CN116675682A - 一种吩恶嗪类化合物及其制备方法和应用 - Google Patents
一种吩恶嗪类化合物及其制备方法和应用 Download PDFInfo
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- CN116675682A CN116675682A CN202310585883.6A CN202310585883A CN116675682A CN 116675682 A CN116675682 A CN 116675682A CN 202310585883 A CN202310585883 A CN 202310585883A CN 116675682 A CN116675682 A CN 116675682A
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- compound
- phenoxazine
- organic solvent
- nmr
- alkaline substance
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- -1 Phenoxazine compound Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- 230000008685 targeting Effects 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims description 37
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 230000009471 action Effects 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 claims description 5
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 claims description 5
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 5
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 108010074870 Histone Demethylases Proteins 0.000 claims description 4
- 102000008157 Histone Demethylases Human genes 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012038 nucleophile Substances 0.000 claims description 4
- 239000012434 nucleophilic reagent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical group [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SSZACLYPEFCREM-UHFFFAOYSA-N 2-benzyl-1,3-dioxolane Chemical compound C=1C=CC=CC=1CC1OCCO1 SSZACLYPEFCREM-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract description 104
- 150000002991 phenoxazines Chemical class 0.000 abstract description 55
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 abstract description 16
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 abstract description 16
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- ZRQQXFMGYSOKDF-UHFFFAOYSA-N 1-propan-2-ylpiperidin-4-amine Chemical group CC(C)N1CCC(N)CC1 ZRQQXFMGYSOKDF-UHFFFAOYSA-N 0.000 description 5
- 108010033040 Histones Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
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- 238000011160 research Methods 0.000 description 4
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 2
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一种吩恶嗪类化合物，具有结构通式
Description
技术领域
本发明属于药物化学技术领域，涉及一种吩恶嗪类化合物及其制备方法和应用。
背景技术
表观遗传学是指在DNA序列不变的情况下，由于基因表达改变而导致的可遗传的表型变化，它包括DNA修饰、组蛋白修饰、非编码RNA以及核小体的重塑等。表观遗传调控异常会使基因错误表达，从而引起各种疾病，甚至发生肿瘤。组蛋白修饰是其中重要的研究方向，包括乙酰化、甲基化、磷酸化、和泛素化等，其中乙酰化和甲基化是最重要的研究内容。2004年，首个组蛋白赖氨酸去甲基化酶1(Lysine Specific Demethylase l，LSD1)被发现，证实了组蛋白去甲基化是一个可逆的过程。机体内组蛋白赖氨酸残基上的甲基化水平主要通过组蛋白甲基转移酶和组蛋白去甲基化酶进行调节，LSD1是一种黄素腺嘌呤二核苷酸依赖性去甲基化酶，能够特异性去除组蛋白H3K4和H3K9的单、双甲基，进而调控基因转录的抑制或激活。
LSD1在小细胞肺癌、膀胱癌、胃癌、前列腺癌、乳腺癌和急性髓系白血病等多种癌细胞中高表达，在肿瘤细胞的增殖、分化、侵袭或转移以及免疫方面起着重要作用。在一些癌细胞系中，通过RNAi敲除抑制LSD1可以激活肿瘤抑制基因(如p53)的表达，以及降低相关靶标基因的表达，因此，LSD1是一个重要的抗肿瘤靶标。研究开发高效低毒的LSD1抑制剂用于肿瘤的预防和治疗是重要的研究方向，已成为当前肿瘤药物研究的热点。
文献检索发现，吩恶嗪衍生物通常具有抗疟疾、抗菌、抗炎等生物活性。但是目前尚无将吩恶嗪类化合物与基于LSD1靶点的抗肿瘤作用相联系起到抗肿瘤作用的报道。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种吩恶嗪类化合物，该化合物骨架新颖，高效低毒，对LSD1具有较好的抑制活性。
本发明的目的之二在于前述吩恶嗪类化合物的制备方法。
本发明的目的之三在于提供吩恶嗪类化合物的应用。
本发明的目的之一采用如下技术方案实现：
一种吩恶嗪类化合物，具有结构通式I
其中，R1选自氢、烷基、氰基、卤代烷基、卤素中的一种；
n取自0至6的整数；
R2选自R、
中的一种；
R选自C1-C4烷基、苯基、苄基、嘧啶基、苄基并二氧戊烷、乙基吗啉、乙酰基、甲酸甲酯、叔丁氧羰基、呋喃甲酰基、甲磺酰基中的一种
作为一些实施方式中，所述R1、R2与R3选自下列基团的一种：
本发明的目的之二采用如下技术方案实现：
吩恶嗪类化合物的制备方法，包括：
合成路线①：将化合物a与3-溴丙炔在碱性物质A的作用下置于有机溶剂A中进行反应，制备得到化合物b；将化合物b与苄基叠氮在碱性物质B和催化剂A的作用下，置于有机溶剂B中进行反应，制备得到化合物I；和/或
合成路线②：将化合物a和环氧溴丙烷加入到有机溶剂C中，在碱性物质C的作用下反应制备得到化合物c；将化合物c与4-二甲氨基哌啶在有机溶剂D中进行反应，制备得到化合物I；和/或
合成路线③：将化合物a与卤代酰卤在碱性物质D和催化剂B的作用下置于有机溶剂E中进行反应，制备得到化合物b；将化合物b与BH3·Me2S在有机溶剂F中进行反应，制备得到化合物c；将化合物c和亲核试剂R2H加入到有机溶剂G中，在碱性物质E和催化剂C的作用下反应制备得到化合物I；和/或
合成路线④：将化合物a和二卤代烃在碱性物质F的作用下在有机溶剂H中进行反应，制备得到化合物c；将化合物c和亲核试剂R2H加入到有机溶剂I中，在碱性物质G的作用下反应制备得到化合物I；
所述X为卤素。
作为一些实施方式中，所述合成路线①中化合物a和3-溴丙炔的反应温度为0℃-80℃，化合物b和苄基叠氮的反应温度为0℃-50℃；合成路线②中化合物a和环氧溴丙烷的反应温度为0℃-50℃，化合物c和4-二甲氨基哌啶的反应温度为50℃-180℃。
作为一些实施方式中，合成路线③中化合物a和卤代酰卤的反应温度为0℃-50℃，化合物d和BH3·Me2S反应温度为0℃-50℃，化合物e与亲核试剂R2H的反应温度为50℃-180℃；合成路线④中化合物a与二卤代烃的反应温度为20℃-150℃，化合物e与亲核试剂R2H的反应温度为50℃-180℃。
作为一些实施方式中，所述有机溶剂A、有机溶剂B、有机溶剂C、有机溶剂D、有机溶剂F、有机溶剂G、有机溶剂H、有机溶剂I选自乙腈、四氢呋喃、二氧六环、环己烷、正己烷、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯、均三甲苯或苯中的一种；有机溶剂E选自二氯甲烷、二氯乙烷、氯仿、四氯化碳、环己烷、正己烷、甲苯、二甲苯、均三甲苯、苯、乙醚或甲基叔丁基醚中的一种。
作为一些实施方式中，所述碱性物质A、碱性物质C、碱性物质E、碱性物质F、碱性物质G选自碳酸钾、氢氧化钾、碳酸氢钠、碳酸钠、氢化钠、氢氧化钠、三乙胺或吡啶中的一种，碱性物质B为抗坏血酸钠，碱性物质D选自三乙胺、二异丙基乙胺、吡啶或碳酸氢钠中的一种。
作为一些实施方式中，所述催化剂A为五水合硫酸铜，催化剂B为4-二甲氨基吡啶，催化剂C选自碘化钠或碘化钾中的一种。
本发明的目的之二采用如下技术方案实现：
上述第一目的提供的吩恶嗪类化合物、第二目的提供的制备方法得到的吩恶嗪类化合物用于制备抗肿瘤药物。
作为一些实施方式中，所述药物为靶向组蛋白赖氨酸去甲基化酶1的抗肿瘤药物。
相比现有技术，本发明的有益效果在于：
本发明提供了一种吩恶嗪类化合物，该化合物以吩恶嗪为母核，骨架新颖，高效低毒，对LSD1具有较好的抑制活性。本发明还提供了上述化合物的制备方法，该方法具有反应条件温和、操作简单、反应收率高的特点。本发明制备吩恶嗪类化合物的方法是以吩恶嗪为原料，在其母体上分别引入活性基团，合成得到新的吩恶嗪类药效团，并以哌嗪类、吗啉类、哌啶类等基团修饰，设计合成了一类吩恶嗪类化合物。该化合物保留了吩恶嗪的活性的同时，也兼具了修饰基团的特性，改善了原有分子的生物学活性，提高了目标分子的抗肿瘤活性。本发明还提供了上述化合物在制备靶向LSD1的抗肿瘤药物中的应用，对LSD1表现出了良好的抑制活性，具有良好的开发潜力。
具体实施方式
下面，结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
一种吩恶嗪类化合物，其制备方法包括：
其中，R2为
将10mmol化合物a溶于20mL MeCN，然后向体系加入20mmol KOH，15min后再向体系中缓慢加入20mmol 3-溴丙炔，于室温条件下反应，TLC监测反应进度。待反应完全后，旋蒸除去MeCN，将残余物溶于100mLEtOAc中，依次用适量水和饱和NaCl溶液洗涤，有机相用无水MgSO4干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物b，收率为17.9％。将1.00mmol化合物b溶于4mL四氢呋喃，然后向其中分别加入0.05mmol五水硫酸铜、0.10mmol抗坏血酸钠、4mL水和1.10mmol苄基叠氮，并于室温下反应，TLC监测反应进度。反应完全后，将体系溶于10mL EtOAc中，依次用适量水和饱和NaCl溶液洗涤，有机相用无水MgSO4干燥，过滤后旋蒸除去有机溶剂，经柱层析分离得到化合物1，收率为59.9％。
1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.37–7.24(m,5H),6.83–6.79(m,4H),6.68–6.67(m,4H),5.56(s,2H),4.87(s,2H).13C NMR(100MHz,DMSO-d6)δ144.19,142.78,136.08,132.87,128.66,128.02,127.75,123.92,123.36,121.13,114.98,112.59,52.68.HRMS(ESI)calcd for C22H18N4O[M+Na]+,377.1373；found,377.1379.
实施例2
一种吩恶嗪类化合物，其制备方法包括：
其中，
将10mmol化合物a溶于20mL四氢呋喃中，然后分批加入20mmol,60％氢化钠。室温反应1h后，加入25mmol 1-溴-2,3-环氧丙烷，室温反应，薄层色谱监测反应进度。反应完成后，加冰水3×50mL淬灭，用EtOAc 3×50mL萃取。有机相用无水MgSO4干燥，过滤，旋蒸除去溶剂后，经柱层析分离得到化合物c，无色油状物，收率为49.7％。然后，将1mmol4-二甲氨基哌啶加入1mmol化合物c的15mL无水乙醇溶液中，回流反应，薄层色谱监测反应进度。反应完成后，旋蒸除去溶剂后，经柱层析分离得到化合物2，收率为36.6％。
1H NMR(400MHz,DMSO-d6)δ6.89(d,J＝8.1Hz,2H),6.76(dd,J＝11.4,5.2Hz,2H),6.60(t,J＝7.2Hz,4H),5.00(s,1H),3.85(s,1H),3.65(dd,J＝15.5,2.6Hz,1H),3.52(dd,J＝15.4,7.4Hz,1H),2.91(dd,J＝23.3,10.7Hz,1H),2.38(d,J＝7.7Hz,1H),2.32(s,1H),2.23(s,6H),2.18–2.12(m,1H),2.06(t,J＝10.5Hz,1H),1.97(t,J＝10.4Hz,1H),1.75(t,J＝13.2Hz,2H),1.46–1.34(m,2H).13C NMR(100MHz,DMSO-d6)δ143.83,133.59,123.54,120.62,114.73,112.80,65.95,62.29,61.55,53.74,52.94,49.34,41.14,28.05,27.75.HRMS(ESI)calcd for C22H30N3O2[M+H]+,368.2333；found,368.2338.
实施例3
一种吩恶嗪类化合物，其制备方法包括：
其中，n＝1，
将10mmol化合物a溶于30mL DCM中，向其中依次加入12mmol三乙胺和1mmol 4-二甲氨基吡啶。然后0℃下，将溶于10mL DCM中的30mmol溴乙酰溴缓慢滴加进体系，室温反应，TLC监测反应进度。反应完全后，用适量饱和NaCl溶液洗涤并用DCM萃取，有机相用无水MgSO4干燥，过滤后旋蒸除去溶剂，经柱层析分离得化合物d，收率为82.1％。将5mmol化合物d溶解于无水10mL DMF中，然后在0℃下滴加BH3.Me2S(2mL，2M)，室温下反应并用TLC监测反应进度。反应完全后，旋蒸除去DMF，将残渣溶于50mL EtOAc中，然后依次用适量水和饱和NaCl溶液洗涤。有机相用无水MgSO4干燥，过滤后旋蒸除去溶剂，经柱层析分离得到化合物e1，收率为54.1％。将1mmol化合物e1溶于10mL MeCN中，然后依次加0.5mmol K2CO3、0.5mmolKI和2.5mmol吗啉，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于10mL EtOAc中，依次用适量水和饱和NaCl溶液洗涤，有机相用无水MgSO4干燥，过滤后旋蒸除去溶剂，经柱层析分离得到目标化合物3，收率为32.4％。
1H NMR(400MHz,CDCl3)δ6.81–6.77(m,2H),6.67–6.61(m,4H),6.54(d,J＝8.1Hz,2H),3.74(t,J＝4.6Hz,4H),3.68(t,J＝7.6Hz,2H),2.62–2.55(m,6H).13C NMR(100MHz,CDCl3)δ145.02,133.23,123.64,121.06,115.44,111.43,66.91,53.56,53.42,42.42.HRMS(ESI)calcd.for C18H21N2O2[M+H]+,297.1598；found,297.1598.
化合物4至化合物51的制备过程如下：
实施例4
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
(1)将550mg，3mmol化合物a溶于30mL MeCN中，然后加120mg NaOH(3mmol)和2.339g 1-溴-3-氯丙烷(15mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用适量水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物e2，产率为56.1％。
(2)将260mg化合物e2(1mmol)溶于10mL MeCN中，然后依次加69mg碳酸钾(0.5mmol)、83mg碘化钾(0.5mmol)和218mg吗啉(2.5mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用适量水和饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋蒸除去溶剂，经柱层析分离得化合物4，产率为74.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.65–6.60(m,4H),6.56(d,J＝8.3Hz,2H),3.74(t,J＝4.6Hz,4H),3.59(t,J＝7.4Hz,2H),2.46–2.41(m,6H),1.85–1.78(m,2H).13CNMR(100MHz,CDCl3)δ144.92,133.33,123.54,120.78,115.35,111.35,67.04,55.75,53.83,41.70,22.29.HRMS(ESI)calcd for C19H23N2O2[M+H]+,311.1754；found,311.1751.
实施例5
一种吩恶嗪类化合物，其中通式I中n＝3，R1＝H，
实施例5与实施例4的区别在于：将步骤(1)中的1-溴-3-氯丙烷替换为1-溴-4-氯丁烷，其余与实施例4相同，制备得到化合物5，产率为81.4％。
1H NMR(400MHz,DMSO-d6)δ6.84–6.79(m,2H),6.74(d,J＝7.8Hz,2H),6.67–6.62(m,4H),3.59–3.54(m,6H),2.35–2.32(m,6H),1.62–1.55(m,4H).13C NMR(100MHz,DMSO-d6)δ144.06,132.87,124.00,120.65,114.94,111.99,66.26,57.05,53.24,42.52,22.43,21.34.HRMS(ESI)calcd for C20H25N2O2[M+H]+,325.1911；found,325.1507.
实施例6
一种吩恶嗪类化合物，其中通式I中n＝4，R1＝H，
实施例6与实施例4的区别在于：将步骤(1)中的1-溴-3-氯丙烷替换为1-溴-5-氯戊烷，其余与实施例4相同，制备得到化合物6，产率为56.2％。
1H NMR(400MHz,CDCl3)δ6.78–6.74(m,2H),6.63–6.60(m,4H),6.45(d,J＝7.8Hz,2H),3.72(t,J＝4.6Hz,4H),3.48(t,J＝7.9Hz,2H),2.44(s,4H),2.35(t,J＝7.4Hz,2H),1.72–1.64(m 2H),1.62–1.54(m,2H),1.47–1.39(m,2H).13C NMR(100MHz,CDCl3)δ145.04,133.37,123.58,120.73,115.37,111.24,77.34,77.02,76.71,66.98,58.90,53.79,43.96,26.28,24.85,24.80.HRMS(ESI)calcd for C21H27N2O2[M+H]+,339.2067；found,339.2065.
实施例7
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例7与实施例4的区别在于：将步骤(2)中的吗啉替换为硫代吗啉，其余与实施例4相同，制备得到化合物7，收率为82.8％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.55(d,J＝8.2Hz,2H),3.57(t,J＝7.3Hz,2H),2.71(s,8H),2.44(t,J＝6.6Hz,2H),1.83–1.76(m,2H).13C NMR(100MHz,CDCl3)δ144.95,133.36,123.54,120.79,115.36,111.37,56.01,55.28,41.65,28.12,22.36.HRMS(ESI)calcd for C19H23N2OS[M+H]+,327.1526；found,327.1529.
实施例8
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例8与实施例4的区别在于：将步骤(2)中的吗啉替换为哌嗪，其余与实施例4相同，制备得到化合物8，收率为66.7％。
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),6.85–6.81(m,2H),6.73(d,J＝7.9Hz,2H),6.68–6.63(m,4H),3.61(t,J＝7.2Hz,2H),3.11(s,4H),2.57(s,4H),2.47(s,2H),1.70(t,J＝6.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ143.99,132.81,124.01,120.76,114.99,112.00,54.20,49.37,43.06,40.72,21.48.HRMS(ESI)calcd for C19H24N3O[M+H]+,310.1914；found,310.1914.
实施例9
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例9与实施例4的区别在于：将步骤(2)中的吗啉替换为N-甲基哌嗪，其余与实施例4相同，制备得到化合物9，收率为56.9％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.56(d,J＝8.1Hz,2H),3.57(t,J＝7.5Hz,2H),2.46–2.40(m,10H),2.33(s,3H),1.82(dt,J＝14.2,6.9Hz,2H).13CNMR(100MHz,CDCl3)δ144.90,133.35,123.56,120.73,115.31,111.38,55.22,55.14,53.11,45.94,41.80,22.61.HRMS(ESI)calcd for C20H26N3O[M+H]+,324.2070；found,324.2072.
实施例10
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例10与实施例4的区别在于：将步骤(2)中的吗啉替换为N-乙基哌嗪，其余与实施例4相同，制备得到化合物10，收率为68.2％。
1H NMR(400MHz,CDCl3)δ6.79–6.73(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.3Hz,2H),3.57(t,J＝7.2Hz,2H),2.53–2.34(m,12H),1.84–1.78(m,2H),1.12(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)δ144.92,133.37,123.57,120.73,115.31,111.42,55.30,53.17,52.86,52.35,41.86,22.65,11.88.HRMS(ESI)calcd for C21H28N3O[M+H]+,338.2227；found,338.2224.
实施例11
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例11与实施例4的区别在于：将步骤(2)中的吗啉替换为正丙基哌嗪，其余与实施例4相同，制备得到化合物11，收率为83.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.56(d,J＝8.2Hz,2H),3.57(t,J＝7.5Hz,1H),2.52–2.31(m,12H),1.85–1.78(m,2H),1.58–1.49(m,2H),0.91(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ144.92,133.38,123.57,120.72,115.30,111.42,60.72,55.32,53.30,53.26,41.88,22.65,19.97,11.96.HRMS(ESI)calcd forC22H30N3O[M+H]+,352.2383；found,352.2390.
实施例12
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例12与实施例4的区别在于：将步骤(2)中的吗啉替换为异丙基哌嗪，其余与实施例4相同，制备得到化合物12，收率为66.6％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.66–6.59(m,4H),6.56(d,J＝8.1Hz,2H),3.57(t,J＝7.4Hz,2H),2.72–2.65(m,2H),2.60–2.47(m,4H),2.43(t,J＝6.9Hz,1H),1.85–1.78(m,2H),1.08(d,J＝6.5Hz,6H).13C NMR(100MHz,CDCl3)δ144.93,133.39,123.57,120.72,115.30,111.43,55.35,54.59,53.53,48.75,41.93,22.66,18.62.HRMS(ESI)calcd for C22H30N3O[M+H]+,352.2384；found,352.2377.
实施例13
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例13与实施例4的区别在于：将步骤(2)中的吗啉替换为环丙基哌嗪，其余与实施例4相同，制备得到化合物13，收率为60.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.56(m,6H),3.58(t,J＝7.4Hz,2H),2.68(s,4H),2.47–2.40(m,6H),1.85–1.78(m,2H),1.66–1.60(m,1H),0.48–0.39(m,4H).13CNMR(100MHz,CDCl3)δ144.91,133.37,123.57,120.72,115.30,111.42,55.31,53.35,53.22,41.85,38.47,22.61,5.69.HRMS(ESI)calcd for C22H28N3O[M+H]+,350.2227；found,350.2226.
实施例14
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例14与实施例4的区别在于：将步骤(2)中的吗啉替换为正丁基哌嗪，其余与实施例4相同，制备得到化合物14，收率为59.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.2Hz,2H),3.57(t,J＝7.5Hz,2H),2.52–2.35(m,12H),1.82(t,J＝7.4Hz,2H),1.54–1.46(m,2H),1.38–1.29(m,,2H),0.93(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ144.93,133.38,123.57,120.72,115.30,111.42,56.86,53.91,51.38,41.88,28.95,22.65,20.81,14.05.HRMS(ESI)calcd for C23H32N3O[M+H]+,366.2540；found,366.2542.
实施例15
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例15与实施例4的区别在于：将步骤(2)中的吗啉替换为叔丁基哌嗪，其余与实施例4相同，制备得到化合物15，收率为55.3％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.56(d,J＝8.1Hz,2H),3.72(q,J＝7.0Hz,1H),3.56(t,J＝7.5Hz,2H),2.64(s,4H),2.52(s,4H),2.42(t,J＝7.0Hz,2H),1.82(dt,J＝14.5,7.1Hz,2H),1.09(s,9H).13C NMR(100MHz,CDCl3)δ144.91,133.37,123.57,120.70,115.28,111.42,58.43,55.33,53.99,45.65,41.97,25.83,22.62.HRMS(ESI)calcd.for C23H32N3O[M+H]+,366.2540；found,366.2549.
实施例16
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，/>
实施例16与实施例4的区别在于：将步骤(2)中的吗啉替换为1-苯基哌嗪，其余与实施例4相同，制备得到化合物16，收率为83.6％。
1H NMR(400MHz,CDCl3)δ7.30–7.27(m,2H),6.95(d,J＝7.9Hz,2H),6.86(t,J＝7.3Hz,1H),6.81–6.74(m,2H),6.65–6.58(m,6H),3.61(t,J＝7.4Hz,2H),3.23(t,J＝4.9Hz,4H),2.63(t,J＝5.0Hz,4H),2.49(t,J＝6.7Hz,2H),1.89–1.82(m,2H).13C NMR(100MHz,CDCl3)δ151.27,144.93,133.36,129.13,123.57,120.78,119.76,116.04,115.35,111.41,55.29,53.36,49.19,41.76,22.62.HRMS(ESI)calcd for C25H28N3O[M+H]+,386.2227；found,386.2224.
实施例17
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例17与实施例4的区别在于：将步骤(2)中的吗啉替换为1-(2-嘧啶基)哌嗪，其余与实施例4相同，制备得到化合物17，收率为72.3％。
1H NMR(400MHz,CDCl3)δ8.31(d,J＝4.7Hz,2H),6.78–6.76(m,2H),6.65–6.60(m,5H),6.58(s,1H),6.49(t,J＝4.7Hz,1H),3.85(t,J＝4.9Hz,4H),3.63(t,J＝7.4Hz,2H),2.52(t,J＝5.0Hz,4H),2.47(t,J＝6.7Hz,2H),1.90–1.83(m,2H).13C NMR(100MHz,CDCl3)δ161.74,157.72,144.94,133.36,125.00,123.57,120.79,115.35,111.40,109.92,55.38,53.22,43.79,41.74,22.59.HRMS(ESI)calcd for C23H26N5O[M+H]+,388.2132；found,388.2130.
实施例18
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例18与实施例4的区别在于：将步骤(2)中的吗啉替换为1-苄基哌嗪，其余与实施例4相同，制备得到化合物18，收率为66.8％。
1H NMR(400MHz,CDCl3)δ7.31–7.27(m,2H),7.22–7.18(m,3H),6.81–6.74(m,2H),6.65–6.59(m,4H),6.57(d,J＝8.3Hz,2H),3.58(t,J＝7.5Hz,2H),2.82(t,J＝7.8Hz,2H),2.64–2.54(m,8H),2.44(t,J＝6.8Hz,2H),1.86–1.80(m,2H).13C NMR(100MHz,CDCl3)δ144.92,140.26,133.37,128.70,128.41,126.08,123.57,120.73,115.31,111.40,60.52,55.31,53.27,41.86,33.59,22.64.
实施例19
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例19与实施例4的区别在于：将步骤(2)中的吗啉替换为1-胡椒基哌嗪，其余与实施例4相同，制备得到化合物19，收率为66.3％。
1H NMR(400MHz,CDCl3)δ6.86(s,1H),6.78–6.73(m,4H),6.64–6.59(m,4H),6.56(d,J＝8.2Hz,2H),5.94(s,2H),3.56(t,J＝7.5Hz,2H),3.43(s,2H),2.48–2.40(m,10H),1.84–1.77(m,2H).13C NMR(100MHz,CDCl3)δ147.61,146.57,144.90,133.37,132.06,123.56,122.23,120.70,115.28,111.40,109.52,107.85,100.87,62.77,55.29,53.32,53.03,41.86,22.61.HRMS(ESI)calcd for C27H30N3O3[M+H]+,444.2282；found,444.2281.
实施例20
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例20与实施例4的区别在于：将步骤(2)中的吗啉替换为1-(2-吗啉乙基)哌嗪，其余与实施例4相同，制备得到化合物20，收率为25.6％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.1Hz,2H),3.72(t,J＝4.6Hz,4H),3.57(t,J＝7.4Hz,2H),2.58–2.43(m,18H),1.86–1.79(m,2H).13CNMR(100MHz,CDCl3)δ144.93,133.35,123.56,120.77,115.34,111.41,66.92,56.14,55.48,55.24,54.11,53.62,52.99,41.80,22.59.HRMS(ESI)calcd for C25H35N4O2[M+H]+,423.2755；found,423.2762.
实施例21
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例21与实施例4的区别在于：将步骤(2)中的吗啉替换为1-乙酰哌嗪，其余与实施例4相同，制备得到化合物21，收率为43.8％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.66–6.61(m,4H),6.56(d,J＝8.1Hz,2H),3.65–3.59(m,4H),3.49(t,J＝4.7Hz,2H),2.47–2.42(m,6H),2.10(s,3H),1.87–1.80(m,2H).13C NMR(100MHz,CDCl3)δ168.96,144.94,133.29,123.53,120.85,115.41,111.34,55.16,53.42,52.87,46.27,41.57,41.40,22.50,21.35.HRMS(ESI)calcd for C21H26N3O2[M+H]+,352.2020；found,352.2022.
实施例22
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例22与实施例4的区别在于：将步骤(2)中的吗啉替换为1-哌嗪甲酸甲酯，其余与实施例4相同，制备得到化合物22，收率为62.6％。
1H NMR(400MHz,CDCl3)δ6.78–6.74(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.3Hz,2H),3.70(s,3H),3.59(t,J＝7.3Hz,2H),3.50(s,4H),2.45–2.41(m,6H),1.85–1.78(m,2H).13CNMR(100MHz,CDCl3)δ155.93,144.95,133.34,123.53,120.82,115.38,111.36,55.30,53.03,52.60,43.84,41.64,22.56.HRMS(ESI)calcd for C21H26N3O3[M+H]+,368.1969；found,368.1968.
实施例23
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例23与实施例4的区别在于：将步骤(2)中的吗啉替换为1-叔丁氧羰基哌嗪，其余与实施例4相同，制备得到化合物23，收率为82.6％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.56(d,J＝8.0Hz,2H),3.59(t,J＝7.3Hz,2H),3.46(s,4H),2.46–2.41(m,6H),1.85–1.80(m,2H),1.47(s,9H).13CNMR(100MHz,CDCl3)δ154.76,144.91,133.31,123.55,120.81,115.37,111.35,79.72,58.47,55.31,53.10,41.63,28.43,22.45.HRMS(ESI)calcd for C24H32N3O3[M+H]+,410.2438；found,410.2444.
实施例24
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例24与实施例4的区别在于：将步骤(2)中的吗啉替换为N-(2-呋喃甲酰基)哌嗪，其余与实施例4相同，制备得到化合物24，收率为67.0％。
1H NMR(400MHz,CDCl3)δ7.482–7.479(m,1H),7.00(d,J＝3.4Hz,1H),6.79–6.75(m,2H),6.66–6.60(m,4H),6.57(d,J＝8.2Hz,2H),6.48(dd,J＝3.4,1.8Hz,1H),3.83(s,4H),3.61(t,J＝7.3Hz,2H),2.51(t,J＝4.9Hz,4H),2.47(t,J＝6.7Hz,2H),1.87–1.80(m,2H).13C NMR(100MHz,CDCl3)δ159.10,147.98,144.95,143.65,133.33,123.55,120.85,116.39,115.41,111.36,111.28,55.20,53.40,41.62,22.54.HRMS(ESI)calcd forC24H26N3O3[M+H]+,404.1969；found,404.1971.
实施例25
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例25与实施例4的区别在于：将步骤(2)中的吗啉替换为N-甲磺酰哌嗪，其余与实施例4相同，制备得到化合物25，收率为67.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.66–6.61(m,4H),6.53(d,J＝8.2Hz,2H),3.59(t,J＝7.2Hz,2H),3.25(t,J＝4.6Hz,4H),2.79(s,3H),2.55(t,J＝4.8Hz,4H),2.48(t,J＝6.7Hz,2H),1.86–1.79(m,2H).13C NMR(100MHz,CDCl3)δ144.99,133.32,123.51,120.89,115.45,111.34,55.01,52.54,45.90,41.59,34.26,22.58.HRMS(ESI)calcd for C20H26N3O3S[M+H]+,388.1689；found,388.1688.
实施例26
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例26与实施例4的区别在于：将步骤(2)中的吗啉替换为2-哌嗪酮，其余与实施例4相同，制备得到化合物26，收率为94.4％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.66–6.60(m,4H),6.54(d,J＝8.1Hz,2H),6.33(s,1H),3.61(t,J＝7.2Hz,2H),3.41–3.37(m,2H),3.17(s,2H),2.66(t,J＝5.5Hz,2H),2.53(t,J＝6.6Hz,2H),1.91–1.77(m,2H).13C NMR(100MHz,CDCl3)δ169.31,144.93,133.25,123.57,120.91,115.44,111.30,57.06,54.46,49.26,41.43,41.36,22.60.HRMS(ESI)calcd for C19H21N3O2[M+Na]+,346.1526；found,346.1528.
实施例27
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例27与实施例4的区别在于：将步骤(2)中的吗啉替换为3-甲基吗啉，其余与实施例4相同，制备得到化合物27，收率为37.6％。
1H NMR(400MHz,CDCl3)δ6.80–6.75(m,2H),6.66–6.60(m,4H),6.55(d,J＝8.1Hz,2H),3.82(dt,J＝11.1,3.1Hz,1H),3.67–3.59(m,2H),3.55–3.47(m,1H),3.31–3.26(m,1H),2.85–2.77(m,2H),2.48–2.41(m,1H),2.33–2.26(m,2H),1.83–1.75(m,2H),0.99(d,J＝6.3Hz,3H).13C NMR(100MHz,CDCl3)δ145.05,133.37,123.57,120.79,115.38,111.35,73.04,67.50,55.40,51.17,50.71,41.95,21.94,13.87.HRMS(ESI)calcd for C20H25N2O2[M+H]+,325.1911；found,325.1913.
实施例28
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例28与实施例4的区别在于：将步骤(2)中的吗啉替换为4-甲基哌啶，其余与实施例4相同，制备得到化合物28，收率为72.0％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.64–6.59(m,4H),6.56(d,J＝7.8Hz,2H),3.55(d,J＝7.6Hz,2H),2.88(d,J＝11.6Hz,2H),2.39(t,J＝7.0Hz,2H),1.93(td,J＝11.6,2.0Hz,2H),1.82(dt,J＝14.4,7.1Hz,2H),1.64(d,J＝12.9Hz,2H),1.39–1.33(m,1H),1.27–1.22(m,2H),0.94(d,J＝6.3Hz,3H).13C NMR(100MHz,CDCl3)δ144.91,133.40,123.58,120.67,115.26,111.42,55.69,54.13,41.99,34.37,30.84,22.70,21.90.HRMS(ESI)calcd for C21H27N2O[M+H]+323.2118；found,323.2120.
实施例29
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例29与实施例4的区别在于：将步骤(2)中的吗啉替换为4-二甲氨基哌啶，其余与实施例4相同，制备得到化合物29，收率为49.5％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.55(d,J＝8.1Hz,2H),3.57(t,J＝7.3Hz,2H),3.21(s,2H),2.99(d,J＝11.7Hz,2H),2.43–2.42(m,1H),2.41(s,6H),1.99–1.91(m,4H),1.85–1.78(m,2H),1.66–1.56(m,2H).13C NMR(100MHz,CDCl3)δ144.93,133.37,123.58,120.76,115.33,111.41,62.69,55.14,52.83,41.79,41.13,27.79,22.85.HRMS(ESI)calcd for C22H30N3O[M+H]+,352.2383；found,352.2387.
实施例30
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例30与实施例4的区别在于：将步骤(2)中的吗啉替换为4-哌啶基哌啶，其余与实施例4相同，制备得到化合物30，收率为59.3％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.64–6.59(m,4H),6.55(d,J＝8.0Hz,2H),3.56(t,J＝7.4Hz,2H),2.99(d,J＝11.8Hz,2H),2.65(s,4H),2.48–2.45(m,1H),2.40(t,J＝6.8Hz,2H),1.99–1.91(m,4H),1.84–1.78(m,2H),1.76–1.69(m,4H),1.67–1.60(m,2H),1.51(d,J＝4.7Hz,2H).13C NMR(100MHz,CDCl3)δ144.91,133.37,123.58,120.73,115.30,111.40,63.19,55.17,53.33,50.16,41.81,27.51,25.50,24.25,22.86.HRMS(ESI)calcd for C25H34N3O[M+H]+,392.2696；found,392.2700.
实施例31
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例31与实施例4的区别在于：将步骤(2)中的吗啉替换为4-叔丁氧羰基氨基哌啶，其余与实施例4相同，制备得到化合物31，收率为68.9％。
1H NMR(400MHz,CDCl3)δ6.76(ddd,J＝8.7,6.5,2.6Hz,2H),6.65–6.60(m,4H),6.55(d,J＝8.1Hz,2H),4.44(s,1H),3.56(t,J＝7.4Hz,2H),3.48(s,1H),2.83(d,J＝11.0Hz,2H),2.40(t,J＝6.8Hz,2H),2.07(dd,J＝19.3,7.6Hz,2H),1.95(d,J＝11.4Hz,2H),1.86–1.74(m,2H),1.68(s,1H),1.45(s,9H).13C NMR(100MHz,CDCl3)δ144.91,133.36,123.54,120.73,115.31,111.35,55.30,52.55,41.84,32.74,28.42,22.88.HRMS(ESI)calcd for C25H34N3O3[M+H]+,424.2595；found,424.2585.
实施例32
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例32与实施例4的区别在于：将步骤(2)中的吗啉替换为哌啶-4-甲酰胺，其余与实施例4相同，制备得到化合物32，收率为61.5％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.64–6.59(m,4H),6.56(d,J＝8.1Hz,2H),5.54(s,1H),5.50(s,1H),3.57(d,J＝7.4Hz,2H),2.96(d,J＝11.6Hz,2H),2.41(t,J＝6.7Hz,2H),2.20–2.13(m,1H),1.99(t,J＝11.5Hz,2H),1.90(d,J＝11.2Hz,2H),1.84–1.72(m,5H).13C NMR(100MHz,CDCl3)δ177.38,144.89,133.36,123.58,120.73,115.30,111.39,55.41,53.31,42.78,41.70,29.04,22.68.HRMS(ESI)calcd for C21H26N3O2[M+H]+,352.2020；found,352.2022.
实施例33
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例33与实施例4的区别在于：将步骤(2)中的吗啉替换为4-氨基哌啶，其余与实施例4相同，制备得到化合物33，收率为47.6％。
1H NMR(400MHz,CDCl3)δ6.76(dd,J＝9.9,4.1Hz,2H),6.62(d,J＝13.1Hz,4H),6.55(d,J＝7.7Hz,2H),4.97(s,1H),3.55(s,2H),2.86(d,J＝10.7Hz,2H),2.70(s,1H),2.40(s,2H),2.02(t,J＝10.8Hz,2H),1.82(s,5H),1.42(d,J＝8.0Hz,2H).13C NMR(100MHz,CDCl3)δ144.90,133.36,123.58,120.72,115.29,111.38,55.24,52.52,48.79,41.83,35.27,22.84.HRMS(ESI)calcd for C20H26N3O[M+H]+,324.2070；found,324.2072.
实施例34
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例34与实施例4的区别在于：将步骤(2)中的吗啉替换为4-氨基-1-甲基哌啶，其余与实施例4相同，制备得到化合物34，收率为43.2％。
1H NMR(400MHz,DMSO-d6)δ6.86–6.82(m,1H),6.77(d,J＝7.9Hz,2H),6.67(dd,J＝8.6,5.2Hz,4H),3.64(t,J＝7.6Hz,2H),2.88(t,J＝6.9Hz,2H),2.81(d,J＝11.7Hz,2H),2.71–2.66(m,1H),2.19(s,3H),1.97(t,J＝11.1Hz,2H),1.88(d,J＝12.3Hz,2H),1.82–1.75(m,2H),1.48–1.40(m,2H).13C NMR(100MHz,DMSO-d6)δ143.99,132.70,124.00,120.86,115.02,112.03,53.81,53.37,45.36,42.19,40.66,29.70,23.13.HRMS(ESI)calcdfor C21H28N3O[M+
H]+,338.2227；found,338.2231.
实施例35
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例35与实施例4的区别在于：将步骤(2)中的吗啉替换为1-异丙基-4-哌啶胺，其余与实施例4相同，制备得到化合物35。收率为80.5％。
1H NMR(400MHz,DMSO-d6)δ6.87–6.83(m,2H),6.79(d,J＝7.7Hz,2H),6.70–6.65(m,4H),3.66(t,J＝7.6Hz,2H),3.00(s,6H),2.33(s,2H),2.02(d,J＝11.2Hz,2H),1.89–1.86(m,2H),1.60(d,J＝8.8Hz,1H),1.25(t,J＝5.4Hz,6H).13C NMR(100MHz,DMSO-d6)δ143.92,132.51,123.94,120.88,114.99,111.98,46.07,40.33,28.20,17.43.HR-MS(ESI):Calcd.C23H31N3O,[M+H]+m/z:366.2540,found:366.2542.HRMS(ESI)calcd for C23H32N3O[M+H]+,366.2540；found,366.2542.
实施例36
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例36与实施例4的区别在于：将步骤(2)中的吗啉替换为1-乙酰哌啶-4-胺，其余与实施例4相同，制备得到化合物36，收率为16.4％。
1H NMR(400MHz,CDCl3)δ6.80–6.74(m,2H),6.66–6.61(m,4H),6.54(d,J＝8.0Hz,2H),4.45(d,J＝13.4Hz,1H),3.78(d,J＝13.7Hz,1H),3.61(t,J＝7.4Hz,2H),3.12–3.05(m,1H),2.80–2.65(m,4H),2.09(s,3H),1.79(s,3H).13C NMR(100MHz,CDCl3)δ168.87,145.03,133.36,123.59,120.87,115.41,111.47,54.91,45.05,43.95,41.82,40.23,32.98,32.14,26.18,21.46.HRMS(ESI)calcd for C22H28N3O2[M+H]+,366.2176；found,366.2172.
实施例37
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例37与实施例4的区别在于：将步骤(2)中的吗啉替换为4-氨基-1-苄基哌啶，其余与实施例4相同，制备得到化合物37，收率为23.2％。
1H NMR(400MHz,CDCl3)δ7.32(d,J＝4.3Hz,4H),7.28–7.23(m,2H),6.77–6.75(m,2H),6.65–6.60(m,4H),6.55(d,J＝8.1Hz,2H),3.59(t,J＝7.4Hz,2H),3.51(s,2H),2.86(d,J＝11.8Hz,2H),2.74(t,J＝6.8Hz,2H),2.50–2.45(m,1H),2.04(t,J＝10.7Hz,2H),1.89–1.81(m,4H),1.47–1.37(m,2H).13C NMR(100MHz,CDCl3)δ144.97,133.38,129.17,128.21,127.04,123.60,120.77,115.32,111.48,63.01,54.99,52.32,43.89,41.94,32.53,26.10.HRMS(ESI)calcd for C27H32N3O[M+H]+,414.2540；found,414.2542.
实施例38
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例38与实施例4的区别在于：将步骤(2)中的吗啉替换为四氢噻喃-4-胺，其余与实施例4相同，制备得到化合物38，收率为62.3％。
1H NMR(400MHz,CDCl3)δ6.80–6.75(m,2H),6.66–6.60(m,4H),6.55(d,J＝8.2Hz,2H),3.60(t,J＝7.4Hz,2H),2.74(t,J＝6.8Hz,2H),2.67(dd,J＝6.5,3.2Hz,2H),2.69–2.66(m,1H),2.48–2.41(m,1H),2.20–2.15(m,2H),1.84–1.77(m,2H),1.56–1.46(m,2H),1.42(s,2H).13C NMR(100MHz,CDCl3)δ145.00,133.38,123.59,120.83,115.37,111.47,56.15,43.76,41.89,34.61,27.61,26.26.HRMS(ESI)calcd for C20H25N2OS[M+H]+,341.1682；found,341.1683.
实施例39
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例39与实施例4的区别在于：将步骤(2)中的吗啉替换为4-氨基四氢吡喃，其余与实施例4相同，制备得到化合物39，收率为39.5％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.66–6.60(m,4H),6.55(d,J＝8.1Hz,2H),3.99–3.96(m,2H),3.61(t,J＝7.4Hz,2H),3.39(td,J＝11.6,1.9Hz,2H),2.76(t,J＝6.8Hz,2H),2.70–2.63(m,1H),1.87–1.80(m,4H),1.54(s,2H).13C NMR(100MHz,CDCl3)δ145.00,133.37,123.60,120.83,115.38,111.47,66.85,54.18,43.60,41.91,33.72,26.16.HRMS(ESI)calcd for C20H25N2O2[M+H]+,325.1911；found,325.1915.
实施例40
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例40与实施例4的区别在于：将步骤(2)中的吗啉替换为四氢吡喃-4-醇，碳酸钾(69mg，0.5mmol)和碘化钾(83mg，0.5mmol)替换为氢氧化钠(40mg，1mmol)，其余与实施例4相同，制备得到化合物40，收率为62.1％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.66–6.57(m,6H),3.98–3.92(m,2H),3.66(t,J＝7.2Hz,2H),3.57(t,J＝5.6Hz,2H),3.48–3.42(m,3H),1.96–1.88(m,4H),1.65–1.56(m,2H).13C NMR(100MHz,CDCl3)δ144.98,133.43,123.57,120.78,115.32,111.48,74.16,65.67,64.64,40.90,32.39,26.09.HRMS(ESI)calcd for C20H24NO3[M+H]+,326.1751；found,326.1681.
实施例41
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例41与实施例4的区别在于：将步骤(2)中的吗啉替换为4-羟基哌啶，碳酸钾(69mg，0.5mmol)和碘化钾(83mg，0.5mmol)替换为氢氧化钠(40mg，1mmol)，其余与实施例4相同，制备得到化合物41，收率为80.1％。
1H NMR(400MHz,CDCl3)δ6.81–6.74(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.2Hz,2H),3.75–3.70(m,1H),3.57(t,J＝7.4Hz,2H),2.78(t,J＝5.9Hz,2H),2.42(t,J＝6.8Hz,2H),2.17(t,J＝9.7Hz,2H),1.94–1.91(m,2H),1.82(dt,J＝14.3,6.9Hz,2H),1.71(s,1H),1.65–1.60(m,2H).13C NMR(100MHz,CDCl3)δ144.92,133.37,123.58,120.74,115.32,111.39,55.18,51.22,41.82,34.52,22.87.HRMS(ESI)calcd for C20H25N2O2[M+H]+,325.1911；found,325.1915.
实施例42
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例42与实施例4的区别在于：将步骤(2)中的吗啉替换为N-羟乙基哌嗪，碳酸钾(69mg，0.5mmol)和碘化钾(83mg，0.5mmol)替换为氢氧化钠(40mg，1mmol)，其余与实施例4相同，制备得到化合物42，收率为48.7％。
1H NMR(400MHz,CDCl3)δ6.79–6.74(m,2H),6.65–6.59(m,4H),6.56(d,J＝8.2Hz,2H),3.62(t,J＝5.4Hz,2H),3.57(t,J＝7.4Hz,2H),2.58–2.41(m,12H),1.85–1.78(m,2H).13CNMR(100MHz,CDCl3)δ144.93,133.37,123.56,120.75,115.33,111.39,59.22,57.72,55.27,53.36,52.95,41.80,22.64.HRMS(ESI)calcd for C21H28N3O2[M+H]+,354.2176；found,354.2174.
实施例43
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例43与实施例4的区别在于：将步骤(2)中的吗啉替换为N-羟乙基吗啉，碳酸钾(69mg，0.5mmol)和碘化钾(83mg，0.5mmol)替换为氢氧化钠(40mg，1mmol)，其余与实施例4相同，制备得到化合物43，收率为33.9％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,2H),6.65–6.60(m,4H),6.54(d,J＝7.9Hz,2H),3.73(t,J＝4.6Hz,4H),3.63(t,J＝7.3Hz,2H),3.58(t,J＝5.7Hz,2H),3.54(t,J＝5.7Hz,2H),2.62(t,J＝5.7Hz,2H),2.55(t,J＝4.4Hz,4H),1.95–1.89(m,2H).13C NMR(100MHz,CDCl3)δ144.93,133.34,123.57,120.78,115.32,111.33,68.79,68.26,66.89,58.32,54.18,40.91,25.67.HRMS(ESI)calcd for C21H26N2O3[M+Na]+,377.1836；found,377.1840.
实施例44
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例44与实施例4的区别在于：将步骤(2)中的吗啉替换为N-氨乙基哌嗪，其余与实施例4相同，制备得到化合物44。收率为28.7％。
1H NMR(400MHz,CDCl3)δ6.79–6.73(m,2H),6.64–6.59(m,4H),6.56(d,J＝8.1Hz,2H),3.57(t,J＝7.4Hz,2H),2.81(t,J＝6.2Hz,2H),2.50–2.41(m,10H),1.89(s,2H),1.89–1.78(m,2H).13C NMR(100MHz,CDCl3)δ144.90,133.36,123.56,120.71,115.29,111.39,60.90,55.31,53.36,53.34,41.83,38.73,22.62.HRMS(ESI)calcd for C21H29N4O[M+H]+,353.2336；found,353.2339.
实施例45
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，/>
实施例45与实施例4的区别在于：将步骤(2)中的二甲胺替换为N-氨乙基吗啉，其余与实施例4相同，制备得到化合物45，收率为35.7％。
1H NMR(400MHz,CDCl3)δ6.82–6.78(m,2H),6.68–6.62(m,4H),6.55(d,J＝7.9Hz,1H),3.68(t,J＝4.5Hz,4H),3.63(t,J＝7.3Hz,2H),2.93(t,J＝7.3Hz,1H),2.87(t,J＝6.0Hz,1H),2.61(t,J＝5.9Hz,1H),2.46(s,2H),2.07(dd,J＝14.0,6.7Hz,2H).13C NMR(100MHz,CDCl3)δ145.06,133.15,123.78,121.16,115.58,111.56,66.82,53.55,46.24,45.07,41.53,24.36.HRMS(ESI)calcd for C21H28N3O2[M+H]+,354.2176；found,354.2179.
实施例46
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例46与实施例4的区别在于：将步骤(2)中的吗啉替换为N-(3-氨丙基)吗啉，其余与实施例2相同，制备得到化合物46，收率为74.5％。
1H NMR(400MHz,CDCl3)δ6.82–6.78(m,2H),6.68–6.62(m,4H),6.56(d,J＝8.0Hz,2H),3.66(t,J＝4.5Hz,4H),3.53(s,2H),2.91–2.87(m,4H),2.48(t,J＝6.3Hz,2H),2.07–2.00(m,2H),1.84(p,J＝6.5Hz,2H).13C NMR(100MHz,CDCl3)δ145.04,133.10,123.78,121.15,115.56,111.53,66.89,57.52,53.64,48.76,46.33,41.53,24.53,24.10.HRMS(ESI)calcd for C22H30N3O2[M+H]+,368.2338；found,368.2334.
实施例47
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例47与实施例4的区别在于：将步骤(2)中的吗啉替换为N,N-二甲基-1,3-二氨基丙烷，其余与实施例4相同，制备得到化合物47，收率为16.0％。
1H NMR(400MHz,CDCl3)δ6.84–6.78(m,2H),6.69–6.62(m,4H),6.55(d,J＝7.9Hz,2H),3.65(t,J＝7.3Hz,1H),2.96(dt,J＝14.9,6.9Hz,2H),2.59(t,J＝6.4Hz,1H),2.33(s,3H),2.13–2.03(m,1H),1.92(p,J＝6.4Hz,1H).13C NMR(100MHz,CDCl3)δ145.09,133.06,123.84,121.23,115.61,111.58,58.47,48.74,45.85,44.90,41.32,23.90,23.52.HRMS(ESI)calcd for C20H28N3O[M+H]+,326.2227；found,326.2226.
实施例48
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例48与实施例4的区别在于：将步骤(2)中的吗啉替换为1-(2-二甲基氨基乙基)-1H-5-巯基-四氮唑，其余与实施例4相同，制备得到化合物48，收率为39.9％。
1H NMR(400MHz,CDCl3)δ6.82–6.77(m,2H),6.68–6.62(m,4H),6.51(d,J＝7.5Hz,2H),4.30(t,J＝6.5Hz,2H),3.69(t,J＝7.4Hz,2H),3.43(t,J＝7.2Hz,2H),2.76(t,J＝6.5Hz,2H),2.26(s,6H),2.20(dt,J＝14.8,7.4Hz,2H).13C NMR(100MHz,CDCl3)δ153.92,145.06,133.04,123.72,121.18,115.60,111.33,57.64,45.55,45.43,42.41,30.69,25.26.HRMS(ESI)calcd for C20H25N6OS[M+H]+,397.1805；found,397.1807.
实施例49
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例49与实施例4的区别在于：将步骤(2)中的吗啉替换为2-巯基嘧啶，其余与实施例4相同，制备得到化合物49，收率为47.1％。
1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.8Hz,2H),6.98(t,J＝4.8Hz,1H),6.76(dd,J＝10.4,6.3Hz,2H),6.63(s,4H),6.55(d,J＝7.6Hz,2H),3.68(s,2H),3.27(t,J＝7.0Hz,2H),2.17–2.09(m,2H).13C NMR(100MHz,CDCl3)δ171.99,157.31,144.99,133.20,123.64,120.88,116.62,115.39,111.34,42.68,28.01,24.67.HRMS(ESI)calcd for C19H17N3OS[M+Na]+,358.0985；found,358.0995.
实施例50
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例50与实施例4的区别在于：将步骤(2)中的吗啉替换为巯基乙酸甲酯，其余与实施例4相同，制备得到化合物50，收率为90.5％。
1H NMR(400MHz,CDCl3)δ6.78(t,J＝7.6Hz,2H),6.65–6.49(m,6H),3.77–3.70(m,5H),3.27(s,2H),2.77(t,J＝6.9Hz,2H),2.00–1.92(m,2H).13C NMR(100MHz,CDCl3)δ170.74,123.59,111.34,58.49,52.49,33.63,30.04,18.45.HRMS(ESI)calcd forC18H20NO3S[M+H]+,330.1158；found,330.1165.
实施例51
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝H，
实施例51与实施例4的区别在于：将步骤(2)中的吗啉替换为3-吡啶甲酰肼，其余与实施例4相同，制备得到化合物51，收率为27.7％。
1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.76(d,J＝4.4Hz,1H),8.09(d,J＝7.9Hz,1H),7.42(dd,J＝7.8,5.0Hz,1H),6.80–6.77(m,2H),6.65–6.61(m,4H),6.56(d,J＝8.0Hz,2H),3.73–3.64(m,2H),3.11(t,J＝6.7Hz,2H),1.95–1.87(m,2H).13C NMR(100MHz,CDCl3)δ165.70,152.59,147.62,145.05,135.20,133.23,123.64,121.00,115.52,111.40,49.43,41.41,23.91.HRMS(ESI)calcd for C21H20N4O2[M+Na]+,383.1478；found,383.1485.
实施例52
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝2-Me，
实施例52与实施例4的区别在于：将步骤(1)中的10H-吩恶嗪(a)替换为2-甲基-10H-吩恶嗪(a2)，将步骤(2)中的吗啉替换为1-异丙基-4-哌啶胺，其余与实施例4相同，制备得到化合物52，收率为32.3％。
1H NMR(400MHz,CDCl3)δ6.79–6.75(m,1H),6.64–6.59(m,1H),6.54(d,J＝8.0Hz,1H),6.51(d,J＝7.9Hz,1H),6.43(d,J＝7.8Hz,1H),6.34(s,1H),3.56(d,J＝7.4Hz,1H),3.00(s,1H),2.64(s,1H),2.45(s,1H),2.42(s,3H),2.20(s,2H),1.99(t,J＝10.4Hz,4H),1.83(dt,J＝14.0,6.9Hz,2H),1.71–1.61(m,2H).13C NMR(100MHz,CDCl3)δ145.06,142.72,133.33,132.93,123.38,120.86,120.73,115.28,115.00,112.24,111.42,62.82,55.14,52.66,41.72,40.86,27.45,22.86,21.23.HRMS(ESI)calcd for C23H32N3O[M+H]+,366.2540；found,366.2540.
实施例53
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝2-CF3，
实施例53与实施例4的区别在于：将步骤(1)中的10H-吩恶嗪(a)替换为2-三氟甲基-10H-吩恶嗪(a3)，将步骤(2)中的吗啉替换为1-异丙基-4-哌啶胺，其余与实施例4相同，制备得到化合物53，收率为40.9％。
1H NMR(400MHz,CDCl3)δ6.88(d,J＝8.1Hz,1H),6.82(td,J＝7.8,1.6Hz,1H),6.69–6.65(m,2H),6.64–6.61(m,2H),6.57(d,J＝8.0Hz,1H),3.60(t,J＝7.3Hz,2H),3.02(d,J＝12.3Hz,2H),2.82–2.76(m,1H),2.56(s,6H),2.44(t,J＝6.4Hz,2H),2.08–2.02(m,4H),1.83–1.77(m,2H),1.73–1.66(m,2H).13C NMR(100MHz,CDCl3)δ147.59,144.29,134.07,132.38,124.23,121.54,118.16,115.62,115.21,111.81,107.91,63.26,54.74,52.43,41.75,40.24,26.76,22.65.HRMS(ESI)calcd for C23H29F3N3O[M+H]+,420.2257；found,420.2258.
实施例54
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝2-CN，
实施例54与实施例4的区别在于：将步骤(1)中的10H-吩恶嗪(a)替换为2-腈基-10H-吩恶嗪(a4)，将步骤(2)中的吗啉替换为1-异丙基-4-哌啶胺，其余与实施例4相同，制备得到化合物54，收率为34.2％。
1H NMR(400MHz,DMSO-d6)δ7.14–7.12(m,1H),7.10(s,1H),6.88(dd,J＝6.3,2.2Hz,1H),6.80 -6.74(m,2H),6.71–6.68(m,2H),3.61(t,J＝7.1Hz,2H),3.03(s,3H),2.69(s,6H),2.46(s,2H),2.03(s,2H),1.96(d,J＝9.5Hz,2H),1.72–1.69(m,2H),1.67–1.58(m,2H).13C NMR(100MHz,DMSO-d6)δ147.87,143.14,134.01,131.62,126.14,124.82,121.59,119.05,115.79,115.33,114.32,112.43,106.45,53.61,51.44,51.42,40.82,25.86.HRMS(ESI)calcd for C23H29N4O[M+H]+,377.2336；found,377.2338.
实施例55
一种吩恶嗪类化合物，其中通式I中n＝2，R1＝3-Br，
实施例55与实施例4的区别在于：将步骤(1)中的10H-吩恶嗪(a)替换为2-溴-10H-吩恶嗪(a5)，将步骤(2)中的吗啉替换为1-异丙基-4-哌啶胺，其余与实施例4相同，制备得到化合物55，收率为62.0％。
1H NMR(400MHz,CDCl3)δ7.08–6.74(m,3H),6.67–6.59(m,3H),6.53(d,J＝8.0Hz,1H),6.40–6.38(m,1H),3.57–3.53(m,2H),3.13(s,1H),3.05(d,J＝11.8Hz,1H),2.71(s,6H),2.47(t,J＝5.8Hz,2H),2.20(d,J＝12.1Hz,2H),2.10(s,2H),1.86–1.77(m,4H).13CNMR(101MHz,CDCl3)δ145.69,144.67,144.52,133.48,132.71,132.36,126.14,124.02,123.96,121.24,118.49,115.62,113.15,112.51,112.05,111.67,111.63,54.62,51.77,41.63,39.86,26.19,22.64.HRMS(ESI)calcd for C22H29BrN3O[M+H]+,430.1489；found,430.1493.
实验例1
LSD1抑制活性测定：
LSD1抑制活性的检测样品为实施例1至55所制备得到的化合物经纯化得到，纯化过程为本领域常规技术手段，在此不再赘述。该纯化过程不对前述化合物本身活性以及前述化合物对LSD1的活性产生影响。样品储备液的配制过程为：称取1～2mg样品置于1.5mLEP管中，用DMSO配制成浓度为20mM的溶液，于4℃环境下保存备用，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白在室温孵育后，加入LSD1底物H3K4me2并孵育反应，最后加入荧光染料Amplex和辣根过氧化酶HRP室温孵育，在酶标仪上激发光530nm、发射光590nm检测荧光数值数值。实验结果采用SPSS软件计算IC50值，结果如表1所示。抑制率的计算公式如下所示：
表1
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由表1可知，本发明提供的一种吩恶嗪类化合物对LSD1具有一定的抑制活性。当化合物浓度为10μM时，如化合物3～6、化合物8～10、化合物14～15、化合物17、化合物21、化合物23、化合物26～27、化合物29～36、化合物38～41、化合物43～44、化合物46～47、化合物49、化合物51～52、化合物54～55等对LSD1的抑制活性较高，抑制率均在80％以上。化合物3～7、化合物8～15、化合物17、化合物20～21、化合物24～27、化合物29～36、化合物38～48、化合物51～54等发挥作用时，IC50值均在1μM以下，在较低浓度下即可对LSD1发挥较好的抑制活性。
综上，本发明提供的吩恶嗪类化合物对LSD1具有良好的抑制活性，显示出良好的开发潜力，为开发新型抗肿瘤药物、药物的联合用药以及新型LSD1抑制剂药物的开发开辟了一条有效途径，具有良好的市场应用前景。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (10)
1.一种吩恶嗪类化合物，其特征在于，具有结构通式Ⅰ
其中，R1选自氢、烷基、氰基、卤代烷基、卤素中的一种；
n取自0至6的整数；
R2选自R、 中的一种；
R选自C1-C4烷基、苯基、苄基、嘧啶基、苄基并二氧戊烷、乙基吗啉、乙酰基、甲酸甲酯、叔丁氧羰基、呋喃甲酰基、甲磺酰基中的一种。
2.如权利要求1所述的吩恶嗪类化合物，其特征在于，所述R1、R2与R3选自下列基团的一种：
3.如权利要求1至2任一项所述的吩恶嗪类化合物的制备方法，其特征在于，包括：
合成路线①：将化合物a与3-溴丙炔在碱性物质A的作用下置于有机溶剂A中进行反应，制备得到化合物b；将化合物b与苄基叠氮在碱性物质B和催化剂A的作用下，置于有机溶剂B中进行反应，制备得到化合物I；和/或
合成路线②：将化合物a和环氧溴丙烷加入到有机溶剂C中，在碱性物质C的作用下反应制备得到化合物c；将化合物c与4-二甲氨基哌啶在有机溶剂D中进行反应，制备得到化合物I；和/或
合成路线③：将化合物a与卤代酰卤在碱性物质D和催化剂B的作用下置于有机溶剂E中进行反应，制备得到化合物b；将化合物b与BH3·Me2S在有机溶剂F中进行反应，制备得到化合物c；将化合物c和亲核试剂R2H加入到有机溶剂G中，在碱性物质E和催化剂C的作用下反应制备得到化合物Ⅰ；和/或
合成路线④：将化合物a和二卤代烃在碱性物质F的作用下在有机溶剂H中进行反应，制备得到化合物c；将化合物c和亲核试剂R2H加入到有机溶剂I中，在碱性物质G的作用下反应制备得到化合物Ⅰ；
所述X为卤素。
4.如权利要求3所述的方法，其特征在于，所述合成路线①中化合物a和3-溴丙炔的反应温度为0℃-80℃，化合物b和苄基叠氮的反应温度为0℃-50℃；合成路线②中化合物a和环氧溴丙烷的反应温度为0℃-50℃，化合物c和4-二甲氨基哌啶的反应温度为50℃-180℃。
5.如权利要求3所述的方法，其特征在于，合成路线③中化合物a和卤代酰卤的反应温度为0℃-50℃，化合物d和BH3·Me2S反应温度为0℃-50℃，化合物e与亲核试剂R2H的反应温度为50℃-180℃；合成路线④中化合物a与二卤代烃的反应温度为20℃-150℃，化合物e与亲核试剂R2H的反应温度为50℃-180℃。
6.如权利要求3所述的方法，其特征在于，所述有机溶剂A、有机溶剂B、有机溶剂C、有机溶剂D、有机溶剂F、有机溶剂G、有机溶剂H、有机溶剂I选自乙腈、四氢呋喃、二氧六环、环己烷、正己烷、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯、均三甲苯或苯中的一种；有机溶剂E选自二氯甲烷、二氯乙烷、氯仿、四氯化碳、环己烷、正己烷、甲苯、二甲苯、均三甲苯、苯、乙醚或甲基叔丁基醚中的一种。
7.如权利要求3所述的方法，其特征在于，所述碱性物质A、碱性物质C、碱性物质E、碱性物质F、碱性物质G选自碳酸钾、氢氧化钾、碳酸氢钠、碳酸钠、氢化钠、氢氧化钠、三乙胺或吡啶中的一种，碱性物质B为抗坏血酸钠，碱性物质D选自三乙胺、二异丙基乙胺、吡啶或碳酸氢钠中的一种。
8.如权利要求3所述的方法，其特征在于，所述催化剂A为五水合硫酸铜，催化剂B为4-二甲氨基吡啶，催化剂C选自碘化钠或碘化钾中的一种。
9.一种吩恶嗪类化合物的应用，其特征在于，如权利要求1至2任一项所述的吩恶嗪类化合物、或如权利要求3至8任一项所述的制备方法得到的吩恶嗪类化合物用于制备抗肿瘤药物。
10.如权利要求9所述的应用，其特征在于，所述药物为靶向组蛋白赖氨酸去甲基化酶1的抗肿瘤药物。
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