 4-methyl-3-thiosemicarbazide Chemical compound CNC(=S)NN PTVZQOAHCSKAAS-UHFFFAOYSA-N 0.000 description 1
- KKIGUVBJOHCXSP-UHFFFAOYSA-N 4-phenylthiosemicarbazide Chemical compound NNC(=S)NC1=CC=CC=C1 KKIGUVBJOHCXSP-UHFFFAOYSA-N 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- DYGBNAYFDZEYBA-UHFFFAOYSA-N n-(cyclopropylmethyl)-2-[4-(4-methoxybenzoyl)piperidin-1-yl]-n-[(4-oxo-1,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-2-yl)methyl]acetamide Chemical compound C1=CC(OC)=CC=C1C(=O)C1CCN(CC(=O)N(CC2CC2)CC=2NC(=O)C=3COCCC=3N=2)CC1 DYGBNAYFDZEYBA-UHFFFAOYSA-N 0.000 description 1
- QDHCWFGGDOOBNB-UHFFFAOYSA-N n-amino-n-ethylhydroxylamine Chemical compound CCN(N)O QDHCWFGGDOOBNB-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 108091035539 telomere Proteins 0.000 description 1
- 102000055501 telomere Human genes 0.000 description 1
- 210000003411 telomere Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种三环类化合物及其制备方法、药物组合物和应用，该类化合物结构如式1，还包含其异构体、药学上可接受的盐或它们的混合物，进一步与药学上可接受的载体形成其药物组合物。该类化合物及其药物组合物可有效抑制PARP酶、PARP‑1酶以及多种肿瘤细胞，在分子水平和细胞水平均可以发挥药效，并且效果优于现有药物，具有良好的应用前景；化合物制备方法通用性良好，利于化合物结构拓展。
Description
技术领域
本发明涉及一种三环类化合物及其制备方法、药物组合物和应用，尤其涉及一种具有PARP抑制活性的三环类化合物及其制备方法、药物组合物和应用。
背景技术
癌症在发生和发展过程中会积累大量的DNA突变，造成癌细胞比正常细胞分裂速度快，并且以一种不受控制的方式增殖扩散，这是癌细胞的个性也是共性。目前临床应用的大部分化疗药物，如铂类药物(顺铂、奥沙利铂、卡铂等)、烷化剂(环磷酰胺、氮介、卡莫司汀等)和拓扑异构酶抑制剂(伊立替康、羟基喜树碱、依托泊苷等)等均是通过造成DNA损伤杀死癌细胞。它们的共同特点是抗癌活性强，但因缺乏对癌细胞的选择性，往往毒副作用较大。随着癌症分子生物学的发展，人们逐渐认识到开发针对与DNA修复途径相关的分子靶向药物是治疗癌症更为行之有效的方法之一。
聚腺苷二磷酸核糖聚合酶(PolyADP-ribose polymerase，PARP)是DNA损伤修复通路中的关键调控因子，在维系基因稳定、保持端粒长度以及细胞应对外界刺激响应等方面发挥重要作用。PARP蛋白家族共有17名成员，其中PARP-1承担着家族90％以上的生物学功能，已被证实可以通过ADP核糖基化反应参与细胞对DNA损伤的反应。目前已有五种PARP抑制剂(PARP inhibitor，PARPi)获批临床应用，多个化合物进入临床研究，它们在BRCA1/2突变的卵巢癌、胰腺癌、三阴乳腺癌和前列腺癌等数十种难治性癌症中表现出良好疗效。不过，随着PARPi在临床上的广泛应用，现有获批的PARPi在临床实践也暴露出许多如下亟待解决的问题：
(1)较差的物化性质，如水溶性较低、生物利用度不高、组织分布较少和制剂不稳定导致的安全风险；
(2)较为严重的毒副作用，在临床应用中会产生不同程度的血液毒性(贫血、中性粒细胞减少、血小板减少等)、非血液毒性(恶心、呕吐、疲劳等)、神经系统毒性、脱靶毒性和心血管系统不良反应等副作用；
(3)应用范围狭窄，仅对同源重组修复缺陷的癌症患者特别是存在BRCA1/2突变的患者有效，而这类患者数量相对较少，如上皮性卵巢癌中BCRA1/2突变患者数量仅占总患者数量的14-15％，胰腺癌中约占7.5％，乳腺癌中仅占2％-3％；
(4)耐药，到目前为止，在临床应用中已出现不同程度的耐药。
因此，基于PARPi在临床应用中存在的问题，需要开发新型的PARPi来克服现有药物的不足。
发明内容
发明目的：本发明的第一目的是提供一种三环类化合物，第二目的是提供一种所述化合物的制备方法，第三目的是提供一种包含所述化合物的药物组合物，第四目的是提供一种所述化合物及其药物组合物在制备抗肿瘤药物中的应用。
技术方案：本发明所述的三环类化合物具有式1的结构，还包含其异构体、药学上可接受的盐或它们的混合物：
其中：
选自/>
R1选自
R2选自卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基。
优选地，所述三环类化合物具有式I的结构，
其中：
R1选自
优选地，所述三环类化合物具有式II的结构，
其中：
选自/>
R1选自优选地，所述三环类化合物具有式III的结构，
其中：
选自/>R2选自4-Cl、4-Br、4-CH3、4-OCH3、5-F、5-Cl、5-Br。
更优选地，所述三环类化合物选自以下任一化合物：
优选地，所述三环类化合物的药学上可接受的盐为其与选自以下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
本发明以苯并呋喃嘧啶酮为母体，以对苯二甲醛、4-乙酰苯甲醛、间苯二甲醛、对羟基苯甲醛、对羟基苯乙酮、2,5-二甲酰基呋喃、4-咪唑甲醛、哌啶-4-酮、3-吡咯烷酮等为连接体，分别与母体化合物和氨基硫脲及其类似物、氨基脲或氨基胍发生缩合反应，得到结构如式I～III的新型化合物。该类化合物对PARP和PARP-1酶活性具有较强的抑制作用，并对多种癌细胞表现出良好的抗增殖作用，可用于制备抗肿瘤药物。
本发明所述的三环类化合物的制备方法选自以下任一方法：
(1)当化合物具有式I的结构时，化合物3a与对苯二甲醛环合，然后化合物4a与R1-NH2缩合得到式I的化合物；
化合物1～11合成路线中环合的反应试剂和条件为原料：对苯二甲醛，催化剂：I2，溶剂：CH3CN；缩合的反应试剂和条件为原料：氨基硫脲、氨基脲及其衍生物，溶剂：乙醇，催化剂：冰醋酸，反应温度：加热回流；
中间体3a的制备方法如下：
(2)当化合物具有式II的结构时，化合物3a分别与对乙酰基苯甲醛、间苯二甲醛、2,4-二醛基呋喃环合，然后化合物5a～6a、10a分别与R1-NH2缩合得到式II的化合物；或化合物3a与2-氯-1,1,1-三甲氧基乙烷环合，然后化合物7a分别与4-羟基苯甲醛、4-羟基苯甲酮、2-醛基咪唑、4-哌啶酮、3-吡咯烷酮偶联，最后化合物8a～9a、11a～13a分别与R1-NH2缩合得到式II的化合物；
化合物12～17、23～25合成路线中环合、缩合的反应试剂和条件如式I化合物的制备方法所示；
化合物18～22合成路线中环合的反应试剂和条件为原料：2-氯-1,1,1-三甲氧基乙烷，催化剂：对甲苯磺酸，溶剂：甲苯，反应温度：110℃；偶联的反应试剂和条件为原料：偶联的芳醛、芳酮衍生物，催化剂：K2CO3、KI，溶剂：DMF，反应温度：80℃；缩合的反应试剂和条件如式I化合物的制备方法所示；
化合物26～32合成路线中偶联的反应试剂和条件为原料：偶联的芳醛或芳酮衍生物，催化剂K2CO3、KI，溶剂：DMF，反应温度：80℃，或者原料：4-哌啶酮水合物盐酸盐、3-吡咯烷酮盐酸盐，催化剂：三乙胺或N-乙基二异丙胺、碘化钾，溶剂：N,N-二甲基乙酰胺，反应温度：80℃；缩合的反应试剂和条件如式I化合物的制备方法所示；
(3)当化合物具有式III的结构时，化合物3b～3h分别与对苯二甲醛环合，然后化合物4b～4c、4f～4h分别与R1-NH2缩合得到式III的化合物；或化合物3b～3h分别与2-氯-1,1,1-三甲氧基乙烷环合，然后化合物7b～7h分别与4-哌啶酮偶联，最后化合物12b～12h分别与R1-NH2缩合得到式III的化合物；
化合物33～44合成路线中环合、缩合、偶联的反应试剂和条件如式I～II化合物的制备方法所示；
中间体3b～3h的制备方法如下：
其中，R1、R2的定义如前所述；
将相应的酸与以上方法制备的式I～III的化合物成盐，即得所述化合物的药学上可接受的盐。
进一步地，本发明所述的三环类化合物添加药学上可接受的载体形成本发明所述的药物组合物；具体通过加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料，制成常见的药用制剂，如片剂、胶囊剂、糖浆剂、悬浮剂或注射剂。
本发明所述的三环类化合物或其药物组合物应用于制备PARP抑制剂药物，具体制备为抗肿瘤药物；尤其是作为PARP-1抑制剂药物，治疗卵巢癌、结肠癌、乳腺癌、三阴性乳腺癌等。
有益效果：与现有技术相比，本发明具有如下显著优点：
该类化合物及其药物组合物可有效抑制PARP酶(抑制率最优高于90％)、PARP-1酶(抑制率最优高于95％)以及多种肿瘤细胞(IC50值最优低于10μM)，在分子水平和细胞水平均可以发挥药效，并且效果优于现有药物，具有良好的应用前景；化合物制备方法通用性良好，利于化合物结构拓展。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例中所有试剂均为分析纯。化合物的核磁光谱由Bruker ARX-600核磁共振仪测定，内标为TMS；高分辨质谱采用Agilent6224 TOF LC/MS仪测定。
实施例1：中间体2a的制备
称取1.0g(8.4mmol)1a于100mL烧瓶中，加入50mL N,N-二甲基乙酰胺(DMA)，搅拌下继续加入6.8g CS2CO3，随后升温至75℃，之后加入1.4g(10mmol)2-溴乙酰胺(2-bromoacetamide)，继续反应3h。薄层层析色谱(TLC)监测反应进程。反应结束后，加入大量水，使之沉淀。过滤，水洗(20mL×3)，取滤饼干燥，得白色固体1.2g，产率79％。1H NMR(600MHz,DMSO-d6)δ7.74(dd,J＝7.6,1.5Hz,1H),7.66-7.63(m,1H),7.45(d,J＝30.1Hz,2H),7.11(t,J＝7.6Hz,1H),7.07(d,J＝8.6Hz,1H),4.67(s,2H)ppm.
实施例2：中间体2b的制备
参考2a的合成方法，以1b为原料替代1a参与反应，得白色固体1.2g，产率78％。1HNMR(600MHz,DMSO-d6)δ7.94(d,J＝2.6Hz,1H),7.72(dd,J＝9.1,2.6Hz,1H),7.49(d,J＝44.4Hz,2H),7.09(d,J＝9.1Hz,1H),4.70(s,2H)ppm.
实施例3：中间体2c的制备
参考2a的合成方法，以1c为原料替代1a参与反应，得白色固体1.1g，产率74％。1HNMR(600MHz,DMSO-d6)δ7.72(d,J＝8.7Hz,1H),7.50(d,J＝35.6Hz,2H),7.34(dd,J＝6.8,1.7Hz,2H),4.75(s,2H)ppm.
实施例4：中间体2d的制备
参考2a的合成方法，以1d为原料替代1a参与反应，得白色固体1.0g，产率72％。1HNMR(600MHz,DMSO-d6)δ7.61(d,J＝7.8Hz,1H),7.45(d,J＝8.1Hz,2H),6.94(d,J＝7.9Hz,1H),6.91(s,1H),4.65(s,2H),2.35(s,3H)ppm.
实施例5：中间体2e的制备
参考2a的合成方法，以1e为原料替代1a参与反应，得白色固体1.1g，产率76％。1HNMR(600MHz,DMSO-d6)δ7.66(d,J＝8.6Hz,1H),7.45(s,2H),6.69(dd,J＝8.6,2.1Hz,1H),6.60(d,J＝2.1Hz,1H),4.67(s,2H),3.82(s,3H)ppm.
实施例6：中间体2f的制备
参考2a的合成方法，以1f为原料替代1a参与反应，得白色固体0.9g，产率71％。1HNMR(600MHz,DMSO-d6)δ7.76(dd,J＝8.1,3.2Hz,1H),7.55(ddd,J＝9.1,8.5,3.2Hz,1H),7.48(d,J＝31.0Hz,2H),7.09(dd,J＝9.4,4.1Hz,1H),4.67(s,2H)ppm.
实施例7：中间体2g的制备
参考2a的合成方法，以1g为原料替代1a参与反应，得白色固体1.2g，产率74％。1HNMR(600MHz,DMSO-d6)δ7.94(d,J＝2.6Hz,1H),7.72(dd,J＝9.1,2.6Hz,1H),7.49(d,J＝44.4Hz,2H),7.09(d,J＝9.1Hz,1H),4.70(s,2H)ppm.
实施例8：中间体2h的制备
参考2a的合成方法，以1h为原料替代1a参与反应，得白色固体1.3g，产率76％。1HNMR(600MHz,DMSO-d6)δ8.03(d,J＝2.4Hz,1H),7.83(dd,J＝9.1,2.4Hz,1H),7.49(d,J＝52.8Hz,2H),7.04(d,J＝9.1Hz,1H),4.70(s,2H)ppm.
实施例9：中间体3a的制备
取1.0g 2a(5.7mmol)于250mL烧瓶中，加入120mL乙醇，搅拌下加入0.95g KOH(17mmol)，升温至80℃，搅拌10h后，TLC监测反应。反应完成后，使用HCl(1mol/L)调节pH＝7，将溶剂旋干，柱层析纯化(VPE:VEA＝2:1)，得白色固体0.93g，产率93％。1H NMR(600MHz,DMSO-d6)δ7.85(d,J＝7.8Hz,1H),7.44-7.40(m,2H),7.24(ddd,J＝8.0,6.3,1.8Hz,3H),6.01(s,2H)ppm.
实施例10：中间体3b的制备
参考3a的合成方法，以2b为原料替代2a参与反应，得白色固体1.0g，产率88％。1HNMR(600MHz,DMSO-d6)δ7.88(d,J＝8.4Hz,1H),7.54(s,1H),7.30(t,J＝14.4Hz,3H),6.09(s,2H)ppm.
实施例11：中间体3c的制备
参考3a的合成方法，以2c为原料替代2a参与反应，得白色固体1.4g，产率91％。1HNMR(600MHz,DMSO-d6)δ7.83(d,J＝8.4Hz,1H),7.67(s,1H),7.44(dd,J＝8.4,1.0Hz,1H),7.30(s,2H),6.10(s,2H)ppm.
实施例12：中间体3d的制备
参考3a的合成方法，以2d为原料替代2a参与反应，得白色固体1.2g，产率91％。1HNMR(600MHz,DMSO-d6)δ7.71(d,J＝8.0Hz,1H),7.21(s,3H),7.06(d,J＝8.0Hz,1H),5.98(s,2H),2.42(s,3H)ppm.
实施例13：中间体3e的制备
参考3a的合成方法，以2e为原料替代2a参与反应，得白色固体1.3g，产率92％。1HNMR(600MHz,DMSO-d6)δ7.73(d,J＝8.6Hz,1H),7.08(s,2H),6.93(s,1H),6.87(d,J＝8.7Hz,1H),6.00(s,2H),3.82(s,3H)ppm.
实施例14：中间体3f的制备
参考3a的合成方法，以2f为原料替代2a参与反应，得白色固体0.74g，产率78％。1HNMR(600MHz,DMSO-d6)δ7.71(dd,J＝8.7,2.7Hz,1H),7.44(dd,J＝9.0,4.0Hz,1H),7.27(td,J＝9.1,2.7Hz,1H),6.31(s,4H)ppm.
实施例15：中间体3g的制备
参考3a的合成方法，以2g为原料替代2a参与反应，得白色固体1.1g，产率90％。1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.45(d,J＝2.2Hz,2H),7.32(s,2H),6.03(s,2H)ppm.
实施例16：中间体3h的制备
参考3a的合成方法，以2h为原料替代2a参与反应，得白色固体1.3g，产率92％。1HNMR(600MHz,DMSO-d6)δ8.11(d,J＝1.9Hz,1H),7.55(dd,J＝8.8,2.0Hz,1H),7.40(d,J＝8.8Hz,1H),7.31(s,2H),6.02(s,2H)ppm.
实施例17：中间体4a的制备
取0.61g(4.5mmol)对苯二甲醛于100mL的烧瓶中，加入30mL乙腈溶解，搅拌下依次加入0.69g(2.7mmol)I2、0.40g(2.3mmol)3a，室温搅拌10h后，TLC监测反应。反应完成后，用硫代硫酸钠溶液淬灭反应，过滤出固体，取滤饼柱层析纯化(VDCM:VMeOH＝180:1)，得淡黄色固体0.39g，产率50％。1HNMR(600MHz,DMSO-d6)δ13.34(s,1H),10.13(s,1H),8.38(d,J＝8.0Hz,2H),8.15(d,J＝7.7Hz,1H),8.10(d,J＝8.2Hz,2H),7.88(d,J＝8.4Hz,1H),7.72(t,J＝7.7Hz,1H),7.55(t,J＝7.5Hz,1H)ppm.
实施例18：中间体4b的制备
参考4a的合成，以3b为原料代替3a参与反应，得淡黄色固体0.42g，产率55％。1HNMR(600MHz,DMSO-d6)δ13.37(s,1H),10.12(s,1H),8.35(d,J＝6.4Hz,2H),8.09(dd,J＝25.0,7.7Hz,4H),7.56(d,J＝7.1Hz,1H)ppm.
实施例19：中间体4c的制备
参考4a的合成，以3c为原料代替3a参与反应，得淡黄色固体0.36g，产率45％。1HNMR(600MHz,DMSO-d6)δ13.36(s,1H),10.12(s,1H),8.35(d,J＝8.2Hz,2H),8.23(d,J＝1.3Hz,1H),8.07(t,J＝8.6Hz,3H),7.69(dd,J＝8.3,1.5Hz,1H)ppm.
实施例20：：中间体4f的制备
参考4a的合成，以3f为原料代替3a参与反应，得淡黄色固体0.27g，产率37％。1HNMR(600MHz,DMSO-d6)δ13.38(s,1H),10.13(s,1H),8.36(d,J＝8.2Hz,2H),8.09(d,J＝8.3Hz,2H),7.96-7.93(m,2H),7.59(td,J＝9.1,2.7Hz,1H)ppm.
实施例21：中间体4g的制备
参考4a的合成，以3g为原料代替3a参与反应，得淡黄色固体0.45g，产率55％。1HNMR(600MHz,DMSO-d6)δ13.42(s,1H),10.13(s,1H),8.37(d,J＝8.1Hz,2H),8.17(d,J＝2.0Hz,1H),8.09(d,J＝8.3Hz,2H),7.94(d,J＝8.9Hz,1H),7.75(dd,J＝8.9,2.2Hz,1H)ppm.
实施例22：中间体4h的制备
参考4a的合成，以3h为原料代替3a参与反应，得淡黄色固体0.36g，产率48％。1HNMR(600MHz,DMSO-d6)δ12.90(s,1H),10.12(s,1H),8.36(d,J＝8.3Hz,2H),8.25(d,J＝2.4Hz,1H),8.07(d,J＝8.4Hz,2H),8.01(dd,J＝8.7,2.4Hz,1H),7.74(d,J＝8.7Hz,1H)ppm.
实施例23：中间体5a的制备
取0.67g(4.5mmol)4-乙酰苯甲醛于100mL烧瓶中，加入40mL乙腈溶解，搅拌下依次加入0.69g(2.7mmol)I2、0.40g(2.3mmol)3a，室温搅拌10h后，TLC监测反应。反应完成后，用硫代硫酸钠溶液淬灭反应，过滤析出的固体，取滤饼柱层析纯化(VDCM:VMeOH＝150:1)，得淡黄色固体0.41mg，产率58％。1HNMR(600MHz,DMSO-d6)δ13.24(s,1H),8.33(d,J＝8.4Hz,2H),8.13(dd,J＝11.4,8.2Hz,3H),7.87(d,J＝8.4Hz,1H),7.73-7.69(m,1H),7.53(t,J＝7.4Hz,1H),2.66(s,3H)ppm.
实施例24：中间体6a的制备
取0.61g(4.5mmol)间苯二甲醛于100mL烧瓶中，加入40mL乙腈溶解，搅拌下依次加入0.69g(2.7mmol)I2、0.40g(2.3mmol)3a，室温搅拌10h后，TLC监测反应。反应完成后，用硫代硫酸钠溶液淬灭反应，过滤析出的固体，取滤饼柱层析纯化(VDCM:VMeOH＝180:1)，得淡黄色固体0.04g，产率60％。1HNMR(600MHz,DMSO-d6)δ13.33(s,1H),10.15(s,1H),8.71(s,1H),8.47(d,J＝7.5Hz,1H),8.14(dd,J＝13.4,7.7Hz,2H),7.88(d,J＝8.4Hz,1H),7.81(t,J＝7.7Hz,1H),7.72(t,J＝7.7Hz,1H),7.54(t,J＝7.5Hz,1H)ppm.
实施例25：中间体7a的制备
称取2.0g(11mmol)3a于100mL烧瓶中，加入50mL甲苯，搅拌下继续加入3.5g(23mmol)2-氯-1,1,1-三甲氧基乙烷、0.20g(1.1mmol)对甲苯磺酸，随后升温至110℃，反应4h，使用TLC监测反应。反应结束后，取下冷却，将产生的沉淀过滤，用甲苯淋洗(10mL×3)，取滤饼干燥，得灰白色固体2.4g，产率90％。1H NMR(600MHz,DMSO-d6)δ13.29(s,1H),8.07(d,J＝7.7Hz,1H),7.86(d,J＝8.4Hz,1H),7.72-7.68(m,1H),7.52(t,J＝7.5Hz,1H),4.67(s,2H)ppm.
实施例26：中间体7b的制备
参考7a的合成方法，以3b为原料代替3a参与反应，得白色固体1.6g，产率68％。1HNMR(600MHz,DMSO-d6)δ13.36(s,1H),8.07(dd,J＝15.8,4.9Hz,2H),7.55(dd,J＝8.4,1.7Hz,1H),4.67(s,2H)ppm.
实施例27：中间体7c的制备
参考7a的合成方法，以3c为原料代替3a参与反应，得白色固体1.4g，产率60％。1HNMR(600MHz,DMSO-d6)δ13.35(s,1H),8.21(s,1H),7.98(d,J＝8.2Hz,1H),7.66(d,J＝8.1Hz,1H),4.65(s,2H)ppm.
实施例28：中间体7d的制备
参考7a的合成方法，以3d为原料代替3a参与反应，得白色固体2.4g，产率92％。1HNMR(600MHz,DMSO-d6)δ13.23(s,1H),7.92(d,J＝8.0Hz,1H),7.67(s,1H),7.34(d,J＝8.0Hz,1H),4.65(s,2H),2.52(s,3H)ppm.
实施例29：中间体7e的制备
参考7a的合成方法，以3e为原料代替3a参与反应，得白色固体2.4g，产率90％。1HNMR(600MHz,DMSO-d6)δ13.18(s,1H),7.91(d,J＝8.7Hz,1H),7.44(d,J＝2.0Hz,1H),7.11(dd,J＝8.7,2.2Hz,1H),4.65(s,2H),3.90(s,3H)ppm.
实施例30：中间体7f的制备
参考7a的合成方法，以3f为原料代替3a参与反应，得白色固体1.7g，产率67％。1HNMR(600MHz,DMSO-d6)δ13.33(s,1H),8.10(s,1H),7.87(d,J＝8.2Hz,1H),7.41(s,1H),4.66(s,2H)ppm.
实施例31：中间体7g的制备
参考7a的合成方法，以3g为原料代替3a参与反应，得白色固体1.6g，产率63％。1HNMR(600MHz,DMSO-d6)δ13.39(s,1H),8.10(s,1H),7.92(d,J＝8.9Hz,1H),7.73(dd,J＝8.9,1.9Hz,1H),4.66(s,2H)ppm.
实施例32：中间体7h的制备
参考7a的合成方法，以3h为原料代替3a参与反应，得白色固体1.3g，产率60％。1HNMR(600MHz,DMSO-d6)δ13.39(s,1H),8.23(s,1H),7.88-7.83(m,2H),4.66(s,2H)ppm.
实施例33：中间体8a的制备
称取0.50g对羟基苯甲醛(4.1mmol)于50mL烧瓶中，加入20mLDMA，搅拌下加入1.7gK2CO3(12mmol)，随后加入1.0g 7a(4.3mmol)、0.71g KI(4.3mmol)，升温至80℃，反应10h，使用TLC监测反应。反应结束后，取下冷却，加入60mL水，用二氯甲烷萃取(80mL×3)，收集有机相旋干，柱层析纯化(VDCM:VMeOH＝150:1)，得黄色固体0.49g，产率38％。1H NMR(600MHz,DMSO-d6)δ13.24(s,1H),9.90(s,1H),8.04(d,J＝7.7Hz,1H),7.92(d,J＝8.6Hz,2H),7.86(d,J＝8.4Hz,1H),7.70(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.29(d,J＝8.6Hz,2H),5.24(s,2H)ppm.
实施例34：中间体9a的制备
称取0.30g(2.2mmol)对羟基苯乙酮于50mL烧瓶中，加入20mL DMF，搅拌下加入0.91g(6.6mmol)K2CO3，随后加入0.54g(2.3mmol)7a、0.37g(2.2mmol)KI，升温至80℃，反应10h，使用TLC监测反应。反应结束后，取下冷却，加入60mL水，用二氯甲烷萃取(80mL×3)，收集有机相旋干，柱层析纯化(VDCM:VMeOH＝190:1)，得黄色固体0.42g，产率57％。1H NMR(600MHz,DMSO-d6)δ13.23(s,1H),8.04(d,J＝6.4Hz,1H),7.97(d,J＝5.9Hz,2H),7.85(dd,J＝8.4,2.1Hz,1H),7.69(t,J＝7.9Hz,1H),7.51(t,J＝6.3Hz,1H),7.19(d,J＝6.0Hz,2H),5.21(s,2H),2.53(s,3H)ppm.
实施例35：中间体10a的制备
取0.51g(4.1mmol)呋喃-2,5-二甲醛于100mL烧瓶中，加入50mL乙腈溶解，搅拌下依次加入0.86g(3.4mmol)I2、0.40g(2.3mmol)3a，室温搅拌10h后，TLC监测反应。反应完成后，用硫代硫酸钠溶液淬灭反应，过滤析出的固体，取滤饼柱层析纯化(VDCM:VMeOH＝190:1)，得淡黄色固体0.40mg，产率63％。1HNMR(600MHz,DMSO-d6)δ13.48(s,1H),9.78(s,1H),8.16(d,J＝7.7Hz,1H),7.88(d,J＝8.4Hz,1H),7.80(d,J＝2.9Hz,1H),7.74-7.71(m,2H),7.60-7.60(m,1H),7.54(t,J＝7.5Hz,1H)ppm.
实施例36：中间体11a的制备
称取0.15g(1.6mmol)4-咪唑甲醛于50mL烧瓶中，加入20mLDMF，搅拌下加入0.75g(5.4mmol)K2CO3，随后加入0.40g(1.7mmol)7a、0.28g(1.7mmol)KI，升温至80℃，反应10h，使用TLC监测反应。反应结束后，取下冷却，加入60mL水，用二氯甲烷萃取(80mL×3)，收集有机相旋干，柱层析纯化(VDCM:VMeOH＝30:1)，得黄色固体0.21mg，产率46％。1HNMR(600MHz,DMSO-d6)δ13.28(s,1H),9.76(s,1H),8.17(d,J＝1.0Hz,1H),8.00(s,1H),7.90(d,J＝7.7Hz,1H),7.83(d,J＝8.4Hz,1H),7.68-7.65(m,1H),7.47(d,J＝7.4Hz,1H),5.41(s,2H)ppm.
实施例37：中间体12a的制备
称取0.20g(1.3mmol)4-哌啶酮一水合物盐酸盐于50mL烧瓶中，加入20mL DMF，搅拌下加入0.26g(2.6mmol)Et3N，搅拌30min，随后加入0.20g(0.85mmol)7a、0.14g(0.85mmol)KI，升温至80℃，反应10h，使用TLC监测反应。反应结束后，加入60mL水，用二氯甲烷萃取(80mL×3)，收集有机相旋干，柱层析纯化(VDCM:VMeOH＝110:1)，得白色固体0.19g，产率77％。1HNMR(600MHz,DMSO-d6)δ12.71(s,1H),8.04(d,J＝7.7Hz,1H),7.81(d,J＝8.4Hz,1H),7.65(t,J＝7.8Hz,1H),7.48(t,J＝7.5Hz,1H),3.71(s,2H),2.87(t,J＝6.0Hz,4H),2.40(t,J＝6.0Hz,4H)ppm.
实施例38：中间体12b的制备
参考12a的合成方法，以7b为原料代替7a参与反应，得白色固体0.17g，产率73％。1H NMR(600MHz,DMSO-d6)δ12.76(s,1H),8.06(dd,J＝10.3,5.0Hz,2H),7.54(dd,J＝8.4,1.8Hz,1H),3.72(s,2H),2.87(t,J＝5.8Hz,4H),2.40(t,J＝6.0Hz,4H)ppm.
实施例39：中间体12c的制备
参考12a的合成方法，以7c为原料代替7a参与反应，得白色固体0.15g，产率68％。1H NMR(600MHz,DMSO-d6)δ12.75(s,1H),8.19(d,J＝1.4Hz,1H),7.98(d,J＝8.3Hz,1H),7.65(dd,J＝8.3,1.6Hz,1H),3.69(d,J＝22.0Hz,2H),2.87(s,4H),2.39(t,J＝5.7Hz,4H)ppm.
实施例40：中间体12d的制备
参考12a的合成方法，以7d为原料代替7a参与反应，得白色固体0.17g，产率69％。1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),7.91(d,J＝7.9Hz,1H),7.65(s,1H),7.32(d,J＝8.0Hz,1H),3.71(s,2H),3.10(s,3H),2.86(s,4H),2.40(s,4H)ppm.
实施例41：中间体12e的制备
参考12a的合成方法，以7e为原料代替7a参与反应，得白色固体0.15mg，产率65％。1HNMR(600MHz,DMSO-d6)δ12.58(s,1H),7.90(d,J＝8.7Hz,1H),7.42(d,J＝2.1Hz,1H),7.08(dd,J＝8.7,2.1Hz,1H),3.89(s,3H),3.70(s,2H),2.86(t,J＝5.2Hz,4H),2.40(t,J＝5.9Hz,4H)ppm.
实施例42：中间体12f的制备
参考12a的合成方法，以7f为原料代替7a参与反应，得白色固体0.12g，产率52％。1H NMR(600MHz,DMSO-d6)δ12.74(s,1H),8.09(dd,J＝8.6,5.6Hz,1H),7.85(dd,J＝9.2,2.0Hz,1H),7.38(td,J＝9.4,2.1Hz,1H),3.72(s,2H),2.87(s,4H),2.40(s,4H)ppm.
实施例43：中间体12g的制备
参考12a的合成方法，以7g为原料代替7a参与反应，得白色固体0.12mg，产率55％。1HNMR(600MHz,DMSO-d6)δ12.76(s,1H),8.09(d,J＝2.1Hz,1H),7.90(d,J＝8.9Hz,1H),7.71(dd,J＝8.9,2.1Hz,1H),3.72(s,2H),2.87(t,J＝6.0Hz,4H),2.40(t,J＝6.0Hz,4H)ppm.
实施例44：中间体12h的制备
参考12a的合成方法，以7h为原料代替7a参与反应，得白色固体0.14g，产率59％。1H NMR(600MHz,DMSO-d6)δ12.80(s,1H),8.14(s,1H),7.75(d,J＝3.6Hz,2H),3.64(s,2H),2.86(s,4H),2.38(s,4H)ppm.
实施例45：中间体13a的制备
称取0.78g(6.4mmol)3-吡咯烷酮盐酸盐于100mL烧瓶中，加入20mL CH3CN，搅拌下加入2.5g(19mmol)DIPEA，搅拌10min，随后加入1.0g(4.3mmol)7a、0.71g(4.3mmol)KI，升温至80℃，反应10h，使用TLC监测反应。反应结束后，取下冷却，旋干反应液，加入60mL水，用二氯甲烷萃取(80mL×3)，收集有机相旋干，柱层析纯化(VDCM:VMeOH＝180:1)，得灰色固体0.43g，产率36％。1H NMR(600MHz,DMSO-d6)δ12.70(s,1H),8.05(d,J＝7.7Hz,1H),7.82(d,J＝8.4Hz,1H),7.69-7.66(m,1H),7.49(t,J＝7.5Hz,1H),3.81(s,2H),3.11(s,2H),3.04(t,J＝6.9Hz,2H),2.38(t,J＝6.9Hz,2H)ppm.
实施例46：化合物1的制备
分别取0.20g(0.69mmol)4a和0.076g(0.83mmol)氨基硫脲于100mL烧瓶中，加入50mL乙醇，滴加2滴乙酸，加热至回流，搅拌10h后，TLC监测反应。反应完成后，冷却过滤，滤饼依次用乙醇、热MeOH:DCM(v:v)＝1:1、冷乙醇(各5mL)淋洗，得淡黄色固体0.21g，产率85％。1H NMR(600MHz,DMSO-d6)δ13.16(s,1H),11.60(s,1H),8.33(s,1H),8.23(d,J＝8.2Hz,2H),8.19-8.14(m,2H),8.12(s,1H),8.01(d,J＝8.4Hz,2H),7.87(d,J＝8.4Hz,1H),7.71(t,J＝7.8Hz,1H),7.54(t,J＝7.5Hz,1H)ppm.13C NMR(150MHz,DMSO-d6)δ178.65,156.80,154.22,153.90,144.11,141.45,138.47,137.43,133.42,130.45,128.69,127.86,124.88,122.87,121.96,113.51ppm.HR-MS(m/z)(ESI):calcd for C18H13N5O2S,[M+H]-:362.0717；found:362.0714.
实施例47：化合物2的制备
以4a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.13g，产率78％。1HNMR(600MHz,DMSO-d6)δ13.16(s,1H),8.51(d,J＝42.2Hz,2H),8.24(d,J＝7.7Hz,2H),8.15(d,J＝7.8Hz,3H),7.98(s,1H),7.87(d,J＝8.2Hz,1H),7.71(t,J＝7.5Hz,1H),7.54(t,J＝7.2Hz,1H),3.82(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.20,156.80,154.24,153.89,144.11,140.39,138.46,137.65,133.36,130.42,128.63,128.35,124.86,122.88,121.94,113.49,33.34ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O2S,[M+H]-:376.0873；found:376.0872.
实施例48：化合物3的制备
以4a和4-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.17g，产率72％。1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),11.66(s,1H),8.68(d,J＝4.4Hz,1H),8.24(d,J＝8.2Hz,2H),8.17-8.11(m,2H),8.00(d,J＝8.3Hz,2H),7.87(d,J＝8.4Hz,1H),7.71(t,J＝7.7Hz,1H),7.54(t,J＝7.5Hz,1H),3.05(d,J＝4.5Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ178.30,156.80,154.19,153.90,144.12,140.89,138.45,137.51,133.31,130.44,128.68,127.73,124.87,122.86,121.95,113.50,31.37ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O2S,[M+H]-:376.0874；found:376.0870.
实施例49：化合物4的制备
以4a和N-乙基肼基硫代酰胺为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率70％。1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),11.60(s,1H),8.73(t,J＝5.8Hz,1H),8.24(d,J＝8.3Hz,2H),8.16-8.11(m,2H),8.00(d,J＝8.4Hz,2H),7.87(d,J＝8.4Hz,1H),7.73-7.70(m,1H),7.54(t,J＝7.5Hz,1H),3.62(dd,J＝13.5,6.8Hz,2H),1.18(t,J＝7.1Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ177.23,156.80,154.19,153.92,144.11,141.00,138.46,137.47,133.34,130.45,128.67,127.78,124.88,122.86,121.95,113.52,38.83,15.07ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O2S,[M+H]-:390.1030；found:390.1030.
实施例50：化合物5的制备
以4a和4,4-二甲基-3-氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率78％。1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),11.13(s,1H),8.31-8.22(m,3H),8.14(d,J＝7.5Hz,1H),7.85(dd,J＝25.1,8.2Hz,3H),7.71(t,J＝7.6Hz,1H),7.54(t,J＝7.4Hz,1H),3.34(s,3H),3.33(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.02,156.82,154.33,153.89,144.14,143.08,137.78,130.44,129.32,128.92,127.22,126.65,124.89,122.89,121.94,113.50,42.65ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O2S,[M+H]-:390.1030；found:390.1030.
实施例51：化合物6的制备
以4a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.13g，产率71％。1H NMR(600MHz,DMSO-d6)δ13.12(s,1H),10.44(s,1H),8.21(d,J＝8.3Hz,2H),8.15(d,J＝7.7Hz,1H),7.92(d,J＝7.6Hz,2H),7.87(d,J＝8.4Hz,1H),7.72(t,J＝3.5Hz,1H),7.53(t,J＝7.5Hz,1H),6.57(d,J＝52.1Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ157.14,157.10,156.82,153.90,139.28,138.56,135.76,130.44,130.03,128.67,127.19,127.11,124.88,122.90,121.96,113.51ppm.HR-MS(m/z)(ESI):calcd for C18H13N5O3,[M+H]-:346.0946；found:346.0941.
实施例52：化合物7的制备
以4a和氨基胍盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.10g，产率72％。1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),12.07(s,1H),8.27(d,J＝5.4Hz,3H),8.15(d,J＝7.6Hz,1H),8.08(d,J＝8.2Hz,2H),7.88(d,J＝8.4Hz,3H),7.72(t,J＝7.7Hz,2H),7.54(t,J＝7.4Hz,1H)ppm.13C NMR(150MHz,DMSO-d6)δ156.81,155.96,154.13,153.91,146.21,144.10,138.52,136.54,134.10,130.47,128.71,128.17,124.90,122.85,121.95,113.52ppm.HR-MS(m/z)(ESI):calcd for C18H14N6O2,[M+H]-:345.1105；found:345.1105.
实施例53：化合物8的制备
以4a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率71％。1H NMR(600MHz,DMSO-d6)δ13.23(s,1H),9.66(s,2H),8.42(s,1H),8.31(d,J＝8.1Hz,2H),8.19-8.11(m,3H),7.88(d,J＝8.4Hz,1H),7.72(t,J＝7.8Hz,1H),7.55(t,J＝7.5Hz,1H),2.76(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ167.12,156.82,153.88,151.21,144.07,138.57,135.60,135.11,130.52,129.04,128.80,126.44,124.94,122.80,121.93,113.54,14.02ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O2S,[M+H]-:376.0874；found:376.0867.
实施例54：化合物9的制备
以4a和4-苯基-3-氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.30g，产率80％。1H NMR(600MHz,DMSO-d6)δ13.19(s,1H),12.00(s,1H),10.28(s,1H),8.28-8.22(m,3H),8.13(dd,J＝19.1,8.1Hz,3H),7.87(d,J＝8.4Hz,1H),7.71(t,J＝7.8Hz,1H),7.56(dd,J＝13.7,7.7Hz,3H),7.40(t,J＝7.8Hz,2H),7.24(t,J＝7.4Hz,1H)ppm.13C NMR(150MHz,DMSO-d6)δ176.75,156.81,154.19,153.91,144.13,142.11,139.53,138.48,137.24,133.58,130.45,128.66,128.57,128.19,126.67,125.98,124.89,122.87,121.96,113.51ppm.HR-MS(m/z)(ESI):calcd for C24H17N5O2S,[M+H]-:438.1030；found:438.1024.
实施例55：化合物10的制备
以4a和4-(4-氯苯)-3-氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率72％。1H NMR(600MHz,DMSO-d6)δ13.19(s,1H),12.08(s,1H),10.30(s,1H),8.30-8.22(m,3H),8.13(dd,J＝20.6,8.0Hz,3H),7.87(d,J＝8.4Hz,1H),7.71(t,J＝7.7Hz,1H),7.62(d,J＝8.6Hz,2H),7.54(t,J＝7.5Hz,1H),7.46(d,J＝8.6Hz,2H)ppm.13CNMR(150MHz,DMSO-d6)δ176.73,156.82,154.17,153.91,144.12,142.46,138.52,137.14,133.66,130.46,129.97,128.66,128.46,128.27,128.23,128.08,124.89,122.87,121.95,113.52ppm.HR-MS(m/z)(ESI):calcd for C24H16ClN5O2S,[M+H]-:472.0640；found:472.0631.
实施例56：化合物11的制备
以4a和1'-[2-(4-吗啉)乙基]-1-氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率76％。1H NMR(600MHz,DMSO-d6)δ13.15(s,1H),11.70(s,1H),8.61(t,J＝5.3Hz,1H),8.26(d,J＝8.3Hz,2H),8.15(d,J＝8.9Hz,2H),7.97(d,J＝8.3Hz,2H),7.87(d,J＝8.4Hz,1H),7.71(t,J＝7.6Hz,1H),7.54(t,J＝7.5Hz,1H),3.70(dd,J＝12.5,6.4Hz,2H),3.65-3.60(m,4H),2.57(t,J＝6.7Hz,2H),2.48(s,4H)ppm.13C NMR(150MHz,DMSO-d6)δ177.51,156.80,154.21,153.98,144.13,141.13,138.48,137.35,133.56,130.44,128.76,127.60,124.88,122.88,121.95,113.51,66.82,56.98,53.70,40.84ppm.HR-MS(m/z)(ESI):calcd for C24H24N6O3S,[M+H]-:475.1558；found:475.1552.
实施例57：化合物12的制备
分别取0.10g(0.33mmol)5a和0.040g(0.39mmol)2-甲基氨基硫脲于100mL烧瓶中，加入50mL乙醇，滴加2滴乙酸，加热至回流，搅拌10h后，TLC监测反应。反应完成后，冷却过滤，取滤饼柱层析纯化(VDCM:VMeOH＝150:1)，得淡黄色固体0.13g，产率48％。1H NMR(600MHz,DMSO-d6)δ13.22(s,1H),8.33(d,J＝8.4Hz,2H),8.11(dd,J＝13.9,8.2Hz,3H),7.82(d,J＝8.4Hz,1H),7.67(t,J＝7.6Hz,1H),7.50(t,J＝7.4Hz,1H),7.09(s,2H),3.45(s,3H),2.37(s,3H)ppm.13CNMR(150MHz,DMSO-d6)δ157.60,156.80,143.36,141.30,130.48,130.42,128.84,128.28,126.56,124.94,124.85,122.91,121.97,113.54,27.47,13.64ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O2S,[M+H]-:390.1030；found:390.1026.
实施例58：化合物13的制备
以5a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物12的合成方法，得淡黄色固体0.076g，产率59％。1H NMR(600MHz,DMSO-d6)δ13.22(s,1H),9.40(s,2H),8.25(d,J＝9.8Hz,4H),8.15(d,J＝7.9Hz,1H),7.88(d,J＝7.8Hz,1H),7.75-7.70(m,1H),7.57-7.52(m,1H),2.72(s,3H),2.49(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ156.82,154.10,153.93,148.79,144.55,144.11,138.55,130.51,128.84,128.35,128.03,127.25,124.92,122.83,121.93,113.55,15.81,14.02ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O2S,[M+H]-:390.1030；found:390.1026.
实施例59：化合物14的制备
以5a和氨基脲盐酸盐为原料参考化合物12的合成方法，得淡黄色固体0.053g，产率44％。1H NMR(600MHz,DMSO-d6)δ9.38(s,1H),8.31(d,J＝8.3Hz,2H),8.05(d,J＝7.6Hz,1H),7.93(d,J＝8.3Hz,2H),7.72(d,J＝8.2Hz,1H),7.57(t,J＝7.6Hz,1H),7.41(t,J＝7.4Hz,1H),6.54(s,2H),3.51(s,1H),2.23(s,3H)ppm.13CNMR(150MHz,DMSO-d6)δ157.68,157.18,157.05,144.00,139.67,139.36,139.10,138.40,137.07,135.17,128.96,127.07,126.82,126.59,13.67ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O3,[M+H]-:360.1102；found:360.1097.
实施例60：化合物15的制备
以6a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.083g，产率80％。1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),8.65(d,J＝25.8Hz,2H),8.46(s,1H),8.25(d,J＝7.9Hz,1H),8.14(d,J＝7.6Hz,1H),8.11(d,J＝7.7Hz,1H),8.02(s,1H),7.87(d,J＝8.4Hz,1H),7.73-7.70(m,1H),7.64(t,J＝7.7Hz,1H),7.54(t,J＝7.3Hz,1H),3.83(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.24,156.87,156.83,154.35,153.89,140.47,138.54,135.53,133.25,131.39,130.48,129.65,126.59,124.92,122.89,121.92,113.54,33.25ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O2S,[M+H]-:376.0874；found:376.0870.
实施例61：化合物16的制备
以6a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.088g，产率84％。1H NMR(600MHz,DMSO-d6)δ13.16(s,1H),9.64(s,2H),8.61(s,1H),8.46(s,1H),8.27(dd,J＝13.5,7.8Hz,2H),8.15(d,J＝7.7Hz,1H),7.88(d,J＝8.4Hz,1H),7.74-7.69(m,2H),7.55(t,J＝7.5Hz,1H),2.77(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ166.99,156.81,154.27,153.82,151.50,144.06,138.54,133.64,131.34,130.85,130.51,129.72,128.85,124.93,122.80,121.96,113.54,14.05ppm.HR-MS(m/z)(ESI):calcd forC19H15N5O2S,[M+H]-:376.0874；found:376.0864.
实施例62：化合物17的制备
以6a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.077g，产率78％。1HNMR(600MHz,DMSO-d6)δ13.09(s,1H),10.42(s,1H),8.46(s,1H),8.16(t,J＝7.5Hz,2H),7.98-7.93(m,2H),7.87(d,J＝8.4Hz,1H),7.73-7.69(m,1H),7.59(t,J＝7.8Hz,1H),7.54(t,J＝7.5Hz,1H),6.62(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ157.18,156.82,153.88,140.23,138.62,135.86,133.32,130.46,129.58,129.52,128.90,127.92,126.22,124.89,124.28,122.89,122.02,113.52ppm.HR-MS(m/z)(ESI):calcd for C18H13N5O3,[M+H]-:346.0946；found:346.0942.
实施例63：化合物18的制备
以8a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.087g，产率84％。1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.30(d,J＝32.6Hz,2H),8.05(d,J＝7.7Hz,1H),7.93(d,J＝8.7Hz,2H),7.86(d,J＝9.7Hz,2H),7.70(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.13(d,J＝8.7Hz,2H),5.17(s,2H),3.76(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ180.73,159.57,156.63,154.34,153.41,143.54,141.25,138.85,130.43,129.91,128.45,124.95,122.58,121.83,115.44,113.52,67.95,33.18ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O3S,[M+H]-:406.0979；found:406.0973.
实施例64：化合物19的制备
以8a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.083g，产率81％。1H NMR(600MHz,DMSO-d6)δ13.22(s,1H),9.48(s,2H),8.29(s,1H),8.04(d,J＝7.8Hz,1H),7.95(d,J＝8.5Hz,2H),7.86(d,J＝8.4Hz,1H),7.70(t,J＝7.8Hz,1H),7.52(t,J＝7.5Hz,1H),7.21(d,J＝8.5Hz,2H),5.21(s,2H),2.73(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ166.01,160.93,156.63,154.17,153.42,151.90,143.52,138.84,130.76,130.47,126.49,124.98,122.55,121.79,115.70,113.55,68.00,13.89ppm.HR-MS(m/z)(ESI):calcd for C20H17N5O3S,[M+H]-:406.0979；found:406.0973.
实施例65：化合物20的制备
以8a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.081g，产率74％。1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),10.12(s,1H),8.05(d,J＝7.5Hz,1H),7.85(d,J＝8.4Hz,1H),7.79(s,1H),7.72-7.67(m,3H),7.51(t,J＝7.9Hz,1H),7.10(d,J＝8.8Hz,2H),6.43(s,2H),5.14(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ158.94,157.27,156.63,154.41,153.41,143.54,139.32,138.84,130.43,128.83,128.50,124.95,122.59,121.84,115.44,113.52,67.95ppm.HR-MS(m/z)(ESI):calcd for C19H15N5O4,[M+H]-:376.1051；found:376.1048.
实施例66：化合物21的制备
以9a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率78％。1H NMR(600MHz,DMSO-d6)δ13.24(s,1H),9.39(s,2H),8.05(d,J＝7.4Hz,2H),7.86(d,J＝8.5Hz,1H),7.72–7.69(m,1H),7.51(dd,J＝11.2,3.9Hz,1H),7.17(dd,J＝25.4,8.9Hz,3H),5.20(s,2H),2.71(s,3H),2.39(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ170.42,156.63,154.31,153.42,143.53,138.82,130.95,130.47,129.66,124.98,122.55,121.81,115.15,115.08,113.55,67.93,15.68,13.99ppm.HR-MS(m/z)(ESI):calcdfor C21H19N5O3S,[M+H]-:420.1136；found:420.1126.
实施例67：化合物22的制备
以9a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率83％。1H NMR(600MHz,DMSO-d6)δ13.21(s,1H),9.23(s,1H),8.06(d,J＝7.7Hz,1H),7.86(d,J＝8.5Hz,1H),7.83(d,J＝8.9Hz,2H),7.71-7.68(m,1H),7.51(t,J＝7.8Hz,1H),7.06(d,J＝9.0Hz,2H),6.46(s,2H),5.14(s,2H),2.15(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ158.54,157.80,156.63,154.51,153.43,144.12,143.55,138.82,132.19,130.43,127.88,124.94,122.58,121.85,114.92,113.52,67.91,13.66ppm.HR-MS(m/z)(ESI):calcd forC20H17N5O4,[M+H]-:390.1208；found:390.1204.
实施例68：化合物23的制备
以10a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.10g，产率77％。1H NMR(600MHz,DMSO-d6)δ13.12(s,1H),8.72(s,1H),8.49(s,1H),8.08(d,J＝7.6Hz,1H),7.86(d,J＝3.4Hz,2H),7.73-7.69(m,1H),7.63(s,1H),7.54(td,J＝7.6,2.6Hz,1H),7.28(t,J＝3.2Hz,1H),3.78(d,J＝2.4Hz,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.13,156.77,153.39,153.08,146.97,145.83,144.05,138.32,130.50,129.74,124.96,122.66,121.88,116.42,115.09,113.52,32.98ppm.HR-MS(m/z)(ESI):calcd forC17H13N5O3S,[M+H]-:366.0666；found:366.0661.
实施例69：化合物24的制备
以10a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率71％。1H NMR(600MHz,DMSO-d6)δ13.11(s,1H),9.45(s,2H),8.31(s,1H),8.11(d,J＝7.8Hz,1H),7.88(d,J＝8.4Hz,1H),7.75-7.73(m,1H),7.71(d,J＝8.4Hz,1H),7.55(t,J＝7.5Hz,1H),7.42(s,1H),2.73(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ178.64,166.83,156.78,153.34,151.17,148.32,145.53,143.91,140.89,138.50,130.58,125.03,122.60,121.94,116.59,113.57,14.01ppm.HR-MS(m/z)(ESI):calcd for C17H13N5O3S,[M+H]-:366.0666；found:366.0660.
实施例70：化合物25的制备
以10a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.10g，产率85％。1H NMR(600MHz,DMSO-d6)δ13.02(s,1H),10.56(s,1H),8.12(d,J＝7.7Hz,1H),7.85(t,J＝4.2Hz,2H),7.70(ddd,J＝8.5,7.3,1.3Hz,1H),7.64(d,J＝3.6Hz,1H),7.54-7.51(m,1H),7.08(d,J＝3.7Hz,1H),6.59(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ182.62,156.83,156.75,151.01,146.23,145.89,144.01,138.19,130.45,128.95,124.89,122.69,122.01,116.51,113.47,112.53ppm.HR-MS(m/z)(ESI):calcd for C16H11N5O4,[M+H]-:336.0738；found:336.0732.
实施例71：化合物26的制备
以11a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.087g，产率84％。1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.57(s,1H),8.18(s,1H),8.04(s,1H),7.99(s,1H),7.94(d,J＝7.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.67(t,J＝7.6Hz,1H),7.59(s,1H),7.48(t,J＝7.6Hz,1H),5.58(s,2H),3.70(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ180.66,156.56,154.21,153.36,143.34,142.50,138.55,133.88,132.71,130.48,128.01,124.91,122.31,121.92,113.46,48.31,33.20ppm.HR-MS(m/z)(ESI):calcd forC17H15N7O2S,[M+H]-:380.0935；found:380.0937.
实施例72：化合物27的制备
以11a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.13g，产率72％。1H NMR(600MHz,DMSO-d6)δ8.13(s,1H),7.94(d,J＝7.6Hz,1H),7.91(s,1H),7.59(d,J＝8.3Hz,1H),7.49-7.45(m,2H),7.30(t,J＝7.4Hz,1H),7.24(s,1H),5.36(s,2H),4.17(s,2H),2.31(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ162.63,162.11,161.40,157.68,155.16,144.60,143.35,141.74,140.14,134.20,124.31,122.97,122.94,121.68,112.64,49.03,12.61ppm.HR-MS(m/z)(ESI):calcd for C17H15N7O2S,[M+H]-:380.0935；found:380.0942.
实施例73：化合物28的制备
以11a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率80％。1HNMR(600MHz,DMSO-d6)δ13.45(s,1H),10.67(s,1H),9.30(s,1H),7.99(s,1H),7.92(d,J＝7.8Hz,1H),7.86-7.83(m,2H),7.68(t,J＝8.4Hz,1H),7.47(t,J＝7.5Hz,1H),6.64(s,2H),5.59(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ156.99,156.54,153.20,152.85,143.30,138.61,130.52,124.97,122.29,122.09,121.08,113.51,50.21ppm.HR-MS(m/z)(ESI):calcd for C16H13N7O3,[M+H]-:350.1007；found:350.1003.
实施例74：化合物29的制备
以12a和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.096g，产率73％。1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),8.72(s,1H),8.05(d,J＝7.7Hz,1H),7.83(d,J＝8.4Hz,1H),7.69-7.66(m,1H),7.49(t,J＝7.5Hz,1H),5.88(s,1H),3.56(s,2H),3.10(s,3H),2.74-2.69(m,2H),2.46-2.41(m,2H),1.70(t,J＝5.1Hz,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.85,156.57,156.53,153.53,143.62,138.65,130.23,124.76,122.76,121.88,113.42,74.11,60.31,49.73,35.03,34.59ppm.HR-MS(m/z)(ESI):calcdfor C18H20N6O2S,[M+H]-:383.1296；found:383.1292.
实施例75：化合物30的制备
以12a和1-氨基-S-甲基异硫脲氢碘酸盐为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率66％。1H NMR(600MHz,DMSO-d6)δ8.00(d,J＝7.8Hz,1H),7.74(d,J＝8.4Hz,1H),7.59(t,J＝7.7Hz,1H),7.42(t,J＝7.5Hz,1H),6.44(s,2H),3.55(s,2H),2.72(t,J＝5.6Hz,2H),2.70-2.66(m,2H),2.60(t,J＝5.7Hz,2H),2.37(d,J＝5.8Hz,2H),2.30(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ168.26,156.57,153.39,143.36,138.77,130.46,124.98,122.50121.92,113.53,53.29,53.24,52.25,30.26,22.18,13.59ppm.HR-MS(m/z)(ESI):calcd for C18H20N6O2S,[M+H]-:383.1296；found:383.1299.
实施例76：化合物31的制备
以12a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.14g，产率71％。1H NMR(600MHz,DMSO-d6)δ13.30(s,1H),9.39(s,1H),8.09(d,J＝7.7Hz,1H),7.88(d,J＝8.4Hz,1H),7.72(t,J＝7.7Hz,1H),7.54(t,J＝7.4Hz,1H),6.28(s,2H),4.46(s,2H),3.44(dd,J＝13.9,6.9Hz,8H)ppm.13C NMR(150MHz,DMSO-d6)δ179.14,157.76,156.56,153.13,143.05,139.15,130.56,125.06,122.38,121.93,113.58,52.70,51.12,25.99,24.07ppm.HR-MS(m/z)(ESI):calcd for C17H18N6O3,[M+H]-:353.1386；found:353.1375.
实施例77：化合物32的制备
以13a和氨基脲盐酸盐为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率69％。1H NMR(600MHz,DMSO-d6)δ13.32(s,1H),11.34(s,1H),9.48(s,2H),8.11(t,J＝8.6Hz,1H),7.88(d,J＝8.4Hz,1H),7.72(t,J＝7.3Hz,1H),7.54(t,J＝7.6Hz,1H),6.35(s,2H),4.60(s,2H),4.15(s,2H),2.77(s,2H)ppm.13C NMR(150MHz,DMSO-d6)δ157.30,157.22,156.59,156.56,153.12,143.82,142.99,138.89,130.58,125.03,121.92,113.59,56.47,56.39,53.69,26.65ppm.HR-MS(m/z)(ESI):calcd for C16H16N6O3,[M+H]-:339.1211；found:339.1209.
实施例78：化合物33的制备
以4b和2-甲基氨基硫脲为原料参考化合物1的合成方法，得黄色固体0.12g，产率79％。1HNMR(600MHz,DMSO-d6)δ13.18(s,1H),8.50(d,J＝47.9Hz,2H),8.22(d,J＝8.2Hz,2H),8.13(dd,J＝8.2,4.3Hz,3H),8.06(s,1H),7.96(s,1H),7.57-7.54(m,1H),3.82(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.22,156.79,154.61,153.72,143.61,140.30,139.05,137.71,134.72,133.20,128.62,128.30,125.46,123.06,121.93,113.94,33.32ppm.HR-MS(m/z)(ESI):calcd for C19H14ClN5O2S,[M+H]-:410.0484；found:410.0473.
实施例79：化合物34的制备
以4c和2-甲基氨基硫脲为原料参考化合物1的合成方法，得黄色固体0.11g，产率75％。1HNMR(600MHz,DMSO-d6)δ13.22(s,1H),8.51(d,J＝44.7Hz,2H),8.22(d,J＝6.4Hz,3H),8.14(d,J＝8.3Hz,2H),8.07(d,J＝8.3Hz,1H),7.97(s,1H),7.69(d,J＝8.2Hz,1H),3.82(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.22,156.94,154.64,153.75,143.64,140.34,137.74,129.99,129.27,128.66,128.34,128.17,123.38,122.95,122.26,116.84,33.34ppm.HR-MS(m/z)(ESI):calcd for C19H14BrN5O2S,[M+H]-:453.9979；found:453.9967.
实施例80：化合物35的制备
以4f和2-甲基氨基硫脲为原料参考化合物1的合成方法，得黄色固体0.11g，产率86％。1HNMR(600MHz,DMSO-d6)δ13.20(s,1H),8.51(d,J＝43.6Hz,2H),8.23(d,J＝8.3Hz,2H),8.15(d,J＝8.4Hz,2H),7.97(s,1H),7.95-7.91(m,2H),7.57(td,J＝9.1,2.6Hz,1H),3.82(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.22,160.32,158.73,154.27,153.87,153.04,143.89,140.35,137.71,133.24,128.64,128.33,123.89(d,J＝10.5Hz),118.26(d,J＝26.2Hz),115.12(d,J＝9.5Hz),107.45(d,J＝25.4Hz),33.33ppm.HR-MS(m/z)(ESI):calcd for C19H14FN5O2S,[M+H]-:394.0779；found:394.0770.
实施例81：化合物36的制备
以4g和2-甲基氨基硫脲为原料参考化合物1的合成方法，得黄色固体0.12g，产率81％。1H NMR(600MHz,DMSO-d6)δ13.24(s,1H),8.55(s,1H),8.49(s,1H),8.24(d,J＝8.3Hz,2H),8.19(d,J＝1.9Hz,1H),8.15(d,J＝8.4Hz,2H),7.98(s,1H),7.93(d,J＝8.9Hz,1H),7.74(dd,J＝8.9,2.0Hz,1H),3.82(s,3H)ppm.13CNMR(150MHz,DMSO-d6)δ181.21,155.18,154.50,153.83,143.20,140.35,139.62,137.76,133.18,130.32,129.34,128.66,128.34,124.46,121.27,115.34,33.34ppm.HR-MS(m/z)(ESI):calcd for C19H14ClN5O2S,[M+H]-:410.0484；found:410.0475.
实施例82：化合物37的制备
以4h和2-甲基氨基硫脲为原料参考化合物1的合成方法，得黄色固体0.11g，产率75％。1HNMR(600MHz,DMSO-d6)δ13.23(s,1H),8.52(d,J＝40.3Hz,2H),8.30(s,1H),8.23(d,J＝8.1Hz,2H),8.15(d,J＝8.2Hz,2H),7.97(s,1H),7.86(d,J＝5.2Hz,2H),3.82(s,3H)ppm.13C NMR(150MHz,DMSO-d6)δ181.17,155.54,154.48,153.80,143.07,140.36,139.39,137.77,133.15,132.99,128.66,128.35,124.99,124.26,117.13,115.73,33.34ppm.HR-MS(m/z)(ESI):calcd for C19H14BrN5O2S,[M+H]-:453.9979；found:453.9971.
实施例83：化合物38的制备
以12b和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.11g，产率85％。1H NMR(600MHz,DMSO-d6)δ12.66(s,1H),8.73(s,1H),8.07-8.05(m,2H),7.53(dd,J＝8.4,1.7Hz,1H),5.87(s,1H),3.55(s,2H),3.11(s,3H),2.74-2.69(m,2H),2.46-2.41(m,2H),1.70(t,J＝4.8Hz,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.82,156.97,156.57,153.37,143.09,139.29,134.52,125.38,123.04,121.80,113.91,74.09,60.28,49.73,35.01,34.55ppm.HR-MS(m/z)(ESI):calcd for C18H19ClN6O2S,[M+H]-:417.0906；found:417.0904.
实施例84：化合物39的制备
以12c和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.10g，产率78％。1H NMR(600MHz,DMSO-d6)δ12.66(s,1H),8.73(s,1H),8.20(s,1H),7.99(d,J＝8.1Hz,1H),7.66(d,J＝7.9Hz,1H),5.87(s,1H),3.55(s,2H),3.11(s,3H),2.70(s,2H),2.44(s,2H),1.70(s,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.84,157.00,156.74,153.40,143.15,139.11,128.08,123.34,122.74,122.14,116.78,74.09,60.28,49.73,35.02,34.56ppm.HR-MS(m/z)(ESI):calcd for C18H19BrN6O2S,[M+H]-:461.0401；found:461.0393.
实施例85：化合物40的制备
以12d和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率80％。1H NMR(600MHz,DMSO-d6)δ12.51(s,1H),8.72(s,1H),7.91(d,J＝8.0Hz,1H),7.64(s,1H),7.32(d,J＝8.1Hz,1H),5.86(s,1H),3.54(s,2H),3.10(s,3H),2.73-2.69(m,2H),2.51(s,3H),2.46-2.41(m,2H),1.70(t,J＝4.9Hz,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.85,157.06,156.42,153.43,143.77,140.80,138.22,126.21,121.37,120.25,113.25,74.11,60.31,49.74,35.02,34.59,22.04ppm.HR-MS(m/z)(ESI):calcd for C19H22N6O2S,[M+H]-:397.1452；found:397.1444.
实施例86：化合物41的制备
以12e和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.15g，产率78％。1H NMR(600MHz,DMSO-d6)δ12.46(s,1H),8.73(s,1H),7.90(d,J＝8.7Hz,1H),7.42(d,J＝2.1Hz,1H),7.08(dd,J＝8.7,2.2Hz,1H),5.86(s,1H),3.89(s,3H),3.53(s,2H),3.10(s,3H),2.73-2.69(m,2H),2.45-2.40(m,2H),1.70(t,J＝5.1Hz,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.83,161.96,158.33,156.51,153.05,144.06,137.89,122.25,115.59,114.30,97.25,74.11,60.29,56.39,49.74,35.01,34.58ppm.HR-MS(m/z)(ESI):calcd for C19H22N6O3S,[M+H]-:413.1401；found:413.1393.
实施例87：化合物42的制备
以12f和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率84％。1HNMR(600MHz,DMSO-d6)δ12.63(s,1H),8.74(s,1H),8.08(dd,J＝8.3,5.6Hz,1H),7.84(d,J＝8.8Hz,1H),7.38(t,J＝8.3Hz,1H),5.88(s,1H),3.56(s,2H),3.11(s,3H),2.72(s,2H),2.44(s,2H),1.70(s,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.83,164.29,162.66,156.88(d,J＝14.4Hz),153.19,143.36,139.36(d,J＝2.9Hz),123.21(d,J＝10.6Hz),119.47,113.49,113.32,101.37,101.19,74.09,60.26,49.73,35.01,34.56ppm.HR-MS(m/z)(ESI):calcd for C18H19FN6O2S,[M+H]-:401.1201；found:401.1199.
实施例88：化合物43的制备
以12g和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.12g，产率85％。1H NMR(600MHz,DMSO-d6)δ12.69(s,1H),8.73(s,1H),8.08(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.70(dd,J＝8.9,2.1Hz,1H),5.87(s,1H),3.55(s,2H),3.11(s,3H),2.74-2.69(m,2H),2.47-2.41(m,2H),1.70(t,J＝4.7Hz,4H)ppm.13C NMR(150MHz,DMSO-d6)δ178.84,156.82,154.94,153.45,142.71,139.84,130.11,129.22,124.28,121.16,115.24,74.09,60.23,49.73,35.02,34.56ppm.HR-MS(m/z)(ESI):calcd forC18H19ClN6O2S,[M+H]-:417.0906；found:417.0903.
实施例89：化合物44的制备
以12h和2-甲基氨基硫脲为原料参考化合物1的合成方法，得淡黄色固体0.13g，产率89％。1H NMR(600MHz,DMSO-d6)δ12.71(s,1H),8.75(s,1H),8.21(s,1H),7.84-7.81(m,2H),5.88(s,1H),3.55(s,2H),3.11(s,3H),2.70(s,2H),2.44(s,2H),1.70(s,4H)ppm.13CNMR(150MHz,DMSO-d6)δ178.81,156.88,155.32,153.47,142.56,139.64,132.83,124.86,124.19,117.04,115.69,74.09,60.27,49.71,35.00,34.56ppm.HR-MS(m/z)(ESI):calcdfor C18H19BrN6O2S,[M+H]-:461.0401；found:461.0391.
实施例90：目标化合物的酶抑制活性评价
1、实验方法
化合物对外源性酶活的抑制作用通过由上海抚生实业有限公司提供的商业化PARP和PARP-1酶联免疫酶活检测试剂盒检测，具体按照试剂盒中提供的使用说明书操作。实验步骤简述为：实验设有空白组、待测组和阳性对照组。将目标蛋白稀释液加入到各孔中，在待测组和阳性对照组分别加入1μmol/L的待测化合物溶液和阳性对照药物奥拉帕尼(Olaparib)。封板后在37℃孵箱中孵育2h。用洗涤液洗涤5次后，除空白组外，在每孔中加入50μL酶标试剂，封板在37℃孵箱中继续温育30min，结束后先加入50μL显色剂A，再加入50μL显色剂B，轻轻震荡摇匀，37℃避光孵育10min。最后在各孔中再加入50.0μL终止液。以空白孔调零，用酶标仪在490nm波长下依序测量各孔的吸光度(OD值)，每个化合物平行三次独立实验，结果取三次实验平均值，计算抑制率。
2、实验结果
表1.化合物1-44(1μM)对PARP酶活的抑制率
表2.化合物(1μM)对PARP-1酶活的抑制率
由表1可见：
(1)在1μM浓度下，奥拉帕尼对PARP酶活的抑制率仅为57.65％，而在所测的化合物中就有27个化合物的抑制率超过奥拉帕尼。其中，化合物3、4、6、7、9、11、21、24和29的抑制率在80％～89％之间，化合物2、8、12和30的抑制率超过90％。化合物8表现最佳，抑制率高达98.60％，是奥拉帕尼的1.7倍。对这些化合物的结构与活性关系分析表明：以氨基硫脲作为活性片段，采用对苯二甲醛结合到苯并呋喃嘧啶酮母体结构中能够有效提高化合物对PARP酶活的抑制作用，如化合物1的抑制率为60.27％，高于奥拉帕尼；当对氨基硫脲结构中的NH基进行单取代时，无论使用短链的烷基还是芳基都有助于提高化合物活性，如化合物2、3、4、9和11的抑制率明显高于化合物1；但对氨基硫脲结构中的NH2基进行双取代时会大幅度降低化合物活性，如化合物5，其抑制率仅为15％，这表明化合物氨基硫脲尾端结构片段中的NH基对保持化合物的生物活性有重要的作用。此外，用氨基脲(化合物6)或者氨基胍(化合物7)替代氨基硫脲片段时化合物仍具有较好的抑制活性。
(2)当采用2-甲基氨基硫脲、氨基脲和1-氨基-S-甲基异硫脲作为活性片段探究不同linker对化合物活性的影响时，发现选用对乙酰基苯甲醛和哌啶-4-酮替换对苯二甲醛时，基本可保持化合物对PARP酶活的抑制作用，如化合物12和30，其抑制率分别达到了90.13％和92.98％。但是当改变linker中取代基位置(间苯二甲醛)或者选用五元杂环(呋喃-2,5-二甲醛、4-咪唑甲醛或3-吡咯烷酮)时，会降低化合物对PARP酶活的抑制作用，如在化合物13-32中，除了化合物21、24、29和30外，其余化合物的抑制率均低于80％。此外，在以哌啶-4-酮为linker时，化合物末端为2-甲基氨基硫脲和1-氨基-S-甲基异硫脲时活性最好，如化合物29和30，抑制率大于86％。
(3)当选用对苯二甲醛和哌啶-4-酮为linker、2-甲基氨基硫脲为活性片段时，在苯并呋喃嘧啶酮结构苯环中引入不同取代基可对化合物的活性造成显著影响。研究发现无论引入吸电子基(-F、-Cl和-Br)，还是引入供电子基(-CH3和-OCH3)，或是改变取代基的位置都会大幅度降低化合物的活性。
由表2可见，所测化合物对PARP-1酶活也表现出较为优越的抑制作用。在1μM浓度下，化合物2、8、12、16、19、27、28和31对PARP-1酶活的抑制率在50％～60％之间；化合物6、13、14、15、17、18、20、22、25、30、32和40对PARP-1酶活的抑制率在60％～80％；化合物3、4、9、11、21、26和29对PARP-1酶活的抑制率都超过80％。在所测化合物中，化合物4对PARP-1的抑制率最高，达到97.45％，高于奥拉帕尼的86.37％。
实施例91：化合物体外细胞毒活性评价
1、实验方法
采用MTT方法对本发明的化合物进行细胞毒活性测试。取对数生长期的细胞计数，接种于96孔培养板内，每孔约8000～10000个细胞。培养过夜，待细胞贴壁后进行给药，分别设给药组和对照组。待测的化合物用DMSO溶液配制成贮液，临用前用细胞培养基稀释成一系列浓度，其中DMSO的终浓度不超过4‰。每个浓度设3个复孔。加药后培养72h，加20μL浓度为5mg/mL的MTT，37℃孵育4h，去上清，加入150μL的DMSO溶解。用酶标仪在490nm波长下测定每孔的OD值，计算抑制率，做浓度-抑制率曲线计算IC50值。
2、实验结果
表3.代表性化合物对癌细胞的抗增殖活性
由表3可见，大多数代表性化合物对所测的五种癌细胞都表现出良好的抗增殖活性，且对正常细胞的毒性也相对较低。除了化合物7和11外，其余化合物对正常肝细胞L02的IC50值均大于50μM，有的化合物的IC50值超过100μM，显示出较低的毒性。所测化合物对卵巢癌细胞较为敏感，其中化合物3、4、8、21和29对SK-OV-3细胞的IC50值低于10μM，化合物4表现最佳，其抗增殖活性是奥拉帕尼的2倍。此外，化合物4、8和29对结直肠癌细胞HCT-116，化合物6、9和21对三阴乳腺癌细胞MDA-MB-231，化合物8对卵巢癌细胞A2780，也比较敏感，细胞毒性与奥拉帕尼相当或优于奥拉帕尼。
综上，本发明以苯并呋喃嘧啶酮为母体化合物，以不同的芳香类化合物为连接体，分别与母体化合物和氨基硫脲及其类似物、氨基脲或氨基胍作用，得到一类新型化合物。该类化合物对PARP酶活和PARP-1酶活具有优异的抑制作用，并对多种癌细胞表现出良好的抗增殖活性，有部分化合物的抑制作用优于阳性药物奥拉帕尼。如化合物3和4，无论是酶抑制活性还是对SK-OV-3细胞的抗增殖活性都优于奥拉帕尼，可用于制备抗肿瘤药物。
Claims (10)
1.一种三环类化合物，其特征在于，具有式1的结构，还包含其异构体、药学上可接受的盐或它们的混合物：
其中：
R2选自卤素、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基。
2.根据权利要求1所述的三环类化合物，其特征在于，具有式I的结构，
3.根据权利要求1所述的三环类化合物，其特征在于，具有式II的结构，
其中：
选自/>
R1选自
4.根据权利要求1所述的三环类化合物，其特征在于，具有式III的结构，
其中：
选自/>
R2选自4-Cl、4-Br、4-CH3、4-OCH3、5-F、5-Cl、5-Br。
5.根据权利要求1所述的三环类化合物，其特征在于，选自以下任一化合物：
6.根据权利要求1所述的三环类化合物，其特征在于，所述药学上可接受的盐为所述化合物与选自以下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
7.一种权利要求1所述的三环类化合物的制备方法，其特征在于，选自以下任一方法：
(1)当化合物具有式I的结构时，化合物3a与对苯二甲醛环合，然后化合物4a与R1-NH2缩合得到式I的化合物；
(2)当化合物具有式II的结构时，化合物3a分别与对乙酰基苯甲醛、间苯二甲醛、2,4-二醛基呋喃环合，然后化合物5a～6a、10a分别与R1-NH2缩合得到式II的化合物；或化合物3a与2-氯-1,1,1-三甲氧基乙烷环合，然后化合物7a分别与4-羟基苯甲醛、4-羟基苯甲酮、2-醛基咪唑、4-哌啶酮、3-吡咯烷酮偶联，最后化合物8a～9a、11a～13a分别与R1-NH2缩合得到式II的化合物；
(3)当化合物具有式III的结构时，化合物3b～3h分别与对苯二甲醛环合，然后化合物4b～4c、4f～4h分别与R1-NH2缩合得到式III的化合物；或化合物3b～3h分别与2-氯-1,1,1-三甲氧基乙烷环合，然后化合物7b～7h分别与4-哌啶酮偶联，最后化合物12b～12h分别与R1-NH2缩合得到式III的化合物；
其中，R1、R2的定义如权利要求1所述；
将相应的酸与以上方法制备的式I～III的化合物成盐，即得所述化合物的药学上可接受的盐。
8.一种药物组合物，其特征在于，所述药物组合物包含权利要求1所述三环类化合物以及药学上可接受的载体。
9.一种权利要求1所述的三环类化合物或权利要求8所述的药物组合物在制备PARP抑制剂药物中的应用。
10.根据权利要9所述的应用，其特征在于，所述药物为抗肿瘤药物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310837130.XA CN116874496A (zh) | 2023-07-10 | 2023-07-10 | 三环类化合物及其制备方法、药物组合物和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310837130.XA CN116874496A (zh) | 2023-07-10 | 2023-07-10 | 三环类化合物及其制备方法、药物组合物和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116874496A true CN116874496A (zh) | 2023-10-13 |
Family
ID=88259777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310837130.XA Pending CN116874496A (zh) | 2023-07-10 | 2023-07-10 | 三环类化合物及其制备方法、药物组合物和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116874496A (zh) |
-
2023
- 2023-07-10 CN CN202310837130.XA patent/CN116874496A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11358955B2 (en) | 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof | |
| KR102075886B1 (ko) | 신규한 피라졸로[3,4-d]피리미딘 화합물 또는 그 염 | |
| KR100226114B1 (ko) | 항증식 작용을 가진 퀴나졸린 화합물 | |
| CN102311434B (zh) | 吴茱萸碱类化合物及其制备方法与应用 | |
| US6479499B1 (en) | 2-phenyl-4-quinazolinone compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions | |
| CA2736097C (en) | Carbazole compounds for inhibition of nf-kb activity | |
| JP5933746B2 (ja) | イミダゾリジンジオン系化合物およびその用途 | |
| EP2915804A1 (en) | Novel amine derivative or salt thereof | |
| WO2015007249A1 (zh) | N-烷基色胺酮衍生物及其制备方法和应用 | |
| CA2687948A1 (en) | Novel 1,2,3,4-tetrahydroquinoxaline derivative which has, as substituent, phenyl group having sulfonic acid ester structure or sulfonic acid amide structure introduced therein andhas glucocorticoid receptor-binding activity | |
| WO2007036131A1 (fr) | Dérivés de carzole sulfamide et leur procédé de préparation | |
| WO2013013614A1 (zh) | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 | |
| WO2016150340A1 (zh) | 喹唑啉衍生物的盐及其制备方法 | |
| Singh et al. | Synthesis and in vitro evaluation of naphthalimide–benzimidazole conjugates as potential antitumor agents | |
| Desai et al. | Microwave assisted synthesis of new coumarin based 3-cyanopyridine scaffolds bearing sulfonamide group having antimicrobial activity | |
| CN116874496A (zh) | 三环类化合物及其制备方法、药物组合物和应用 | |
| EP1854787B1 (en) | Novel cyclic compound having quinolylalkylthio group | |
| CN102617478B (zh) | 苯并咪唑、噁唑和噻唑衍生物的合成及其应用 | |
| CN102010418B (zh) | 高喜树碱类化合物及其作为药物的用途 | |
| US9643959B2 (en) | Tubulin polymerization inhibitor and method for synthesizing same | |
| CN102229563A (zh) | 4-氨基喹啉衍生物及其制备方法和用途 | |
| CN102146076B (zh) | 苯胺喹唑啉衍生物及其制备方法 | |
| CN112876456A (zh) | 噌啉化合物pi3k激酶抑制剂及其制备方法与在制药中的应用 | |
| CN108484594B (zh) | 一种烷氧基取代四氢吡啶并嘧啶类化合物或其可用盐及其制备方法与应用 | |
| WO2004026846A1 (en) | Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |