CN117229224A - 喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 - Google Patents
喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 Download PDFInfo
- Publication number
- CN117229224A CN117229224A CN202210633592.5A CN202210633592A CN117229224A CN 117229224 A CN117229224 A CN 117229224A CN 202210633592 A CN202210633592 A CN 202210633592A CN 117229224 A CN117229224 A CN 117229224A
- Authority
- CN
- China
- Prior art keywords
- acid
- quinazolin
- methyl
- amino
- trifluoromethyl
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 101000735473 Homo sapiens Protein mono-ADP-ribosyltransferase TIPARP Proteins 0.000 claims abstract description 20
- 102100034905 Protein mono-ADP-ribosyltransferase TIPARP Human genes 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- -1 quinazolin-4 (3H) -one compound Chemical class 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 20
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 3H-quinazolinyl-4-one Natural products C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 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
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 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
- 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 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 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
- 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
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- TWSIYGATPWEKBK-UHFFFAOYSA-N 4h-1,3-benzodioxine Chemical group C1=CC=C2OCOCC2=C1 TWSIYGATPWEKBK-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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-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
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 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
- 229940114124 ferulic acid Drugs 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
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229960000448 lactic acid Drugs 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
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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
- 229960001367 tartaric acid Drugs 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000009169 immunotherapy Methods 0.000 abstract description 3
- 229940088592 immunologic factor Drugs 0.000 abstract description 2
- 239000000367 immunologic factor Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000006243 chemical reaction Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 108010033040 Histones Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000011095 buffer preparation Methods 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229960001388 interferon-beta Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- KYLVAMSNNZMHSX-UHFFFAOYSA-N methyl 6-bromohexanoate Chemical compound COC(=O)CCCCCBr KYLVAMSNNZMHSX-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- XGOYIMQSIKSOBS-UHFFFAOYSA-N vadimezan Chemical compound C1=CC=C2C(=O)C3=CC=C(C)C(C)=C3OC2=C1CC(O)=O XGOYIMQSIKSOBS-UHFFFAOYSA-N 0.000 description 2
- 229950008737 vadimezan Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IIGCYQPNZRSCLY-UHFFFAOYSA-N 1,1-dimethyl-3-prop-1-enylurea Chemical group CC=CNC(=O)N(C)C IIGCYQPNZRSCLY-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- JJPIVRWTAGQTPQ-UHFFFAOYSA-N 2-amino-3-nitrobenzoic acid Chemical compound NC1=C(C(O)=O)C=CC=C1[N+]([O-])=O JJPIVRWTAGQTPQ-UHFFFAOYSA-N 0.000 description 1
- WSZRCNZXKKTLQE-UHFFFAOYSA-N 2-chloro-5-iodopyrimidine Chemical compound ClC1=NC=C(I)C=N1 WSZRCNZXKKTLQE-UHFFFAOYSA-N 0.000 description 1
- XTJVJOAIAAVWAM-UHFFFAOYSA-N 2-methyl-8-nitro-1h-quinazolin-4-one Chemical compound C1=CC=C2C(=O)NC(C)=NC2=C1[N+]([O-])=O XTJVJOAIAAVWAM-UHFFFAOYSA-N 0.000 description 1
- UQZCQKXJAXKZQH-LBPRGKRZSA-N 4-[[(2S)-1-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy]propan-2-yl]amino]-5-(trifluoromethyl)-1H-pyridazin-6-one Chemical compound O=C(CCOC[C@H](C)NC1=C(C(NN=C1)=O)C(F)(F)F)N1CCN(CC1)C1=NC=C(C=N1)C(F)(F)F UQZCQKXJAXKZQH-LBPRGKRZSA-N 0.000 description 1
- 108010049290 ADP Ribose Transferases Proteins 0.000 description 1
- 102000009062 ADP Ribose Transferases Human genes 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VTHYFRPSXRHMGT-UHFFFAOYSA-N Cl.FC(F)(F)c1cnc(nc1)N1CCNCC1 Chemical compound Cl.FC(F)(F)c1cnc(nc1)N1CCNCC1 VTHYFRPSXRHMGT-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 101001054328 Mus musculus Interferon beta Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229940044665 STING agonist Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 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
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种喹唑啉‑4(3H)‑酮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(I),其包含其异构体、药学上可接受的盐或它们的混合物。该类化合物及其药物组合物对PARP7具有高效的抑制作用,抑制活性达到纳摩尔浓度水平;还可以显著促进免疫因子释放,用于肿瘤的免疫治疗,在分子水平、细胞水平均可以发挥良好的药效。此外,该类化合物的制备方法简便易行。
Description
技术领域
本发明涉及一种喹唑啉-4(3H)-酮类化合物及其制备方法、药物组合物和应用,尤其涉及一种可制备为PARP7抑制剂药物、具有抗肿瘤活性的喹唑啉-4(3H)-酮类化合物及其制备方法、药物组合物和应用。
背景技术
人体内大多数PARP家族成员展现的是monoADP核糖转移酶活性。MonoPARP蛋白家族与癌症、炎症及神经退行性疾病的发生和发展密切相关。PARP7是monoPARP 蛋白家族的成员之一,它是一种新的细胞中核酸感应器的负调控因子,其在多种肿瘤细胞中过度表达。由于癌细胞可以借助PARP-7来抑制干扰素信号,而使其“躲藏”在免疫系统之外,因此,许多癌细胞都依赖PARP-7而存活。研究发现,抑制PARP7可恢复细胞内的干扰素信号传导,恢复机体的先天和适应性免疫,进而抑制癌细胞的生长。在肺癌、结直肠癌等癌症模型中,PARP7抑制剂表现出持久的肿瘤生长抑制作用。目前尚未有PARP-7抑制剂被批准上市,Ribon公司开发的RBN-2397是首个对PARP-7具有较强抑制活性的化合物,目前已进入临床I期研究(NCT04053673)。针对目前该靶点并未有其他结构类型的抑制剂,因此,设计并合成一系列全新结构类型的PARP7抑制剂并进行生物活性评价,将为该靶点的进一步研究提供基础。
发明内容
发明目的:针对现有化合物存在的结构类型比较单一、活性有限等问题,本发明旨在提供一种具有优异的抗肿瘤活性的喹唑啉-4(3H)-酮类化合物及其制备方法、药物组合物和应用。
技术方案:作为本发明涉及的第一方面,本发明的喹唑啉-4(3H)-酮类化合物具有式(I)的结构,所述化合物包含其异构体、药学上可接受的盐或它们的混合物:
其中:
n选自0、1、2、3、4或5;
m选自0或1;
R1选自氢、卤素、氰基、三氟甲基、C1~C6烷基、C1~C6烷氧基、甲硫基、甲磺酰基或氨甲酰基;
R2或R3分别独立地选自氢、C1~C6烷基、C3~C6环烷基、杂环烷基、氰基、卤素、二氟甲基或三氟甲基,或者R2和R3与所连碳原子一起形成C3~C6环烷基;所述C3~C6环烷基被一个或多个一下基团取代:氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基;
R4选自芳基、杂芳基或1,3-苯并二噁烷基,所述杂芳基或1,3-苯并二噁烷基被一个或多个以下基团取代:氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C1~C6烷基、C1~C6烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰基或硝基;
R5选自氢、氰基、三氟甲基、C1~C6烷基、C1~C6烷氧基或甲磺酰基;
A1选自-NH-、-O-、-S-或-N(CH3)-;
A2选自-NH-、-O-、-CH2-、C3~C6环烷基、C3~C6杂环烷基或者5~8元芳环或杂芳环,所述C3~C6环烷基、杂环烷基或5~8元芳环或杂芳环的任意位置被一个或多个以下基团取代:氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基;
A3选自: 其中,R6、R7或R8分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基。
优选,上述结构中:
n选自0、1、2、3或4;
R1选自氢或卤素;
R2或R3分别独立地选自氢、甲基、氟或乙基;当R2、R3不同时,与R2、R3相连的碳原子为消旋构型、R构型或S构型;
R4选自:其中,Y1和Y2分别独立地代表N、CH或CH-R9, R9选自氢、三氟甲基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或 4-三氟甲基苯基;
R5选自氢、甲基或三氟甲基;
A1选自-NH-或-O-;
A2选自:-NH-、-CH2-、其中,X1、X2或X3各自独立地选自CH或N,R10选自一个或多个氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基;
A3选自:
进一步优选,上述结构中:
R1选自氢或氟;
R2或R3分别独立地选自氢或甲基;
A2选自:
A3选自:
更进一步优选,上述结构中:
R4选自:
最优选地,上述喹唑啉-4(3H)-酮类化合物选自以下任一化合物:
上述喹唑啉-4(3H)-酮类化合物的药学上可接受的盐为上述化合物与酸形成的盐,所述酸选自盐酸、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、杏仁酸或阿魏酸。
作为本发明涉及的第二方面,上述喹唑啉-4(3H)-酮类化合物的制备方法为:
化合物(II)与化合物(III),经取代、水解、酰化、脱保护反应得到化合物(I);
其中,m、n、A1、A2、Y1、Y2、R1、R2、R3、R5、R7、R8、R10的定义如前所述;
具体地,由化合物II制备化合物IV,是将II和III溶于溶剂,加入缚酸剂进行取代反应得到。反应溶剂为N,N-二甲基丙烯基脲(DMPU)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、四氢呋喃(THF)、1,4-二氧六环、乙二醇二甲醚或乙腈,优选DMPU;缚酸剂为碳酸钠、碳酸钾、碳酸铯、三乙胺或N,N-二异丙基乙胺(DIPEA),优选碳酸铯。
由化合物IV制备化合物V,是将IV溶于溶剂,加入碱的水溶液进行水解反应得到。反应溶剂为THF、甲醇、乙腈或任意两者的混合溶剂,优选THF与甲醇混合溶剂;碱为氢氧化钠、氢氧化锂或氢氧化钾,优选氢氧化钠。
由化合物V制备化合物VII,是将V溶于溶剂,加入缩合剂,再加入碱和化合物 VI进行缩合反应得到。溶剂为二氯甲烷、THF、DMF、1,4-二氧六环、乙二醇二甲醚或乙腈,优选DMF;缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBT)、N,N'-二环己基碳二亚胺(DCC)、 N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 (HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、六氟磷酸苯并三唑-1- 基-氧基三吡咯烷基(PyBop),优选EDCI或HOBT;碱为三乙胺、碳酸钠、碳酸钾或 DIPEA,优选DIPEA。
由化合物VII制备化合物I,是将VII溶于溶剂,加入三氟甲磺酸进行脱保护反应得到。反应溶剂为三氟乙酸、醋酸、THF、甲醇、乙腈或任意两者的混合溶剂,优选三氟乙酸。
将相应的酸与以上方法制备的化合物(I)成盐,即得所述化合物的药学上可接受的盐。
作为本发明涉及的第三方面,上述喹唑啉-4(3H)-酮类化合物以及药学上可接受的载体形成药物组合物。
具体地,上述喹唑啉-4(3H)-酮类化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/ 固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面,上述喹唑啉-4(3H)-酮类化合物及其药物组合物可制备为PARP7抑制剂药物;更具体地,作为抗肿瘤药物,具体治疗肺鳞腺癌、结肠癌、乳腺癌等癌症。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类化合物可有效抑制PARP7酶活性,酶抑制IC50值均达到纳摩尔浓度水平,最优小于100nM;同时还可以显著促进免疫因子释放,用于肿瘤的免疫治疗;
(2)该类化合物及其药物组合物应用广泛,可制备为抗肿瘤药物,在分子水平、细胞水平均可以发挥药效;
(3)化合物制备方法简便可行。
附图说明
图1为本发明的化合物对干扰素释放的促进作用结果。
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1:2-甲基-8-((6-氧代-6-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)己基)氨基)喹唑啉-4(3H)-酮(I-1)的合成
2-甲基-8-硝基喹唑啉-4(3H)-酮(II-1-1)的合成
于100mL反应瓶中加入2-氨基-3硝基苯甲酸(5.00g,27.45mmol)和乙酸酐50.0mL并搅拌,得黄色浑浊溶液,加热升温至80℃保温反应2小时,薄层色谱(V石油醚:V 乙酸乙酯=1:1)监测原料反应完全;停止加热,冷却至室温后向反应液中加入冰水 150.0mL淬灭,然后用乙酸乙酯(50mL×3)萃取,合并有机相,然后用饱和氯化钠水溶液(100mL×3)洗涤,无水硫酸钠干燥后减压浓缩得黄色固体残余物。向所得固体残余物中加入25%~28%的氨水50.0mL,得黄色略微浑浊溶液,室温下继续搅拌反应1 小时,TLC点板(V石油醚:V乙酸乙酯=1:1)监测原料反应完全;停止反应,抽滤,滤饼用水(30mL×3)洗涤,真空干燥得白色固体(II-1-1),滤液用乙酸乙酯(30mL ×3)萃取,有机相经无水硫酸钠干燥后,减压浓缩得黄白色固体(II-1-1),合并得(II-1-1) 4.41g,收率78.29%。m.p.268~270℃。
1H NMR(400MHz,DMSO-d6)δ(ppm):12.36(s,1H),8.30(dd,J=8.0,1.5Hz,1H),8.23(dd,J=7.8,1.5Hz,1H),7.59(t,J=7.9Hz,1H),2.38(s,3H).
3-(4-甲氧基苄基)-2-甲基-8-硝基喹唑啉-4(3H)-酮(II-1-2)的合成
于100mL反应瓶中加入化合物II-1-1(3.74g,18.24mmol)、PMB-Cl(3.43g,21.89mmol)和碳酸钾(3.78g,27.36mmol),然后加入DMF 50.0mL并搅拌,得黄色浑浊溶液,升温至60℃保温反应2小时,薄层色谱(V石油醚:V乙酸乙酯=1:1)监测原料反应完全;停止加热,冷却至室温后向反应液中加入水150mL,乙酸乙酯(50mL× 3)萃取,有机相经饱和氯化钠水溶液(100mL×3)洗涤,无水硫酸钠干燥,粗品经硅胶柱层析(V石油醚:V乙酸乙酯=5:1)纯化,得白色固体(II-1-2)5.48g,收率92.36%。 m.p.118~120℃。
1H NMR(300MHz,DMSO-d6)δ(ppm):8.38(dd,J=8.0,1.5Hz,1H),8.29(dd,J=7.8,1.5Hz,1H),7.65(t,J=7.9Hz,1H),7.20(d,J=8.7Hz,2H),6.91(d,J=8.7Hz,2H),5.31(s,2H),3.73(s,3H),2.52(s,3H).
8-氨基-3-(4-甲氧基苄基)-2-甲基喹唑啉-4(3H)-酮(II-1)的合成
于100mL反应瓶中加入II-1-2(6.05g,18.60mmol)和氯化亚锡二水合物(25.18g,111.60mmol),然后加入乙酸乙酯50.0mL并搅拌,得黄色澄清溶液,加热升温至70℃保温反应1小时,薄层色谱(V石油醚:V乙酸乙酯=1:1)监测原料反应完全;停止加热,冷却至室温后向反应液中加入氢氧化钠溶液调节pH至13~14,然后用乙酸乙酯 (50mL×3)萃取,有机相经饱和氯化钠水溶液(100mL×3)洗涤,无水硫酸钠干燥后,粗品经硅胶柱层析(V石油醚:V乙酸乙酯=3:1)纯化,得白色固体(II-1)4.66 g,收率84.83%。m.p.132~134℃。
1H NMR(300MHz,DMSO-d6)δ(ppm):7.27(dd,J=7.9,1.5Hz,1H),7.19(t,J=7.7Hz,1H),7.14(d,J=8.6Hz,2H),6.97(dd,J=7.7,1.5Hz,1H),6.90(d,J=8.6Hz,2H),5.65(s,2H),5.28(s,2H),3.72(s,3H),2.51(s,3H).
6-((3-(4-甲氧基苄基)-2-甲基-4-氧代-3,4-二氢喹唑啉-8-基)氨基)己酸甲酯(IV-1)的合成
于25mL反应瓶中加入8-氨基-3-(4-甲氧基苄基)-2-甲基喹唑啉-4(3H)-酮(II-1)(0.60 g,2.03mmol),6-溴己酸甲酯(III-1)(1.06g,5.08mmol),碳酸铯(1.3g,4.06mmol)和碘化钠(0.31g,2.03mmol),然后加入DMF 10.0mL并搅拌,得黄色浑浊溶液,升温至105℃反应5小时,薄层色谱(V石油醚:V乙酸乙酯=1:1)监测原料反应完全;停止加热,冷却至室温后向反应液中加入30mL水,然后用乙酸乙酯(20mL×3)萃取,有机相经饱和氯化钠水溶液(50mL×3)洗涤,无水硫酸钠干燥后,粗品经硅胶柱层析 (V石油醚:V乙酸乙酯=8:1)纯化,得0.65g黄色油状物(IV-1),收率75.90%。
1H NMR(300MHz,DMSO-d6)δ(ppm):7.29–7.22(m,2H),7.13(d,J=8.7Hz,2H), 6.90(d,J=8.7Hz,2H),6.81(dd,J=6.2,3.1Hz,1H),5.92(t,J=5.9Hz,1H),5.29(s,2H), 3.72(s,3H),3.57(s,3H),3.18(q,J=6.6Hz,2H),2.51(s,3H),2.30(q,J=7.8Hz,2H),1.63 –1.55(m,4H),1.42–1.36(m,2H).
6-((3-(4-甲氧基苄基)-2-甲基-4-氧代-3,4-二氢喹唑啉-8-基)氨基)己酸(V-1)的合成
于25mL反应瓶中加入化合物IV-1(0.62g,1.46mmol),氢氧化钠(0.16g,3.92mmol),然后加入甲醇1.0mL、水1.0mL和THF 3.0mL并搅拌,得白色浑浊溶液,加热升温至50℃保温反应0.5小时,得无色澄清溶液,薄层色谱(V石油醚:V乙酸乙酯=1:1)监测原料反应完全;停止加热,冷却至室温后向反应液中加入10mL水,然后用乙酸乙酯(10mL×3)萃取,有机相弃去;水相加2M的稀盐酸溶液2.0mL调节pH 至酸性,再用乙酸乙酯(10mL×3)萃取,有机相经无水硫酸钠干燥后,减压浓缩后得白色固体(V-1)0.55g,收率91.75%。m.p.124~126℃。
1H NMR(300MHz,DMSO-d6)δ(ppm):12.01(s,1H),7.29–7.22(m,2H),7.14(d,J=8.7Hz,2H),6.90(d,J=8.7Hz,2H),6.81(dd,J=6.3,2.9Hz,1H),5.92(t,J=5.9Hz,1H),5.29(s,2H),3.72(s,3H),3.18(q,J=6.7Hz,2H),2.51(s,3H),2.22(t,J=7.3Hz,2H),1.66–1.50(m,4H),1.43–1.31(m,2H).
4-叔丁基-1-(5-碘嘧啶-2-基)哌嗪甲酸酯(VI-1-1)的合成
于250mL反应瓶中加入2-氯-5-碘嘧啶(12.50g,51.99mmol),哌嗪-1-甲酸叔丁酯(11.62g,62.39mmol)和碳酸钾(8.3g,60.14mmol),然后加入50mL的N-甲基吡咯烷酮(NMP),升温至100℃反应6小时。薄层色谱(V石油醚:V乙酸乙酯=8:1) 监测反应完全,加入200mL水,析出白色固体,充分搅拌后抽滤,滤饼真空干燥,得白色固体(VI-1-1)19.93g,收率98.24%。m.p.113~115℃。
1H NMR(300MHz,Chloroform-d)δ(ppm):8.40(s,2H),3.81–3.71(m,4H),3.53–3.43(m,4H),1.49(s,9H).
4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羧酸叔丁酯(VI-1-2)的合成
于500mL三颈瓶中加入4-叔丁基-1-(5-碘嘧啶-2-基)哌嗪甲酸酯(VI-1-1)(23.64g, 60.58mmol),碘化亚铜(23.08g,121.16mmol),然后加入100mL NMP,氮气保护,于室温下缓慢滴加2,2-二氟-2-(氟磺酰基)乙酸甲酯(23.28g,121.16mmol),加毕,升温至100℃后反应8小时,薄层色谱(V石油醚:V二氯甲烷:V甲醇=15:10:2)监测反应完全,加入200mL水,乙酸乙酯(100mL×3)萃取,合并有机相,分别用饱和氯化钠水溶液(40mL×3)洗涤,无水硫酸钠干燥,抽滤,浓缩,粗品通过硅胶柱层析 (V二氯甲烷:V甲醇=15:1)纯化得白色固体(VI-1-2)19.14g,收率95.06%。m.p. 125~127℃。
1H NMR(300MHz,Chloroform-d)δ(ppm):8.50(s,2H),3.93–3.86(m,4H),3.54–3.48(m,4H),1.49(s,9H).
2-(哌嗪-1-基)-5-三氟甲基嘧啶盐酸盐(VI-1)的合成
于25mL反应瓶中加入4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羧酸叔丁酯(VI-1-2)((1.88 g,5.66mmol),然后加入10mL饱和的HCl的EA溶液,得白色浑浊溶液。室温下搅拌 1小时后,薄层色谱(V二氯甲烷:V甲醇=15:1)监测反应完全。抽滤,滤饼用乙酸乙酯洗涤(5mL×3),真空干燥,得白色固体(VI-1)1.45g,收率95.61%。m.p.>270℃。
1H NMR(400MHz,DMSO-d6)δ(ppm):9.71(s,2H),8.79(s,2H),4.12–4.06(m,4H),3.21–3.13(m,4H).
3-(4-甲氧基苄基)-2-甲基-8-((6-氧代-6-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)己基)氨基)喹唑啉-4(3H)-酮(VII-1)的合成
于10mL反应瓶中加入化合物V-1(0.15g,0.37mmol),化合物VI-1(0.10g,0.37mmol),EDCI(0.14g,0.73mmol),HOBt(0.1g,0.73mmol),DIEA(0.19g,1.47mmol),然后加入DMF 3.0mL并搅拌,得浅黄色澄清溶液,室温反应12小时,薄层色谱(V二氯甲烷:V甲醇=15:1)监测原料反应完全;向反应液中加入5.0mL水,然后用乙酸乙酯(5mL×3)萃取,有机相经饱和氯化钠溶液(15mL×3)洗涤,无水硫酸钠干燥后,粗品经硅胶柱层析(V石油醚:V乙酸乙酯=1:1)纯化,得白色固体(VII-1)0.14 g,收率59.97%。m.p.135~137℃。
1H NMR(300MHz,DMSO-d6)δ(ppm):8.73(d,J=0.9Hz,2H),7.30–7.19(m,2H), 7.13(d,J=8.7Hz,2H),6.90(d,J=8.7Hz,2H),6.82(dd,J=6.9,2.3Hz,1H),5.93(t,J=5.9Hz,1H),5.28(s,2H),3.87–3.81(m,2H),3.81–3.75(m,2H),3.72(s,3H),3.59–3.51 (m,4H),3.20(q,J=6.6Hz,2H),2.51(s,3H),2.38(t,J=7.3Hz,2H),1.69–1.51(m,4H,),1.46–1.34(m,2H).
2-甲基-8-((6-氧代-6-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)己基)氨基)喹唑啉-4(3H)- 酮(I-1)的合成
于10mL反应瓶中加入化合物VII-1(96.00mg,0.15mmol),然后加入TFA 3.0mL 和TfOH 0.3mL并搅拌,得紫红色澄清溶液,室温反应3小时,薄层色谱(V二氯甲烷: V甲醇=15:1)监测原料反应完全;停止反应,向反应液中加入饱和碳酸氢钠溶液调节 pH至碱性,然后用乙酸乙酯(10mL×3)萃取,有机相经饱和氯化钠水溶液(10mL ×3)洗涤,无水硫酸钠干燥后,粗品经硅胶柱层析(V石油醚:V乙酸乙酯=1:2)纯化,得白色固体(I-1)53.00mg,收率68.38%。m.p.199~201℃。
1H NMR(300MHz,DMSO-d6)δ(ppm):12.11(s,1H-),8.73(s,2H),7.23–7.13(m, 2H),6.78(dd,J=7.1,2.2Hz,1H),5.84(t,J=5.8Hz,1H),3.87–3.82(m,2H),3.81–3.77 (m,2H),3.58–3.53(m,4H),3.18(q,J=6.6Hz,2H),2.39(t,J=7.3Hz,2H),2.35(s,3H), 1.68–1.53(m,4H),1.46–1.35(m,2H).
1H NMR(300MHz,DMSO-d6,D2O)δ(ppm):8.71(s,2H),7.27–7.14(m,2H),6.81 (dd,J=7.4,1.9Hz,1H),3.86–3.81(m,2H),3.81–3.76(m,2H),3.59–3.52(m,4H),3.18 (t,J=7.0Hz,2H),2.40(t,J=7.2Hz,2H),2.36(s,3H),1.70–1.52(m,4H),1.47–1.35(m, 2H).
13C NMR(101MHz,DMSO)δ(ppm):171.34,162.47,162.24,156.26(q,J=3.5Hz),152.08,144.09,136.70,126.99,124.86(q,J=271.0Hz),120.76,112.24(q,J=33.2Hz),110.99,110.93,44.87,44.10,43.77,42.91,41.04,32.71,28.87,26.85,25.02,21.93.
HRMS(ESI):m/z[M+H]+Calcd for C24H28F3N7O2:504.2335,Found:504.2325.
参照实施例1的制备方法,制备得到以下化合物:
/>
实施例2:化合物对PARP7的酶抑制活性
实验材料:PARP7 Chemiluminescent Assay Kit,BPS Bioscience;DMSO,国药,Nivo, PerkinElmer。
实验方法:
(1)溶液与缓冲液的配置:
10X PBS配制:分别称取720mg KH2PO4,45g NaCl和5.311g Na2HPO4·12H2O溶解在500mL去离子水中,将体系的pH调为7.4,在121℃下灭菌30min,冷却后放置于 4℃备用。
1X PBS配制:将10X PBS用去离子水稀释10倍,即1份10X PBS加入9份去离子水稀释。
Wash buffer配制:1X PBS含有0.05%Tween-20。
1X PARP buffer配制:(现用现配)使用去离子水将10X PARP buffer进行10倍稀释,放置在冰上备用。
(2)化合物工作液浓度的配制:
根据检测要求,将待测化合物用100%DMSO稀释至所需浓度,然后用1X PARPbuffer进行10倍稀释,配制成10X的化合物工作液。
(3)实验步骤:
a.实验前一天,冰上解冻5X histone mixture;
b.1X histone mixture配制,使用1X PBS将5X histone mixture配制成1Xhistone mixture;每孔取25μL 1X histone mixture到测试板中,在4℃下孵育过夜;
c.每孔取100μL Blocking buffer加入到测试板中,在25℃下孵育90min;
d.结束孵育后,甩干测试板中液体,重复洗板3次;
e.每孔取2.5μL的化合物工作液,按照实验排布图加入到测试板中;阳性对照孔中(Positive control)加入相应体积含有10%DMSO的1X PARP buffer,空白对照(Blank) 中加入相应体积的1X PARP buffer;
f.酶完全溶解后,用1X PARP buffer将酶原液稀释到6ng/μL;
g.取10μL每孔酶溶液加入到测试孔板中,空白对照孔加入对应体积的1X PARPbuffer,此时酶量为60ng每孔。注意:此步骤需要在冰上操作;
h.向测试板的各个孔中加入12.5μL master mixture(12.5μL master mixture包括1.25 μL 10X PARP buffer,1.25μL Opti-PARP 10X Assay mixture和10μL水);将测试板封膜置于25℃下孵育60min;
i.孵育结束后,甩干测试板中的液体,重复洗板3次;
j.将试剂盒中的Streptavidin-HRP用Blocking buffer溶液稀释50倍,每孔各25μL 加入到测试板中,在25℃下孵育30min;
k.孵育结束后,甩干测试板中的液体,重复洗板3次;
l.按照1:1混合试剂盒中的ELISA ECL Substrate A和ELISA ECL Substrate B,向测试板中加入每孔50μL混合液,并且马上使用Nivo进行Luminescence检测,读取发光值(RLU);
m.酶率计算:
%Enzyme Activity=(RLU(Sample)-RLU(Blank))/(RLU(Pos.Ctrl)-RLU(Blank))×100%;酶抑制率=1-%Enzyme Activity,使用Prism GraphPad软件进行IC50拟合,具体结果如下表1所示。
表1.受试化合物对PARP7的酶抑制活性
/>
注:“+++”为IC50<100nM;“++”为100nM<IC50<500nM。
如表1所示,本发明的化合物对PARP7酶均表现出良好的抑制活性,IC50值达到纳摩尔水平。其中,化合物I-4~I-6、I-8对PARP7酶活性的IC50值均小于100nM。
实施例3:化合物对干扰素释放的促进作用
在STING激动剂DMXAA存在的条件下,测定CT-26通过PARP7抑制剂诱导干扰素-β的水平。将生长至对数生长期的CT-26细胞涂铺于96孔板中,37℃,5%CO2培养箱中孵育过夜至贴壁。细胞用一定浓度的PARP7抑制剂和50μg/mL DMXAA共处理 24h并收集上清液,通过ELISA(R&D,Mouse IFN--beta DuoSet Elisa)根据试剂盒说明书进行处理,结果参见图1。由图1可见,本发明的化合物能明显促进干扰素β释放,因而可以用于肿瘤的免疫治疗。
Claims (10)
1.一种喹唑啉-4(3H)-酮类化合物,其特征在于,具有式(I)的结构,所述化合物包含其异构体、药学上可接受的盐或它们的混合物:
其中:
n选自0、1、2、3、4或5;
m选自0或1;
R1选自氢、卤素、氰基、三氟甲基、C1~C6烷基、C1~C6烷氧基、甲硫基、甲磺酰基或氨甲酰基;
R2或R3分别独立地选自氢、C1~C6烷基、C3~C6环烷基、杂环烷基、氰基、卤素、二氟甲基或三氟甲基,或者R2和R3与所连碳原子一起形成C3~C6环烷基;所述C3~C6环烷基被一个或多个一下基团取代:氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基;
R4选自芳基、杂芳基或1,3-苯并二噁烷基,所述杂芳基或1,3-苯并二噁烷基被一个或多个以下基团取代:氢、卤素、氰基、三氟甲基、2,2-二氟乙基、C1~C6烷基、C1~C6烷氧基、羟基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰基或硝基;
R5选自氢、氰基、三氟甲基、C1~C6烷基、C1~C6烷氧基或甲磺酰基;
A1选自-NH-、-O-、-S-或-N(CH3)-;
A2选自-NH-、-O-、-CH2-、C3~C6环烷基、C3~C6杂环烷基或者5~8元芳环或杂芳环,所述C3~C6环烷基、杂环烷基、5~8元芳环或杂芳环的任意位置被一个或多个以下基团取代:氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基;
A3选自: 其中,R6、R7或R8分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基。
2.根据权利要求1所述的喹唑啉-4(3H)-酮类化合物,其特征在于,所述结构中:
n选自0、1、2、3或4;
R1选自氢或卤素;
R2或R3分别独立地选自氢、甲基、氟或乙基;当R2、R3不同时,与R2、R3相连的碳原子为消旋构型、R构型或S构型;
R4选自:其中,Y1或Y2分别独立地代表N、CH或CH-R9,R9选自氢、三氟甲基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或4-三氟甲基苯基;
R5选自氢、甲基或三氟甲基;
A1选自-NH-或-O-;
A2选自:其中,X1、X2或X3各自独立地选自CH或N,R10选自一个或多个氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基;
A3选自:
3.根据权利要求1或2所述的喹唑啉-4(3H)-酮类化合物,其特征在于,所述结构中:
R1选自氢或氟;
R2或R3分别独立地选自氢或甲基;
A2选自:-CH2-、
A3选自:
4.根据权利要求1或2所述的喹唑啉-4(3H)-酮类化合物,其特征在于,所述结构中:
R4选自:
5.根据权利要求1或2所述的喹唑啉-4(3H)-酮类化合物,其特征在于,选自以下任一化合物:
2-甲基-8-((6-氧代-6-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)己基)氨基)喹唑啉-4(3H)-酮(I-1),
2-甲基-8-((2-氧代-2-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)乙基)氨基)喹唑啉-4(3H)-酮(I-2),
2-甲基-8-((1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙-2-基)氨基)喹唑啉-4(3H)-酮(I-3),
2-甲基-8-((3-氧代-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙基)氨基)喹唑啉-4(3H)-酮(I-4),
2-甲基-8-((4-氧代-4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丁基)氨基)喹唑啉-4(3H)-酮(I-5),
2-甲基-8-((5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)氨基)喹唑啉-4(3H)-酮(I-6),
2-甲基-8-((3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)氨基)喹唑啉-4(3H)-酮(I-7),
8-((4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)-4-氧丁基)氨基)-2-甲基喹唑啉-4(3H)-酮(I-8),
2-甲基-8-((4-氧代-4-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)丁基)氨基)喹唑啉-4(3H)-酮(I-9),
2-甲基-8-((5-(4-(5-甲基嘧啶-2-基)哌嗪-1-基)-5-氧代戊基)氨基)喹唑啉-4(3H)-酮(I-10),
8-((5-(4-(5-氟嘧啶-2-基)哌嗪-1-基)-5-氧代戊基)氨基)-2-甲基喹唑啉-4(3H)-酮(I-11),
8-((5-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-基)-5-氧代戊基)氨基)-2-甲基喹唑啉-4(3H)-酮(I-12),
2-甲基-8-((5-氧代-5-(4-(嘧啶-2-基)哌嗪-1-基)戊基)氨基)喹唑啉-4(3H)-酮(I-13),
2-甲基-8-((5-氧代-5-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)戊基)氨基)喹唑啉-4(3H)-酮(I-14),
8-((5-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)哌嗪-1-基)-5-氧代戊基)氨基)-2-甲基喹唑啉-4(3H)-酮(I-15)。
6.根据权利要求1或2所述的喹唑啉-4(3H)-酮类化合物,其特征在于,所述药学上可接受的盐为所述化合物与酸形成的盐,所述酸选自盐酸、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、杏仁酸或阿魏酸。
7.一种权利要求1~6任一所述的喹唑啉-4(3H)-酮类化合物的制备方法,其特征在于,所述制备方法为:
化合物(II)与化合物(III),经取代、水解、酰化、脱保护反应得到化合物(I);
其中,m、n、A1、A2、Y1、Y2、R1、R2、R3、R5、R7、R8、R10的定义如权利要求1~5任一所述;
将相应的酸与以上方法制备的化合物(I)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,包含权利要求1~6任一所述喹唑啉-4(3H)-酮类化合物以及药学上可接受的载体。
9.一种权利要求1~6任一所述的喹唑啉-4(3H)-酮类化合物或者权利要求8所述的药物组合物在制备PARP7抑制剂药物中的应用。
10.根据权利要求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 |
---|---|---|---|
CN202210633592.5A CN117229224A (zh) | 2022-06-07 | 2022-06-07 | 喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210633592.5A CN117229224A (zh) | 2022-06-07 | 2022-06-07 | 喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117229224A true CN117229224A (zh) | 2023-12-15 |
Family
ID=89084915
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210633592.5A Pending CN117229224A (zh) | 2022-06-07 | 2022-06-07 | 喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117229224A (zh) |
-
2022
- 2022-06-07 CN CN202210633592.5A patent/CN117229224A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO323952B1 (no) | Substituerte indoler for modulering av NFκB-aktivitet, fremgangsmate for fremstilling, legemiddel omfattende disse, deres anvendelse og en fremgangsmate for fremstilling av et legemiddel. | |
KR101908333B1 (ko) | 나프틸아미드계 화합물, 이의 제조 방법과 용도 | |
CN115160309B (zh) | Krasg12c突变蛋白杂环类抑制剂的制备及其应用 | |
WO2014154723A1 (en) | Novel pyrrole derivatives for the treatment of cancer | |
CN115353508B (zh) | 5-吡啶-1h-吲唑类化合物、药物组合物和应用 | |
WO2023005280A1 (zh) | 一种选择性靶向cdk9的氨基嘧啶类衍生物的制备及其应用 | |
Shan et al. | Discovery of novel VEGFR-2 inhibitors. Part 5: Exploration of diverse hinge-binding fragments via core-refining approach | |
CN106946868B (zh) | 一氧化氮供体型香豆素衍生物、其制备方法及医药用途 | |
TWI694824B (zh) | 甲醯胺類化合物、其製備方法及其應用 | |
CN114920759A (zh) | 杂环-三氮唑并噻二唑杂环串联化合物、合成方法、药物组合物及用途 | |
CN103382182B (zh) | 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 | |
WO2019100743A1 (zh) | 含有苯并呋喃的parp-1和pi3k双靶点抑制剂 | |
CN117229224A (zh) | 喹唑啉-4(3h)-酮类化合物、制法、组合物和应用 | |
WO2019170088A1 (zh) | 一种噁嗪并喹唑啉与噁嗪并喹啉类化合物及其制备方法和应用 | |
CN112174958B (zh) | 一种吡啶并[2,3-d]嘧啶类化合物及其制备方法和用途 | |
KR102629854B1 (ko) | 단백질 키나제 저해제로서 유용한 피리도퀴나졸린 유도체 | |
CN117430587A (zh) | 2h-吲唑-7-甲酰胺类parp7抑制剂和应用 | |
CN110746398A (zh) | 4-杂环取代喹唑啉类衍生物及其制备方法和用途 | |
CN116535395A (zh) | 2h-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用 | |
WO2019170086A1 (zh) | 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用 | |
CN108610332A (zh) | 诱导MDM2自我降解E3泛素连接酶二聚体酯类小分子PROTACs | |
CN108707145A (zh) | 含五元杂环结构的喹啉类化合物及其制备和应用 | |
CN110294745B (zh) | 五元杂环类衍生物及其制备方法和其在医药上的用途 | |
CN111065635B (zh) | 作为mth1抑制剂的新型嘧啶衍生物 | |
WO2016082737A1 (zh) | 一种取代的噻吩并嘧啶化合物及其制备方法 |
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 |