CN112638901A - 用于治疗自身免疫性疾病的新型吡咯烷基酰胺化合物 - Google Patents
用于治疗自身免疫性疾病的新型吡咯烷基酰胺化合物 Download PDFInfo
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- CN112638901A CN112638901A CN201880097010.8A CN201880097010A CN112638901A CN 112638901 A CN112638901 A CN 112638901A CN 201880097010 A CN201880097010 A CN 201880097010A CN 112638901 A CN112638901 A CN 112638901A
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- China
- Prior art keywords
- carboxamide
- methyl
- trifluoromethyl
- pyrrolidine
- azaspiro
- Prior art date
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- 238000011282 treatment Methods 0.000 title claims description 11
- 208000023275 Autoimmune disease Diseases 0.000 title description 2
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical class NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 152
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 heterocyclic radical Chemical class 0.000 claims description 247
- 238000002360 preparation method Methods 0.000 claims description 83
- 150000003254 radicals Chemical class 0.000 claims description 23
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 19
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 17
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 14
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 14
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 14
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 239000005557 antagonist Substances 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 10
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000007821 HATU Substances 0.000 claims description 6
- MONKKYYPSOQKLA-UHFFFAOYSA-N N-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12COCC(CC(C1)NC(=O)C1CN(CC11CC1)C1=C3N=CC=NC3=C(C=C1)C(F)(F)F)N2 MONKKYYPSOQKLA-UHFFFAOYSA-N 0.000 claims description 6
- YMPKXEIGARIBAI-UHFFFAOYSA-N N-(4-aminocyclohexyl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound NC1CCC(CC1)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F YMPKXEIGARIBAI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001735 carboxylic acids Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 239000007822 coupling agent Substances 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- YAFRKHWZRDFWNG-QGZVFWFLSA-N (7R)-5-(8-cyanoquinoxalin-5-yl)-N-(1-methylpiperidin-4-yl)-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)[C@H](C1)C(=O)NC1CCN(CC1)C YAFRKHWZRDFWNG-QGZVFWFLSA-N 0.000 claims description 4
- YAFRKHWZRDFWNG-KRWDZBQOSA-N (7S)-5-(8-cyanoquinoxalin-5-yl)-N-(1-methylpiperidin-4-yl)-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)[C@@H](C1)C(=O)NC1CCN(CC1)C YAFRKHWZRDFWNG-KRWDZBQOSA-N 0.000 claims description 4
- YAFRKHWZRDFWNG-UHFFFAOYSA-N 5-(8-cyanoquinoxalin-5-yl)-N-(1-methylpiperidin-4-yl)-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NC1CCN(CC1)C YAFRKHWZRDFWNG-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- LOSDYMVYKZGBTL-YYQUZTFQSA-N (3S,4S)-1-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-4-methylpyrrolidine-3-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1C[C@H]([C@@H](C1)C)C(=O)N[C@H]1CNC[C@H]1F LOSDYMVYKZGBTL-YYQUZTFQSA-N 0.000 claims description 3
- NKQCPRCMYHQJJA-MANSERQUSA-N (3S,4S)-1-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-4-propan-2-ylpyrrolidine-3-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1C[C@H]([C@@H](C1)C(C)C)C(=O)N[C@H]1CNC[C@H]1F NKQCPRCMYHQJJA-MANSERQUSA-N 0.000 claims description 3
- MWZRZVPAFGKLJJ-WUKPUPCQSA-N (3S,4S)-N-(azepan-4-yl)-1-(8-cyanoquinolin-5-yl)-4-methylpyrrolidine-3-carboxamide Chemical compound N1CCC(CCC1)NC(=O)[C@@H]1CN(C[C@H]1C)C1=C2C=CC=NC2=C(C=C1)C#N MWZRZVPAFGKLJJ-WUKPUPCQSA-N 0.000 claims description 3
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 claims description 3
- QYUIXSLVYQVZME-UHFFFAOYSA-N 5-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NC1CCN(CC1)C QYUIXSLVYQVZME-UHFFFAOYSA-N 0.000 claims description 3
- GGNHIQATTOAYSE-UHFFFAOYSA-N 5-(8-cyanoquinolin-5-yl)-N-[(1-methylpiperidin-3-yl)methyl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NCC1CN(CCC1)C GGNHIQATTOAYSE-UHFFFAOYSA-N 0.000 claims description 3
- LVCQDAHQNMGLKG-UHFFFAOYSA-N 5-(8-cyanoquinolin-5-yl)-N-[(4-methylmorpholin-2-yl)methyl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NCC1CN(CCO1)C LVCQDAHQNMGLKG-UHFFFAOYSA-N 0.000 claims description 3
- FCRLSZPGIVMALJ-UHFFFAOYSA-N 5-(8-cyanoquinoxalin-5-yl)-N-(morpholin-2-ylmethyl)-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NCC1CNCCO1 FCRLSZPGIVMALJ-UHFFFAOYSA-N 0.000 claims description 3
- FCRLSZPGIVMALJ-AAFJCEBUSA-N 5-(8-cyanoquinoxalin-5-yl)-N-[[(2R)-morpholin-2-yl]methyl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NC[C@H]1CNCCO1 FCRLSZPGIVMALJ-AAFJCEBUSA-N 0.000 claims description 3
- FCRLSZPGIVMALJ-VYRBHSGPSA-N 5-(8-cyanoquinoxalin-5-yl)-N-[[(2S)-morpholin-2-yl]methyl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C(#N)C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)C(C1)C(=O)NC[C@@H]1CNCCO1 FCRLSZPGIVMALJ-VYRBHSGPSA-N 0.000 claims description 3
- VETFARDCEXEGLL-FVFSQFTHSA-N 5-[(3S,4S)-3-(2,7-diazaspiro[4.4]nonane-2-carbonyl)-4-methylpyrrolidin-1-yl]quinoline-8-carbonitrile Chemical compound C1N(CCC11CNCC1)C(=O)[C@@H]1CN(C[C@H]1C)C1=C2C=CC=NC2=C(C=C1)C#N VETFARDCEXEGLL-FVFSQFTHSA-N 0.000 claims description 3
- ZZHHMMRZSJFGIF-WIYYLYMNSA-N 5-[(3S,4S)-3-(3,9-diazaspiro[5.5]undecane-3-carbonyl)-4-methylpyrrolidin-1-yl]quinoline-8-carbonitrile Chemical compound C1CN(CCC11CCNCC1)C(=O)[C@@H]1CN(C[C@H]1C)C1=C2C=CC=NC2=C(C=C1)C#N ZZHHMMRZSJFGIF-WIYYLYMNSA-N 0.000 claims description 3
- WUJCLROPQBGIQT-UHFFFAOYSA-N 5-[7-(3-aminoazetidine-1-carbonyl)-5-azaspiro[2.4]heptan-5-yl]quinoline-8-carbonitrile Chemical compound NC1CN(C1)C(=O)C1CN(CC11CC1)C1=C2C=CC=NC2=C(C=C1)C#N WUJCLROPQBGIQT-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- SZASOJNHRFIDEJ-UHFFFAOYSA-N N-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C1NCC2C1CC(C2)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F SZASOJNHRFIDEJ-UHFFFAOYSA-N 0.000 claims description 3
- PTJFPVNWNUNQGR-UHFFFAOYSA-N N-(2-azabicyclo[2.2.1]heptan-5-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12NCC(C(C1)NC(=O)C1CN(CC11CC1)C1=C3N=CC=NC3=C(C=C1)C(F)(F)F)C2 PTJFPVNWNUNQGR-UHFFFAOYSA-N 0.000 claims description 3
- ZDSCXSHXBCRIRB-UHFFFAOYSA-N N-(3-aminocyclobutyl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound NC1CC(C1)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F ZDSCXSHXBCRIRB-UHFFFAOYSA-N 0.000 claims description 3
- FTMUWPQMTGVMOO-UHFFFAOYSA-N N-(3-azabicyclo[3.2.1]octan-8-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12CNCC(CC1)C2NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F FTMUWPQMTGVMOO-UHFFFAOYSA-N 0.000 claims description 3
- CDYGSRKGXOSDLX-UHFFFAOYSA-N N-(3-azabicyclo[3.3.1]nonan-7-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12CNCC(CC(C1)NC(=O)C1CN(CC11CC1)C1=C3N=CC=NC3=C(C=C1)C(F)(F)F)C2 CDYGSRKGXOSDLX-UHFFFAOYSA-N 0.000 claims description 3
- GDSIDOAOMFPIRQ-UHFFFAOYSA-N N-(3-azabicyclo[3.3.1]nonan-9-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12CNCC(CCC1)C2NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F GDSIDOAOMFPIRQ-UHFFFAOYSA-N 0.000 claims description 3
- TTXRQMWOJNJIPJ-UHFFFAOYSA-N N-(3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12COCC(CNC1)C2NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F TTXRQMWOJNJIPJ-UHFFFAOYSA-N 0.000 claims description 3
- HOYFZTIFWZPCAE-UHFFFAOYSA-N N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound CN1CC2(CC2)C(C1)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F HOYFZTIFWZPCAE-UHFFFAOYSA-N 0.000 claims description 3
- UNDQPFUIDPDVHB-UHFFFAOYSA-N N-(6-aminospiro[3.3]heptan-2-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound NC1CC2(CC(C2)NC(=O)C2CN(CC22CC2)C2=C3N=CC=NC3=C(C=C2)C(F)(F)F)C1 UNDQPFUIDPDVHB-UHFFFAOYSA-N 0.000 claims description 3
- XPWGQTFENRTLDN-UHFFFAOYSA-N N-(7-azaspiro[3.5]nonan-2-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C1C(CC11CCNCC1)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F XPWGQTFENRTLDN-UHFFFAOYSA-N 0.000 claims description 3
- HMIOCESACXOKQS-UHFFFAOYSA-N N-(8-azabicyclo[3.2.1]octan-3-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12CC(CC(CC1)N2)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F HMIOCESACXOKQS-UHFFFAOYSA-N 0.000 claims description 3
- CJISUAUWUKRNHY-UHFFFAOYSA-N N-(9-azabicyclo[3.3.1]nonan-3-yl)-5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C12CC(CC(CCC1)N2)NC(=O)C1CN(CC11CC1)C1=C2N=CC=NC2=C(C=C1)C(F)(F)F CJISUAUWUKRNHY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZESSUGFCRIHCEV-SULGFLJSSA-N methyl (2R,4R)-4-[[5-[8-(trifluoromethyl)quinoxalin-5-yl]-5-azaspiro[2.4]heptane-7-carbonyl]amino]pyrrolidine-2-carboxylate Chemical compound FC(C=1C=CC(=C2N=CC=NC=12)N1CC2(CC2)C(C1)C(=O)N[C@@H]1C[C@@H](NC1)C(=O)OC)(F)F ZESSUGFCRIHCEV-SULGFLJSSA-N 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- IQHXABCGSFAKPN-UHFFFAOYSA-N pyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCNC1 IQHXABCGSFAKPN-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000001819 mass spectrum Methods 0.000 description 92
- 238000005160 1H NMR spectroscopy Methods 0.000 description 79
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 74
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
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- PEAPNBGPRYMRNJ-UHFFFAOYSA-N tert-butyl 7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C1OCC2CC(N)CC1N2C(=O)OC(C)(C)C PEAPNBGPRYMRNJ-UHFFFAOYSA-N 0.000 description 27
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- 239000000243 solution Substances 0.000 description 24
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
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- JSCQBEIFXJTRRF-UHFFFAOYSA-N 5-bromo-8-(trifluoromethyl)quinoxaline Chemical compound BrC1=C2N=CC=NC2=C(C=C1)C(F)(F)F JSCQBEIFXJTRRF-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- YCOKHOLOSGJEGL-UHFFFAOYSA-N tert-butyl 4-aminoazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(N)CC1 YCOKHOLOSGJEGL-UHFFFAOYSA-N 0.000 description 10
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Abstract
本发明涉及式(I)化合物及其药学上可接受的盐、对映体或非对映体,以及包含所述化合物的组合物和使用所述化合物的方法,其中R1、R2、R3和R4如本文所述。
Description
本发明涉及用于哺乳动物的治疗和/或预防的有机化合物,尤其涉及用于治疗系统性红斑狼疮或狼疮性肾炎的TLR7和/或TLR8和/或TLR9的拮抗剂。
技术领域
自身免疫性结缔组织病(CTD)包括典型的自身免疫综合征,例如系统性红斑狼疮(SLE)、原发性干燥综合征(pSjS)、混合性结缔组织病(MCTD)、皮肌炎/多发性肌炎(DM/PM)、类风湿关节炎(RA)和系统性硬化症(SSc)。除RA以外,患者没有真正有效、安全的疗法。SLE代表典型的CTD,其发病率为20-150/100,000,并在不同器官引起广泛的炎症和组织损伤,从皮肤和关节的常见症状到肾、肺或心力衰竭。传统上,SLE已经用非特异性抗炎或免疫抑制药物治疗。但是,长期使用免疫抑制药物(例如皮质类固醇)仅部分有效,并伴有不良的毒性和副作用。贝利木单抗是过去50年中唯一获得FDA批准的用于狼疮的药物,即使其仅对部分SLE患者具有适度且延迟的疗效(Navarra,S.V.等人,Lancet 2011,377,721.)。其他生物制剂,例如抗CD20 mAb、针对特定细胞因子的mAb或特定细胞因子的可溶性受体,已在大多数临床研究中失败。因此,需要新型的疗法,其在更大比例的患者组中提供持续的改善,并且对于在许多自身免疫性疾病以及自身炎症性疾病中的长期使用而言更安全。
Toll样受体(TLR)是模式识别受体(PRR)的重要家族,其可以在多种免疫细胞中引发广泛的免疫应答。内体TLR7、TLR7 8和TLR7 9作为天然的宿主防御传感器,可识别源自病毒、细菌的核酸,具体地,TLR7/8和TLR9分别识别单链RNA(ssRNA)和单链CpG-DNA。然而,TRL7/8/9的异常核酸传感被认为是广泛的自身免疫性疾病和自身炎症性疾病的关键节点(Krieg,A.M.等人,Immunol.Rev.2007,220,251.Jimenez-Dalmaroni,M.J.等人,AutoimmunRev.2016,15,1.Chen,J.Q.等人,Clinical Reviews in Allergy&Immunology 2016,50,1.)。因此,TLR7/8/9代表了自身免疫性疾病和自身炎症性疾病的新治疗靶点,针对这些疾病,不存在有效的不含类固醇且无细胞毒性的口服药物,并且从非常上游就抑制了这些途径可能会带来令人满意的治疗效果。从安全性角度来看,因为存在多个核酸传感途径(例如,其他TLR、cGAS/STING),这种冗余仍应允许在TLR7/8/9抑制的存在下对感染有所应答。因此,我们提出并发明了靶向和抑制TLR7/8/9的口服化合物,用于治疗自身免疫性疾病和自身炎症性疾病。
发明内容
本发明涉及式(I)新型化合物,
其中
R5为氰基、C1-6烷基、卤素、卤代C1-6烷基或硝基;
X为N或CH;
R2和R3独立地选自H、C1-6烷基、C3-7环烷基、卤代C1-6烷基,或者R2和R3与其所连接的碳一起形成C3-7环烷基;
R4为杂环基、杂环基氨基、杂环基C1-6烷基氨基、(C1-6烷基)2氨基C1-6烷基氨基、氨基C3-7环烷基氨基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基氨基、氨基C3-7环烷基C1-6烷基氨基或氨基C1-6烷基氨基;
或其药学上可接受的盐、对映体或非对映体。
本发明的另一目的涉及式(I)新型化合物、其生产、基于根据本发明化合物的药物及其制备以及式(I)化合物作为TLR7和/或TLR8和/或TLR9拮抗剂的用途,及用于治疗或预防系统性红斑狼疮或狼疮性肾炎的用途。式(I)化合物显示出优异的TLR7和/或TLR8和/或TLR9拮抗活性。另外,式(I)化合物还显示出良好的细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
具体实施方式
定义
术语“C1-6烷基”表示含有1至6个,特别是1至4个碳原子的饱和、直链或支链烷基基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。特别的“C1-6烷基”基团是甲基、乙基和异丙基。
术语“卤素”和“卤代”在本文可互换使用,表示氟、氯、溴或碘。
术语“卤代C1-6烷基”表示烷基基团,其中烷基基团的至少一个氢原子已被相同或不同的卤素原子,特别是氟原子取代。卤代C1-6烷基的实例包括单氟-、二氟-或三氟甲基、-乙基或-丙基、例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基、二氟甲基、三氟甲基和三氟乙基。
术语“C3-7环烷基”表示含有3至7个碳原子特别是3至6个碳原子的饱和碳环,例如环丙基、环丁基、环戊基、环己基、环庚基等。特别的“C3-7环烷基”基团是环丙基和环己基。
术语“卤代吡咯烷基”表示吡咯烷基基团,其中吡咯烷基基团的至少一个氢原子已被相同或不同的卤素原子,特别是氟原子替代。卤代吡咯烷基的实例包括氟吡咯烷基和二氟吡咯烷基。
术语“杂环基”表示3至12个环原子的单价饱和或部分不饱和的单环或双环的环系统,其包含1个、2个或3个选自N、O和S的杂原子,剩余的环原子是碳。在特定实施例中,杂环基是4至10个环原子的单价饱和单环的环系统,其包含1个、2个或3个选自N、O和S的环杂原子,剩余的环原子是碳。单环饱和杂环基的实例是氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚烷基、二氮杂环庚烷基、高哌嗪基或氧氮杂环庚烷基。杂环基可以是完全或部分饱和的。双环饱和杂环基的实例是双环[3.1.0]己基、螺[3.3]庚烷基、氮杂双环[2.2.1]庚烷基、氮杂双环[3.2.1]辛烷基、氮杂双环[3.3.1]壬烷基、氮杂螺[3.5]壬烷基、二氮杂螺[4.4]壬烷基、二氮杂螺[5.5]十一烷基、1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯基、氧氮杂双环[3.3.1]壬烷基。部分饱和杂环基的实例是二氢呋喃基、咪唑啉基、二氢噁唑基、四氢吡啶基和二氢吡喃基。单环或双环杂环基可进一步经卤素、羟基、氨基、C1-6烷基、卤代C1-6烷基或杂环基取代。
术语“杂环基氨基”表示杂环基-NH-,其中“杂环基”如上文定义。
术语“对映体”表示化合物的两种立体异构体,它们是彼此不可重叠的镜像。
术语“非对映体”表示具有两个或更多个手性中心并且其分子并非彼此镜像的立体异构体。非对映体具有不同的物理性质,例如熔点、沸点、光谱特性和反应性。
术语“药学上可接受的盐”表示在生物学上或其他方面不是不期望的盐。“药学上可接受的盐”包括酸加成盐和碱加成盐。
术语“药用酸加成盐”是指与无机酸和有机酸形成的那些药学上可接受的盐,所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸,所述有机酸选自脂肪族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,诸如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双氢萘酸、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸和水杨酸。
术语“药用碱加成盐”表示与有机或无机碱形成的那些药学上可接受的盐。可接受的无机碱的实例包括钠、钾、铵、钙、镁、铁、锌、铜、锰和铝盐。衍生自药用有机无毒碱的盐包括伯胺、仲胺和叔胺,取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、氨丁三醇、二环己胺,赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶和多胺树脂)的盐。
术语“药物活性代谢物”表示通过特定化合物或其盐在体内代谢产生的药理活性产物。进入人体后,大多数药物都是化学反应的底物,这些化学反应可能会改变其物理性质和生物学效应。这些通常影响本发明化合物极性的代谢转化改变了药物在体内分布和从体内排泄的方式。然而,在某些情况下,药物代谢是治疗效果所必需的。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,施用途径和形式,主治医学或兽医的判断和其他因素。
术语“药物组合物”表示包含治疗有效量的活性药物成分和一起施用于哺乳动物(例如需要其的人)的药用的赋形剂的混合物或溶液。
TLR7和/或TLR8和/或TLR9的拮抗剂
本发明涉及式(I)化合物,
其中
R5为氰基、C1-6烷基、卤素、卤代C1-6烷基或硝基;
X为N或CH;
R2和R3独立地选自H、C1-6烷基、C3-7环烷基、卤代C1-6烷基,或者R2和R3与其所连接的碳一起形成C3-7环烷基;
R4为杂环基、杂环基氨基、杂环基C1-6烷基氨基、(C1-6烷基)2氨基C1-6烷基氨基、氨基C3-7环烷基氨基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基氨基、氨基C3-7环烷基C1-6烷基氨基或氨基C1-6烷基氨基;
或其药学上可接受的盐、对映体或非对映体。
本发明的另一实施例是(ii),其是式(I)化合物,其中
R5为氰基、C1-6烷基、卤素、卤代C1-6烷基或硝基;
X为N或CH;
R2为H;
R3为H、C1-6烷基、C3-7环烷基、卤代C1-6烷基;
或者R2和R3与其所连接的碳一起形成C3-7环烷基;
R4为杂环基、杂环基氨基、杂环基C1-6烷基氨基、(C1-6烷基)2氨基C1-6烷基氨基、氨基C3-7环烷基氨基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基氨基、氨基C3-7环烷基C1-6烷基氨基或氨基C1-6烷基氨基;
或其药学上可接受的盐、对映体或非对映体。
本发明的另一实施例是(iii),其是根据(ii)所述的式(I)化合物,其中R4为(C1-6烷基)2氨基C1-6烷基氨基、(C1-6烷基吗啉基)C1-6烷基氨基、(C1-6烷基哌啶基)C1-6烷基氨基、(吗啉基C1-6烷基)氨基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基氨基、氨基氮杂环丁烷基、氨基双环[3.1.0]己烷基氨基、氨基C1-6烷基氨基、氨基C3-7环烷基氨基、氨基C3-7环烷基C1-6烷基氨基、氨基螺[3.3]庚烷基氨基、氮杂双环[2.2.1]庚烷基氨基、氮杂双环[3.2.1]辛烷基氨基、氮杂双环[3.3.1]壬烷基氨基、氮杂螺[3.5]壬烷基氨基、氮杂环庚烷基氨基、C1-6烷氧基羰基吡咯烷基氨基、C1-6烷基氮杂螺[2.4]庚烷基氨基、C1-6烷基哌啶基氨基、二氮杂螺[4.4]壬烷基、二氮杂螺[5.5]十一烷基、卤代吡咯烷基氨基、吗啉基C1-6烷基氨基、八氢环戊并[c]吡咯基氨基、氧氮杂双环[3.3.1]壬烷基氨基或哌啶基哌啶基氨基。
本发明的另一实施例是(iv),其是根据(iii)所述的式(I)化合物,其中R5为氰基、甲基、氯、三氟甲基或硝基。
本发明的另一实施例是(v),其是根据(iv)所述的式(I)化合物,其中R3为H、甲基、乙基、异丙基、二氟甲基、三氟甲基或环丙基;或者R2和R3与其所连接的碳一起形成环丙基。
本发明的另一实施例是(vi),其是根据(v)所述的式(I)化合物,其中R3为甲基或三氟甲基;或者R2和R3与其所连接的碳一起形成环丙基。
本发明的另一实施例是(vii),其是根据(v)或(vi)所述的式(I)化合物,其中R4为(3-氨基环丁基)甲基氨基、(二甲基氨基)乙基氨基、(甲基吗啉基)甲基氨基、(甲基哌啶基)甲基氨基、(吗啉基乙基)氨基、(吗啉基甲基)氨基、[(二甲基氨基)甲基]环丁基氨基、1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-5-基氨基、2,7-二氮杂螺[4.4]壬烷基、2-氮杂双环[2.2.1]庚烷-5-基氨基、3,9-二氮杂螺[5.5]十一烷基、3-氮杂双环[3.2.1]辛烷-8-基氨基、3-氮杂双环[3.3.1]壬烷-7-基氨基、3-氮杂双环[3.3.1]壬烷-9-基氨基、3-氧杂-7-氮杂双环[3.3.1]壬烷-9-基氨基、3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基氨基、5-甲基-5-氮杂螺[2.4]庚烷-7-基氨基、6-氨基螺[3.3]庚烷-2-基氨基、7-氮杂螺[3.5]壬烷-2-基氨基、8-氮杂双环[3.2.1]辛烷-3-基氨基、9-氮杂双环[3.3.1]壬烷-3-基氨基、氨基-2-双环[3.1.0]己烷基氨基、氨基氮杂环丁烷基、氨基环丁基氨基、氨基环己基氨基、氨基甲基丙基氨基、氮杂环庚烷基氨基、氟吡咯烷基氨基、甲氧基羰基吡咯烷基氨基、甲基哌啶基氨基或哌啶基哌啶基氨基。
本发明的另一实施例是(viii),其是根据(vii)所述的式(I)化合物,其中R4为甲基哌啶基氨基。
本发明的另一实施例是(ix),其是选自以下项的式(I)特定化合物:
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
(3R,4R)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
N-(3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(7R)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(7S)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(9-氮杂双环[3.3.1]壬烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(1-甲基-4-哌啶基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氮杂双环[3.2.1]辛烷-8-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-(吗啉-2-基甲基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(3-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-[2-(二甲基氨基)乙基]吡咯烷-3-甲酰胺;
N-(5-甲基-5-氮杂螺[2.4]庚烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(6-氨基螺[3.3]庚烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(8-氮杂双环[3.2.1]辛烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3S,4S)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
N-[3-[(二甲基氨基)甲基]环丁基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-硝基-5-喹啉基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-乙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-[(3-氨基环丁基)甲基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-5-[3-(3,9-二氮杂螺[5.5]十一烷-3-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-甲基喹喔啉-5-基)吡咯烷-3-甲酰胺;
N-(7-氮杂螺[3.5]壬烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-[1-(4-哌啶基)-4-哌啶基]-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-[(1R,2S,4R,5S)-4-氨基-2-双环[3.1.0]己烷基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-异丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(3-氨基环丁基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氧杂-7-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
顺式-N-(3-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(7-氰基吡唑并[1,5-a]吡啶-4-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氯-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-(2-氮杂双环[2.2.1]庚烷-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-异丙基-吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-[(1-甲基-3-哌啶基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-甲基-吡咯烷-3-甲酰胺;
反式-5-[3-(2,7-二氮杂螺[4.4]壬烷-2-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈;
(3S,4S)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(2-吗啉乙基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-甲基-吡咯烷-3-甲酰胺;
N-(氮杂环庚烷-4-基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3S,4S)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-(2-氨基-2-甲基-丙基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-[1-(4-哌啶基)-4-哌啶基]吡咯烷-3-甲酰胺;
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(二氟甲基)吡咯烷-3-甲酰胺;
(3S,4S)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-[(4-甲基吗啉-2-基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-[7-(3-氨基氮杂环丁烷-1-羰基)-5-氮杂螺[2.4]庚烷-5-基]喹啉-8-腈;
(2R,4R)-4-[[5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-羰基]氨基]吡咯烷-2-甲酸甲酯;
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-[(3S,4R)-4-氟吡咯烷-3-基]吡咯烷-3-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-[[(2R)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;和
5-(8-氰基喹喔啉-5-基)-N-[[(2S)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
或其药学上可接受的盐、对映体或非对映体。
合成
本发明的化合物可以通过任何常规方法制备。在以下方案和实例中提供了合成这些化合物及其原料的合适方法。除非另有说明,否则所有取代基,特别是R1至R5如上所定义。此外,除非另有明确说明,否则所有反应、反应条件、缩写和符号均具有有机化学领域普通技术人员众所周知的含义。
制备式(I)化合物的一般合成路线如下所示。
方案1
其中R6为C1-6烷基;R7和R8独立地选自H、杂环基、杂环基C1-6烷基、(C1-6烷基)2氨基C1-6烷基、氨基C3-7环烷基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基、氨基C3-7环烷基C1-6烷基或氨基C1-6烷基;或者R7和R8与其所连接的氮一起形成杂环基。
卤化物(IV)与式(III)化合物的偶联可以通过在碱(诸如DIPEA或K2CO3)的存在下或在Buchwald-Hartwig胺化条件下(参见:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in Current Chemistry,2002,219,131-209;和其中引用的参考文献),使用催化剂(诸如Ruphos Pd G2)和碱(诸如Cs2CO3)进行,以提供式(V)化合物。式(V)化合物在碱性条件下(诸如LiOH在THF/水中)的水解得到羧酸(VI),该羧酸与胺(VII)在偶联剂(诸如HATU)的存在下缩合,以得到式(II)化合物。在一些实施例中,式(VI)化合物与胺(VII)偶联可得到含有源自胺(VII)的保护基团(例如,Boc)的产物,该保护基团将在获得最终的式(I)化合物之前被除去。
本发明还涉及制备式(I)化合物的方法,所述方法包括以下步骤:
a)羧酸(VI)
与胺(VII)在偶联剂的存在下缩合;
其中R2、R3、R5、R6、R7、R8和X如上文所定义。
在步骤a)中,偶联剂可以是例如HATU。
根据上述方法生产的式(I)或(II)化合物也是本发明的目的。
本发明的化合物可以以非对映体或对映体的混合物形式获得,它们可以通过本领域熟知的方法分离,例如(手性)HPLC或SFC。
适应症和治疗方法
本发明提供了可用作TLR7和/或TLR8和/或TLR9拮抗剂的化合物,其抑制通过TLR7和/或TLR8和/或TLR9的途径激活以及相应的下游生物学事件,所述下游生物学事件包括但不限于通过产生所有类型的细胞因子和所有形式的自身抗体介导的先天性和适应性免疫应答。因此,本发明的化合物可用于在表达此类受体的所有类型的细胞中阻断TLR7和/或TLR8和/或TLR9,所述细胞包括但不限于浆细胞样树突细胞、B细胞、T细胞,巨噬细胞、单核细胞、嗜中性粒细胞、角质形成细胞、上皮细胞。这样,所述化合物可用作系统性红斑狼疮和狼疮性肾炎的治疗剂或预防剂。
本发明提供在有需要的患者中治疗或预防系统性红斑狼疮和狼疮性肾炎的方法。
另一个实施例包括在需要这种治疗的哺乳动物中治疗或预防系统性红斑狼疮和狼疮性肾炎的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式(I)化合物、其立体异构体、互变异构体、前药或药学上可接受的盐。
实例
通过参考以下实例将更充分地理解本发明。但是,它们不应被解释为限制本发明的范围。
缩写
通过参考以下实例将更充分地理解本发明。但是,它们不应被解释为限制本发明的范围。
本文使用的缩写如下:
ACN: 乙腈
Boc2O: 二碳酸二叔丁酯
DCM: 二氯甲烷
DIPEA或DIEA: N,N-二异丙基乙胺
TEA 三乙胺
EA或EtOAc: 乙酸乙酯
FA: 甲酸
HATU: 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸盐
IC50: 半数抑制浓度
LCMS 液相色谱-质谱
MS: 质谱
PE: 石油醚
制备型HPLC: 制备型高效液相色谱
rt: 室温
RT: 保留时间
RuPhos Pd G2: 氯(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)第二代
SFC: 超临界流体色谱
TFA: 三氟乙酸
v/v 体积比
DDI 药物-药物相互作用
LYSA 冻干溶解度测定
HLM 人肝微粒体
一般实验条件
使用以下仪器之一通过快速色谱法纯化中间体和最终化合物:i)Biotage SP1系统和Quad 12/25Cartridge模块。ii)ISCO combi-flash色谱仪。硅胶品牌和孔径:i)KP-SIL粒径:40-60μm;ii)CAS登录号:硅胶:63231-67-4,粒度:47-60微米硅胶;iii)青岛海洋化学有限公司的ZCX,孔:200-300或300-400。
中间体和最终化合物在反相色谱柱上通过制备型HPLC纯化,反相色谱柱使用XBridgeTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱、SunFireTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱、Phenomenex Synergi-C18(10μm,25×150mm)或Phenomenex Gemini-C18(10μm,25×150mm)。Waters自动纯化系统(样品管理器2767,泵2525,检测器:微量物质ZQ和UV2487,溶剂体系:乙腈和0.1%氢氧化铵的水溶液;乙腈和0.1%FA的水溶液,或乙腈和0.1%TFA的水溶液)。或Gilson-281纯化系统(泵322,检测器:UV 156,溶剂体系:乙腈和0.05%氢氧化铵的水溶液;乙腈和0.225%的FA的水溶液;乙腈和0.05%HCl的水溶液;乙腈和0.075%TFA的水溶液;或乙腈和水)。
对于SFC手性分离,使用Mettler Toledo Multigram III系统SFC,Waters 80Q制备型SFC或Thar 80制备型SFC,通过手性柱(Daicel chiralpak IC,5μm,30×250mm),AS(10μm,30×250mm)或AD(10μm,30×250mm)分离中间体,溶剂系统为:CO2和IPA(0.5%TEA的IPA溶液)或CO2和MeOH(0.1%NH3·H2O的MeOH溶液),背压100bar,在254或220nm下检测UV@。
使用LC/MS(WatersTM Alliance 2795-Micromass ZQ,Shimadzu Alliance2020-Micromass ZQ或Agilent Alliance 6110-Micromass Zq)获得化合物的LC/MS光谱,LC/MS条件如下(运行时间3或1.5分钟):
酸性条件I:A:0.1%TFA的H2O溶液;B:0.1%TFA的乙腈溶液;
酸性条件II:A:0.0375%TFA的H2O溶液;B:0.01875%TFA的乙腈溶液;
碱性条件I:A:0.1%NH3·H2O的H2O溶液;B:乙腈;
碱性条件II:A:0.025%NH3·H2O的H2O溶液;B:乙腈;
中性条件:A:H2O;B:乙腈。
质谱(MS):通常只报告指示母体质量的离子,除非另有说明,否则所引用的质量离子为正质量离子(MH)+。
使用Bruker Avance 400MHz获得NMR光谱。
微波辅助反应在Biotage Initiator Sixty微波合成仪中进行。所有涉及空气敏感试剂的反应均在氩气或氮气气氛下进行。除非另有说明,否则试剂按从商业供应商收到的状况使用,未经进一步纯化。
制备实例
以下实例旨在说明本发明的含义,但绝不代表本发明含义的限制:
中间体A
5-溴-8-(三氟甲基)喹噁啉
详细的合成途径提供在以下方案中
化合物A1的制备
在0℃,向2-溴-5-(三氟甲基)苯胺(7.4g,30.0mmol,1eq)和TEA(6.1g,60.0mmol,2eq)的DCM(160mL)溶液中逐滴加入乙酰氯(7.0g,90.0mmol,3eq)。将混合物在20℃搅拌2小时,然后用NaHCO3碱化并且用水(100mL)洗涤。水层用DCM(100mL)萃取两次。将合并的有机层干燥并在真空下浓缩。将粗产物在PE中研磨以得到化合物A1(6.2g,75.6%),为白色固体。MS:calc’d 282(MH+),测得282(MH+)。
化合物A2的制备
在0℃,将H2SO4(40mL)缓慢加入含有HNO3(25mL)的烧瓶中,接着在40分钟内以少量多次的方式加入化合物A1(6.2g,22.1mmol,1eq)。将混合物在0℃再搅拌20分钟后,升温至25℃并搅拌1小时,并且用EA(200mL)萃取两次。合并的有机层用sat.NaHCO3和盐水(100mL)洗涤两次,干燥并在真空下浓缩以得到化合物A2(8.1g,粗制),为红色固体。MS:calc’d 325(MH+),测得325(MH+)。
化合物A3的制备
在90℃,将化合物A2(8.1g,24.8mmol,1eq)和HCl(6M,40mL)的MeOH(160mL)溶液搅拌18小时。混合物用NaHCO3水溶液碱化并且用EA(200mL)萃取两次。合并的有机层用盐水(100mL)洗涤两次,干燥并在真空下浓缩以得到粗产物,粗产物通过柱层析纯化以得到化合物A3(1.9g,26.7),为黄色固体。MS:calc’d 285(MH+),测得285(MH+)。
化合物A4的制备
在50℃,将化合物A3(1.9g,6.7mmol,1eq)和Fe(1.9g,33.5mmol,5eq)的AcOH(60mL)溶液搅拌3小时。通过过滤去除固体,滤液用sat.NaHCO3中和并且用EA(200mL)萃取两次。合并的有机层用盐水(100mL)洗涤两次,经Na2SO4干燥并浓缩以得到粗产物,粗产物通过柱层析(EA/PE=1/10)纯化以得到化合物A4(1.3g,76.5%),为黄色固体。MS:calc’d 255(MH+),测得255(MH+)。
中间体A的制备
在80℃,将化合物A4(1.9g,4.7mmol,1eq)和乙二醛(6.8g,47.0mmol,10eq)的EtOH(30mL)溶液搅拌2小时。混合物用NaHCO3水溶液(100mL)中和并且用EA(200mL)萃取两次。将有机层合并,并且用盐水(100mL)洗涤两次。将有机层干燥并在真空下浓缩以得到粗产物,粗产物通过柱层析(EA/PE=1/8)纯化以得到中间体A(0.95g,67.8%),为黄色固体。MS:calc’d 277(MH+),测得277(MH+)。
实例1
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
根据以下方案制备标题化合物:
步骤1:(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸甲酯(化合物1c)的制备
向(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b,22mg,94μmol,Pharmablock,PBXA3229-1)和8-溴喹喔啉-5-腈(化合物1a,20mg,85.5μmol)(参考文献:WO2017/106607)的1,4-二氧六环(2mL)溶液中加入K2CO3(59mg,427μmol)。将混合物脱气三次,然后加入Ruphos Pd G2(CAS:1375325-68-0,6.6mg,8.55μmol)。将反应混合物在90℃在N2下搅拌5小时后,将其冷却至室温,用EA(50mL)稀释,并且用水洗涤。将有机层蒸发以得到粗产物(30mg),粗产物不经纯化而用于下一步。MS:calc’d 351(MH+),测得351(MH+)。
步骤2:(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸(化合物1d)的制备
向(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸甲酯(化合物1c,30mg,85.6μmol)的乙腈(10mL)溶液中加入氢氧化锂(20.5mg,856μmol)的水(2mL)溶液。将混合物在室温搅拌4小时后,在真空下去除溶剂以得到粗产物。将粗产物溶解在10mL H2O中并且用EA洗涤。使用1M HCl将水层酸化至PH 4-5。水溶液用100mL EA萃取。分离有机相,经Na2SO4干燥,并且在真空下蒸发以得到粗产物(28mg),粗产物不经进一步纯化而用于下一步。MS:calc’d 337(MH+),测得337(MH+)。
步骤3:(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺(实例1)
向(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸(化合物1d,28mg,83.3μmol)和1-甲基哌啶-4-胺(化合物1e,10mg,91.6μmol,WuXi Apptec,CAS:41838-46-4)的DCM(10mL)溶液中加入HATU(95mg,250μmol)和三乙胺(84mg,833μmol)。将混合物在室温搅拌过夜,然后用DCM(50mL)稀释并且用水(50mL)洗涤。将有机层在真空下蒸发以得到油状物,油状物通过制备型HPLC纯化以得到实例1(30mg),为黄色固体。MS:calc’d 433(MH+),测得433(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(d,J=1.7Hz,1H),8.81(d,J=1.7Hz,1H),8.02(d,J=8.7Hz,1H),6.85(d,J=8.7Hz,1H),4.45-4.21(m,3H),4.10-3.99(m,2H),3.69-3.53(m,3H),3.24-3.08(m,2H),2.91(s,3H),2.29-2.02(m,3H),1.85-1.66(m,2H)。
实例2
(3R,4R)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用5-溴-8-(三氟甲基)喹喔啉(中间体A)代替溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例2(40mg),为黄色固体。MS:calc’d 476(MH+),测得476(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.74(d,J=1.7Hz,1H),8.69(d,J=1.7Hz,1H),7.86(d,J=8.7Hz,1H),6.78-6.66(m,1H),4.27-4.15(m,2H),4.14(d,J=8.4Hz,2H),3.96-3.82(m,2H),3.56-3.38(m,2H),3.14-2.99(m,2H),2.79(s,3H),2.19-1.92(m,3H),1.77-1.51(m,2H)。
实例3
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b),制备标题化合物。获得实例3(18mg),为黄色固体。MS:calc’d 379(MH+),测得379(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.82(d,J=1.7Hz,1H),8.75(d,J=1.6Hz,1H),7.95(d,J=8.7Hz,1H),6.74(d,J=8.7Hz,1H),4.28-4.12(m,3H),4.07-3.93(m,1H),3.66-3.45(m,3H),3.25-3.11(m,2H),2.91(s,3H),2.77-2.53(m,2H),2.31-2.04(m,2H),1.86-1.70(m,2H),1.24-1.15(m,3H)。
实例4
(3R,4R)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用5-溴喹啉-8-腈代替溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例4(62mg),为黄色固体。MS:calc’d432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.72(br dd,J=1.5,8.6Hz,1H),8.66-8.53(m,1H),8.09(d,J=8.2Hz,1H),7.60(dd,J=4.2,8.6Hz,1H),7.12-6.99(m,1H),4.08-3.81(m,5H),4.05-3.45(m,3H),3.23-3.06(m,2H),2.90(s,3H),2.33-2.02(m,3H),1.87-1.62(m,2H)。
实例5
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和5-溴-8-(三氟甲基)喹喔啉(中间体A)代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例5(35mg),为黄色固体。MS:calc’d 422(MH+),测得422(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.80(d,J=1.7Hz,1H),8.75(d,J=1.7Hz,1H),7.92(d,J=8.7Hz,1H),6.78-6.68(m,1H),4.22-3.94(m,4H),3.64-3.50(m,3H),3.17(dt,J=2.2,13.0Hz,2H),2.91(s,3H),2.74-2.53(m,2H),2.31-2.01(m,2H),1.85-1.69(m,2H),1.21(d,J=6.4Hz,3H)。
实例6
N-(3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
根据以下方案制备标题化合物:
步骤1:5-氮杂螺[2.4]庚烷-7-甲酸(化合物6b)的制备
向5-(叔丁氧基羰基)-5-氮杂螺[2.4]庚烷-7-甲酸(化合物6a,0.5g,2.07mmol,Pharmablock,PBLJ7032)的DCM(5mL)溶液中加入2,2,2-三氟乙酸(1.65g,1.08mL,14.5mmol)。将反应混合物在室温搅拌3小时,然后在真空中浓缩以得到粗产物(282mg),粗产物不经纯化而用于下一步。MS:calc’d 142(MH+),测得142(MH+)。
步骤2:5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酸(化合物6c)的制备
向5-溴-8-(三氟甲基)喹喔啉(中间体A,554mg,2mmol)、5-氮杂螺[2.4]庚烷-7-甲酸(化合物6b,282mg,2mmol)和TEA(1.01g,1.39mL,10mmol)的DMSO(10mL)的混合物中充入氩气。将混合物用微波在130℃加热3小时,然后在EA和水之间分液。分离的水层用EA萃取两次。将合并的有机层用Na2SO4干燥,并且在真空中浓缩。残余物通过以PE:EA梯度(100:10至100:50)洗脱的硅胶柱层析进行纯化以得到5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酸(化合物6c,200mg),为黄色固体。MS:calc’d 338(MH+),测得338(MH+)。
步骤3:7-(5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酰胺基)-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6e)的制备
向5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酸(化合物6c,50mg,148μmol)、7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d,72mg,296μmol)和DIEA(38mg,51.8μL,296μmol)的CH2Cl2(2mL)溶液中加入2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基异脲阳离子六氟磷酸盐(V)(113mg,296μmol)。将反应混合物在室温搅拌2小时。将混合物在EA和水之间分液。分离的水层用EA萃取两次。将合并的有机相用Na2SO4干燥,并且在真空中浓缩。残余物通过硅胶柱层析在12g柱上,使用MPLC系统(CombiFlash Companion,Isco Inc.),以PE:EA梯度(100:10至100:50)洗脱)纯化以得到7-(5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酰胺基)-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6e,80mg),为黄色固体。MS:calc’d 562(MH+),测得562(MH+)。
步骤4:N-(3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺(实例6)的制备
向7-(5-(8-(三氟甲基)喹喔啉-5-基)-5-氮杂螺[2.4]庚烷-7-甲酰胺基)-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6e,80mg,142μmol)的CH2Cl2(3mL)溶液中加入2,2,2-三氟乙酸(49mg,427μmol)。将反应混合物在室温搅拌3小时,然后将反应混合物在真空中浓缩。残余物通过制备型HPLC纯化以得到实例6(70mg),为黄色固体。MS:calc’d462(MH+),测得462(MH+)。1H NMR(400MHz,甲醇-d4)δ8.82(d,J=1.59Hz,1H),8.77(d,J=1.71Hz,1H),8.37(d,J=9.54Hz,1H),6.79(d,J=8.68Hz,1H),4.42-4.51(m,1H),4.37(dd,J=1.65,11.31Hz,1H),4.20-4.31(m,2H),3.95-4.02(m,1H),3.84-3.93(m,3H),3.51-3.62(m,3H),2.65-2.73(m,1H),2.43-2.58(m,2H),1.96(t,J=15.53Hz,2H),0.95-1.04(m,1H),0.74-0.93(m,3H)。
实例7
5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用8-溴喹喔啉-5-腈和1-甲基哌啶-4-胺代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例7(200mg),为黄色固体。MS:calc’d 391(MH+),测得391(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.83(d,J=1.5Hz,1H),8.75(d,J=1.5Hz,1H),7.98(d,J=8.7Hz,1H),6.76(d,J=8.8Hz,1H),4.43-4.33(m,1H),4.33-4.26(m,1H),4.15(d,J=11.2Hz,1H),3.99-3.86(m,1H),3.77(d,J=11.3Hz,1H),3.60-3.50(m,2H),3.21-3.06(m,2H),2.81(s,3H),2.80-2.73(m,1H),2.24-2.10(m,2H),1.83-1.67(m,2H),0.91-0.75(m,4H)。
SFC-HPLC分离得到了两种异构体实例7A(17mg)和实例7B(20mg)。两种异构体的化合物名称是(7R)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺和(7S)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺。
实例7A:MS:calc’d 391(MH+),测得391(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(d,J=1.5Hz,1H),8.73(d,J=1.8Hz,1H),7.96(d,J=8.8Hz,1H),6.74(d,J=8.8Hz,1H),4.39-4.31(m,1H),4.31-4.24(m,1H),4.17-4.08(m,1H),3.94-3.84(m,1H),3.79-3.70(m,1H),3.53(br d,J=12.5Hz,2H),3.16-3.04(m,2H),2.85(s,3H),2.74(dd,J=3.1,6.9Hz,1H),2.20-2.08(m,2H),1.75(q,J=12.8Hz,2H),0.86-0.73(m,4H)。
实例7B:MS:calc’d 391(MH+),测得391(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.82(d,J=1.8Hz,1H),8.74(d,J=1.8Hz,1H),7.96(d,J=8.5Hz,1H),6.75(d,J=8.8Hz,1H),4.46-4.33(m,1H),4.33-4.23(m,1H),4.18-4.09(m,1H),3.91(tt,J=4.0,11.9Hz,1H),3.78-3.71(m,1H),3.55(br d,J=12.5Hz,2H),3.16-3.05(m,2H),2.86(s,3H),2.77(dd,J=3.5,7.0Hz,1H),2.24-2.09(m,2H),1.85-1.72(m,2H),0.88-0.75(m,4H)。
实例8
N-(3-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用9-氨基-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例8(14mg),为黄色固体。MS:calc’d 460(MH+),测得460(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=1.71Hz,1H),8.64(d,J=1.71Hz,1H),7.82(d,J=8.80Hz,1H),6.64(d,J=8.68Hz,1H),4.20-4.29(m,1H),4.12-4.19(m,1H),3.94-4.05(m,2H),3.57(d,J=10.76Hz,1H),3.35-3.42(m,2H),3.26-3.33(m,2H),2.82(dd,J=3.30,6.85Hz,1H),1.87-2.11(m,4H),1.59-1.72(m,4H),0.67-0.81(m,4H)。
实例10
N-(9-氮杂双环[3.3.1]壬烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用3-氨基-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例10(62mg),为黄色固体。MS:calc’d 460(MH+),测得460(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.67-8.71(m,1H),8.63(d,J=1.71Hz,1H),7.81(d,J=8.68Hz,1H),6.62(d,J=8.68Hz,1H),4.58(dt,J=6.24,12.23Hz,1H),4.21-4.29(m,1H),4.10-4.16(m,1H),3.94-4.02(m,1H),3.60(s,3H),2.60-2.68(m,1H),2.05-2.23(m,2H),1.94(m,8H),0.62-0.78(m,4H)。
实例11
N-(1-甲基-4-哌啶基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用1-甲基哌啶-4-胺代替和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例11(20mg),为黄色固体。MS:calc’d 434(MH+),测得434(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.92(d,J=1.71Hz,1H),8.81(d,J=1.71Hz,1H),7.84(d,J=7.70Hz,1H),6.70(d,J=8.68Hz,1H),4.13-4.22(m,1H),4.06(dd,J=4.40,11.37Hz,1H),3.92(d,J=11.13Hz,1H),3.71(d,J=10.64Hz,1H),3.48(s,1H),2.64-2.79(m,3H),2.13(s,3H),1.91(m,2H),1.67(m,2H),1.30-1.45(m,2H),0.59-0.80(m,4H)。
实例12
N-(3-氮杂双环[3.2.1]辛烷-8-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用8-氨基-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯代替和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例12(65mg),为黄色固体。MS:calc’d 446(MH+),测得446(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.80(d,J=1.71Hz,1H),8.74(d,J=1.59Hz,1H),7.93(d,J=8.80Hz,1H),6.74(d,J=8.80Hz,1H),4.31-4.44(m,1H),4.21-4.31(m,1H),4.06-4.15(m,1H),3.75-3.97(m,1H),3.70(d,J=10.76Hz,1H),3.36-3.42(m,2H),3.21-3.28(m,1H),3.01-3.13(m,1H),2.79-2.96(m,1H),2.37-2.60(m,2H),2.00-2.19(m,2H),1.76-1.89(m,2H),0.74-0.94(m,4H)。
实例13
5-(8-氰基喹喔啉-5-基)-N-(吗啉-2-基甲基)-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用溴喹喔啉-5-腈和2-(氨基甲基)吗啉-4-甲酸叔丁酯(CAS:140645-53-0)代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例13(44mg),为黄色固体。MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.72(d,J=1.83Hz,1H),8.63(d,J=1.71Hz,1H),7.86(d,J=8.68Hz,1H),6.64(d,J=8.80Hz,1H),4.15-4.30(m,2H),3.96-4.11(m,2H),3.57-3.73(m,3H),3.30-3.41(m,1H),3.23-3.29(m,1H),3.12-3.18(m,2H),2.95-3.07(m,1H),2.72-2.82(m,1H),2.64-2.72(m,1H),0.76-0.85(m,1H),0.66-0.76(m,3H)。
实例14
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-环丙基吡咯烷-3-甲酸乙酯HCl盐(Pharmablock,PBXA3214-1)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例14(8mg),为黄色固体。MS:calc’d 404(MH+),测得404(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.67(dd,J=1.4,4.6Hz,1H),8.29(br d,J=7.2Hz,1H),7.87-7.76(m,1H),7.45-7.30(m,1H),6.73-6.54(m,1H),3.95-3.48(m,5H),3.35(br d,J=12.8Hz,2H),3.00-2.87(m,3H),2.86-2.68(m,2H),2.13-1.81(m,3H),1.74-1.46(m,3H),0.70-0.52(m,1H),0.32(br d,J=8.4Hz,2H),0.06-0.07(m,2H)。
实例15
N-(3-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用7-氨基-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例15(17mg),为黄色固体。MS:calc’d 460(MH+),测得460(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(d,J=1.71Hz,1H),8.75(d,J=1.71Hz,1H),7.93(d,J=8.80Hz,1H),6.74(d,J=8.80Hz,1H),4.32-4.41(m,1H),4.20-4.29(m,1H),4.10(d,J=10.76Hz,1H),3.89-4.00(m,1H),3.72(d,J=10.76Hz,1H),3.14-3.21(m,2H),3.04-3.13(m,2H),2.78(dd,J=3.79,7.09Hz,1H),2.34-2.49(m,4H),1.97(d,J=13.45Hz,1H),1.47(d,J=13.69Hz,1H),1.30-1.41(m,2H),0.76-0.91(m,4H)。
实例16
(3R,4R)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例16(10mg),为黄色固体。MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.86(dd,J=1.5,4.3Hz,1H),8.77(dd,J=1.5,8.8Hz,1H),7.95(d,J=8.6Hz,1H),7.47(dd,J=4.2,8.7Hz,1H),6.78(d,J=8.6Hz,1H),4.06(t,J=9.6Hz,1H),3.88-3.69(m,2H),3.53(t,J=9.8Hz,1H),2.95-2.83(m,2H),2.80-2.65(m,1H),2.31(s,3H),2.26-2.08(m,3H),1.99-1.84(m,3H),1.77-1.51(m,2H),1.24-1.16(m,3H)。
实例17
反式-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3194-1)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例17(8mg),为黄色固体。MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.84(dd,J=1.5,4.2Hz,1H),8.58(dd,J=1.6,8.7Hz,1H),7.97(d,J=8.2Hz,1H),7.48(dd,J=4.3,8.7Hz,1H),6.96(d,J=8.3Hz,1H),3.81-3.62(m,3H),3.59-3.48(m,1H),3.43-3.35(m,2H),2.89(s,3H),2.38-2.20(m,2H),2.16-2.05(m,1H),1.91-1.81(m,3H),1.65-1.45(m,3H)。
实例18
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用4-(三氟甲基)吡咯烷-3-甲酸甲酯和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例18(6mg),为黄色固体。MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.96(dd,J=1.6,4.3Hz,1H),8.74-8.67(m,1H),8.09(d,J=8.3Hz,1H),7.64-7.54(m,1H),7.16-7.03(m,1H),4.11-3.93(m,1H),3.98-3.52(m,7H),3.25-3.09(m,2H),2.97-2.85(m,3H),2.35-2.02(m,3H),1.84-1.61(m,2H)。
实例19
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-[2-(二甲基氨基)乙基]吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-环丙基吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3214-1)、5-溴喹啉-8-腈和N',N'-二甲基乙烷-1,2-二胺代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)、溴喹喔啉-5-腈(化合物1a)和1-甲基哌啶-4-胺(化合物1e),制备标题化合物。获得实例19(20mg),为黄色固体。MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.03(dd,J=1.4,8.7Hz,1H),8.90(dd,J=1.5,4.6Hz,1H),8.03(d,J=8.7Hz,1H),7.61(dd,J=4.6,8.8Hz,1H),6.87(d,J=8.7Hz,1H),4.15-4.01(m,1H),3.98-3.85(m,2H),3.83-3.62(m,2H),3.58-3.41(m,1H),3.11-2.89(m,9H),1.97-1.84(m,1H),0.94-0.79(m,1H),0.62-0.50(m,2H),0.24(q,J=4.4Hz,2H)。
实例20
N-(5-甲基-5-氮杂螺[2.4]庚烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-甲基-5-氮杂螺[2.4]庚烷-7-胺代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例20(47mg),为黄色固体。MS:calc’d 446(MH+),测得446(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=1.59Hz,1H),8.63(s,1H),7.81(d,J=8.68Hz,1H),6.61(d,J=8.68Hz,1H),4.22-4.32(m,1H),4.09-4.21(m,1H),3.95-4.09(m,2H),3.60-3.90(m,1H),3.37-3.58(m,3H),3.01-3.17(m,1H),2.80-2.93(m,3H),2.52-2.68(m,1H),0.63-0.86(m,8H)。
实例21
N-(1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-氨基-3,3a,4,5,6,6a-六氢-1H-环戊并[c]吡咯-2-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例21(25mg),为黄色固体。MS:calc’d 446(MH+),测得446(MH+)。1HNMR(400MHz,甲醇-d4)δ=8.80(d,J=1.83Hz,1H),8.75(d,J=1.71Hz,1H),7.93(d,J=8.68Hz,1H),6.74(d,J=8.68Hz,1H),4.31-4.41(m,1H),4.20-4.26(m,1H),4.03-4.12(m,2H),3.73(d,J=10.76Hz,1H),3.35-3.44(m,2H),3.19(td,J=3.82,11.92Hz,2H),2.84-2.94(m,2H),2.77(dd,J=3.85,7.03Hz,1H),2.30-2.46(m,2H),1.26-1.39(m,2H),0.73-0.91(m,4H)。
实例22
N-(6-氨基螺[3.3]庚烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-(6-氨基螺[3.3]庚烷-2-基)氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例22(32mg),为黄色固体。MS:calc’d 446(MH+),测得446(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.71Hz,1H),8.62(d,J=1.71Hz,1H),7.80(d,J=8.80Hz,1H),6.61(d,J=8.80Hz,1H),4.18-4.24(m,1H),4.01-4.14(m,2H),3.95(d,J=10.76Hz,1H),3.51-3.63(m,2H),2.53-2.64(m,1H),2.36-2.47(m,2H),2.19-2.28(m,2H),1.99-2.12(m,2H),1.91(q,J=8.40Hz,2H),0.58-0.77(m,4H)。
实例23
N-(8-氮杂双环[3.2.1]辛烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用3-氨基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例23(27mg),为黄色固体。MS:calc’d 446(MH+),测得446(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.71Hz,1H),8.63(d,J=1.71Hz,1H),7.81(d,J=8.68Hz,1H),6.62(d,J=8.68Hz,1H),4.18-4.29(m,1H),4.02-4.16(m,2H),3.91-4.02(m,3H),3.59(d,J=10.76Hz,1H),2.63(dd,J=3.67,7.09Hz,1H),1.91-2.06(m,6H),1.58-1.74(m,2H),0.60-0.75(m,4H)。
实例24
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-(4-氨基环己基)氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例24(6mg),为黄色固体。MS:calc’d 434(MH+),测得434(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.83Hz,1H),8.63(d,J=1.83Hz,1H),7.81(d,J=8.68Hz,1H),6.62(d,J=8.80Hz,1H),4.19-4.29(m,1H),4.08-4.16(m,1H),3.96(d,J=10.64Hz,1H),3.62(d,J=10.64Hz,1H),3.55(dd,J=3.79,7.70Hz,1H),2.93-3.04(m,1H),2.63(dd,J=3.79,6.97Hz,1H),1.85-2.03(m,4H),1.34-1.45(m,2H),1.18-1.33(m,2H),0.61-0.74(m,4H)。
实例25
(3S,4S)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用5-溴-8-(三氟甲基)喹喔啉和(3S,4S)-4-甲基吡咯烷-3-甲酸甲酯盐酸盐(Pharmablock,PBXA3220-1)代替溴喹喔啉-5-腈(化合物1a)和(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b),制备标题化合物。获得实例25(8mg),为黄色固体。MS:calc’d 422(MH+),测得422(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.86-8.72(m,2H),7.98-7.86(m,1H),6.74(d,J=8.7Hz,1H),4.22-3.96(m,3H),3.67-3.49(m,3H),3.23-3.09(m,2H),2.98-2.87(m,3H),2.77-2.55(m,2H),2.38-2.07(m,3H),1.90-1.74(m,2H),1.21(d,J=6.4Hz,3H)。
实例26
N-[3-[(二甲基氨基)甲基]环丁基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用3-[(二甲基氨基)甲基]环丁胺(CAS:1479049-07-4)代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例26(8mg),为黄色固体。MS:calc’d448(MH+),测得448(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.71Hz,1H),8.63(d,J=1.59Hz,1H),7.81(d,J=8.68Hz,1H),6.61(d,J=8.68Hz,1H),4.17-4.28(m,2H),4.06-4.14(m,1H),3.96(d,J=10.76Hz,1H),3.57-3.66(m,1H),2.84-3.02(m,2H),2.38-2.69(m,9H),2.11(dt,J=3.85,7.67Hz,2H),1.64(q,J=9.82Hz,1H),0.62-0.77(m,4H)。
实例27
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-硝基-5-喹啉基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和5-溴-8-硝基喹啉代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例27(6mg),为黄色固体。MS:calc’d 398(MH+),测得398(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.89(dd,J=1.5,4.2Hz,1H),8.80(dd,J=1.6,8.8Hz,1H),8.27(d,J=8.9Hz,1H),7.51(dd,J=4.3,8.8Hz,1H),6.78(d,J=9.0Hz,1H),4.09(t,J=9.6Hz,1H),4.01-3.92(m,1H),3.84(ddd,J=7.3,9.9,19.3Hz,2H),3.61-3.46(m,1H),3.13-2.88(m,3H),2.79-2.69(m,3H),2.41(m,1H),2.33-1.99(m,3H),1.84-1.63(m,2H),1.37(t,J=7.3Hz,1H),1.22(d,J=6.5Hz,3H)。
实例28
反式-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-甲基吡咯烷-3-甲酸甲酯(Bepharm,B162777)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例28(5mg),为黄色固体。MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(dd,J=1.5,4.2Hz,1H),8.79(dd,J=1.5,8.7Hz,1H),7.98(d,J=8.6Hz,1H),7.49(dd,J=4.2,8.7Hz,1H),6.82(d,J=8.6Hz,1H),4.07(t,J=9.5Hz,1H),3.95-3.75(m,3H),3.62-3.49(m,1H),3.25(br d,J=12.5Hz,2H),2.85-2.56(m,7H),2.18-2.00(m,2H),1.72(br d,J=12.3Hz,2H),1.21(d,J=6.4Hz,3H)。
实例29
反式-1-(8-氰基-5-喹啉基)-4-乙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用5-溴喹啉-8-腈和反式-4-乙基吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3209-1)代替溴喹喔啉-5-腈(化合物1a)和(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b),制备标题化合物。获得实例29(43mg),为黄色固体。MS:calc’d 392(MH+),测得392(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.84-8.71(m,2H),7.88(d,J=8.6Hz,1H),7.48-7.37(m,1H),6.74(d,J=8.7Hz,1H),3.95-3.83(m,2H),3.81-3.68(m,2H),3.53-3.42(m,3H),3.11-2.98(m,2H),2.84-2.76(m,3H),2.74-2.63(m,1H),2.47-2.38(m,1H),2.11(dt,J=2.6,10.0Hz,2H),2.00-1.89(m,1H),1.71-1.40(m,3H),0.93(t,J=7.5Hz,3H)。
实例30
N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(三氟甲基)吡咯烷-3-甲酰胺
根据以下方案制备标题化合物。
1-(8-氰基喹啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸(实例30c)的制备
类似于实例1的(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸(化合物1d)的制备方法,使用4-(三氟甲基)吡咯烷-3-甲酸甲酯和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备化合物30c。
N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(三氟甲基)吡咯烷-3-甲酰胺(实例30)的制备
向1-(8-氰基喹啉-5-基)-4-(三氟甲基)吡咯烷-3-甲酸(化合物30c,15mg,44.7μmol)和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d,9.6mg,44.7μmol)的DCM(10mL)溶液中加入三乙胺(22.6mg,224μmol)和HATU(51mg,134μmol)。将混合物在室温搅拌12小时后,在真空下去除溶剂。然后将残余物溶解在DCM(2.0mL)中,将TFA(0.5mL)加入其中。将混合物在室温搅拌2小时后,将反应混合物浓缩以得到粗产物,粗产物通过制备型HPLC纯化以得到两种异构体:实例30A(5mg)和实例30B(5mg)。
实例30A:MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.70(dd,J=1.5,8.7Hz,1H),8.59(br d,J=7.3Hz,1H),8.09(d,J=8.2Hz,1H),7.60(dd,J=4.2,8.7Hz,1H),7.08(d,J=8.2Hz,1H),4.09-3.97(m,1H),3.93-3.72(m,4H),3.65(td,J=8.2,16.4Hz,1H),3.29-3.12(m,4H),2.29-1.59(m,7H)。
实例30B:MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.70(dd,J=1.5,8.7Hz,1H),8.58(br d,J=7.3Hz,1H),8.08(d,J=8.2Hz,1H),7.60(dd,J=4.3,8.7Hz,1H),7.08(d,J=8.3Hz,1H),4.09-3.96(m,1H),3.93-3.60(m,5H),3.30-3.14(m,4H),2.25-1.57(m,7H)。
实例31
N-[(3-氨基环丁基)甲基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-[3-(氨基甲基)环丁基]氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例31(33mg),为黄色固体。MS:calc’d 420(MH+),测得420(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.59Hz,1H),8.62(d,J=1.71Hz,1H),7.80(d,J=8.68Hz,1H),6.61(d,J=8.68Hz,1H),4.16-4.28(m,1H),4.10-4.16(m,1H),3.93-4.02(m,1H),3.65-3.76(m,1H),3.47-3.63(m,1H),3.24-3.31(m,1H),3.05-3.16(m,1H),2.64(dd,J=3.79,6.97Hz,1H),2.28-2.54(m,2H),2.04-2.26(m,2H),1.64-1.78(m,1H),0.59-0.77(m,4H)。
实例32
反式-5-[3-(3,9-二氮杂螺[5.5]十一烷-3-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈
类似于实例30的制备方法,使用反式-4-甲基吡咯烷-3-甲酸甲酯和3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例32(10mg),为黄色固体。MS:calc’d 418(MH+),测得418(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.90-8.76(m,2H),7.98(d,J=8.4Hz,1H),7.50(dd,J=4.3,8.8Hz,1H),6.82(d,J=8.6Hz,1H),4.00-3.79(m,3H),3.69(br t,J=5.7Hz,4H),3.60-3.48(m,1H),3.22(br s,5H),2.80-2.67(m,1H),1.87-1.74(m,4H),1.71-1.56(m,4H),1.22(d,J=6.6Hz,3H)。
实例33
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-甲基喹喔啉-5-基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和5-溴-8-甲基喹啉代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例33(10mg),为黄色固体。MS:calc’d 368(MH+),测得368(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.13-8.99(m,1H),9.03-8.92(m,1H),7.82(q,J=8.0Hz,2H),4.35-4.22(m,1H),4.19-3.97(m,3H),3.77-3.52(m,3H),3.26-3.00(m,4H),2.97-2.75(m,7H),2.32-2.15(m,2H),1.88-1.69(m,2H),1.35-1.27(m,3H)。
实例34
N-(7-氮杂螺[3.5]壬烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用2-氨基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例34(26mg),为黄色固体。MS:calc’d 460(MH+),测得460(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.71Hz,1H),8.63(d,J=1.71Hz,1H),7.80(d,J=8.68Hz,1H),6.61(d,J=8.68Hz,1H),4.07-4.26(m,3H),3.96(d,J=10.76Hz,1H),3.60(d,J=10.76Hz,1H),3.01-3.07(m,2H),2.94-3.01(m,2H),2.62(dd,J=3.91,7.09Hz,1H),2.17-2.31(m,2H),1.65-1.80(m,6H),0.63-0.76(m,4H)。
实例35
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-[1-(4-哌啶基)-4-哌啶基]-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用4-(4-氨基-1-哌啶基)哌啶-1-甲酸叔丁酯代替4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d,制备标题化合物。获得实例35(15mg),为黄色固体。MS:calc’d 502(MH+),测得502(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.89(d,J=1.7Hz,1H),8.83(d,J=1.8Hz,1H),8.04(d,J=8.7Hz,1H),6.87(d,J=8.8Hz,1H),4.46-4.20(m,2H),4.13-3.99(m,1H),3.81-3.52(m,2H),3.24-3.11(m,3H),3.00(br d,J=11.7Hz,3H),2.76-2.60(m,2H),2.57-2.31(m,3H),1.94(br d,J=11.7Hz,4H),1.66-1.43(m,4H)。
实例36
N-[(1R,2S,4R,5S)-4-氨基-2-双环[3.1.0]己烷基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-[(1S,2R,4S,5R)-4-氨基-2-双环[3.1.0]己烷基]氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例36(34mg),为黄色固体。MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.02(d,J=1.71Hz,1H),8.96(s,1H),8.14(d,J=8.68Hz,1H),6.95(d,J=8.68Hz,1H),4.70(m,1H),4.52-4.61(m,1H),4.41-4.51(m,1H),4.30(dd,J=4.28,10.76Hz,1H),4.01-4.11(m,1H),3.94(dd,J=2.81,10.76Hz,1H),3.02(dt,J=3.91,7.09Hz,1H),2.48-2.66(m,1H),1.95-2.07(m,1H),1.86-1.95(m,1H),1.24-1.35(m,1H),0.96-1.19(m,5H),0.84-0.94(m,1H)。
实例37
反式-1-(8-氰基-5-喹啉基)-4-异丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-异丙基-吡咯烷-3-甲酸甲酯盐酸盐(CAS:1820575-33-4)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例37(50mg),为黄色固体。MS:calc’d 406(MH+),测得406(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.93-8.85(m,2H),8.00(d,J=8.6Hz,1H),7.56(dd,J=4.5,8.7Hz,1H),6.87(d,J=8.7Hz,1H),4.05-3.88(m,2H),3.90-3.74(m,2H),3.71-3.50(m,3H),3.25-3.09(m,2H),2.97-2.85(m,4H),2.62-2.49(m,1H),2.30-2.04(m,2H),1.86-1.67(m,3H),1.12-0.95(m,6H)。
实例38
N-(3-氨基环丁基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-(3-氨基环丁基)氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例38(25mg),为黄色固体。MS:calc’d 406(MH+),测得406(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.68(d,J=1.71Hz,1H),8.62(d,J=1.71Hz,1H),7.80(d,J=8.68Hz,1H),6.61(d,J=8.68Hz,1H),4.30-4.42(m,1H),4.19-4.29(m,1H),4.04-4.14(m,1H),3.88-4.03(m,1H),3.72-3.81(m,1H),3.53-3.63(m,1H),2.58-2.71(m,2H),2.27-2.47(m,3H),0.63-0.81(m,4H)。
实例39
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用N-(4-氨基环己基)氨基甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例39(33mg),为黄色固体。MS:calc’d 434(MH+),测得434(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=1.71Hz,1H),8.63(d,J=1.71Hz,1H),7.81(d,J=8.68Hz,1H),6.63(d,J=8.68Hz,1H),4.19-4.27(m,1H),4.10-4.18(m,1H),3.97(d,J=10.76Hz,1H),3.76(s,1H),3.62(d,J=10.76Hz,1H),3.12(s,1H),2.75(dd,J=3.97,7.03Hz,1H),1.69-1.84(m,4H),1.53-1.69(m,4H),0.63-0.80(m,4H)。
实例40
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用5-溴喹啉-8-腈和反式-4-(二氟甲基)吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3200-1)代替溴喹喔啉-5-腈(化合物1a)和(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b),制备标题化合物。获得实例40(11mg),为黄色固体。MS:calc’d414(MH+),测得414(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.93(dd,J=1.5,4.2Hz,1H),8.75(dd,J=1.6,8.7Hz,1H),8.05(d,J=8.4Hz,1H),7.56(dd,J=4.2,8.7Hz,1H),7.00(d,J=8.4Hz,1H),6.14-5.94(m,1H),3.91-3.69(m,5H),3.29-3.13(m,2H),3.06-2.92(m,2H),2.45-2.25(m,5H),1.97(br t,J=13.1Hz,2H),1.70-1.51(m,2H)。
实例41
5-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-溴喹啉-8-腈和1-甲基哌啶-4-胺代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例41(30mg),为黄色固体。MS:calc’d 390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.87(dd,J=1.5,4.2Hz,1H),8.83(dd,J=1.6,8.8Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.2,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.15(dd,J=6.8,10.0Hz,1H),4.03-3.93(m,2H),3.75-3.64(m,1H),3.47(d,J=9.5Hz,1H),2.97-2.87(m,2H),2.81(dd,J=4.2,6.7Hz,1H),2.35(s,3H),2.31-2.16(m,2H),1.97-1.83(m,2H),1.63-1.50(m,2H),0.90-0.74(m,4H)。
SFC-HPLC分离得到了两种异构体:实例41A(5mg)和实例41B(5mg)。
实例41A:MS:calc’d 390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.87(dd,J=1.5,4.2Hz,1H),8.83(dd,J=1.5,8.8Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.2,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.15(dd,J=6.9,10.1Hz,1H),4.05-3.91(m,2H),3.76-3.59(m,1H),3.47(d,J=9.7Hz,1H),2.95-2.74(m,3H),2.31(s,3H),2.24-2.08(m,2H),1.96-1.77(m,2H),1.65-1.44(m,2H),0.95-0.68(m,4H)。
实例41B:MS:calc’d 390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(dd,J=1.5,4.2Hz,1H),8.83(dd,J=1.5,8.7Hz,1H),7.99(d,J=8.6Hz,1H),7.49(dd,J=4.3,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.15(dd,J=6.9,10.1Hz,1H),4.06-3.89(m,2H),3.77-3.61(m,1H),3.47(d,J=9.7Hz,1H),2.95-2.74(m,3H),2.31(s,3H),2.23-2.07(m,2H),1.97-1.80(m,2H),1.65-1.46(m,2H),0.92-0.71(m,4H)。
实例42
N-(3-氧杂-7-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用9-氨基-3-氧杂-7-氮杂双环[3.3.1]壬烷-7-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例42(22mg),为黄色固体。MS:calc’d462(MH+),测得462(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(d,J=1.59Hz,1H),8.70-8.78(m,1H),7.93(d,J=8.68Hz,1H),6.75(dd,J=2.93,8.68Hz,1H),4.34-4.44(m,1H),4.24-4.34(m,1H),4.06-4.24(m,4H),3.96-4.06(m,1H),3.91(dd,J=5.56,12.04Hz,1H),3.62-3.74(m,2H),3.41-3.55(m,3H),2.92(ddd,J=3.36,7.03,12.47Hz,1H),2.02-2.22(m,2H),0.79-0.96(m,4H)。
实例43
顺式-N-(3-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用顺式-N-(3-氨基环己基)氨基甲酸叔丁酯(Pharmablock,PBZS1047,CAS:849616-22-4)代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例43(29mg),为黄色固体。MS:calc’d 434(MH+),测得434(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=1.47Hz,1H),8.63(d,J=1.59Hz,1H),7.81(d,J=8.68Hz,1H),6.62(d,J=8.68Hz,1H),4.19-4.29(m,1H),4.07-4.17(m,1H),3.96(dd,J=3.73,10.82Hz,1H),3.57-3.69(m,2H),2.99-3.10(m,1H),2.63(ddd,J=3.85,7.00,10.79Hz,1H),2.04-2.21(m,1H),1.74-1.96(m,3H),1.28-1.46(m,1H),1.06-1.25(m,3H),0.61-0.77(m,4H)。
实例44
(3R,4R)-1-(7-氰基吡唑并[1,5-a]吡啶-4-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和4-溴吡唑并[1,5-a]吡啶-7-腈(CAS:1268520-74-6,Pharmablock)代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例44(35mg),为黄色固体。MS:calc’d 367(MH+),测得367(MH+)。1H NMR(400MHz,甲醇-d4)δ=7.92(d,J=2.6Hz,1H),7.32(d,J=8.3Hz,1H),7.06(d,J=2.6Hz,1H),5.99(d,J=8.4Hz,1H),4.09-3.87(m,3H),3.85-3.66(m,1H),3.55-3.36(m,2H),2.97(br d,J=11.6Hz,2H),2.82-2.70(m,1H),2.69-2.48(m,1H),2.43-2.23(m,3H),2.03-1.90(m,2H),1.70-1.53(m,2H),1.37(t,J=7.3Hz,1H),1.20(d,J=6.6Hz,3H)。
实例46
反式-1-(8-氯-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3194-1)和5-溴-8-氯喹啉代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例46(27mg),为黄色固体。MS:calc’d 441(MH+),测得441(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.93-8.84(m,1H),7.88-7.78(m,1H),7.76-7.67(m,1H),7.49(dd,J=4.4,8.4Hz,1H),7.19-7.12(m,1H),3.97-3.82(m,1H),3.67-3.38(m,7H),3.14-2.97(m,3H),2.84-2.72(m,3H),2.16-1.94(m,2H),1.70-1.54(m,2H)。
实例47
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例30和实例1的制备方法,使用反式-4-三氟甲基吡咯烷-3-甲酸甲酯和(3S,4R)-3-氨基-4-氟吡咯烷-1-甲酸叔丁酯和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a)和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例47(7mg),为黄色固体。MS:calc’d422(MH+),测得422(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.84(dd,J=1.5,4.2Hz,1H),8.57(dd,J=1.6,8.7Hz,1H),7.97(d,J=8.2Hz,1H),7.48(dd,J=4.3,8.7Hz,1H),6.98(d,J=8.3Hz,1H),5.30-5.11(m,1H),4.71-4.54(m,1H),3.85-3.76(m,1H),3.74-3.54(m,6H),3.52-3.46(m,1H),3.39(q,J=7.6Hz,1H),3.10(t,J=11.4Hz,1H)。
实例48
N-(2-氮杂双环[2.2.1]庚烷-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-氨基-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例48(21mg),为黄色固体。MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.80(d,J=1.47Hz,1H),8.75(s,1H),7.93(d,J=8.56Hz,1H),6.74(d,J=8.68Hz,1H),4.34-4.43(m,1H),4.26(dt,J=4.16,7.83Hz,1H),3.89-4.19(m,3H),3.63-3.75(m,1H),3.36-3.41(m,1H),3.09-3.23(m,1H),2.90-3.06(m,1H),2.84(dd,J=3.48,7.03Hz,1H),2.21-2.39(m,1H),1.90-2.00(m,1H),1.73-1.87(m,1H),1.46-1.71(m,1H),0.69-0.93(m,4H)。
实例49
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-异丙基-吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用反式-4-异丙基吡咯烷-3-甲酸甲酯和(3S,4R)-3-氨基-4-氟吡咯烷-1-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例49(12mg),为黄色固体。MS:calc’d 396(MH+),测得396(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.90(dd,J=1.5,4.3Hz,1H),8.79(dd,J=1.6,8.8Hz,1H),8.00(d,J=8.6Hz,1H),7.52(dd,J=4.3,8.8Hz,1H),6.89(d,J=8.6Hz,1H),5.44-5.23(m,1H),4.80-4.63(m,1H),4.00-3.89(m,1H),3.87-3.56(m,5H),3.28-2.95(m,3H),2.66-2.54(m,1H),1.82(qd,J=6.9,14.0Hz,1H),1.05(dd,J=5.2,6.7Hz,6H)。
实例50
(3R,4R)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和5-溴-8-氯-喹啉代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例50(3mg),为黄色固体。MS:calc’d 387(MH+),测得387(MH+)。1H NMR(400Mhz,甲醇-d4)δ=9.03(dd,J=1.3,5.4Hz,1H),8.04(d,J=9.0Hz,1H),7.92(dd,J=5.5,8.6Hz,1H),7.55(dd,J=4.4,8.4Hz,1H),7.15-7.03(m,1H),4.13-3.96(m,2H),3.93-3.76(m,2H),3.64-3.52(m,3H),3.27-3.09(m,3H),2.98-2.61(m,4H),2.23(br t,J=12.5Hz,2H),1.88-1.72(m,2H),1.29-1.16(m,3H)。
实例51
5-(8-氰基-5-喹啉基)-N-[(1-甲基-3-哌啶基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-溴喹啉-8-腈和(1-甲基-3-哌啶基)甲胺代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例51(9mg),为黄色固体。MS:calc’d 404(MH+),测得404(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(d,J=4.0Hz,1H),8.83(d,J=8.8Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.3,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.22(dd,J=7.0,9.9Hz,1H),4.07-3.92(m,2H),3.41(d,J=9.7Hz,1H),3.31-3.25(m,2H),3.25-3.08(m,2H),2.84-2.68(m,5H),2.61-2.46(m,1H),2.05-1.63(m,4H),1.29-1.14(m,1H),0.95-0.74(m,4H)。
实例52
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-甲基-吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用反式-4-甲基吡咯烷-3-甲酸甲酯(Bepharm,B162777)代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐,制备标题化合物。制备型HPLC分离得到了两种异构体实例52A(12mg)和实例52B(8mg)。
实例52A:MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.09(dd,J=1.3,8.8Hz,1H),8.92(dd,J=1.5,4.8Hz,1H),8.06(d,J=8.8Hz,1H),7.65(dd,J=4.8,8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.13-3.98(m,2H),3.92(ddd,J=7.3,10.1,14.2Hz,2H),3.60(t,J=9.8Hz,1H),3.30-3.17(m,3H),2.82-2.53(m,2H),2.26-1.64(m,7H),1.22(d,J=6.6Hz,3H)。
实例52B:MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.09(dd,J=1.3,8.8Hz,1H),8.92(dd,J=1.3,4.8Hz,1H),8.06(d,J=8.7Hz,1H),7.65(dd,J=4.8,8.8Hz,1H),6.89(d,J=8.7Hz,1H),4.15-3.99(m,2H),3.92(ddd,J=7.3,10.1,14.2Hz,2H),3.60(t,J=9.8Hz,1H),3.27-3.13(m,3H),2.82-2.61(m,2H),2.31-1.61(m,7H),1.22(d,J=6.5Hz,3H)。
实例53
反式-5-[3-(2,7-二氮杂螺[4.4]壬烷-2-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈
类似于实例30的制备方法,使用反式-4-甲基吡咯烷-3-甲酸甲酯(Bepharm,B162777)和2,7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例53(4mg),为黄色固体。MS:calc’d390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.00-8.88(m,2H),8.03(d,J=8.6Hz,1H),7.64-7.53(m,1H),6.87(d,J=8.7Hz,1H),4.06-3.96(m,2H),3.94-3.85(m,1H),3.81(br t,J=7.2Hz,1H),3.66-3.41(m,7H),3.25-3.05(m,1H),2.83-2.69(m,1H),2.25-1.97(m,5H),1.25(d,J=6.6Hz,3H)。
实例54
(3S,4S)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3S,4S)-4-甲基吡咯烷-3-甲酸甲酯盐酸盐(PBXA3220-1,Pharmablock)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例54(50mg),为黄色固体。MS:calc’d 378(MH+),测得378(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.87-8.68(m,2H),7.92(d,J=8.6Hz,1H),7.44(dd,J=4.2,8.7Hz,1H),6.75(d,J=8.6Hz,1H),4.11-3.96(m,1H),3.84-3.69(m,3H),3.50(t,J=9.7Hz,1H),3.01-2.88(m,2H),2.75-2.53(m,2H),2.38-2.17(m,5H),1.99-1.84(m,2H),1.59(q,J=11.4Hz,2H),1.18(d,J=6.4Hz,3H)。
实例55
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(2-吗啉乙基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用反式-4-环丙基吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3214-1)和2-吗啉代乙胺和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a)和1-甲基哌啶-4-胺(化合物1e),制备标题化合物。获得实例55(13mg),为黄色固体。MS:calc’d 420(MH+),测得420(MH+)。1H NMR(400MHz,甲醇-d4)δ=9.16(d,J=8.7Hz,1H),8.92(dd,J=1.2,4.9Hz,1H),8.08(d,J=8.8Hz,1H),7.68(dd,J=4.9,8.8Hz,1H),6.92(d,J=8.8Hz,1H),4.14-4.03(m,3H),3.96(td,J=7.1,10.1Hz,2H),3.85-3.62(m,5H),3.62-3.45(m,2H),3.28-2.95(m,5H),1.99-1.86(m,1H),0.96-0.80(m,1H),0.60-0.50(m,2H),0.32-0.21(m,2H)。
实例56
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-甲基-吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用反式-4-甲基吡咯烷-3-甲酸甲酯和(3S,4R)-3-氨基-4-氟吡咯烷-1-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例56(4mg),为黄色固体。MS:calc’d 368(MH+),测得368(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.94-8.75(m,2H),7.99(d,J=8.4Hz,1H),7.51(dd,J=4.3,8.8Hz,1H),6.84(d,J=8.6Hz,1H),5.43-5.19(m,1H),4.07(t,J=9.5Hz,1H),3.92-3.48(m,7H),3.25(t,J=11.3Hz,1H),2.95-2.80(m,1H),2.73-2.60(m,1H),1.23(d,J=6.6Hz,3H)。
实例57
N-(氮杂环庚烷-4-基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-溴喹啉-8-腈和4-氨基氮杂环庚烷-1-甲酸叔丁酯代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。制备型HPLC分离得到了两种异构体实例57A(7mg)和实例57B(7mg)。
实例57A:MS:calc’d 390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(d,J=3.3Hz,1H),8.83(d,J=8.9Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.3,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.18(dd,J=7.0,9.9Hz,1H),4.02-3.83(m,3H),3.45(d,J=9.4Hz,1H),3.28-3.17(m,2H),3.17-3.00(m,2H),2.78(dd,J=3.7,6.5Hz,1H),2.18-1.89(m,3H),1.88-1.73(m,2H),1.73-1.56(m,1H),0.91-0.70(m,4H)。
实例57B:MS:calc’d 390(MH+),测得390(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(dd,J=1.5,4.2Hz,1H),8.83(dd,J=1.5,8.7Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.3,8.8Hz,1H),6.84(d,J=8.6Hz,1H),4.18(dd,J=6.8,10.0Hz,1H),4.02-3.87(m,3H),3.45(d,J=9.7Hz,1H),3.31-3.22(m,2H),3.21-3.09(m,2H),2.79(dd,J=3.7,6.8Hz,1H),2.22-1.95(m,3H),1.93-1.74(m,2H),1.70-1.56(m,1H),0.90-0.74(m,4H)。
实例58
(3S,4S)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3S,4S)-4-(三氟甲基)吡咯烷-3-甲酸甲酯盐酸盐(Pharmablock,PBXA3228-1)和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例58(19mg),为黄色固体。MS:calc’d 432(MH+),测得432(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.95(dd,J=1.5,4.2Hz,1H),8.70(dd,J=1.6,8.7Hz,1H),8.07(d,J=8.2Hz,1H),7.59(dd,J=4.2,8.7Hz,1H),7.07(d,J=8.3Hz,1H),3.94-3.72(m,3H),3.69-3.57(m,1H),3.49(q,J=7.3Hz,2H),3.06-2.90(m,3H),2.43-2.27(m,5H),1.97(br t,J=12.7Hz,2H),1.70-1.54(m,2H)。
实例59
N-(2-氨基-2-甲基-丙基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-溴喹啉-8-腈和N-(2-氨基-1,1-二甲基-乙基)氨基甲酸叔丁酯代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例59(13mg),为黄色固体。MS:calc’d 364(MH+),测得364(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.89-8.86(m,1H),8.83(d,J=8.7Hz,1H),7.99(dd,J=1.3,8.4Hz,1H),7.49(dd,J=4.3,8.7Hz,1H),6.83(d,J=8.6Hz,1H),4.24(dd,J=6.7,10.0Hz,1H),4.10-3.94(m,2H),3.50(d,J=14.3Hz,1H),3.41(d,J=9.5Hz,1H),3.17(d,J=14.1Hz,1H),2.87-2.80(m,1H),1.31(s,3H),1.30(s,3H),0.97-0.78(m,4H)。
实例60
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-[1-(4-哌啶基)-4-哌啶基]吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用(3R,4R)-4-甲基吡咯烷-3-甲酸甲酯HCl盐(Pharmablock,PBXA3221-1)和4-(4-氨基-1-哌啶基)哌啶-1-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例60(10mg),为黄色固体。MS:calc’d 448(MH+),测得448(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(d,J=1.6Hz,1H),8.72(d,J=1.5Hz,1H),7.92(d,J=8.6Hz,1H),6.70(d,J=8.7Hz,1H),4.27-3.96(m,4H),3.75-3.48(m,6H),3.29-3.04(m,4H),2.81-2.22(m,6H),2.09-1.78(m,4H),1.22(d,J=6.5Hz,3H)。
实例61
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(二氟甲基)吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用反式-4-二氟甲基-吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3200-1)代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b),制备标题化合物。制备型HPLC分离得到了两种异构体实例61A(14mg)和实例61B(8mg)。
实例61A:MS:calc’d 414(MH+),测得414(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(dd,J=1.5,4.2Hz,1H),8.64(dd,J=1.6,8.7Hz,1H),7.93(d,J=8.3Hz,1H),7.44(dd,J=4.2,8.7Hz,1H),6.88(d,J=8.3Hz,1H),6.08-5.84(m,1H),3.89(tt,J=4.6,9.4Hz,1H),3.79-3.60(m,5H),3.17-2.97(m,5H),2.12-1.46(m,6H)。
实例61B:MS:calc’d 414(MH+),测得414(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81(dd,J=1.5,4.2Hz,1H),8.64(dd,J=1.6,8.7Hz,1H),7.93(d,J=8.3Hz,1H),7.44(dd,J=4.2,8.7Hz,1H),6.88(d,J=8.3Hz,1H),6.08-5.84(m,1H),3.89(tt,J=4.6,9.4Hz,1H),3.79-3.60(m,5H),3.17-2.97(m,5H),2.12-1.46(m,6H)。
实例62
(3S,4S)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用(3S,4S)-4-甲基吡咯烷-3-甲酸甲酯盐酸盐(Pharmablock,PBXA3220-1)和5-溴-8-氯-喹啉代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例62(35mg),为黄色固体。MS:calc’d 387(MH+),测得387(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.75(dd,J=1.5,4.2Hz,1H),8.63(dd,J=1.6,8.7Hz,1H),7.60(d,J=8.3Hz,1H),7.42(dd,J=4.3,8.7Hz,1H),6.85(d,J=8.4Hz,1H),3.74(dd,J=8.1,9.2Hz,1H),3.66-3.57(m,1H),3.45-3.28(m,2H),3.18-3.09(m,1H),2.91-2.74(m,2H),2.62-2.47(m,2H),2.23-2.19(m,3H),2.14-1.99(m,2H),1.89-1.75(m,2H),1.54-1.38(m,2H),1.10(d,J=6.4Hz,3H)。
实例63
5-(8-氰基-5-喹啉基)-N-[(4-甲基吗啉-2-基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用5-溴喹啉-8-腈和(4-甲基吗啉-2-基)甲胺代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例63(14mg),为黄色固体。MS:calc’d 406(MH+),测得406(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.88(dd,J=1.3,4.2Hz,1H),8.83(d,J=8.7Hz,1H),7.99(d,J=8.4Hz,1H),7.49(dd,J=4.3,8.7Hz,1H),6.84(d,J=8.6Hz,1H),4.18(ddd,J=2.9,7.0,10.0Hz,1H),4.05-3.94(m,3H),3.75-3.62(m,2H),3.48-3.36(m,2H),3.30-3.17(m,1H),3.13-2.97(m,2H),2.83(dt,J=3.7,6.6Hz,1H),2.65-2.50(m,1H),2.58(s,3H),2.32(d,J=7.9Hz,1H),0.96-0.75(m,4H)。
实例64
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺
类似于实例1的制备方法,使用吡咯烷-3-甲酸甲酯和5-溴喹啉-8-腈代替(3R,4R)-4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐(化合物1b)和溴喹喔啉-5-腈(化合物1a),制备标题化合物。获得实例64(3mg),为黄色固体。MS:calc’d 364(MH+),测得364(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.81-8.62(m,2H),7.88(d,J=8.3Hz,1H),7.43-7.33(m,1H),6.75(d,J=8.4Hz,1H),3.74-3.45(m,5H),2.86(t,J=4.2Hz,3H),2.29-1.81(m,3H),1.34-0.98(m,8H)。
实例65
5-[7-(3-氨基氮杂环丁烷-1-羰基)-5-氮杂螺[2.4]庚烷-5-基]喹啉-8-腈
类似于实例6的制备方法,使用5-溴喹啉-8-腈和N-(氮杂环丁烷-3-基)氨基甲酸叔丁酯代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例65(13mg),为黄色固体。MS:calc’d 348(MH+),测得348(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.87(d,J=4.2Hz,1H),8.80(d,J=8.8Hz,1H),7.97(d,J=8.4Hz,1H),7.53-7.44(m,1H),6.83(d,J=8.6Hz,1H),4.55-4.36(m,1H),4.29-4.08(m,2H),4.06-3.84(m,4H),3.74(dd,J=5.3,10.8Hz,1H),3.48(dd,J=3.9,9.5Hz,1H),3.05-2.95(m,1H),0.95-0.74(m,4H)。
实例66
(2R,4R)-4-[[5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-羰基]氨基]吡咯烷-2-甲酸甲酯
类似于实例6的制备方法,使用(2R,4R)-4-氨基吡咯烷-2-甲酸甲酯(Pharmablock,PB05111,CAS:1217474-04-8)代替7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例66(16mg),为黄色固体。MS:calc’d 464(MH+),测得464(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=1.71Hz,1H),8.63(d,J=1.34Hz,1H),7.81(d,J=8.68Hz,1H),6.62(d,J=8.68Hz,1H),4.37-4.59(m,1H),4.20-4.35(m,2H),4.09-4.19(m,1H),3.94-4.03(m,1H),3.72-3.81(m,3H),3.46-3.60(m,2H),3.11-3.19(m,1H),2.36-2.72(m,2H),1.99-2.35(m,1H),0.61-0.80(m,4H)。
实例67
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-[(3S,4R)-4-氟吡咯烷-3-基]吡咯烷-3-甲酰胺
类似于实例30的制备方法,使用反式-4-二氟甲基-吡咯烷-3-甲酸乙酯盐酸盐(Pharmablock,PBXA3200-1)和(3S,4R)-3-氨基-4-氟吡咯烷-1-甲酸叔丁酯代替4-(三氟甲基)吡咯烷-3-甲酸甲酯HCl盐和4-氨基氮杂环庚烷-1-甲酸叔丁酯(化合物30d),制备标题化合物。获得实例67(11mg),为黄色固体。MS:calc’d 404(MH+),测得404(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.82(dd,J=1.6,4.3Hz,1H),8.64(dd,J=1.6,8.8Hz,1H),7.94(d,J=8.3Hz,1H),7.45(dd,J=4.3,8.7Hz,1H),6.90(d,J=8.4Hz,1H),6.08-5.86(m,1H),5.28-5.10(m,1H),4.70-4.51(m,1H),3.83-3.74(m,1H),3.69-3.53(m,3H),3.54-3.42(m,1H),3.31-3.24(m,3H),3.18-3.01(m,2H)。
实例70
5-(8-氰基喹喔啉-5-基)-N-[[(2R)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用8-溴喹喔啉-5-腈和(2S)-2-(氨基甲基)吗啉-4-甲酸叔丁酯(CAS:879403-42-6,Pharmablock,PBN 20121306)代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例70(79mg),为黄色固体。MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.72(d,J=1.83Hz,1H),8.64(d,J=1.71Hz,1H),7.87(d,J=8.68Hz,1H),6.65(d,J=8.80Hz,1H),4.15-4.31(m,2H),3.96-4.10(m,2H),3.61-3.74(m,3H),3.29-3.39(m,1H),3.24-3.28(m,1H),3.10-3.17(m,2H),2.95-3.07(m,1H),2.77(dt,J=5.20,12.07Hz,1H),2.63-2.72(m,1H),0.62-0.86(m,4H)。
SFC-HPLC(40%CO2/0.5%NH3的甲醇溶液作为洗脱剂,在Daicel AD-H柱上进行)分离得到了两种单一异构体实例70A(14mg)和实例70B(14mg)。
实例70A:MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.84(d,J=1.71Hz,1H),8.75(d,J=1.71Hz,1H),7.98(d,J=8.68Hz,1H),6.76(d,J=8.68Hz,1H),4.27-4.42(m,2H),4.07-4.20(m,2H),3.72-3.84(m,3H),3.40-3.52(m,1H),3.30(m,1H),3.21-3.29(m,2H),3.10-3.19(m,1H),2.85-2.96(m,1H),2.81(dd,J=3.55,6.85Hz,1H),0.74-0.93(m,4H)。
实例70B:MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.82(d,J=1.83Hz,1H),8.74(d,J=1.71Hz,1H),7.97(d,J=8.68Hz,1H),6.74(d,J=8.80Hz,1H),4.26-4.40(m,2H),4.18(d,J=11.25Hz,1H),4.12(dd,J=3.48,13.02Hz,1H),3.71-3.87(m,3H),3.36-3.43(m,2H),3.25-3.30(m,2H),3.08-3.17(m,1H),2.88(dd,J=11.49,12.59Hz,1H),2.80(dd,J=3.30,6.85Hz,1H),0.90-0.97(m,1H),0.78-0.90(m,3H)。
实例71
5-(8-氰基喹喔啉-5-基)-N-[[(2S)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺
类似于实例6的制备方法,使用8-溴喹喔啉-5-腈和(2R)-2-(氨基甲基)吗啉-4-甲酸叔丁酯(CAS:1174913-80-4,Pharmablock,PBN 20121305)代替5-溴-8-(三氟甲基)喹喔啉(中间体A)和7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物6d),制备标题化合物。获得实例71(84mg),为黄色固体。MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.72(d,J=1.71Hz,1H),8.64(d,J=1.71Hz,1H),7.87(d,J=8.68Hz,1H),6.65(d,J=8.68Hz,1H),4.15-4.32(m,2H),3.95-4.12(m,2H),3.59-3.73(m,3H),3.30-3.41(m,1H),3.24-3.29(m,1H),3.07-3.16(m,2H),2.95-3.07(m,1H),2.77(dt,J=5.07,12.07Hz,1H),2.63-2.72(m,1H),0.65-0.84(m,4H)。
SFC-HPLC(40%CO2/0.5%NH3的甲醇溶液作为洗脱剂,在Daicel AD-H柱上进行)分离得到了两种单一异构体实例71A(14mg)和实例71B(18mg)。
实例71A:MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.84(d,J=1.71Hz,1H),8.76(d,J=1.71Hz,1H),7.96-8.01(m,1H),6.77(d,J=8.80Hz,1H),4.35-4.43(m,1H),4.27-4.35(m,1H),4.19(d,J=11.25Hz,1H),4.12(dd,J=3.36,13.14Hz,1H),3.72-3.85(m,3H),3.36-3.40(m,2H),3.27(d,J=10.27Hz,2H),3.08-3.17(m,1H),2.84-2.93(m,1H),2.79(dd,J=3.24,6.79Hz,1H),0.87-0.96(m,1H),0.77-0.87(m,3H)。
实例71B:MS:calc’d 393(MH+),测得393(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.82(d,J=1.71Hz,1H),8.74(d,J=1.83Hz,1H),7.97(d,J=8.68Hz,1H),6.74(d,J=8.80Hz,1H),4.27-4.42(m,2H),4.08-4.20(m,2H),3.72-3.86(m,3H),3.40-3.52(m,1H),3.22-3.30(m,3H),3.09-3.20(m,1H),2.90(s,1H),2.82(d,J=3.30Hz,1H),0.88(s,1H),0.76-0.86(m,3H)。
实例72
HEK293-Blue-hTLR-7/8/9细胞测定
为了确定式(I)化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行以下检测。
HEK293-Blue-hTLR-7细胞测定:
稳定的HEK293-Blue-hTLR-7细胞系购自InvivoGen(目录号:hkb-htlr7,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的激活来研究人类TLR7的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR7配体刺激HEK-Blue hTLR7细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如R848(Resiquimod)的刺激下,孵育20小时后,TLR7拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
HEK293-Blue-hTLR7细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20μMR848的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在处读取吸光度。TLR7激活导致下游NF-κB激活的信号传导途径已被广泛接受,并因此对类似的报告基因测定方法进行了修改以评估TLR7拮抗剂。
HEK293-Blue-hTLR-8细胞测定:
稳定的HEK293-Blue-hTLR-8细胞系购自InvivoGen(目录号:hkb-htlr8,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的激活来研究人类TLR8的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR8配体刺激HEK-Blue hTLR8细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如R848的刺激下,孵育20小时后,TLR8拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
HEK293-Blue-hTLR8细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的60μMR848的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在处读取吸光度。TLR8激活导致下游NF-κB激活的信号传导途径已被广泛接受,并因此对类似的报告基因测定方法进行了修改以评估TLR8拮抗剂。
HEK293-Blue-hTLR-9细胞测定:
稳定的HEK293-Blue-hTLR-9细胞系购自InvivoGen(目录号:hkb-htlr9,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的激活来研究人类TLR9的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR9配体刺激HEK-Blue hTLR9细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如ODN2006(Resiquimod)(目录号:tlrl-2006-1,Invivogen,圣地亚哥,加利福尼亚,美国)的刺激下,孵育20小时后,TLR9拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
HEK293-Blue-hTLR9细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20μMODN2006的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在处读取吸光度。TLR9激活导致下游NF-κB激活的信号传导途径已被广泛接受,并因此对类似的报告基因测定方法进行了修改以评估TLR9拮抗剂。
式(I)化合物具有<0.5μM,尤其是<0.020μM的人类TLR7和/或TLR8抑制活性(IC50值)。此外,本发明的特定化合物还具有<10μM的人类TLR9抑制活性。表1显示了本发明化合物的活性数据。
表1:本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
Claims (21)
3.根据权利要求2所述的化合物,其中R4为(C1-6烷基)2氨基C1-6烷基氨基、(C1-6烷基吗啉基)C1-6烷基氨基、(C1-6烷基哌啶基)C1-6烷基氨基、(吗啉基C1-6烷基)氨基、[(C1-6烷基)2氨基C1-6烷基]C3-7环烷基氨基、氨基氮杂环丁烷基、氨基双环[3.1.0]己烷基氨基、氨基C1-6烷基氨基、氨基C3-7环烷基氨基、氨基C3-7环烷基C1-6烷基氨基、氨基螺[3.3]庚烷基氨基、氮杂双环[2.2.1]庚烷基氨基、氮杂双环[3.2.1]辛烷基氨基、氮杂双环[3.3.1]壬烷基氨基、氮杂螺[3.5]壬烷基氨基、氮杂环庚烷基氨基、C1-6烷氧基羰基吡咯烷基氨基、C1-6烷基氮杂螺[2.4]庚烷基氨基、C1-6烷基哌啶基氨基、二氮杂螺[4.4]壬烷基、二氮杂螺[5.5]十一烷基、卤代吡咯烷基氨基、吗啉基C1-6烷基氨基、八氢环戊并[c]吡咯基氨基、氧氮杂双环[3.3.1]壬烷基氨基或哌啶基哌啶基氨基。
4.根据权利要求3所述的化合物,其中R5为氰基、甲基、氯、三氟甲基或硝基。
5.根据权利要求4所述的化合物,其中R3为H、甲基、乙基、异丙基、二氟甲基、三氟甲基或环丙基;或者R2和R3与其所连接的碳一起形成环丙基。
6.根据权利要求5所述的化合物,其中R3为甲基或三氟甲基;或者R2和R3与其所连接的碳一起形成环丙基。
7.根据权利要求5或6所述的化合物,其中R4为(3-氨基环丁基)甲基氨基、(二甲基氨基)乙基氨基、(甲基吗啉基)甲基氨基、(甲基哌啶基)甲基氨基、(吗啉基乙基)氨基、(吗啉基甲基)氨基、[(二甲基氨基)甲基]环丁基氨基、1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-5-基氨基、2,7-二氮杂螺[4.4]壬烷基、2-氮杂双环[2.2.1]庚烷-5-基氨基、3,9-二氮杂螺[5.5]十一烷基、3-氮杂双环[3.2.1]辛烷-8-基氨基、3-氮杂双环[3.3.1]壬烷-7-基氨基、3-氮杂双环[3.3.1]壬烷-9-基氨基、3-氧杂-7-氮杂双环[3.3.1]壬烷-9-基氨基、3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基氨基、5-甲基-5-氮杂螺[2.4]庚烷-7-基氨基、6-氨基螺[3.3]庚烷-2-基氨基、7-氮杂螺[3.5]壬烷-2-基氨基、8-氮杂双环[3.2.1]辛烷-3-基氨基、9-氮杂双环[3.3.1]壬烷-3-基氨基、氨基-2-双环[3.1.0]己烷基氨基、氨基氮杂环丁烷基、氨基环丁基氨基、氨基环己基氨基、氨基甲基丙基氨基、氮杂环庚烷基氨基、氟吡咯烷基氨基、甲氧基羰基吡咯烷基氨基、甲基哌啶基氨基或哌啶基哌啶基氨基。
8.根据权利要求7所述的化合物,其中R4为甲基哌啶基氨基。
9.根据权利要求3所述的化合物,其选自:
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
(3R,4R)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
N-(3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(7R)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(7S)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(9-氮杂双环[3.3.1]壬烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(1-甲基-4-哌啶基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氮杂双环[3.2.1]辛烷-8-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-(吗啉-2-基甲基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(3-氮杂双环[3.3.1]壬烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-[2-(二甲基氨基)乙基]吡咯烷-3-甲酰胺;
N-(5-甲基-5-氮杂螺[2.4]庚烷-7-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(6-氨基螺[3.3]庚烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(8-氮杂双环[3.2.1]辛烷-3-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3S,4S)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
N-[3-[(二甲基氨基)甲基]环丁基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-硝基-5-喹啉基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-乙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-[(3-氨基环丁基)甲基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-5-[3-(3,9-二氮杂螺[5.5]十一烷-3-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-(8-甲基喹喔啉-5-基)吡咯烷-3-甲酰胺;
N-(7-氮杂螺[3.5]壬烷-2-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-[1-(4-哌啶基)-4-哌啶基]-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-[(1R,2S,4R,5S)-4-氨基-2-双环[3.1.0]己烷基]-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-异丙基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
N-(3-氨基环丁基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(4-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
N-(3-氧杂-7-氮杂双环[3.3.1]壬烷-9-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
顺式-N-(3-氨基环己基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(7-氰基吡唑并[1,5-a]吡啶-4-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氯-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-(2-氮杂双环[2.2.1]庚烷-5-基)-5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-异丙基-吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-[(1-甲基-3-哌啶基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-甲基-吡咯烷-3-甲酰胺;
反式-5-[3-(2,7-二氮杂螺[4.4]壬烷-2-羰基)-4-甲基-吡咯烷-1-基]喹啉-8-腈;
(3S,4S)-1-(8-氰基-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-4-环丙基-N-(2-吗啉乙基)吡咯烷-3-甲酰胺;
反式-1-(8-氰基-5-喹啉基)-N-[(3S,4R)-4-氟吡咯烷-3-基]-4-甲基-吡咯烷-3-甲酰胺;
N-(氮杂环庚烷-4-基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3S,4S)-1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
N-(2-氨基-2-甲基-丙基)-5-(8-氰基-5-喹啉基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-[1-(4-哌啶基)-4-哌啶基]吡咯烷-3-甲酰胺;
反式-N-(氮杂环庚烷-4-基)-1-(8-氰基-5-喹啉基)-4-(二氟甲基)吡咯烷-3-甲酰胺;
(3S,4S)-1-(8-氯-5-喹啉基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-(8-氰基-5-喹啉基)-N-[(4-甲基吗啉-2-基)甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
1-(8-氰基-5-喹啉基)-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
5-[7-(3-氨基氮杂环丁烷-1-羰基)-5-氮杂螺[2.4]庚烷-5-基]喹啉-8-腈;
(2R,4R)-4-[[5-[8-(三氟甲基)喹喔啉-5-基]-5-氮杂螺[2.4]庚烷-7-羰基]氨基]吡咯烷-2-甲酸甲酯;
反式-1-(8-氰基-5-喹啉基)-4-(二氟甲基)-N-[(3S,4R)-4-氟吡咯烷-3-基]吡咯烷-3-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-[[(2R)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;和
5-(8-氰基喹喔啉-5-基)-N-[[(2S)-吗啉-2-基]甲基]-5-氮杂螺[2.4]庚烷-7-甲酰胺;
或其药学上可接受的盐、对映体或非对映体。
10.根据权利要求9所述的化合物,其选自:
(3R,4R)-1-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)吡咯烷-3-甲酰胺;
(3R,4R)-N-(1-甲基-4-哌啶基)-4-(三氟甲基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
(3R,4R)-1-(8-氰基喹喔啉-5-基)-4-甲基-N-(1-甲基-4-哌啶基)吡咯烷-3-甲酰胺;
(3R,4R)-4-甲基-N-(1-甲基-4-哌啶基)-1-[8-(三氟甲基)喹喔啉-5-基]吡咯烷-3-甲酰胺;
5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
(7R)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;和
(7S)-5-(8-氰基喹喔啉-5-基)-N-(1-甲基-4-哌啶基)-5-氮杂螺[2.4]庚烷-7-甲酰胺;
或其药学上可接受的盐、对映体或非对映体。
12.一种根据权利要求1至10中任一项所述的化合物或药学上可接受的盐、对映体或非对映体,其用作治疗活性物质。
13.一种药物组合物,其包含根据权利要求1至10中任一项所述的化合物以及治疗惰性载体。
14.根据权利要求1至10中任一项所述的化合物用于治疗或预防系统性红斑狼疮或狼疮性肾炎的用途。
15.根据权利要求1至10中任一项所述的化合物用于制备用于治疗或预防系统性红斑狼疮或狼疮性肾炎的药物的用途。
16.根据权利要求1至10中任一项所述的化合物作为TLR7或TLR8或TLR9拮抗剂的用途。
17.根据权利要求1至10中任一项所述的化合物作为TLR7和TLR8和TLR9拮抗剂的用途。
18.一种根据权利要求1至10中任一项所述的化合物或药学上可接受的盐、对映体或非对映体,其用于治疗或预防系统性红斑狼疮或狼疮性肾炎。
19.一种根据权利要求1至10中任一项所述的化合物或药学上可接受的盐、对映体或非对映体,其根据权利要求11所述的方法生产。
20.一种用于治疗或预防系统性红斑狼疮或狼疮性肾炎的方法,所述方法包括施用治疗有效量的如权利要求1至10中任一项所定义的化合物。
21.如前所述的发明。
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EP3847169A1 (en) | 2018-09-04 | 2021-07-14 | F. Hoffmann-La Roche AG | Benzothiazole compounds for the treatment of autoimmune diseases |
JP2022502353A (ja) | 2018-09-06 | 2022-01-11 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 自己免疫疾患の処置のための新規の環状アミジン化合物 |
WO2022194237A1 (zh) * | 2021-03-18 | 2022-09-22 | 成都百裕制药股份有限公司 | 喹啉衍生物及其在制备自身免疫药物上的应用 |
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JPS6354363A (ja) * | 1986-08-26 | 1988-03-08 | Ss Pharmaceut Co Ltd | キノリン誘導体 |
CN101248069A (zh) * | 2004-05-17 | 2008-08-20 | 阿卡蒂亚药品公司 | 雄激素受体调节剂及用其治疗疾病的方法 |
WO2016096778A1 (en) * | 2014-12-18 | 2016-06-23 | F. Hoffmann-La Roche Ag | Benzazepine sulfonamide compounds |
CN105732636A (zh) * | 2014-12-30 | 2016-07-06 | 广东东阳光药业有限公司 | 杂芳化合物及其在药物中的应用 |
WO2016141092A1 (en) * | 2015-03-04 | 2016-09-09 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
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JPS6354363A (ja) * | 1986-08-26 | 1988-03-08 | Ss Pharmaceut Co Ltd | キノリン誘導体 |
CN101248069A (zh) * | 2004-05-17 | 2008-08-20 | 阿卡蒂亚药品公司 | 雄激素受体调节剂及用其治疗疾病的方法 |
WO2016096778A1 (en) * | 2014-12-18 | 2016-06-23 | F. Hoffmann-La Roche Ag | Benzazepine sulfonamide compounds |
CN105732636A (zh) * | 2014-12-30 | 2016-07-06 | 广东东阳光药业有限公司 | 杂芳化合物及其在药物中的应用 |
WO2016141092A1 (en) * | 2015-03-04 | 2016-09-09 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
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