CN112062758A - Selenophenol quinoline derivative and preparation method and application thereof - Google Patents
Selenophenol quinoline derivative and preparation method and application thereof Download PDFInfo
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- CN112062758A CN112062758A CN202010886926.0A CN202010886926A CN112062758A CN 112062758 A CN112062758 A CN 112062758A CN 202010886926 A CN202010886926 A CN 202010886926A CN 112062758 A CN112062758 A CN 112062758A
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- Prior art keywords
- substituted
- preparation
- compound
- ethyl acetate
- anhydrous
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- 238000002360 preparation method Methods 0.000 title claims abstract description 155
- -1 Selenophenol quinoline derivative Chemical class 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 30
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 22
- 150000002367 halogens Chemical class 0.000 claims abstract description 21
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 16
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 12
- 150000001768 cations Chemical class 0.000 claims abstract 2
- 229910052751 metal Inorganic materials 0.000 claims abstract 2
- 239000002184 metal Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 85
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 150000003958 selenols Chemical class 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 150000002240 furans Chemical class 0.000 claims description 8
- 150000003222 pyridines Chemical class 0.000 claims description 8
- 150000003233 pyrroles Chemical class 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229930192474 thiophene Natural products 0.000 claims description 8
- 150000003577 thiophenes Chemical class 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006619 Stille reaction Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 2
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 125000001680 trimethoxyphenyl group Chemical group 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 16
- 201000011510 cancer Diseases 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 239000013641 positive control Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 354
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 122
- 239000012074 organic phase Substances 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 239000007787 solid Substances 0.000 description 84
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 78
- 239000002904 solvent Substances 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- 238000001704 evaporation Methods 0.000 description 72
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 70
- 238000001035 drying Methods 0.000 description 69
- 238000001914 filtration Methods 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 60
- 238000003818 flash chromatography Methods 0.000 description 57
- 239000007832 Na2SO4 Substances 0.000 description 56
- 229910052938 sodium sulfate Inorganic materials 0.000 description 56
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 49
- 239000000203 mixture Substances 0.000 description 45
- 238000005406 washing Methods 0.000 description 44
- 239000008346 aqueous phase Substances 0.000 description 42
- 238000001816 cooling Methods 0.000 description 42
- 239000011669 selenium Substances 0.000 description 42
- 229910052786 argon Inorganic materials 0.000 description 39
- 238000000746 purification Methods 0.000 description 37
- 238000000926 separation method Methods 0.000 description 37
- 238000003756 stirring Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000012300 argon atmosphere Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000007789 gas Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 229910015900 BF3 Inorganic materials 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 102000006587 Glutathione peroxidase Human genes 0.000 description 4
- 108700016172 Glutathione peroxidases Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- ZXZKYYHTWHJHFT-UHFFFAOYSA-N quinoline-2,8-diol Chemical compound C1=CC(=O)NC2=C1C=CC=C2O ZXZKYYHTWHJHFT-UHFFFAOYSA-N 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZKSOJQDNSNJIQW-UHFFFAOYSA-N 1-(bromomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1 ZKSOJQDNSNJIQW-UHFFFAOYSA-N 0.000 description 3
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 3
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- MABNMNVCOAICNO-UHFFFAOYSA-N selenophene Chemical compound C=1C=C[se]C=1 MABNMNVCOAICNO-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- MPEMEHFDNKQRRM-UHFFFAOYSA-N 2-chloro-5,8-dimethoxyquinoline Chemical compound ClC1=CC=C2C(OC)=CC=C(OC)C2=N1 MPEMEHFDNKQRRM-UHFFFAOYSA-N 0.000 description 2
- UCUNHDIRXPEPHS-UHFFFAOYSA-N 5,8-dimethoxyquinoline Chemical compound C1=CC=C2C(OC)=CC=C(OC)C2=N1 UCUNHDIRXPEPHS-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 102000008114 Selenoproteins Human genes 0.000 description 2
- 108010074686 Selenoproteins Proteins 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 102000013090 Thioredoxin-Disulfide Reductase Human genes 0.000 description 2
- 108010079911 Thioredoxin-disulfide reductase Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- DZQURIUJAGTAFW-UHFFFAOYSA-N tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1B1OC(C)(C)C(C)(C)O1 DZQURIUJAGTAFW-UHFFFAOYSA-N 0.000 description 2
- HQYNSFAFYFMRLG-UHFFFAOYSA-N tribromo phosphite Chemical compound BrOP(OBr)OBr HQYNSFAFYFMRLG-UHFFFAOYSA-N 0.000 description 2
- UKTDFYOZPFNQOQ-UHFFFAOYSA-N tributyl(thiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CS1 UKTDFYOZPFNQOQ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- LCSHATKNSDVDRY-UHFFFAOYSA-N 5,8-dibromoquinoline Chemical compound C1=CC=C2C(Br)=CC=C(Br)C2=N1 LCSHATKNSDVDRY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 231100000716 Acceptable daily intake Toxicity 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000273649 Citrus hassaku Species 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WDODWFPDZYSKIA-UHFFFAOYSA-N benzeneselenol Chemical group [SeH]C1=CC=CC=C1 WDODWFPDZYSKIA-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002700 inhibitory effect on cancer Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 102000017712 iodothyronine deiodinase Human genes 0.000 description 1
- 108060004088 iodothyronine deiodinase Proteins 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- HFJXYNUVULQBTH-UHFFFAOYSA-N pyrimidine;quinoline Chemical class C1=CN=CN=C1.N1=CC=CC2=CC=CC=C21 HFJXYNUVULQBTH-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 150000005082 selenophenes Chemical class 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a selenophenol quinoline derivative and a preparation method and application thereof. The structure of the selenophene quinoline derivative is shown as a formula I, a formula II or a formula III; wherein, R is1Is hydrogen, C1～6Alkyl radical, C1～6Alkoxy, substituted keto, phenyl, benzyl, substituted phenyl, or substituted benzyl; the R is1 +Is a monovalent metal cation; the R is2Is hydrogen, halogen, C1～4Alkyl radical, C1～4Alkoxy or C1～4One or more of haloalkyl; the R is3Is a substituted five-membered heterocycle or a substituted six-membered heterocycle; wherein the heteroatom is one or more of N, O, S or Se. The compound has a novel structure, is simple in preparation process, shows a good inhibition effect on various cancer cells, particularly shows excellent inhibition effects on various cancer cells of the compounds 34, 44, 45, 98, 104, 115 and 116, has the effect equivalent to that of positive control DDP (dichloro-diphenyl-p), can be prepared into an anticancer drug for application below 5 mu M, and has a wide prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a selenophenol quinoline derivative and a preparation method and application thereof.
Background
Selenium is considered to be an indispensable trace element for maintaining normal physiological functions of the human body. The human body cannot synthesize or store selenium by itself, and can only obtain selenium by external food intake. Selenium is widely accepted by the scientific community as achieving various physiological effects through selenoprotein formation with proteins in the body. Common selenoproteins are: selenium-dependent glutathione peroxidases (GPxs), Thioredoxin Reductases (TRs) of cellular oxidoreductases and iodothyronine deiodinases (TDIs) required for energy metabolism.
Hydrogen peroxide and phospholipid hydroxide can generate various Reactive Oxygen Species (ROS) in cells, and ROS are considered to be the leading cause of cancer. It has been found that selenium can catalyse the breakdown of hydrogen peroxide or phospholipids by forming GPxs, further oxidising Glutathione (GSH) and thereby reducing the hydrogen peroxide and phospholipid hydroxide content of the cells. Studies have also found that the occurrence of certain acute or chronic diseases in humans is associated with a decrease in plasma selenium and GPxs activity. It is also believed that selenium may facilitate the immune system to monitor the metastasis of cancer cells, and when additional selenium is ingested as a precaution, some of the immune indicators are found to be significantly restored or enhanced. Selenium may restrict carcinogen-DNA and affect its metabolic processes, possibly inhibiting the formation of early stage cancer. In addition, selenium can inhibit the growth of cancer cells and interfere with their spread. Microvasculature in tumors or growth-related lesions is also inhibited by selenium.
At present, quinoline compounds are researched more, and not only compound structures and preparation methods but also application researches are more comprehensive. However, few studies on compounds with selenophenol structures are currently available, and the main study is the application of luminescent compounds or fluorescent compounds, and few studies are made on the aspect of anticancer. Currently, there are few reports of related anticancer drugs, such as CN201080016304.7 and its use in the treatment of malignant melanoma and other cancers, which disclose some selenophen compounds, as well as their use in antitumor effect. However, the number of the compounds disclosed therein is relatively small, and the types of tumor or cancer cells targeted by the compounds are also small, so that the compounds need to be studied more extensively to provide more selenophene compounds with better activity or value.
Because the research on the selenophenol group modified quinoline compound is less, the synthesis method of the compound is immature, simple, rapid, low-cost and high-yield at present, and further research is needed, so that the research is further applied to the popularization and application of the selenophenol quinoline compound.
Disclosure of Invention
The invention aims to provide a selenophenol quinoline compound.
The invention also aims to provide a preparation method of the selenophenoquinoline compound.
The invention further aims to provide application of the selenophenoquinoline compound.
The above object of the present invention is achieved by the following scheme:
a selenophenol quinoline compound has a structure shown in a formula I or a formula II:
wherein, R is1Is hydrogen, C1～6Alkyl radical, C1～6Alkoxy, substituted keto, phenyl, benzyl, substituted phenyl or substituted
Benzyl, wherein the substituents in the substituted keto, substituted phenyl and substituted benzyl are each independently halogen, hydroxy, C1～6Alkyl or C1～6An alkoxy group;
the R is1 +Is a monovalent metalA cation;
the R is2Is hydrogen, halogen, C1～4Alkyl radical, C1～4Alkoxy or C1～4One or more of haloalkyl;
the R is3Is a substituted five-membered heterocycle or a substituted six-membered heterocycle; wherein the heteroatom in the substituted five-membered heterocycle and the substituted six-membered heterocycle is one or more of N, O, S or Se, and the substituents are respectively and independently hydrogen, hydroxyl, halogen, C1～6Alkyl radical, C1～6Alkoxy radical, C1～6Halogenated alkyl, benzene ring, phenol, C1～6Alkyl-substituted phenyl, C1～6Alkoxy-substituted phenyl or C1～6Haloalkyl substituted phenyl.
Preferably, said R is3Is a substituted five-membered single heterocyclic ring, a substituted five-membered double heterocyclic ring, a substituted six-membered single heterocyclic ring or a substituted six-membered heterocyclic ring; wherein the heterocyclic ring is an aromatic ring containing one or more of N, O, S or Se; the substituents in the heterocycle are each independently hydrogen, hydroxy, halogen, C1～4Alkyl radical, C1～4Alkoxy radical, C1～4Halogenated alkyl, benzene ring, phenol, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl or C1～4Haloalkyl substituted phenyl.
Preferably, said R is3Substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine, substituted benzimidazole or substituted selenol; wherein the substituent of the substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine, substituted imidazole or substituted selenol is hydrogen, hydroxyl, halogen or C1～4Alkyl radical, C1～4Alkoxy radical, C1～4Halogenated alkyl, benzene ring, phenol, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl or C1～4Haloalkyl substituted phenyl.
Preferably, when R is3When the substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine or substituted benzimidazole is adopted, the substituent in the substituted thiophene, substituted furan, substituted pyrrole or substituted pyridine is hydrogen, methyl, ethyl, halogenated methyl or halogenated ethyl;
when R is3When the substituted selenol is substituted selenol, the substituent in the substituted selenol is hydrogen, halogen, methyl, ethyl, propylmethoxy, ethoxy, trifluoromethyl, trifluoroethyl, phenyl, 2-phenol, 3-phenol, 4-phenol, benzenediol, benzenetriol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, dimethoxyphenyl or trimethoxyphenyl.
Preferably, said R is1Is hydrogen, C1～4Alkyl radical, C1～4Alkoxy, substituted keto, phenyl, benzyl, substituted phenyl or substituted benzyl, wherein the substituents in the substituted keto, substituted phenyl and substituted benzyl are each independently halogen, hydroxy, C1～4Alkyl or C1～4An alkoxy group;
the R is1 +Is sodium ion or potassium ion;
the R is2Is one or more of hydrogen, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl.
Preferably, said R is1Is hydrogen, methyl, ethyl, acetonyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl or 4-methoxybenzyl.
Preferably, the structure of the selenophenoquinoline compound is shown as any one of the following structures:
the compound of the invention can be used as an anti-cancer drug and can also transmit selenium element which can inhibit the growth of cancer cells to the body.
The invention also provides a preparation method of the compound, which comprises the step of reacting five-membered heterocyclic rings (mainly selenophen) containing different substituents with tributyltin chloride under the action of n-butyllithium to obtain the organotin reagent of the five-membered heterocyclic rings (mainly selenophen). Followed by Stille coupling with a 2-substituted halogenated quinoline to give the above compound.
Firstly, in the synthesis process, the Suzuki coupling of quinoline substituted by 2-site halogen and five-membered heterocyclic borate is tried, but the target compound cannot be synthesized desirably; then, 2-bit borate substituted quinoline and five-membered heterocycle substituted by halogen are tried to undergo Suzuki coupling, and the reaction result is also not ideal; and finally, selecting 2-halogen substituted quinoline and a five-membered heterocyclic organic tin reagent to perform Stille coupling through a plurality of tests, and finally obtaining a coupling product smoothly.
Preferably, when the compound has the structure shown in formula I or formula III, R is attached to3Organotin reagents of the group R3-SnBu3、R3-Sn(n-Bu)3Or
With 2-halogenated quinolines
Stille coupling is carried out to obtain a target compound, wherein R1、R2And R3As set forth in claim 1, X is halogen.
Preferably, R3Is a substituted five-membered heterocyclic ring or a substituted six-membered heterocyclic ring, when the heteroatom in the substituted five-membered heterocyclic ring and the substituted six-membered heterocyclic ring is O, S or Se, R3-SnBu3Or R3-Sn(n-Bu)3And
stille coupling occurs to obtain the target compound.
Preferably, R3Is a substituted five-membered heterocyclic ring or a substituted six-membered heterocyclic ring, when the heteroatom in the substituted five-membered heterocyclic ring and the substituted six-membered heterocyclic ring is N,
and
stille coupling occurs to obtain the target compound.
Preferably, when the structure of the compound is shown as formula II, the compound shown as formula I or formula III is used as a raw material, and the raw material and inorganic base or inorganic acid are subjected to salt forming reaction to obtain the target product.
Preferably, the inorganic base is sodium hydroxide, potassium hydroxide, or the like, which is commonly used in the art.
Preferably, the inorganic acid is hydrochloric acid, nitric acid, and the like, which are commonly used in the art.
The application of the pyrimidine quinoline derivative in preparing anti-cancer drugs is also within the protection scope of the invention.
Preferably, the anti-cancer drug is a drug for resisting cervical cancer, colon cancer, non-small cell lung cancer, enterophagia squamous cell carcinoma, gastric adenocarcinoma, breast cancer, liver cancer or chronic myelogenous leukemia.
Compared with the prior art, the invention has the following beneficial effects:
the compound has a novel structure, is simple in preparation process, shows a good inhibition effect on various cancer cells, particularly shows excellent inhibition effects on various cancer cells of the compounds 34, 44, 45, 98, 104, 115 and 116, has the effect equivalent to that of positive control DDP (dichloro-diphenyl-p), can be prepared into an anticancer drug for application below 5 mu M, and has a wide prospect.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
EXAMPLE 1 preparation of Compound XM _ A0032
The preparation of compound XM _ a0032 was as follows:
QM150.2g was weighed into a 25mL two-necked flask, and Pd (PPh) was added thereto3)2Cl235mg and 140mg of lithium chloride, sealing the reaction device, and replacing argon for protection; adding anhydrous THF (5 mL), stirring at room temperature for 10min, adding 2-tributylstannyl thiophene (0.41 mL), heating in oil bath at 85 ℃, and reacting overnight. Cooling to room temperature, adding 50mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (20 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (15% EA/PE), reduced pressure evaporation of solvent, yellow solid 232 mg. (XM013-LG02, P93) yield: 94 percent.
1H NMR(400MHz,CDCl3)8.10(d,J＝8.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.73(dd,J＝1.2,3.6Hz,1H),7.44(dd,J＝0.8,4.8Hz,1H),7.40(t,J＝8Hz,1H),7.34(dd,J＝0.8,8Hz,1H),7.14(dd,J＝3.6Hz,1H),7.04(dd,J＝0.8,7.6Hz,1H),4.09(s,3H)..
13C NMR(100MHz,CDCl3)155.2,151.3,145.4,139.9,136.6,128.3,128.2,128.0,126.3,125.7,119.4,118.2,108.4,56.20.
Example 2 preparation of Compound XM _ A0033
The preparation of compound XM _ a0033 was as follows:
QM130.3g was weighed into a 25mL two-necked flask, and Pd (PPh) was added thereto3)2Cl235mg and 136mg of lithium chloride, sealing the reaction device, and replacing argon for protection; adding anhydrous THF (5 mL), stirring at room temperature for 10min, adding 2-tributylstannyl thiophene (0.4 mL), heating in oil bath at 85 ℃, and reacting overnight. Cooling to room temperature, adding 50mL of ethyl acetate and 100mL of water, shaking to homogenize, separating the organic phase, extracting the aqueous phase with ethyl acetate (20 mL. times.2), combining the organic phases, and saturating with saturated waterNaCl solution wash (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (10% EA/PE) and evaporation of the solvent under reduced pressure gave 340mg of a yellow solid. Yield: 98 percent.
1H NMR(400MHz,CDCl3)8.12(d,J＝6.8Hz,1H),7.82(d,J＝6.8Hz,1H),7.73(d,J＝2.8Hz,1H),7.45(d,J＝4Hz,1H),7.39–7.35(m,2H),7.33(t,J＝6,6.4Hz,1H),7.26(s,1H),7.20(d,J＝6Hz,1H),7.16–7.13(m,2H),6.88(dd,J＝1.6,6.4Hz,1H),5.42(s,2H),3.87(s,3H).
13C NMR(100MHz,CDCl3)159.8,154.4,151.2,145.9,140.5,139.1,136.6,129.4,128.5,128.4,128.0,126.2,125.5,120.2,119.2,117.8,113.7,112.0,111.9,71.24,55.33.
HRMS(IT-TOF)：C21H17NO2S for[M+H]+，calculated 348.1053,found 348.1043.
Example 3 preparation of Compound XM _ A0034
The preparation of compound XM _ a0034 was as follows:
weighing QM 0350 mg in a 25mL two-neck flask, adding Pd (PPh) respectively3)2Cl225mg and 38mg of lithium chloride, sealing the reaction device, and replacing argon for protection; adding 3mL of anhydrous THF, stirring at room temperature for 10min, adding 0.11mL of 2-tri-n-butylstannyl pyridine, heating in an oil bath at 85 ℃, and reacting overnight. Cooling to room temperature, adding 50mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (20 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (5% EA/PE) and evaporation of the solvent under reduced pressure gave 30mg of a yellow oil. Yield: 49.5 percent.
1H NMR(400MHz,CDCl3)8.14(d,J＝7.2Hz,1H),7.82(d,J＝8.8Hz,1H),7.73(d,J＝2.8Hz,1H),7.48(d,J＝4Hz,1H),7.40(t,J＝6.4Hz,1H),7.30(d,J＝6.8Hz,1H),7.18–7.16(m,2H).
13C NMR(100MHz,CDCl3)151.9,150.2,144.6,137.6,136.8,128.7,128.2,127.3,126.0,117.7,110.5,109.6.
EXAMPLE 4 preparation of Compound XM _ A0043
The preparation of compound XM _ a0043 is as follows:
1. preparation of LuB-24
In a 500mL two-necked flask, 7.0g (43.44mmol, 1.0eq) of 2, 8-quinolinediol was weighed, and 12g (86.87mmol, 2.0eq) of K was added2CO3And 150mL of acetone, stirring at room temperature; then 5.0mL (6.57g, 52.12mmol, 1.2eq) of dimethyl sulfate was added and heated to reflux for 4 h. After the reaction was cooled to room temperature, the reaction solution was transferred to a separatory funnel, 300mL of ethyl acetate and 300mL of water were added, mixed well, the organic phase was separated, the aqueous phase was extracted 2 times with ethyl acetate (150mL × 2), the organic phases were combined and washed with a saturated NaCl solution (400mL × 2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. And (5) performing column chromatography separation and purification (75% -100% EA/PE) to obtain 5.28g of white solid. Yield: 72.9%, white solid.
1H NMR(400MHz,CDCl3)9.16(s,1H),7.73(d,J＝9.2Hz,1H),7.34(t,J＝8.0,7.6Hz,1H),7.17(dd,J＝8.0,7.6,1.2,0.8Hz,1H),7.11(t,J＝8.0,7.6Hz,1H),6.66(d,J＝9.6Hz,1H),4.07(s,3H).
2. LuC-24 preparation
LuB-242.5 g (14.27mmol, 1.0eq) was weighed into a dry solutionIn a 100mL two-neck flask, under the protection of nitrogen atmosphere, 12.27g (42.81mmol, 3.0eq) of tribromooxyphosphorus and 25mL of anhydrous 1, 2-dichloroethane were sequentially added, heated to reflux, and reacted overnight. Standing and cooling to room temperature; 30mL of ice water was added, the mixture was stirred well, transferred to a separatory funnel, extracted 3 times with ethyl acetate (75 mL. times.3), the organic phases were combined, and saturated NaHCO was used successively3Solution wash (150 mL. times.2), saturated NaCl solution wash (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Column chromatography separation and purification (10% EA/PE) gave 3.0g of white solid. Yield: 88.2% yellow solid.
1H NMR(400MHz,CDCl3)8.07(d,J＝8.4Hz,1H),7.48(t,J＝8.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.38(dd,J＝8.4,8.0,1.2,0.8Hz,1H),7.09(dd,J＝8.0,0.8Hz,1H),4.07(s,3H).
3. Preparation of LuN-24
Under the protection of argon atmosphere, 0.21mL of selenophene (2.29mmol, 1.0eq) and 10mL of anhydrous THF are stirred and cooled to-78 ℃, and 0.92mL (2.29mmol, 1.0eq, 2.5M in Hexane) of n-butyllithium solution is slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 0.75mL (2.75mmol, 1.2eq) of tributyltin chloride solution, and keeping the temperature for reacting for 2h after dropwise adding; saturated NaHCO was slowly added dropwise at this temperature3After the solution is added by 10mL, moving to room temperature and stirring for 10 min; extraction 3 times with ethyl acetate (30 mL. times.3), combining the organic phases and washing with saturated NaCl solution (50 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. This gave 0.942g of a yellow solid. Yield: 98.1%, colourless oil.
1H NMR(400MHz,CDCl3)8.36(d,J＝4.8Hz,1H),7.52～7.50(m,2H),1.60～1.54(m,6H),1.35～1.30(m,6H),1.12～1.08(m,6H),0.93～0.90(m,9H),
4. Preparation of XM-A0043
LuC-240.3g (1.26mmol, 1.0eq), LuN-240.794 g (1.89mmol, 1.5eq) and Pd (PPh) are weighed respectively3)2Cl245mg (63umol, 0.05eq) was placed in a 25mL two-necked flask, and the reaction apparatus was sealed and replaced with argon gas under protection; 3mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 40mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (30 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (10% EA/PE) gave 360mg of a yellow solid. Yield: 99.0% yellow solid.
1H NMR(400MHz,CDCl3)8.12–8.08(m,2H),7.88(dd,J＝1.2,4Hz,1H),7.82(d,J＝8.4Hz,1H),7.42–7.38(m,2H),7.34(dd,J＝1.2,8Hz,1H),7.04(dd,J＝1.2,7.6Hz,1H),4.09(s,3H).
13C NMR(100MHz,CDCl3)155.2,152.7,152.5,140.1,136.5,133.7,130.7,128.4,127.3,126.3,119.4,117.3,108.7,56.33.
HRMS(IT-TOF)：C14H11NOSe for[M+H]+，calculated 290.0079,found 290.0085.
EXAMPLE 5 preparation of Compound XM _ A0044
The preparation of compound XM _ a0044 is as follows:
1. preparation of LuB-25
5.0g (31.03mmol, 1.0eq) of 2, 8-quinolinediol was weighed into a 500mL two-necked flask, and 7.72g K was added2CO3(55.85mmol，1.8eq) and 200mL acetonitrile, stirring at room temperature; 4.8mL (34.13mmol, 1.1eq) of 3-methoxybenzyl bromide was added, and the mixture was heated to reflux and reacted overnight. Adding 300mL of ethyl acetate and 300mL of water into the reaction solution, uniformly mixing, separating an organic phase, extracting the aqueous phase with ethyl acetate for 2 times (100mL multiplied by 2), combining the organic phases, and washing with a saturated NaCl solution (400mL multiplied by 2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Column chromatography separation and purification (75% EA/PE) gave 7.0g of a white solid. Yield: 80.2%, white solid.
1H NMR(400MHz,CDCl3)9.16(s,1H),7.73(d,J＝9.2Hz,1H),7.34(t,J＝8.0,7.6Hz,1H),7.17(dd,J＝8.0,7.6,1.2,0.8Hz,1H),7.11(t,J＝8.0,7.6Hz,1H),7.05～7.00(m,2H),6.96(m,1H),6.92(dd,J＝8.0,2.4Hz,1H),6.66(d,J＝9.6Hz,1H),5.16(s,2H),3.83(s,3H).
2. Preparation of XM-A0044
LuC-250.35g (1.02mmol, 1.0eq), LuN-240.641 g (1.53mmol, 1.5eq) and Pd (PPh) are weighed respectively3)2Cl236mg (51umol, 0.05eq) in a 25mL two-necked flask, the reaction apparatus was sealed, and argon gas was replaced; 3mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 40mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (30 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (10% EA/PE) gave 370mg of a yellow solid. Yield: 93.0%, yellow solid.
1H NMR(400MHz,CDCl3)8.10(t,J＝4.8,4.4Hz,2H),7.88(d,J＝4Hz,1H),7.83(d,J＝8.8Hz,1H),7.41(dd,J＝3.6Hz,1H),7.38–7.36(m,2H),7.33(d,J＝8Hz,1H),7.25(s,1H),7.22(d,J＝7.6Hz,1H),7.15–7.12(m,2H),6.88(dd,J＝2,8Hz,1H),5.40(s,2H),3.87(s,3H).
13C NMR(100MHz,CDCl3)159.8,156.4,154.4,153.0,152.5,140.7,139.1,136.5,133.8,130.7,129.4,128.5,127.1,126.2,120.2,119.3,116.9,113.6,112.1,71.32,55.38.
HRMS(IT-TOF)：C21H17NO2Se for[M+H]+，calculated 396.0498,found 396.0505.
EXAMPLE 6 preparation of Compound XM _ A0045
The preparation of compound XM _ a0045 is as follows:
1. preparation of LuB-26
Weighing 5.0g of 2, 8-quinolinediol in a 100mL round-bottom flask, adding 25mL of acetic anhydride, heating in an oil bath to 130 ℃ and reacting for 8 h; standing, cooling to room temperature, performing suction filtration, washing a filter cake with a large amount of ethyl acetate, and performing vacuum drying to obtain 5.52g of white solid. Yield 87.6%, white solid.
1H NMR(400MHz,DMSO)11.63(s,1H),7.94(d,J＝9.6Hz,1H),7.56(dd,J＝7.6,1.2Hz,1H),7.29(dd,J＝7.6,1.2Hz,1H),7.18(t,J＝8.0Hz,1H),6.54(d,J＝9.6Hz,1H),2.37(s,3H).
2. LuC-26 preparation
Weighing QM011.24 g into a 100mL two-neck flask, adding 50mL of chlorobenzene and POCl in sequence under the protection of argon atmosphere33.34mL, anhydrous pyridine 0.164mL, anhydrous DMF 0.02mL, heated to reflux, and reacted overnight. After TLC tracking reaction, standing and cooling to room temperature; with supersaturated NaHCO3The pH was adjusted to 8, extracted 3 times with ethyl acetate (50 mL. times.3), the organic phases were combined and successively saturated NaHCO3Solution wash (100 mL. times.2), saturated NaCl solution wash(100ml × 2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Column chromatography (10% EA/PE) gave 0.26 g. white solid.
1H NMR(400MHz,CDCl3)8.01(d,J＝8.8Hz,1H),7.69(s,1H),7.47(t,J＝8.0Hz,1H),7.40(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,8.0,1.2,0.8Hz,1H),7.22(dd,J＝7.6,1.2Hz,1H).
2. Preparation of XM-A0045
LuC-260.1 g (0.446mmol, 1.0eq), LuN-240.281 g (0.67mmol, 1.5eq) and Pd (PPh) are weighed respectively3)2Cl216mg (23umol, 0.05eq) was put in a 25mL two-necked flask, and the reaction apparatus was closed to replace the protection of argon gas; 2mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 40mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (30 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (5% EA/PE) gave 78mg of a yellow solid. Yield: 65.0% yellow solid.
1H NMR(400MHz,CDCl3)8.14–8.12(m,2H),8.02(m,1H),7.89(dd,J＝0.8,3.6Hz,1H),7.73(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.43–7.38(m,2H),7.29(dd,J＝0.8,8Hz,1H),7.17(dd,J＝0.8,7.6Hz,1H).
13C NMR(100MHz,CDCl3)151.8,151.7,137.8,136.8,134.0,130.9,127.9,127.4,127.3,117.8,117.5,110.6.
HRMS(IT-TOF)：C13H9NOSe for[M+H]+，calculated 275.9923,found 275.9917.
EXAMPLE 7 preparation of Compound XM _ A0048
The preparation of compound XM _ a0048 is as follows:
1. preparation of QM08
5.0g of 2, 8-quinolinediol was weighed into a 500mL two-necked flask, and 7.72g K was added2CO3And 300mL acetonitrile, stirring at room temperature; 4.8mL (6.86g) of 3-methoxybenzyl bromide was added, and the mixture was heated to reflux and reacted overnight. Adding 300mL of ethyl acetate and 300mL of water into the reaction solution, uniformly mixing, separating an organic phase, extracting the aqueous phase with ethyl acetate for 2 times (100mL multiplied by 2), combining the organic phases, and washing with a saturated NaCl solution (400mL multiplied by 2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Column chromatography separation and purification (75% EA/PE) gave 6.36g of white solid, 6.36g (72.9%) yield, white solid.
1H NMR(400MHz,CDCl3)9.16(s,1H),7.73(d,J＝9.2Hz,1H),7.34(t,J＝8.0,7.6Hz,1H),7.17(dd,J＝8.0,7.6,1.2,0.8Hz,1H),7.11(t,J＝8.0,7.6Hz,1H),7.05～7.00(m,2H),6.96(m,1H),6.92(dd,J＝8.0,2.4Hz,1H),6.66(d,J＝9.6Hz,1H),5.16(s,2H),3.83(s,3H).
2. Preparation of QM21
QMa083.3g and tribromooxyphosphorus are weighed into a dry 250mL two-neck flask, 30mL of anhydrous 1, 2-dichloroethane is added under the protection of argon atmosphere, and the mixture is heated to reflux and reacted overnight. After TLC tracking reaction, standing and cooling to room temperature; poured into 50mL of ice water, extracted 3 times with ethyl acetate (150 mL. times.3), the organic phases combined and successively saturated NaHCO3Solution wash (200 mL. times.2), saturated NaCl solution wash (200 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Column chromatography separation and purification (10% EA/PE) was carried out to obtain 2.0g of a white solid.
Yield 2.0g (49.5%), white solid.
1H NMR(400MHz,CDCl3)8.06(d,J＝8.4Hz,1H),7.41(d,J＝8.8Hz,1H),7.37～7.35(m,2H),7.28(t,J＝8.0Hz,1H),7.10～7.09(m,1H),7.08～7.05(m,2H),6.83(dd,J＝8.4,2.4Hz,1H),5.43(s,2H),3.80(s,3H).
3. Preparation of XM _ A0048
QM 210.35g was weighed into a 25mL two-necked flask, and 358mg of lithium chloride, 358mg of N-Boc-pyrrole-2-boronic acid pinacol ester and Pd (PPh) were added thereto, respectively3)459mg, sealing the reaction device, and replacing argon for protection; 5mL of anhydrous toluene and 5mL of anhydrous ethanol are sequentially added, stirring is carried out for 10min at room temperature, 270mg of sodium carbonate is weighed into a 5mL Ep tube, 1.27mL of water is added to fully dissolve the sodium carbonate to obtain a 2M solution, the solution is injected into a two-neck flask, and the two-neck flask is heated in an oil bath at 80 ℃ to react overnight. Cooling to room temperature, adding 80mL of ethyl acetate and 150mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (50 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (10% EA/PE) gave 200mg of a yellow solid. (XM013-LG02, P151)
Yield 200mg (59.5%) yellow solid.
1H NMR(500MHz,CDCl3)10.18(s,1H),8.03(d,J＝8.5Hz,1H),7.70(d,J＝9Hz,1H),7.36–7.29(m,3H),7.15–7.09(m,3H),6.92(s,1H),6.88(dd,J＝2,8Hz,1H),6.84(t,J＝1.5Hz,1H),6.30(s,1H),6.32(s,1H),5.34(s,2H),3.81(s,3H).
13C NMR(125MHz,CDCl3)159.8,154.0,149.3,140.0,138.9,136.2,132.1,129.6,127.9,125.2,120.9,120.4,119.6,118.0,113.5,112.8,111.6,110.1,108.9,71.32,55.22.
EXAMPLE 8 preparation of Compound XM _ A0049
The preparation of compound XM _ a0049 is as follows:
QM150.25g was weighed into a 25mL two-necked flask, and 89mg of lithium chloride, 370mg of N-Boc-pyrrole-2-boronic acid pinacol ester and Pd (PPh) were added thereto, respectively3)461mg, sealing the reaction device, and replacing argon for protection; 5mL of anhydrous toluene and 5mL of anhydrous ethanol are sequentially added, stirring is carried out for 10min at room temperature, 278mg of sodium carbonate is weighed into a 5mL Ep tube, 1.3mL of water is added to fully dissolve the sodium carbonate to obtain a 2M solution, the solution is injected into a two-neck flask, and the two-neck flask is heated in an oil bath at 80 ℃ for reaction overnight. Cooling to room temperature, adding 80mL of ethyl acetate and 150mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (50 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous MgSO (MgSO)4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (15% EA/PE) gave 75mg of a yellow solid. (XM013-LG02, P143)
Yield 75mg (22.0%) of a yellow solid.
1H NMR(400MHz,CDCl3)10.39(s,1H),8.03(d,J＝8.8Hz,1H),7.72(d,J＝8.8Hz,1H),7.37–7.32(m,2H),7.02(dd,J＝2.4,6.8Hz,1H),6.99(s,1H),6.85(d,J＝3.2Hz,1H),6.32(s,1H),4.06(s,3H).
13C NMR(100MHz,CDCl3)154.6,149.5,139.5,136.2,132.0,127.7,125.2,121.0,119.7,118.2,110.1,109.0,108.2,55.85.
EXAMPLE 9 preparation of the Compound XM _ A0064
The preparation of compound XM _ a0064 is as follows:
1. GsA-01 preparation
Under the protection of argon atmosphere0.460mL selenophen (5.0mmol, 1.0eq) and 10.0mL anhydrous THF were placed in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 2.0mL of an n-butyllithium solution (5.0mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 0.315mL of methyl iodide (5.05mmol, 1.01eq), and keeping the temperature for reacting for 2h after dropwise adding; at this temperature, 10mL of saturated NaHCO were slowly added dropwise3After the solution is added, moving to room temperature and stirring for 10 min; extraction 3 times with dichloromethane (30 mL. times.3), combining the organic phases and washing with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.655g of pale yellow liquid: 89.7 percent.
2. GsB-01 preparation
Under the protection of argon atmosphere, 0.655g of GsA-01(4.5mmol, 1.0eq) and 10.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 1.8mL of an n-butyllithium solution (4.5mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 1.8mL of tributyltin chloride solution (4.5mmol, 1.0eq), and keeping the temperature for reacting for 2h after dropwise adding; at this temperature, 10.0mL of saturated NaHCO was slowly added dropwise3After the solution is added, moving to room temperature and stirring for 10 min; extraction 3 times with ethyl acetate (30 mL. times.3), combining the organic phases and washing with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 2.17g of pale yellow liquid: 99.5 percent.
3. Preparation of XM _ A0064
2.170g of GsB-01(4.5mmol, 2.25eq), 0.600gQM-13(2.0mmol, 1.0eq) and 0.033g of Pd (PPh) were weighed out separately3)2Cl2(0.1mol, 0.05eq) in a 50mL two-necked flask, and the flask was sealedAnd (5) replacing the argon for protection in the reaction device. 30.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 40mL of ethyl acetate and 100mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (30 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (150 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.292g of yellow solid, yield: 35.7 percent.
1H NMR(500MHz,DMSO-d6)8.28(d,J＝8.7Hz,1H),8.04(d,J＝8.7Hz,1H),7.91(d,J＝3.8Hz,1H),7.48(d,J＝7.8Hz,1H),7.42(t,J＝7.9Hz,1H),7.35(t,J＝7.9Hz,1H),7.26(d,J＝7.4Hz,1H),7.23–7.15(m,2H),7.07(d,J＝2.7Hz,1H),6.90(dd,J＝8.1,2.2Hz,1H),5.35(s,2H),3.80(s,3H),2.57(s,3H).
13C NMR(126MHz,DMSO)159.38,153.53,152.11,149.93,149.72,139.70,139.19,136.60,129.58,129.48,128.45,127.98,126.20,120.08,119.00,116.74,113.18,112.19,111.85,69.90,55.09,18.22.
HRMS(IT-TOF)：C22H19NO2Se for[M+H]+，calculated 410.0655,found 410.0651.
EXAMPLE 10 preparation of Compound XM _ A0072
The compound XM _ a0072 was prepared as follows:
1. GsA-02 preparation
Under the protection of argon atmosphere, 0.46mL of selenophene (5.0mmol, 1.0eq) and 10.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 2.0mL of an n-butyllithium solution (5.0mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowlyDropwise adding a solution prepared from 1.4g of iodine particles (5.5mmol, 1.1eq) and 5.0mL of anhydrous THF, and keeping the temperature for reacting for 2h after the dropwise addition; at this temperature, 10mL of saturated NaHCO were slowly added dropwise3After the solution is added, moving to room temperature and stirring for 10 min; extraction 3 times with dichloromethane (30 mL. times.3), combining the organic phases and washing with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 1.48g of pale yellow liquid: 99.0 percent.
2. GsB-02 preparation
Under the protection of argon atmosphere, 0.129g of GsA-02(0.5mmol, 1.0eq), 0.086g of phenylboronic acid (0.7mmol, 1.4eq),0.003g of palladium acetate (0.015mmol, 0.03eq) were dissolved in a 50mL two-necked flask in 5.0mL of anhydrous DME, and stirred at room temperature for 15 min. 0.309g of potassium carbonate (2.4mmol, 4.8eq) was taken in with 1.2mL of water to prepare a potassium carbonate solution. The potassium carbonate solution was poured into the above two-necked flask. The reaction was transferred to an oil bath, heated to reflux at 90 ℃ and kept at temperature for 1 h. Cooled to room temperature, extracted 3 times with dichloromethane (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.103g of pale yellow liquid: 99.0 percent.
3. GsC-01 preparation
Under the protection of argon atmosphere, 0.103g of GssB-02(0.5mmol, 1.0eq) and 5.0mL of anhydrous THF were placed in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.2mL of an n-butyllithium solution (0.5mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 0.136mL of tributyltin chloride solution (0.5mmol, 1.0eq), and keeping the temperature for reacting for 2h after dropwise adding; at this temperature 5.0mL of saturated NaHCO was slowly added dropwise3The solution is transferred to room temperature to be stirred after the addition is finishedFor 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.25g of pale yellow liquid: 92.4 percent.
4. Preparation of XM _ A0072
0.25g GsC-01(0.5mmol, 1.0eq), 0.5g QM-13(0.5mmol, 1.0eq) and 0.008g Pd (PPh) were weighed out separately3)2Cl2(0.025mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.011g yellow solid, yield: 4.7 percent.
1H NMR(400MHz,Chloroform-d)8.09(d,J＝8.5Hz,1H),7.83(dd,J＝12.8,5.9Hz,2H),7.65(d,J＝7.2Hz,2H),7.55(d,J＝3.2Hz,1H),7.42–7.32(m,7H),7.20(d,J＝7.2Hz,1H),7.16–7.12(m,1H),6.93–6.86(m,1H),5.41(s,2H),3.89(s,3H).
13C NMR(126MHz,CDCl3)160.07,154.44,153.43,152.52,152.00,140.86,139.31,136.70,136.52,129.57,129.10,128.66,128.26,128.04,126.53,126.35,126.30,120.39,119.28,116.71,113.64,112.34,112.23,71.31,55.55.
HRMS(IT-TOF)：C27H21NO2Se for[M+H]+,calculated 472.0812,found 472.0809.
EXAMPLE 11 preparation of XM _ A0088 Compound
The preparation of compound XM _ a0088 is as follows:
0.218g GsB-01(0.5mmol, 1.0eq), 0.097g LuC-24(0.5mmol, 1.0eq) and 0.008g Pd (PPh) were weighed out separately3)2Cl2(0.025mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.051g of yellow solid, yield: 33.7 percent.
1H NMR(500MHz,Chloroform-d)8.07–8.00(m,1H),7.76–7.69(m,1H),7.68–7.64(m,1H),7.40–7.33(m,1H),7.31(d,J＝7.8Hz,1H),7.01(d,J＝7.3Hz,1H),6.98(s,1H),4.07(s,3H),2.61(s,3H).
13C NMR(126MHz,CDCl3)155.24,152.94,150.27,149.99,140.17,136.41,129.14,128.25,127.59,126.07,119.52,117.18,108.75,56.40,18.70.
HRMS(IT-TOF)：C15H13NOSe for[M+H]+,calculated 304.0223,found 304.0231.
EXAMPLE 12 preparation of XM _ A0089 Compound
The preparation of compound XM _ a0089 was as follows:
0.061g XM _ A0088(0.2mmol, 1.0eq) was weighed into a 50mL large tube, dissolved in 2.0mL water and then dissolved with 1.0mL methanol. Slowly add 0.6mL hydrobromic acid (48% in H) dropwise2O, 26eq), heated at 100 ℃ under reflux for 6 h. Cooled to room temperature, 10.0mL of ethyl acetate and 30.0mL of water are added, the mixture is shaken well, the organic phase is separated, the aqueous phase is extracted with ethyl acetate (10 mL. times.2), and the organic phase and the aqueous phase are combinedThe organic phase was washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.055g of yellow solid, yield: 95.2 percent.
1H NMR(400MHz,Chloroform-d)8.07(d,J＝8.7Hz,1H),8.01(s,1H),7.74(d,J＝8.7Hz,1H),7.66(d,J＝3.8Hz,1H),7.37(t,J＝7.9Hz,1H),7.26(dd,J＝8.1,1.0Hz,1H),7.15(dd,J＝7.6,1.1Hz,1H),7.01–6.96(m,1H),2.68–2.57(m,3H).
13C NMR(101MHz,CDCl3)151.94,151.83,150.74,148.84,137.87,136.60,129.34,128.17,127.30,127.09,117.88,117.33,110.60,18.73.
HRMS(IT-TOF)：C14H11NOSe for[M+H]+,calculated 290.0079,found 209.0072.
EXAMPLE 13 preparation of XM _ A0090 Compound
The preparation of compound XM _ a0090 was as follows:
0.498g of GsC-01(1.0mmol, 1.0eq), 0.193g of LuC-24(1.0mmol, 1.0eq) and 0.016g of Pd (PPh) are weighed out separately3)2Cl2(0.05mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 5.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.017g of yellow solid, yield: 4.7 percent.
1H NMR(400MHz,Chloroform-d)8.08(d,J＝8.6Hz,1H),7.85(d,J＝4.1Hz,1H),7.80(d,J＝8.6Hz,1H),7.68–7.61(m,2H),7.54(d,J＝4.1Hz,1H),7.44–7.29(m,5H),7.07–7.00(m,2H),4.10(s,3H).
13C NMR(126MHz,CDCl3)155.32,153.38,152.63,151.44,140.25,136.61,136.55,129.07,128.46,128.00,126.48,126.39,126.34,126.31,119.57,117.08,108.85,77.41,77.16,76.91,56.47.
HRMS(IT-TOF)：C20H15NOSe for[M+H]+,calculated 366.0393,found 366.0356.
EXAMPLE 14 preparation of XM _ A0091 compound
The preparation of compound XM _ a0091 is as follows:
0.092g of XM _ A0090(0.2mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 3.0mL of dichloromethane and stirred at-15 ℃ for 5 min. Slowly adding 0.12mL of boron trifluoride (1.25mmol, 5.0eq) dropwise, continuing stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.044g of white solid, yield: 50.1 percent.
1H NMR(500MHz,Chloroform-d)7.95(d,J＝8.6Hz,1H),7.92(s,1H),7.70(d,J＝4.1Hz,1H),7.64(d,J＝8.6Hz,1H),7.52(d,J＝7.4Hz,2H),7.40(d,J＝4.1Hz,1H),7.33–7.27(m,3H),7.23(t,J＝7.3Hz,1H),7.17–7.14(m,1H),7.07(d,J＝7.6Hz,1H).
13C NMR(126MHz,CDCl3)153.68,151.82,151.57,150.03,137.86,136.64,136.25,129.11,129.03,128.24,127.43,127.31,126.50,126.29,117.92,117.20,110.73.
HRMS(IT-TOF)：C19H13NOSe for[M+H]+,calculated 352.0236,found 352.0378.
EXAMPLE 15 preparation of XM _ A0092 compound
The preparation of compound XM _ a0092 was as follows:
0.138g XM _ A0045(0.5mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 5.0mL acetic anhydride and stirred at room temperature for 24 h. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.155g of yellow solid, yield: 97.8 percent.
1H NMR(500MHz,Chloroform-d)8.15–8.11(m,2H),7.87(d,J＝3.9Hz,1H),7.82(d,J＝8.7Hz,1H),7.69–7.65(m,1H),7.47(t,J＝7.8Hz,1H),7.44(d,J＝1.4Hz,1H),7.43–7.40(m,1H),2.60(s,3H).
13C NMR(126MHz,CDCl3)169.92,153.44,152.56,147.57,140.75,136.67,134.34,130.97,128.59,127.82,125.83,125.55,121.73,117.22,21.07.
HRMS(IT-TOF)：C15H11NO2Se for[M+H]+,calculated 318.0028,found 317.9995.
EXAMPLE 16 preparation of XM _ A0093 Compound
The preparation of compound XM _ a0093 was as follows:
1. GsB-03 preparation
Under the protection of argon atmosphere, 0.46mL of selenophene (2.0mmol, 1.0eq) and 10.0mL of anhydrous THF are added50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.8mL (2.0mmol, 1.0eq, 2.5M in Hexane) of an n-butyllithium solution was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly adding 0.238mL of benzyl bromide (2.0mmol, 1.0eq) dropwise, and keeping the temperature for reacting for 2h after the dropwise addition is finished; at this temperature, 10.0mL of saturated NaHCO was slowly added dropwise3After the solution is added, moving to room temperature and stirring for 10 min; extraction 3 times with dichloromethane (30 mL. times.3), combining the organic phases and washing with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.41g of pale yellow liquid: 91.6 percent.
2. GsB-03 preparation
Under the protection of argon atmosphere, 0.593g of GsA-03(2.0mmol, 1.0eq) and 5.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.8mL of an n-butyllithium solution (2.0mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly adding 0.545mL of tributyltin chloride solution (2.0mmol, 1.0eq) dropwise, and keeping the temperature for reacting for 2h after the dropwise addition is finished; saturated 5.0mL of NaHCO was slowly added dropwise at this temperature3After the solution was added, the mixture was stirred at room temperature for 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 1.024g brown liquid: 99.9 percent.
3. Preparation of XM _ A0093
0.512g GsB-03(0.5mmol, 1.0eq), 0.090g LuC-26(0.5mmol, 1.0eq) and 0.018g Pd (PPh) were weighed respectively3)2Cl2(0.025mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. Adding5.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ and reacted overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.088g of yellow solid, yield: 48.2 percent.
1H NMR(500MHz,Chloroform-d)8.06(d,J＝8.7Hz,1H),7.93(s,1H),7.74(d,J＝8.7Hz,1H),7.69(d,J＝3.9Hz,1H),7.39–7.30(m,5H),7.29–7.24(m,2H),7.13(d,J＝7.6Hz,1H),7.06(d,J＝3.7Hz,1H),4.22(s,2H).
13C NMR(126MHz,CDCl3)155.76,151.86,151.83,149.73,140.50,137.85,136.65,128.87,128.81,127.95,127.36,127.19,126.94,117.87,117.26,110.65,77.41,77.16,76.91,39.37.
HRMS(IT-TOF)：C20H15NOSe for[M+H]+,calculated 366.0393,found 366.0379.
EXAMPLE 17 preparation of XM _ A0094
The preparation of compound XM _ a0094 was as follows:
0.138g of XM _ A0045(0.5mmol, 1.0eq) was weighed into a 50mL two-necked flask, dissolved in 5.0mL of dichloromethane, and the reaction apparatus was sealed and purged with argon. 0.077mL of liquid bromine was slowly added dropwise via syringe and stirred at room temperature for 8 h. Orange precipitate appeared in the solution, and the filter cake was taken out after suction filtration. 0.088g of an orange solid was obtained, yield: 34.6 percent.
1H NMR(500MHz,DMSO-d6)10.40(s,1H),8.39(dd,J＝9.0,1.9Hz,1H),8.23(dd,J＝9.0,1.8Hz,1H),8.05(dd,J＝4.4,1.8Hz,1H),8.00(d,J＝1.9Hz,1H),7.55(dd,J＝4.3,1.8Hz,1H).
13C NMR(126MHz,DMSO)152.28,151.84,150.12,138.62,136.35,135.10,132.77,130.79,125.47,120.58,118.76,109.31,106.43.
HRMS(IT-TOF)：C13H6Br3NOSe for[M-H]+,calculated 510.8648,found 510.8633.
EXAMPLE 18 preparation of XM _ A0095 Compound
The preparation of compound XM _ a0095 was as follows:
1. GsB-04
Under the protection of argon atmosphere, 0.256g of GsA-02(1.0mmol, 1.0eq), 0.152g of 4-methoxyphenylboronic acid (1.0mmol, 1.0eq), and 0.007g of palladium acetate (0.03mmol, 0.03eq) were dissolved in a 50mL two-necked flask in 3.0mL of anhydrous DME, and stirred at room temperature for 15 min. 0.664g of potassium carbonate (4.8mmol, 4.8eq) was taken to prepare a potassium carbonate solution with 2.4mL of water. The potassium carbonate solution was poured into the above two-necked flask. The reaction was transferred to an oil bath, heated to reflux at 90 ℃ and kept at temperature for 1 h. Cooled to room temperature, extracted 3 times with dichloromethane (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.22g of pale yellow liquid: 92.4 percent.
2. GsC-02 preparation
Under the protection of argon atmosphere, 0.240g of GsB-04(1.0mmol, 1.0eq) and 5.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.4mL of an n-butyllithium solution (1.0mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then 0.271mL of tributyltin chloride solution (1.0mmol, 1.0eq) was slowly added dropwise, and after dropping, the solution was keptKeeping the temperature for reaction for 2 hours; at this temperature 5.0mL of saturated NaHCO was slowly added dropwise3After the solution was added, the mixture was stirred at room temperature for 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.264g of pale yellow liquid: 50.0 percent.
3. Preparation of XM _ A0095
0.264g of GsC-02(0.5mmol, 1.0eq), 0.090g of LuC-26(0.5mmol, 1.0eq) and 0.018g of Pd (PPh) were weighed out separately3)2Cl2(0.025mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.138g of yellow solid, yield: 72.4 percent.
1H NMR(500MHz,Chloroform-d)8.09(d,J＝8.3Hz,1H),8.02(s,1H),7.85–7.80(m,1H),7.78(d,J＝8.4Hz,1H),7.57(t,J＝8.2Hz,2H),7.41(dd,J＝8.7,4.9Hz,2H),7.37(d,J＝7.9Hz,1H),7.32–7.24(m,2H),7.17(t,J＝7.3Hz,1H),6.94(t,J＝8.2Hz,2H),3.85(s,3H).
13C NMR(126MHz,CDCl3)159.90,153.78,151.84,151.76,148.92,137.93,136.64,129.21,129.17,127.62,127.40,127.24,125.41,117.94,117.26,114.54,110.72,55.55.
HRMS(IT-TOF)：C20H15NO2Se for[M]-,calculated 381.0274,found 381.0999.
EXAMPLE 19 preparation of compound XM _ A0097
The preparation of compound XM _ a0097 was as follows:
0.085g of LuN-24(0.2mmol, 1.0eq), 0.082g of LQM-04(0.2mmol, 1.0eq) and 0.007g of Pd (PPh) were weighed out separately3)2Cl2(0.01mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.075g of yellow solid, yield: 91.4 percent.
1H NMR(400MHz,Chloroform-d)8.10–8.02(m,1H),7.95(dd,J＝8.5,4.0Hz,1H),7.81(t,J＝3.4Hz,1H),7.74(dd,J＝8.5,4.0Hz,1H),7.37(dq,J＝7.5,4.1Hz,1H),7.32(dd,J＝7.8,4.1Hz,1H),7.27–7.19(m,4H),7.12(s,1H),6.98–6.94(m,1H),6.91–6.84(m,1H),5.35(d,J＝3.4Hz,2H),3.86(d,J＝4.2Hz,2H),2.45(d,J＝3.4Hz,3H).
13C NMR(101MHz,CDCl3)159.93,154.05,153.25,151.76,139.29,139.25,136.44,135.89,133.49,130.81,129.54,128.58,126.84,119.44,119.37,116.98,114.28,113.72,112.17,71.29,55.49,22.18.
HRMS(IT-TOF)：C22H19NO2Se for[M+H]+,calculated 410.0655,found 410.0645.
EXAMPLE 20 preparation of XM _ A0098 Compound
The preparation of compound XM _ a0098 is as follows:
0.085g of LuN-24(0.2mmol, 1.0eq) and 0.083g of LQF were weighed out separately04(0.2mmol, 1.0eq) and 0.007g Pd (PPh)3)2Cl2(0.01mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.082g of yellow solid, yield: 99.3 percent.
1H NMR(500MHz,Chloroform-d)8.10(dd,J＝5.6,1.2Hz,1H),8.01(dd,J＝8.7,1.3Hz,1H),7.85(d,J＝3.9Hz,1H),7.82(d,J＝8.7Hz,1H),7.40(m,J＝5.5,3.9,1.3Hz,1H),7.37–7.32(m,1H),7.23–7.18(m,2H),6.99(m,J＝8.7,2.6,1.3Hz,1H),6.93–6.87(m,2H),5.36(s,2H),3.87(d,J＝1.3Hz,3H).
13C NMR(126MHz,CDCl3)161.52,160.08,159.56,156.12,156.03,152.76,152.01,151.99,138.40,138.07,136.07,136.02,133.89,130.89,129.73,128.53,128.44,127.21,119.34,117.98,113.96,112.27,103.21,103.04,102.74,102.51,71.40,55.55.
HRMS(IT-TOF)：C21H16FNO2Se for[M+H]+,calculated 414.0404,found 414.0454.
Preparation of the Compound XM _ A0099 example 21
The preparation of compound XM _ a0099 was as follows:
0.085g of LuN-24(0.2mmol, 1.0eq), 0.086g of LQCl-04(0.2mmol, 1.0eq) and 0.007g of Pd (PPh) were weighed out separately3)2Cl2(0.01mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL ethyl acetate and 30.0mL water, shaking uniformly,the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.078g of yellow solid, yield: 95.4 percent.
1H NMR(400MHz,Chloroform-d)8.12(dd,J＝5.6,1.0Hz,1H),7.98(d,J＝8.7Hz,1H),7.86(dd,J＝3.9,1.0Hz,1H),7.81(d,J＝8.6Hz,1H),7.40(dd,J＝5.6,3.8Hz,1H),7.37–7.32(m,2H),7.24–7.18(m,2H),7.08(d,J＝2.1Hz,1H),6.90(dd,J＝8.9,2.2Hz,1H),5.35(s,2H),3.87(s,3H).
13C NMR(126MHz,CDCl3)160.01,155.09,152.76,152.58,139.36,138.43,135.72,134.31,131.77,130.96,129.71,128.71,127.56,119.33,118.95,117.95,113.93,112.85,112.21,71.33,55.54.
HRMS(IT-TOF)：C21H16ClNO2Se for[M+H]+,calculated 430.0106,found 430.0275.
Example 22 preparation of compound XM _ A0101
The preparation of compound XM _ a0101 is as follows:
0.041g of XM _ A0097(0.1mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 3.0mL of dichloromethane, and stirred at-15 ℃ for 5 min. Slowly adding 0.030mL of boron trifluoride (0.3mmol, 3.0eq) dropwise, continuing stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.024g of yellow solid, yield: 83.0 percent.
1H NMR(500MHz,Chloroform-d)8.10(dd,J＝5.6,1.0Hz,1H),7.99(d,J＝8.7Hz,1H),7.93(s,1H),7.84(dd,J＝4.0,1.0Hz,1H),7.75(d,J＝8.6Hz,1H),7.40(dd,J＝5.6,3.9Hz,1H),7.05(t,J＝1.3Hz,1H),7.02(d,J＝1.7Hz,1H),2.47(d,J＝0.9Hz,3H).
13C NMR(126MHz,CDCl3)151.57,151.47,150.88,137.79,136.49,136.08,133.65,130.96,127.58,127.48,117.60,117.08,112.69,22.31.
HRMS(IT-TOF)：C14H11NOSe for[M+H]+,calculated 290.0079,found 290.0177.
EXAMPLE 23 preparation of compound XM _ A0102
The preparation of compound XM _ a0102 is as follows:
0.041g of XM _ A0098(0.1mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 3.0mL of dichloromethane, and stirred at-15 ℃ for 5 min. Slowly adding 0.030mL of boron trifluoride (0.3mmol, 3.0eq) dropwise, continuing stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.027g of yellow solid, yield: 92.2 percent.
1H NMR(400MHz,Chloroform-d)8.14(s,1H),8.13(t,J＝6.2Hz,1H),8.01(d,J＝8.7Hz,1H),7.84(d,J＝4.5Hz,1H),7.79(d,J＝8.7Hz,1H),7.39(dd,J＝5.6,3.9Hz,1H),6.92(ddd,J＝18.3,9.6,2.6Hz,2H).
13C NMR(101MHz,CDCl3)162.68,160.23,153.62,153.47,151.10,151.07,150.90,136.29,136.23,135.21,134.05,131.01,128.00,127.61,127.49,118.66,101.77,101.48,101.44,101.21.
19F NMR(376MHz,CDCl3)-110.00,-110.03,-110.05.
HRMS(IT-TOF)：C13H8FNOSe for[M+H]+,calculated 293.9828,found 293.9798.
EXAMPLE 24 preparation of compound XM _ A0103
The preparation of compound XM _ a0103 is as follows:
0.043g of XM _ A0099(0.1mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 3.0mL of dichloromethane and stirred at-15 ℃ for 5 min. Slowly adding 0.030mL of boron trifluoride (0.3mmol, 3.0eq) dropwise, continuing stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.029g of yellow solid, yield: 93.9 percent.
1H NMR(400MHz,Chloroform-d)8.17–8.12(m,1H),8.02(s,1H),7.96(d,J＝8.7Hz,1H),7.86–7.83(m,1H),7.77(d,J＝8.7Hz,1H),7.39(dd,J＝5.6,3.9Hz,1H),7.24(d,J＝2.0Hz,1H),7.12(d,J＝2.1Hz,1H).
13C NMR(101MHz,CDCl3)152.59,151.88,150.78,136.54,135.90,134.44,132.95,131.06,128.34,127.62,118.59,116.84,112.08.
HRMS(IT-TOF)：C13H8ClNOSe for[M+H]+,calculated 309.9530,found 309.9557.
EXAMPLE 25 preparation of compound XM _ A0104
The preparation of compound XM _ a0104 is as follows:
0.045g of XM _ A0095(0.11mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon, dissolved in 3.0mL of dichloromethane and stirred at-15 ℃ for 5 min. Slowly adding 0.032mL boron trifluoride (0.33mmol, 3.0eq) dropwise, continuing stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (30% EA/PE) to obtain 0.011g of orange solid, wherein the yield is as follows: 27.2 percent.
1H NMR(400MHz,Acetone-d6)8.74(s,1H),8.48(s,1H),8.30(d,J＝8.7Hz,1H),8.18–7.99(m,2H),7.66–7.52(m,3H),7.47–7.36(m,2H),7.13(dd,J＝7.1,1.8Hz,1H),6.98–6.86(m,2H).
13C NMR(101MHz,Acetone)158.82,154.84,153.19,152.90,149.15,138.78,137.74,130.92,128.86,128.53,128.28,127.95,125.96,118.78,118.20,116.81,111.83.
HRMS(IT-TOF)：C19H13NO2Se for[M+H]+,calculated 368.0185,found 368.1065.
EXAMPLE 26 preparation of compound XM _ A0106
The preparation of compound XM _ a0106 is as follows:
0.055g XM _ A0045(0.2mmol, 1.0eq) was weighed into a 50mL eggplant-shaped bottle, dissolved in 10.0mL methanol, and stirred at room temperature for 5 min. In another 50mL eggplant-shaped bottle, 0.008g of sodium hydroxide (0.2mmol, 1.0eq) was weighed and dissolved in 10.0mL of methanol. While stirring, a methanol solution of sodium hydroxide was slowly added dropwise to a methanol solution of XM _ a0045, and stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give a golden yellow solid 0.058g, yield: 97.7 percent.
1H NMR(400MHz,DMSO-d6)8.13(d,J＝5.6Hz,1H),7.97(d,J＝8.5Hz,1H),7.90(d,J＝3.9Hz,1H),7.69(d,J＝8.5Hz,1H),7.36(t,J＝4.6Hz,1H),7.09(t,J＝7.8Hz,1H),6.50(d,J＝7.8Hz,2H).
13C NMR(101MHz,DMSO)167.90,153.38,147.54,143.83,136.33,132.17,130.80,129.99,129.02,126.16,116.31,114.33,105.24.
HRMS(IT-TOF)：C13H8NNaOSe for[M+H]+,calculated 275.9923,found 275.9918.
Example 27 preparation of compound XM _ A0107
The preparation of compound XM _ a0107 is as follows:
0.055g XM _ A0045(0.2mmol, 1.0eq) was weighed into a 50mL eggplant-shaped bottle, dissolved in 10.0mL methanol, and stirred at room temperature for 5 min. 0.011g of potassium hydroxide (0.2mmol, 1.0eq) was weighed into another 50mL eggplant-shaped bottle and dissolved in 10.0mL of methanol. While stirring, a methanol solution of potassium hydroxide was slowly added dropwise to a methanol solution of XM _ a0045, and stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give a golden yellow solid 0.061g, yield: 97.4 percent.
1H NMR(400MHz,DMSO-d6)8.10(d,J＝5.6Hz,1H),7.93(d,J＝8.6Hz,1H),7.87(d,J＝3.9Hz,1H),7.71(d,J＝8.6Hz,1H),7.37(dd,J＝5.6,3.8Hz,1H),7.07(t,J＝7.8Hz,1H),6.48(t,J＝7.6Hz,2H).
13C NMR(101MHz,DMSO)167.54,154.16,147.18,143.77,135.90,131.99,130.77,130.12,128.88,125.43,115.38,114.19,105.21.
HRMS(IT-TOF)：C13H8KNOSe for[M+H]+,calculated 275.9923,found 275.9887.
Example 28 preparation of compound XM _ A0108
The preparation of compound XM _ a0108 is as follows:
0.055g XM _ A0045(0.2mmol, 1.0eq) was weighed into a 50mL eggplant-shaped bottle, dissolved in 10.0mL dichloromethane, and stirred at room temperature for 5 min. 0.5mL of hydrochloric acid (1.0mmol, 5.0eq,2M in EA) was weighed into another 50mL eggplant-shaped bottle and dissolved in 10.0mL of methylene chloride. While stirring, an ethyl acetate solution of hydrochloric acid was slowly added dropwise to a dichloromethane solution of XM _ a0045, and stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give a golden yellow solid 0.058g, yield: 93.2 percent.
1H NMR(400MHz,DMSO-d6)8.37–8.29(m,2H),8.19(d,J＝3.9Hz,1H),8.07(d,J＝8.7Hz,1H),7.45(dd,J＝5.6,3.8Hz,1H),7.40–7.36(m,2H),7.14(dd,J＝6.2,2.7Hz,1H),5.45(s,5H).
13C NMR(101MHz,DMSO)152.60,151.52,151.18,137.91,137.05,135.38,130.93,129.00,127.83,127.02,117.88,117.55,112.23.
HRMS(IT-TOF)：C13H10ClNOSe for[M+H]+,calculated 275.9923,found 275.9938.
Example 29 preparation of compound XM _ A0109
The preparation of compound XM _ a0109 is as follows:
0.054g of LuC-26(0.3mmol, 1.0eq), 0.107g of 2- (tri-n-butyltin) furan (0.3mmol, 1.0eq) and 0.011g of Pd (PPh) were weighed out separately3)2Cl2(0.015mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and vacuum evaporating to remove solventAnd (3) preparing. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.034g of white solid, yield: 53.7 percent.
1H NMR(400MHz,Chloroform-d)8.15(d,J＝8.6Hz,2H),7.86(d,J＝8.6Hz,1H),7.62(s,1H),7.41(t,J＝7.9Hz,1H),7.30(d,J＝8.2Hz,1H),7.25(d,J＝3.3Hz,1H),7.20(d,J＝7.5Hz,1H),6.68–6.52(m,1H).
13C NMR(101MHz,CDCl3)153.55,152.08,147.01,144.02,137.92,136.80,127.36,117.99,117.88,112.46,110.47,110.02.
HRMS(IT-TOF)：C13H9NO2 for[M+H]+,calculated 212.0706,found 212.0717.
EXAMPLE 30 preparation of Compound XM _ A0115
The compound XM _ a0115 was prepared as follows:
1. GsB-05 preparation
Under the protection of argon atmosphere, 0.386g of GsA-02(2.8mmol, 1.4eq), 0.152g of 2-methoxyphenylboronic acid (2.0mmol, 1.0eq), and 0.014g of palladium acetate (0.06mmol, 0.03eq) were weighed out in a 50mL two-necked flask, dissolved in 5.0mL of anhydrous DME, and stirred at room temperature for 15 min. 1.327g of potassium carbonate (9.6mmol, 4.8eq) was mixed with 4.8mL of water to prepare a potassium carbonate solution. The potassium carbonate solution was poured into the above two-necked flask. The reaction was transferred to an oil bath, heated to reflux at 90 ℃ and kept at temperature for 1 h. Cooled to room temperature, extracted 3 times with dichloromethane (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.222g of white solid: 49.6 percent.
2. GsC-03 preparation
Under the protection of argon atmosphere, 0.222g of GsB-05(1.0mmol, 1.0eq) was weighed into a 50mL two-necked flask, dissolved in 5.0mL of anhydrous dichloromethane, and stirred at room temperature for 5 min. 0.496mL of N, N-diisopropylethylamine (3.0mmol, 3.0eq) was metered by syringe, and 0.152mL of chloromethyl methyl ether (2.0mmol, 2.0eq) was added and stirred at room temperature for 8 h. Subsequently, the reaction was quenched by the addition of 5.0mL of saturated ammonium chloride solution. 50.0mL of water was added, extracted 3 times with dichloromethane (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. 0.185g of yellow oil is obtained, yield: 69.0 percent.
3. Preparation of GsD-01
Under the protection of argon atmosphere, 0.185g of GsC-03(0.7mmol, 1.0eq) and 3.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.28mL of an n-butyllithium solution (0.7mmol, 1.0eq, 2.5M in Hexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 0.190mL of tributyltin chloride solution (0.7mmol, 1.0eq), and keeping the temperature for reacting for 2h after dropwise adding; at this temperature 5.0mL of saturated NaHCO was slowly added dropwise3After the solution was added, the mixture was stirred at room temperature for 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.382g of pale yellow oil: 97.8 percent.
4. GsE-01 preparation
0.100g LuC-26(0.56mmol, 1.0eq), 0.458g GsD-01(0.82mmol, 1.5eq) and 0.012g Pd (PPh) were weighed out separately3)2Cl2(0.017mol, 0.03eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed and replaced with argon under protection. 5.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography (10% EA/PE) gave 0.187g of yellow solid, yield: 81.2 percent.
5. Preparation of XM _ A0115
Under an argon atmosphere, 0.041g GsE-01(0.1mmol, 1.0eq) was weighed into a 50mL two-necked flask and dissolved in 5.0mL of dichloromethane. 0.100mL of hydrochloric acid (0.2mmol, 2.0eq, 2.0M HCl in EA) was measured by syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.011g yellow solid, yield: 30.0 percent.
1H NMR(400MHz,Acetone-d6)9.70(s,1H),8.65(s,1H),8.36(d,J＝8.7Hz,1H),8.20(d,J＝4.2Hz,1H),8.13(d,J＝8.7Hz,1H),8.00(d,J＝4.2Hz,1H),7.93(d,J＝7.9Hz,1H),7.54–7.42(m,2H),7.31–7.24(m,1H),7.23–7.19(m,1H),7.15(d,J＝8.0Hz,1H),7.04(t,J＝7.5Hz,1H).
13C NMR(101MHz,Acetone)154.06,153.61,153.21,150.74,148.14,138.85,137.62,129.60,129.47,128.45,127.79,127.62,127.44,123.85,121.00,118.73,118.57,117.18,111.68.
HRMS(IT-TOF)：C19H13NO2Se for[M+H]+,calculated 368.0185,found 368.0161.
EXAMPLE 31 preparation of Compound XM _ A0116
The compound XM _ a0116 was prepared as follows:
under an argon atmosphere, 0.041g of GsE-02(0.1mmol, 1.0eq) was weighed into a 50mL two-necked flask and dissolved in 5.0mL of dichloromethane. 0.100mL of hydrochloric acid (0.2mmol, 2.0eq, 2.0M HCl in EA) was measured by syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Separating and purifying by flash column chromatography (10% EA/PE) to obtain 0.006g of orange solid, yield: 16.3 percent.
1H NMR(400MHz,Acetone-d6)8.60(s,1H),8.50(s,1H),8.29(d,J＝8.7Hz,1H),8.08(d,J＝4.1Hz,1H),8.03(d,J＝8.7Hz,1H),7.64(d,J＝4.1Hz,1H),7.46–7.34(m,3H),7.26(t,J＝8.1Hz,1H),7.18(dd,J＝4.4,2.5Hz,4H),7.14(dd,J＝7.3,1.4Hz,1H),6.90–6.83(m,2H).
13C NMR(101MHz,Acetone)158.87,154.25,153.22,152.66,150.70,138.76,138.37,137.81,131.07,130.69,128.62,128.10,127.57,118.78,118.22,118.18,116.17,113.54,111.92.
HRMS(IT-TOF)：C19H13NO2Se for[M+H]+,calculated 368.0185,found 368.0126.
EXAMPLE 32 preparation of Compound XM _ A0117
The compound XM _ a0117 was prepared as follows:
1. GsF-01 preparation
Under the protection of argon atmosphere, 0.041g GsE-01(0.1mmol, 1.0eq) and 0.028g potassium carbonate (0.2mmol, 2.0eq) are weighed into a 50mL two-neck flask, and 3.0mL anhydrous acetonitrile is added to dissolve. 0.007mL of methyl iodide (0.11mmol, 1.1eq) was injected at room temperature, heated in an oil bath at 55 ℃ and reacted for 8 hours. Cooling to room temperature, adding 10.0mL of ethyl acetate and 50.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (20 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (30 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (15% EA/PE) to obtain 0.034g of an orange solid, wherein the yield is as follows: 80.0 percent.
2. Preparation of XM _ A0117
Under an argon atmosphere, 0.034g of GsF-01(0.08mmol, 1.0eq) was weighed into a 50mL two-neck flask and dissolved in 5.0mL of dichloromethane. 0.100mL of hydrochloric acid (0.2mmol, 2.5eq, 2.0M HCl in EA) was taken in a syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (25% EA/PE) gave 0.009g yellow solid, yield: 29.5 percent.
1H NMR(400MHz,Acetone-d6)9.51(s,1H),8.23(d,J＝8.7Hz,1H),8.08–8.01(m,2H),7.91(d,J＝4.3Hz,1H),7.84(dd,J＝7.9,1.6Hz,1H),7.46–7.39(m,2H),7.21–7.13(m,2H),7.05(dd,J＝8.1,1.3Hz,1H),6.95(ddd,J＝8.2,7.2,1.3Hz,1H),4.04(s,3H).
13C NMR(101MHz,Acetone)156.45,154.08,153.93,152.44,147.73,141.10,137.12,129.40,129.26,128.38,127.61,127.51,127.00,124.12,120.99,120.38,117.70,117.19,110.13,56.55.
HRMS(IT-TOF)：C20H15NO2Se for[M+H]+,calculated 382.0342,found 382.0524.
EXAMPLE 33 preparation of Compound XM _ A0118
The compound XM _ a0118 was prepared as follows:
under an argon atmosphere, 0.037g of GsF-02(0.09mmol, 1.0eq) was weighed into a 50mL two-necked flask and dissolved in 5.0mL of dichloromethane. 0.100mL of hydrochloric acid (0.2mmol, 2.2eq, 2.0M HCl in EA) was taken in a syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (25% EA/PE) to obtain 0.006g yellow solid, yield: 17.5 percent.
1H NMR(400MHz,Acetone-d6)8.57(s,1H),8.27(d,J＝8.7Hz,1H),8.13–7.98(m,2H),7.65(d,J＝4.1Hz,1H),7.45(d,J＝4.5Hz,2H),7.30–7.21(m,2H),7.20–7.16(m,2H),6.88–6.80(m,1H),4.06(s,3H).
13C NMR(101MHz,Acetone)157.98,155.55,152.86,152.09,151.56,140.11,137.71,136.46,130.17,128.70,128.52,126.60,126.47,119.49,117.36,116.51,115.13,112.63,109.36,55.71.
HRMS(IT-TOF)：C20H15NO2Se for[M+H]+,calculated 382.0342,found 382.0284.
Example 34 preparation of Compound XM _ A0119
The compound XM _ a0119 was prepared as follows:
under the protection of argon atmosphere, 0.026g GsF-03(0.06mmol, 1.0 e) was weighedq) was dissolved in 5.0mL of methylene chloride in a 50mL two-necked flask. 0.100mL of hydrochloric acid (0.2mmol, 3.3eq, 2.0M HCl in EA) was measured by syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (25% EA/PE) to obtain 0.011g yellow solid, yield: 48.1 percent.
1H NMR(400MHz,Acetone-d6)8.83–8.61(m,1H),8.23(d,J＝8.6Hz,1H),8.06–7.96(m,2H),7.62–7.55(m,2H),7.52(d,J＝4.1Hz,1H),7.44(t,J＝4.1Hz,2H),7.18(q,J＝4.3Hz,1H),6.96–6.87(m,2H),4.05(s,3H).
13C NMR(101MHz,Acetone)158.66,156.40,154.28,153.16,150.87,141.01,137.21,129.76,129.29,129.08,128.25,127.15,125.82,120.37,117.36,116.75,110.21,56.58.
HRMS(IT-TOF)：C20H15NO2Se for[M+H]+,calculated 382.0342,found 382.0322.
EXAMPLE 35 preparation of XM _ A0120
The preparation process of compound XM _ a0120 is as follows:
1. GsF-04
Under the protection of argon atmosphere, 0.108g of GsE-01(0.26mmol, 1.0eq) and 0.072g of potassium carbonate (0.52mmol, 2.0eq) are weighed into a 50mL two-neck flask, and 5.0mL of anhydrous acetonitrile is added to dissolve. 0.040mL of 3-methoxybenzyl bromide (0.29mmol, 1.1eq) was injected at room temperature, and the mixture was heated in an oil bath at 55 ℃ to react for 8 hours. Cooling to room temperature, adding 10.0mL ethyl acetate and 50.0mL water, shaking, separating organic phase, adding water phase with ethyl acetateExtraction (20 mL. times.2), combining the organic phases, washing with saturated NaCl solution (30 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (15% EA/PE) to obtain 0.110g of yellow solid, yield: 79.7 percent.
2. Preparation of XM _ A0120
Under an argon atmosphere, 0.110g of GsF-04(0.21mmol, 1.0eq) was weighed into a 50mL two-necked flask and dissolved in 5.0mL of dichloromethane. 0.100mL of hydrochloric acid (0.42mmol, 2.0eq, 2.0M HCl in EA) was taken in a syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (25% EA/PE) to obtain 0.079g of orange solid, yield: 77.2 percent.
1H NMR(400MHz,Acetone-d6)8.61(s,1H),8.25(d,J＝8.7Hz,1H),8.09–7.94(m,2H),7.64(d,J＝4.1Hz,1H),7.50–7.39(m,3H),7.34(t,J＝7.9Hz,1H),7.28(dd,J＝8.8,7.3Hz,2H),7.25–7.13(m,3H),6.95–6.83(m,2H),5.40(s,2H),3.88(s,3H).
13C NMR(101MHz,Acetone)160.97,158.85,155.21,153.82,153.04,152.65,141.40,140.48,138.64,137.40,131.04,130.19,129.58,129.49,127.56,127.27,121.02,119.69,118.21,117.30,116.01,113.68,113.55,113.29,112.83,71.20,55.66.
HRMS(IT-TOF)：C27H21NO3Se for[M+H]+,calculated 488.0761,found 488.0754.
EXAMPLE 36 preparation of Compound XM _ A0121
The preparation process of compound XM _ a0121 is as follows:
under an argon atmosphere, 0.039g of GsF-05(0.080mmol, 1.0eq) was weighed into a 50mL two-necked flask and dissolved in 5.0mL of dichloromethane. 0.080mL of hydrochloric acid (0.16mmol, 2.0eq, 2.0M HCl in EA) was measured by syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (25% EA/PE) to obtain 0.023g of orange solid, wherein the yield is as follows: 59.0 percent.
1H NMR(400MHz,Acetone-d6)8.61(s,1H),8.25(d,J＝8.7Hz,1H),8.09–7.94(m,2H),7.64(d,J＝4.1Hz,1H),7.50–7.39(m,3H),7.34(t,J＝7.9Hz,1H),7.28(dd,J＝8.8,7.3Hz,2H),7.25–7.13(m,3H),6.95–6.83(m,2H),5.40(s,2H),3.88(s,3H).
13C NMR(101MHz,Acetone)160.97,158.85,155.21,153.82,153.04,152.65,141.40,140.48,138.64,137.40,131.04,130.19,129.58,129.49,127.56,127.27,121.02,119.69,118.21,117.30,116.01,113.68,113.55,113.29,112.83,71.20,55.66.
HRMS(IT-TOF)：C27H21NO3Se for[M+H]+,calculated 488.0761,found 488.0741.
EXAMPLE 37 preparation of XM _ A0122
The preparation process of compound XM _ a0122 is as follows:
under an argon atmosphere, 0.029g of GsF-05(0.054mmol, 1.0eq) was weighed into a 50mL two-neck flask and dissolved in 5.0mL of dichloromethane. 0.055mL of hydrochloric acid (0.110mmol, 2.0eq, 2.0M HCl in EA) was taken in a syringe and slowly added dropwise to the two-necked flask. Moving to an oil bath and heating for 24h at 35 ℃. 50.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (25% EA/PE) to obtain 0.022g of an orange solid, wherein the yield is as follows: 83.6 percent.
1H NMR(400MHz,Acetone-d6)8.72(d,J＝1.3Hz,1H),8.24(d,J＝8.7Hz,1H),8.05–7.96(m,2H),7.61–7.55(m,2H),7.52(d,J＝4.1Hz,1H),7.47(dd,J＝8.3,1.5Hz,1H),7.44–7.38(m,2H),7.35(t,J＝7.9Hz,1H),7.27(dd,J＝7.5,1.5Hz,1H),7.25–7.20(m,1H),6.95–6.89(m,3H),5.41(s,2H),3.88(s,3H).
13C NMR(101MHz,Acetone)160.96,158.67,155.20,154.34,153.23,151.10,141.45,140.53,137.29,130.20,129.76,129.39,129.12,128.20,127.08,125.90,121.06,119.74,117.27,116.78,113.72,113.29,112.94,71.29,55.65.
HRMS(IT-TOF)：C27H21NO3Se for[M+H]+,calculated 488.0761,found 488.0686.
EXAMPLE 38 preparation of compound XM _ A0129
The preparation process of compound XM a0129 is as follows:
1. GsB-06 preparation
Under the protection of argon atmosphere, 0.256g of GsA-02(1.0mmol, 1.0eq), 0.212g of 3,4, 5-trimethoxyphenylboronic acid (1.0mmol, 1.0eq),0.007g of palladium acetate (0.03mmol, 0.03eq) were dissolved in a 50mL two-necked flask in 3.0mL of anhydrous DME, and stirred at room temperature for 15 min. 0.664g of potassium carbonate (4.8mmol, 4.8eq) was taken to prepare a potassium carbonate solution with 2.4mL of water. The potassium carbonate solution was poured into the above two-necked flask. The reaction was transferred to an oil bath, heated to reflux at 90 ℃ and kept at temperature for 1 h. Cooled to room temperature, extracted 3 times with dichloromethane (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.292g of pale yellow liquid: 98.0 percent.
2. GsC-04
Under the protection of argon atmosphere, 0.292g of GsB-06(1.0mmol, 1.0eq) and 5.0mL of anhydrous THF were put in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.4mL of an n-butyllithium solution (1.0mmol, 1.0eq, 2.5M inHexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly dropwise adding 0.271mL of tributyltin chloride solution (1.0mmol, 1.0eq), and keeping the temperature for reacting for 2h after dropwise adding; at this temperature 5.0mL of saturated NaHCO was slowly added dropwise3After the solution was added, the mixture was stirred at room temperature for 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.57g of pale yellow liquid: 96.9 percent.
3. Preparation of XM _ A0129
0.600g GsC-04(0.5mmol, 2.0eq), 0.090g LuC-26(0.5mmol, 1.0eq) and 0.018g Pd (PPh) were weighed out separately3)2Cl2(0.025mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) gave 0.172g of yellow solid, yield: 78.0 percent.
1H NMR(400MHz,Chloroform-d)8.10(d,J＝8.6Hz,1H),7.99(s,1H),7.85–7.76(m,2H),7.45(d,J＝4.1Hz,1H),7.39(t,J＝7.9Hz,1H),7.28(dd,J＝8.3,1.2Hz,1H),7.17(dd,J＝7.6,1.2Hz,1H),6.83(s,2H),3.95(s,6H),3.90(s,3H).
13C NMR(101MHz,CDCl3)153.75,153.66,151.82,151.54,149.96,138.49,137.89,136.73,132.12,128.88,127.47,127.38,126.36,117.96,117.16,110.79,103.76,61.13,56.36.
HRMS(IT-TOF)：C22H19NO4Se for[M+H]+,calculated 442.0479,found 442.0438.
EXAMPLE 39 preparation of Compound XM _ A0130
The preparation process of the compound XM _ A0130 is as follows:
0.172g XM _ A0129(0.40mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon shield, dissolved in 3.0mL dichloromethane and stirred at-15 ℃ for 5 min. Slowly dropwise adding 0.347mL of boron tribromide (3.6mmol, 9.0eq), continuously stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Separating and purifying by flash column chromatography (30% EA/PE) to obtain 0.051g of orange solid, and obtaining the yield: 12.8 percent.
1H NMR(400MHz,Methanol-d4)8.08(d,J＝8.7Hz,1H),7.84(d,J＝4.1Hz,1H),7.80(d,J＝8.7Hz,1H),7.34–7.27(m,2H),7.23(d,J＝7.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.66(s,2H).
13C NMR(126MHz,CDCl3)156.09,153.28,153.17,148.96,147.29,138.95,137.97,135.14,130.85,128.92,128.90,127.98,125.96,119.09,118.34,112.19,106.45.
HRMS(IT-TOF)：C19H13NO4Se for[M+H]+,calculated 400.0084,found 400.0077.
EXAMPLE 40 preparation of Compound XM _ A0133
The preparation process of the compound XM _ A0133 is as follows:
1. preparation of 5,8-dimethoxyquinoline
0.855g of 5, 8-dibromoquinoline (3.0mmol, 1.0eq), 0.430g of cuprous bromide (3.0mmol, 1.0eq) and 0.356g of sodium methoxide (0.025mol, 2.2eq) were weighed respectively in a 50mL two-necked flask, the reaction apparatus was sealed, and argon gas was replaced. 10.0mL of anhydrous methanol was added, and the mixture was heated in an oil bath at 90 ℃ under reflux for 3 hours. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (20% EA/PE) to obtain 0.544g of yellow solid, yield: 96.0 percent.
2. Preparation of 5,8-dimethoxyquinoline 1-oxide
0.544g of 5,8-dimethoxyquinoline (2.9mmol, 1.0eq), 0.710g of m-chloroperoxybenzoic acid (3.5mmol, 1.2eq, 85%) were weighed out separately in a 50mL round-bottomed flask. 20.0mL of anhydrous dichloromethane was added, and the mixture was placed in an ice bath to react for 3 h. Warming to room temperature, adding 10.0mL of dichloromethane and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with dichloromethane (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); is free ofWater Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (60% EA/PE) to obtain 0.493g of yellow oily matter, yield: 83.0 percent.
3. Preparation of 2-chloro-5,8-dimethoxyquinoline
0.493g of 5,8-dimethoxyquinoline oxide (2.4mmol, 1.0eq), 0.630g of triphenylphosphine (2.4mmol, 3.0eq) and 0.244mL of trichloroacetonitrile (2.4mol, 3.0eq) were weighed respectively in a 50mL two-necked flask, and the reaction apparatus was closed and replaced with argon for protection. 10.0mL of anhydrous toluene was added, and the mixture was heated in an oil bath at 115 ℃ under reflux for 4 hours. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (15% EA/PE) to obtain 0.487g of light yellow solid, wherein the yield is as follows: 91.0 percent.
4. GsE-03 preparation
0.487g of 2-chloro-5,8-dimethoxyquinoline (2.2mmol, 2.2eq), 0.528g of GsC-02(1.0mmol, 1.0eq) and 0.035g of Pd (PPh) were weighed out separately3)2Cl2(0.05mol, 0.05eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed, and then argon gas was replaced. 5.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.361g yellow solid, yield: 85.0 percent.
5. Preparation of XM _ A0133
0.361g GsE-03(0.85mmol, 1.0eq) was weighed into a 50mL two-necked flask, argon replaced, dissolved in 3.0mL dichloromethane, and stirred at-15 ℃ for 5 min. Slowly dropwise adding 0.737mL boron tribromide (7.65mmol, 9.0eq), continuously stirring at-15 ℃ for 10min, and cooling to-78 ℃ for reaction for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. And (3) separating and purifying by flash column chromatography (30% EA/PE) to obtain 0.040g of orange solid, wherein the yield is as follows: 10.4 percent.
1H NMR(400MHz,Methanol-d4)8.33(d,J＝8.4Hz,1H),8.12(d,J＝8.4Hz,1H),8.04(d,J＝4.2Hz,1H),7.52(d,J＝8.7Hz,2H),7.47(d,J＝4.2Hz,1H),7.14–6.99(m,2H),6.82(d,J＝8.7Hz,2H).
HRMS(IT-TOF)：C19H13NO3Se for[M+H]+,calculated 383.0061,found 383.0066.
EXAMPLE 41 preparation of Compound XM _ A0140
The preparation process of compound XM _ a0140 is as follows:
1. GsB-07 preparation
Under the protection of argon atmosphere, 0.386g of GsA-02(2.8mmol, 1.4eq), 0.152g of 4-methoxyphenylboronic acid (2.0mmol, 1.0eq), and 0.014g of palladium acetate (0.06mmol, 0.03eq) were weighed into a 50mL two-necked containerThe flask was taken up in 5.0mL of anhydrous DME and stirred at room temperature for 15 min. 1.327g of potassium carbonate (9.6mmol, 4.8eq) was mixed with 4.8mL of water to prepare a potassium carbonate solution. The potassium carbonate solution was poured into the above two-necked flask. The reaction was transferred to an oil bath, heated to reflux at 90 ℃ and kept at temperature for 1 h. Cooled to room temperature, extracted 3 times with dichloromethane (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.42g of white solid: 93.3 percent.
2. GsC-05 preparation
Under the protection of argon atmosphere, 0.450g of GsB-05(2.0mmol, 1.0eq) was weighed into a 50mL two-necked flask, dissolved in 5.0mL of anhydrous dichloromethane, and stirred at room temperature for 5 min. 0.496mL of N, N-diisopropylethylamine (3.0mmol, 3.0eq) was metered by syringe, and 0.152mL of chloromethyl methyl ether (4.0mmol, 2.0eq) was added and stirred at room temperature for 8 h. Subsequently, the reaction was quenched by the addition of 5.0mL of saturated ammonium chloride solution. 50.0mL of water was added, extracted 3 times with dichloromethane (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (50 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.455g of pale yellow oil: 85.0 percent.
3. Preparation of GsD-02
Under the protection of argon atmosphere, 0.455g of GsC-05(1.7mmol, 1.0eq) and 3.0mL of anhydrous THF were placed in a 50mL eggplant-shaped bottle. Cooled to-78 ℃ with stirring, and 0.68mL of an n-butyllithium solution (1.7mmol, 1.0eq, 2.5M inHexane) was slowly added dropwise; after dripping, keeping the temperature for reaction for 1 h; raising the temperature to-30 ℃ for reaction for 1 h; then slowly adding 0.460mL of tributyltin chloride solution (1.7mmol, 1.0eq) dropwise, and keeping the temperature for reacting for 2h after the dropwise addition is finished; at this temperature 5.0mL of saturated NaHCO was slowly added dropwise3The solution is transferred to room temperature to be stirred after the addition is finishedStirring for 10 min. 20.0mL of water was added, extracted 3 times with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Yield 0.942g of brown oil: 99.3 percent.
4. Preparation of XM _ A0140
0.179g of LuC-26(1.0mmol, 1.0eq), 0.961g of GsD-01(1.7mmol, 1.7eq) and 0.021g of Pd (PPh) were weighed out separately3)2Cl2(0.03mol, 0.03eq) was placed in a 50mL two-necked flask, and the reaction apparatus was sealed and replaced with argon gas under protection. 5.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.160g of yellow solid, yield: 89.0 percent.
1H NMR(400MHz,Chloroform-d)8.08(d,J＝8.7Hz,1H),7.82(d,J＝4.1Hz,1H),7.78(d,J＝8.7Hz,1H),7.59–7.54(m,2H),7.42(d,J＝4.1Hz,1H),7.37(d,J＝7.8Hz,1H),7.29(t,J＝1.3Hz,1H),7.17(dd,J＝7.6,1.3Hz,1H),7.10–7.05(m,2H),5.22(s,2H),3.51(s,3H).
13C NMR(101MHz,CDCl3)157.46,153.56,151.83,151.71,149.20,137.91,136.65,130.31,129.14,127.59,127.41,127.26,125.68,117.94,117.25,116.80,110.73,94.49,56.24.
HRMS(IT-TOF)：C21H17NO3Se for[M+H]+,calculated 412.0448,found 412.0431.
EXAMPLE 42 preparation of Compound XM _ A0143
The preparation process of compound XM _ a0143 is as follows:
1. GsB-08 preparation
0.579g of LuC-26(3.0mmol, 1.0eq) were weighed into a 100mL two-necked flask. 30mL of nitric acid and 10mL of sulfuric acid are uniformly mixed at 0 ℃, and are dropwise added into LuC-26 to react for 1h at 0 ℃. Subsequently, the reaction was allowed to warm to room temperature and reacted at room temperature for 5 h. The reaction mixture was slowly poured into 500mL of an ice-water mixture, stirred until no more pale yellow solid was formed, and filtered under suction. The filter cake was washed 3 times with ice water and dried to give 614mg (86%) of a pale yellow solid. The light yellow solid is separated by column chromatography to obtain GsB-08, 162.1mg light yellow solid.
2. Preparation of XM _ A0143
0.1621g GsB-08(0.68mmol, 1.0eq), 0.396g GsC-02(0.75mmol, 1.1eq) and 0.014g Pd (PPh) were weighed out separately3)2Cl2(0.02mol, 0.03eq) was placed in a 50mL large tube, and the reaction apparatus was sealed and replaced with argon gas under protection. 3.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperature, adding 5.0mL of ethyl acetate and 15.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (5 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (5 mL. times.2); anhydrous Na2SO4Drying, filtering and evaporating the solvent under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) gave 0.362g of yellow solid, yield: 82.3 percent.
1H NMR(500MHz,Chloroform-d)9.11(d,J＝9.2Hz,1H),8.39(d,J＝8.8Hz,1H),7.97(d,J＝9.2Hz,1H),7.87(d,J＝2.8Hz,1H),7.57(d,J＝7.5Hz,2H),7.42(d,J＝2.7Hz,1H),7.00(d,J＝8.8Hz,1H),6.93(d,J＝7.6Hz,2H),4.17(s,3H),3.85(s,3H).
13C NMR(126MHz,CDCl3)160.51,159.86,154.80,153.46,148.44,139.45,137.82,132.82,129.97,129.11,127.54,126.45,125.45,121.59,119.77,114.42,105.96,77.29,77.04,76.78,56.94,55.42.
HRMS(IT-TOF)：C21H16N2O4Se for[M+H]+,calculated 441.0275,found 441.0288.
EXAMPLE 43 preparation of Compound XM _ A0144
The preparation process of compound XM _ a0144 was as follows:
1. GsB-09 preparation
0.579g of LuC-26(3.0mmol, 1.0eq) were weighed into a 100mL two-necked flask. 30mL of nitric acid and 10mL of sulfuric acid are uniformly mixed at 0 ℃, and are dropwise added into LuC-26 to react for 1h at 0 ℃. Subsequently, the reaction was allowed to warm to room temperature and reacted at room temperature for 5 h. The reaction mixture was slowly poured into 500mL of an ice-water mixture, stirred until no more pale yellow solid was formed, and filtered under suction. The filter cake was washed 3 times with ice water and dried to give 614mg (86%) of a pale yellow solid. Separating and purifying by flash column chromatography to obtain pale yellow solid GsB-09, 429.8 mg.
2. GsC-06 preparation
0.4298g of GsB-09(1.8mmol, 1.0eq), 1.045g of GsC-02(1.98mmol, 1.1eq) and 0.038g of Pd (PPh) were weighed out separately3)2Cl2(0.054mol, 0.03eq) in a 50mL eggplant-shaped bottle, the reaction apparatus was sealed, and argon gas was replaced. 10.0mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110 ℃ to react overnight. Cooling to room temperatureAdding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating out the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); dried over anhydrous Na2SO4, filtered, and the solvent evaporated under reduced pressure. Flash column chromatography separation and purification (10% EA/PE) to obtain 0.379g of yellow solid, yield: 86.1 percent.
3. Preparation of XM _ A0144
0.379g of GsC-06(0.86mmol, 1.0eq) and 0.240g of GsC-02(4.3mmol, 5.0eq) are weighed respectively into a 50mL large test tube, and 5mL of anhydrous methanol is added. The reaction device is sealed, hydrogen is replaced, and the reaction is carried out for 8 hours at room temperature. The mixture was filtered through celite, and the filtrate was collected, and the solvent was evaporated from the filtrate to give a yellow solid. Flash column chromatography separation and purification (20% EA/PE) gave 0.279g of yellow solid, yield: 79.2 percent.
1H NMR(400MHz,Chloroform-d)8.14(d,J＝8.8Hz,1H),7.82(d,J＝4.1Hz,1H),7.76(d,J＝8.9Hz,1H),7.57(d,J＝8.8Hz,2H),7.42(d,J＝4.1Hz,1H),6.92(dd,J＝8.5,6.8Hz,3H),6.70(d,J＝8.2Hz,1H),4.05(s,3H),3.85(s,3H).
13C NMR(101MHz,CDCl3)159.71,153.46,152.57,150.27,149.12,140.75,135.33,130.59,129.60,128.58,127.60,125.37,119.27,115.68,114.49,110.42,110.37,57.14,55.55.
HRMS(IT-TOF)：C21H18N2O2Se for[M+H]+,calculated 411.0607,found 411.0682.
EXAMPLE 44 preparation of Compound XM _ A0145
The preparation process of compound XM _ a0145 was as follows:
0.137g XM \uwas weighedA0045(0.5mmol, 1.0eq), 0.193g iodobenzene acetate (0.6mmol, 1.2eq)In a 50mL eggplant-shaped bottle, 3mL of acetonitrile was dissolved. The reaction was carried out at room temperature for 5 h. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a yellow solid, 105.5mg (73%).
1H NMR(400MHz,Chloroform-d)8.33(d,J＝8.3Hz,1H),8.26(dd,J＝5.6,1.0Hz,1H),7.98–7.91(m,2H),7.41(dd,J＝5.6,3.9Hz,1H),7.09(d,J＝10.4Hz,1H),7.00(d,J＝10.4Hz,1H).
13C NMR(101MHz,CDCl3)184.28,182.95,158.50,149.72,147.61,138.92,138.01,137.21,135.30,131.33,129.67,127.24,121.56.
HRMS(IT-TOF)：C13H9NO2Se for[M+H]+,calculated 291.9872,found 291.9717.
EXAMPLE 45 preparation of Compound XM _ A0146
The preparation process of compound XM _ a0146 was as follows:
0.184g of XM _ A0104(0.5mmol, 1.0eq) and 0.193g of iodobenzene acetate (0.6mmol, 1.2eq) were weighed out and dissolved in a 50mL eggplant-shaped bottle with 3mL of acetonitrile. The reaction was carried out at room temperature for 5 h. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a yellow solid, 149mg (78.3%).
1H NMR(500MHz,Chloroform-d)8.34(d,J＝8.4Hz,1H),7.95–7.90(m,2H),7.52(d,J＝8.5Hz,2H),7.44(d,J＝4.2Hz,1H),7.11(d,J＝10.3Hz,1H),7.02(d,J＝10.4Hz,1H),6.88(d,J＝8.5Hz,2H).
HRMS(IT-TOF)：C19H13NO3Se for[M+H]+,calculated 383.0061,found 383.0092.
EXAMPLE 46 preparation of XM _ A0164 Compound
The preparation process of the compound XM _ A0164 is as follows:
0.088g GsC-06(0.2mmol, 1.0eq) was weighed into a 50mL two-necked flask, replaced with argon, dissolved in 3.0mL dichloromethane and stirred at-15 ℃ for 5 min. Slowly adding 0.116mL boron trifluoride (1.2mmol, 3.0eq) dropwise, continuing stirring at-15 ℃ for 10min, cooling to-78 ℃ and reacting for 8 h. 3.0mL of a saturated ammonium chloride solution was added, and the mixture was allowed to warm to room temperature and stirred. Adding 10.0mL of ethyl acetate and 30.0mL of water, shaking uniformly, separating the organic phase, extracting the aqueous phase with ethyl acetate (10 mL. times.2), combining the organic phases, and washing with saturated NaCl solution (10 mL. times.2); dried over anhydrous Na2SO4, filtered, and the solvent evaporated under reduced pressure. Flash column chromatography separation and purification (30% EA/PE) to obtain 0.071g of yellow solid, yield: 86.2 percent.
1H NMR(400MHz,Acetone-d6)8.76(s,1H),8.42(d,J＝8.7Hz,1H),8.19(d,J＝8.7Hz,1H),8.12(d,J＝4.1Hz,1H),7.96(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.63–7.55(m,3H),6.97–6.89(m,2H).
HRMS(IT-TOF)：C19H12N2O4Se for[M+H]+,calculated 412.9962,found 412.9938.
EXAMPLE 47 preparation of XM _ A0172 compound
The preparation process of the compound XM _ A0172 is as follows:
0.137g of XM _ A0045(0.5mmol, 1.0eq), 0.178g of Fmoc-Gly-OH (0.6mmol, 1.2eq), 0.192g of EDC hydrochloride (1.0mmol, 2.0eq), 0.068g of 1-hydroxybenzotriazole (0.5mmol, 1.0eq) were weighed out in a 50mL eggplant-shaped bottle and dissolved in 3mL of dichloromethane. The reaction was carried out at room temperature for 3 h. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a white solid, 149mg (78.3%).
1H NMR(400MHz,DMSO-d6)8.44(d,J＝8.7Hz,1H),8.34(d,J＝5.5Hz,1H),8.21–8.14(m,2H),8.10(t,J＝6.1Hz,1H),7.91–7.86(m,3H),7.73(d,J＝7.5Hz,2H),7.61–7.51(m,2H),7.46(dd,J＝5.6,3.8Hz,1H),7.40(t,J＝7.4Hz,2H),7.31(td,J＝7.5,1.1Hz,2H),4.35(dd,J＝11.1,6.5Hz,4H),4.26(t,J＝6.9Hz,1H).
13C NMR(101MHz,DMSO)169.65,156.98,153.69,151.89,146.75,144.25,141.20,140.27,137.65,136.22,131.75,129.75,128.59,128.11,127.54,126.43,125.66,122.42,120.60,118.03,66.35,47.06,42.71,40.61,40.40,40.20,39.98,39.78,39.57,39.36.
HRMS(IT-TOF)：C30H22N2O4Se for[M+H]+,calculated 555.0745,found 555.0778.
EXAMPLE 48 preparation of XM _ A0174 Compound
The preparation process of compound XM _ a0174 is as follows:
0.289g of XM _ A0043(1.0mmol, 1.0eq), 0.013g of silver trifluoromethanesulfonate (0.05mmol, 0.05eq) and 0.433g of phenylsilane (4.0mmol, 4.0eq) were weighed out in a 50mL eggplant-shaped bottle, dissolved in 5mL of absolute ethanol and reacted at room temperature for 8 hours. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a yellow oil, 28mg (10.0%).
1H NMR(400MHz,Chloroform-d)7.91(dt,J＝5.1,1.6Hz,1H),7.21(p,J＝2.3,1.8Hz,2H),6.66(q,J＝2.7,1.6Hz,3H),4.73(dd,J＝9.1,3.0Hz,2H),3.83(d,J＝1.3Hz,4H),2.99–2.92(m,2H),2.84(t,J＝4.9Hz,1H),2.22(d,J＝4.4Hz,1H),2.11–2.03(m,2H).
13C NMR(101MHz,CDCl3)157.07,146.31,133.86,129.23,129.13,125.57,121.50,121.13,116.77,107.73,55.58,53.72,33.06,26.09.
HRMS(IT-TOF)：C14H15NOSe for[M+H]+,calculated 294.0392,found 294.0379.
EXAMPLE 49 preparation of XM _ A0175 Compound
The preparation process of the compound XM _ A0175 is as follows:
0.275g of XM _ A0045(1.0mmol, 1.0eq), 0.013g of silver trifluoromethanesulfonate (0.05mmol, 0.05eq) and 0.433g of phenylsilane (4.0mmol, 4.0eq) were weighed out in a 50mL eggplant-shaped bottle, dissolved in 5mL of absolute ethanol and reacted at room temperature for 8 hours. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a yellow oil, 25mg (8.9%).
1H NMR(400MHz,Chloroform-d)7.94–7.88(m,1H),7.21(d,J＝4.0Hz,2H),6.70–6.50(m,3H),4.60(s,2H),2.94(dd,J＝10.6,5.8Hz,1H),2.82(dd,J＝12.8,8.1Hz,1H),2.25(m,J＝13.9,4.9Hz,1H),2.05(s,1H),1.59(s,1H).
HRMS(IT-TOF)：C13H13NOSe for[M+H]+,calculated 280.0236,found 280.0233.
EXAMPLE 50 preparation of Compound XM _ A0176
0.367g of XM _ A0104(1.0mmol, 1.0eq), 0.013g of silver trifluoromethanesulfonate (0.05mmol, 0.05eq) and 0.433g of phenylsilane (4.0mmol, 4.0eq) were weighed out in a 50mL eggplant-shaped bottle, dissolved in 5mL of absolute ethanol, and reacted at room temperature for 8 hours. 10mL of water was added, extraction was performed with 20mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a yellow oil, 30mg (8.0%).
1H NMR(400MHz,Methanol-d4)7.42–7.38(m,2H),7.20(d,J＝3.8Hz,1H),7.11(dd,J＝3.8,0.7Hz,1H),6.85–6.77(m,2H),6.60(dd,J＝7.0,2.2Hz,1H),6.57–6.46(m,2H),4.65(dd,J＝8.5,2.8Hz,1H),2.91(m,J＝15.6,9.6,5.6Hz,1H),2.79(m,J＝16.5,5.3Hz,1H),2.25–2.17(m,1H),2.05(s,1H).
13C NMR(101MHz,MeOD)158.21,155.85,150.27,145.01,134.02,129.84,128.14,127.34,123.99,122.97,121.29,118.26,116.60,112.72,54.98,33.78,26.62.
EXAMPLE 51 preparation of XM _ A0181 Compound
0.138g of XM _ A0045(0.5mmol, 1.0eq), 0.056g of chloroacetamide (0.6mmol, 1.2eq), 0.173g of potassium carbonate (1.25mmol, 2.5eq) and 0.017g of potassium iodide (0.1mmol, 0.2eq) were weighed into a 50mL two-necked flask, argon was replaced, dissolved in 5mL of anhydrous DMF and placed in an oil bath at 90 ℃ for reaction for 1 h. The reaction was then continued for 5h with warming to 150 ℃ under an oil bath. After cooling to room temperature, 20mL of water was added, and the mixture was extracted with 10mL of ethyl acetate 3, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a tan solid, 50mg (30.1%).
1H NMR(500MHz,Chloroform-d)8.22(s,1H),8.13(t,J＝6.7Hz,2H),7.92–7.82(m,2H),7.52–7.39(m,3H),7.16(d,J＝7.4Hz,1H),5.81(s,1H),4.79(s,2H).
13C NMR(126MHz,CDCl3)171.89,153.97,153.16,152.15,140.59,136.97,134.21,131.21,128.68,128.03,126.48,121.86,117.52,114.03,77.42,77.16,76.91,70.46.
DEPT135：13C NMR(126MHz,CDCl3)136.97,134.21,131.21,128.03,126.48,121.86,117.52,114.03,77.36,70.46.
EXAMPLE 52 preparation of Compound XM _ A0182
0.138g of XM _ A0045(0.5mmol, 1.0eq), 0.056g of chloroacetamide (0.6mmol, 1.2eq), 0.173g of potassium carbonate (1.25mmol, 2.5eq) and 0.017g of potassium iodide (0.1mmol, 0.2eq) were weighed into a 50mL two-necked flask, argon was replaced, dissolved in 5mL of anhydrous DMF and placed in an oil bath at 90 ℃ for reaction for 1 h. The reaction was then continued for 5h with warming to 150 ℃ under an oil bath. After cooling to room temperature, 20mL of water was added, and the mixture was extracted with 10mL of ethyl acetate 3, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Flash column chromatography gave a tan solid, 28mg (16.9%).
1H NMR(500MHz,Chloroform-d)8.06(d,J＝5.3Hz,1H),8.00(d,J＝8.6Hz,1H),7.81(s,1H),7.73(d,J＝8.5Hz,1H),7.38(s,1H),7.26(t,J＝8.2Hz,1H),7.09(d,J＝8.0Hz,1H),6.89(d,J＝7.4Hz,1H),4.96(s,2H).
13C NMR(126MHz,CDCl3)152.76,150.94,143.72,137.93,136.66,133.30,130.90,127.84,127.15,127.01,116.81,115.98,110.71.
The structures of the compounds prepared in examples 1 to 52 above are shown in table 1.
Structure of the Compounds of Table 1
Example 47 Activity assay
Experimental methods
(1) Cells in logarithmic growth phase were grown at 5x103The seed/well was seeded on a 96-well plate and placed in an incubator (37 ℃ C., 5% CO)2) Culturing;
(2) the cells were aspirated 24h into the incubator. The experiment was divided into a blank control group and a drug treatment group. Replacing blank group culture medium with full culture. The drug groups were treated with the experimental design drug concentrations;
(3) the treated cells were placed in an incubator for 48h and removed, and 10. mu.L of CCK8 was added to each well. Placing in an incubator for about 2h, and taking out in a multifunctional microplate reader to measure the absorbance value (wavelength of 450 nm). Calculating the survival condition of the cells according to the absorbance value, and arranging 3 multiple holes for each group;
(4) mapping analysis was performed using GraphPad prism7 software.
The types of cancer cells tested are shown in table 2:
TABLE 2 cancer cell types tested
| Species of cancer cell is abbreviated | Cancer cell type full scale | Culture medium |
| A549 | Human non-small cell cancer cells | High-glucose DMEM + 10% FBS |
| HCT116 | Human colon cancer cells | High-glucose DMEM + 10% FBS |
| HeLa | Human cervical cancer cell | High-glucose DMEM + 10% FBS |
| Kyse150 | Human esophageal squamous carcinoma cell | High-glucose DMEM + 10% FBS |
| HL-60 | Human promyelocytic leukemia cells | High sugar 1640+ 10% FBS |
| SGC-7901 | Human gastric cancer cell | High-glucose DMEM + 10% FBS |
| MCF-7 | Human breast cancer cell | High-glucose DMEM + 10% FBS |
| HuH-7 | Human liver cancer cell | High-glucose DMEM + 10% FBS |
| K562 | Human chronic myelogenous leukemia cell | High sugar 1640+ 10% FBS |
| MRC-5 | Human embryonic lung fibroblasts | High sugar MEM + 10% FBS |
The IC of each compound was determined for the above 5 cancer cells using cisplatin (DDP) as a positive control50The values are shown in tables 3 and 4:
activity of the Compounds of Table 3
Note: in Table 3, "na" is "not available" and indicates that no test was performed. "+ + + + +" in the table indicates IC50Below 5 μ M; "+ + + +" denotes IC505-10 mu M; "+ +" denotes IC50At 10-20 μ M; "+" denotes IC50At > 20. mu.M.
TABLE 4 Activity of Compounds 106-108
Note: in Table 4, "na" is "not available", indicating that no test was performed. "+ + + + +" in the table indicates IC50Below 5 μ M; "+ + + +" denotes IC505-10 mu M; "+ +" denotes IC50At 10-20 μ M; "+" denotes IC50At > 20. mu.M.
From the above table, it is clear that the compound of the present invention shows a good inhibitory effect on cancer cells in 5 above, and especially compounds 34, 44, 45, 98, 104, 115 and 116 show excellent inhibitory effects on various cancer cells, and the effect is equivalent to that of the positive control DDP, and the compound is below 5 μ M, and can be prepared into an anticancer drug for application, thus having a broad prospect.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A selenophene quinoline derivative is characterized in that the structure is shown as formula I, formula II or formula III:
wherein, R is1Is hydrogen, C1～6Alkyl radical, C1～6Alkoxy, substituted keto, phenyl, benzyl, substituted phenyl or substituted benzyl, wherein the substituents in the substituted keto, substituted phenyl and substituted benzyl are each independently halogen, hydroxy, C1～6Alkyl or C1～6An alkoxy group;
the R is1 +Is a monovalent metal cation;
the R is2Is hydrogen, halogen, C1～4Alkyl radical, C1～4Alkoxy or C1～4One or more of haloalkyl;
the R is3Is a substituted five-membered heterocycle or a substituted six-membered heterocycle; wherein the heteroatom in the substituted five-membered heterocycle and the substituted six-membered heterocycle is one or more of N, O, S or Se, and the substituents are respectively and independently hydrogen, hydroxyl, halogen, C1～6Alkyl radical, C1～6Alkoxy radical, C1～6Halogenated alkyl, benzene ring, phenol, C1～6Alkyl-substituted phenyl, C1～6Alkoxy-substituted phenyl or C1～6Haloalkyl substituted phenyl.
2. The selenophenequinoline derivative of claim 1, wherein said R is3Is a substituted five-membered single heterocyclic ring, a substituted five-membered double heterocyclic ring, a substituted six-membered single heterocyclic ring or a substituted six-membered heterocyclic ring; wherein the heterocyclic ring is an aromatic ring containing one or more of N, O, S or Se; the substituents in the heterocycle are each independently hydrogen, hydroxy, halogen, C1～4Alkyl radical, C1～4Alkoxy radical, C1～4Halogenated alkyl, benzene ring, phenol, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl or C1～4Haloalkyl substituted phenyl.
3. The selenophenequinoline derivative of claim 2, wherein said R is3Substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine, substituted benzimidazole or substituted selenol;wherein the substituent of the substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine, substituted imidazole or substituted selenol is hydrogen, hydroxyl, halogen or C1～4Alkyl radical, C1～4Alkoxy radical, C1～4Halogenated alkyl, benzene ring, phenol, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl or C1～4Haloalkyl substituted phenyl.
4. The selenophenequinoline derivative of claim 3, wherein when R is3When the substituted thiophene, substituted furan, substituted pyrrole, substituted pyridine or substituted benzimidazole is adopted, the substituent in the substituted thiophene, substituted furan, substituted pyrrole or substituted pyridine is hydrogen, methyl, ethyl, halogenated methyl or halogenated ethyl;
when R is3When the substituted selenol is substituted selenol, the substituent in the substituted selenol is hydrogen, halogen, methyl, ethyl, propylmethoxy, ethoxy, trifluoromethyl, trifluoroethyl, phenyl, 2-phenol, 3-phenol, 4-phenol, benzenediol, benzenetriol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, dimethoxyphenyl or trimethoxyphenyl.
5. The selenophenequinoline derivative of claim 1, wherein said R is1Is hydrogen, C1～4Alkyl radical, C1～4Alkoxy, substituted keto, phenyl, benzyl, substituted phenyl or substituted benzyl, wherein the substituents in the substituted keto, substituted phenyl and substituted benzyl are each independently halogen, hydroxy, C1～4Alkyl or C1～4An alkoxy group;
the R is1 +Is sodium ion or potassium ion;
the R is2Is one or more of hydrogen, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl.
6. A selenophenquinoline derivative according to claim 5, wherein said R is1Is hydrogen, methyl, ethyl ketone, benzeneA benzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group or a 4-methoxybenzyl group.
7. A process for the preparation of a compound according to any one of claims 1 to 6, wherein when the compound has the formula I or III, R is substituted3Organotin reagents of the group R3-SnBu3、R3-Sn(n-Bu)3With 2-halogenated quinolines
Stille coupling is carried out to obtain a target compound, wherein R1、R2And R3As set forth in claim 1, X is halogen.
8. The preparation method of the compound as shown in claim 7, wherein when the structure of the compound is shown as formula II, the compound of formula I or formula III is used as a raw material, and the raw material and inorganic base or inorganic acid are subjected to salt forming reaction to obtain the target product.
9. Use of a selenophenoquinoline derivative according to any one of claims 1 to 6 for the preparation of an anticancer drug.
10. The use of claim 9, wherein the anti-cancer drug is a drug against cervical cancer, colon cancer, non-small cell lung cancer, enterophagous squamous carcinoma, gastric adenocarcinoma, breast cancer, liver cancer or chronic myeloid leukemia.
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Application publication date: 20201211 |