CN114805205A - 一种吖啶类化合物及其制备方法和应用 - Google Patents
一种吖啶类化合物及其制备方法和应用 Download PDFInfo
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- CN114805205A CN114805205A CN202210452864.1A CN202210452864A CN114805205A CN 114805205 A CN114805205 A CN 114805205A CN 202210452864 A CN202210452864 A CN 202210452864A CN 114805205 A CN114805205 A CN 114805205A
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- acridine
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- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 title claims abstract description 272
- -1 Acridine compound Chemical class 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims abstract description 92
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 150000001251 acridines Chemical class 0.000 claims abstract description 59
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 claims abstract description 32
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 claims abstract description 32
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000003960 organic solvent Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 17
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 abstract description 5
- 150000004982 aromatic amines Chemical class 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 109
- 238000004896 high resolution mass spectrometry Methods 0.000 description 56
- ZGZFEDUYJFEJAW-UHFFFAOYSA-N n-(4-aminophenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=C(N)C=C1 ZGZFEDUYJFEJAW-UHFFFAOYSA-N 0.000 description 28
- BZORFPDSXLZWJF-UHFFFAOYSA-N N,N-dimethyl-1,4-phenylenediamine Chemical compound CN(C)C1=CC=C(N)C=C1 BZORFPDSXLZWJF-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- VVAKEQGKZNKUSU-UHFFFAOYSA-N 2,3-dimethylaniline Chemical compound CC1=CC=CC(N)=C1C VVAKEQGKZNKUSU-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- OTVGARFFAAFRAC-UHFFFAOYSA-N 2-bromo-1,4-dioxane Chemical compound BrC1COCCO1 OTVGARFFAAFRAC-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 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 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 3
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
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Abstract
本发明属于药物化学领域,具体涉及一种吖啶类化合物及其制备方法和应用。本发明的吖啶类化合物,为式Ⅰ所示的化合物或其药学上可接受的盐:
Description
技术领域
本发明属于药物化学领域,具体涉及一种吖啶类化合物及其制备方法和应用。
背景技术
组蛋白赖氨酸去甲基化酶1(Lysine Specific Demethylase l,LSD1)是由哈佛大学施扬教授于2004年发现的第一个组蛋白赖氨酸去甲基化酶,其主要功能是能够特异性去除组蛋白H3K4的单、双甲基化,从而抑制基因转录以及调控基因表达。LSD1还可与雌激素受体或雄激素受体相互作用,特异性去除H3K9me1/2的甲基化,引起激素受体依赖的基因转录激活。此外,LSD1还可对p53、E2F1、DNMT1和STAT3等非组蛋白底物发挥去甲基化作用,并进一步调节它们下游细胞的功能。此外,越来越多研究证实LSD1在小细胞肺癌、胃癌、前列腺癌、乳腺癌、膀胱癌和白血病等肿瘤中高表达,与肿瘤的分化、增殖、转移、侵袭、免疫及不良预后相关,使用LSD1抑制剂或RNAi下调LSD1表达可显著抑制肿瘤的发生发展。
因此,LSD1是一种极具潜力的抗肿瘤靶标,针对高效低毒的LSD1抑制剂的研究开发,使之有效用于肿瘤的预防和治疗,已成为当前肿瘤药物研究的热点,也是未来重要的研究方向。
目前,已有研究报道证实,吖啶类化合物具有抗菌、抗疟、抗癌等生物和药理活性。吖啶类化合物作为新型的具有抗肿瘤潜力的化合物,已成为药物研发的热点和重点。但是,目前尚无将吖啶类化合物与基于LSD1靶点的抗肿瘤作用相联系起到抗肿瘤作用的研究报道。
因此,针对性开发一种对LSD1具有良好抑制活性的新型吖啶类药物,对基于LSD1靶点的抗肿瘤药物的研发和相关疾病的研究治疗具有重要意义。
发明内容
为了解决上述问题,本发明的目的在于提供一种吖啶类化合物,该化合物对LSD1具有较强的抑制活性。
本发明的目的还在于提供一种吖啶类化合物的制备方法,其能够有效制备得到对LSD1具有较强的抑制活性的吖啶类化合物。
本发明的目的还在于提供一种吖啶类化合物的应用,具体是在制备基于LSD1靶点的抗肿瘤药物中的应用。
本发明的吖啶类化合物,所采用的技术方案是:
一种吖啶类化合物,为式Ⅰ所示的化合物或其药学上可接受的盐:
其中,R1选自H、F、CH3、OCH3或CF3;R2选自H、Cl、F、CH3、CH2CH3、(CH3)2CH、SCH3、CN、N(CH3)2、OCH3或C6H5;
本发明的吖啶类化合物,在吖啶的9-位引入特征的脂肪胺、芳胺、苯酚和苯硫酚基团修饰,为一种骨架新颖、高效低毒的吖啶类化合物。经LSD1抑制活性试验证实,具有上述特征结构的吖啶类化合物对LSD1具有较好的抑制活性,能够为开发高效的基于LSD1靶点的抗肿瘤药物提供全新的结构骨架。
为了进一步提高吖啶类化合物对LSD1的抑制活性,优选地,所述R2选自H、Cl、F、CH3、CH2CH3、(CH3)2CH、SCH3、CN、OCH3或C6H5;
根据对吖啶类化合物的制备成本和抑制活性的需求差异,在实际药物制备应用中,R1、R2、R3可选自如下典型的R1、R2、R3基团组,从而构建得到编号为1~56的吖啶类化合物。具体地,R1、R2、R3选自如下基团组:
为进一步优化吖啶类化合物对LSD1的抑制活性,优选地,R1、R2、R3选自第1-3、5-6、11-14、16-20、25-31、33-42、44-56基团组,得到吖啶类化合物1-3、5-6、11-14、16-20、25-31、33-42、44-56,对于LSD1的抑制率可达80%以上。更为优选地,R1、R2、R3选自第1-3、5-6、11-14、16-17、19-20、25-30、33-42、44-56基团组,得到吖啶类化合物1-3、5-6、11-14、16-17、19-20、25-30、33-42、44-56,对于LSD1的抑制率可达90%以上。
本发明的吖啶类化合物的制备方法的技术方案是:
一种吖啶类化合物的制备方法,选自合成路线①或合成路线②;所述合成路线①,包括以下步骤:
1)将式Ⅱ化合物、式Ⅲ化合物、碱性物质A、催化剂A于有机溶剂A中反应,制得式Ⅳ化合物;2)将式Ⅳ化合物在三氯氧磷或氯化亚砜的作用下于有机溶剂B中反应,制得式Ⅴ化合物;3)将式Ⅴ化合物、R3H、催化剂B在有机溶剂C中反应,得到式Ⅰ所示的吖啶类化合物;
所述合成路线②,包括以下步骤:
a)将式Ⅱ化合物、式Ⅲ化合物、碱性物质A、催化剂A于有机溶剂A中反应,制得式Ⅳ化合物;b)将式Ⅳ化合物在三氯氧磷或氯化亚砜的作用下于有机溶剂B中反应,制得式Ⅴ化合物;c)将式Ⅴ化合物、胺类物质在有机溶剂D中反应,制得式Ⅵ化合物;所述胺类物质为碳酸胺、硫酸铵、氨水中的一种;d)将式Ⅵ化合物、R3X、碱性物质B、催化剂C于有机溶剂E中反应,得到式Ⅰ所示的吖啶类化合物;其中X为Br、Cl中的一种。
本发明的制备方法,具有反应条件温和、操作简单、收率高的特点。本发明以简单易得的邻氯苯甲酸和不同取代的苯胺为起始原料,首先合成含不同取代基的9-氯吖啶或9-氨基吖啶,并以不同的脂肪胺、芳胺、苯酚和苯硫酚等在吖啶环的9位进行基团修饰,设计合成了本发明的化合物,该类化合物在保留吖啶的活性的同时,也兼具修饰基团的特性,改善了原有分子的生物学活性,对LSD1表现出良好的一致性,提高了目标分子的抗肿瘤活性。
为提高合成效率和合成效果,优选地,采用合成路线①进行吖啶类化合物1-2、6-29、33-56的合成,采用合成路线②进行吖啶类化合物3-5、30-32的合成。
优选地,所述有机溶剂A、B、C、E各自独立的选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氧六环、甲醇、乙醇、甲苯中的一种;所述有机溶剂D为苯酚、二甲基亚砜、N,N-二甲基甲酰胺、聚乙二醇中的一种。
为更好地降低副反应的发生,进一步提高反应的选择性,优选地,所述催化剂A为铜粉;所述催化剂B为冰醋酸、盐酸、硫酸中的一种;所述催化剂C为四(三苯基膦)钯、双(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯中的一种。
为进一步促进原料的转化,减少副反应的发生,所述碱性物质A为碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、三乙胺、吡啶、氢氧化钠、氢氧化钾中的一种;所述碱性物质B为叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠中的一种。
基于降低反应能耗并保证转化效果的考虑,优选地,步骤1)和步骤a)的反应温度为80~160℃;步骤2)和步骤b)的反应温度为60~150℃;步骤3)的反应温度为20~80℃;步骤c)的反应温度为90~180℃;步骤d)的反应温度为60~150℃。
本发明的吖啶类化合物的应用的技术方案是:
一种吖啶类化合物的应用,具体是吖啶类化合物在制备基于LSD1靶点的抗肿瘤药物中的应用。
本发明提供的吖啶类化合物在制备基于LSD1靶点的抗肿瘤药物中的应用,所涉及的吖啶类化合物对LSD1表现出了良好的抑制活性,显示出良好的药物开发潜力,为基于LSD1靶点的药物研发提供了新方向。
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。以下实施例所涉及的化学原料,均可通过常规市售渠道获得。其中,本发明的吖啶类化合物,均符合式Ⅰ所示的结构通式,为了表述方便,以下实施例中,仅对吖啶类化合物的取代基团R1、R2、R3进行具体限定。此外,实施例1-50所涉及的吖啶类化合物1-2、6-29、33-56,采用合成路线①制备得到;实施例51-56所涉及的吖啶类化合物3-5、30-32,采用合成路线②制备得到。
实施例1
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物1的制备方法,包括以下步骤:
1)将式Ⅱ化合物(1.57g,10mmol)、式Ⅲ化合物(0.931g,12mmol)溶于无水N,N-二甲基甲酰胺(15mL)中,然后依次加入无水碳酸钾(2.346g,17mmol)和铜粉(0.256g,4mmol),回流反应,TLC监测反应进度。反应完成后,抽滤,向所得滤液中缓慢加入适量水,然后用盐酸(6mol/L)调PH至4,抽滤并烘干所得到的固体即为中间体式Ⅳ化合物粗产品;
2)将中间体式Ⅳ化合物(213mg,1mmol)溶于无水1,4-二氧六环(5mL),然后缓慢滴加三氯氧磷(1mL),回流反应,TLC监测反应进度。反应完成后,旋蒸除去1,4-二氧六环,冷却后,往所得油渣中加入浓氨水(1mL)、碎冰(4g)、二氯甲烷(5mL)的混合溶液,室温搅拌约30分钟,将体系溶于二氯甲烷(25mL)中,用饱和食盐水(3×25mL)洗涤,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到式Ⅴ(1)化合物,收率为82.1%。
3)将式Ⅴ化合物(107mg,0.5mmol)溶于N-甲基吡咯烷酮(2mL)中,然后加入4-甲磺酰胺基苯胺(132mg,1mmol),室温反应,TLC监测反应进度。反应完成后,旋蒸除去N-甲基吡咯烷酮,将残余物溶于乙酸乙酯中,依次用水和饱和食盐水洗涤,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到吖啶类化合物1,收率为58.8%。1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.06(d,J=6.9Hz,2H),7.81–7.73(m,4H),7.26(d,J=8.7Hz,2H),7.24–7.20(m,2H),7.10(d,J=8.1Hz,2H),3.01(s,3H).13C NMR(100MHz,DMSO-d6)δ152.69,140.75,134.69,133.14,126.25,122.27,122.08,121.88,118.85,115.75,48.55.HR-MS(ESI):Calcd.C20H17N3O2S,[M+H]+m/z:364.1119,found:364.1116.
实施例2
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物2的制备方法,与实施例1基本相同,区别仅在于:将步骤3)中的4-甲磺酰胺基苯胺替换为苯胺,制备得到化合物2,收率为60.7%。结构表征为:1H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.7Hz,2H),8.15(d,J=8.5Hz,2H),8.00(t,J=7.7Hz,2H),7.53(t,J=7.8Hz,2H),7.56–7.49(m,5H).13C NMR(100MHz,DMSO-d6)δ155.19,140.95,140.09,135.20,129.90,127.44,125.76,124.61,123.70,119.20,113.63.HR-MS(ESI):Calcd.C19H14N2,[M+H]+m/z:271.1235,found:271.1232.
实施例3
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物6的制备方法,与实施例1的步骤1)、2)相同,步骤3)为:将式Ⅴ化合物(107mg,0.5mmol)溶解于乙腈(2mL)中,然后加入1-氨基哌啶(100.16mg,1mmol),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,依次用水和饱和食盐水洗涤,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到吖啶类化合物6,收率为49.6%。1H NMR(400MHz,CDCl3)δ9.17(s,2H),7.80(d,J=8.1Hz,2H),7.39(t,J=7.2Hz,2H),7.13(t,J=7.6Hz,2H),3.21(s,4H),1.79(t,J=5.1Hz,4H),1.34(s,1H),1.28–1.26(d,J=10.2Hz,2H).13C NMR(100MHz,CDCl3)δ151.12,140.10,132.88,127.15,122.29,118.48,113.34,55.74,25.57,23.07.HR-MS(ESI):Calcd.C18H19N3,[M+H]+m/z:278.1657,found:278.1655.
实施例4
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物7的制备方法,与实施例6的区别在于:实施例6中的1-氨基哌啶替换为N-(2-氨基乙基)吗啉,制备得到吖啶类化合物7,收率为42.3%。结构表征为:1H NMR(400MHz,CDCl3)δ8.35(d,J=8.6Hz,2H),8.15(d,J=8.8Hz,2H),7.62(t,J=7.7Hz,2H),7.32(t,J=7.9Hz,2H),4.30(t,J=5.9Hz,2H),3.85(t,J=4.2Hz,4H),3.03(t,J=5.9Hz,2H),2.74(s,4H).13C NMR(100MHz,DMSO-d6)δ157.82,140.30,135.22,126.21,123.80,119.22,113.10,66.61,56.58,53.21,46.04.HR-MS(ESI):Calcd.C19H21N3O,[M+H]+m/z:308.1763,found:308.1760.
实施例5
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物8的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为对甲苯胺,制备得到化合物8,收率为56.2%。结构表征为:1H NMR(400MHz,CDCl3)δ8.00(d,J=8.6Hz,2H),7.95(d,J=7.7Hz,2H),7.62(t,J=7.6Hz,2H),7.25(t,J=7.6Hz,2H),7.05(d,J=8.1Hz,2H),6.79(d,J=8.3Hz,2H),2.31(s,3H).13C NMR(100MHz,CDCl3)δ131.36,130.36,129.99,124.51,123.74,119.99,118.01,20.74.HR-MS(ESI):Calcd.C20H16N2,[M+H]+m/z:285.1391,found:285.1387.
实施例6
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物9的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为对异丙基苯胺,制备得到化合物9,收率81.6%。结构表征为:1H NMR(400MHz,CDCl3)δ8.01(d,J=8.6Hz,4H),7.64(t,J=7.5Hz,2H),7.28(d,J=7.5Hz,2H),7.11(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,2H),2.87(dt,J=13.8,6.9Hz,1H),1.24(d,J=6.9Hz,6H).13C NMR(100MHz,CDCl3)δ142.55,130.38,127.34,124.41,123.87,120.04,117.87,33.42,24.12.HR-MS(ESI):Calcd.C22H20N2,[M+H]+m/z:313.1704,found:313.1705.
实施例7
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物10的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为对氰基苯胺,制备得到化合物10,收率48.8%。结构表征为:1H NMR(400MHz,DMSO-d6)δ8.33(d,J=8.8Hz,2H),8.25(d,J=8.6Hz,2H),8.07(t,J=7.7Hz,2H),7.88(d,J=8.6Hz,2H),7.58–7.51(m,4H).13C NMR(100MHz,DMSO-d6)δ154.25,140.32,135.61,133.72,125.89,124.66,122.63,119.61,118.75,115.81,107.16.HR-MS(ESI):Calcd.C20H13N3,[M+H]+m/z:296.1187,found:296.1186.
实施例8
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物11的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为对苯二胺,制备得到啶类化合物11,收率60.2%。结构表征为:1H NMR(400MHz,DMSO-d6)δ8.19(s,2H),7.92(d,J=8.4Hz,2H),7.84(t,J=7.6Hz,2H),7.30(t,J=7.5Hz,2H),7.00(d,J=8.4Hz,2H),6.66(d,J=8.5Hz,2H),6.59(s,1H).13C NMR(100MHz,DMSO-d6)δ153.95,147.74,140.45,134.00,125.81,124.79,122.61,119.07,114.61,113.91.HR-MS(ESI):Calcd.C19H15N3,[M+H]+m/z:286.1344,found:286.1349.
实施例9
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物12的制备方法,与实施例1的步骤1)、2)相同,步骤3)为:将式Ⅴ化合物(107mg,0.5mmol)溶解于1,4-二氧六环(5mL)中,然后加入对氨基苯酚(100.16mg,1mmol)和氢氧化钠(40mg,1mmol),回流反应,TLC监测反应进度。反应完成后,旋蒸除去溶剂,将残余物溶于乙酸乙酯中,依次用水和饱和食盐水洗涤,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到吖啶类化合物12,收率为49.9%。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.04(s,1H),8.23(d,J=8.2Hz,2H),8.07(d,J=8.5Hz,2H),7.93(t,J=7.6Hz,2H),7.39(t,J=7.7Hz,2H),7.26(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ156.98,155.00,140.07,134.75,126.18,125.72,123.21,118.97,116.48,113.20.HR-MS(ESI):Calcd.C19H14N2O,[M+H]+m/z:287.1184,found:287.1182.
实施例10
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物13的制备方法,与实施例1的步骤1)、2)相同,步骤3)为:将式Ⅴ化合物(107mg,0.5mmol)溶解于1,4-二氧六环(5mL)中,然后加入对氨基苯硫酚(100.16mg,1mmol),回流反应,TLC监测反应进度。反应完成后,旋蒸除去溶剂,将残余物溶于乙酸乙酯中,依次用水和饱和食盐水洗涤,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到吖啶类化合物13,收率为49.5%。结构表征为:1H NMR(400MHz,DMSO-d6)δ8.81(d,J=8.8Hz,2H),8.20(d,J=8.7Hz,2H),7.88(dd,J=8.3,7.0Hz,2H),7.71(t,J=7.9Hz,2H),7.01(d,J=8.5Hz,2H),6.42(d,J=8.6Hz,2H),5.28(s,2H).13C NMR(100MHz,DMSO-d6)δ149.97,148.55,148.46,142.06,134.31,131.90,130.58,130.44,129.98,129.84,127.74,127.66,127.36,127.10,126.54,126.32,119.19,114.69,114.13.HR-MS(ESI):Calcd.C19H14N2S,[M+H]+m/z:303.0956,found:303.0957.
实施例11
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物14的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为邻苯二胺,制备得到化合物14,收率为88.1%。结构表征为:1H NMR(400MHz,DMSO-d6)δ8.21(s,2H),7.87(d,J=27.7Hz,4H),7.27(s,2H),7.12(s,1H),6.90(t,J=8.7Hz,2H),6.60(t,J=7.4Hz,1H),5.39(s,2H).13C NMR(100MHz,DMSO-d6)δ155.04,139.98,133.96,125.98,122.47,118.37,116.55,115.52,114.27.HR-MS(ESI):Calcd.C19H15N3,[M+H]+m/z:286.1344,found:286.1345.
实施例12
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物15的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为间苯二胺,其余与实施例1相同,制备得到化合物15,收率为53.4%。结构表征为:HR-MS(ESI):Calcd.C19H15N3,[M+H]+m/z:286.1344,found:286.1341.
实施例13
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物16的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为N-甲基对苯二胺,其余与实施例1相同,制备得到化合物16,收率为42.1%。1HNMR(400MHz,DMSO-d6)δ10.60(s,1H),7.95(s,1H),7.51–7.45(m,4H),7.01(s,1H),6.92(dd,J=8.4,6.4Hz,2H),6.68(s,3H),6.55(d,J=8.4Hz,2H),5.51(s,1H),2.67(s,6H).13CNMR(100MHz,DMSO-d6)δ130.92,125.60,119.38,116.41,112.44,40.67.HR-MS(ESI):Calcd.C20H17N3,[M+H]+m/z:300.1500,found:300.1503.
实施例14
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物17的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为3-甲氧基苯胺,其余与实施例1相同,制备得到化合物17,收率为45.3%。
结构表征为:1H NMR(400MHz,CDCl3)δ7.97(d,J=8.4Hz,2H),7.87(d,J=6.2Hz,2H),7.59(t,J=7.5Hz,2H),7.21(t,J=7.5Hz,2H),6.89–6.82(m,4H),3.79(s,3H).13C NMR(100MHz,CDCl3)δ155.33,147.02,130.39,124.74,123.22,120.29,119.23,114.83,55.57.HR-MS(ESI):Calcd.C20H16N2O,[M+H]+m/z:301.1341,found:301.1342.
实施例15
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物18的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-(甲硫基)苯胺,制备得到化合物18,收率为69.8%。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.89(s,2H),7.52(s,4H),7.24(d,J=8.4Hz,2H),7.03(s,2H),6.76(d,J=8.4Hz,2H),2.46(s,3H).13C NMR(100MHz,DMSO-d6)δ131.07,128.79,128.57,118.66,16.09.HR-MS(ESI):Calcd.C20H16N2S,[M+H]+m/z:317.1112,found:317.1106.
实施例16
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物19的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为N,N-二甲基-1,4-苯二胺,制备得到化合物19,收率为76.9%。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.77(s,4H),7.23(s,2H),7.04(d,J=8.4Hz,2H),6.79(d,J=8.7Hz,2H),2.94(s,6H).13C NMR(100MHz,DMSO-d6)δ152.40,147.91,141.12,132.83,126.03,122.69,121.88,119.23,115.56,113.24,40.33.HR-MS(ESI):Calcd.C21H19N3,[M+H]+m/z:314.1657,found:314.1654.
实施例17
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物20的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为N,N-二乙基对苯二胺,制备得到化合物20,收率为92.9%。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=6.2Hz,2H),8.00(d,J=8.5Hz,2H),7.89(t,J=7.6Hz,2H),7.35(t,J=7.6Hz,2H),7.19(d,J=8.8Hz,2H),6.77(d,J=8.7Hz,2H),3.39(dd,J=14.0,7.0Hz,4H),1.13(t,J=7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ154.36,146.63,140.19,134.48,125.70,125.49,122.98,118.99,113.52,112.17,43.76,12.29.HR-MS(ESI):Calcd.C23H23N3,[M+H]+m/z:342.1970,found:342.1968.
实施例18
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物21的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-氨基乙酰苯胺,制备得到化合物21,收率为55.7%。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.06(d,J=8.0Hz,2H),7.80–7.74(m,4H),7.66(d,J=8.7Hz,2H),7.22(t,J=7.2Hz,2H),7.08(d,J=8.4Hz,2H),2.08(s,3H).13C NMR(100MHz,DMSO-d6)δ168.11,152.73,140.67,136.26,133.18,126.09,122.07,121.94,120.06,118.84,115.50,23.89.HR-MS(ESI):Calcd.C21H17N3O,[M+H]+m/z:328.1450,found:328.1446.
实施例19
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物22的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-氨基-N,N-二甲基苄基胺,制备得到化合物22,收率为48.2%。1H NMR(400MHz,CDCl3)δ7.96(d,J=8.5Hz,2H),7.86(d,J=8.6Hz,2H),7.52(t,J=7.5Hz,2H),7.21(d,J=8.3Hz,2H),7.12(t,J=7.7Hz,2H),6.90(d,J=8.3Hz,2H),3.50(s,2H),2.31(s,6H).13C NMR(100MHz,CDCl3)δ147.84,146.44,145.28,131.13,130.83,130.64,125.30,124.20,123.28,119.12,118.63,63.06,44.36.HR-MS(ESI):Calcd.C22H21N3,[M+H]+m/z:328.1813,found:328.1809.
实施例20
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物23的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-氨基-N,N-二甲基苯甲酰胺,制备得到化合物23,收率为45.7%。1H NMR(400MHz,CDCl3)δ8.01(d,J=8.5Hz,2H),7.83(d,J=7.9Hz,2H),7.58(t,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.19(t,J=7.5Hz,2H),6.86(d,J=8.4Hz,2H),3.07(s,6H).13C NMR(100MHz,CDCl3)δ171.79,131.03,129.14,128.73,125.44,123.55,120.00,117.07.HR-MS(ESI):Calcd.C22H19N3O,[M+H]+m/z:342.1606,found:342.1602.
实施例21
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物24的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-哌啶基苯胺,制备得到化合物24,收率为48.9%。1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.91(s,2H),7.51(d,J=6.5Hz,4H),7.00(s,2H),6.90(d,J=8.8Hz,2H),6.71(d,J=8.6Hz,2H),3.07–3.04(m,2H),1.66–1.61(m,4H),1.52(dd,J=10.7,5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ147.17,130.96,126.44,120.58,119.28,117.35,50.36,25.37,23.76.HR-MS(ESI):Calcd.C24H23N3,[M+H]+m/z:354.1970,found:354.1967.
实施例22
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物25的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-哌嗪基苯胺,制备得到化合物25,收率为41.7%。1H NMR(400MHz,DMSO-d6)δ7.98(s,2H),7.66–7.59(m,4H),7.11(s,2H),6.98(d,J=8.8Hz,2H),6.89(d,J=8.2Hz,2H),3.53(t,J=4.5Hz,4H),3.11(t,J=4.7Hz,4H).13C NMR(100MHz,DMSO-d6)δ155.07,147.08,132.10,126.33,124.50,121.40,120.90,117.28,52.35,43.31.HR-MS(ESI):Calcd.C23H22N4,[M+H]+m/z:355.1922,found:413.2.
实施例23
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物26的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-吗啉基苯胺,制备得到化合物26,收率为71.8%。1H NMR(400MHz,DMSO-d6)δ7.97(s,2H),7.61(s,4H),7.10(s,2H),6.96(d,J=8.7Hz,2H),6.88(d,J=8.4Hz,2H),3.79–3.71(m,4H),3.09(d,J=4.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ147.15,131.94,126.34,121.26,120.67,116.33,66.11,48.90.HR-MS(ESI):Calcd.C23H21N3O,[M+H]+m/z:356.1763,found:356.1766.
实施例24
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物27的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-(4-甲基哌嗪)苯胺,制备得到化合物27,收率为49.9%。1H NMR(400MHz,MeOD)δ8.09(d,J=8.8Hz,2H),7.86–7.79(m,4H),7.29(t,J=7.5Hz,2H),7.22(d,J=8.9Hz,2H),7.05(d,J=8.9Hz,2H),3.38(s,4H),3.05(s,4H),2.65(s,3H).13C NMR(100MHz,MeOD)δ156.99,151.31,141.91,136.43,134.18,126.95,126.79,125.03,120.30,118.38,115.03,64.16,55.13,44.64.HR-MS(ESI):Calcd.C24H24N4,[M+H]+m/z:369.2079,found:369.2076.
实施例25
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物28的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-(4-乙基哌嗪-1-基)苯胺,制备得到化合物28,收率为46.6%。1H NMR(400MHz,DMSO-d6)δ7.91(s,2H),7.53(d,J=5.2Hz,4H),7.01(s,2H),6.94(d,J=8.7Hz,2H),6.76(d,J=8.5Hz,2H),3.21(s,4H),2.82(s,4H),2.68(s,2H),1.14(t,J=7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ145.93,131.22,126.51,120.71,119.58,117.03,51.56,51.20,47.86,10.78.HR-MS(ESI):Calcd.C25H26N4,[M+H]+m/z:383.2235,found:383.2232.
实施例26
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物29的制备方法,与实施例1的区别在于:将步骤3)中的4-甲磺酰胺基苯胺替换为4-(4-苄基哌嗪基)苯胺,制备得到化合物29,收率为86.3%。1H NMR(400MHz,DMSO-d6)δ8.08(d,J=7.0Hz,2H),7.79–7.71(m,4H),7.40–7.31(m,5H),7.19(t,J=7.3Hz,2H),6.99(q,J=9.2Hz,4H),3.68(s,2H),3.23(s,4H),2.66(s,4H).13C NMR(100MHz,DMSO-d6)δ131.63,129.01,128.19,127.07,126.41,121.02,120.29,116.71,61.85,52.46,48.61.HR-MS(ESI):Calcd.C30H28N4,[M+H]+m/z:445.2392,found:445.2396.
实施例27
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物33的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为对甲苯胺,制备得到式Ⅴ(2)化合物,收率为63.1%;将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(2)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物33,收率为40.2%。1H NMR(400MHz,DMSO-d6)δ8.07–8.02(m,2H),7.91(d,J=8.5Hz,1H),7.85(d,J=8.6Hz,1H),7.77(t,J=7.6Hz,1H),7.69(d,J=8.7Hz,1H),7.22(t,J=7.7Hz,1H),7.09(d,J=8.7Hz,2H),6.80(d,J=8.9Hz,2H),2.94(s,6H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)δ148.08,134.75,132.58,131.62,125.94,124.46,122.96,121.82,119.98,119.75,113.12,40.31,20.99.HR-MS(ESI):Calcd.C22H21N3,[M+H]+m/z:328.1813,found:328.1810.
实施例28
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物34的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为对氯苯胺,制备得到式Ⅴ(3)化合物,收率为45.1%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(3)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物34,收率为79.2%。结构表征为:1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.22(s,1H),7.53(s,4H),7.01(s,2H),6.74(s,4H),2.87(s,6H).13C NMR(100MHz,DMSO-d6)δ146.49,130.90,130.69,119.51,113.83,40.65.HR-MS(ESI):Calcd.C21H18ClN3,[M+H]+m/z:348.1267,found:348.1265.
实施例29
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物35的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为对氨基苯腈,制备得到式Ⅴ(4)化合物,收率为55.9%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(4)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物35,收率为43.7%。结构表征为:1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.40(d,J=134.3Hz,1H),7.77(s,1H),7.45(d,J=39.7Hz,4H),6.74(dd,J=29.7,8.1Hz,5H),2.88(s,6H).13C NMR(100MHz,DMSO-d6)δ149.33,146.72,132.80,131.64,119.25,119.08,114.10,40.73.HR-MS(ESI):Calcd.C22H18N4,[M+H]+m/z:339.1609,found:339.1605.
实施例30
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物36的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为对甲氧基苯胺,制备得到式Ⅴ(5)化合物,收率为77.7%;将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(5)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物36,收率为67.4%。1H NMR(400MHz,DMSO-d6)δ8.04(d,J=8.5Hz,1H),7.82(t,J=8.3Hz,2H),7.64(t,J=7.5Hz,1H),7.49(s,1H),7.40(dd,J=9.2,2.3Hz,1H),7.21(t,J=7.5Hz,1H),6.91(d,J=8.7Hz,2H),6.75(d,J=8.8Hz,2H),3.67(s,3H),2.87(s,6H).13CNMR(100MHz,DMSO-d6)δ154.39,147.00,130.32,125.02,124.19,122.30,121.69,113.42,55.10,40.53.HR-MS(ESI):Calcd.C22H21N3O,[M+H]+m/z:344.1763,found:344.1767.
实施例31
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物37的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为3-甲氧基苯胺,其它条件相同,制备得到式Ⅴ(6)化合物,收率为47.8%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(6)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到化合物37,收率为75.6%。1H NMR(400MHz,DMSO-d6)δ8.34(d,J=8.4Hz,1H),8.03(d,J=9.6Hz,1H),7.97(d,J=8.3Hz,1H),7.89(t,J=7.6Hz,1H),7.40–7.37(m,2H),7.22(d,J=8.9Hz,2H),6.97(dd,J=9.6,2.3Hz,1H),6.81(d,J=8.9Hz,2H),3.95(s,3H),2.97(s,6H).13C NMR(100MHz,DMSO-d6)δ163.74,153.78,149.25,142.91,139.71,134.26,129.15,127.79,125.48,125.37,123.02,118.56,115.23,113.37,112.60,107.71,97.94,55.88,39.92.HR-MS(ESI):Calcd.C22H21N3O,[M+H]+m/z:344.1763,found:344.1761.
实施例32
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物38的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为邻甲氧基苯胺,制备得到式Ⅴ(7)化合物,收率为76.2%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(7)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到化合物38,收率为42.5%。1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),8.04(d,J=8.6Hz,2H),7.68(t,J=7.5Hz,2H),7.27(d,J=7.7Hz,1H),7.14(dt,J=16.1,7.3Hz,2H),6.95(d,J=8.4Hz,2H),6.76(d,J=8.7Hz,2H),4.06(s,3H),2.91(s,6H).13C NMR(100MHz,DMSO-d6)δ152.06,148.69,147.70,140.85,132.37,125.90,122.33,122.04,121.49,120.08,117.41,113.25,111.13,56.29,40.38.HR-MS(ESI):Calcd.C22H21N3O,[M+H]+m/z:344.1763,found:344.1766.
实施例33
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物39的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为邻甲苯胺,制备得到式Ⅴ(8)化合物,收率为66.0%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(8)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物39,收率为52.7%。1H NMR(400MHz,CDCl3)δ8.03(d,J=7.9Hz,1H),7.92(dd,J=19.0,8.6Hz,2H),7.57(t,J=7.6Hz,1H),7.44(d,J=6.7Hz,1H),7.20–7.11(m,2H),6.89(d,J=8.9Hz,2H),6.68(d,J=8.9Hz,2H),2.91(s,6H),2.81(s,3H).13C NMR(100MHz,CDCl3)δ147.10,130.29,130.03,124.48,123.22,123.04,122.39,120.82,118.73,118.53,113.96,41.16,18.61.HR-MS(ESI):Calcd.C22H21N3,[M+H]+m/z:328.1813,found:328.1809.
实施例34
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物40的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2-乙基苯胺,其它条件相同,制备得到式Ⅴ(9)化合物,收率为55.2%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(9)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物40,收率为70.8%。1H NMR(400MHz,CDCl3)δ8.15(d,J=7.2Hz,1H),7.95(t,J=7.4Hz,2H),7.52(s,1H),7.40(s,1H),7.14(d,J=5.8Hz,2H),6.97(d,J=7.1Hz,2H),6.67(d,J=7.8Hz,2H),3.32(d,J=5.8Hz,2H),2.92(s,6H),1.40(t,J=6.0Hz,3H).13C NMR(100MHz,CDCl3)δ147.55,135.20,130.70,129.09,124.68,123.22,122.53,121.60,118.03,117.57,113.71,41.02,24.51,14.02.HR-MS(ESI):Calcd.C23H23N3,[M+H]+m/z:342.1970,found:342.1968.
实施例35
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物41的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2-异丙基苯胺,制备得到式Ⅴ(10)化合物,收率为87.3%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(10),将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物41,收率为85.3%。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.06(d,J=36.1Hz,3H),7.65(s,1H),7.54(s,1H),7.28(s,2H),6.79(s,2H),6.67(d,J=8.3Hz,2H),4.46(s,1H),2.83(s,6H),1.36(d,J=6.5Hz,6H).13C NMR(100MHz,DMSO-d6)δ146.20,129.64,125.15,122.83,120.31,113.51,40.64,26.61,23.37.HR-MS(ESI):Calcd.C24H25N3,[M+H]+m/z:356.2126,found:356.2118.
实施例36
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物42的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2-甲巯基苯胺,其它条件相同,制备得到式Ⅴ(11)化合物,收率为59.7%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(11)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物42,收率为65.6%。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.13(d,J=8.0Hz,1H),7.98(d,J=8.6Hz,1H),7.88(d,J=8.2Hz,1H),7.68(t,J=7.4Hz,1H),7.36–7.23(m,3H),6.86(d,J=8.7Hz,2H),6.67(d,J=8.9Hz,2H),2.85(s,6H),2.49(s,3H).13C NMR(100MHz,DMSO-d6)δ147.98,146.60,139.88,135.10,129.84,129.41,124.36,123.23,122.85,122.16,121.24,119.60,118.20,117.26,113.30,40.54,13.57.HR-MS(ESI):Calcd.C22H21N3S,[M+H]+m/z:360.1534,found:360.1531.
实施例37
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物43的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为N,N-二甲基邻苯二胺,制备得到式Ⅴ(12)化合物,收率为44.3%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(12)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物43,收率为43.8%。结构表征为:1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),7.97(s,1H),7.92(d,J=8.5Hz,1H),7.63(s,1H),7.54(t,J=7.4Hz,1H),7.16(d,J=6.8Hz,1H),7.09(s,1H),7.01(s,1H),6.72(dd,J=19.2,8.9Hz,4H),2.89(s,6H),2.85(s,6H).13C NMR(100MHz,DMSO-d6)δ146.33,130.37,125.59,121.55,119.96,113.71,44.09,40.68.HR-MS(ESI):Calcd.C23H24N4,[M+H]+m/z:357.2079,found:357.2081.
实施例38
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物44的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2-氨基联苯,制备得到式Ⅴ(13)化合物,收率为46.2%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(13)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物44,收率为89.7%。结构表征为:1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.18(s,2H),7.78–7.72(m,3H),7.60(s,2H),7.51(t,J=7.5Hz,2H),7.42(t,J=7.4Hz,1H),7.37–7.25(m,2H),6.84(d,J=7.2Hz,2H),6.69(d,J=8.8Hz,2H),2.85(s,6H).13C NMR(100MHz,DMSO-d6)δ146.37,130.48,129.88,127.83,127.01,120.46,113.53,40.62.HR-MS(ESI):Calcd.C27H23N3,[M+H]+m/z:390.1970,found:390.1969.
实施例39
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物45的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为3,4-二氟苯胺,其它条件相同,制备得到式Ⅴ(14)化合物,收率为50.3%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(14),将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物45,收率为48.1%。结构表征为:1H NMR(400MHz,DMSO-d6)δ10.83(s,0.5H),9.16(s,0.5H),8.04(s,2H),7.59(s,3H),7.16(s,1H),6.79–6.72(m,4H),2.87(s,6H).13C NMR(100MHz,DMSO-d6)δ146.69,130.74,113.59,40.52.HR-MS(ESI):Calcd.C21H17F2N3,[M+H]+m/z:350.1469,found:350.1468.
实施例40
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物46的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为3,4-二甲基苯胺,其它条件相同,制备得到式Ⅴ(15)化合物,收率为81.1%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(15)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物46,收率为44.2%。1H NMR(400MHz,DMSO-d6)δ8.10(d,J=8.7Hz,1H),7.99–7.89(m,2H),7.79(t,J=7.6Hz,1H),7.68(s,1H),7.25(t,J=7.7Hz,1H),7.10(d,J=8.7Hz,2H),6.80(d,J=8.9Hz,2H),2.95(s,6H),2.42(s,3H),2.22(s,3H).13C NMR(100MHz,DMSO-d6)δ171.95,152.60,148.82,144.81,140.65,139.68,133.32,132.40,125.73,124.82,124.50,124.34,122.33,119.56,118.73,114.00,112.96,48.55,20.13,19.64.HR-MS(ESI):Calcd.C23H23N3,[M+H]+m/z:342.1970,found:342.1974.
实施例41
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物47的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2,4-二甲基苯胺,制备得到式Ⅴ(16)化合物,收率66.5%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(16)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到吖啶类化合物47,收率为50.0%。1H NMR(400MHz,CDCl3)δ8.11(d,J=8.4Hz,1H),7.90(d,J=8.7Hz,1H),7.69(s,1H),7.58(t,J=7.4Hz,1H),7.34(s,1H),7.19(t,J=7.5Hz,1H),6.87(d,J=8.8Hz,2H),6.68(d,J=8.9Hz,2H),2.90(s,6H),2.83(s,3H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ146.92,136.43,133.27,132.85,129.55,124.53,123.37,120.39,120.00,119.35,118.75,114.05,41.26,21.92,18.65.HR-MS(ESI):Calcd.C23H23N3,[M+H]+m/z:342.1970,found:342.1969.
实施例42
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物48的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(17)化合物,收率55.2%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(17)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物48,收率为45.7%。结构表征为:1H NMR(400MHz,CDCl3)δ8.08(d,J=8.5Hz,1H),7.91(d,J=8.6Hz,1H),7.82(d,J=8.8Hz,1H),7.55(t,J=7.5Hz,1H),7.14(t,J=7.6Hz,1H),7.04(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,2H),6.67(d,J=8.9Hz,2H),2.91(s,6H),2.76(s,3H),2.42(s,3H).13C NMR(100MHz,CDCl3)δ147.18,138.16,136.17,130.07,126.77,124.35,123.02,121.35,121.07,117.83,117.02,113.90,41.15,20.87,13.72.HR-MS(ESI):Calcd.C23H23N3,[M+H]+m/z:342.1970,found:342.1967.
实施例43
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物49的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-3-甲基苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(18)化合物,收率41.1%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(18)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到吖啶类化合物49,收率为47.1%。1H NMR(400MHz,CDCl3)δ7.82(d,J=23.6Hz,2H),7.50(s,1H),7.15(s,2H),6.83(d,J=7.6Hz,2H),6.66(d,J=8.2Hz,2H),6.52(s,1H),2.89(s,12H),2.49(s,3H).13C NMR(100MHz,CDCl3)δ147.07,146.51,136.64,128.92,127.42,124.44,123.96,123.47,123.17,121.17,119.89,119.10,118.69,117.72,114.08,41.25,20.66,18.52,13.46.HR-MS(ESI):Calcd.C24H25N3,[M+H]+m/z:356.2126,found:356.2119.
实施例44
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物50的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-4-甲基苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(19)化合物,收率71.7%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(19)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到吖啶类化合物50,收率为89.9%。1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.89(d,J=8.6Hz,1H),7.70(d,J=8.8Hz,1H),6.99(t,J=9.0Hz,3H),6.88(d,J=8.2Hz,1H),6.68(d,J=8.8Hz,2H),2.93(s,6H),2.73(s,3H),2.44(s,3H),2.39(s,3H).13C NMR(100MHz,CDCl3)δ147.82,126.30,125.31,124.61,122.33,122.05,115.72,114.42,113.55,40.94,21.89,20.99,13.91.HR-MS(ESI):Calcd.C24H25N3,[M+H]+m/z:356.2126,found:356.2124.
实施例45
本实施例的吖啶类化合物的结构以及制备方法如下:
化合物51的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-5-甲基苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(20)化合物,收率47.8%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(20),将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物51,收率为74.7%。1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.72(s,2H),7.48(s,1H),7.08(s,1H),6.81(d,J=8.1Hz,2H),6.67(d,J=7.7Hz,2H),6.45(s,1H),2.88(s,9H),2.47(s,3H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ146.58,132.09,119.77,114.20,41.35,21.95,20.76,13.70.HR-MS(ESI):Calcd.C24H25N3,[M+H]+m/z:356.2126,found:356.2125.
实施例46
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物52的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-6-甲基苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(21)化合物,收率48.8%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(21),将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物52,收率为88.2%。结构表征为:1HNMR(400MHz,CDCl3)δ7.61(s,1H),7.51(s,1H),7.32(s,1H),6.98(s,1H),6.80(s,1H),6.72(d,J=8.3Hz,2H),6.66(d,J=7.9Hz,2H),2.90(s,6H),2.77(s,3H),2.56(s,3H),2.37(s,3H).13C NMR(100MHz,CDCl3)δ146.31,137.56,129.14,125.99,124.01,120.89,119.14,114.42,41.43,23.63,20.68,13.00.HR-MS(ESI):Calcd.C24H25N3,[M+H]+m/z:356.2126,found:356.2116.
实施例47
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物53的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-5-(三氟甲基)苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(22)化合物,收率48.4%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(22)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到吖啶类化合物53,收率为91.1%。结构表征为:1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),7.79–7.57(m,2H),7.03(d,J=7.0Hz,1H),6.86(d,J=8.7Hz,2H),6.69(d,J=8.7Hz,2H),2.90(s,6H),2.70(s,3H),2.44(s,3H).13C NMR(400MHz,CDCl3)δ147.57,138.61,125.71,124.97,123.01,121.17,117.04,114.13,41.17,20.80,13.50.HR-MS(ESI):Calcd.C23H22N4O2,[M+H]+m/z:387.1821,found:387.1818.
实施例48
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物54的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-5-氟苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(23)化合物,收率93.8%。将步骤2)中的式Ⅴ(1)化合物替换为式Ⅴ(23)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物54,收率为92.5%。1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.75(d,J=8.8Hz,1H),7.52(d,J=9.8Hz,1H),7.43(t,J=7.5Hz,1H),7.19(d,J=7.4Hz,1H),6.82(d,J=8.9Hz,2H),6.67(d,J=8.8Hz,2H),6.43(s,1H),2.90(s,6H),2.86(s,3H),2.50(s,3H).13C NMR(100MHz,CDCl3)δ159.73,157.28,146.87,136.85,133.19,128.23,120.67,120.40,120.24,119.62,118.81,118.02,114.04,106.18,41.18,20.72,13.68.HR-MS(ESI):Calcd.C24H22F3N3,[M+H]+m/z:360.1876,found:360.1873.
实施例49
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物55的制备方法,与实施例1的区别在于:
将步骤1)中的式Ⅱ化合物替换为2-氯-4,5-二氟苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(24)化合物,收率62.5%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(24)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,制备得到化合物55,收率为92.6%。1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.75(d,J=8.9Hz,1H),7.59(dd,J=11.6,9.4Hz,1H),7.20(d,J=8.4Hz,1H),6.83(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.48(s,1H),2.91(s,6H),2.82(s,3H),2.50(s,3H).13C NMR(100MHz,CDCl3)δ154.14,153.96,151.60,151.42,147.19,137.47,135.08,128.13,120.81,119.14,117.52,115.05,113.94,109.08,41.09,20.77,13.69.HR-MS(ESI):Calcd.C23H21F2N3,[M+H]+m/z:378.1782,found:378.1779.
实施例50
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物56的制备方法,与实施例1的区别在于:将步骤1)中的式Ⅱ化合物替换为2-氯-4,5-二甲氧基苯甲酸,式Ⅲ化合物替换为2,3-二甲基苯胺,制备得到式Ⅴ(25)化合物,收率49.6%。将步骤2)中的式Ⅴ(1)化合物替换为以上合成的式Ⅴ(25)化合物,将4-甲磺酰胺基苯胺替换为N,N-二甲基对苯二胺,其它条件相同,制备得到吖啶类化合物56,收率为66.4%。结构表征为:1H NMR(400MHz,CDCl3)δ7.85(d,J=8.5Hz,1H),7.69(s,1H),7.14–6.97(m,4H),6.67(d,J=8.8Hz,2H),4.06(s,3H),3.65(s,3H),2.90(s,6H),2.77(s,3H),2.42(s,3H).13C NMR(100MHz,CDCl3)δ154.31,147.56,147.28,126.47,122.02,113.64,102.37,56.36,55.59,41.06,20.90,13.91.HR-MS(ESI):Calcd.C25H27N3O2,[M+H]+m/z:402.2181,found:402.2178.
实施例51
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物3的制备方法,采用实施例1的步骤1)和2),得到式Ⅴ化合物,还包含以下步骤:3)将式Ⅴ化合物(107mg,0.5mmol)溶于苯酚(5mL),加入碳酸铵(192.18mg,1mmol),加热至120℃反应,TLC监测反应进度。反应完成后,向反应体系中加入乙酸乙酯和水,萃取,有机相用无水硫酸镁干燥,过滤,旋蒸除去溶剂后,经柱层析分离得到中间体式Ⅵ化合物,收率为83.2%。4)将中间体式Ⅵ化合物(214mg,1.1mmol)、6-溴-1,4-苯并恶烷(215mg,1mmol)、双(二亚苄基丙酮)钯(35mg,0.06mmol)、四氟硼酸三叔丁基膦(17mg,0.06mmol)和叔丁醇钠(111mg,1.15mmol)溶于干燥的1,4-二氧六环(10mL),氮气保护的条件下回流反应10小时,冷却至室温,向反应体系中依次加入去离子水(50mL)、饱和亚硫酸钠(15mL)、二氯甲烷(50mL),搅拌约30分钟,有机相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,旋蒸除去溶剂后,经柱层析分离得到吖啶类化合物3,收率为63.2%。结构表征为:1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.93–7.42(m,1H),7.00(s,2H),6.78(d,J=8.4Hz,1H),6.25(dd,J=14.9,6.4Hz,2H),4.23(s,4H).13C NMR(100MHz,DMSO-d6)δ144.04,138.12,131.02,117.73,110.99,106.53,64.20,63.87.HR-MS(ESI):Calcd.C21H16N2O2,[M+H]+m/z:329.1290,found:329.1289.
实施例52
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物4的制备方法,与实施例51的区别在于:将实施例51中的6-溴-1,4-苯并恶烷替换为6-溴-2-甲基喹啉,制备得到吖啶类化合物4,收率为46.6%。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.03(d,J=7.1Hz,2H),7.86(d,J=8.9Hz,1H),7.52–6.96(m,9H),2.62(s,3H).13C NMR(100MHz,DMSO-d6)δ155.72,143.73,134.82,131.33,129.53,127.58,123.57,122.14,24.55.HR-MS(ESI):Calcd.C23H17N3,[M+H]+m/z:336.1500,found:336.1507.
实施例53
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物5的制备方法,与实施例51的区别在于:将实施例51中的6-溴-1,4-苯并恶烷替换为2-溴-9-乙基-9H-咔唑,制备得到吖啶类化合物5,收率为57.7%。1H NMR(400MHz,CDCl3)δ8.05(dd,J=16.8,8.7Hz,4H),7.84(d,J=8.2Hz,2H),7.49–7.36(m,4H),7.22(s,2H),7.08(dt,J=32.0,7.6Hz,3H),4.29(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO)δ153.24,140.79,140.10,137.27,133.28,126.16,123.01,122.12,122.00,120.79,120.65,118.90,118.76,115.29,113.75,110.18,109.32,37.14,13.74.HR-MS(ESI):Calcd.C27H21N3,[M+H]+m/z:388.1813,found:388.1715.
实施例54
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物30的制备方法,与实施例51的区别在于:将实施例51中的6-溴-1,4-苯并恶烷替换为2-溴-5-二甲基氨基吡啶,制备得到吖啶类化合物30,收率为44.7%。1HNMR(400MHz,DMSO-d6)δ11.36(s,1H),7.96(s,2H),7.78(s,1H),7.58–7.50(m,4H),7.14(dd,J=8.9,2.3Hz,1H),7.05(s,2H),6.67(d,J=8.9Hz,1H),3.02(s,6H).13C NMR(100MHz,DMSO-d6)δ155.55,138.22,131.56,129.61,126.42,120.75,118.34,106.19,37.96.HR-MS(ESI):Calcd.C20H18N4,[M+H]+m/z:315.1609,found:315.1605.
实施例55
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物31的制备方法,与实施例51的区别在于:将实施例51中的6-溴-1,4-苯并恶烷替换为4-溴-4',4”-二甲基三苯胺,制备得到吖啶类化合物31,收率为68.4%。1HNMR(400MHz,DMSO-d6)δ10.93(s,1H),7.92(s,2H),7.52–7.40(m,4H),7.08(d,J=8.3Hz,4H),7.02(s,2H),6.95(d,J=8.6Hz,2H),6.90(d,J=8.3Hz,4H),6.73(d,J=8.5Hz,2H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ145.27,141.30,131.09,130.81,129.73,125.93,122.63,119.24,20.20.HR-MS(ESI):Calcd.C33H27N3,[M+H]+m/z:466.2283,found:466.2282.
实施例56
本实施例的吖啶类化合物的结构以及制备方法如下:
吖啶类化合物32的制备方法,与实施例51的区别在于:将实施例51中的6-溴-1,4-苯并恶烷替换为9-(4-溴苯基)-咔唑,制备得到吖啶类化合物32,收率为46.3%。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.36–7.93(m,4H),7.72–7.39(m,10H),7.29(t,J=7.4Hz,2H),7.05(d,J=8.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ140.60,131.39,128.23,126.14,122.45,120.45,119.69,109.55.HR-MS(ESI):Calcd.C31H21N3,[M+H]+m/z:436.1813,found:436.1812.
实验例1
LSD1抑制活性测定:样品为实施例1~56所制备得到的吖啶类化合物经纯化得到,阳性化合物ORY-1001购买自MedChemExpress公司。样品储备液的配制过程为:分别称取1~2mg样品,用DMSO配制成浓度为20mM的溶液,于4℃环境下保存备用,实验时用DMSO稀释至所需浓度。将待测样品与LSD1蛋白在室温孵育后,加入LSD1底物H3K4me2并孵育,最后加入荧光染料Amplex和辣根过氧化物酶HRP室温孵育,在酶标仪上激发光530nm、发射光590nm检测荧光数值,抑制率计算公式如下所示。实验结果采用SPSS软件计算IC50值,结果如表1所示。
表1本发明吖啶类化合物的LSD1抑制活性和IC50
由表1可知,本发明提供的吖啶类化合物对LSD1有不同程度的抑制活性。其中,当化合物浓度为10μM时,吖啶类化合物5-6、11-14、16-20、25-31、33-42、44-56对LSD1的抑制活性较高,抑制率均达80%以上,吖啶类化合物1-3、5-6、11-14、16-17、19-20、25-30、33-42、44-56抑制活性更高,对LSD1的抑制率可达90%以上。此外,吖啶类化合物16、19、20、27、36、38、39、41、42、48、50、51、53、54、56发挥作用时,IC50值较低,均低于0.1μM,说明上述吖啶类化合物发挥有效抑制活性的浓度较低,具有较小的生物毒性。
综上,本发明提供的吖啶类化合物对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。
Claims (9)
4.一种权利要求1所述的吖啶类化合物的制备方法,其特征在于,选自合成路线①或合成路线②;
所述合成路线①,包括以下步骤:
1)将式Ⅱ化合物、式Ⅲ化合物、碱性物质A、催化剂A于有机溶剂A中反应,制得式Ⅳ化合物;
2)将式Ⅳ化合物在三氯氧磷或氯化亚砜的作用下于有机溶剂B中反应,制得式Ⅴ化合物;
3)将式Ⅴ化合物、R3H、催化剂B在有机溶剂C中反应,得到式Ⅰ所示的吖啶类化合物;
所述合成路线②,包括以下步骤:
a)将式Ⅱ化合物、式Ⅲ化合物、碱性物质A、催化剂A于有机溶剂A中反应,制得式Ⅳ化合物;
b)将式Ⅳ化合物在三氯氧磷或氯化亚砜的作用下于有机溶剂B中反应,制得式Ⅴ化合物;
c)将式Ⅴ化合物、胺类物质在有机溶剂D中反应,制得式Ⅵ化合物;所述胺类物质为碳酸胺、硫酸铵、氨水中的一种;
d)将式Ⅵ化合物、R3X、碱性物质B、催化剂C于有机溶剂E中反应,得到式Ⅰ所示的吖啶类化合物;其中X为Br、Cl中的一种。
5.如权利要求4所述的吖啶类化合物的制备方法,其特征在于,所述有机溶剂A、B、C、E各自独立的选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氧六环、甲醇、乙醇、甲苯中的一种;所述有机溶剂D为苯酚、二甲基亚砜、N,N-二甲基甲酰胺、聚乙二醇中的一种。
6.如权利要求4所述的吖啶类化合物的制备方法,其特征在于,所述催化剂A为铜粉;所述催化剂B为冰醋酸、盐酸、硫酸中的一种;所述催化剂C为四(三苯基膦)钯、双(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯中的一种。
7.如权利要求4所述的吖啶类化合物的制备方法,其特征在于,所述碱性物质A为碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、三乙胺、吡啶、氢氧化钠、氢氧化钾中的一种;所述碱性物质B为叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠中的一种。
8.如权利要求4所述的吖啶类化合物的制备方法,其特征在于,步骤1)和步骤a)的反应温度为80~160℃;步骤2)和步骤b)的反应温度为60~150℃;步骤3)的反应温度为20~80℃;步骤c)的反应温度为90~180℃;步骤d)的反应温度为60~150℃。
9.如权利要求1~3任一项所述的吖啶类化合物的应用,其特征在于,所述吖啶类化合物在制备基于LSD1靶点的抗肿瘤药物中的应用。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
WO2024110649A1 (en) | 2022-11-24 | 2024-05-30 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors and menin inhibitors for treating cancer |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200529832A (en) * | 2004-03-12 | 2005-09-16 | Academia Sinica | 9-anilinoacridine alkylating agents |
CN102134220A (zh) * | 2011-01-18 | 2011-07-27 | 清华大学深圳研究生院 | 9-苯胺基吖啶衍生物及其制备方法与应用 |
US20120220537A1 (en) * | 2009-11-01 | 2012-08-30 | Ariel-University Research And Development Company Ltd. | 9-aminoacridine derivatives, their preparation and uses |
CN103254130A (zh) * | 2013-05-09 | 2013-08-21 | 清华大学深圳研究生院 | 吖啶衍生物及其制备方法和用途 |
CN103896918A (zh) * | 2014-03-14 | 2014-07-02 | 清华大学深圳研究生院 | 化合物及其制备方法和用途 |
US20170022166A1 (en) * | 2014-03-31 | 2017-01-26 | MiRx Pharmaceuticals, LLC | Novel hdmx inhibitors and their use for cancer treatment |
-
2022
- 2022-04-27 CN CN202210452864.1A patent/CN114805205A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200529832A (en) * | 2004-03-12 | 2005-09-16 | Academia Sinica | 9-anilinoacridine alkylating agents |
US20120220537A1 (en) * | 2009-11-01 | 2012-08-30 | Ariel-University Research And Development Company Ltd. | 9-aminoacridine derivatives, their preparation and uses |
CN102134220A (zh) * | 2011-01-18 | 2011-07-27 | 清华大学深圳研究生院 | 9-苯胺基吖啶衍生物及其制备方法与应用 |
CN103254130A (zh) * | 2013-05-09 | 2013-08-21 | 清华大学深圳研究生院 | 吖啶衍生物及其制备方法和用途 |
CN103896918A (zh) * | 2014-03-14 | 2014-07-02 | 清华大学深圳研究生院 | 化合物及其制备方法和用途 |
US20170022166A1 (en) * | 2014-03-31 | 2017-01-26 | MiRx Pharmaceuticals, LLC | Novel hdmx inhibitors and their use for cancer treatment |
Non-Patent Citations (6)
Title |
---|
ACS: "STN检索报告", 《STN REGISTRY数据库》, pages 1 - 14 * |
ANA BOROTA等: "A QSAR study using MTD method and Dragon descriptors for a series of selective ligands of α2C adrenoceptor", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 46, pages 879 * |
HAIXIAO JIN等: "Acetylcholinesterase and Butyrylcholinesterase Inhibitory Properties of Functionalized Tetrahydroacridines and Related Analogs", 《MED CHEM》, vol. 4, no. 10, pages 5 - 48 * |
HUA GAO等: "Quantitative structure–activity relationships (QSAR) for 9-anilinoacridines: a comparative analysis", 《CHEMICO-BIOLOGICAL INTERACTIONS》, vol. 116, pages 163 - 164 * |
SWARNA A. GAMAGE等: "Structure-Activity Relationships for the Antileishmanial and Antitrypanosomal Activities of 1\'-Substituted 9-Anilinoacridines", 《J. MED. CHEM》, vol. 40, no. 16, pages 2635 * |
郭佩佩等: "吖啶衍生物合成及其在医药领域的应用进展", 《精细与专用化学品》, vol. 29, no. 12, pages 27 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
WO2024110649A1 (en) | 2022-11-24 | 2024-05-30 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors and menin inhibitors for treating cancer |
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