CN111116590A - Indole compound and application and preparation method thereof - Google Patents
Indole compound and application and preparation method thereof Download PDFInfo
- Publication number
- CN111116590A CN111116590A CN201911268284.1A CN201911268284A CN111116590A CN 111116590 A CN111116590 A CN 111116590A CN 201911268284 A CN201911268284 A CN 201911268284A CN 111116590 A CN111116590 A CN 111116590A
- Authority
- CN
- China
- Prior art keywords
- substituted
- alkyl
- compound
- hydrogen
- indole compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Indole compound Chemical class 0.000 title claims abstract description 41
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 36
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 36
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 150000002475 indoles Chemical class 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 20
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000005620 boronic acid group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- GAEKPEKOJKCEMS-UHFFFAOYSA-N gamma-valerolactone Chemical compound CC1CCC(=O)O1 GAEKPEKOJKCEMS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052723 transition metal Inorganic materials 0.000 claims description 4
- 150000003624 transition metals Chemical class 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 230000002491 angiogenic effect Effects 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 210000002919 epithelial cell Anatomy 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 54
- 210000002889 endothelial cell Anatomy 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 208000034038 Pathologic Neovascularization Diseases 0.000 abstract description 3
- 210000003606 umbilical vein Anatomy 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 129
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 128
- 238000003756 stirring Methods 0.000 description 61
- 229910052757 nitrogen Inorganic materials 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000007787 solid Substances 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 47
- 239000000047 product Substances 0.000 description 42
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 33
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000012512 characterization method Methods 0.000 description 32
- 238000004896 high resolution mass spectrometry Methods 0.000 description 32
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 23
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 16
- 238000002955 isolation Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 239000002480 mineral oil Substances 0.000 description 15
- 235000010446 mineral oil Nutrition 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 238000012216 screening Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000000746 purification Methods 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- ZXCUOCHXNYWBBG-ZQWQDMLBSA-N (1s,2s,3s,4s)-3,4-bis[2-methylpropyl-[(4-phenoxyphenyl)methyl]carbamoyl]cyclobutane-1,2-dicarboxylic acid Chemical compound O=C([C@H]1[C@@H]([C@@H]([C@H]1C(O)=O)C(O)=O)C(=O)N(CC(C)C)CC=1C=CC(OC=2C=CC=CC=2)=CC=1)N(CC(C)C)CC(C=C1)=CC=C1OC1=CC=CC=C1 ZXCUOCHXNYWBBG-ZQWQDMLBSA-N 0.000 description 1
- GNPHAOQLHRZODS-ZQWQDMLBSA-N (1s,2s,3s,4s)-3,4-bis[butyl-[(4-phenoxyphenyl)methyl]carbamoyl]cyclobutane-1,2-dicarboxylic acid Chemical compound O=C([C@H]1[C@@H]([C@@H]([C@H]1C(O)=O)C(O)=O)C(=O)N(CCCC)CC=1C=CC(OC=2C=CC=CC=2)=CC=1)N(CCCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 GNPHAOQLHRZODS-ZQWQDMLBSA-N 0.000 description 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- AHZCYZMNFBGXAC-UHFFFAOYSA-N 1-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-7-(2-piperazin-1-ylpyridin-4-yl)-3,4-dihydro-2h-pyrido[2,3-b]pyrazine Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1CN1C2=CC(C=3C=C(N=CC=3)N3CCNCC3)=CN=C2NCC1 AHZCYZMNFBGXAC-UHFFFAOYSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- ORQHHLPTMSGMQT-UHFFFAOYSA-N 2-[4-(5-fluoropyridin-2-yl)piperazin-1-yl]-n-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)acetamide Chemical compound N1=CC(F)=CC=C1N1CCN(CC(=O)NC=2SC=3CCCCC=3N=2)CC1 ORQHHLPTMSGMQT-UHFFFAOYSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- UFMQJYHLIUACCG-UHFFFAOYSA-N 8-nitroindolo[2,1-b]quinazoline-6,12-dione Chemical compound C1=CC=C2C(=O)N3C4=CC=C([N+](=O)[O-])C=C4C(=O)C3=NC2=C1 UFMQJYHLIUACCG-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XJTWGMHOQKGBDO-GOSISDBHSA-N N-[(3-Fluorophenyl)methyl]-1-[(1r)-1-Naphthalen-1-Ylethyl]piperidine-4-Carboxamide Chemical compound C1CN([C@H](C)C=2C3=CC=CC=C3C=CC=2)CCC1C(=O)NCC1=CC=CC(F)=C1 XJTWGMHOQKGBDO-GOSISDBHSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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Abstract
The invention relates to indole compounds and application and a preparation method thereof. The structural formula of the indole compound is shown as a formula (I). Novel compounds of the inventionThe indole compounds have inhibiting effect on the tube cavity formation of umbilical vein endothelial cells (HUVEC), can be suitable for treating pathological angiogenesis related diseases, and is especially suitable for preventing and treating tumor and rheumatoid arthritis, and has great application value.
Description
Technical Field
The invention relates to the field of medicines, in particular to an indole compound and an application and preparation method thereof.
Background
Malignant tumor is one of diseases which pose great threats to human health, and the morbidity and mortality of the malignant tumor in China have been known to be on the rise in recent years according to relevant data counted by the Chinese tumor management center. According to the global cancer statistical data report of the American cancer society official journal of clinicians, 2018, the most new and dead cancers are lung cancer, breast cancer, prostatic cancer, colon cancer, skin non-melanoma, stomach cancer, liver cancer, rectal cancer and the like in sequence. In clinic, the treatment of tumor is still mainly drug therapy. However, the current clinically applied antitumor drugs far fail to meet the requirements of treatment, and drugs for effectively treating tumors are still lacking. Therefore, the further development of novel antitumor drugs is of great significance.
Disclosure of Invention
Based on the above, one of the objects of the present invention is to provide a novel indole compound and its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule, which has a good effect of preventing and treating tumors.
The specific technical scheme is as follows:
an indole compound and pharmaceutically acceptable salts thereof or stereoisomers or prodrug molecules thereof, wherein the structural formula of the indole compound is shown as a formula (I),
wherein the content of the first and second substances,
x is selected from-C (R)1) -or-N-;
n is a positive integer from 0 to 3;
R1each independently selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8SubstitutionC1-C10 alkoxy, R8Substituted C6-C20 aryl, R8A substituted C6-C20 aryloxy, boronic acid group, or C2-C10 boronic acid ester group;
R2selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8Substituted C1-C10 alkoxy, R8Substituted C6-C20 aryl or R8Substituted C6-C20 aryloxy;
R3is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C10 cycloalkyl, R8Substituted C1-C10 alkoxy or R8Substituted C6-C20 aryl;
R4selected from hydrogen or
R5Selected from C1-C10 alkoxycarbonyl, C1-C10 alkylaminocarbonyl or C1-C10 alkylcarbonyl;
R6is selected from R8Substituted C6-C20 aryl;
R7is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C20 cycloalkyl or R8Substituted C6-C20 aryl;
R8each independently selected from hydrogen, halogen, C1-C10 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, morpholine, piperazine, imidazole, piperidine or C1-C10 alkyl substituted amine.
The invention also aims to provide application of the indole compound and the pharmaceutically acceptable salt thereof or the stereoisomer thereof or prodrug molecule thereof in preparing medicines for preventing and treating angiogenesis diseases.
The invention also aims to provide a pharmaceutical composition, the active ingredients of which comprise the indole compound and the pharmaceutically acceptable salts thereof or the stereoisomers thereof or the prodrug molecules thereof, and a pharmaceutically acceptable carrier.
The invention also aims to provide a preparation method of the indole compound,
(1) when said R is4When hydrogen is used, the method comprises the following steps: starting materials 1 and 2 in the presence of hydrogenUnder the action of sodium chloride, the compound of formula (I) is generated
(2) When R is4Is composed of
The method comprises the following steps: the raw materials 1 and 2 generate an intermediate 3 under the action of sodium hydride, and the intermediate 3 and
reacting to produce the compound of formula (I)
Wherein, X, n, R1、R2、R3、R5、R6、R7、R8The meaning of (A) is as defined above.
Compared with the prior art, the invention has the following beneficial effects:
the novel indole compound has an inhibiting effect on the tube cavity formation of umbilical vein endothelial cells (HUVEC), and the tube cavity formation of the endothelial cells is an important step of angiogenesis, so the indole compound is suitable for treating pathological angiogenesis-related diseases, and is particularly suitable for preventing and treating tumors and rheumatoid arthritis. The novel indole compound (especially the compounds 5f, 5k and 5m) has good inhibition effect on the growth of lung cancer cells and breast cancer cells, shows obvious anticancer effect and has great application value.
Drawings
FIG. 1 is a graph showing the inhibitory effect of N-purine indoles on HUVEC luminal formation; a is a representative picture, and B is a statistical result; experimental data are expressed as mean ± SEM, n ═ 3; relative to the Vehicle treatment group, P ≦ 0.05, P ≦ 0.001.
Detailed Description
In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the compounds of the invention, when any variable (e.g. R)1、R8Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted.
The term "substituted" as used herein means that one or more substitutable hydrogen atoms in a given structure are substituted with a particular substituent, a substituted group may have one substituent at each substitutable position of the group, and when more than one position in a given formula can be substituted with one or more substituents of a particular group, then the substituents may be substituted at each position, either identically or differently.
The embodiment provides an indole compound and pharmaceutically acceptable salts thereof or stereoisomers or prodrug molecules thereof, wherein the structural formula of the indole compound is shown as a formula (I),
wherein the content of the first and second substances,
x is selected from-C (R)1) -or-N-;
n is a positive integer from 0 to 3;
R1each independently selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8Substituted C1-C10 alkoxy, R8Substituted C6-C20 aryl, R8A substituted C6-C20 aryloxy, boronic acid group, or C2-C10 boronic acid ester group;
R2selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8Substituted C1-C10 alkoxy, R8Substituted C6-C20 aryl or R8Substituted C6-C20 aryloxy;
R3is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C10 cycloalkyl, R8Substituted C1-C10 alkoxy or R8Substituted C6-C20 aryl;
R4selected from hydrogen or
R5Selected from C1-C10 alkoxycarbonyl, C1-C10 alkylaminocarbonyl or C1-C10 alkylcarbonyl;
R6is selected from R8Substituted C6-C20 aryl;
R7is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C20 cycloalkyl or R8Substituted C6-C20 aryl;
R8each independently selected from hydrogen, halogen, C1-C10 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, morpholine, piperazine, imidazole, piperidine or C1-C10 alkyl substituted amine.
The term "Cx-Cy" denotes a compound containing x to y carbon atoms;
the term "alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. "C1-C10 alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon group having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and may include, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl … ….
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, cyclopentyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
The term "halogen" is meant to include chlorine, fluorine, bromine or iodine.
The term "alkoxycarbonyl" refers to a group consisting of an alkyl group having a specific number of carbon atoms and a carbonyloxy group (-O-C (═ O) -), such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and the like.
"aryl" refers to a group having an aromatic character with a specified number of carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, and the like.
The term "alkoxy" refers to a group consisting of alkyl and oxygen atoms having the specified number of carbon atoms, and includes methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy and the like. Phenyl-substituted methoxy groups include benzyloxy.
In some of these embodiments, each R1Each independently selected from hydrogen, halogen, R8Substituted C1-C6 alkyl, R8A substituted C1-C6 alkoxy group, a boronic acid group or a C2-C6 boronic acid ester group.
In some of these embodiments, each R1Each independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, phenyl-substituted C1-C6 alkoxy or
In some of these embodiments, each R1Each independently selected from hydrogen, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, phenyl-substituted C1-C3 alkoxy or
Specifically, each R1Each independently selected from hydrogen, chlorine, fluorine, bromine, iodine, methyl and ethylAlkyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, benzyloxy or
In some of these embodiments, n is 0, 1,2, or 3.
In some of these embodiments, R2Selected from hydrogen or R8Substituted C1-C6 alkyl.
In some of these embodiments, R2Selected from hydrogen or C1-C6 alkyl.
Specifically, R2Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl or n-propyl.
In some of these embodiments, R3Is selected from R8Substituted C1-C6 alkyl or R8Substituted C1-C6 alkoxy.
In some of these embodiments, R3Selected from C1-C6 alkyl or phenyl substituted C1-C6 alkyl.
Specifically, R3Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl or benzyl.
In some of these embodiments, R5Selected from C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl or C1-C6 alkylcarbonyl.
Specifically, R5Selected from methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl or n-butoxycarbonyl.
In some of these embodiments, R6Selected from C6-C10 aryl.
Specifically, R6Selected from phenyl and naphthyl.
In some of these embodiments, R7Is selected from R8Substituted C1-C6 alkyl, R8Substituted C3-C8 cycloalkyl or R8Substituted C6-C10 aryl.
In some of these embodiments, R7Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl or phenyl substituted by C1-C6 alkyl.
Specifically, R7Is selected from methylEthyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl or tolyl.
In some of these embodiments, each R8Each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, morpholine, piperazine, imidazole, piperidine, or C1-C6 alkyl substituted amine.
In some of these embodiments, each R8Each independently selected from hydrogen, iodine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, morpholine, piperazine, imidazole, or piperidine.
In some of these embodiments, R1Each independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, benzyloxy or
R2Selected from hydrogen or C1-C6 alkyl;
R3selected from C1-C6 alkyl or benzyl;
R5selected from C1-C6 alkoxycarbonyl;
R6is selected from phenyl;
R7is selected from C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkyl substituted phenyl.
The embodiment also provides application of the indole compound and pharmaceutically acceptable salts thereof or stereoisomers or prodrug molecules thereof in preparing medicines for preventing and treating angiogenesis diseases.
In some of these embodiments, the angiogenic disease is a tumor or rheumatoid arthritis.
In some of these embodiments, the tumor is one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, colon cancer, liver cancer, leukemia, small cell lung cancer, skin cancer, epithelial cell cancer, prostate cancer, non-small cell lung cancer, nasopharyngeal carcinoma, glioblastoma, lymphoma, or melanoma.
In some of these embodiments, the tumor is one or more of lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, and breast cancer.
The embodiment also provides a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises the indole compound and the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof, and a pharmaceutically acceptable carrier.
In some of these embodiments, the pharmaceutical composition is an injection, tablet, pill, capsule, suspension, or emulsion.
The embodiment also provides a preparation method of the indole compound,
(1) when said R is4When hydrogen is used, the method comprises the following steps: under the action of sodium hydride, the raw materials 1 and 2 generate the compound of the formula (I)
(2) When R is4Is composed of
The method comprises the following steps: the raw materials 1 and 2 generate an intermediate 3 under the action of sodium hydride, and the intermediate 3 and
reacting to produce the compound of formula (I)
Wherein, X, n, R1、R2、R3、R5、R6、R7、R8The meaning of (A) is as defined above.
In some of these embodiments, when R is4Is composed of
The method comprises the following steps: the raw materials 1 and 2 generate an intermediate 3 under the action of sodium hydride3 in the presence of a transition metal catalyst, an additive and a solvent
Reacting to generate a compound shown in a formula (I), wherein the solvent is toluene, 1,4-dioxane, 1, 2-dichloroethane, water, tetrahydrofuran, N-dimethylformamide or gamma-valerolactone; and/or, the transition metal catalyst is a manganese catalyst or a rhenium catalyst; and/or the additive is acetate; and/or the reaction temperature is 40-80 ℃; and/or the reaction time is 8-16h, preferably 12-16 h.
In some of these embodiments, the metal catalyst is MnBr (CO)5And the acetate is NaOAc.
The present invention will be described in further detail with reference to specific examples.
The general reaction route is as follows:
EXAMPLE 1 Synthesis of Compound 3a
A100 mL reaction flask was evacuated, purged with nitrogen and repeated three times, followed by addition of 2a (421mg, 3.6mmol) to the flask, followed by DMF (30mL), stirring at 0 deg.C and slow addition of NaH (60% in mineral oil, 180mg, 4.5mmol) in portions to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration and spin-drying of the filtrate (solvent was evaporated under reduced pressure) gave product 3a (749mg, 90%) as a yellow solid, which was isolated by silica gel column chromatography (petroleum ether/ethyl acetate: 5/1). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.18(d,J＝3.7Hz,1H),9.06(d,J＝8.3Hz,1H),8.83(s,1H),8.07(s,1H),7.64(d,J＝7.7Hz,1H),7.41–7.33(m,1H),7.30–7.24(m,1H),6.80(d,J＝3.7Hz,1H),5.01–4.91(m,1H),1.66(d,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ＝152.4,151.8,150.0,140.2,136.2,130.8,128.7,124.0,122.9,120.9,117.3,108.5,47.5,22.7.HR-MS(ESI)m/z calcd for C16H16N5[M+H]+278.1400,found 278.1394.
EXAMPLE 2 Synthesis of Compound 3b
2a (421mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C, and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1b (497mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.4), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column chromatography gave product 3b as a yellow solid (523mg, 70%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.11(d,J＝2.9Hz,1H),9.03(d,J＝8.3Hz,1H),8.79(s,1H),7.86(s,1H),7.62(d,J＝7.6Hz,1H),7.36(t,J＝7.7Hz,1H),7.29–7.24(m,1H),6.77(d,J＝3.6Hz,1H),3.79(s,3H)。13C NMR(100MHz,CDCl3)δ＝152.9,152.1,149.8,143.0,136.1,130.8,128.6,124.0,122.9,122.2,120.8,117.4,108.5,30.0。HR-MS(ESI)m/z calcd for C14H12N5[M+H]+250.1087,found 250.1081。
EXAMPLE 3 Synthesis of Compound 3c
2a (421mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen as described in example 1, thenThereafter DMF (30mL) was added, stirring was carried out at 0 ℃ and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution. After stirring at 0 ℃ for 30 min, 1c (732mg, 3mmol) was added and the reaction stirred at room temperature for 20 h to give product 3c as a white solid (580mg, 60%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.17(d,J＝3.7Hz,1H),9.09(d,J＝8.5Hz,1H),8.86(s,1H),7.94(s,1H),7.65(d,J＝7.7Hz,1H),7.40–7.29(m,7H),6.80(d,J＝3.6Hz,1H)。13CNMR(100MHz,CDCl3)δ＝152.8,152.3,150.0,142.3,136.2,135.3,130.8,129.2,128.7,128.6,127.9,124.0,123.0,122.3,120.9,117.4,108.6,47.4。HR-MS(ESI)m/z calcd forC20H16N5[M+H]+326.1400,found 326.1394.
example 4: synthesis of Compound 3d
2b (472mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C, and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and separation by silica gel column chromatography gave the product 3d as a white solid (566mg, 65%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.05(d,J＝8.3Hz,1H),8.95(d,J＝1.2Hz,1H),8.80(s,1H),8.07(s,1H),7.58(d,J＝7.7Hz,1H),7.40–7.36(m,1H),7.32–7.28(m,1H),4.96(hept,J＝6.8Hz,1H),2.41(d,J＝1.3Hz,3H),1.66(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝152.2,151.8,149.9,139.8,136.5,131.7,125.3,124.0,122.6,118.8,117.8,117.4,47.4,22.7,10.0。HR-MS(ESI)m/z calcd for C17H18N5[M+H]+292.1557,found 292.1548。
example 5: synthesis of Compound 3e
2c (486mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C, and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and separation by silica gel column chromatography gave product 3e as a white solid (800mg, 91%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.16(d,J＝3.8Hz,1H),8.84–8.81(m,2H),8.10(s,1H),7.31–7.25(m,1H),6.98–6.92(m,1H),6.89(dd,J＝3.7,0.6Hz,1H),4.97(hept,J＝6.8Hz,1H),1.67(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝155.9(d,1JC-F＝247.7Hz),152.5,151.7,149.7,140.5,138.3(d,3JC-F＝10.5Hz),128.7,124.5(d,3JC-F＝6.3Hz),123.0,119.5(d,2JC-F＝22.0Hz),113.4(d,4JC-F＝3.3Hz),108.0(d,2JC-F＝16.4Hz),103.8,47.6,22.7。HR-MS(ESI)m/z calcd for C16H15FN5[M+H]+296.1306,found 296.1298。
example 6: synthesis of Compound 3f
According to the method described in example 1, 2d (529mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirring at 0 ℃ and NaH was added slowly in portions (distributed in mineral oil)With a content of 60%, 180mg, 4.5mmol) into the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and isolation by silica gel column chromatography gave product 3f as a white solid (335mg, 56%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.17(d,J＝3.6Hz,1H),8.96(d,J＝9.1Hz,1H),8.80(s,1H),8.07(s,1H),7.10(d,J＝2.5Hz,1H),6.99(dd,J＝9.1,2.6Hz,1H),6.73(d,J＝3.6Hz,1H),4.96(p,J＝6.8Hz,1H),3.89(s,3H),1.66(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝156.1,152.3,151.8,149.8,140.0,131.7,131.1,129.3,122.7,118.2,112.7,108.4,103.3,55.8,47.4,22.8。HR-MS(ESI)m/z calcd forC17H18N5O[M+H]+308.1506,found 308.1501。
example 7: synthesis of Compound 3g
2e (705mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C, and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column chromatography gave 3g (829mg, 78%) of the product as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.17(d,J＝3.6Hz,1H),8.91(d,J＝8.9Hz,1H),8.79(s,1H),8.07(s,1H),7.72(d,J＝1.7Hz,1H),7.41(dd,J＝8.9,1.8Hz,1H),6.70(d,J＝3.6Hz,1H),4.95(hept,J＝6.8Hz,1H),1.66(d,J＝6.8Hz,6H)。13CNMR(100MHz,CDCl3)δ＝152.5,151.7,149.5,140.4,134.8,132.4,129.8,126.6,123.3,122.8,118.7,116.1,107.6,47.6,22.7。HR-MS(ESI)m/z calcd for C16H15BrN5[M+H]+356.0505,found 356.0499。
example 8: synthesis of Compound 3h
2e (803mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C, and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column chromatography gave the product as a white solid for 3h (466mg, 41%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.18(d,J＝3.6Hz,1H),8.98(d,J＝9.1Hz,1H),8.81(s,1H),8.07(s,1H),7.50(d,J＝7.4Hz,2H),7.42–7.38(m,2H),7.35–7.31(m,1H),7.19(d,J＝2.4Hz,1H),7.08(dd,J＝9.1,2.4Hz,1H),6.73(d,J＝3.6Hz,1H),5.16(s,2H),4.97(hept,J＝6.9Hz,1H),1.67(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝155.3,152.3,151.8,149.8,140.0,137.6,131.6,131.2,129.3,128.7,128.0,127.7,122.7,118.2,113.5,108.5,104.8,70.7,47.4,22.7。HR-MS(ESI)m/z calcdfor C23H22N5O[M+H]+384.1819,found 384.1810。
example 9: synthesis of Compound 3i
According to the method described in example 1, 2f (472mg, 3.6mmol) was added to a 100mL reaction flask under nitrogen, followed by DMF (30mL), stirred at 0 deg.C and NaH (60% content in mineral oil distributed) was added slowly in portions180mg, 4.5mmol) to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and isolation by silica gel column chromatography gave product 3i as a white solid (610mg, 70%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.16(d,J＝3.6Hz,1H),8.93(d,J＝8.5Hz,1H),8.82(s,1H),8.08(s,1H),7.43(s,1H),7.19(d,J＝8.4Hz,1H),6.73(d,J＝3.6Hz,1H),4.97(hept,6.8Hz,1H),2.48(s,3H),1.66(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝152.3,151.9,150.0,140.0,134.5,132.4,131.0,128.7,125.4,122.8,120.8,117.0,108.3,47.4,22.7,21.5。HR-MS(ESI)m/z calcd for C17H18N5[M+H]+292.1557,found 292.1547。
example 10: synthesis of Compound 3j
2g (875mg, 3.6mmol) of DMF (30mL) was added to a 100mL reaction flask under nitrogen, stirred at 0 deg.C and NaH (60% in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and isolation by silica gel column chromatography gave product 3j (616mg, 51%) as a white solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.15(d,J＝3.7Hz,1H),8.84–8.80(m,2H),8.09(s,1H),7.95(d,J＝1.6Hz,1H),7.60(dd,J＝8.8,1.7Hz,1H),6.70(d,J＝3.6Hz,1H),4.97(hept,J＝6.8Hz,1H),1.67(d,J＝6.8Hz,6H)。13C NMR(100MHz,CDCl3)δ＝152.5,151.7,149.6,140.5,135.4,133.1,132.3,129.6,129.5,123.0,119.2,107.4,87.0,47.6,22.7。HR-MS(ESI)m/z calcd for C16H15IN5[M+H]+404.0367,found404.0360。
example 11: synthesis of Compound 3k
To a 100mL reaction flask, under nitrogen, was added 2h (486mg, 3.6mmol) followed by DMF (30mL) as described in example 1, stirred at 0 deg.C and NaH (60% in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and isolation on silica gel column chromatography gave the product 3k as a white solid (469mg, 53%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.23(d,J＝3.6Hz,1H),9.01(dd,J＝9.1,4.9Hz,1H),8.80(s,1H),8.08(s,1H),7.28–7.25(m,1H),7.09–7.05(m,1H),6.74(d,J＝3.6Hz,1H),4.97(hept,J＝6.8Hz,1H),1.67(d,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ＝159.4(d,1JC-F＝238.6Hz),152.4,151.7,149.6,140.3,132.6,131.6(d,3JC-F＝10.7Hz),130.3,122.8,118.3(d,3JC-F＝9.4Hz),111.6(d,2JC-F＝24.9Hz),108.2(d,4JC-F＝3.9Hz),106.1(d,2JC-F＝23.3Hz),47.5,22.7.HR-MS(ESI)m/z calcd for C16H15FN5[M+H]+296.1306,found 296.1299.
example 12: synthesis of Compound 3l
2i (666mg, 3.6mmol) and then DMF (30 m) were added to a 100mL reaction flask under nitrogen as described in example 1L), stirring at 0 ℃ and slowly adding NaH (60% content in mineral oil, 180mg, 4.5mmol) in portions to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column chromatography gave 3l (354mg, 34%) of the product as a white solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.27(d,J＝3.7Hz,1H),9.15(d,J＝8.8Hz,1H),8.85(s,1H),8.12(s,1H),7.91(s,1H),7.59(dd,J＝8.8,1.4Hz,1H),6.85(d,J＝3.7Hz,1H),4.99(hept,J＝6.8Hz,1H),1.68(d,J＝6.8Hz,6H)。13CNMR(100MHz,CDCl3)δ＝152.7,151.7,149.5,140.7,137.6,130.4,125.0(q,2JC-F＝31.0Hz),125.0(q,1JC-F＝272.5Hz),123.0(q,3JC-F＝3.0Hz),120.6(q,3JC-F＝3.9Hz),118.3,117.5,108.4,47.7,22.7。HR-MS(ESI)m/z calcd for C17H15F3N5[M+H]+346.1274,found346.1268。
example 13: synthesis of Compound 3m
To a 100mL reaction flask was added 2j (874mg, 3.6mmol) under nitrogen followed by DMF (30mL) as described in example 1, stirred at 0 deg.C and NaH (60% in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column chromatography gave the product as a white solid, 3m (813mg, 68%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.17(d,J＝3.7Hz,1H),9.03(d,J＝8.5Hz,1H),8.84(s,1H),8.15(s,1H),8.07(s,1H),7.81(dd,J＝8.4,1.0Hz,1H),6.80(d,J＝3.6Hz,1H),4.95(hept,J＝6.8Hz,1H),1.65(d,J＝6.8Hz,6H),1.38(s,12H)。13C NMR(100MHz,CDCl3)δ＝152.4,151.8,149.9,140.3,138.2,130.4,130.2,128.7,128.3,123.0,116.6,108.7,83.7,47.5,25.0,22.7。HR-MS(ESI)m/z calcd forC22H27BN5O2[M+H]+404.2252,found 404.2249。
example 14: synthesis of Compound 3n
To a 100mL reaction flask, 2k (706mg, 3.6mmol) followed by DMF (30mL) was added under nitrogen, stirred at 0 deg.C, and NaH (60% in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution as described in example 1. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column chromatography gave the product 3n as a white solid (382mg, 36%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.29(d,J＝1.6Hz,1H),9.17(d,J＝3.7Hz,1H),8.83(s,1H),8.09(s,1H),7.48(d,J＝8.3Hz,1H),7.38(dd,J＝8.3,1.8Hz,1H),6.75(d,J＝3.6Hz,1H),4.97(hept,J＝6.8Hz,1H),1.67(d,J＝6.8Hz,6H)。13CNMR(100MHz,CDCl3)δ＝152.5,151.8,149.5,140.5,136.7,129.6,129.3,126.0,122.8,121.8,120.3,117.5,108.2,47.6,22.7。HR-MS(ESI)m/z calcd for C16H15BrN5[M+H]+356.0505,found 356.0498。
example 15: synthesis of Compound 3o
100mL of the reaction mixture was heated under nitrogen in the same manner as in example 12l (425mg, 3.6mmol) followed by DMF (30mL) was added to the flask, stirred at 0 ℃ and NaH (60% content in mineral oil, 180mg, 4.5mmol) was added slowly in portions to the stirred solution. After stirring at 0 ℃ for 30 minutes, 1a (590mg, 3.0mmol) was added, and after stirring at room temperature for 20 hours, the reaction was quenched with 100mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column chromatography gave the product 3o as a white solid (440mg, 53%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.18–9.16(m,1H),8.94(s,1H),8.83(d,J＝5.2Hz,2H),8.48(dd,J＝5.8,2.3Hz,1H),8.10(d,J＝1.9Hz,1H),6.85–6.82(m,1H),4.96(hept,J＝6.7Hz,1H),1.66(dd,J＝6.8,1.7Hz,6H)。13C NMR(100MHz,CDCl3)δ＝152.8,151.7,149.3,143.7,143.6,141.0,140.1,129.5,127.0,123.0,112.1,106.6,77.2,47.7,22.7。HR-MS(ESI)m/z calcd for C15H15N6[M+H]+279.1353,found279.1350。
example 16: synthesis of Compound 5a
A15 mL reaction tube was taken and 3a (70mg, 0.25mmol), [ MnBr (CO) ]was added to the tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), was stirred at 80 ℃ for 16 hours, then the reaction was quenched by addition of 10mL of water, extracted with ethyl acetate (5 mL. times.4), and the organic phase was dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 3/1) gave product 5a (137mg, 99%) as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.44(d,J＝9.6Hz,1H),8.80(s,1H),8.04(s,1H),7.61(d,J＝8.0Hz,1H),7.56(d,J＝6.6Hz,1H),7.24-7.12(m,2H),6.82-6.75(m,1H),6.70-6.62(m,5H),5.02(hept,J＝6.8Hz,1H),4.06(q,J＝7.1Hz,2H),3.33-3.20(m,1H),1.95-1.86(m,1H),1.73(d,J＝6.8Hz,3H),1.70(d,J＝6.8Hz,3H),1.60-1.52(m,2H),1.43(s,2H),1.40-1.34(m,1H),1.20-1.14(m,2H),1.11(t,J＝7.1Hz,3H),1.06-0.96(m,1H),0.92-0.82(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.2,153.0,151.5,148.0,141.1,137.2,136.3,132.9,131.2,128.3,126.6,126.5,125.2,123.8,122.0,121.1,113.4,110.9,98.5,59.1,53.8,47.6,35.4,34.0,27.0,25.6,24.7,24.6,22.7,14.5。HR-MS(ESI)m/z calcd forC33H37N6O2[M+H]+549.2973,found 549.2964。
example 17: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), vacuum, nitrogen and the operation was repeated three times, and then 1,4-dioxane (1mL), 4a (82mg, 0.30mmol) was added to the flask under nitrogen, and after stirring at 40 ℃ for 16 hours, the isolation and purification method of example 16 was followed to give 5a (130mg, 95%) as a yellow solid.
Example 18: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), vacuum, nitrogen and the operation was repeated three times, then 1,4-dioxane (1mL), 4a (82mg, 0.30mmol) was added to the flask under nitrogen, and after stirring at 60 ℃ for 16 hours, the isolation and purification method of example 16 was followed to give 5a (137mg, 99%) as a yellow solid.
Example 19: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuation, charging nitrogen gas, repeating the operation three times, subsequently adding 1,4-dioxane (1mL), 4a (82mg, 0.30mmol) to the flask under nitrogen atmosphere, stirring at 80 ℃ for 16 hours to obtain the product 5a (137) as a yellow solid according to the isolation and purification method of example 16mg，99％)。
Example 20: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuated, flushed with nitrogen and repeated three times, after which H was added to the flask under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16 hours, the isolation and purification procedure of example 16 was followed to give the product 5a (134mg, 98%) as a yellow solid.
Example 21: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuated and charged with nitrogen three times, followed by addition of DCE (1mL), 4a (82mg, 0.30mmol) to the flask under nitrogen, stirring at 80 ℃ for 16 hours to give the product 5a (137mg, 99%) as a yellow solid according to the isolation and purification method of example 16.
Example 22: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), vacuum, nitrogen and repetition three times, followed by addition of gamma-Valerolone (1mL), 4a (82mg, 0.30mmol) to the flask under nitrogen, stirring at 80 ℃ for 16 hours, and isolation and purification as in example 16 afforded product 5a (115mg, 84%) as a yellow solid.
Example 23: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), vacuum evacuation, charging nitrogen gas, repeating the operation three times, subsequently adding DMF (1mL), 4a (82mg, 0.30mmol) to the flask under nitrogen atmosphere, stirring at 80 ℃ for 16 hours to obtain the product according to the separation and purification method of example 16Product 5a (137mg, 99%) as a yellow solid.
Example 24: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuated, flushed with nitrogen and repeated three times, after which H was added to the flask under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 60 ℃ for 8 hours, the isolation and purification procedure of example 16 was followed to give the product 5a (106mg, 78%) as a yellow solid.
Example 25: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuated, flushed with nitrogen and repeated three times, after which H was added to the flask under nitrogen2O (1mL), 4a (82mg, 0.30mmol), was stirred at 60 ℃ for 12 hours, and the isolation and purification method of example 16 was followed to give 5a (123mg, 90%) as a yellow solid.
Example 26: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.1mg, 0.05mmol), evacuated, flushed with nitrogen and repeated three times, after which H was added to the flask under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 60 ℃ for 16 hours, the isolation and purification procedure of example 16 was followed to give the product 5a (126mg, 92%) as a yellow solid.
Example 27: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), evacuation, charging nitrogen, repeating the operation three times, and then adding H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 60 ℃ for 16h, the pure isolate according to example 16The procedure gave product 5a as a yellow solid (137mg, 99%).
Example 28: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), NaOAc (4.1mg, 0.05mmol) and NaOAc were added to a 15mL reaction tube, evacuated, purged with nitrogen and repeated three times, and then H was added to the flask under nitrogen2O (1mL), 4a (82mg, 0.30mmol), was stirred at 60 ℃ for 16 hours, and the isolation and purification method of example 16 was followed to give 5a (0mg, 0%) as a yellow solid.
Example 29: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), was stirred at 60 ℃ for 16 hours, and the isolation and purification method of example 16 was followed to give 5a (100mg, 73%) as a yellow solid.
Example 30: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16 hours, the isolation and purification method of example 16 was followed to give the product 5a (137mg, 99%) as a yellow solid.
Example 31: screening of reaction conditions for Synthesis of Compound 5a
According to the method described in example 16, 3a (70mg, 0.25mmol), [ Re (CO) ] was charged into a 15mL reaction tube10](4.1mg, 0.00625mmol), NaOAc (2.0mg, 0.025mmol), evacuation, charging nitrogen, repeating the operation three times, then adding 1,4-dioxane (1mL), 4a (82mg, 0.30mmol) to the flask under nitrogen, stirring at 120 deg.C for 16 hours, separating pure according to example 16The procedure gave product 5a as a yellow solid (137mg, 99%).
Example 32: synthesis of Compound 5b
According to the method described in example 16, 3b (63mg, 0.25mmol), [ MnBr (CO) was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5b as a yellow solid (118mg, 91%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.44(d,J＝9.6Hz,1H),8.82(s,1H),7.96(s,1H),7.61–7.55(m,2H),7.21–7.14(m,2H),6.80–6.76(m,1H),6.71–6.63(m,5H),4.05(q,J＝7.1Hz,2H),3.92(s,3H),3.35–3.25(m,1H),1.95–1.88(m,1H),1.69–1.58(m,3H),1.48–1.33(m,3H),1.20–1.14(m,2H),1.13–1.07(m,4H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.2,153.7,151.8,148.0,144.1,137.2,136.3,132.9,131.2,128.3,126.4,126.0,125.2,123.8,122.0,121.1,113.4,111.0,98.6,59.1,53.8,35.4,34.0,30.1,25.6,24.7,24.6,14.5。HR-MS(ESI)m/z calcd for C31H33N6O2[M+H]+521.2660,found 521.2652。
example 33: synthesis of Compound 5c
According to the method described in example 16, 3c (81mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5c as a yellow solid (98mg, 66%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.43(d,J＝9.7Hz,1H),8.85(s,1H),7.98(s,1H),7.62(d,J＝7.8Hz,1H),7.57(d,J＝6.8Hz,1H),7.42–7.37(m,5H),7.20–7.16(m,2H),6.78–6.74(m,1H),6.69(s,1H),6.66–6.59(m,4H),5.51(s,2H),4.07(q,J＝7.0Hz,2H),3.32–3.22(m,1H),1.93–1.87(m,1H),1.68–1.53(m,3H),1.44–1.35(m,3H),1.20–1.14(m,2H),1.12(d,J＝7.1Hz,3H),1.04–0.94(m,1H)。13CNMR(100MHz,CDCl3)δ＝170.2,155.2,153.5,152.0,148.1,143.3,137.3,136.3,135.5,132.9,131.2,129.3,128.8,128.4,127.9,126.5,126.1,125.2,123.8,122.0,121.2,113.4,111.0,98.6,59.1,53.8,47.6,35.4,34.0,29.8,25.6,24.7,14.5。HR-MS(ESI)m/zcalcd for C37H37N6O2[M+H]+597.2973,found 597.2963。
example 34: synthesis of Compound 5d
According to the method described in example 16, 3d (73mg, 0.25mmol), [ MnBr (CO) ] was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5d as a yellow solid (98mg, 70%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.38(d,J＝10.0Hz,1H),8.82(s,1H),8.05(s,1H),7.54(d,J＝8.0Hz,1H),7.47(d,J＝7.1Hz,1H),7.23–7.14(m,2H),6.85(d,J＝7.0Hz,2H),6.81–6.77(m,1H),6.72–6.68(m,2H),5.02(hept,J＝6.7Hz,1H),4.15–4.04(m,2H),3.04–2.93(m,1H),2.18(s,3H),1.73(d,J＝6.8Hz,3H),1.68(d,J＝6.8Hz,3H),1.63–1.57(m,4H),1.49–1.32(m,3H),1.24–1.19(m,1H),1.15(t,J＝7.1Hz,3H),1.11–1.06(m,2H)。13C NMR(100MHz,CDCl3)δ＝170.4,154.5,153.0,151.7,148.2,141.0,137.7,136.0,131.2,129.6,129.5,126.5,126.4,125.1,123.7,121.5,119.3,117.1,113.4,99.6,59.2,53.5,47.6,35.3,33.8,25.6,24.6,24.5,22.8,22.7,14.6,9.8。HR-MS(ESI)m/z calcd for C34H39N6O2[M+H]+563.3120,found563.3117。
example 35: synthesis of Compound 5e
According to the method described in example 16, 3e (75mg, 0.25mmol), [ MnBr (CO) was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5e as a yellow solid (148mg, 99%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.41(d,J＝9.8Hz,1H),8.82(s,1H),8.05(s,1H),7.36(d,J＝8.4Hz,1H),7.13–7.08(m,1H),6.86–6.78(m,2H),6.77(s,1H),6.71–6.63(m,4H),5.01(hept,J＝6.8Hz,1H),4.06(q,J＝7.1Hz,2H),3.28–3.17(m,1H),1.94–1.88(m,1H),1.72(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.67–1.59(m,1H),1.59–1.49(m,2H),1.48–1.39(m,2H),1.39–1.34(m,1H),1.20–1.14(m,2H),1.11(t,J＝7.2Hz,3H),1.06–0.93(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.1,156.0(d,1JC-F＝248.4Hz),154.4,153.1,151.4,147.6,141.5,138.3(d,3JC-F＝9.6Hz),137.0,131.1,128.9,126.6,126.5,125.3,124.2(d,3JC-F＝7.2Hz),117.5(d,2JC-F＝23.7Hz),109.5(d,4JC-F＝3.4Hz),106.8(d,2JC-F＝17.9Hz),106.1,99.0,59.1,53.8,47.7,35.3,33.9,27.0,25.5,24.6,24.5,22.6,14.4。HR-MS(ESI)m/z calcd for C33H36FN6O2[M+H]+567.2878,found 567.2871。
example 36: synthesis of Compound 5f
According to the method described in example 16, 3f (77mg, 0.25mmol), [ MnBr (CO) was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5f as a yellow solid (143mg, 99%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.45(d,J＝9.8Hz,1H),8.78(s,1H),8.02(s,1H),7.53(d,J＝8.8Hz,1H),7.01(d,J＝2.5Hz,1H),6.86–6.82(m,1H),6.80–6.75(m,1H),6.69–6.60(m,5H),5.00(hept,J＝6.0Hz,1H),4.06(q,2H),3.83(s,3H),3.32–3.19(m,1H),1.94–1.85(m,1H),1.72(d,J＝4.2Hz,3H),1.68(d,3H),1.67–1.62(m,1H),1.60–1.53(m,2H),1.51–1.30(m,3H),1.21–1.14(m,2H),1.11(t,J＝7.1Hz,3H),1.06–0.96(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.5,155.3,152.9,151.4,147.9,140.9,137.3,133.3,131.2,131.1,129.0,126.4,126.3,125.1,114.4,113.5,110.7,102.8,98.3,59.1,55.8,53.8,47.5,35.3,34.0,25.5,24.7,24.6,22.7,22.7,14.5。HR-MS(ESI)m/z calcd for C34H39N6O3[M+H]+579.3078,found579.3070。
example 37: synthesis of Compound 5g
According to the method described in example 16, 3g (90mg, 0.25mmol) of [ MnBr (CO) ] was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave 5g (147mg, 94%) of the product as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.37(d,J＝9.8Hz,1H),8.81(s,1H),8.04(s,1H),7.68(d,J＝1.7Hz,1H),7.46(d,J＝8.8Hz,1H),7.28–7.24(m,1H),6.79(t,J＝6.8Hz,1H),6.70–6.63(m,4H),6.59(s,1H),5.01(hept,J＝6.5Hz,1H),4.09–4.01(m,2H),3.19–3.09(m,1H),1.88–1.82(m,1H),1.72(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.60–1.48(m,2H),1.46–1.41(m,2H),1.35–1.31(m,1H),1.20–1.14(m,2H),1.10(t,J＝7.1Hz,3H),1.03–0.95(m,1H),0.91–0.81(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.1,154.4,153.1,151.5,147.5,141.5,137.1,134.8,134.0,131.1,129.9,129.0,128.2,126.5,125.3,123.5,115.2,115.0,109.8,98.9,59.2,53.8,47.7,35.3,33.9,25.5,24.6,24.6,22.7,22.7,14.4。HR-MS(ESI)m/z calcd for C33H36BrN6O2[M+H]+627.2078,found 627.2070。
example 38: synthesis of Compound 5h
According to the method described in example 16, 3h (96mg, 0.25mmol), [ MnBr (CO) was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol) gave, after stirring at 80 ℃ for 16h, the product as a yellow solid for 5h (150mg, 94%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.44(d,J＝9.8Hz,1H),8.77(s,1H),8.01(s,1H),7.53(d,J＝9.1Hz,1H),7.46(d,J＝7.0Hz,2H),7.41–7.37(m,2H),7.34–7.30(m,1H),7.08(d,J＝2.4Hz,1H),6.92(dd,J＝9.1,2.6Hz,1H),6.80–7.76(m,1H),6.69–6.60(m,5H),5.09(s,2H),5.01(p,J＝6.8Hz,1H),4.05(q,J＝7.0Hz,2H),3.31–3.20(m,1H),1.92–1.86(m,1H),1.72(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.58(s,3H),1.55–1.50(m,1H),1.48–1.37(m,2H),1.19–1.13(m,2H),1.10(t,J＝7.1Hz,3H),1.08–0.93(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.3,154.8,153.0,151.5,147.9,141.0,137.6,137.3,133.4,131.4,131.1,129.0,128.6,127.9,127.6,126.4,126.3,125.2,114.4,114.2,110.8,104.2,98.4,70.7,59.1,53.8,47.5,35.4,34.0,27.0,25.6,24.7,24.7,22.7,14.5。HR-MS(ESI)m/z calcd for C40H43N6O3[M+H]+655.3391,found 655.3381。
example 39: synthesis of Compound 5i
According to the method described in example 16, 3i (73mg, 0.25mmol), [ MnBr (CO) ] was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5i (139mg, 99%) as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.45(d,J＝9.7Hz,1H),8.80(s,1H),8.03(s,1H),7.51(d,J＝8.5Hz,1H),7.35(s,1H),7.03(d,J＝8.6Hz,1H),6.80–6.74(m,1H),6.69–6.61(m,5H),5.01(hept,J＝6.8Hz,1H),4.07(q,J＝7.1Hz,2H),3.31–3.02(m,1H),2.42(s,3H),1.93–1.86(m,1H),1.72(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.67–1.61(m,1H),1.59–1.53(m,2H),1.44(s,2H),1.38–1.34(m,1H),1.21–1.14(m,2H),1.11(t,J＝7.1Hz,3H),1.06–0.98(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.4,152.9,151.4,148.0,141.0,137.3,134.5,132.7,131.3,131.1,128.6,126.4,126.4,125.3,125.2,120.7,113.2,110.5,98.3,59.0,53.8,47.5,35.4,34.0,27.0,25.6,24.7,24.6,22.7,21.4,14.5。HR-MS(ESI)m/z calcd for C34H39N6O2[M+H]+563.3119,found 563.3116。
example 40: synthesis of Compound 5j
According to the method described in example 16, 3j (101mg, 0.25mmol), [ MnBr (CO) ] was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, charging nitrogen, repeating the operation three times, and then adding into the bottle under nitrogen atmosphereH2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5j (165mg, 99%) as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.36(d,J＝9.8Hz,1H),8.81(s,1H),8.04(s,1H),7.89(d,J＝8.8Hz,1H),7.43(dd,J＝8.8,1.6Hz,1H),7.37-7.34(m,1H),6.81-6.75(m,1H),6.71-6.63(m,4H),6.58(s,1H),5.01(hept,J＝6.8Hz,1H),4.08-4.02(m,2H),3.13(ddt,J＝14.1,9.7,6.1Hz,1H),1.88-1.83(m,1H),1.72(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.67-1.63(m,1H),1.57-1.52(m,1H),1.46-1.41(m,2H),1.38-1.27(m,2H),1.21-1.14(m,2H),1.10(t,J＝7.1Hz,3H),1.04-0.95(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.1,154.4,153.1,151.5,147.4,141.5,137.2,135.3,133.7,132.0,131.2,130.6,129.8,129.1,128.2,126.5,125.4,115.5,109.5,98.9,85.8,59.2,53.9,47.7,35.4,33.9,25.5,24.7,24.6,22.7,14.5。HR-MS(ESI)m/z calcdfor C33H36IN6O2[M+H]+675.1939,found 675.1943。
example 41: synthesis of Compound 5k
According to the method described in example 16, 3k (75mg, 0.25mmol), [ MnBr (CO) was added to a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave the product 5k as a yellow solid (106mg, 75%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.40(d,J＝9.7Hz,1H),8.80(s,1H),8.04(s,1H),7.53(dd,J＝9.1,4.4Hz,1H),7.19(dd,J＝9.0,2.5Hz,1H),6.94–6.90(m,1H),6.81–6.77(m,1H),6.70–6.61(m,5H),5.02(hept,J＝6.7Hz,1H),4.06(q,J＝7.0Hz,2H),3.25–3.13(m,1H),1.92–1.82(m,1H),1.73(d,J＝6.8Hz,3H),1.70(d,J＝6.8Hz,3H),1.65–1.62(m,1H),1.60–1.50(m,2H),1.49–1.30(m,3H),1.21–1.14(m,2H),1.10(t,J＝7.1Hz,3H),1.06–0.97(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,160.2,157.8,154.7,153.1,151.6,147.7,141.3,137.2,135.8(d,1JC-F＝277.3Hz),134.5,132.6,131.2,128.9(d,3JC-F＝9.2Hz),126.5,126.5,125.3,114.5(d,3JC-F＝10.3Hz),112.0(d,2JC-F＝23.2Hz),110.5(d,4JC-F＝2.3Hz),106.0(d,2JC-F＝24.5Hz),98.7,59.2,53.9,47.7,35.4,34.0,25.6,24.7,24.6,22.8,22.7,14.5。HR-MS(ESI)m/zcalcd for C33H36FN6O2[M+H]+567.2876,found 567.2866。
example 42: synthesis of Compound 5l
According to the method described in example 16, 3l (88mg, 0.25mmol), [ MnBr (CO) ]was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4a (82mg, 0.30mmol), after stirring at 80 ℃ for 16h, 5l (88mg, 57%) of the product was obtained as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.37(d,J＝9.8Hz,1H),8.85(s,1H),8.07(s,1H),7.86(s,1H),7.64(d,J＝8.7Hz,1H),7.42(d,J＝8.8Hz,1H),6.82–6.77(m,1H),6.73(s,1H),6.71–6.65(m,4H),5.03(hept,J＝6.8Hz,1H),4.11–4.03(m,2H),3.18–3.08(m,1H),1.90–1.84(m,1H),1.74(d,J＝6.8Hz,3H),1.71(d,J＝6.8Hz,3H),1.68–1.64(m,1H),1.62–1.48(m,2H),1.43(s,3H),1.38–1.34(m,1H),1.23–1.15(m,2H),1.11(t,J＝7.2Hz,3H),1.02–0.94(m,1H)。13C NMR(100MHz,CDCl3)δ＝170.2,154.1,153.2,151.6,147.4,141.8,137.4,139.5(q,1JC-F＝238.2Hz),131.2,127.7,126.7,126.6,126.4,125.5,124.3(q,2JC-F＝33.0Hz),123.7,120.4(q,3JC-F＝3.0Hz),118.8(q,3JC-F＝4.1Hz),113.8,110.7,99.2,77.2,59.3,54.0,47.8,35.4,34.0,27.0,25.5,24.7,24.6,22.7,14.5。HR-MS(ESI)m/z calcd for C34H36F3N6O2[M+H]+617.2845,found617.2835。
example 43: synthesis of Compound 5m
According to the method described in example 16, 3m (101mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](7.0mg, 0.025mmol), NaOAc (4.2mg, 0.05mmol), evacuated, flushed with nitrogen and repeated three times, then 1,4-diomane (1mL), 4a (82mg, 0.30mmol) was added to the flask under nitrogen and after stirring for 16h at 80 ℃ the product was obtained as a yellow solid 5m (163mg, 97%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.35(d,J＝9.8Hz,1H),8.81(s,1H),8.08(s,1H),8.03(s,1H),7.64(d,J＝9.5Hz,1H),7.56(d,J＝8.3Hz,1H),6.79-6.75(m,1H),6.68-6.66(m,5H),5.04-4.98(m,1H),4.08–4.04(m,2H),3.26-3.11(m,1H),1.87-1.82(m,1H),1.73(d,J＝6.8Hz,3H),1.69(d,J＝6.8Hz,3H),1.66-1.63(m,1H),1.59-1.49(m,2H),1.45-1.41(m,2H),1.37(s,1H),1.34(s,12H),1.13-1.09(m,6H)。13C NMR(100MHz,CDCl3)δ＝170.2,155.0,153.1,151.5,147.9,141.3,138.2,137.3,133.0,131.2,129.7,128.8,128.0,126.5,125.3,122.0,121.1,112.8,111.2,98.8,83.7,59.2,53.8,47.6,35.4,34.0,31.6,30.3,29.8,25.6,25.1,24.9,24.7,24.6,22.8,14.5。HR-MS(ESI)m/z calcd for C39H48BN6O4[M+H]+675.3825,found675.3819。
example 44: synthesis of Compound 5n
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol) and NaOAc (2.0mg, 0.025mmol), vacuum-pumping, charging nitrogen, and repeating the operationThree times, then H was added to the bottle under nitrogen2O (1mL), 4b (84mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave product 5n as a yellow solid (74mg, 53%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝11.12(s,1H),8.83(s,1H),7.92(s,1H),7.60(d,J＝8.3Hz,1H),7.42(d,J＝7.7Hz,1H),7.20–7.16(m,1H),7.13–7.09(m,1H),6.96(d,J＝7.6Hz,2H),6.88–6.79(m,3H),6.63(d,J＝8.3Hz,2H),6.51(d,J＝6.6Hz,3H),5.03–4.92(m,1H),4.21–4.11(m,2H),2.07(s,3H),1.70(d,J＝6.8Hz,6H),1.20(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3)δ＝170.3,152.8,151.3,150.6,147.8,140.5,137.7,137.1,136.1,132.2,131.6,129.0,128.3,126.7,126.1,125.6,124.0,121.9,121.3,121.2,113.6,113.2,102.0,59.8,47.4,22.7,20.7,14.5。HR-MS(ESI)m/z calcd for C34H33N6O2[M+H]+557.2660,found 557.2650。
example 45: synthesis of Compound 5o
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4c (66mg, 0.30mmol), after stirring at 80 ℃ for 16h, gave the product 5O as a yellow solid (86mg, 69%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.35(t,J＝5.5Hz,1H),8.78(s,1H),8.03(s,1H),7.66–7.61(m,1H),7.60–7.55(m,1H),7.21–7.14(m,2H),6.80–6.75(m,2H),6.66–6.62(m,2H),6.49(d,J＝7.2Hz,2H),5.01(hept,J＝6.8Hz,1H),4.11–3.96(m,2H),3.36–3.28(m,2H),1.73(d,J＝2.4Hz,3H),1.71(d,J＝2.4Hz,3H),1.20(t,J＝7.2Hz,3H),1.09(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3)δ＝170.2,156.4,153.0,151.5,148.1,141.1,136.9,136.3,132.7,131.1,129.2,128.4,128.3,126.5,126.5,125.3,123.9,122.1,121.0,113.6,110.9,98.6,59.2,47.6,40.7,22.8,22.8,16.0,14.5。HR-MS(ESI)m/z calcd for C29H31N6O2[M+H]+495.2503,found495.2494。
example 46: synthesis of Compound 5p
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O (1mL), 4d (70mg, 0.30mmol) gave, after stirring at 80 ℃ for 16h, the product 5p as a yellow solid (116mg, 91%). The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.27(d,J＝9.7Hz,1H),8.80(s,1H),8.03(s,1H),7.62–7.54(m,2H),7.22–7.14(m,2H),6.79–6.75(m,1H),6.73(d,J＝0.7Hz,1H),6.66–6.62(m,2H),6.61–6.56(m,2H),5.01(hept,J＝6.8Hz,1H),4.05(q,J＝7.1Hz,2H),3.71–3.58(m,1H),1.73(d,J＝6.8Hz,3H),1.71(d,J＝6.8Hz,3H),1.21(d,J＝6.4Hz,3H),1.12–1.07(m,6H).13C NMR(100MHz,CDCl3)δ＝170.2,155.3,153.0,151.4,147.9,141.1,137.1,136.3,132.9,131.1,128.3,126.5,126.5,125.3,123.8,122.1,121.1,113.5,110.8,98.7,59.2,47.6,47.4,25.1,23.8,22.8,22.7,14.5.HR-MS(ESI)m/z calcd for C30H33N6O2[M+H]+509.2660,found 509.2653。
example 47: synthesis of Compound 5q
According to the method described in example 16, 3a (70mg, 0.25mmol), [ MnBr (CO) was charged into a 15mL reaction tube5](3.5mg, 0.0125mmol), NaOAc (2.0mg, 0.025mmol), vacuum, nitrogen sparge, and repeat three times, then add H to the bottle under nitrogen2O(1mL), 4e (78mg, 0.30mmol) to yield, after stirring at 80 ℃ for 16h, 5q (126mg, 95%) of the product as a yellow solid. The characterization data for this compound are as follows:1H NMR(400MHz,CDCl3)δ＝9.52(d,J＝9.4Hz,1H),8.78(s,1H),8.02(s,1H),7.66–7.61(m,1H),7.61–7.56(m,1H),7.21–7.16(m,2H),6.79–6.74(m,2H),6.66–6.62(m,2H),6.52(d,J＝7.3Hz,2H),5.01(hept,J＝6.8Hz,1H),4.07–4.00(m,2H),3.91–3.83(m,1H),1.92–1.85(m,1H),1.73–1.70(m,6H),1.64–1.59(m,2H),1.43(s,2H),1.37(s,1H),1.34(s,1H),1.29(s,2H),1.09(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝170.2,155.7,153.0,151.4,148.0,141.1,137.1,136.2,133.0,131.1,128.3,126.5,126.4,125.2,123.8,122.0,121.0,113.5,111.0,98.2,59.1,57.4,47.6,35.1,34.1,29.8,23.8,22.7,14.5.HR-MS(ESI)m/z calcd for C32H35N6O2[M+H]+535.2806,found535.2809。
example 48: inhibition of vascular endothelial cells by N-purine indoles
The N-purine indoles compound is evaluated for the influence on the capability of forming a lumen of umbilical vein endothelial cells (HUVEC) by using a lumen formation experiment: HUVEC cells were collected by trypsinization and seeded into matrigel (30. mu.L) coated 96-well plates at 2X 10 per well4The cells, N-purine indoles and HUVEC were added simultaneously at a drug concentration of 10 μ M (non-toxic dose), 3 wells per group were incubated at 37 ℃ for 6h, the lumen formation was recorded by taking pictures with an inverted microscope, the magnification was 100X, and the experiment was repeated 3 times. The number of lumens in each group was counted using Image-Pro Plus 6.0 software, and the number of lumens in the vehicle group was set to 100%.
Experimental results show that the N-purine indole compound has a certain inhibition effect on the tube cavity forming capability of HUVEC, and particularly the inhibition effect of 5l and 5q is more obvious: the number of endothelial cell lumens was significantly reduced in the 5l and 5q groups compared to the vehicle group, and 5i and 5n also had some inhibitory effect (as shown in A and B in FIG. 1). The tube cavity formation of endothelial cells is an important step of angiogenesis, and the experimental results show that the N-purine indole compound can be used for preparing medicines for treating pathological angiogenesis-related diseases such as tumor, rheumatoid arthritis and the like.
Example 49: inhibition of tumor cell growth by N-purine indoles
The influence of the in vitro cell proliferation activity of the synthesized N-purine indole compound is measured by adopting an MTT method: cells in logarithmic growth phase were seeded at 4000/well in 96-well cell culture plates, N-purine indoles at different concentrations were added after 24 hours, MTT (thiazole blue, 2.5mg/mL, 50. mu.L/well) was added after 48 hours of action, and incubation at 37 ℃ for 4 hours. After the supernatant was discarded and 100. mu.L of formazan in lysed cells was added to each well, the cells were shaken well, and then OD570 was measured for absorbance by a microplate reader. The concentration of the compound at which the compound inhibited cell growth by 50% was calculated as IC50The values are represented.
The results show that (as shown in table 1), the N-purine indole compound has strong inhibition effect on lung cancer tumor cells (A549 cells) and breast cancer tumor cells (MCF-7 cells), and the inhibition rate is in positive correlation with the drug concentration. Therefore, the N-purine indole compound can be used for preparing anticancer drugs.
TABLE 1 inhibition of tumor cell line growth by N-purine Indoles (IC)50/μM)
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (16)
1. An indole compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, which is characterized in that the structural formula of the indole compound is shown as the formula (I),
wherein the content of the first and second substances,
x is selected from-C (R)1) -or-N-;
n is a positive integer from 0 to 3;
each R1Each independently selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8Substituted C1-C10 alkoxy, R8Substituted C6-C20 aryl, R8A substituted C6-C20 aryloxy, boronic acid group, or C2-C10 boronic acid ester group;
R2selected from hydrogen, halogen, R8Substituted C1-C10 alkyl, R8Substituted C1-C10 alkoxy, R8Substituted C6-C20 aryl or R8Substituted C6-C20 aryloxy;
R3is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C10 cycloalkyl, R8Substituted C1-C10 alkoxy or R8Substituted C6-C20 aryl;
R4selected from hydrogen or
R5Selected from C1-C10 alkoxycarbonyl, C1-C10 alkylaminocarbonyl or C1-C10 alkylcarbonyl;
R6is selected from R8Substituted C6-C20 aryl;
R7is selected from R8Substituted C1-C10 alkyl, R8Substituted C3-C20 cycloalkyl or R8Substituted C6-C20 aryl;
R8each independently selected from hydrogen, halogen, C1-C10 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, morpholine, piperazine, imidazole, piperidine or C1-C10 alkyl substituted amine.
2. The indole compound of claim 1, wherein each R is independently selected from the group consisting of R1Each independently selected from hydrogen, halogen, R8Substituted C1-C6 alkyl, R8A substituted C1-C6 alkoxy group, a boronic acid group or a C2-C6 boronic acid ester group.
3. The indole compound of claim 2, wherein each R is independently selected from the group consisting of R1Each independently selected from hydrogen, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, phenyl-substituted C1-C3 alkoxy or
4. The indole compound of claim 1, wherein R is R, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof2Selected from hydrogen or R8Substituted C1-C6 alkyl.
5. The indole compound of claim 1, wherein R is R, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof3Selected from C1-C6 alkyl or phenyl substituted C1-C6 alkyl.
6. The indole compound and pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof according to any one of claims 1 to 5,
R5selected from C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl or C1-C6 alkylcarbonyl;
and/or, R6Selected from C6-C10 aryl;
and/or, R7Is selected from R8Substituted C1-C6 alkyl, R8Substituted C3-C8 cycloalkyl or R8Substituted C6-C10 aryl.
7. The indole compound of any of claims 1-5, wherein each R is independently selected from the group consisting of R8Each independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, morpholine, piperazine, imidazole, piperidine or C1-C6 alkyl substituted amine.
8. The indole compound of claim 7, wherein each R is independently selected from the group consisting of R8Each independently selected from hydrogen, iodine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, morpholine, piperazine, imidazole, or piperidine.
9. The indole compound of claim 1, and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof,
each R1Each independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, benzyloxy or
R2Selected from hydrogen or C1-C6 alkyl;
R3selected from C1-C6 alkyl or benzyl;
R5selected from C1-C6 alkoxycarbonyl;
R6is selected from phenyl;
R7is selected from C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted phenyl.
10. The indole compound of claim 1, wherein the indole compound is selected from the group consisting of:
11. use of the indoles of any one of claims 1-10 as well as pharmaceutically acceptable salts, or stereoisomers, or prodrug molecules thereof for the manufacture of a medicament for the treatment of an angiogenic disease.
12. The use according to claim 11, wherein the angiogenic disease is a tumor or rheumatoid arthritis.
13. The use of claim 12, wherein the tumor is one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, colon cancer, liver cancer, leukemia, small cell lung cancer, skin cancer, epithelial cell cancer, prostate cancer, non-small cell lung cancer, nasopharyngeal cancer, glioblastoma, lymphoma, or melanoma.
14. A pharmaceutical composition, wherein the active ingredient comprises the indole compound of any of claims 1-10, or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, and a pharmaceutically acceptable carrier.
15. A process for the preparation of the indoles of any one of claims 1-10, which comprisesCharacterized in that when R is4When hydrogen is used, the method comprises the following steps: under the action of sodium hydride, the raw materials 1 and 2 generate the compound of the formula (I)
When R is4Is composed of
The method comprises the following steps: the raw materials 1 and 2 generate an intermediate 3 under the action of sodium hydride, and the intermediate 3 and
reacting to produce the compound of formula (I)
Wherein, X, n, R1、R2、R3、R5、R6、R7、R8As defined in any one of claims 1 to 10.
16. The method of claim 15, wherein when R is4Is composed of
When the intermediate 3 is reacted with a catalyst containing a transition metal, an additive and a solvent
Reacting to generate a compound shown in a formula (I);
the solvent is toluene, 1,4-dioxane, 1, 2-dichloroethane, water, tetrahydrofuran, N-dimethylformamide or gamma-valerolactone;
and/or, the transition metal catalyst is a manganese catalyst or a rhenium catalyst;
and/or the additive is acetate; and/or the reaction temperature is 40-80 ℃.
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| CN113143919B (en) * | 2021-03-22 | 2022-12-06 | 广州医科大学 | Novel application of bisindole maleimide compound |
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