CN115710251A - 一种髓样分化因子88抑制剂及其制备方法和应用 - Google Patents
一种髓样分化因子88抑制剂及其制备方法和应用 Download PDFInfo
- Publication number
- CN115710251A CN115710251A CN202211458016.8A CN202211458016A CN115710251A CN 115710251 A CN115710251 A CN 115710251A CN 202211458016 A CN202211458016 A CN 202211458016A CN 115710251 A CN115710251 A CN 115710251A
- Authority
- CN
- China
- Prior art keywords
- compound
- nitrophenyl
- piperazin
- methyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 title claims abstract description 40
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 title claims abstract description 40
- 239000003112 inhibitor Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 206010061218 Inflammation Diseases 0.000 claims abstract description 17
- 230000004054 inflammatory process Effects 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 6
- -1 2-methoxypyridin-5-yl Chemical group 0.000 claims description 142
- 150000001875 compounds Chemical class 0.000 claims description 108
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000002156 mixing Methods 0.000 claims description 26
- 230000035484 reaction time Effects 0.000 claims description 25
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 206010040047 Sepsis Diseases 0.000 claims description 11
- 206010069351 acute lung injury Diseases 0.000 claims description 11
- 239000012298 atmosphere Substances 0.000 claims description 11
- 230000001681 protective effect Effects 0.000 claims description 11
- RZTFYZSXSDRAIB-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfinic acid Chemical compound OS(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 RZTFYZSXSDRAIB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- SEWNAJIUKSTYOP-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC(S(Cl)(=O)=O)=CC=C1Cl SEWNAJIUKSTYOP-UHFFFAOYSA-N 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 239000013067 intermediate product Substances 0.000 claims description 7
- 235000010265 sodium sulphite Nutrition 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IGJDIGJIINCEDE-UHFFFAOYSA-N 1,3,5-trimethylpiperidine Chemical compound CC1CC(C)CN(C)C1 IGJDIGJIINCEDE-UHFFFAOYSA-N 0.000 claims description 6
- BMEMBBFDTYHTLH-UHFFFAOYSA-N 1-(2-methoxyethyl)piperazine Chemical compound COCCN1CCNCC1 BMEMBBFDTYHTLH-UHFFFAOYSA-N 0.000 claims description 6
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 2
- 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 claims description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
- 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 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 2
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 claims description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 2
- 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 claims description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 claims description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 2
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 claims description 2
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 claims description 2
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 claims description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 claims description 2
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 claims description 2
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 claims description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 2
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 claims description 2
- RUHKZVAPXHIWJH-UHFFFAOYSA-N 2-amino-4-methylbenzamide Chemical compound CC1=CC=C(C(N)=O)C(N)=C1 RUHKZVAPXHIWJH-UHFFFAOYSA-N 0.000 claims description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 claims description 2
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 claims description 2
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 claims description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 claims description 2
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 claims description 2
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 claims description 2
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 claims description 2
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims description 2
- 229940126639 Compound 33 Drugs 0.000 claims description 2
- 229940127007 Compound 39 Drugs 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 claims description 2
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 claims description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-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
- 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 claims 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 claims description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims 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 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims description 2
- 229940126543 compound 14 Drugs 0.000 claims description 2
- 229940125758 compound 15 Drugs 0.000 claims description 2
- 229940126142 compound 16 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940125810 compound 20 Drugs 0.000 claims description 2
- 229940126086 compound 21 Drugs 0.000 claims description 2
- 229940126208 compound 22 Drugs 0.000 claims description 2
- 229940125833 compound 23 Drugs 0.000 claims description 2
- 229940125961 compound 24 Drugs 0.000 claims description 2
- 229940125846 compound 25 Drugs 0.000 claims description 2
- 229940125851 compound 27 Drugs 0.000 claims description 2
- 229940127204 compound 29 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229940125877 compound 31 Drugs 0.000 claims description 2
- 229940125878 compound 36 Drugs 0.000 claims description 2
- 229940125807 compound 37 Drugs 0.000 claims description 2
- 229940127573 compound 38 Drugs 0.000 claims description 2
- 229940126540 compound 41 Drugs 0.000 claims description 2
- 229940125936 compound 42 Drugs 0.000 claims description 2
- 229940125844 compound 46 Drugs 0.000 claims description 2
- 229940127271 compound 49 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 229940126545 compound 53 Drugs 0.000 claims description 2
- 229940127113 compound 57 Drugs 0.000 claims description 2
- 229940125900 compound 59 Drugs 0.000 claims description 2
- 229940126179 compound 72 Drugs 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 claims description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 claims description 2
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 claims description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 claims 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims 1
- ATNMJYCSSCNVMR-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NCC1=CC=CC=N1 ATNMJYCSSCNVMR-UHFFFAOYSA-N 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 108090000695 Cytokines Proteins 0.000 abstract description 2
- 102000004127 Cytokines Human genes 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 185
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 134
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 55
- 241000699670 Mus sp. Species 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 12
- 239000002158 endotoxin Substances 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 229920006008 lipopolysaccharide Polymers 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 239000012530 fluid Substances 0.000 description 8
- 108090001005 Interleukin-6 Proteins 0.000 description 7
- 102000002689 Toll-like receptor Human genes 0.000 description 7
- 108020000411 Toll-like receptor Proteins 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 231100000915 pathological change Toxicity 0.000 description 4
- 230000036285 pathological change Effects 0.000 description 4
- 102000007863 pattern recognition receptors Human genes 0.000 description 4
- 108010089193 pattern recognition receptors Proteins 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- XNLFHCPVTULKIV-VAWYXSNFSA-N (e)-3-(4-methylphenyl)-1-phenylprop-2-en-1-one Chemical compound C1=CC(C)=CC=C1\C=C\C(=O)C1=CC=CC=C1 XNLFHCPVTULKIV-VAWYXSNFSA-N 0.000 description 3
- BMJRJOGXNMESQI-UHFFFAOYSA-N 4-benzylsulfonyl-1-chloro-2-nitrobenzene Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(S(=O)(=O)CC=2C=CC=CC=2)=C1 BMJRJOGXNMESQI-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101000595548 Homo sapiens TIR domain-containing adapter molecule 1 Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102100036073 TIR domain-containing adapter molecule 1 Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 102000035181 adaptor proteins Human genes 0.000 description 3
- 108091005764 adaptor proteins Proteins 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000015788 innate immune response Effects 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000003437 trachea Anatomy 0.000 description 3
- UTEHUKGJDLVHIH-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-quinazolin-4-one Chemical compound C1=CC(C)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 UTEHUKGJDLVHIH-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000012064 NLR Proteins Human genes 0.000 description 2
- 108091005686 NOD-like receptors Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091005685 RIG-I-like receptors Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 1
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- PMUNIMVZCACZBB-UHFFFAOYSA-N 2-hydroxyethylazanium;chloride Chemical compound Cl.NCCO PMUNIMVZCACZBB-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UUVDJIWRSIJEBS-UHFFFAOYSA-N 6-methoxypyridin-3-amine Chemical compound COC1=CC=C(N)C=N1 UUVDJIWRSIJEBS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101000870361 Arabidopsis thaliana Glutathione S-transferase Z1 Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000003930 C-Type Lectins Human genes 0.000 description 1
- 108090000342 C-Type Lectins Proteins 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101000956314 Homo sapiens Maleylacetoacetate isomerase Proteins 0.000 description 1
- 101000685982 Homo sapiens NAD(+) hydrolase SARM1 Proteins 0.000 description 1
- 101000595554 Homo sapiens TIR domain-containing adapter molecule 2 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000649115 Homo sapiens Translocating chain-associated membrane protein 1 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 102100038560 Maleylacetoacetate isomerase Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 description 1
- 102100023356 NAD(+) hydrolase SARM1 Human genes 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 102100027965 Translocating chain-associated membrane protein 1 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940073579 ethanolamine hydrochloride Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 230000011542 interferon-beta production Effects 0.000 description 1
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 1
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- DYGBNAYFDZEYBA-UHFFFAOYSA-N n-(cyclopropylmethyl)-2-[4-(4-methoxybenzoyl)piperidin-1-yl]-n-[(4-oxo-1,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-2-yl)methyl]acetamide Chemical compound C1=CC(OC)=CC=C1C(=O)C1CCN(CC(=O)N(CC2CC2)CC=2NC(=O)C=3COCCC=3N=2)CC1 DYGBNAYFDZEYBA-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000849 selective androgen receptor modulator Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 108091008743 testicular receptors 4 Proteins 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于有机合成技术领域,提供了一种新的髓样分化因子88抑制剂及其制备方法和应用。所述新的髓样分化因子88抑制剂可以抑制炎症细胞因子超出正常量表达和释放,并以此为药理机制治疗过度炎症相关的疾病。实验表明,本发明提供的MyD88抑制剂具有有效的炎症因子的抑制作用以及更优的体内抗炎活性。
Description
技术领域
本发明涉及有机物合成技术领域,尤其涉及一种髓样分化因子88抑制剂及其制备方法和应用。
背景技术
固有免疫是人体应对外源性或内源性异质物刺激的生理过程。通常情况下,固有免疫能通过炎症反应清除产生刺激的异质物,保护人体健康。但当某些疾病发生时,免疫调节出现异常,使病变部位产生过量的炎症反应,即炎症风暴,进一步损害人体健康。
固有免疫系统依赖于种系编码受体,即模式识别受体(pattern recognitionreceptors,PRRs),这些受体可以识别一种或多种病原相关模式分子(pathogen-associated molecular pattern,PAMPs),以及损伤相关分子模式(damage-associatedmolecular pattern,DAMPs),是启动固有免疫应答的免疫受体的代表。常见的模式识别受体包括Toll样受体(Toll-like receptors),RIG-I样受体(RIG-I like receptors),NOD样受体(NOD like receptors),AIM2样受体(AIM2 like receptors)和C型凝集素受体,以及cGas和其他细胞内DNA传感器。Toll样受体是研究最多的PRR之一,哺乳动物中目前共发现有10种Toll样受体,其识别DAMPs或PAMPs后通过下游的衔接蛋白进行信号转导。目前发现5种衔接蛋白,分别为MyD88,TRIF,TRAM,MAI和SARM,其中MyD88和TRIF作为主要的衔接蛋白将信号转导至下游。TRIF参与TLR3和TLR4的信号转导,介导IFNβ的产生,主要作为MyD88非依赖途径参与炎性信号转导,而MyD88则参与除TLR3外的所有TLRs家族的信号转导,其是TLRs/IL-1R信号转导的中心分子,也是炎症相关信号通路调节的关键蛋白。
MyD88的激活,一方面导致下游MAPKs/p38/JNK通路激活,从而使AP-1活化,另一方面激活TAK1/TAB复合物,激活NF-κB,使其入核,进而产生促炎因子如TNF-α和IL-6,使得大量炎症相关因子和化学因子转录和表达。有多项研究表明,基因敲除MyD88的小鼠对脂多糖以及葡萄球菌肠毒素诱导的死亡有所耐受。MyD88作为TLRs/IL-R信号通路的一个关键蛋白靶点,有作为治疗炎症相关疾病的潜在能力,已逐渐受到越来越多的研究者关注。但是,目前现有技术中MyD88抑制剂却有限,亟需研发一些新的MyD88抑制剂。
发明内容
本发明的目的在于提供一种髓样分化因子88抑制剂及其制备方法和应用,以弥补现有技术的不足。
本发明提供了一种髓样分化因子88抑制剂,为结构如式(Ⅰ)所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药;
其中:X和Y独立的包含CH2,NH,C(O),S(O)2中的一种;R1包含H,可以被1至3个相同或不同的取代基任选取代的芳基、可以被1至3个相同或不同的取代基任选取代的杂环基或可以被1至3个相同或不同的取代基任选取代的杂芳基,所述取代基选自烷基、卤素、烷氧基、取代芳基和取代杂芳基;R2包含氢或硝基;R3和R4独立地包含氢、烷基和芳基,或者R3和R4独立地成环从而使得-C(R3)R4形成取代杂环基或取代杂芳基,或者R3和X、Y独立地成环使得-XYCR3形成取代杂环基或取代芳杂基。
优选的,为以下化合物及其药学上可接受的盐、溶剂化物或前药:
化合物1:N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物2:4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物3:N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物4:N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物5:4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物6:N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物7:N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
化合物8:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物9:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物10:4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
化合物11:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物12:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物13:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物14:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物15:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
化合物16:2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
化合物17:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
化合物18:4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物19:4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物20:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物21:4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物22:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物23:4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物24:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物25:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物26:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
化合物27:4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物28:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物29:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物30:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
化合物31:4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物32:3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物33:N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物34:1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
化合物35:1-[4-(苄基磺酰基)-2-硝基苯基]-4-甲基哌嗪
化合物36:1-[4-(苄基磺酰基)-2-硝基苯基]-4-乙基哌嗪
化合物37:1-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-酮
化合物38:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(4-硝基苯基)哌嗪
化合物39:2-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-醇
化合物40:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(2-甲氧基乙基)哌嗪
化合物41:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(3-硝基苄基)哌嗪
化合物42:4-[(3-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物43:1-乙基-4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪
化合物44:1-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物45:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物46:2-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物47:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物48:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物49:4-[(4-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物50:1-乙基-4-[4-(4-氟苄基)磺酰基]-2-硝基苯基哌嗪
化合物51:1-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物52:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物53:2-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物54:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物55:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物56:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苄基)哌嗪
化合物57:1-乙基-4-[4-(4-甲基苄基)磺酰基]-2-硝基苯基)哌嗪
化合物58:1-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物59:1-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物60:2-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物61:1-(2-甲氧基乙基)-4-[4-(4-甲基苄基)磺酰基]2-硝基苯基)哌嗪
化合物62:4-[(4-甲氧基苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物63:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物64:1-乙基-4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物65:1-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物66:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物67:2-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物68:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物69:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物70:4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物71:4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物72:4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物73:4-{4-[(苯并[d][1,3]噻唑-2-基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物74:4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物75:4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物76:4-{4-[(戊基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物77:6-(4-甲氧基苯基)-4-{4-[(戊基氨基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物78:4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物79:6-(4-溴苯基)-4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物80:4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物81:6-(4-溴苯基)-4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物82:6-(4-甲氧基苯基)-4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物83:6-(4-溴苯基)-4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物84:4-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-6-(4-溴苯基)-1,2-二氢嘧啶-2-酮
化合物85:2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物86:2-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物87:2-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物88:2-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-3,4-二氢喹唑啉-4-酮
化合物89:7-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物90:7-{[4-(2-羟基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物91:7-{[4-(4-硝基苯基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物92:7-[(4-乙酰基哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
化合物93:7-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮。
本发明还提供了所述髓样分化因子88抑制剂的制备方法,化合物1~33的制备方法包含如下步骤:
(2)将含R1化合物、碳酸钾、碘化钠和无水四氢呋喃混合后进行反应,生成化合物1~33中的一种;所述含R1化合物、碳酸钾、碘化钠和无水四氢呋喃的用量比为0.1~0.2mmol:0.1~0.3mmol:0.2~0.4mmol:0.2~0.4mmol:4~8mL;所述反应的温度为60~80℃,时间为1~10h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法,化合物34~69的制备方法包含如下步骤:
(1)将碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水混后合后进行反应,生成4-氯-3-硝基苯亚磺酸;所述碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水的用量比为7~9mmol:7~9mmol:3~5mmol:20~40mL;所述反应的温度为室温,时间为1~5h;
(2)将4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺混合后进行反应,生成所述4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺的用量比为0.4~0.5mmol:0.6~0.8mmol:2~8mL;所述反应的温度为70~90℃,时间为1~5h;
(3)将碘化钾、三甲基哌啶、碳酸钾和乙腈混合后进行反应,生成化合物34~69中的一种;所述碘化钾、三甲基哌啶、碳酸钾和乙腈的用量比为0.09~0.11mmol:0.05~0.2mmol:0.05~0.2mmol:0.05~0.2mmol:2~8ml;所述反应的温度为80~90℃,时间为1~5h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法,化合物70~84的制备方法包含如下步骤:
(1)将苯乙酮、氢氧化钠、和乙醇混合后进行反应,生成所述苯乙酮、氢氧化钠、和乙醇的用量比为15~18mmol:23~28mmol:15~18mmol:5~15mL;所述反应的温度为室温,时间为5~15h;
(2)在保护气氛下,将N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳混合后进行反应,生成所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为2~2.5mmol:2~3mmol:0.2~0.8mmol:15~25mL;所述反应的温度为80~90℃,时间为1~5h;
(3)将含R1化合物、三乙胺和乙腈混合后进行反应,生成所述含R1化合物、三乙胺和乙腈的用量比为0.5~0.8mmol:0.8~1.2mmol:0.8~1.2mmol:5~15mL;所述反应的温度为80~90℃,时间为1~5h;
(4)在保护气氛下,将脲、叔丁醇钠和四氢呋喃混合后进行反应,生成化合物70~84中的一种;所述脲、叔丁醇钠和四氢呋喃的用量比为0.2~0.4mmol:0.3~0.5mmol:0.3~0.4mmol:1~10mL;所述反应的温度为80~90℃,时间为1~5h。
本发明还提供了所述髓样分化因子88抑制剂的制备方法,化合物85~93的制备方法包含如下步骤:
所述反应的温度为80~90℃,时间为1~5h;
所述R5和R1有一个为H;
所述反应的温度为80~90℃,时间为1~5h;
(3)在保护气氛下,将中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈混合后进行反应,生成化合物85~93中的一种;
所述中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈的用量比为0.1~0.5mmol:0.1~0.5mmol:45~55μL:5~15mL;
所述反应的温度为80~90℃,时间为1~5h。
本发明还提供了所述髓样分化因子88抑制剂在制备治疗炎症相关疾病的药物制剂中的应用。
优选的,所述炎症相关疾病包含急性肺损伤和/或脓毒血症。
本发明提供了一种新的髓样分化因子88抑制剂及其制备方法和应用。所述新的髓样分化因子88抑制剂可以抑制炎症细胞因子超出正常量表达和释放,并以此为药理机制治疗过度炎症相关的疾病。实验表明,本发明提供的MyD88抑制剂具有有效的炎症因子的抑制作用以及更优的体内抗炎活性。
本发明通式I的MyD88抑制剂可以与酸生成它的药学上可接受的盐。酸可以包括无机酸或有机酸,与下列酸形成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、酒石酸、苯磺酸、苯甲酸或对甲苯磺酸等。
本发明还包括通式IMyD88抑制剂的前药。依据本发明,前药是通式I化合物的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明可以含有上述通式I含有MyD88抑制剂,及其药学上可接受的盐、水合物或溶剂化物作为活性成份,与药学上可接受的载体或赋型剂混合制备成组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他不利的作用,例如过敏反应。
发明的药用组合物可配制成若干种剂型,其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下不稳定的,可将其配制成肠衣片剂。
附图说明
图1为实施例3化合物与MyD88蛋白的结合亲和力与浓度的关系。
图2为部分实施例化合物抑制LPS刺激J774A.1细胞释放IL-6的量效关系。
图3为部分实施例化合物抑制LPS刺激J774A.1细胞释放TNF-α的量效关系。
图4为以急性肺损伤为例,实施例3化合物缓解炎症引起的小鼠生理学变化效果。A湿重/干重比(W/D);B肺泡灌洗液中白细胞蛋白浓度;C肺泡灌洗液中IL-6表达量;D肺泡灌洗液中TNF-α表达量;E血清中IL-6表达量;F血清TNF-α表达量。
图5为以急性肺损伤中肺组织为例,实施例3化合物缓解炎症引起的病理学变化。
图6为以脓毒血症为例,实施例3化合物缓解炎症引起小鼠死亡的变化。
图7为以脓毒血症为例,实施例3化合物缓解炎症引起小鼠脾脏的病理学变化。
具体实施方式
按照本发明的通式Ⅰ化合物,R1,R2,R3,R4,R5,X,Y如前述内容部分所定义,均可按以下路线的方法制备而成。
抑或:
抑或:
抑或:
化合物1~33的制备方法中:
步骤(1)所述反应的温度为-5~5℃,优选为-2~2℃,进一步优选为0℃;时间为5~15h,优选为8~12h,进一步优选为10h;
所述含R1化合物、碳酸钾、碘化钠和无水四氢呋喃的用量比为0.1~0.2mmol:0.1~0.3mmol:0.2~0.4mmol:0.2~0.4mmol:4~8mL,优选为0.12~0.18mmol:0.15~0.28mmol:0.25~0.35mmol:0.25~0.35mmol:5~7mL,进一步优选为0.14~0.16mmol:0.2~0.25mmol:0.3~0.32mmol:0.3~0.33mmol:5~6mL;
步骤(2)所述反应的温度为60~80℃,优选为65~75℃,进一步优选为70~72℃;时间为1~10h,优选为2~8h,进一步优选为4~6h。
化合物34~69的制备方法中:
所述碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水的用量比为7~9mmol:7~9mmol:3~5mmol:20~40mL,优选为8mmol:8mmol:4mmol:25~30mL;
步骤(1)所述反应的温度为室温,时间为1~5h,优选为2~4h;
所述4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺的用量比为0.4~0.5mmol:0.6~0.8mmol:2~8mL,优选为0.42~0.45mmol:0.65~0.7mmol:4~6mL;
步骤(2)所述反应的温度为70~90℃,优选为75~85℃,进一步优选为80℃;时间为1~5h,优选为2~4h,进一步优选为3h;
所述碘化钾、三甲基哌啶、碳酸钾和乙腈的用量比为0.09~0.11mmol:0.05~0.2mmol:0.05~0.2mmol:0.05~0.2mmol:2~8ml,优选为0.095~0.10mmol:0.1~0.12mmol:0.1~0.12mmol:0.1~0.12mmol:4~6ml;
步骤(3)所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~4h。
化合物70~84的制备方法中:
步骤(1)中所述反应的温度为室温,时间为5~15h,优选为8~12h;
步骤(2)所述保护气氛优选为氮气或者氩气;
所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为2~2.5mmol:2~3mmol:0.2~0.8mmol:15~25mL,优选为2.2~2.3mmol:2.4~2.7mmol:0.4~0.6mmol:19~22mL;
步骤(2)所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h;
所述含R1化合物、三乙胺和乙腈的用量比为0.5~0.8mmol:0.8~1.2mmol:0.8~1.2mmol:5~15mL,优选为0.6~0.7mmol:0.9~1.1mmol:0.9~1.1mmol:9~12mL;
步骤(3)所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h;
步骤(4)所述保护气氛优选为氮气或者氩气;
所述脲、叔丁醇钠和四氢呋喃的用量比为0.2~0.4mmol:0.3~0.5mmol:0.3~0.4mmol:1~10mL,优选为0.3~0.35mmol:0.35~0.4mmol:0.33~0.37mmol:4~7mL;
步骤(4)所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h。
化合物85~93的制备方法中:
所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h;
步骤(2)中所述N-溴代琥珀酰亚胺、偶氮二异丁腈和四氯化碳的用量比为7~8mmol:7~9mmol:1~2mmol:25~35mL,优选为7.3~7.8mmol:7.9~8.5mmol:1.2~1.7mmol:28~32mL;
所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h;
步骤(3)中所述中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈的用量比为0.1~0.5mmol:0.1~0.5mmol:45~55μL:5~15mL,优选为0.2~0.3mmol:0.3~0.4mmol:48~53μL:8~12mL;
所述反应的温度为80~90℃,优选为85~87℃;时间为1~5h,优选为2~3h;
步骤(2)和步骤(3)中所述保护气氛独立的包含氮气或氩气。
本发明按照制备通式I的方法,分别制得实施例1~93的化合物,结构式如下表1所示。
表1实施例1~93的结构式
实施例1、N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
步骤一:4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
在25mL圆底烧瓶中加入二氯甲烷(5mL)溶解5-氨基-2-甲氧基吡啶(200mg,1.61mmol),而后在0℃下分批加入4-氯-3-硝基苯磺酰氯(413mg,1.61mmol),室温反应过夜。减压蒸干二氯甲烷,加入水中溶解产物,并用EtOAc萃取水层。将合并的有机提取物用无水硫酸钠干燥。减压蒸干乙酸乙酯,柱层析分离(PE:EA=4:1)得,即为4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺,收率为70%。
步骤二:N-(6-甲氧基吡啶-3-基)-3-硝基-4-(4-嘧啶-2-基)哌嗪-1-基)苯磺酰胺
在25mL圆底烧瓶中依次将步骤一中合成的4-氯-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺(50mg,0.15mmol),2-(哌嗪-1-基)嘧啶(35mg,0.22mmol),碳酸钾(40mg,0.29mmol),碘化钠(44mg,0.29mmol)加入6mL无水四氢呋喃中,70℃下回流4h。反应结束后减压蒸干四氢呋喃,用EA萃取,有机层用饱和氯化钠溶液洗涤三次,无水硫酸镁干燥。减压蒸干EA,柱层析分离(DCM:Methanol=20:1)得,即为N-(6-甲氧基吡啶-3-基)-3-硝基-4-(4-嘧啶-2-基)哌嗪-1-基)苯磺酰胺,收率为90%。
1H NMR(400MHz,Chloroform-d)δ8.34(d,J=4.8Hz,2H),8.20(d,J=2.3Hz,1H),7.79(d,J=2.7Hz,1H),7.67(dd,J=8.9,2.3Hz,1H),7.50(dd,J=8.8,2.8Hz,1H),7.09(d,J=8.9Hz,1H),6.93–6.75(brs,1H),6.72(d,J=8.8Hz,1H),6.57(t,J=4.8Hz,1H),4.04–3.97(m,4H),3.89(s,3H),3.34–3.27(m,4H),2.18(s,1H).13C NMR(100MHz,Chloroform-d)δ158.89,156.09,149.23,137.04,130.48,129.62,122.83,122.16,113.70,62.30,55.32,52.99,52.73,52.65,49.01,47.73ppm.MS(ESI,m/z):472.2[M+H]+.
按照实施例1的方法,分别制得实施例2~33化合物
实施例2、4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.14(d,J=2.3Hz,1H),7.79(d,J=2.7Hz,1H),7.63(dd,J=8.9,2.3Hz,1H),7.48(dd,J=8.8,2.8Hz,1H),7.38–7.22(m,5H),7.03(d,J=9.0Hz,1H),6.69(d,J=8.8Hz,1H),3.87(s,3H),3.56(s,2H),3.19(t,J=4.9Hz,4H),2.62–2.55(m,4H).13C NMR(100MHz,Chloroform-d)δ162.74,148.43,142.70,139.18,137.49,136.04,131.93,129.26,128.59,128.45,127.44,126.86,126.37,120.14,111.36,62.84,53.85,52.45,50.62ppm.MS(ESI,m/z):484.2[M+H]+.
实施例3、N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(d,J=2.0Hz,1H),8.18–8.10(m,2H),7.79(d,J=2.7Hz,1H),7.72–7.61(m,2H),7.56–7.45(m,2H),7.05(d,J=8.9Hz,1H),6.70(d,J=8.8Hz,1H),3.88(s,3H),3.67(s,2H),3.22(t,J=4.8Hz,4H),2.66–2.58(m,4H),1.27(d,J=7.1Hz,0H).13C NMR(100MHz,Chloroform-d)δ162.76,148.47,148.38,142.71,140.14,139.35,136.05,135.12,132.02,129.43,128.93,126.80,126.33,123.77,122.55,120.24,111.35,61.77,53.85,52.46,50.60ppm.MS(ESI,m/z):529.2[M+H]+.
实施例4、N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.23–8.15(m,3H),8.10(s,1H),7.79(d,J=2.8Hz,1H),7.65(dd,J=8.9,2.3Hz,1H),7.55–7.45(m,3H),7.05(d,J=8.9Hz,1H),6.70(d,J=8.8Hz,1H),3.88(s,3H),3.67(s,2H),3.26–3.16(m,4H),2.66–2.56(m,4H).13C NMR(100MHz,Chloroform-d)δ162.82,148.37,147.39,145.73–145.43(m),142.75,139.42,136.13,132.03,129.64,129.03,126.80,126.24,123.74,120.23,111.43,61.89,53.85,52.55,50.60ppm.MS(ESI,m/z):529.2[M+H]+.
实施例5、4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
1H NMR(500MHz,Chloroform-d)δ8.13(d,J=2.3Hz,1H),7.76(d,J=2.8Hz,1H),7.62(dd,J=8.9,2.3Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),7.24(d,J=8.5Hz,2H),7.03(d,J=8.9Hz,1H),6.87(d,J=8.6Hz,2H),6.72(d,J=8.8Hz,1H),6.39(s,1H),3.90(s,3H),3.81(s,3H),3.51(s,2H),3.20(t,J=4.9Hz,4H),2.60–2.55(m,4H),2.05(s,1H),1.27(t,J=7.2Hz,2H).13C NMR(100MHz,Chloroform-d)δ162.74,158.97,148.42,142.73,139.11,136.06,131.92,130.50,129.38,128.50,126.86,126.34,120.15,113.81,111.35,62.20,55.37,55.34,53.88,53.85,52.32,50.58ppm.MS(ESI,m/z):514.2[M+H]+.
实施例6、N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.05(d,J=3.1Hz,1H),7.81(d,J=3.0Hz,1H),7.70–7.65(m,1H),7.40(dd,J=8.8,2.8Hz,1H),7.35(d,J=9.0Hz,1H),7.28(s,1H),6.74(d,J=8.8Hz,1H),3.77(s,3H),3.69(s,2H),3.14(t,J=4.8Hz,4H),2.48(s,4H),2.11(s,3H).13C NMR(100MHz,Chloroform-d)δ168.16,162.60,148.27,142.50,139.49,135.89,134.69,132.07,129.37,126.73,126.62,120.15,111.39,54.14,53.76,52.10,50.63,23.23ppm.MS(ESI,m/z):548.2[M+H]+.
实施例7、N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.44–8.34(m,2H),8.26(t,J=2.0Hz,1H),8.14(ddd,J=8.2,2.4,1.1Hz,1H),8.04(dd,J=8.6,2.3Hz,1H),7.91–7.81(m,3H),7.75–7.66(m,2H),7.55–7.43(m,4H),7.11(d,J=8.7Hz,1H),3.67(s,2H),3.25–3.17(m,4H),2.68–2.59(m,4H).13C NMR(100MHz,Chloroform-d)δ164.10,148.48,148.01,140.60,140.28,134.98,134.16,132.60,132.15,129.30,128.74,127.88,126.57,126.47,126.13,125.80,125.65,123.71,122.43,122.04,121.06,120.13,61.82,52.63,50.88ppm.HRMS(ESI,m/z):512.3[M+H]+.
实施例8、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.22(d,J=20.7Hz,2H),8.14(d,J=8.3Hz,1H),7.84(d,J=8.8Hz,1H),7.67(d,J=7.7Hz,1H),7.65–7.57(m,1H),7.51(s,1H),7.16(d,J=7.9Hz,2H),7.04(d,J=8.8Hz,1H),6.12(s,1H),4.29(s,2H),3.66(s,2H),3.18(s,4H),2.62(s,4H).13C NMR(100MHz,Chloroform-d)δ154.40,149.07,148.48,148.03,140.18,139.71,136.89,134.95,131.84,130.66,129.33,126.45,123.69,122.76,122.46,122.10,120.12,61.77,52.49,50.67,47.38ppm.HRMS(ESI,m/z):513.2671[M+H]+.
实施例9、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(d,J=4.9Hz,1H),8.23–8.15(m,3H),7.83(dd,J=8.9,2.3Hz,1H),7.61(t,J=7.6Hz,1H),7.53(d,J=8.4Hz,2H),7.16(dd,J=14.1,8.0Hz,2H),7.04(d,J=8.8Hz,1H),6.29(d,J=6.2Hz,1H),4.28(d,J=2.8Hz,2H),3.67(s,2H),3.21–3.14(m,4H),2.64–2.57(m,4H).13C NMR(100MHz,Chloroform-d)δ154.56,149.06,147.99,147.27,145.71,139.59,136.94,131.82,130.66,129.51,126.40,123.61,122.76,122.22,120.18,61.85,52.55,50.66,47.46ppm.HRMS(ESI,m/z):513.2305[M+H]+.
实施例10、4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.21(t,J=5.9Hz,1H),8.51(ddd,J=4.7,1.8,0.9Hz,1H),8.38(d,J=2.2Hz,1H),8.07(dd,J=8.8,2.2Hz,1H),7.75(td,J=7.7,1.8Hz,1H),7.39–7.22(m,8H),4.55(d,J=5.8Hz,2H),3.54(s,2H),3.11(t,J=4.8Hz,4H),2.48(s,4H).13C NMR(100MHz,Chloroform-d)δ165.13,156.20,149.01,147.86,140.75,137.54,137.06,132.31,129.32,128.42,127.40,125.93,125.76,122.63,122.40,119.96,62.92,52.68,50.90,44.81ppm.MS(ESI,m/z):432.2[M+H]+.
实施例11、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.23(t,J=5.9Hz,1H),8.51(ddd,J=4.8,1.8,0.9Hz,1H),8.39(d,J=2.2Hz,1H),8.26–8.18(m,2H),8.09(dd,J=8.7,2.2Hz,1H),7.75(td,J=7.7,1.8Hz,1H),7.68–7.60(m,2H),7.39–7.23(m,3H),4.56(d,J=6.0Hz,2H),3.69(s,2H),3.14(t,J=4.7Hz,4H),2.53(t,J=4.9Hz,4H).13C NMR(100MHz,Chloroform-d)δ165.05,156.15,149.00,147.77,147.31,145.90,140.91,137.08,132.31,129.61,126.23,125.76,123.67,122.65,122.40,120.04,61.98,52.80,50.95,44.80ppm.MS(ESI,m/z):477.3[M+H]+.
实施例12、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.23(t,J=5.9Hz,1H),8.51(ddd,J=4.9,1.8,0.9Hz,1H),8.38(d,J=2.2Hz,1H),8.23–8.04(m,3H),7.85–7.71(m,2H),7.70–7.60(m,1H),7.39–7.23(m,3H),4.56(d,J=5.9Hz,2H),3.17–3.10(m,4H),2.55(q,J=5.6,4.9Hz,4H).13C NMR(100MHz,Chloroform-d)δ165.03,156.01,149.03,148.51,147.82,140.97,140.39,137.05,135.07,132.33,129.35,126.29,125.70,123.78,122.65,122.46,122.38,120.07,67.13,61.89,52.72,50.97,44.77ppm.MS(ESI,m/z):477.2[M+H]+.
实施例13、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.33(d,J=2.3Hz,1H),8.29(t,J=2.0Hz,1H),8.20–8.15(m,1H),8.03(dd,J=8.7,2.3Hz,1H),7.91(s,1H),7.72(d,J=7.7Hz,1H),7.68–7.64(m,2H),7.55(t,J=7.9Hz,1H),7.41(t,J=7.9Hz,2H),7.23–7.15(m,2H),3.71(s,2H),3.28–3.21(m,4H),2.68(dd,J=5.9,3.7Hz,4H).13C NMR(100MHz,Chloroform-d)δ163.28,148.09,140.39(d,J=9.9Hz),137.62,135.03,132.59,129.36,129.21,126.34,125.51,124.89,123.77,122.50,120.32(d,J=11.6Hz),61.87,52.66,50.92.HRMS(ESI,m/z):462.1767[M+H]+.
实施例14、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.47(d,J=2.2Hz,1H),8.24(d,J=8.4Hz,2H),8.16(dd,J=8.8,2.3Hz,1H),7.77(d,J=8.0Hz,2H),7.65(d,J=8.3Hz,2H),7.43–7.32(m,3H),7.12(t,J=7.4Hz,1H),3.72(s,2H),3.18(t,J=4.6Hz,4H),2.56(t,J=4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ164.24,147.79,147.22,145.56,137.94,132.90,129.67,128.86,126.53,125.89,124.63,123.60,120.82,120.02,61.90,52.68,50.74.HRMS(ESI,m/z):462.1767[M+H]+.
实施例15、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.55(d,J=2.1Hz,1H),8.18(dd,J=8.8,2.2Hz,1H),8.11–8.03(m,3H),7.74(d,J=8.0Hz,2H),7.30(t,J=7.9Hz,3H),7.07(t,J=7.4Hz,1H),6.95(d,J=9.3Hz,2H),3.67(dd,J=6.6,3.7Hz,4H),3.43–3.36(m,4H).13C NMR(100MHz,DMSO-d6)δ163.62,154.70,147.21,139.42(d,J=13.4Hz),137.43,133.46,129.14,126.59,126.28,125.75,124.26,120.92,119.92,112.73,49.58,46.02.HRMS(ESI,m/z):448.1610[M+H]+.
实施例16、2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.51(d,J=2.3Hz,1H),8.11(dd,J=8.7,2.3Hz,1H),7.70(d,J=8.0Hz,2H),7.33(t,J=7.8Hz,2H),7.16–7.05(m,2H),3.66(t,J=5.4Hz,2H),3.19(t,J=4.8Hz,4H),2.68(t,J=4.8Hz,4H),2.62(t,J=5.4Hz,2H).13C NMR(100MHz,Methanol-d4)δ164.83,147.70,140.91,138.17,132.60,128.63,126.56,126.07,124.55,121.17,120.03,59.86,58.37,52.91,50.35.HRMS(ESI,m/z):371.1712[M+H]+.
实施例17、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.35–8.26(m,1H),8.02–7.93(m,1H),7.64(d,J=7.9Hz,2H),7.33(t,J=7.7Hz,2H),7.14(t,J=7.4Hz,1H),7.04(d,J=8.7Hz,1H),3.56(t,J=5.3Hz,2H),3.39(s,3H),3.16(t,J=4.7Hz,4H),2.64(q,J=4.5,3.8Hz,6H).13C NMR(100MHz,Chloroform-d)δ163.43,148.10,140.23,137.70,132.64,129.17,126.04,125.56,124.83,120.45,120.09,69.93,59.04,57.87,53.08,50.73.HRMS(ESI,m/z):385.1861[M+H]+.
实施例18、4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.19(d,J=2.3Hz,1H),7.82(dd,J=2.8,0.6Hz,1H),7.69(dd,J=8.9,2.3Hz,1H),7.53(dd,J=8.8,2.8Hz,1H),7.08(d,J=8.9Hz,1H),6.73(dd,J=8.8,0.7Hz,1H),3.91(s,3H),3.70(t,J=5.3Hz,2H),3.27–3.22(m,4H),2.73–2.69(m,4H),2.67(t,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ162.84,148.34,142.81,139.45,136.20,132.03,129.09,126.78,126.15,120.13,111.50,59.22,57.81,53.84,52.30,50.67.HRMS(ESI,m/z):438.1447[M+H]+.
实施例19、4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.15(d,J=2.3Hz,1H),7.82(d,J=2.7Hz,1H),7.66(dd,J=8.9,2.3Hz,1H),7.51(dd,J=8.8,2.8Hz,1H),7.05(d,J=8.9Hz,1H),6.70(d,J=8.8Hz,1H),3.88(s,3H),3.55(t,J=5.4Hz,2H),3.36(s,3H),3.25–3.20(m,4H),2.69–2.63(m,6H).13C NMR(100MHz,Chloroform-d)δ162.62,148.33,142.52,139.19,135.92,131.96,128.79,126.77,126.46,120.07,111.32,69.76,58.96,57.68,53.84,52.82,50.37.HRMS(ESI,m/z):452.1595[M+H]+.
实施例20、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.42(t,J=4.7Hz,1H),8.13(dd,J=4.0,2.3Hz,1H),7.79(ddt,J=8.9,4.0,2.5Hz,1H),7.60(dtt,J=7.7,4.0,1.9Hz,1H),7.19(dd,J=7.9,3.4Hz,1H),7.13(dt,J=7.8,4.1Hz,1H),7.03(dd,J=8.8,3.6Hz,1H),6.80(s,1H),4.29(t,J=3.5Hz,2H),3.53(dt,J=8.9,4.0Hz,2H),3.36(d,J=3.6Hz,3H),3.18(dd,J=6.1,3.4Hz,4H),2.69–2.59(m,6H).13C NMR(100MHz,Chloroform-d)δ154.39,149.14,148.14,139.53,136.91,131.88,130.26,126.60,122.81,122.12,119.96,69.93,59.05,57.82,52.95,50.55,47.39.HRMS(ESI,m/z):436.1654[M+H]+.
实施例21、4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.47–8.42(m,1H),8.18(d,J=2.2Hz,1H),7.85(dd,J=8.8,2.3Hz,1H),7.63(td,J=7.7,1.8Hz,1H),7.22(d,J=7.8Hz,1H),7.16(dd,J=7.5,4.9Hz,1H),7.07(d,J=8.9Hz,1H),6.63(s,1H),4.30(s,2H),3.69(t,J=5.3Hz,2H),3.19(t,J=4.9Hz,4H),2.69(dd,J=5.9,3.7Hz,4H),2.65(t,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.54,149.10,148.05,139.71,137.01,131.95,130.76,126.54,122.84,122.26,120.17,59.33,57.83,52.38,50.72,47.46.HRMS(ESI,m/z):422.1495[M+H]+.
实施例22、4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.21(d,J=2.3Hz,1H),7.74(dd,J=8.9,2.3Hz,1H),7.34–7.28(m,3H),7.21–7.15(m,1H),7.15–7.11(m,2H),7.05(d,J=8.9Hz,1H),3.56(t,J=5.4Hz,2H),3.39(s,3H),3.27–3.20(m,4H),2.67(td,J=5.2,2.3Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.36,139.23,136.12,131.88,129.58,129.11,126.82,125.73,121.63,119.93,69.87,59.01,57.76,52.88,50.44.HRMS(ESI,m/z):421.1544[M+H]+.
实施例23、4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(d,J=2.3Hz,1H),7.76(dd,J=8.8,2.3Hz,1H),7.29(dd,J=8.8,6.9Hz,2H),7.15(tt,J=8.3,1.2Hz,3H),7.05(d,J=8.9Hz,1H),3.70(t,J=5.3Hz,2H),3.23–3.17(m,4H),2.70–2.66(m,4H),2.65(d,J=5.3Hz,2H).13CNMR(100MHz,Chloroform-d)δ139.56,135.95,131.96,129.63,126.73,125.92,121.79,120.00,59.24,57.78,52.31,50.68.HRMS(ESI,m/z):407.1409[M+H]+.
实施例24、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.24(dd,J=9.5,2.1Hz,2H),8.18–8.11(m,1H),7.77(dt,J=8.9,1.8Hz,1H),7.70(dt,J=7.7,1.4Hz,1H),7.53(t,J=8.0Hz,1H),7.33–7.24(m,2H),7.19–7.10(m,3H),7.06(d,J=8.9Hz,1H),3.68(s,2H),3.25–3.17(m,4H),2.63(dd,J=6.0,3.7Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.44,148.35,140.18,139.30,136.21,135.13,131.96,129.56,129.42,129.35,126.79,125.67,123.76,122.53,121.60,120.16,61.77,52.46,50.60.HRMS(ESI,m/z):498.1435[M+H]+.
实施例25、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.22(dd,J=9.3,2.2Hz,3H),7.76(dd,J=8.9,2.3Hz,1H),7.55(d,J=8.5Hz,2H),7.33–7.26(m,2H),7.20–7.09(m,4H),7.06(d,J=8.9Hz,1H),3.69(s,2H),3.22(t,J=4.8Hz,4H),2.63(t,J=4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.34,147.35,145.64,139.39,136.07,131.95,129.58,129.42,126.79,125.78,123.72,121.64,120.12,61.90,52.55,50.62.HRMS(ESI,m/z):498.1438[M+H]+.
实施例26、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
1H NMR(400MHz,Methanol-d4)δ8.23(d,J=2.2Hz,1H),8.16–8.12(m,2H),7.80(dd,J=8.9,2.3Hz,1H),7.28–7.22(m,2H),7.19(d,J=8.9Hz,1H),7.14–7.07(m,3H),6.91–6.87(m,2H),3.68–3.64(m,4H),3.44–3.39(m,4H).13C NMR(100MHz,DMSO-d6)δ154.50,147.61,137.96,137.50,137.30,131.81,129.83,128.79,126.37(d,J=17.5Hz),124.82,120.61,120.42,112.46,49.07,45.58.HRMS(ESI,m/z):484.1277[M+H]+.
实施例27、4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(s,1H),8.16(s,1H),7.80(d,J=8.9Hz,1H),7.60(s,1H),7.32(s,4H),7.28(d,J=7.0Hz,1H),7.19–7.10(m,2H),7.02(d,J=8.8Hz,1H),6.34(s,1H),4.28(s,2H),3.56(s,2H),3.15(d,J=5.3Hz,4H),2.58(s,4H).13CNMR(100MHz,Chloroform-d)δ154.52,149.07,148.07,139.47,137.55,136.85,131.75,130.23,129.15,128.35,127.32,126.51,122.72,122.10,119.97,62.83,52.46,50.68,47.41ppm.HRMS(ESI,m/z):468.3416[M+H]+
实施例28、3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.22(d,J=20.7Hz,2H),8.14(d,J=8.3Hz,1H),7.84(d,J=8.8Hz,1H),7.67(d,J=7.7Hz,1H),7.65–7.57(m,1H),7.51(s,1H),7.16(d,J=7.9Hz,2H),7.04(d,J=8.8Hz,1H),6.12(s,1H),4.29(s,2H),3.66(s,2H),3.18(s,4H),2.62(s,4H).13C NMR(100MHz,Chloroform-d)δ154.40,149.07,148.48,148.03,140.18,139.71,136.89,134.95,131.84,130.66,129.33,126.45,123.69,122.76,122.46,122.10,120.12,61.77,52.49,50.67,47.38ppm.HRMS(ESI,m/z):513.2671[M+H]+
实施例29、3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.43(d,J=4.9Hz,1H),8.23–8.15(m,3H),7.83(dd,J=8.9,2.3Hz,1H),7.61(t,J=7.6Hz,1H),7.53(d,J=8.4Hz,2H),7.16(dd,J=14.1,8.0Hz,2H),7.04(d,J=8.8Hz,1H),6.29(d,J=6.2Hz,1H),4.28(d,J=2.8Hz,2H),3.67(s,2H),3.21–3.14(m,4H),2.64–2.57(m,4H).13C NMR(100MHz,Chloroform-d)δ154.56,149.06,147.99,147.27,145.71,139.59,136.94,131.82,130.66,129.51,126.40,123.61,122.76,122.22,120.18,61.85,52.55,50.66,47.46ppm.HRMS(ESI,m/z):513.2305[M+H]+
实施例30、3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ8.39(d,J=4.8Hz,1H),8.35(s,1H),8.10(dd,J=5.9,3.4Hz,3H),7.82(dd,J=8.9,2.3Hz,1H),7.34(dd,J=21.0,8.4Hz,2H),7.20(dd,J=7.5,4.9Hz,1H),7.00(d,J=9.3Hz,2H),4.13(s,2H),3.68(dd,J=6.9,3.7Hz,4H),3.40(dd,J=6.7,3.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ154.28,154.22,148.99,147.61,139.55,139.08,137.18,132.07,131.23,126.66,126.08,122.95,122.26,119.64,112.68,49.81,47.31,46.42ppm.HRMS(ESI,m/z):499.2028[M+H]+
实施例31、4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
1H NMR(400MHz,Chloroform-d)δ8.47–8.40(m,1H),8.18(d,J=2.3Hz,1H),7.81(dd,J=8.8,2.3Hz,1H),7.60(td,J=7.7,1.8Hz,1H),7.23(d,J=8.4Hz,4H),7.14(t,J=7.0Hz,2H),7.02(d,J=8.9Hz,1H),6.91–6.83(m,2H),5.99(t,J=5.3Hz,1H),4.28(d,J=5.1Hz,2H),3.81(s,3H),3.50(s,2H),3.19–3.11(m,4H),2.60–2.52(m,4H).13C NMR(100MHz,Chloroform-d)δ158.90,154.50,149.07,148.06,139.40,136.87,131.74,130.35,130.17,129.48,126.49,122.73,122.14,119.98,113.71,62.19,55.27,52.33,50.66,47.42ppm.MS(ESI,m/z):398.2[M+H]+
实施例32、3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ8.41(d,J=4.7Hz,2H),8.38(dt,J=5.8,3.0Hz,2H),8.09(d,J=2.3Hz,1H),7.81(dd,J=8.9,2.3Hz,1H),7.68(td,J=7.7,1.8Hz,1H),7.38(d,J=9.0Hz,1H),7.31(d,J=7.8Hz,1H),7.20(dd,J=7.6,4.8Hz,1H),6.69(t,J=4.7Hz,1H),4.14(s,2H),3.91–3.84(m,4H),3.29–3.21(m,4H).13C NMR(100MHz,Chloroform-d)δ161.49,157.88,154.49,149.05,148.20,139.48,137.09,131.93,130.70,126.67,122.87,122.29,119.97,110.61,50.41,47.42,43.21ppm.MS(ESI,m/z):456.2[M+H]+
实施例33、N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.39–8.30(m,2H),8.03(d,J=2.3Hz,1H),7.77(dd,J=8.9,2.3Hz,1H),7.67(td,J=7.7,1.8Hz,1H),7.34–7.27(m,3H),7.19(dd,J=7.6,4.9Hz,1H),4.12(d,J=5.8Hz,2H),3.71(s,2H),3.13(t,J=4.7Hz,4H),2.52(s,4H),2.12(s,3H).13C NMR(100MHz,DMSO-d6)δ168.72,157.10,149.24,137.09,136.62,131.97,128.33,125.93,122.90,122.36,121.44,53.72,52.15,50.74,48.47,22.94ppm.MS(ESI,m/z):532.2[M+H]+
实施例34、1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
步骤一:4-氯-3-硝基苯亚磺酸
在25mL圆底烧瓶中将碳酸氢钠(656.16mg,7.81mmol),亚硫酸钠(984.46mg,7.81mmol),4-氯-3-硝基苯磺酰氯(1.00g,3.91mmol)依次加入水(30mL)中,室温反应2小时。减压蒸干乙醇,用EA萃取,乙醇重结晶得,即为4-氯-3-硝基苯亚磺酸,收率为90%。
步骤二:4-苄基磺酰基-1-氯-2-硝基苯
在25mL圆底烧瓶中将步骤一制得的4-氯-3-硝基苯亚磺酸(100.00mg,0.45mmol),溴苄(115.77mg,0.67mmol),依次加入DMF(5mL)中,80℃反应2小时。加入冰水淬灭反应,用EA萃取,柱层析分离(DCM:MeOH=20:1)得,即为4-苄基磺酰基-1-氯-2-硝基苯,收率为36%。
步骤三:1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
在25mL圆底烧瓶中将步骤二制得的4-苄基磺酰基-1-氯-2-硝基苯(30mg,0.096mmol),碘化钾(19.17mg,0.12mmol),三甲基哌啶(11.45mg,0.12mmol),碳酸钾(15.96mg,0.12mmol)依次加入乙腈(5mL)中,85℃反应2小时。加入冰水淬灭反应,用EA萃取,柱层析分离(DCM:MeOH=20:1)得,即为1-(4-苄基磺酰基)-2-硝基苯基-3-甲基哌啶,收率为76%。
1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.2Hz,1H),7.49(dd,J=8.9,2.2Hz,1H),7.36(dd,J=13.8,7.0Hz,3H),7.18(d,J=7.4Hz,2H),7.02(d,J=9.0Hz,1H),4.34(s,2H),3.31(dd,J=24.7,12.7Hz,2H),2.98(td,J=12.0,3.3Hz,1H),2.74–2.64(m,1H),1.98–1.69(m,4H),1.18(qd,J=11.5,4.4Hz,1H),0.96(d,J=6.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ149.12,138.42,132.84,130.91,129.04,128.76,128.60,128.09,126.28,119.56,63.16,58.29,51.39,32.24,30.93,24.94,19.00.ESI-MS m/z:397.1[M+Na]+.
按照实施例34的方法,分别制得实施例35~69化合物
实施例35、1-[4-(苄基磺酰基)-2-硝基苯基]-4-甲基哌嗪
1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.2Hz,1H),7.56(dd,J=8.8,2.3Hz,1H),7.40–7.31(m,3H),7.19–7.15(m,2H),7.05(d,J=8.9Hz,1H),4.35(s,2H),3.28(t,J=4.9Hz,4H),2.65(t,J=4.9Hz,4H),2.43(s,3H).13C NMR(100MHz,Chloroform-d)δ148.74,139.20,133.12,130.90,129.11,128.80,128.28,127.94,127.71,119.56,63.12,54.38,50.52,46.00.ESI-MS m/z:376.1[M+H]+.
实施例36、1-[4-(苄基磺酰基)-2-硝基苯基]-4-乙基哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(t,J=2.8Hz,1H),7.55(dt,J=8.9,2.8Hz,1H),7.41–7.31(m,3H),7.20–7.14(m,2H),7.04(dd,J=8.8,3.0Hz,1H),4.34(d,J=3.0Hz,2H),3.27(p,J=3.3Hz,4H),2.74–2.61(m,4H),2.55(qd,J=7.3,2.8Hz,2H),1.17(td,J=7.3,2.9Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.72,139.13,133.10,130.90,129.10,128.79,128.27,127.96,127.61,119.49,63.12,52.21,52.14,50.56,11.95.ESI-MS m/z:390.1[M+H]+.
实施例37、1-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-酮
1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.2Hz,1H),7.56(dd,J=8.8,2.3Hz,1H),7.41–7.31(m,3H),7.19–7.15(m,2H),7.05(d,J=8.8Hz,1H),4.35(s,2H),3.28(t,J=4.9Hz,4H),2.65(t,J=4.9Hz,4H),2.43(s,3H).13C NMR(100MHz,Chloroform-d)δ169.34,148.54,139.48,133.34,130.89,129.19,128.87,128.84,128.22,127.80,119.65,63.07,50.75,49.96,45.54,40.84,21.40.ESI-MS m/z:426.1[M+Na]+.
实施例38、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.23–8.18(m,2H),8.03(d,J=2.2Hz,1H),7.61(dd,J=8.8,2.2Hz,1H),7.42–7.31(m,3H),7.21–7.16(m,2H),7.08(d,J=8.8Hz,1H),6.89–6.82(m,2H),4.37(s,2H),3.72–3.64(m,4H),3.51–3.44(m,4H).13C NMR(100MHz,DMSO-d6)δ154.47,148.12,137.46,137.33,133.11,131.56,129.20,128.95,128.81,128.32,127.30,126.29,119.74,112.42,61.31,49.04,45.52.ESI-MS m/z:505.2[M+Na]+.
实施例39、2-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-醇
1H NMR(400MHz,Chloroform-d)δ7.89(d,J=2.2Hz,1H),7.48(dd,J=8.8,2.2Hz,1H),7.27(ddd,J=14.4,7.9,6.2Hz,3H),7.11–7.06(m,2H),6.96(d,J=8.8Hz,1H),4.26(s,2H),3.62(t,J=5.3Hz,2H),3.22–3.15(m,4H),2.62(dd,J=10.4,5.6Hz,5H),2.58(d,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.69,139.25,133.17,130.90,129.12,128.80,128.24,127.92,119.62,63.09,59.31,57.89,52.31,50.63.ESI-MS m/z:406.1[M+H]+.
实施例40、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J=2.2Hz,1H),7.55(dd,J=8.9,2.3Hz,1H),7.41–7.30(m,3H),7.19–7.14(m,2H),7.03(d,J=8.9Hz,1H),4.34(s,2H),3.59(t,J=5.3Hz,2H),3.40(s,3H),3.29(t,J=4.9Hz,4H),2.78–2.67(m,6H).13C NMR(100MHz,Chloroform-d)δ148.74,139.15,133.11,130.91,129.11,128.80,128.29,127.97,127.61,119.44,69.98,63.15,59.03,57.79,52.88,50.45.ESI-MS m/z:420.2[M+H]+.
实施例41、1-[4-(苄基磺酰基)-2-硝基苯基]-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(d,J=2.0Hz,1H),8.17(dd,J=8.3,2.4Hz,1H),7.97(d,J=2.3Hz,1H),7.71(d,J=7.5Hz,1H),7.58–7.52(m,2H),7.40–7.30(m,3H),7.17(d,J=6.8Hz,2H),7.04(d,J=8.8Hz,1H),4.35(s,2H),3.70(s,2H),3.26(t,J=4.8Hz,4H),2.66(t,J=4.8Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.73,148.52,140.16,139.30,135.00,133.18,130.90,129.41,129.13,128.81,128.23,127.95,127.92,123.72,122.54,119.60,63.11,61.78,52.43,50.58.ESI-MS m/z:519.1[M+Na]+.
实施例42、4-[(3-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ8.03(d,J=2.3Hz,1H),7.50(dd,J=9.1,2.3Hz,1H),7.31(td,J=8.1,5.8Hz,1H),7.09(td,J=8.4,2.5Hz,1H),7.00–6.89(m,3H),4.32(s,2H),3.03(s,6H).13C NMR(100MHz,Chloroform-d)δ148.58,136.39,132.28,130.46,130.38,130.34,130.25,128.87,126.68,126.65,124.28,117.98,117.76,117.00,116.20,115.99,62.64,42.25.ESI-MS m/z:361.0[M+Na]+.
实施例43、1-乙基-4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ8.03(d,J=2.2Hz,1H),7.57(dd,J=8.9,2.3Hz,1H),7.36–7.31(m,1H),7.13–7.03(m,2H),6.99–6.88(m,2H),4.32(s,2H),3.27(t,J=4.9Hz,4H),2.63(t,J=5.0Hz,4H),2.53(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.85,139.10,133.04,130.42,130.34,128.29,127.32,126.69,126.66,119.62,118.02,117.79,116.33,116.12,62.58,52.22,52.13,50.56,29.76,11.94.ESI-MS m/z:408.1[M+H]+.
实施例44、1-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,Chloroform-d)δ8.05(d,J=2.2Hz,1H),7.59(dd,J=8.8,2.2Hz,1H),7.33–7.24(m,1H),7.06(t,J=9.2Hz,2H),6.97–6.86(m,2H),4.33(s,2H),3.80(t,J=5.1Hz,2H),3.66(dd,J=6.4,3.5Hz,2H),3.24(dq,J=7.8,4.4,4.0Hz,4H),2.14(s,3H).13CNMR(100MHz,Chloroform-d)δ169.35,148.69,139.29,133.23,130.47,130.39,130.09,130.01,128.42,128.22,126.73,126.69,119.81,117.99,117.77,116.35,116.14,62.43,50.65,49.93,45.48,40.79,21.40.ESI-HRMS m/z:422.1172[M+H]+.
实施例45、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.14–8.08(m,3H),7.72(dd,J=9.0,2.3Hz,1H),7.44–7.35(m,2H),7.25–7.18(m,1H),7.11–7.03(m,2H),7.01–6.95(m,2H),4.78(s,2H),3.71(dd,J=7.0,3.7Hz,4H),3.53–3.43(m,4H).13C NMR(100MHz,DMSO-d6)δ154.46,148.19,137.43,137.33,133.09,130.83,130.74,128.36,127.73,127.03,126.29,119.78,118.33,118.12,115.99,115.78,112.42,60.63,49.03,45.51.ESI-HMS m/z:501.1231[M+H]+.
实施例46、2-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.05(d,J=2.2Hz,1H),7.60(dd,J=8.8,2.3Hz,1H),7.33(dd,J=8.0,5.9Hz,1H),7.13–7.05(m,2H),6.98(dd,J=7.6,1.6Hz,1H),6.92(dt,J=9.2,2.1Hz,1H),4.33(s,2H),3.73(t,J=5.3Hz,2H),3.30(t,J=4.9Hz,4H),2.80–2.74(m,4H),2.71(t,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.82,139.22,133.08,130.42,128.25,127.63,126.68,126.65,119.71,117.99,117.77,116.33,116.12,62.55,59.28,57.87,52.27,50.64.ESI-MS m/z:424.2[M+H]+.
实施例47、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.01(d,J=2.2Hz,1H),7.55(dd,J=8.9,2.3Hz,1H),7.32–7.25(m,1H),7.06(td,J=8.7,3.1Hz,2H),6.98–6.88(m,2H),4.31(s,2H),3.55(t,J=5.3Hz,2H),3.38(s,3H),3.26(t,J=4.9Hz,4H),2.67(t,J=4.6Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.85,138.99,133.02,130.40,130.23,128.27,127.24,126.71,126.68,119.64,118.00,117.78,116.28,116.07,69.93,62.51,59.03,59.00,57.75,52.84,50.40.ESI-MS m/z:438.1[M+H]+.
实施例48、1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(t,J=2.1Hz,1H),8.17(dd,J=8.3,2.3Hz,1H),8.04(d,J=2.2Hz,1H),7.71(d,J=7.6Hz,1H),7.60–7.56(m,1H),7.54(d,J=7.9Hz,1H),7.32(td,J=8.0,5.8Hz,2H),7.10(dd,J=8.2,2.5Hz,1H),7.06(d,J=8.8Hz,1H),6.99–6.96(m,1H),6.92(dt,J=9.2,2.2Hz,1H),4.33(s,2H),3.70(s,2H),3.30–3.25(m,4H),2.66(dd,J=6.2,3.6Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.85,148.52,140.14,139.23,135.00,133.08,130.42,129.41,128.23,127.61,126.68,123.72,122.55,119.71,117.99,117.77,116.33,116.12,62.55,61.77,52.41,50.58.ESI-MS m/z:537.1[M+Na]+.
实施例49、4-[(4-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ8.06(d,J=2.3Hz,1H),7.46(dd,J=9.0,2.3Hz,1H),7.20–7.14(m,2H),7.04(t,J=8.6Hz,2H),6.96(d,J=9.1Hz,1H),4.31(s,2H),3.03(s,7H).13C NMR(100MHz,Chloroform-d)δ148.51,132.71,132.63,132.37,128.82,124.40,124.08,116.91,115.98,115.77,62.28,42.25.ESI-MS m/z:361.1[M+Na]+.
实施例50、1-乙基-4-[4-(4-氟苄基)磺酰基]-2-硝基苯基哌嗪
1H NMR(400MHz,Chloroform-d)δ8.03(d,J=2.2Hz,1H),7.52(dd,J=8.9,2.3Hz,1H),7.20–7.11(m,2H),7.03(q,J=8.9Hz,3H),4.30(s,2H),3.29–3.22(m,4H),2.65–2.58(m,4H),2.51(q,J=7.2Hz,2H),1.13(t,J=7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ148.78,139.09,133.07,132.76,132.68,128.22,127.36,123.87,123.83,119.62,116.02,q115.81,62.18,62.14,62.11,52.21,52.14,50.57,29.74,11.96.ESI-MS m/z:408.1[M+H]+.
实施例51、1-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,DMSO-d6)δ8.06(d,J=2.3Hz,1H),7.68(dd,J=8.9,2.3Hz,1H),7.39(d,J=9.0Hz,1H),7.28–7.22(m,2H),7.22–7.15(m,2H),4.73(s,2H),3.61(q,J=5.4Hz,4H),3.31–3.21(m,4H),2.04(s,3H).13C NMR(100MHz,Chloroform-d)δ169.31,148.61,139.53,133.32,132.74,132.65,128.74,128.15,123.68,123.65,119.71,116.10,115.88,62.14,50.76,49.97,45.53,40.82,21.40.ESI-MS m/z:444.1[M+Na]+.
实施例52、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.08–8.02(m,2H),8.01(d,J=2.2Hz,1H),7.62(dd,J=8.9,2.4Hz,1H),7.34(d,J=9.0Hz,1H),7.23–7.16(m,2H),7.12(dd,J=9.9,7.8Hz,2H),6.95–6.88(m,2H),4.67(s,2H),3.64(dd,J=7.1,3.6Hz,4H),3.46–3.37(m,4H).13C NMR(100MHz,DMSO-d6)δ154.47,148.16,137.47,137.33,133.67,133.59,133.13,128.36,127.06,126.29,125.58,125.55,119.76,115.90,115.68,112.42,60.32,49.04,45.52.ESI-MS m/z:523.1[M+Na]+.
实施例53、2-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.06(d,J=2.3Hz,1H),7.56(dd,J=8.8,2.3Hz,1H),7.18(dd,J=8.5,5.0Hz,2H),7.08–7.01(m,3H),4.32(s,2H),3.71(t,J=5.3Hz,2H),3.27(t,J=4.9Hz,4H),2.72(t,J=4.9Hz,4H),2.68(t,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ148.75,139.26,133.13,132.75,132.66,128.17,127.72,123.81,123.78,119.71,116.04,115.82,62.14,59.30,57.89,52.29,50.63.ESI-MS m/z:424.2[M+H]+.
实施例54、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.01(d,J=2.2Hz,1H),7.51(dd,J=8.9,2.3Hz,1H),7.19–7.10(m,2H),7.02(q,J=8.7Hz,3H),4.29(s,2H),3.54(t,J=5.4Hz,2H),3.37(s,3H),3.29–3.22(m,4H),2.66(t,J=4.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ148.79,139.04,133.06,132.77,132.69,128.21,127.32,123.88,123.84,119.62,116.00,115.79,69.94,62.11,59.02,58.99,57.76,52.85,50.42.ESI-MS m/z:438.1[M+H]+.
实施例55、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.27(t,J=2.0Hz,1H),8.17(ddd,J=8.2,2.4,1.1Hz,1H),8.05(d,J=2.3Hz,1H),7.71(dt,J=7.6,1.4Hz,1H),7.59–7.50(m,2H),7.21–7.12(m,2H),7.09–6.99(m,3H),4.32(s,2H),3.71(s,2H),3.30–3.23(m,4H),2.69–2.62(m,4H).13C NMR(100MHz,Chloroform-d)δ148.78,148.54,140.14,139.34,134.97,133.14,132.73,132.65,129.41,128.15,127.78,123.72,122.56,119.67,116.06,115.84,62.18,61.78,52.42,50.58.ESI-MS m/z:537.1[M+Na]+.
实施例56、1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.26–8.21(m,2H),8.06(d,J=2.2Hz,1H),7.59–7.53(m,3H),7.20–7.15(m,2H),7.04(t,J=8.7Hz,3H),4.32(s,2H),3.71(s,2H),3.29–3.24(m,4H),2.65(dd,J=5.8,3.9Hz,4H).13C NMR(100MHz,DMSO-d6)δ148.61,147.17,146.75,138.52,133.66,133.58,133.29,130.35,128.10,127.74,123.92,120.99,115.89,115.68,61.18,60.27,52.53,50.55.ESI-MS m/z:537.1[M+Na]+.
实施例57、1-乙基-4-[4-(4-甲基苄基)磺酰基]-2-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.93(d,J=2.2Hz,1H),7.56(dd,J=8.9,2.3Hz,1H),7.17–7.00(m,5H),4.29(s,2H),3.31–3.19(m,4H),2.61(t,J=4.8Hz,4H),2.51(q,J=7.2Hz,2H),2.35(s,3H),1.14(t,J=7.2Hz,4H).13C NMR(100MHz,Chloroform-d)δ148.70,139.17,139.14,133.13,130.78,129.50,128.28,127.77,124.82,119.52,62.83,52.23,52.17,50.59,29.75,21.28,11.98.ESI-MS m/z:404.2[M+H]+.
实施例58、1-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,Chloroform-d)δ8.00(d,J=2.0Hz,1H),7.62(dd,J=8.5,2.2Hz,1H),7.14(d,J=7.7Hz,2H),7.09–7.02(m,3H),4.32(s,2H),3.76(d,J=62.6Hz,4H),3.25(s,4H),2.37(s,3H),2.18(s,3H).13C NMR(100MHz,Chloroform-d)δ169.30,148.50,139.61,139.27,133.37,130.75,129.54,129.13,128.21,124.64,119.63,62.81,50.82,50.00,45.58,40.85,21.40,21.28.ESI-MS m/z:440.1[M+Na]+.
实施例59、1-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.25–8.18(m,2H),8.02(d,J=2.1Hz,1H),7.65(dd,J=8.8,2.2Hz,1H),7.15(d,J=7.8Hz,2H),7.08(dd,J=15.0,8.3Hz,3H),6.88(d,J=9.3Hz,2H),4.33(s,2H),3.69(dd,J=6.6,3.7Hz,4H),3.48(dd,J=6.5,3.8Hz,4H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ154.48,148.09,138.35,137.52,137.33,133.11,131.43,129.40,128.26,127.44,126.30,126.09,119.76,112.44,61.02,49.05,45.54,21.27.
实施例60、2-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ7.95(d,J=2.2Hz,1H),7.57(dd,J=8.8,2.3Hz,1H),7.12(d,J=7.8Hz,2H),7.04(dd,J=8.4,6.5Hz,3H),4.30(s,2H),3.69(t,J=5.3Hz,2H),3.31–3.22(m,4H),2.70(t,J=4.9Hz,4H),2.66(t,J=5.3Hz,2H),2.56(s,1H),2.36(s,3H).13C NMR(100MHz,Chloroform-d)δ148.67,139.31,139.18,133.21,130.78,129.52,128.25,128.11,124.76,119.64,62.81,59.33,57.89,52.33,50.63,21.29.ESI-MS m/z:420.2[M+H]+.
实施例61、1-(2-甲氧基乙基)-4-[4-(4-甲基苄基)磺酰基]2-硝基苯基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.93(d,J=2.2Hz,1H),7.55(dd,J=8.8,2.3Hz,1H),7.12(d,J=7.9Hz,2H),7.06–7.01(m,3H),4.29(s,2H),3.56(t,J=5.3Hz,2H),3.39(s,3H),3.30–3.21(m,4H),2.67(t,J=5.1Hz,7H),2.35(s,3H).13C NMR(100MHz,Chloroform-d)δ148.71,139.14,133.13,130.77,129.49,128.27,127.76,124.81,119.49,69.95,62.86,62.83,59.04,59.01,57.78,52.88,50.44,21.27.ESI-MS m/z:434.2[M+H]+.
实施例62、4-[(4-甲氧基苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.3Hz,1H),7.50(dd,J=9.0,2.3Hz,1H),7.24–7.18(m,1H),6.95(d,J=9.1Hz,1H),6.92–6.87(m,1H),6.70(dd,J=7.1,1.4Hz,2H),4.29(s,2H),3.78(s,3H),3.01(s,6H).13C NMR(100MHz,Chloroform-d)δ159.73,148.49,136.42,132.39,129.70,129.51,128.92,124.60,123.19,116.86,116.32,114.73,63.22,55.34,42.23,29.75.ESI-MS m/z:373.1[M+Na]+.
实施例63、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ7.99(d,J=2.2Hz,1H),7.58(dd,J=8.9,2.3Hz,1H),7.26–7.19(m,1H),7.05(d,J=8.9Hz,1H),6.91(ddd,J=8.4,2.4,1.1Hz,1H),6.76–6.67(m,2H),4.31(s,2H),3.79(s,3H),3.25–3.18(m,4H),3.08–3.02(m,4H).13C NMR(100MHz,DMSO-d6)δ159.46,148.76,138.36,133.31,130.54,129.86,128.19,127.72,123.75,120.90,117.06,114.56,61.27,55.51,50.94,45.06.ESI-MS m/z:392.1[M+H]+.
实施例64、1-乙基-4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J=2.2Hz,1H),7.56(dd,J=8.9,2.3Hz,1H),7.21(dd,J=8.8,7.6Hz,1H),7.04(d,J=8.9Hz,1H),6.93–6.87(m,1H),6.74–6.68(m,2H),4.30(s,2H),3.77(s,3H),3.29–3.20(m,4H),2.61(t,J=4.9Hz,4H),2.51(q,J=7.2Hz,2H),1.14(t,J=7.2Hz,3H).13C NMR(100MHz,Chloroform-d)δ159.76,148.73,139.20,133.12,129.77,129.26,128.28,127.68,123.17,119.46,116.31,114.82,63.16,55.35,52.22,52.14,50.55,11.92.ESI-MS m/z:420.2[M+H]+.
实施例65、1-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
1H NMR(400MHz,DMSO-d6)δ8.05(d,J=2.3Hz,1H),7.71(dd,J=8.9,2.3Hz,1H),7.40(d,J=9.0Hz,1H),7.24(t,J=7.9Hz,1H),6.95–6.89(m,1H),6.79(dt,J=7.6,1.2Hz,1H),6.74(t,J=2.0Hz,1H),4.69(s,2H),3.68(s,3H),3.61(q,J=5.3Hz,4H),3.26(dd,J=15.1,4.8Hz,4H),2.05(s,3H).13C NMR(100MHz,Chloroform-d)δ169.36,159.77,148.57,139.39,133.31,129.80,129.13,128.78,128.22,123.17,119.73,116.49,114.70,63.02,55.39,55.36,50.68,49.98,45.53,40.83,21.40.ESI-MS m/z:456.1(M+Na)+.
实施例66、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
1H NMR(400MHz,DMSO-d6)δ8.15–8.08(m,2H),8.06(d,J=2.2Hz,1H),7.73(dd,J=8.9,2.3Hz,1H),7.41(d,J=9.0Hz,1H),7.25(t,J=7.9Hz,1H),7.02–6.96(m,2H),6.92(dd,J=8.1,2.6Hz,1H),6.79(d,J=7.6Hz,1H),6.76(t,J=2.0Hz,1H),4.69(s,2H),3.70(d,J=11.6Hz,7H),3.51–3.45(m,4H).13C NMR(100MHz,DMSO-d6)δ159.47,154.47,148.12,137.51,137.34,133.16,130.56,129.86,128.35,127.29,126.29,123.75,119.72,117.10,114.53,112.44,61.30,55.52,49.06,45.53.
实施例67、2-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
1H NMR(400MHz,Chloroform-d)δ8.00(d,J=2.2Hz,1H),7.59(dd,J=8.8,2.3Hz,1H),7.23(t,J=8.2Hz,1H),7.05(d,J=8.8Hz,1H),6.94–6.89(m,1H),6.71(dd,J=6.9,1.5Hz,2H),4.31(s,2H),3.79(s,3H),3.71(t,J=5.3Hz,2H),3.30–3.23(m,4H),2.72(dd,J=6.0,3.7Hz,4H),2.68(t,J=5.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ159.45,148.53,138.41,133.29,130.54,129.85,128.13,127.66,123.74,120.77,117.03,114.57,61.28,60.43,58.90,55.51,53.05,50.48.ESI-MS m/z:458.2[M+Na]+.
实施例68、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
1H NMR(400MHz,Chloroform-d)δ7.97(d,J=2.2Hz,1H),7.56(dd,J=8.9,2.3Hz,1H),7.29(d,J=3.9Hz,1H),7.21(t,J=8.2Hz,1H),7.02(d,J=8.9Hz,1H),6.98–6.93(m,1H),6.92–6.83(m,2H),6.70(dt,J=6.6,1.6Hz,2H),4.69(s,1H),4.29(s,2H),3.83(s,2H),3.77(s,3H),3.56(t,J=5.3Hz,2H),3.38(s,3H),3.25(t,J=4.9Hz,4H),2.67(t,J=4.6Hz,6H).13C NMR(100MHz,Chloroform-d)δ159.75,148.74,139.13,133.11,129.76,129.26,128.27,127.59,123.17,119.45,116.31,114.80,69.94,63.13,59.01,57.77,55.35,52.86,50.43.ESI-MS m/z:450.2[M+H]+.
实施例69、1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
1H NMR(400MHz,Chloroform-d)δ8.28(t,J=1.9Hz,1H),8.18(ddd,J=8.2,2.3,1.1Hz,1H),7.99(d,J=2.2Hz,1H),7.71(dt,J=7.6,1.4Hz,1H),7.59(dd,J=8.9,2.3Hz,1H),7.55(t,J=7.9Hz,1H),7.23(dd,J=8.7,7.6Hz,1H),7.05(d,J=8.9Hz,1H),6.94–6.89(m,1H),6.71(dd,J=6.9,1.4Hz,2H),4.32(s,2H),3.79(s,3H),3.71(s,2H),3.29–3.23(m,4H),2.66(dd,J=5.9,3.7Hz,4H).13C NMR(100MHz,DMSO-d6)δ159.44,148.57,148.36,140.86,138.52,136.12,133.32,130.47,130.30,129.87,128.08,127.83,123.75,122.64,120.93,117.02,114.59,61.28,60.96,55.50,52.39,50.54.ESI-MS m/z:549.1[M+Na]+.
实施例70、4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
步骤一:(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮
在25mL圆底烧瓶中将苯乙酮(2.00g,16.65mmol),氢氧化钠(1.00g,25.00mmol),对甲基苯甲醛(2.00g,16.65mmol)依次加入乙醇(10mL)中,室温反应过夜。抽滤得,即为(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮,收率为90%。
步骤二:(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮
在25mL圆底烧瓶中将步骤一制得的(E)-1-苯基-3-(对甲苯基)丙-2-烯-1-酮(500.00mg,2.25mmol),N-溴代琥珀酰亚胺(440.38mg,2.47mmol),偶氮二异丁腈(73.87mg,0.45mmol)依次加入四氯化碳(20mL)中,氮气保护下85℃反应2h。旋蒸蒸干四氯化碳,EA萃取。蒸干EA,柱层析(PE:EA=10:1)得,即为(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮,收率为60%。
步骤三:(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮
在25mL圆底烧瓶中将步骤二制得的(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮(200mg,0.66mmol),2-羟乙基哌嗪(129.68mg,1.00mmol),三乙胺(100.80mg,1.00mmol)依次加入乙腈(10mL)中,85℃反应2h。旋蒸蒸干乙腈,EA萃取。蒸干EA,柱层析(PE:EA=1:1)得,即为(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮,收率为60%。
步骤四:4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
在25mL圆底烧瓶中将步骤三制得的E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮(100.00mg,0.29mmol),脲(25.70mg,0.43mmol),叔丁醇钠(32.91mg,0.34mmol)依次加入四氢呋喃(5mL)中,氮气保护下85℃反应2h。旋蒸蒸干四氢呋喃,EA萃取。蒸干EA,柱层析(PE:EA=1:1)得,即为4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮,收率为40%。
1H NMR(400MHz,DMSO-d6)δ8.22–8.12(m,4H),7.56(dd,J=18.4,8.1Hz,6H),3.84(s,2H),2.57(d,J=7.2Hz,2H),1.49(t,J=7.2Hz,2H),1.30(td,J=9.3,8.4,4.7Hz,4H),0.88(h,J=4.9Hz,2H).13C NMR(100MHz,Chloroform-d)δ160.39,142.20,134.08,133.10,131.95,129.57,129.47,129.18,127.82,127.74,127.69,99.88,52.84,49.09,29.76,28.62,22.53,14.07ppm.HRMS(ESI,m/z):calcd.for C22H26N3O[M+H]+,348.2076;found,348.2075.
按照实施例70的方法,分别制得实施例71~84化合物
实施例71、4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.14–8.09(m,2H),8.04(d,J=7.9Hz,2H),7.54(d,J=7.9Hz,2H),7.10(d,J=4.7Hz,2H),7.08(d,J=1.5Hz,1H),3.93(d,J=1.3Hz,3H),3.63(s,2H),3.57(t,J=5.6Hz,2H),3.38(d,J=1.3Hz,3H),2.74–2.51(m,10H).13C NMR(100MHz,Chloroform-d)δ162.87,160.43,142.47,129.86,129.55,127.62,114.61,99.10,69.92,62.52,58.96,57.81,55.58,53.49,52.75.ESI-MS m/z:435.2388[M+H]+.
实施例72、4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.13–8.07(m,2H),8.04(d,J=8.0Hz,2H),7.59(dd,J=5.3,1.9Hz,3H),7.54(d,J=8.1Hz,2H),7.16(s,1H),3.75–3.70(m,2H),3.68(t,J=5.1Hz,2H),3.63(d,J=5.7Hz,4H),2.65(t,J=5.3Hz,2H),2.60(s,8H).13C NMR(100MHz,Chloroform-d)δ160.38,142.67,134.24,132.88,131.92,129.81(d,J=4.8Hz),129.15,128.87,127.68(d,J=2.8Hz),126.63,125.20,99.85,72.50,67.35,62.44,61.92,57.88,53.18(d,J=5.5Hz),52.64(d,J=14.7Hz).ESI-MS m/z:435.2397[M+H]+.
实施例73、4-{4-[(苯并[d][1,3]噻唑-2-基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),9.51(s,1H),8.24–8.06(m,4H),7.61–7.55(m,3H),7.41(d,J=8.3Hz,2H),7.37(t,J=7.6Hz,2H),7.17–7.11(m,1H),7.01(td,J=7.6,1.3Hz,1H),4.19(s,2H).13C NMR(100MHz,Methanol-d4)δ142.01,140.38,137.06,132.01,130.67,129.58,129.08,128.38–126.81(m),127.63,123.37,115.07,100.35,39.86.ESI-MS m/z:411.1279[M+H]+.
实施例74、4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.14–8.08(m,2H),8.04(d,J=8.0Hz,2H),7.54(d,J=8.1Hz,2H),7.12–7.06(m,3H),3.93(s,3H),3.69(q,J=4.8Hz,2H),3.64(s,2H),2.73–2.51(m,10H).13C NMR(100MHz,Methanol-d4)δ162.25,141.79,129.84,129.38,127.45,126.17,114.20,113.66,99.29,61.93,59.81,58.27,54.72,52.81(d,J=15.3Hz),52.11(d,J=19.6Hz).ESI-MS m/z:421.2232[M+H]+.
实施例75、4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.05(dd,J=17.2,8.1Hz,4H),7.57(d,J=7.9Hz,2H),7.32(s,1H),7.15–7.09(m,2H),3.92(s,3H),3.68(dd,J=8.2,4.2Hz,6H),3.60–3.54(m,2H),2.78–2.67(m,6H),2.67–2.55(m,4H).13C NMR(100MHz,Chloroform-d)δ162.89,160.33,142.58,129.84,129.54,127.62,114.61,99.09,72.50,67.32,62.49,62.05,57.92,55.58,53.22,52.76.ESI-MS m/z:465.2489[M+H]+.
实施例76、4-{4-[(戊基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ8.22–8.12(m,4H),7.56(dd,J=18.4,8.1Hz,6H),3.84(s,2H),2.57(d,J=7.2Hz,2H),1.49(t,J=7.2Hz,2H),1.30(td,J=9.3,8.4,4.7Hz,4H),0.88(h,J=4.9Hz,2H).13C NMR(100MHz,Chloroform-d)δ160.39,142.20,134.08,133.10,131.95,129.57,129.47,129.18,127.82,127.74,127.69,99.88,52.84,49.09,29.76,28.62,22.53,14.07.ESI-MS m/z:348.2075[M+H]+.
实施例77、6-(4-甲氧基苯基)-4-{4-[(戊基氨基)甲基]苯基}-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,DMSO-d6)δ8.22–8.15(m,2H),8.14–8.09(m,2H),7.53(d,J=8.1Hz,2H),7.49(s,1H),7.15–7.09(m,2H),3.88(s,3H),3.82(s,2H),2.56(s,2H),1.53–1.43(m,2H),1.30(h,J=3.7Hz,4H),0.93–0.85(m,2H).13C NMR(100MHz,Chloroform-d)δ162.82,160.49,143.54,133.05,129.54,129.08,127.78,126.27,114.56,99.09,55.55,53.31,49.36,29.76,29.30,22.62,14.11.ESI-MS m/z:378.2128[M+H]+.
实施例78、4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮1H NMR(400MHz,Chloroform-d)δ8.07(dd,J=6.8,2.9Hz,2H),8.03(d,J=8.0Hz,2H),7.55(dd,J=5.1,1.9Hz,3H),7.51(d,J=8.0Hz,2H),7.14(s,1H),3.59(s,2H),3.53(t,J=5.6Hz,2H),3.35(s,3H),2.62(q,J=5.1,4.5Hz,2H),2.57(s,8H).13C NMR(100MHz,Chloroform-d)δ160.46,142.72,134.21,132.83,132.00,129.90,129.23,127.72,127.67,100.00,69.97,62.52,58.94,57.80,53.46,52.81.ESI-MS m/z:405.2295[M+H]+.
实施例79、6-(4-溴苯基)-4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.03(t,J=8.8Hz,4H),7.77–7.73(m,2H),7.59(d,J=8.2Hz,2H),7.40(s,1H),3.81(t,J=5.6Hz,2H),3.73(s,2H),3.02(s,4H),2.94(t,J=5.6Hz,2H),2.73(s,4H).13C NMR(100MHz,Chloroform-d)δ160.23,143.01,132.42,129.98,129.31,127.57,126.99,99.69,62.48,59.32,57.67,53.03,52.87.ESI-MS m/z:469.1238[M+H]+.
实施例80、4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.20–8.14(d,2H),8.09(d,J=7.5Hz,4H),7.61(d,J=7.2Hz,5H),7.18(s,1H),6.86(d,J=9.4Hz,2H),3.72(s,2H),3.51(s,4H),2.70(s,4H).13C NMR(100MHz,DMSO-d6)δ155.23,137.36,132.00,129.76,129.35,128.07,126.23,113.14,61.84,52.67,46.84.ESI-MS m/z:468.2027[M+H]+.
实施例81、6-(4-溴苯基)-4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J=8.4,3.6Hz,4H),7.73–7.68(m,2H),7.56–7.52(m,2H),7.12(s,1H),3.74–3.69(m,4H),3.64(d,J=6.0Hz,4H),2.71(q,J=5.6Hz,6H),2.63(s,4H).13C NMR(100MHz,Chloroform-d)δ160.33,142.80,133.65,132.41,132.09,131.38,131.25,129.99,129.32,127.63,126.96,99.75,72.55,67.07,62.30,61.92,57.70,53.11,52.40.ESI-MS m/z:513.1497[M+H]+.
实施例82、6-(4-甲氧基苯基)-4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Chloroform-d)δ8.20–8.06(m,6H),7.60(d,J=7.8Hz,2H),7.14(s,1H),7.10(d,J=8.5Hz,2H),6.86(d,J=9.1Hz,2H),3.94(s,3H),3.72(s,2H),3.51(s,4H),2.70(s,4H).13C NMR(100MHz,Chloroform-d)δ162.96,160.25,154.91,142.06,138.42,129.66(d,J=22.5Hz),127.75,126.00,114.64,112.69,99.06,62.46,55.58,52.65,47.07.ESI-MS m/z:498.2139[M+H]+.
实施例83、6-(4-溴苯基)-4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ8.06–8.00(m,4H),7.78–7.73(m,2H),7.58(d,J=8.1Hz,2H),7.39(d,J=3.4Hz,1H),3.66(s,2H),3.58(t,J=5.5Hz,2H),3.37(s,3H),2.69(t,J=5.4Hz,6H),2.60(s,4H).13C NMR(100MHz,Chloroform-d)δ160.21,132.42,130.01,129.33,127.53,126.95,99.64,69.99,62.51,58.98,57.88,53.56,52.85.ESI-MS m/z:483.1391[M+H]+.
实施例84、4-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-6-(4-溴苯基)-1,2-二氢嘧啶-2-酮
1H NMR(400MHz,Methanol-d4)δ7.97(t,J=8.0Hz,4H),7.73–7.69(m,2H),7.56(d,J=8.1Hz,2H),7.26(s,1H),3.66(s,2H),3.63(t,J=5.2Hz,2H),3.57(t,J=5.1Hz,2H),2.54(t,J=5.1Hz,2H),2.49(t,J=5.1Hz,2H),2.11(s,3H).13C NMR(100MHz,Methanol-d4)δ170.08,159.57,141.92,132.27,131.44,129.91,129.20,127.61,126.81,100.15,62.10,52.94,52.49,46.17,41.38,20.67.ESI-MS m/z:467.1081[M+H]+.
实施例85、2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
步骤一:2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将2-氨基苯甲酰胺(1.00g,7.34mmol),碘(2.05g,8.08mmol),对甲基苯甲醛(1.06g,8.81mmol)依次加入乙醇(10mL)中,85℃反应2小时。5%亚硫酸钠溶液淬灭反应,抽滤得,即为2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮,收率为90%。
步骤二:2-[4-(溴甲基)苯基]-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将步骤一制得的2-(4-甲基苯基)-3,4-二氢喹唑啉-4-酮(1.70g,7.20mmol),N-溴代琥珀酰亚胺(1.41g,7.91mmol),偶氮二异丁腈(236.30mg,1.44mmol)依次加入四氯化碳(30mL)中,氮气保护下85℃反应2h。旋蒸蒸干四氯化碳,EA萃取。蒸干EA,柱层析(PE:EA=5:1)得,即为2-[4-(溴甲基)苯基]-3,4-二氢喹唑啉-4-酮,收率为60%。
步骤三:2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
在25mL圆底烧瓶中将步骤二制得的(E)-3-[4-(溴甲基)苯基]-1-苯基丙-2-烯-1-酮(100mg,0.32mmol),2-甲氧基乙基哌嗪(50.33mg,0.35mmol),三乙胺(48.51μL)依次加入乙腈(10mL)中,氮气保护下85℃反应2h。旋蒸蒸干乙腈,EA萃取。蒸干EA,柱层析(PE:EA=1:1)得,即为(E)-3-(4-{[4-(2-羟乙基)哌嗪-1-基]甲基}苯基)-1-苯基丙-2-烯-1-酮,收率为60%。
1H NMR(400MHz,Methanol-d4)δ8.29–8.24(m,1H),8.07–8.01(m,2H),7.86–7.78(m,2H),7.57–7.49(m,3H),3.69(s,2H),3.63(t,J=5.3Hz,2H),3.37(s,3H),2.95–2.79(m,6H),2.69(s,4H).13C NMR(100MHz,Methanol-d4)δ140.54,134.98,129.87,127.71,127.40,126.94,126.20,68.54,61.90,58.67,57.06,52.84,51.34.ESI-MS m/z:379.2132[M+H]+.
按照实施例85的方法,分别制得实施例86~93化合物
实施例86、2-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ8.17(dd,J=8.3,3.0Hz,3H),7.85(t,J=7.6Hz,1H),7.75(d,J=8.1Hz,1H),7.53(t,J=7.5Hz,1H),7.48(d,J=7.9Hz,2H),3.55(s,2H),3.50(t,J=6.3Hz,2H),2.41(q,J=11.0,6.3Hz,10H).13C NMR(100MHz,Chloroform-d)δ163.88,151.69,149.56,142.28,134.99,131.73,129.79,128.01,127.39,126.82,126.43,120.85,62.58,59.33,57.74,53.09,52.86.ESI-MS m/z:365.1987[M+H]+.
实施例87、2-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.22–8.15(m,3H),8.10–8.04(m,2H),7.86(ddd,J=8.5,7.0,1.6Hz,1H),7.76(d,J=8.1Hz,1H),7.54(dd,J=7.6,6.1Hz,3H),7.07–7.00(m,2H),3.65(s,2H),3.50(t,J=5.1Hz,4H),2.56(d,J=5.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ162.74,155.19,152.62,149.28,142.14,137.35,135.12,132.00,129.50,128.11,127.03,126.29,121.46,113.10,61.81,52.64,46.81.ESI-MS m/z:442.1871[M+H]+.
实施例88、2-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Chloroform-d)δ10.86(s,1H),8.37(d,J=7.9Hz,1H),8.20(d,J=7.8Hz,2H),7.86(dd,J=5.9,1.7Hz,2H),7.62(s,2H),7.56(ddd,J=8.2,6.0,2.2Hz,1H),3.71(s,4H),3.56(s,2H),2.54(s,4H),2.13(s,3H).13C NMR(100MHz,Chloroform-d)δ169.09,163.86,151.59,149.56,141.85,135.02,131.93,129.71,128.06,127.51,126.87,126.41,120.87,62.48,53.17,52.88,46.32,41.47,21.43.ESI-MS m/z:363.1826[M+H]+.
实施例89、7-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Methanol-d4)δ8.23(d,J=8.2Hz,1H),8.07–8.02(m,2H),7.77(d,J=1.5Hz,1H),7.61–7.51(m,5H),3.72(s,2H),3.56(t,J=5.6Hz,2H),3.36(s,3H),2.74–2.54(m,10H).13C NMR(100MHz,Chloroform-d)δ163.76,151.95,149.60,146.41,132.93,131.68,129.09,127.92,127.80,127.44,126.34,119.74,70.13,62.75,58.96,57.97,53.65,53.06.ESI-MS m/z:379.2141[M+H]+.
实施例90、7-{[4-(2-羟基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.16–8.10(m,2H),8.06(d,J=8.1Hz,1H),7.61(s,1H),7.58–7.44(m,4H),7.41(dd,J=8.2,1.6Hz,1H),4.49(s,1H),3.60(s,2H),3.47(t,J=6.3Hz,2H),2.62(s,7H),2.66–2.45(m,10H).13C NMR(100MHz,Chloroform-d)δ167.43,157.44,153.17,149.23,136.87,135.57,132.83,131.99,131.76,131.50,130.26,123.80,66.23,63.68,61.86,56.90,56.12.ESI-MS m/z:365.1968[M+H]+.
实施例91、7-{[4-(4-硝基苯基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.23–8.18(m,2H),8.15(d,J=8.1Hz,1H),8.10–8.03(m,2H),7.72(d,J=1.6Hz,1H),7.65–7.51(m,5H),7.07–7.01(m,2H),3.73(s,2H),3.51(t,J=5.0Hz,4H),2.58(dd,J=6.6,3.6Hz,4H).13C NMR(100MHz,DMSO-d6)δ162.69,155.09,152.78,145.43,137.67,131.57,128.84,128.12,127.50(d,J=23.7Hz),126.27,126.00,112.96,62.15,52.68,46.96.ESI-MS m/z:442.1874[M+H]+.
实施例92、7-[(4-乙酰基哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,Chloroform-d)δ11.26(s,1H),8.33(dd,J=8.1,1.8Hz,1H),8.28–8.22(m,2H),7.84(s,1H),7.63(dd,J=4.9,2.6Hz,3H),7.56(d,J=8.1Hz,1H),3.74(s,2H),3.69(d,J=6.0Hz,2H),3.53(t,J=5.0Hz,2H),2.54(d,J=6.5Hz,4H),2.13(d,J=1.8Hz,3H).13C NMR(100MHz,Methanol-d4)δ170.16,145.42,131.48,128.74,127.63,127.60,127.26,126.16,62.06,52.91,52.52,47.91,47.69,47.48,46.20,41.42,20.34.ESI-MS m/z:363.1823[M+H]+.
实施例93、7-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.23–8.17(m,2H),8.12(d,J=8.1Hz,1H),7.67(d,J=1.5Hz,1H),7.65–7.53(m,3H),7.48(dd,J=8.2,1.6Hz,1H),3.66(s,2H),3.54(t,J=5.8Hz,2H),3.50(t,J=5.1Hz,2H),3.43(d,J=5.1Hz,4H),2.65–2.54(m,4H),2.50–2.41(m,4H).13C NMR(100MHz,DMSO-d6)δ162.57,152.90,149.28,146.07,133.21,131.90,129.12,128.23,127.60(d,J=13.6Hz),126.32,120.30,72.69,68.15,61.93,60.69,57.50,53.46,52.75.ESI-MS m/z:409.2237[M+H]+.
本发明产物的药理研究
(1)实施例化合物与MyD88蛋白的结合亲和力与浓度的关系
本实施例测试了实施例3化合物与MyD88蛋白的结合亲和力与浓度的关系。具体方法如下:利用标准氨基化学偶联法固定rh MyD88蛋白于CM7传感芯片表面,先20μg/mL蛋白溶于醋酸缓冲液(pH 5.5、5.0、4.5、4.0)以静电吸附作用预富集在CM7传感芯片(流速10μL/min),再以100μL的0.05M NHS和0.2M EDC混合溶液活化,反应10min催化蛋白的氨基和芯片上的活性羧基基团交联。最后用150μL的1M盐酸乙醇胺封闭未反应的活性羧基基团并洗去非共价吸附的物质(蛋白偶联量至少25000RFU)。PBSP缓冲液冲洗直至基线稳定。取出CM7芯片备用。动力学测定时,实施例3化合物用PBSP(含5%DMSO)稀释50μM,分别注射到已固定rhMyD88的CM7传感芯片上,每次注射50μl,测定3次。每次测定后,用含10mM Gly-Hcl(pH 2.5)溶液再生传感芯片,然后进行下一次测定。实验结果用评估软件BIAevaluation评估其结合力。实验结果如图1所示,所测试的实施例3化合物可直接结合MyD88,其结合亲和力的Kd值为5.3×10-5M。
(2)实施例化合物抑制LPS刺激巨噬细胞释放炎症因子的量效关系
本实施例测试了部分活性实施例化合物抑制LPS刺激J774A.1小鼠巨噬细胞释放IL-6和TNF-α的量效关系。具体方法如下:1.2×106个小鼠巨噬细胞用DMEM培养液培养于37℃,24小时后更新培养液,并加入受测化合物(终浓度为10μM)预处理2h,再用0.5μg/mL的LPS继续处理22小时,收集培养液用ELISA法检测IL-6和TNF-α含量;收集细胞检测总蛋白浓度,ELISA结果用相应的总蛋白浓度相除较准,以LPS对照组的IL-6和TNF-α含量定标为100,计算平均值和误差值。实验结果如图2、图3所示,由图2可知,所测试的实施例化合物1、3、4、5、6、7、8、9、10、11、12、16、17、20、21、22、23、24、25、26、70、71、72、73、75、77、81、83、85、88对于IL-6的释放具有明显的抑制作用。由图3可知,所测试的实施例化合物1、3、4、5、6、7、8、9、10、11、12、16、17、20、21、22、23、24、25、26、70、71、72、73、75、77、81、83、85、88对于TNF-α的释放具有明显的抑制作用。这些实施例化合物都具有新颖的化合物骨架结构,也融入了具有优秀抗炎活性的片段,这突出表明了本发明通式结构的创新性所在。
(3)实施例化合物缓解由炎症引起的小鼠生理学变化
以缓解急性肺损伤所引起的生理学变化为例。用0.5%羧甲基纤维素钠与实施例化合物制成混悬液用于腹腔给药。各组小鼠乙醚麻醉后暴露气管,除对照组外,其余各组气管内缓慢滴入50μL 5mg/kg LPS,造成小鼠急性肺损伤,对照组以相同的方式滴入等量生理盐水,缝合伤口,建立急性肺损伤模型。动物造模24h后,按照5mL/kg的剂量腹腔注射10%的水合氯醛麻醉老鼠,开胸结扎左肺,右肺用1mL生理盐水进行支气管肺泡灌洗,收集灌洗液,相同操作重复3次。
肺泡灌洗液收集后,4℃1000rpm离心5分钟,取上清液,测肺泡灌洗液的蛋白浓度。肺泡灌洗液离心后,用50μL生理盐水重悬沉淀,混匀后取20μL用细胞计数仪Standard计数肺泡灌洗液中的总细胞数。此外,取右肺上叶,滤纸吸去组织上的水分后称取湿重,放入60℃烘烤48h以上,直到其重量不再发生变化为止,称取干重,计算肺组织湿重/干重比(W/D),判断肺水肿程度。以实施例3化合物为例,实验数据见图4,其中3代表实施例3化合物,结果表明实施例化合物在生理学上可有效缓解小鼠急性肺损伤。
(4)实施例化合物缓解炎症引起的小鼠病理学变化试验
以缓解由急性肺损伤引起的小鼠肺组织病理学变化为例。实验数据见图5,正常对照组小鼠肺泡腔清晰,结构完整,壁光滑;气管滴注LPS造成急性肺损伤模型后,肺泡壁明显水肿、增厚,炎症细胞浸润增加;给予实施例3化合物治疗后细胞水肿、增厚显著减弱,且炎症细胞浸润明显减少,与正常组差别不大,说明实施例3化合物可有效缓解急性肺损伤中肺组织损伤。
(5)实施例化合物缓解炎症引起的小鼠生存率变化试验
以缓解脓毒血症所引起的小鼠生存率变化为例。用0.5%羧甲基纤维素钠与实施例3化合物制成混悬液用于腹腔给药。各组小鼠乙醚麻醉后暴露气管,除对照组外,其余各组腹腔注射20μL 20mg/kg LPS,造成小鼠脓毒血症,对照组以相同的方式注射等量生理盐水,建立脓毒血症模型。动物造模7天内,每日记录小鼠存活情况。实验数据见图6,结果表明实施例化合物可以有效降低脓毒血症引起的小鼠的死亡率。
(6)实施例化合物缓解炎症引起的小鼠脾脏病理学变化试验
以缓解由脓毒血症引起的小鼠脾脏组织病理学变化为例。实验数据见图7,正常对照组小鼠脾脏清晰,结构完整,白髓红髓分明;腹腔注射LPS造成脓毒血症模型后,小鼠脾脏肿大,白髓扩散;给予实施例3化合物治疗后脾脏肿大减少,白髓与正常组差别不大,说明实施例3化合物可有效缓解脓毒血症引起的脾脏损伤。
从上述试验结果可以清楚地看出,本发明所要保护的通式Ⅰ的化合物,具有良好的抗炎活性。
Claims (10)
1.一种髓样分化因子88抑制剂,其特征在于,为结构如式(Ⅰ)所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药;
其中:
X和Y独立的包含CH2,NH,C(O),S(O)2中的一种;
R1包含H,可以被1至3个相同或不同的取代基任选取代的芳基、可以被1至3个相同或不同的取代基任选取代的杂环基或可以被1至3个相同或不同的取代基任选取代的杂芳基,所述取代基选自烷基、卤素、烷氧基、取代芳基和取代杂芳基;
R2包含氢或硝基;
R3和R4独立地包含氢、烷基和芳基,或者R3和R4独立地成环从而使得-C(R3)R4形成取代杂环基或取代杂芳基,或者R3和X、Y独立地成环使得-XYCR3形成取代杂环基或取代芳杂基。
4.根据权利要求1所述髓样分化因子88抑制剂,其特征在于,为以下化合物及其药学上可接受的盐、溶剂化物或前药:
化合物1:N-(2-甲氧基吡啶-5-基)-3-硝基-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物2:4-(4-苄基哌嗪-1-基)-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物3:N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物4:N-(2-甲氧基吡啶-5-基)-3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}苯磺酰胺
化合物5:4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-N-(2-甲氧基吡啶-5-基)-3-硝基苯磺酰胺
化合物6:N-(5-{[4-(4-{[(6-甲氧基吡啶-3-基)氨基]二氧亚基-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物7:N-(萘-1-基)-3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}苯甲酰胺
化合物8:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物9:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物10:4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯甲酰胺
化合物11:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物12:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯甲酰胺
化合物13:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物14:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯甲酰胺
化合物15:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯甲酰胺
化合物16:2-(4-{2-硝基-4-[(苯基氨基)甲基]苯基}哌嗪-1-基)乙-1-醇
化合物17:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯甲酰胺
化合物18:4-[4-(2-羟基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物19:4-[4-(2-甲氧基乙基)哌嗪-1-基]-N-(6-甲氧基吡啶-3-基)-3-硝基苯磺酰胺
化合物20:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物21:4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物22:4-[4-(2-甲氧基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物23:4-[4-(2-羟基乙基)哌嗪-1-基]-3-硝基-N-苯基苯磺酰胺
化合物24:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物25:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-苯基苯磺酰胺
化合物26:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-苯基苯磺酰胺
化合物27:4-(4-苄基哌嗪-1-基)-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物28:3-硝基-4-{4-[(3-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物29:3-硝基-4-{4-[(4-硝基苯基)甲基]哌嗪-1-基}-N-(吡啶-2-基甲基)苯磺酰胺
化合物30:3-硝基-4-[4-(4-硝基苯基)哌嗪-1-基]-N-(吡啶-2-基甲基)苯磺酰胺
化合物31:4-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}-3-硝基-N-(吡啶-2-基甲基)苯磺酰胺
化合物32:3-硝基-N-(吡啶-2-基甲基)-4-[4-(嘧啶-2-基)哌嗪-1-基]苯磺酰胺
化合物33:N-(5-{[4-(4-{二氧亚基[(吡啶-2-基甲基)氨基]-λ6-硫基}-2-硝基苯基)哌嗪-1-基]甲基}-1,3-噻唑-2-基)乙酰胺
化合物34:1-[4-(苄基磺酰基)-2-硝基苯基]-3-甲基哌啶
化合物35:1-[4-(苄基磺酰基)-2-硝基苯基]-4-甲基哌嗪
化合物36:1-[4-(苄基磺酰基)-2-硝基苯基]-4-乙基哌嗪
化合物37:1-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-酮
化合物38:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(4-硝基苯基)哌嗪
化合物39:2-{4-[4-(苄基磺酰基)-2-硝基苯基]哌嗪-1-基}乙-1-醇
化合物40:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(2-甲氧基乙基)哌嗪
化合物41:1-[4-(苄基磺酰基)-2-硝基苯基]-4-(3-硝基苄基)哌嗪
化合物42:4-[(3-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物43:1-乙基-4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪
化合物44:1-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物45:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物46:2-(4-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物47:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物48:1-{4-[(3-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物49:4-[(4-氟苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物50:1-乙基-4-[4-(4-氟苄基)磺酰基]-2-硝基苯基哌嗪
化合物51:1-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物52:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物53:2-(4-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物54:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物55:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物56:1-{4-[(4-氟苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苄基)哌嗪
化合物57:1-乙基-4-[4-(4-甲基苄基)磺酰基]-2-硝基苯基)哌嗪
化合物58:1-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物59:1-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物60:2-(4-{4-[(4-甲基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物61:1-(2-甲氧基乙基)-4-[4-(4-甲基苄基)磺酰基]2-硝基苯基)哌嗪
化合物62:4-[(4-甲氧基苄基)磺酰基]-N,N-二甲基-2-硝基苯胺
化合物63:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物64:1-乙基-4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪
化合物65:1-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-酮
化合物66:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(4-硝基苯基)哌嗪
化合物67:2-(4-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}哌嗪-1-基)乙-1-醇
化合物68:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(2-甲氧基乙基)哌嗪
化合物69:1-{4-[(3-甲氧基苄基)磺酰基]-2-硝基苯基}-4-(3-硝基苄基)哌嗪
化合物70:4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物71:4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物72:4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物73:4-{4-[(苯并[d][1,3]噻唑-2-基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物74:4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物75:4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-6-(4-甲氧基苯基)-1,2-二氢嘧啶-2-酮
化合物76:4-{4-[(戊基氨基)甲基]苯基}-6-苯基-1,2-二氢嘧啶-2-酮
化合物77:6-(4-甲氧基苯基)-4-{4-[(戊基氨基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物78:4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物79:6-(4-溴苯基)-4-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物80:4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-6-苯基-1,2-二氢嘧啶-2-酮
化合物81:6-(4-溴苯基)-4-{4-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]苯基}-1,2-二氢嘧啶-2-酮
化合物82:6-(4-甲氧基苯基)-4-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物83:6-(4-溴苯基)-4-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-1,2-二氢嘧啶-2-酮
化合物84:4-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-6-(4-溴苯基)-1,2-二氢嘧啶-2-酮
化合物85:2-(4-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物86:2-(4-{[4-(2-羟基乙基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物87:2-(4-{[4-(4-硝基苯基)哌嗪-1-基]甲基}苯基)-3,4-二氢喹唑啉-4-酮
化合物88:2-{4-[(4-乙酰基哌嗪-1-基)甲基]苯基}-3,4-二氢喹唑啉-4-酮
化合物89:7-{[4-(2-甲氧基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物90:7-{[4-(2-羟基乙基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物91:7-{[4-(4-硝基苯基)哌嗪-1-基]甲基}-2-苯基-3,4-二氢喹唑啉-4-酮
化合物92:7-[(4-乙酰基哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮
化合物93:7-[(4-{2-[(2-羟基乙基)氧基]乙基}哌嗪-1-基)甲基]-2-苯基-3,4-二氢喹唑啉-4-酮。
5.权利要求4所述髓样分化因子88抑制剂的制备方法,其特征在于,化合物1~33的制备方法包含如下步骤:
所述反应的温度为-5~5℃,时间为5~15h;
所述反应的温度为60~80℃,时间为1~10h。
6.权利要求4所述髓样分化因子88抑制剂的制备方法,其特征在于,化合物34~69的制备方法包含如下步骤:
(1)将碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水混后合后进行反应,生成4-氯-3-硝基苯亚磺酸;
所述碳酸氢钠、亚硫酸钠、4-氯-3-硝基苯磺酰氯和水的用量比为7~9mmol:7~9mmol:3~5mmol:20~40mL;
所述反应的温度为室温,时间为1~5h;
所述4-氯-3-硝基苯亚磺酸、溴苄类物质和N,N-二甲基甲酰胺的用量比为0.4~0.5mmol:0.6~0.8mmol:2~8mL;
所述反应的温度为70~90℃,时间为1~5h;
所述反应的温度为80~90℃,时间为1~5h。
7.权利要求4所述髓样分化因子88抑制剂的制备方法,其特征在于,化合物70~84的制备方法包含如下步骤:
所述反应的温度为室温,时间为5~15h;
所述反应的温度为80~90℃,时间为1~5h;
所述反应的温度为80~90℃,时间为1~5h;
所述反应的温度为80~90℃,时间为1~5h。
8.权利要求4所述髓样分化因子88抑制剂的制备方法,其特征在于,化合物85~93的制备方法包含如下步骤:
所述反应的温度为80~90℃,时间为1~5h;
所述R5和R1有一个为H;
所述反应的温度为80~90℃,时间为1~5h;
(3)在保护气氛下,将中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈混合后进行反应,生成化合物85~93中的一种;
所述中间产物、2-甲氧基乙基哌嗪、三乙胺和乙腈的用量比为0.1~0.5mmol:0.1~0.5mmol:45~55μL:5~15mL;
所述反应的温度为80~90℃,时间为1~5h。
9.权利要求1~4任意一项所述髓样分化因子88抑制剂在制备治疗炎症相关疾病的药物制剂中的应用。
10.根据权利要求9所述的应用,其特征在于,所述炎症相关疾病包含急性肺损伤和/或脓毒血症。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211458016.8A CN115710251B (zh) | 2022-11-16 | 2022-11-16 | 一种髓样分化因子88抑制剂及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211458016.8A CN115710251B (zh) | 2022-11-16 | 2022-11-16 | 一种髓样分化因子88抑制剂及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115710251A true CN115710251A (zh) | 2023-02-24 |
CN115710251B CN115710251B (zh) | 2024-05-28 |
Family
ID=85234348
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211458016.8A Active CN115710251B (zh) | 2022-11-16 | 2022-11-16 | 一种髓样分化因子88抑制剂及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115710251B (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102166214A (zh) * | 2011-03-02 | 2011-08-31 | 华中科技大学同济医学院附属同济医院 | 氨基噻唑类MyD88特异性抑制剂在医学上的用途 |
-
2022
- 2022-11-16 CN CN202211458016.8A patent/CN115710251B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102166214A (zh) * | 2011-03-02 | 2011-08-31 | 华中科技大学同济医学院附属同济医院 | 氨基噻唑类MyD88特异性抑制剂在医学上的用途 |
Non-Patent Citations (1)
Title |
---|
CAS: "RN=2778670-88-3,RN-=2787901-31-7", 《REG》, pages 1 - 2 * |
Also Published As
Publication number | Publication date |
---|---|
CN115710251B (zh) | 2024-05-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5933746B2 (ja) | イミダゾリジンジオン系化合物およびその用途 | |
KR101820645B1 (ko) | Kcnq2/3 조절제로서의 치환된 6아미노니코틴아미드 | |
CN110997669B (zh) | 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 | |
JP2852659B2 (ja) | ピペラジン誘導体およびその塩 | |
US20040152739A1 (en) | Acyclic pyrazole compounds for the inhibition of mitogen activated protein kinase-activated protein kinase-2 | |
NZ577611A (en) | Dihydropyridine derivatives useful as protein kinase inhibitors | |
KR20190099209A (ko) | 8,9-디하이드로이미다졸[1,2-a]피리미도[5,4-e]피리미딘-5(6H)-케톤계 화합물 | |
JPWO2005075431A1 (ja) | 1−(2h)−イソキノロン誘導体 | |
CS247073B2 (en) | Production method of 2-substituted 4-amino-6,7-dimethoxyghinolins | |
BRPI0716860A2 (pt) | Composto, medicamento, composição farmacêutica, antagonista de receptor 5-ht6, método para preparar composições farmacêuticas, preparação de combinação, processo para preparar composto, uso de um composto, métodos para antagonizar receptores 5-ht6, e para tratar doença, e, embalagem comercial. | |
KR20090031605A (ko) | 신규한 피리딘 유사체 | |
EP0384228A1 (en) | Medicament for treating cerebral insufficiency diseases containing 2-(1-piperazinyl)-4-phenylcycloalkanopyrimidine derivatives, and process for the production thereof | |
CN112020496A (zh) | 作为rho激酶抑制剂的苯并吡唑类化合物 | |
SE466309B (sv) | 1-pyrimidinyloxi-3-hetarylalkylamino-2-propanoler, farmaceutisk komposition och framstaellning daerav | |
CN115703761A (zh) | 作为wwp1抑制剂的化合物及其应用 | |
CN113045559B (zh) | 一种二芳基脲类PI3Kα/mTOR双靶点抑制剂及其药物组合物和应用 | |
JP2004513126A (ja) | 窒素性複素環式化合物、ならびに窒素性複素環式化合物およびその中間体を作製するための方法 | |
JP3295277B2 (ja) | 抗腎疾患剤及びベンズイミダゾール誘導体 | |
EA007066B1 (ru) | Производные триазолохинолина, применимые в качестве лигандов аденозиновых рецепторов | |
KR20130095755A (ko) | Kcnq2/3 조절제로서의 치환된 2-옥소- 및 2-티옥소-디하이드로퀴놀린-3-카복스아미드 | |
CN107474039B (zh) | 含三氮唑酮和咪唑的4-苯氧基取代喹啉类化合物及其应用 | |
CN115710251A (zh) | 一种髓样分化因子88抑制剂及其制备方法和应用 | |
CN114845996A (zh) | 一种含苯环的化合物及其应用 | |
KR20240042619A (ko) | 유기 피리딘-피라졸 화합물 및 이의 용도 | |
EP3484875B1 (en) | Pyrazolylaminobenzimidazole derivatives as jak inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |