CN107428754B - 二环喹唑啉酮衍生物 - Google Patents
二环喹唑啉酮衍生物 Download PDFInfo
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- CN107428754B CN107428754B CN201680016801.4A CN201680016801A CN107428754B CN 107428754 B CN107428754 B CN 107428754B CN 201680016801 A CN201680016801 A CN 201680016801A CN 107428754 B CN107428754 B CN 107428754B
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- China
- Prior art keywords
- methyl
- oxoquinazolin
- substituted
- acetamide
- dichlorophenyl
- Prior art date
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- -1 Bicyclic quinazolinone derivatives Chemical class 0.000 title claims description 442
- 150000001875 compounds Chemical class 0.000 claims abstract description 235
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 106
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 69
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 61
- 238000002360 preparation method Methods 0.000 claims description 52
- 125000001188 haloalkyl group Chemical group 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 28
- 125000003107 substituted aryl group Chemical group 0.000 claims description 27
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 20
- 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 20
- 238000011282 treatment Methods 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 18
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 17
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 208000022873 Ocular disease Diseases 0.000 claims description 7
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 7
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical class C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
- GLALTMTYDCCMKH-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)Cl)=O GLALTMTYDCCMKH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 5
- IPERVJZOLDOLKB-HSZRJFAPSA-N (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)-N-methylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N[C@H](CC(=O)NC)C1=CC=C(C=C1)Cl)=O IPERVJZOLDOLKB-HSZRJFAPSA-N 0.000 claims description 4
- NOCAIBYMDMOXIX-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)Cl)=O NOCAIBYMDMOXIX-UHFFFAOYSA-N 0.000 claims description 4
- HJJOBEITCVFWHP-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O HJJOBEITCVFWHP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 4
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- MBTDWYFVHQQPOB-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxopyrido[3,4-d]pyrimidin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C1=CC2=C(N=CN(C2=O)CC(=O)N(C)CC2=CC(=C(C=C2)C#N)Cl)C=N1 MBTDWYFVHQQPOB-UHFFFAOYSA-N 0.000 claims description 3
- SEYPWJAXDVEKRI-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[[4-chloro-3-(trifluoromethoxy)phenyl]methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)OC(F)(F)F)=O SEYPWJAXDVEKRI-UHFFFAOYSA-N 0.000 claims description 3
- QGEPSJRORVPVGA-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-8-fluoro-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=C(C=1)F)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)Cl)=O QGEPSJRORVPVGA-UHFFFAOYSA-N 0.000 claims description 3
- FEMDVYZKXVIVSV-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-ethylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(CC)CC1=CC(=C(C=C1)Cl)Cl)=O FEMDVYZKXVIVSV-UHFFFAOYSA-N 0.000 claims description 3
- NCANVBWZSKKPDX-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)C(C(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)C)=O NCANVBWZSKKPDX-UHFFFAOYSA-N 0.000 claims description 3
- VLNTWOLCPCIQHD-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-propan-2-ylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C(C)C)CC1=CC(=C(C=C1)Cl)Cl)=O VLNTWOLCPCIQHD-UHFFFAOYSA-N 0.000 claims description 3
- KOXMVIQHMPDSKS-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3,5-difluorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C(=C1)F)C#N)F)=O KOXMVIQHMPDSKS-UHFFFAOYSA-N 0.000 claims description 3
- XABRQIMWCDTTQX-UHFFFAOYSA-N 2-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound C1(CC1)CN1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O XABRQIMWCDTTQX-UHFFFAOYSA-N 0.000 claims description 3
- CZFKTYGPOYWJDJ-UHFFFAOYSA-N 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]-N-methylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(CCC(=O)NC)CC1=CC(=C(C=C1)Cl)Cl)=O CZFKTYGPOYWJDJ-UHFFFAOYSA-N 0.000 claims description 3
- MCSFLNGVQGYPLK-UHFFFAOYSA-N 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]-[(3,4-dichlorophenyl)methyl]amino]propanoic acid Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(CCC(=O)O)CC1=CC(=C(C=C1)Cl)Cl)=O MCSFLNGVQGYPLK-UHFFFAOYSA-N 0.000 claims description 3
- PGJHYUWEUZKSNZ-UHFFFAOYSA-N 3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(3,4-dichlorophenyl)-N-methylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)NC(CC(=O)NC)C1=CC(=C(C=C1)Cl)Cl)=O PGJHYUWEUZKSNZ-UHFFFAOYSA-N 0.000 claims description 3
- KTSPAELZEIOVCH-UHFFFAOYSA-N 4-[3-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]-N-propan-2-ylpiperazine-1-carboxamide Chemical compound ClC=1C=C(C=CC=1Cl)CNC(CN1C=NC2=CC=C(C=C2C1=O)N1CCN(CC1)C(=O)NC(C)C)=O KTSPAELZEIOVCH-UHFFFAOYSA-N 0.000 claims description 3
- OOPJDBSRGWWQGB-UHFFFAOYSA-N N-[(3-chloro-4-cyanophenyl)methyl]-2-[6-[1-(3-cyanopropanoyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide Chemical compound ClC=1C=C(CN(C(CN2C=NC3=CC=C(C=C3C2=O)C2CCN(CC2)C(CCC#N)=O)=O)C)C=CC=1C#N OOPJDBSRGWWQGB-UHFFFAOYSA-N 0.000 claims description 3
- PXWIBTULLAMTPP-UHFFFAOYSA-N N-[(3-chloro-4-cyanophenyl)methyl]-2-[8-fluoro-6-[1-(3-methoxypropanoyl)piperidin-4-yl]-4-oxoquinazolin-3-yl]-N-methylacetamide Chemical compound ClC=1C=C(CN(C(CN2C=NC3=C(C=C(C=C3C2=O)C2CCN(CC2)C(CCOC)=O)F)=O)C)C=CC=1C#N PXWIBTULLAMTPP-UHFFFAOYSA-N 0.000 claims description 3
- KEBQMKOQADRWHB-UHFFFAOYSA-N [2-[4-[3-[2-[(3-chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperidin-1-yl]-2-oxoethyl] nitrate Chemical compound [N+](=O)(OCC(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)Cl)=O)[O-] KEBQMKOQADRWHB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- ZQACLUSFRIMNQA-UHFFFAOYSA-N methyl 4-[3-[2-[(3-chloro-4-cyanophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperidine-1-carboxylate Chemical compound ClC=1C=C(CN(C(CN2C=NC3=CC=C(C=C3C2=O)C2CCN(CC2)C(=O)OC)=O)C)C=CC=1C#N ZQACLUSFRIMNQA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 claims description 3
- UHVSNBLWPNAGAS-XMMPIXPASA-N (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)-N,N-dimethylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N[C@H](CC(=O)N(C)C)C1=CC=C(C=C1)Cl)=O UHVSNBLWPNAGAS-XMMPIXPASA-N 0.000 claims description 2
- LIQLJOYGASVTSQ-MUUNZHRXSA-N (3R)-3-[[2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]acetyl]amino]-3-(4-chlorophenyl)-N-phenylpropanamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N[C@H](CC(=O)NC1=CC=CC=C1)C1=CC=C(C=C1)Cl)=O LIQLJOYGASVTSQ-MUUNZHRXSA-N 0.000 claims description 2
- VDADZGLBQYYLSK-UHFFFAOYSA-N 2-[4-[3-[2-[(3,4-dichlorophenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-6-yl]piperazin-1-yl]-N-phenylacetamide Chemical compound N(C1=CC=CC=C1)C(CN1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O)=O VDADZGLBQYYLSK-UHFFFAOYSA-N 0.000 claims description 2
- XUTBXGJGPRFREN-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O XUTBXGJGPRFREN-UHFFFAOYSA-N 0.000 claims description 2
- ONUVAJMIVDPZRI-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(4-chloro-3-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)C#N)=O ONUVAJMIVDPZRI-UHFFFAOYSA-N 0.000 claims description 2
- KATWLLNRCULLRB-UHFFFAOYSA-N 2-[6-(1-acetylpiperidin-4-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3-fluorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCC(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)F)=O KATWLLNRCULLRB-UHFFFAOYSA-N 0.000 claims description 2
- JQEIJSUNPUIILF-UHFFFAOYSA-N 2-[6-(4-acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(3-chloro-4-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CCC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)Cl)=O JQEIJSUNPUIILF-UHFFFAOYSA-N 0.000 claims description 2
- MCNSCCICKMJYQM-UHFFFAOYSA-N 2-[6-(4-acetyl-1,4-diazepan-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chloro-3-cyanophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CCC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)C#N)=O MCNSCCICKMJYQM-UHFFFAOYSA-N 0.000 claims description 2
- DQMULKHZQVNGOO-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-(1,3-benzodioxol-5-ylmethyl)acetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)NCC1=CC2=C(OCO2)C=C1)=O DQMULKHZQVNGOO-UHFFFAOYSA-N 0.000 claims description 2
- VWBLYEAETDREAI-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(2,6-dichloropyridin-4-yl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=NC(=C1)Cl)Cl)=O VWBLYEAETDREAI-UHFFFAOYSA-N 0.000 claims description 2
- QTWYJQLHPAVRFA-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-chlorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC=C(C=C1)Cl)=O QTWYJQLHPAVRFA-UHFFFAOYSA-N 0.000 claims description 2
- JPMNFOQIUAXWAS-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(4-cyano-3-fluorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)C#N)F)=O JPMNFOQIUAXWAS-UHFFFAOYSA-N 0.000 claims description 2
- VSVDTTGNCIIZJV-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[1-(4-chlorophenyl)ethyl]acetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)NC(C)C1=CC=C(C=C1)Cl)=O VSVDTTGNCIIZJV-UHFFFAOYSA-N 0.000 claims description 2
- BCCOMQQMPVHDLP-UHFFFAOYSA-N 2-[6-(4-acetylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[2-(3,4-dichlorophenyl)ethyl]acetamide Chemical compound C(C)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)NCCC1=CC(=C(C=C1)Cl)Cl)=O BCCOMQQMPVHDLP-UHFFFAOYSA-N 0.000 claims description 2
- MZDGHLLVYPHPIP-UHFFFAOYSA-N 2-[6-(4-cyclopropylsulfonylpiperazin-1-yl)-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound C1(CC1)S(=O)(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O MZDGHLLVYPHPIP-UHFFFAOYSA-N 0.000 claims description 2
- KEMNXRYBVAROIY-UHFFFAOYSA-N 2-[6-[4-(1-acetylazetidine-3-carbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound C(C)(=O)N1CC(C1)C(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O KEMNXRYBVAROIY-UHFFFAOYSA-N 0.000 claims description 2
- MWMSNOAWOVVSMP-UHFFFAOYSA-N 2-[6-[4-(3-chlorocyclobutanecarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]-N-[(3,4-dichlorophenyl)methyl]-N-methylacetamide Chemical compound ClC1CC(C1)C(=O)N1CCN(CC1)C=1C=C2C(N(C=NC2=CC=1)CC(=O)N(C)CC1=CC(=C(C=C1)Cl)Cl)=O MWMSNOAWOVVSMP-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供具有通式(I)的新型化合物,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、A1、A2、A3、n和m如本文中所述。
Description
本发明涉及可用于哺乳动物中的治疗或预防的有机化合物,并且特别涉及自分泌运动因子(autotaxin)(ATX)抑制剂,其是溶血磷脂酸(LPA)生产的抑制剂,并且因此是LPA水平和相关信号传导的调节剂,用于肾脏病症、肝脏病症、炎性病症、神经系统病症、呼吸系统病症、血管和心血管病症、纤维变性疾病、癌症、眼病症、代谢病症、胆汁淤积性(cholestatic)及其他形式的慢性瘙痒症(pruritus)以及急性和慢性器官移植排斥反应的治疗或预防。
本发明提供新的式(I)化合物
R1是羟基烷基、二羟基烷基、羟基环烷基、烷氧基、卤代烷氧基、烷氧基烷氧基烷基、烷氧基烷基、卤代烷氧基烷基、烷基、卤代烷基、烷基磺酰基、卤代烷基磺酰基、氨基磺酰基烷基、氰基烷基、硝酸烷基、取代的环烷基、取代的环烷基烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷基羰基、羧基、卤素和氰基;
R2和R3独立地选自H、烷基和环烷基;
或者R2和R3与它们连接的碳一起形成环烷基;
A1是-CH-、-C(OH)-或-N-;
A2是-C(O)-、-C(O)CH2-、-CH2-、-NR11C(O)-、-NR11C(O)CH2-、-S(O)2-;
A3是-CR8-或-N-;
R4和R5中的一个是H或烷基并且另一个是H、烷氧基烷基、烷氧基羰基烷基、卤代烷氧基羰基烷基、烷基、卤代烷基、羧基烷基、环烷基或取代的氨基羰基烷基,其中取代的氨基羰基烷基在氮原子上被两个独立地选自以下各项的取代基取代:H、烷基、环烷基和取代的苯基,其中取代的苯基被一至三个独立地选自以下各项的取代基取代:H、烷基、卤代烷基和环烷基;
或者R4和R5与它们连接的氮和碳原子一起形成杂环烷基;
R6是H或烷基;
R7、R8和R9独立地是H、烷基、环烷基、卤素或氰基;
R10是取代的芳基或取代的杂芳基,其中取代的芳基或取代的杂芳基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基、卤代烷基磺酰基和五氟-λ6-硫烷基;
R11是H、烷基或环烷基;
R12和R13都是H或R12和R13一起形成-(CH2)p-;
R14是H、烷基或羟基;
n、m和p独立地为零、1或2;
或药用盐。
自分泌运动因子(ATX)是一种也称作外核苷酸焦磷酸酶/磷酸二酯酶2或溶血磷脂酶D的分泌型酶,其对于将溶血磷脂酰胆碱(LPC)转化为生物活性的信号分子溶血磷脂酸(LPA)而言是重要的。已经表明,血浆LPA水平与ATX活性良好地相关,并且因此相信ATX是胞外LPA的重要来源。早期用原型ATX抑制剂的实验已经证实了,这样的化合物能够抑制在小鼠血浆中的LPA合成活性。在1970年代和1980年代早期进行的工作证明了,LPA可以引起各种各样的细胞响应;包括平滑肌细胞收缩、血小板活化、细胞增殖、趋化性等等。LPA经由向若干G蛋白偶联受体(GPCR)发出信号来介导它的效果;第一批成员最初被表示为Edg(内皮细胞分化基因)受体或心室区基因-1(vzg-1),但现在称为LPA受体。现在,原型群由LPA1/Edg-2/VZG-1、LPA2/Edg-4和LPA3/Edg-7组成。最近,已经描述了三种附加的LPA受体LPA4/p2y9/GPR23、LPA5/GPR92和LPA6/p2Y5,它们与原型LPA1-3受体相比,更加紧密地与核苷酸选择性嘌呤能受体相关。ATX-LPA信号轴涉及多种多样的生理和病理生理功能,包括例如,神经系统功能、血管发育、心血管生理学、繁殖、免疫系统功能、慢性炎症、肿瘤转移和进展、器官纤维变性及肥胖症(obesity)和/或其他代谢疾病如糖尿病(diabetes mellitus)。因此,提高的ATX活性和/或提高的LPA水平,改变的LPA受体表达和改变的对LPA的响应可以有助于与ATX/LPA轴相关的大量不同的病理生理病症的引发、进展和/或结果。
按照本发明,可以使用式(I)化合物或它们的药用盐和酯用于治疗或预防与自分泌运动因子的活性和/或溶血磷脂酸(LPA)的生物活性相关的疾病、障碍或病症。
本文的式(I)化合物或它们的药用盐和酯抑制自分泌运动因子活性,并且因此抑制LPA生产和调节LPA水平及相关的信号。本文所述的自分泌运动因子抑制剂可用作用于治疗或预防疾病或病症的药剂:在所述疾病或病症中,ATX活性和/或LPA信号参与、涉及所述疾病的病原学或病理学,或者以其他方式与所述疾病的至少一种症状相关。ATX-LPA轴已经牵连于例如血管发生、慢性炎症、自体免疫疾病、纤维变性疾病、癌症和肿瘤转移和进展、眼病症、代谢病症如肥胖症和/或糖尿病、病症如胆汁淤积性或其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应中。
本发明的目的是式(I)化合物和它们的上述的盐和酯,以及它们作为治疗活性物质的用途,用于制备所述化合物的方法,中间体,药用组合物,含有所述化合物的药物,它们的药用盐或酯,所述化合物、盐或酯用于治疗或预防与ATX活性和/或溶血磷脂酸(LPA)的生物活性相关的障碍或病症的用途,特别是治疗或预防肾脏病症、肝脏病症、炎性病症、神经系统病症、呼吸系统病症、血管和心血管病症、纤维变性疾病、癌症、眼病症、代谢病症、胆汁淤积性及其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应,以及所述化合物、盐或酯用于制备药物的用途,所述药物用于治疗或预防肾脏病症、肝脏病症、炎性病症、神经系统病症、呼吸系统病症、血管和心血管病症、纤维变性疾病、癌症、眼病症、代谢病症、胆汁淤积性及其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应。更特别地,式(I)的化合物及其前述盐和酯以及其作为治疗活性物质的用途、用于制备所述化合物的方法,中间体,药物组合物,含有所述化合物、其药用盐或酯的药物,所述化合物、盐或酯用于治疗或预防眼病症的用途,此外特别是青光眼的用途。
术语“烷氧基”表示式-O-R’的基团,其中R’是烷基。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。特别实例是甲氧基。
术语“烷氧基烷基”表示其中烷基的至少一个氢原子被烷氧基替代的烷基。特别是实例是甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、异丙氧基甲基和异丙氧基乙基。
术语“烷氧基羰基”表示式-C(O)-R’的基团,其中R’是烷氧基。特别实例是式-C(O)-R’的基团,其中R’是甲氧基。
术语“烷氧基羰基烷基”表示其中烷基的至少一个氢原子被烷氧基羰基替代的基团。特别实例是甲氧基羰基乙基。
术语“烷基”表示1至12个碳原子的一价直链或支链的饱和烃基。在特别的实施方案中,烷基具有1至7个碳原子,且在更特别的实施方案中具有1至4个碳原子。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基和戊基。特别的烷基包括甲基、乙基、异丙基、正丁基和仲丁基。
术语“烷基羰基”表示式-C(O)-R’的基团,其中R’是烷基。
术语“烷基磺酰基”表示式-S(O)2-R’的基团,其中R’是烷基。特别实例是甲基磺酰基。
术语“氨基”表示-NH2基团。
术语“氨基磺酰基”表示-S(O)2-NH2基团。
术语“氨基磺酰基烷基”表示其中烷基的至少一个氢原子被氨基磺酰基替代的烷基。实例是氨基磺酰基甲基、氨基磺酰基乙基和氨基磺酰基丙基。特别实例是氨基磺酰基甲基和氨基磺酰基丙基。
术语“芳基”表示包含6至10个碳环原子的一价芳族碳环单环或二环体系。芳基的实例包括苯基和萘基。特别的芳基是苯基。
术语“羰基”表示-C(O)-基团。
术语“羧基”表示-COOH基团。
术语“羧基烷基”表示其中烷基的至少一个氢原子被羧基替代的烷基。特别实例是羧基乙基。
术语“氰基”表示-C≡N基团。
术语“氰基烷基”表示其中烷基的一个氢原子被氰基替代的烷基。特别实例是氰基甲基和氰基乙基。
术语“环烷基”表示3至10个环碳原子的一价饱和单环或双环烃基。在特别的实施方案中,环烷基表示3至8个环碳原子的一价饱和单环烃基。双环表示由具有两个共同碳原子的两个饱和碳环组成的环体系。单环环烷基的实例是环丙基、环丁基、环戊基、环己基或环庚基。双环环烷基的实例是双环[2.2.1]庚基(heptanyl)或双环[2.2.2]辛基。特别的单环环烷基是环丙基、环丁基、环戊基和环己基。
术语“环烷基烷基”表示其中烷基的至少一个氢原子被环烷基替代的烷基。环烷基烷基的特别实例是环丁基甲基。
术语“二羟基烷基”表示其中烷基的两个氢原子各自被羟基替代的烷基。特别实例是二羟基乙基和二羟基丙基。
术语“卤代烷氧基”表示其中烷氧基的至少一个氢原子已被相同或不同卤素原子替代的烷氧基。特别实例是三氟甲氧基和三氟乙基。
术语“卤代烷氧基烷基”表示其中烷基的至少一个氢原子已被卤代烷氧基替代的烷基。
术语“卤代烷氧基羰基”表示式-C(O)-R’的基团,其中R’是卤代烷氧基。
术语“卤代烷氧基羰基烷基”表示其中烷基的至少一个氢原子被卤代烷氧基羰基替代的烷基。
术语“卤代烷基”表示其中烷基的至少一个氢原子已被相同或不同卤素原子替代的烷基。术语“全卤代烷基”表示烷基,其中烷基的全部氢原子已经被相同或不同的卤素原子代替。卤代烷基的实例包括氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲基乙基和五氟乙基。特别的卤代烷基是三氟甲基。
术语“卤代烷基磺酰基”表示式-S(O)2-R’的基团,其中R’是卤代烷基。
术语“卤素”和“卤代”在本文可互换使用并且表示氟、氯、溴或碘。特别的卤素是氯和氟。
术语“杂芳基”表示5至12个环原子的一价芳族杂环单环或二环体系,其包含1、2、3或4个选自N、O和S的杂原子,剩余原子是碳。杂芳基的实例包括吡咯基、呋喃基、噻吩基、咪唑基、唑基、噻唑基、三唑基、二唑基、噻二唑基、四唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基、三嗪基、氮杂基、二氮杂基、异唑基、苯并呋喃基、异噻唑基、苯并噻吩基、吲哚基、异吲哚基、异苯并呋喃基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、苯并二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、和苯并噻吩基。特别的杂芳基是呋喃基、唑二唑基、唑基、异唑基、吡咯基、咪唑基、苯并间二氧杂环戊烯基和吡啶基。
术语“杂环烷基”表示具有4至9个环原子的单价饱和或部分不饱和单环或二环体系,所述环原子包含1、2或3个选自N、O和S的环杂原子,其余的环原子是碳。二环表示由两个共享两个环原子的环组成,即将两个环分开的桥是单键或一个或两个环原子的链。单环饱和杂环烷基的实例是二烷基、4,5-二氢-唑基、氧杂环丁烷基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、唑烷基、异唑烷基、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、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、3-氧杂-9-氮杂-二环[3.3.1]壬基或3-硫杂-9-氮杂-二环[3.3.1]壬基。部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、二氢-唑基、四氢-吡啶基或二氢吡喃基。杂环烷基的特别的实例是二烷基、吗啉基、四氢吡喃基、四氢呋喃基、氮杂环丁烷基和氧杂环丁基。
术语“羟基”表示-OH基团。
术语“羟基烷基”表示其中烷基的一个氢原子被羟基替代的烷基。特别实例是羟基甲基、羟基乙基、羟基丙基和羟基丁基。
术语“羟基环烷基”表示其中环烷基的一个氢原子被羟基替代的环烷基。特别实例是羟基环丙基和羟基环丁基。
术语“硝酸基(nitrate)”表示-NO3基团。
术语“硝酸烷基”表示其中烷基的一个氢原子被硝酸基替代的烷基。特别实例是硝酸甲基。
术语“硝基”表示-NO2基团。术语“磺酰基”表示-S(O)2基团。
术语“药用盐”是指保持游离碱或游离酸的生物学效用和性质的那些盐,它们不是在生物学或其他方面不适宜的。所述盐与以下酸形成:无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,特别是盐酸,以及有机酸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、N-乙酰半胱氨酸等。此外,可以通过向游离酸中加入无机碱或有机碱来制备这些盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。衍生自有机碱的盐包括但不限于以下各项的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺、环胺和碱性离子交换树脂,如异丙胺,三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚亚胺树脂等。特别的式(I)化合物的药用盐是盐酸盐、甲磺酸盐和柠檬酸盐。
“药用酯”是指通式(I)化合物可以在官能团处衍生以提供能够在体内转化回母体化合物的衍生物。这样的化合物的实例包括生理学上可接受的且在代谢上不稳定的酯衍生物,如甲氧基甲酯,甲硫基甲酯和新戊酰氧基甲酯。另外,类似于在代谢上不稳定的酯,能够在体内生成通式(I)的母体化合物的通式(I)化合物的任何生理上可接受的等价物都在本发明的范围内。
术语“保护基团”(PG)表示这样的基团,在与其在合成化学中相关的传统含义中选择性地阻挡多官能化合物中的反应性位点以使得化学反应可以在另一个未保护的反应性位点选择性地进行。可以将保护基团在合适的点移除。示例性保护基团是氨基-保护基团、羧基-保护基团或羟基-保护基团。特别的保护基团是叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)、芴基甲氧基羰基(Fmoc)和苄基(Bn)基团。更特别的保护基团是叔丁氧基羰基(Boc)和芴基甲氧基羰基(Fmoc)基团。更特别的保护基团是叔丁氧基羰基(Boc)基团。
缩写uM表示微摩尔浓度且等价于符号μM。
缩写uL表示微升且等价于符号μL。
缩写ug表示微克且等价于符号μg。
式(I)化合物可以含有数个不对称中心,并且其存在形式可以是光学纯对映异构体,对映异构体的混合物,如例如外消旋物,光学纯非对映异构体,非对映异构体的混合物,非对映异构体外消旋物或非对映异构体外消旋物的混合物。
根据Cahn-Ingold-Prelog Convention,不对称碳原子可以为“R”或“S”构型。
本发明的还一个实施方案是根据本文所述的式(I)化合物及其药用盐或酯,特别是根据本文所述的式(I)化合物及其药用盐,更特别是根据本文所述的式(I)化合物。
本发明的一个特别实施方案是如本文所述的根据式(I)的化合物,其中
R1是烷氧基、卤代烷氧基、烷氧基烷基、卤代烷氧基烷基、烷基、卤代烷基、烷基磺酰基、卤代烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷基羰基、羧基、卤素和氰基;
R2和R3独立地选自H、烷基和环烷基;
或者R2和R3与它们连接的碳一起形成环烷基;
A1是-CH-或-N-;
A2是-C(O)-、-C(O)CH2-、-CH2-、-NR11C(O)-、-NR11C(O)CH2-、-S(O)2-;
R4和R5中的一个是H或烷基并且另一个是H、烷氧基羰基烷基、卤代烷氧基羰基烷基、烷基、卤代烷基、羧基烷基、环烷基或取代的氨基羰基烷基,其中取代的氨基羰基烷基在氮原子上被两个独立地选自以下各项的取代基取代:H、烷基、环烷基和取代的苯基,其中取代的苯基被一至三个独立地选自以下各项的取代基取代:H、烷基、卤代烷基和环烷基;
或者R4和R5与它们连接的氮和碳原子一起形成杂环烷基;
R6是H或烷基;
R7、R8和R9独立地是H、烷基、环烷基、卤素或氰基;
R10是取代的芳基或取代的杂芳基,其中取代的芳基或取代的杂芳基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基、卤代烷基磺酰基和五氟-λ6-硫烷基;
R11是H、烷基或环烷基;
R12和R13都是H或R12和R13一起形成-(CH2)p-;
R14是H、烷基或羟基;
n、m和p独立地为零、1或2;
或药用盐。本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R1是羟基烷基、二羟基烷基、羟基环烷基、烷氧基、烷氧基烷氧基烷基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、氰基、硝酸烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
本发明的一个特别实施方案是如本文所述的根据式(I)的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的二烷基、取代的氮杂环丁烷基、取代的吗啉基和或取代的苯基,其中,取代的环烷基、取代的环烷基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的二烷基、取代的氮杂环丁烷基、取代的吗啉基和取代的苯基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
本发明的一个特别实施方案是如本文所述的根据式(I)的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的氮杂环丁烷基、取代的吗啉基和或取代的苯基,其中,取代的环烷基、取代的环烷基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的氮杂环丁烷基、取代的吗啉基和取代的苯基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
本发明的另一个特别实施方案是如本文所述的根据式(I)的化合物,其中R1是烷氧基烷基、烷基、取代的环烷基或取代的环烷基烷基,其中取代的环烷基和取代的环烷基烷基被一至三个选自以下各项的取代基取代:H、卤代烷基和卤素。
本发明的一个更特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是烷氧基烷基或烷基。
本发明的一个此外特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是烷基。
本发明的另一个更特别的实施方案是如本文所述的根据式(I)的化合物,其中A1是-CH-或-N-。
本发明的另一个更特别的实施方案是如本文所述的根据式(I)的化合物,其中R2是H或烷基。
而且本发明的一个更特别的实施方案是如本文所述的根据式(I)的化合物,其中R3是H。
而且本发明的一个此外特别的实施方案是如本文所述的根据式(I)的化合物,其中R2和R3是H。
本发明的一个特别的实施方案是如本文所述的根据式(I)的化合物,其中R4是H、烷氧基羰基烷基、烷基、羧基烷基、环烷基或在氮原子上被一个H和一个烷基取代的氨基羰基烷基。
本发明的另一个特别的实施方案是如本文所述的根据式(I)的化合物,其中R5是H、烷氧基烷基、烷基、在氮原子上被两个独立地选自H和烷基的取代基取代的氨基羰基烷基。
本发明的另一个特别的实施方案是如本文所述的根据式(I)的化合物,其中R5是H、烷基,在氮原子上被两个独立地选自H和烷基的取代基取代的氨基羰基烷基。
本发明的一个此外特别的实施方案是如本文所述的根据式(I)的化合物,其中R4是H或烷基和R5是H。
而且本发明的一个实施方案是如本文所述的根据式(I)的化合物,其中R6是H。
本发明的另一个特别的实施方案是如本文所述的根据式(I)的化合物,其中R7、R8和R9是H。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R10是取代的苯基、取代的苯并间二氧杂环戊烯基、取代的异唑基、取代的二唑基或取代的吡啶基,其中取代的苯基、取代的苯并间二氧杂环戊烯基、取代的异唑基、取代的二唑基或取代的吡啶基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基和五氟-λ6-硫烷基。
本发明的一个更特别的实施方案是如本文所述的根据式(I)的化合物,其中R10是被一至三个选自H、卤素和氰基中的取代基取代的苯基。
本发明的一个实施方案是如本文所述的根据式(I)的化合物,其中R11是H和烷基。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中n为1并且m为1或2。
本发明的另一个特别的实施方案是如本文所述的根据式(I)的化合物,其中n和m为1。
本发明的一个特别的实施方案是如本文所述的根据式(I)的化合物,其中p为1。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R12和R13都是H。
本发明的一个特别的实施方案是如本文所述的根据式(I)的化合物,其中R14是H。
本发明的一个特别的实施方案是如本文所述的根据式(I)的化合物,其中A2是-C(O)-。
本发明的一个特别的实施方案是如本文所述的根据式(I)的化合物,其中A3是-CR8-。
本发明的一个此外特别的实施方案是如本文所述的根据式(I)的化合物,其中
R1是烷氧基烷基或烷基;
R2和R3是H;
A1是-CH-或-N-;
A2是-C(O)-;
R4是H或烷基并且R5是H;
或者R4和R5与它们连接的氮和碳原子一起形成杂环烷基;
R6是H;
R7、R8和R9是H;
R10是取代的芳基或取代的杂芳基,其中取代的芳基或取代的杂芳基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基、卤代烷基磺酰基和五氟-λ6-硫烷基;
R11是H、烷基或环烷基;
R12和R13都是H或R12和R13一起形成-(CH2)p-;
R14是H、烷基或羟基;
n、m和p独立地为零、1或2;
或药用盐。
如本文所述的式(I)的化合物的特别实例选自:
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-甲基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N,N-二甲基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-苯基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-甲基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N,N-二甲基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-(2-甲基丙基)-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-苯基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-苄基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-甲基-3-(4-硝基苯基)丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(6-氯吡啶-3-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(5-氯吡啶-2-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[1-(4-氯苯基)乙基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-(1,3-苯并二氧杂环戊烯-5-基甲基)乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[6-(三氟甲基)吡啶-3-基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(6-氰基吡啶-3-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-硝基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氟-3-(三氟甲氧基)苯基]甲基]乙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2,6-二氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2-甲氧基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氰基-2-(2,2,2-三氟乙氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氰基-2-甲基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2-氯吡啶-4-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-硝基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(五氟-λ6-硫烷基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-甲基-4-甲基磺酰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4,5-二氯吡啶-2-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-甲基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2,6-二氯吡啶-4-基)甲基]-N-甲基乙酰胺;
6-(4-乙酰基哌嗪-1-基)-3-[2-[2-(4-氯苯基)吡咯烷-1-基]-2-氧代乙基]喹唑啉-4-酮;
6-(4-乙酰基哌嗪-1-基)-3-[2-[(2R)-2-(4-甲基苯基)吡咯烷-1-基]-2-氧代乙基]喹唑啉-4-酮;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[2-(3,4-二氯苯基)乙基]乙酰胺;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(3,4-二氯苯基)-N-甲基丙酰胺;
甲基3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸甲酯;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]-N-甲基丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3,5-二氟苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-甲基丁酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-(4-戊酰基哌嗪-1-基)喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-甲氧基乙酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(2,2,2-三氟乙酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-[4-(环戊烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-[4-(环己烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-(4-丙酰基哌嗪-1-基)喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(2-甲基丙酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(3-氨基氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(2-氨磺酰基乙酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(4-氨磺酰基丁酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-氟环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3,3-二氟环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[4-[1-(三氟甲基)环丁烷羰基]哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(3-氯环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-甲氧基环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(3-甲基氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(1-乙酰基氮杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-丙-2-基哌嗪-1-甲酰胺;
N-环丙基-4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酰胺;
N-环戊基-4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-(2-甲氧基乙基)哌嗪-1-甲酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-吡啶-3-基哌嗪-1-甲酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-(4-甲基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-(4-环戊基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-环己基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-环丙基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-[4-(环丁基甲基磺酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-基]乙酸甲酯;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-羟基乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2,3-二羟基丙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[(1-甲基吡咯-2-基)甲基]哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(1H-咪唑-2-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(1H-咪唑-5-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
3-[[4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-基]甲基]呋喃-2-甲酸;
2-[6-[4-(环丙基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-甲氧基乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(氧杂环丁烷-3-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-[2-(甲基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[2-(二甲基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[4-[2-氧代-2-(丙-2-基氨基)乙基]哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[2-(二乙基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(2-吗啉-4-基-2-氧代乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(2-苯胺基-2-氧代乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(2-氯-4-氰基苯基)甲基]-2-[6-[4-(氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-乙基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-丙-2-基乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧基)苯基]甲基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-羟基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-甲氧基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(2-丙-2-基氧基乙酰基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(环丙烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-氟环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-氯环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3,3-二氟环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-[1-(氧杂环丁烷-2-羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-[1-(氧杂环丁烷-3-羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-(1-甲基磺酰基哌啶-4-基)-4-氧代喹唑啉-3-基]乙酰胺;
N-环丙基-N-[(3,4-二氯苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[2-乙酰基-2-氮杂二环[2.2.1]庚-5-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基丙酰胺;
1-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]环丙烷-1-甲酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-2-甲基-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-2,4-二氧代-1H-喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
及其药用盐。
而且如本文所述的式(I)的化合物的特别实例选自:
2-(6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3(4H)-基)-N-(1-(3,4-二氯苯基)-3-甲氧基丙基)乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(2-氰基乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(3-氰基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
4-(3-(2-((3-氯-4-氰基苄基)(甲基)氨基)-2-氧代乙基)-4-氧代-3,4-二氢喹唑啉-6-基)哌啶-1-甲酸甲酯;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(3-氯-5-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(4-氟-3-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(4-氯-3-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(3,5-二氯苄基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(2-氨磺酰基乙酰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-(2-甲氧基乙氧基)乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-2-甲基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(1-羟基环丁烷羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2,3-二羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(1-羟基环丙烷羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(四氢呋喃-2-羰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(6-(1-(2-甲基四氢呋喃-2-羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(四氢呋喃-3-羰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-#N!-[(3,4-二氯苯基)甲基]-#N!-甲基乙酰胺;
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-#N!-[(3-氯-4-氰基苯基)甲基]-#N!-甲基乙酰胺;
硝酸[2-[4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌啶-1-基]-2-氧代乙基]酯;
2-(6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3(4H)-基)-N-(3-氯-4-氰基苄基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(8-氟-6-(1-(3-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3(4H)-基)-N-(3-氯-4-氰基苄基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(3-甲氧基丙酰基)哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3(4H)-基)-N-甲基乙酰胺;
及其药用盐。
如本文所述的式(I)的化合物的此外特别实例选自:
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
及其药用盐。
用于制备如本文所述的式(I)化合物的方法是本发明的一个目的。
本发明的式(I)化合物的制备可以以顺序的或汇集的合成路线进行。本发明的合成显示在以下通用方案中。进行反应和所得产物的纯化所需的技能是本领域技术人员已知的。在反应过程中产生对映异构体或非对映异构体的混合物的情况下,可以通过本文描述的方法或者本领域技术人员已知的方法例如(手性)层析法或结晶法分离这些对映异构体或非对映异构体。以下方法的描述中使用的取代基和标志具有本文给出的含义。
通式(I)的化合物,其中R5是取代的氨基羰基烷基,可以在偶联剂存在下通过结构A(A1=N)的羧酸结构单元和胺1a之间的酰胺偶联反应制备,其中R15和R16独立地选自H、烷基、环烷基和取代的苯基,其中取代的苯基被一至三个独立地选自以下各项的取代基取代:H、烷基、卤代烷基和环烷基(方案1)。这种类型的酰胺偶联在文献(例如,ComprehensiveOrganic Transformations:A Guide to Functional Group Preparations,2ndEdition,Richard C.Larock,John Wiley&Sons,New York,NY.1999)中广泛描述并且对于本领域技术人员是熟知的。酰胺键形成可以通过使用适当偶联剂如O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲(uronium)四氟硼酸盐(TBTU)、1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-3-氧化物六氟磷酸盐(HATU)、N,N’-羰二咪唑(CDI)、N,N’-二环己基碳二亚胺(DCC)、N-(3-二甲基氨基丙基)-N’-乙基-碳二亚胺-盐酸盐(EDCI)、1-羟基-1,2,3-苯并三唑(HOBT)、2-氯-1-甲基吡啶碘化物(Mukaiyama试剂;E.Bald,K.Saigo,T.Mukaiyama,Chem.Lett.1975,4,1163-1166)或苯并三唑-1-基氧基三(二甲基氨基)六氟磷酸盐(BOP)实现。用于此转化的合适碱是二异丙基乙胺(DIPEA,Huenig’s碱)、三乙胺、N-甲基吗啉或4-(二甲基氨基)吡啶。反应在适当溶剂如例如N,N-二甲基甲酰胺(DMF)、二甲基乙酰胺(DMAc)、二氯甲烷和二烷或其混合物中在室温或升高的温度(典型地不超过150℃)下进行。由此,加热可以通过常规方式如通过利用油浴或优选地利用微波辐照实现。
方案1
通常,酰胺键形成反应可以使用分批或通过采用连续模式(流动)反应方案进行。连续模式合成使用定制、集成的流动合成和制备型HPLC纯化系统进行。将来自Vapourtec的商用R4流动反应器模块连接至制备型HPLC纯化系统,该纯化系统组装了Gilson LH 215自动取样器、两个Gilson819注射模块、两个Agilent 1100系列泵、一个Agilent 1200系列DADA检测器、两个Varian制备星泵(star pumps)、一个Dionex UV检测器、一个PolymerLaboratory光散射检测器和一个Dionex P-680泵。试剂和起始物料经由LH 215自动取样器注射到流动反应器试剂循环(Gilson 819注射模块)上并从那里注射到装配有100psi背压调节器(BPR)的PFA(全氟烷氧基聚合物)管式反应器盘管(10mL)上。为了在其进行通过流动反应器时限制分散作用和维持反应区内的一致浓度,在反应段前后注入小空气气泡。在流动反应完成之后,将粗反应混合物直接加载到制备型HPLC注射环上以进行HPLC纯化。纯化的化合物经由LH 215自动取样器收集。整个过程使用来自Dionex的色谱管理系统软件Chromeleon版本6.80来控制。集成的流动合成和纯化平台已描述于M.Werner,C.Kuratli,R.E.Martin,R.Hochstrasser,D.Wechsler,T.Enderle,A.I.Alanine,H.Vogel,Angew.Chem.Int.Ed.2014,53,1704-1708中。
备选地,通式(I)的化合物可以依照方案2a和2b中概括的顺序由结构B(A1=N)或C(A1=C)的羧酸结构单元制备。羧酸B或C与胺1a利用前述方法(方案2a,步骤a)的偶联和随后胺保护基(例如,PG=Fmoc、Boc)通过利用本领域技术人员熟知的标准方法的断裂(方案2a,步骤b)得到中间体3。随后胺3与适当衍生物的反应提供式(I)的化合物(方案2b)。与羧酸4的反应得到其中A2是-C(O)-的通式(I)化合物(方案2b,步骤c)。备选地,其中A2是-C(O)-的通式(I)的目标结构可以通过在适当溶剂如例如二氯甲烷或DMF和碱如例如二异丙基乙胺(DIPEA,Huenig’s碱)、三乙胺、N-甲基吗啉或4-(二甲基氨基)吡啶中偶联中间体3与酰氯5获得,从而这些反应可以在范围为环境温度至所采用溶剂的回流温度的宽温度范围内发生(方案2b,步骤d)。
方案2a
方案2b
如果需要,通过在催化量的DMF存在下,用例如亚硫酰氯或草酰氯处理,酰氯5可以由羧酸4制备。另一种得到其中A2是-C(O)-的式(I)化合物的方法是羧酸酐[(R1-C=O)2O]与胺3在适当溶剂如例如二氯甲烷或DMF中在碱如例如二异丙基乙胺(DIPEA,Huenig’s碱)、三乙胺、N-甲基吗啉或4-(二甲基氨基)吡啶存在下反应,所有方法对于本领域技术人员是熟知的。备选地,通式(I)的目标结构可以由羧酸烷基酯(例如,方案3中的化合物14,其是结构单元B的甲基酯,其中PG=乙酰基)和胺1a通过在溶剂如THF中并在升高的温度下加热,例如用二(三甲基铝)或二(三甲基铝)-1,4-二氮杂二环[2.2.2]辛烷加合物处理而获得。
其中A2是-S(O)2-的通式(I)化合物可以通过采用典型的溶剂如例如二氯甲烷、DMF或THF在碱如例如二异丙基乙胺(DIPEA,Huenig’s碱)、三乙胺、N-甲基吗啉或4-(二甲基氨基)吡啶存在下、在0℃至溶剂的沸点的温度下,利用常规加热方法或通过微波辐照由中间体3和磺酰氯6制备(方案2b,步骤e)。
其中A2是-NR11C(O)-并且R11是H的通式(I)化合物,可以通过采用典型的溶剂如例如二氯甲烷或THF在0℃至溶剂的沸点的温度下,利用常规加热方法或通过微波辐照由结构3的胺和异氰酸酯7制备(方案2b,步骤f)。
其中A2是-CH2-的通式(I)化合物可以在一个步骤程序中在溶剂如甲醇、乙醇、异丙醇或THF中在催化量的酸如乙酸存在下,优选地在大约室温至溶剂的回流温度下,通过用合适还原剂如NaBH4、LiBH4、NaBH3CN或NaBH(OAc)3处理,由结构3的胺和醛8a或酮8b通过还原胺化程序(例如,Leuckart-Wallach反应)制备(方案2b,步骤g)。备选地,反应也可以在两个步骤程序中进行,即通过首先在异丙醇钛(IV)存在下,在没有另外的溶剂的情况下,在0℃至室温下或者在溶剂如甲醇或甲苯中,优选地在环境温度至所采用溶剂的回流温度之间的温度下,用胺3处理醛8a或酮8b,并且随后添加还原剂如NaBH4,优选地在0℃至室温下进行。
在另一个实施方案中,其中A2是-CH2-的通式(I)化合物可以在碱如氢化钠或碳酸钾存在下,在适当溶剂如DMF、乙腈或THF或其混合物中,在室温至升高的温度下,通过用烷基卤9(例如,2-溴乙酸甲酯或溴甲基环丙烷)烷基化中间体3得到(方案2b,步骤h)。通式(I)的目标化合物可以通过经典手段如二氧化硅柱色谱、MPLC或制备型HPLC纯化。
通式结构B的羧酸结构单元的合成可以如方案3中所概述地实现。利用之前讨论的方法,羧酸10(例如,PG=Fmoc;如US2010/0069307A1第9页中所述制备)和适当保护的氨基酸(例如,PG1=甲基、乙基、叔丁基)如11(例如,甘氨酸甲酯,2-氨基乙酸叔丁酯)之间的酰胺偶联反应得到通式结构12的酰胺(方案3,步骤a)。利用本领域技术人员已知的的典型标准程序(例如,Zn、HCl;SnCl2·2H2O、HCl或HOAc),化合物12中的硝基的还原提供类型13的邻氨基苯甲酸(方案3,步骤b)。化合物12与例如原甲酸三甲酯(R14=H)在乙酸存在下、在环境至升高的温度下反应(方案3,步骤c),接着通过利用本领域已知的方法使喹唑啉酮14的羧酸保护基(例如,PG1=甲基、乙基、叔丁基)断裂,得到通式结构B的喹唑啉酮结构单元(方案3,步骤d)。在另一个实施方案中,另外的通式结构B的喹唑啉酮结构单元采用类似反应顺序,用例如原乙酸三甲酯(R14=CH3)或N,N’-羰二咪唑(R14=OH)代替原甲酸三甲酯来制备(方案3,步骤d)。
方案3
通式结构A的羧酸结构单元的合成可以如方案4中所述实现。通过本领域技术人员已知的方法使胺保护基(例如,PG=Fmoc、Boc)断裂得到类型15的喹唑啉酮结构单元(方案4,步骤a),其采用之前讨论的方法通过与羧酸偶联生成羧酸中间体16(方案4,步骤b)。利用标准酰胺偶联方法,化合物16与适当保护(例如,苄酯)的氨基酸17反应,得到通式结构18的酰胺(方案4,步骤c)。
方案4
通过利用本领域技术人员熟知的标准方法,除去保护基得到通式结构A的喹唑啉酮结构单元(方案4,步骤d)。
通式结构C的羧酸结构单元的制备可以如方案5中概述的实现。利用之前讨论的方法,羧酸19(例如,X=Br、I、OTf)和适当保护的氨基酸(例如,PG1=甲基、乙基、叔丁基)如11(例如,甘氨酸甲酯,2-氨基乙酸叔丁酯)之间的酰胺偶联反应,得到通式结构20的酰胺(方案5,步骤a)。在钯(0)或镍(0)催化(例如,Pd(OAc)2、Pd(PPh3)4、PdCl2(dppf)、NiCl2(dppf))下并且在合适配体(例如,PPh3、JohnPhos、Xphos、dppf;参见:R.Martin,S.L.Buchwald,Acc.Chem.Res.2008,41,1461-1473)存在下、在典型的溶剂如例如二烷、THF、1,2-二甲氧基乙烷和水或其混合物中、在碱如例如碳酸钾、碳酸钠或磷酸钾存在下、在0℃至溶剂的沸点的温度下,利用常规加热方法或通过微波辐照,芳基化合物20和类型21的硼酸或硼酸烷基酯(PG=Fmoc、Boc)之间的Suzuki-Miyaura反应(N.Miyaura,K.Yamada,A.Suzuki,Tetrahedron Lett.1979,20,3437-3440;N.Miyaura,A.Suzuki,Chem.Rev.1995,95,2457-2483),得到通式类型22的偶联产物(方案5,步骤b)。如果需要,该反应可以以这样的方式调整,即通过小心选择反应条件(例如,碱的性质,溶剂,反应温度和时间),可以实现化合物22中的羧酸保护基(例如,PG1=甲基、乙基)的同时水解。通过利用本领域技术人员熟知的的方法如例如氢化(例如,H2、Pd/C),化合物22中的烯烃和硝基基团的伴随还原,得到喹唑啉酮中间体23(方案5,步骤c)。在乙酸存在下、在环境至升高的温度下,苯胺化合物23用例如原甲酸三甲酯(R14=H)处理(方案5,步骤d),接着通过利用本领域已知的方法使喹唑啉酮24的羧酸保护基(例如,PG1=甲基、乙基、叔丁基)断裂,得到喹唑啉酮25(方案5,步骤e)。最后,将保护基PG切换为pG2得到通式结构C的结构单元(方案5,步骤f)。
方案5
不可商购获得的其中R10是取代的芳基并且R5和R6是H的胺1b,可以如方案6中所述制备。通过利用例如N-氯代琥珀酰亚胺或N-溴代琥珀酰亚胺,在溶剂如四氯化碳和自由基引发剂如过氧苯甲酰或偶氮二异丁腈(AIBN)中并且在用UV光(例如,λ=365nm)辐照下,在0℃至溶剂的沸点的温度下,用氯或溴对化合物26的自由基取代,得到类型27的苄基卤(X=Cl、Br)(方案6,步骤a)。在适当溶剂如DMF、乙腈或THF或其混合物中,在室温至升高的温度下,化合物27用通式结构28的胺处理得到通式结构1的苄基胺(方案6,步骤b)。备选地,采用之前讨论的对本领域技术人员熟知的方法,通过用胺29的还原性胺化程序,化合物1b可以由苯甲醛28获得。
方案6
此外,本发明的一个实施方案是一种用于在式(VII)的化合物存在下制备式(VI)化合物的化合物方法,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、A1、A3、n和m如权利要求1至25中任一项所定义并且A2是-C(O)-。
特别地,在偶联剂如1,1′-羰二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-六氟磷酸盐存在下,特别是在O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐存在下,在疏质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,特别是在N,N-二甲基甲酰胺中,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下,特别是在存在4-甲基吗啉的情况下,在-78℃至回流的温度,特别是在-10℃至室温的温度进行。
此外,本发明的一个目的是如本文所述的根据式(I)化合物,所述化合物用作治疗活性物质。
同样,本发明的一个目的是一种药物组合物,所述药物组合物包含如本文所述的根据式(I)化合物和治疗惰性载体。
本发明的一个特别实施方案是如本文所述的根据式(I)的化合物,其用于治疗或预防眼病症,特别是青光眼。
本发明还涉及如本文所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防眼病症,特别是青光眼。
此外,本发明的一个目的是一种用于治疗或预防眼病症,特别是青光眼的方法,该方法包括给药有效量的如本文所述的根据式(I)的化合物。
肾脏病症包括,但是不限于,包括末期肾病(ESRD)在内的伴有或不伴有蛋白尿症(proteinuria)的急性肾损伤(kidney injury)和慢性肾病(renal disease)。更详细地,这包括降低的肌酸酐清理和降低的肾小球过滤速率,微白蛋白尿(micro-albuminuria),白蛋白尿(albuminuria)和蛋白尿症(proteinuria),具有伴有或不伴有明显细胞过多(hypercellularity)的网状系膜基质扩增(expansion of reticulated mesangialmatrix)的肾小球硬化症(glomerulosclerosis)(特别是糖尿病性肾病(diabeticnephropathy)和淀粉样变性(amyloidosis)),肾小球毛细管的局灶性血栓形成(focalthrombosis)(特别是血栓形成性微血管病(thrombotic microangiopathies)),整体性纤维蛋白样坏死(global fibrinoid necrosis),缺血性损害(ischemic lesions),恶性肾硬化症(malignant nephrosclerosis)(如缺血性缩回(ischemic retraction)、降低的肾血流量和肾动脉病(arteriopathy)),如同在肾小球肾炎病种(glomerular nephritisentities)中的毛细血管内(内皮和系膜)和/或毛细血管外细胞(新月体)的肿胀和增殖,局灶性节段性肾小球硬化症(focal segmental glomerular sclerosis),IgA肾病,血管炎(vasculitides)/系统性疾病(systemic diseases)以及急性和慢性肾移植排斥反应。
肝脏病症包括,但是不限于,肝硬变(liver cirrhosis),肝充血(hepaticcongestion),包括瘙痒症在内的胆汁淤积性肝脏病症,非酒精性脂肪肝炎(nonalcoholicsteatohepatitis)以及急性和慢性肝移植排斥反应。
炎性病症包括,但是不限于,关节炎(arthritis),骨关节炎(osteoarthritis),多发性硬化(multiple sclerosis),全身性红斑狼疮(systemic lupus erythematodes),炎性肠病(inflammatory bowel disease),反常排泄紊乱(abnormal evacuation disorder)等,以及炎性气道疾病如特发性肺纤维变性(idiopathic pulmonary fibrosis)(IPF),慢性阻塞性肺病(chronic obstructive pulmonary disease)(COPD)或慢性支气管哮喘(asthma bronchiale)。
其他呼吸系统病症包括,但是不限于,其他不同病因的弥散性实质性肺疾病(diffuse parenchymal lung diseases),包括医源性药物引起的纤维变性,职业和/或环境引起的纤维变性,系统性疾病和血管炎,肉芽肿疾病(granulomatous diseases)(结节病(sarcoidosis)、超敏性肺炎(hypersensitivity pneumonia)),胶原血管疾病(collagenvascular disease),肺泡蛋白沉积症(alveolar proteinosis),朗格汉斯细胞肉芽肿病(Langerhans cell granulomatosis),淋巴管平滑肌瘤病(lymphangioleiomyomatosis),遗传疾病(赫曼斯基-普德拉克综合征(Hermansky-Pudlak Syndrome)、结节性硬化(tuberous sclerosis)、纤维神经瘤(neurofibromatosis)、代谢存储障碍(metabolicstorage disorders)、家族性间质性肺病(familial interstitial lung disease)),辐射引起的纤维变性,矽肺病,石棉引起的肺纤维变性(pulmonary fibrosis)或急性呼吸窘迫综合征(acute respiratory distress syndrome)(ARDS)。
神经系统病症包括,但是不限于,神经痛(neuropathic pain),精神分裂症(schizophrenia),神经炎症(neuro-inflammation)(例如,星形胶质细胞增生(astrogliosis)),外部和/或自发的(糖尿病)神经病(neuropathies)等。
血管病症包括,但是不限于,动脉粥样硬化(atherosclerosis),血栓形成性血管疾病(thrombotic vascular disease)以及血栓形成性微血管病(thromboticmicroangiopathies),增生性动脉病(proliferative arteriopathy)(如被粘蛋白的细胞外基质包围的肿胀肌内膜细胞和小结增厚),动脉粥样硬化(atherosclerosis),降低的血管顺应性(如刚性、降低的腔室顺应性和降低的血管顺应性),内皮机能障碍(endothelialdysfunction)等。
心血管病症包括,但是不限于,急性冠状动脉综合征(acute coronarysyndrome),冠心病(coronary heart disease),心肌梗死(myocardial infarction),动脉的和肺部的高血压(hypertension),心率失常(cardiac arrhythmia)如心房颤动(atrialfibrillation),卒中(stroke)及其他血管损伤。
纤维变性疾病包括,但是不限于心肌和血管纤维变性,肾纤维变性,肝纤维变性,肺纤维变性,皮肤纤维变性,硬皮病(scleroderma)和被囊性腹膜炎(encapsulatingperitonitis)。
癌症和癌症转移包括,但是不限于,乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤(mesothelioma)、神经胶质瘤(glioma)、肝癌、肠胃癌和它们的进展和转移性侵占(metastatic aggressiveness)。
眼病症包括,但是不限于,增殖性和非增殖性(糖尿病)视网膜病(retinopathy)、干性和湿性老年黄斑退化(age-related macular degeneration)(AMD)、黄斑水肿(macular edema)、主动脉/静脉闭塞(central arterial/venous occlusion)、外伤性损伤、青光眼(glaucoma)等。特别地,所述眼病症是青光眼。
代谢病症包括,但是不限于,肥胖症和糖尿病。
此外,本发明的一个实施方案是根据所述方法中任一种制备的如本文所述的式(I)化合物。
测定步骤
具有和不具有HIS标记的人全长ATX的制备
自分泌运动因子(ATX-ENPP2)克隆:cDNA由商用人造血细胞总RNA制备,并且在重叠PCR中用作模板以产生具有或不具有3’-6xHis标记的全长人ENPP2ORF。将这些全长插入物克隆到pcDNA3.1V5-HisTOPO(Invitrogen)载体中。检验若干个单克隆的DNA序列。来自正确全长克隆的DNA用于转染Hek293细胞以检验蛋白表达。编码ENPP2的序列符合Swissprot条目Q13822,具有或不具有额外的C-末端6xHis标记。
ATX发酵:通过在20L受控的搅拌槽生物反应器(Sartorius)中大规模瞬时转染制备重组的蛋白。在细胞生长和转染期间,将温度、搅拌速度、pH和溶解氧浓度分别保持在37℃、120rpm、7.1和30%DO。在FreeStyle293培养基(Invitrogen)中悬浮培养FreeStyle293-F细胞(Invitrogen),并使用X-tremeGENE Ro-1539(商品,Roche Diagnostics)作为复合剂以约1-1.5x 10E6细胞/mL用上述质粒DNAs转染。将细胞进料至浓缩的营养液(J.Immunol.Methods 1996,194,1-199(第193页))并在转染后72h由丁酸钠(2mM)诱导及在转染后96h收获。表达通过Western Blot、酶测定和/或分析型IMAC层析分析。在将细胞悬浮液在流通式热交换器冷却至4℃之后,通过经过Zeta Plus 60M02E16(Cuno)和Sartopore2XLG(Sartorius)过滤单元的过滤,进行细胞分离和上清液的无菌过滤。在纯化之前,将上清液在4℃储存。
ATX纯化:通过添加Brij 35至0.02%的最终浓度和通过使用1M HCl调节pH至7.0,调节20L的培养物上清液用于超滤。随后首先将上清液经过0.2μm Ultran-Pilot OpenChannel PES过滤器(Whatman)微过滤,随后通过具有30kDa MWCO的Ultran-Pilot ScreenChannel PES过滤器(Whatman)浓缩至1L。在IMAC层析之前,加入NiSO4至1mM的最终浓度。随后将清澈了的上清液施加至预先在50mM Na2HPO4pH 7.0、0.5M NaCl、10%甘油、0.3%CHAPS、0.02%NaN3中平衡的HisTrap柱(GEHealthcare)。分别用相同的含有20mM、40mM和50mM咪唑的缓冲液分步洗涤该柱。随后使用线性梯度至0.5M咪唑,以15柱体积洗脱蛋白。使用配备有30kDa PES过滤膜的Amicon池将含有ATX的级分汇集并浓缩。随后在Superdex S-200制备级(XK 26/100;GE Healthcare)上,在20mM BICINEpH8.5、0.15M NaCl、10%甘油、0.3%CHAPS、0.02%NaN3中,通过尺寸排阻层析将蛋白进一步纯化。在纯化后蛋白的最终收率为5-10mg ATX/升培养物上清液。将蛋白在-80℃储存。
人ATX酶抑制测定
使用特别标记的底物模拟物(MR121底物),通过荧光猝灭测定,测量ATX抑制。为了获得此MR121底物,用MR121荧光团[CAS RN185308-24-1]、1-(3-羧基丙基)-11-乙基-1,2,3,4,8,9,10,11-八氢-二吡啶并[3,2-b:2’,3’-i]吩嗪-13-)在乙醇胺侧的游离胺上标记BOC和TBS保护的6-氨基-己酸(R)-3-({2-[3-(2-{2-[2-(2-氨基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰氨基]-乙氧基}-羟基-磷酰氧基)-2-羟基-丙酯(Ferguson等,Org.Lett.2006,8,2023),并随后,在脱保护后,接着用色氨酸在氨基己酸侧上标记。
测定工作溶液如下制备:
测定缓冲液(50mM Tris-HCl、140mM NaCl、5mM KCl、1mMCaCl2、1mM MgCl2、0.01%Triton-X-100、pH 8.0;
ATX溶液:ATX(人His-标记的)储备溶液(1.08mg/mL,在20mMN-二(羟乙基)甘氨酸中,pH 8.5、0.15M NaCl、10%甘油、0.3%CHAPS、0.02%NaN3),在测定缓冲液中稀释至1.4-2.5x最终浓度;
MR121底物溶液:MR121底物储备溶液(800μM MR121底物,在DMSO中),在测定缓冲液中稀释至2-5x最终浓度。
在384孔样品板(Corning Costar#3655)中获得测试化合物(10mM储备,在DMSO中,8μL),并用8μL DMSO稀释。通过将8μL化合物溶液转移至下一行直至第O行,进行逐行地连续稀释。将化合物和对照溶液混合五次,并将2μL转移至384孔测定板(Corning Costar#3702)。随后,添加15μL的41.7nM ATX溶液(30nM最终浓度),混合五次并随后在30℃温育15分钟。添加10μL的MR121底物溶液(1μM最终浓度),混合30次,随后在30℃温育15分钟。随后每2min测定荧光,持续1h(Perkin Elmer板:视觉多模态读出装置);光强度:2.5%;暴露时间:1.4s,过滤器:Fluo_630/690nm),且从这些读数计算IC50值。
本文所述的式(I)化合物和它们的药用盐或酯具有0.00001μM至1000μM之间的IC50值,特别的化合物具有0.0005μM至500μM之间的IC50值,进一步特别的化合物具有0.0005μM至50μM之间的IC50值,更特别的化合物具有0.0005μM至5μM的IC50值。这些结果已经通过使用上述酶测定获得。
式(I)化合物及其药用盐可以用作药物(例如以药物制剂的形式)。药物制剂可以以下列方式内部给药:如经口(例如以片剂,包衣片剂,糖衣丸,硬和软明胶胶囊,溶液剂,乳剂或混悬剂的形式),经鼻(例如以鼻喷雾的形式)或经直肠(例如以栓剂的形式)或局部经眼部(例如以溶液,软膏,凝胶或水溶性聚合物插入物的形式)。然而,给药也可以在肠胃外实现,如肌肉内、静脉内或眼内(例如以无菌注射液的形式)。
式(I)化合物及其药用盐可以用药物惰性的、无机或有机辅料处理,用于制备片剂、包衣片剂、糖衣丸、硬明胶胶囊、注射液或局部制剂。例如可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等作为这样的用于片剂、糖衣丸和硬明胶胶囊的辅料。
合适的用于软明胶胶囊的辅料是例如植物油、蜡、脂肪、半固体物质和液体多元醇等。
合适的用于制备溶液剂和糖浆剂的辅料是例如水、多元醇、蔗糖、转化糖、葡萄糖等。
合适的用于注射液的辅料是例如水、醇、多元醇、甘油、植物油等。
合适的用于栓剂的辅料是例如天然或硬化油、蜡、脂肪、半固体或液体多元醇等。
合适的用于局部眼部制剂的辅料是例如环糊精、甘露醇或本领域中已知的许多其他载体和赋形剂。
此外,药物制剂可以含有防腐剂、增溶剂、增粘物质、稳定剂、润湿剂、乳化剂、增甜剂、着色剂、香料、用于调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它有治疗价值的物质。
剂量可以在宽范围内变化,并且当然将适合每种特定情况下的个体需求。通常,在经口给药的情况下,每kg体重为约0.1mg至20mg、优选每kg体重为约0.5mg至4mg(例如每人约300mg)的每日剂量,优选分成1-3个可以例如由相同量组成的单个剂量,其应当是适合的。在局部给药的情况中,制剂可以包含0.001重量%至15重量%的药物,并且所需剂量(可以为0.1至25mg)可以通过每天或每周单次剂量给药,或通过每天多次剂量(2至4)给药,或通过每周多次剂量给药。然而,将清楚的是,当明确指示时,可以超过本文给出的上限或下限。
以下通过非限制性的实施例阐明本发明。
在制备实施例是作为对映异构体混合物的形式获得的情况下,可以通过本文中描述的方法或本领域技术人员已知的方法诸如例如手性层析法或结晶来获得纯的对映异构体。
实施例
如果不另外规定,所有实施例和中间体都在氮气氛下制备。
CDI=N,N’-羰二咪唑[CAS RN 530-62-1],DCC=N,N’-二环己基碳二亚胺[CAS RN538-75-0],DCM=二氯甲烷,DIPEA=二异丙基乙胺=iPr2NEt=N-乙基二异丙胺=Huenig’s碱,DMF=N,N-二甲基甲酰胺,dppf=1,1′-二(二苯基膦基)二茂铁[CAS RN 12150-46-8],EtOAc=乙酸乙酯,h=小时,HATU=1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-3-氧化物六氟磷酸盐[CAS RN148893-10-1],HOBT=1-羟基-1,2,3-苯并三唑[CASRN 123333-53-9],HPLC=高效液相色谱,MPLC=中压液相色谱,MS=质谱,NaBH3CN=氰基硼氢化钠,NaBH(OAc)3=三乙酰氧基硼氢化钠,NH4OAc=乙酸铵,OAc=乙酸根或盐或酯,PFA=全氟烷氧基聚合物,Ph=苯基,PYBOP=(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐[CAS RN 128625-52-5],rt=室温,TBTU=O-苯并三唑-1-基-N,N,N’,N’-四甲基脲四氟硼酸盐[CAS RN 125700-67-6],THF=四氢呋喃。
中间体A-1
2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸
[A]2-硝基-5-哌嗪-1-基苯甲酸
将5-氯-2-硝基苯甲酸(5.0g,24.87mmol;[CAS RN 2516-95-2])和哌嗪(5.34g,62.19mmol;[CAS RN 110-85-0])在DMF(10mL)中的混合物在110℃加热6h。将反应混合物冷却至室温,接着将冰水(50mL)加入到反应混合物中并在室温搅拌15min。沉淀的固体通过过滤收集,用水(3x 50mL)洗涤并在真空下干燥。获得标题化合物,为黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(4.3g,69%)。MS:m/e=252.1[M+H]+。
[B]5-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-2-硝基苯甲酸
在0℃,向2-硝基-5-哌嗪-1-基苯甲酸(4.0g,15.94mmol)在二烷(40mL)和10%NaHCO3水溶液(30mL)中的悬浮液中逐滴加入在二烷(40mL)中的氯甲酸9-芴基甲酯(4.4g,16.73mmol;[CAS RN 28920-43-6])持续15min。将所得混合物在室温搅拌20h。将粗反应混合物在减压下浓缩并在水(50mL)和EtOAc(50mL)之间分配。将有机相分离并将水相用EtOAc(2x 50mL)萃取。之后,将水相通过加入35%浓HCl(2.0mL)中和以得到固体沉淀。获得的固体通过过滤收集,接着用水(2x 25mL)洗涤并在真空下干燥。获得标题化合物,为黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(4.8g,62%)。MS:m/e=474.2[M+H]+。
[C]4-[3-[[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]氨基甲酰基]-4-硝基苯基]
哌嗪-1-甲酸9H-芴-9-基甲酯
在氮气气氛下,向5-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-2-硝基苯甲酸(4.5g,9.53mmol)在DMF(50mL)中的溶液中加入TBTU(5.4g,14.30mmol;[CAS RN 125700-67-6])和DIPEA(4.0mL,28.60mmol)。然后,加入2-氨基乙酸叔丁酯(1.87g,14.30mmol;[CASRN 6456-74-2])并将反应混合物在室温搅拌18h。将冰水(50mL)加入到反应物料中并在室温搅拌30min。沉淀出来的固体通过过滤收集,接着用水(3x 50mL)洗涤并在真空下干燥。获得标题化合物,为浅黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(3.0g,54%)。MS:m/e=587.0[M+H]+。
[D]4-[4-氨基-3-[[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]氨基甲酰基]苯基]
哌嗪-1-甲酸9H-芴-9-基甲酯
向4-[3-[[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]氨基甲酰基]-4-硝基苯基]哌嗪-1-甲酸9H-芴-9-基甲酯(2.75g,4.69mmol)在乙酸(25mL)中的搅拌溶液中在10min内分批加入锌粉(1.5g,23.46mmol;[CAS RN:7440-66-6]),然后在室温剧烈搅拌6h。反应混合物通过过滤,接着用乙酸(2x10mL)洗涤。将滤液在减压下浓缩,得到粘性液体,将其在水(25mL)和EtOAc(25mL)之间分配。水相用EtOAc(2x 25mL)萃取,合并的有机相用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用40%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为灰白色固体(1.3g,50%)。MS:m/e=557.2[M+H]+。
[E]4-[3-[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-
1-甲酸9H-芴-9-基甲酯
在氮气气氛下,将4-[4-氨基-3-[[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]氨基甲酰基]苯基]哌嗪-1-甲酸9H-芴-9-基甲酯(1.2g,2.16mmol)和原甲酸三乙酯(5mL,30.1mmol;[CAS RN 122-51-0])在EtOH(5mL)中的混合物在油浴中加热至80℃持续12h。将反应混合物冷却至室温并在减压下浓缩。将粗反应产物在水(25mL)和EtOAc(25mL)之间分配并将水相用EtOAc(2x 25mL)萃取。合并的有机相用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用50%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为灰色固体(0.75g,61%)。MS:m/e=567.2[M+H]+。
[F]2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中
间体A-1;[CAS RN 269078-82-2])
向4-[3-[2-[(2-甲基丙-2-基)氧基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(0.6g,1.06mmol)在二烷(2.5mL)中的搅拌溶液中加入在二烷中的4M HCl(10mL)并将反应混合物在室温搅拌8h。将溶剂在减压下除去,加入10%NaHCO3溶液的水溶液(25mL)并将反应用EtOAc(3x 25mL)萃取。之后水相通过加入35%浓HCl(0.5mL)中和并用在DCM(3x 25mL)中的5%甲醇进行萃取。合并的有机相用无水Na2SO4干燥并在减压下浓缩,得到标题化合物,为灰白色固体(0.36g,66%)。MS:m/e=511.2[M+H]+。
中间体A-2
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸
在0℃,在氮气气氛下,向2-(4-氧代-6-哌嗪-1-基喹唑啉-3-基)乙酸(5.0g,17.34mmol;[CAS RN 889958-08-1])在DCM(100mL)中的悬浮液中加入三乙胺(6.02mL,43.40mmol)。将反应混合物在0℃搅拌15min,然后在0℃缓慢地加入乙酸酐(1.97mL,20.83mmol)并将反应混合物在室温搅拌4h。在反应完成之后,将溶剂在减压下浓缩至最小体积(30mL)并且将获得的固体过滤并用己烷洗涤。分离标题化合物,为灰白色固体(5.44g,95%)。MS:m/e=331.2[M+H]+。
中间体A-3
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯-苯基)丙酸
[A](3R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯
在室温,在氮气气氛下,向(R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]丙酸(1.0g,3.34mmol;[CAS RN 479064-93-2])在DCM(20mL)中的溶液中加入EDC·HCl(1.08g,5.65mmol)和HOBt(0.76g,5.65mmol)。然后,加入DIPEA(1.97mL,11.30mmol)并将反应混合物在室温搅拌30min,接着加入苄醇(0.49mL,4.71mmol)。在搅拌16h之后,加入水(100mL)并将反应混合物用DCM(2x 100mL)萃取。合并的有机相用水(50mL)、饱和氯化钠水溶液(50mL)洗涤,用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用10%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为白色固体(0.7g,54%)。MS:m/e=390.4[M+H]+。
[B](3R)-3-氨基-3-(4-氯苯基)丙酸苄酯盐酸盐
在0℃,在Ar气氛下,向(R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]-丙酸苄酯(0.7g,1.80mmol)中加入HCl(15mL,4.0M溶液,在二烷中)。将反应混合物在室温搅拌4h,然后在减压下浓缩。将获得的固体过滤并用无水二乙醚洗涤。分离标题化合物,为白色固体(0.51g,87%),并在未经进一步纯化下用于连续反应步骤。MS:m/e=290.1[M+H]+。
[C](3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-
3-(4-氯苯基)丙酸苄酯
在室温,在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(0.63g,1.91mmol)在无水DMF(10mL)中的溶液中加入EDC·HC1(0.50g,2.61mmol)和HOBt(0.35g,2.61mmol)。然后,加入DIPEA(0.91mL,5.22mmol)并将反应混合物在室温搅拌30min,接着加入(R)-3-氨基-3-(4-氯苯基)丙酸苄酯盐酸盐(0.50g,1.73mmol)。在搅拌16h之后,反应混合物通过加入至冰猝灭并且沉淀用冰冷水(3x30mL)、二乙醚(3x 30mL)和己烷(2x 30mL)洗涤。获得标题化合物,为灰白色固体(0.75g,65%)。MS:m/e=602.2[M+H]+。
[D](3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-
3-(4-氯苯基)丙酸(中间体A-3)
向(R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸苄酯(0.50g,0.83mmol)在EtOAc(40mL)中的脱气溶液中加入10%Pd/C(0.040g,0.038mmol)并将反应混合物在氢气(大气压力)下、在室温搅拌4h。反应混合物通过使用乙醇过滤,有机相在真空下浓缩并且固体材料通过用二乙醚(3x 20mL)和DCM(1x 30mL)洗涤纯化。获得标题化合物,为灰白色固体(0.23g,54%),并在未经进一步纯化下用于连续反应步骤。MS:m/e=512.3[M+H]+。
中间体A-4
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-[4-(三氟甲基)苯基]丙酸
[A](3R)-3-[(2-甲基丙-2-基)氧基羰基氨基]-3-[4-(三氟甲基)苯基]-丙酸苄酯
类似于用于制备(R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯(中间体A-3,步骤A)所述的程序,用(R)-3-[(2-甲基丙-2-基)氧基羰基氨基]-3-[4-(三氟甲基)苯基]丙酸(1.0g,3.00mmol;[CAS RN501015-19-6])代替(R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]丙酸,制备标题化合物。通过柱色谱(100-200目径硅胶),使用10%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为白色固体(1.11g,87%)。MS:m/e=424.2[M+H]+。
[B](3R)-3-氨基-3-[4-(三氟甲基)苯基]丙酸苄酯盐酸盐
类似于用于制备(R)-3-氨基-3-(4-氯苯基)丙酸苄酯盐酸盐(中间体A-3,步骤B)所述的程序,用(R)-3-[(2-甲基丙-2-基)氧基羰基氨基]-3-[4-(三氟甲基)苯基]丙酸苄酯(1.11g,2.62mmol)代替(R)-3-(4-氯苯基)-3-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯,制备标题化合物。分离标题化合物,为白色固体并在未经进一步纯化下用于连续反应步骤(0.84g,89%)。MS:m/e=324.2[M+H]+。
[C](3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-
3-[4-(三氟甲基)苯基]丙酸苄酯
类似于用于制备(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸苄酯(中间体A-3,步骤C)所述的程序,用(3R)-3-氨基-3-[4-(三氟甲基)苯基]丙酸苄酯盐酸盐(0.84g,2.60mmol)代替(3R)-3-氨基-3-(4-氯苯基)丙酸苄酯盐酸盐,制备标题化合物。获得标题化合物,为灰白色固体(1.40g,77%)。MS:m/e=636.2[M+H]+。
[D](3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-
3-[4-(三氟甲基)苯基]丙酸(中间体A-4)
类似于用于制备(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸(中间体A-3,步骤D)所述的程序,用(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-[4-(三氟甲基)苯基]丙酸苄酯(0.70g,1.10mmol)代替(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸苄酯,制备标题化合物。在真空下浓缩有机相之后,固体材料通过用DCM(3x 30mL)和己烷(2x 20mL)洗涤纯化。获得标题化合物,为黄色固体(0.30g,50%),并在未经进一步纯化下用于连续反应步骤。MS:m/e=546.2[M+H]+。
中间体A-5
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN 269078-82-2])(3.0g,5.88mmol)在无水DMF(30mL)中的溶液中加入PYBOP(3.1g,5.88mmol;[CASRN 128625-52-5])和DIPEA(1.23mL,7.05mmol)。然后,加入(3,4-二氯苯基)甲胺(1.24g,7.05mmol;[CAS RN 102-49-8])并将反应混合物在室温搅拌2h。加入庚烷(100mL),将白色沉淀滤出,固体材料用庚烷(50mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体,并在未经进一步纯化下直接用于连续反应步骤中(2.20g,56%)。MS:m/e=670.6[M+H]+。
中间体A-6
4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN 269078-82-2])(0.75g,1.47mmol)在DCM(20mL)中的溶液中加入TBTU(0.71g,2.21mmol;[CAS RN125700-67-6])和DIPEA(0.77mL,4.41mmol)。然后,加入1-(3,4-二氯苯基)-N-甲基甲胺(0.31g,1.62mmol;[CAS RN 5635-67-6])并将反应混合物在室温搅拌2h。加入庚烷(100mL),将白色沉淀滤出,固体材料用庚烷(50mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体,并在未经进一步纯化下直接用于连续反应步骤中(0.85g,85%)。MS:m/e=683.3[M+H]+。
中间体A-7
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸甲酯
[A]5-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酸
将5-氯-2-硝基苯甲酸(2.0g,9.95mmol;[CAS RN 2516-95-2]和1-哌嗪-1-基乙酮(6.1g,47.7mmol;[CAS RN 13889-98-0])中的混合物在110℃加热18h。然后,将反应混合物冷却至室温,并保持温度在10℃将剩余物通过加入50%NaOH水溶液(6.0mL)碱化至pH 10-12。向澄清溶液中加入35%HCl水溶液(1.3mL),形成的沉淀通过过滤分离,将固体材料用EtOAc(2x 20mL)洗涤并在高真空下干燥。获得标题化合物,为浅黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(1.5g,51%)。MS:m/e=294.1[M+H]+。
[B]2-[[5-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酰基]氨基]乙酸甲酯
在室温,在氮气气氛下,向5-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酸(0.7g,2.39mmol)在无水DMF(10mL)中的搅拌溶液中加入HATU(1.36g,3.58mmol;[CAS RN 148893-10-1])和DIPEA(1.7mL,9.5mmol)。在搅拌30min之后,加入甘氨酸甲酯盐酸盐(0.4g,3.58mmol;[CAS RN 5680-79-5])。在搅拌18h小时之后,将反应混合物在减压下浓缩,接着加入冰水(40mL)。将获得的固体过滤并在真空下干燥。获得标题化合物,为浅黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(0.45g,52%)。MS:m/e=364.9[M+H]+。
[C]2-[[5-(4-乙酰基哌嗪-1-基)-2-氨基苯甲酰基]氨基]乙酸甲酯
向2-[[5-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酰基]氨基]乙酸甲酯(3.25g,11.09mmol)在甲醇(50mL)中的脱气溶液中加入10%Pd/C(0.15g,0.14mmol)并将反应混合物在氢气(大气压力)下、在室温搅拌6h。反应混合物通过使用甲醇过滤,有机相在减压下浓缩并且固体材料通过用二乙醚(3x 20mL)洗涤纯化。获得标题化合物,为浅褐色固体,并在未经进一步纯化下直接用于连续反应步骤中(2.75g,74%)。MS:m/e=335.2[M+H]+。
[D]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸甲酯(中间体A-7)
在氮气气氛下,将2-[[5-(4-乙酰基哌嗪-1-基)-2-氨基苯甲酰基]氨基]乙酸甲酯(2.75g,8.23mmol)在原甲酸三乙酯(20mL,0.12mol;[CAS RN122-51-0])中的溶液在油浴中加热至140℃持续36h。将反应混合物冷却至室温,在减压下浓缩并且粗产物通过柱色谱(100-200目径硅胶)使用10%甲醇-DCM作为洗脱剂纯化。获得标题化合物,为白色固体(2.0g,71%)。MS:m/e=345.4[M+H]+。
中间体A-8
2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸
[A]2-[(5-溴-2-硝基苯甲酰基)氨基]乙酸甲酯
在氮气气氛下,向5-溴-2-硝基苯甲酸(10.0g,40.6mmol;[CAS RN6950-43-2]在DMF(50mL)中的搅拌溶液中加入HATU(23g,60mmol)和DIPEA(35mL,203.2mmol)。然后,加入甘氨酸甲酯盐酸盐(6.0g,48.7mmol;[CAS RN 5680-79-5])并将反应混合物在室温搅拌18h。在反应完成之后,将溶剂在减压下蒸发,得到黄色固体。加入水(25ml)并将所得的黄色固体滤出,沉淀用水(4x 25mL)洗涤并在减压下干燥。获得标题化合物,为浅黄色固体,并在未经进一步纯化下直接用于连续反应步骤中(7.0g,63%)。MS:m/e=318.1[M+H]+。
[B]4-[3-[(2-甲氧基-2-氧代乙基)氨基甲酰基]-4-硝基苯基]-3,6-二氢-2H-吡
啶-1-甲酸叔丁酯
向2-[(5-溴-2-硝基苯甲酰基)氨基]乙酸甲酯(4.0g,12.61mmol)在二烷(80mL)中的溶液中加入4-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(4.28g,13.88mmol;[CAS RN286961-14-6])和小心干燥的K2CO3(3.91g,28.39mmol)。通过鼓泡通过氮气将反应混合物脱气5min,然后加入[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷配合物(0.922g,1.26mmol;[CAS RN 95464-05-4])。将所得反应混合物进一步脱气5min,然后在90℃干燥3h。将反应混合物冷却至室温,加入EtOAc(250mL)并将有机相用水(100mL)和饱和NaCl水溶液(100mL)洗涤。有机层用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用25%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为黄色固体(3.5 g,62%)。MS:m/e=418.2[M-H]-。
[C]4-[4-氨基-3-[(2-甲氧基-2-氧代乙基)氨基甲酰基]苯基]哌啶-1-甲酸叔丁
酯
向4-[3-[(2-甲氧基-2-氧代乙基)氨基甲酰基]-4-硝基苯基]-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(2.3g,5.48mmol)在甲醇(50mL)中的溶液中加入10%Pd/C(0.23g,0.22mmol)并将反应混合物在氢气(大气压力)下、在室温搅拌3h。反应混合物通过使用甲醇过滤,并且有机相在真空下浓缩。获得粗物料,为灰白色固体并在未经进一步纯化下用于连续反应步骤(2.0g,粗产物)。MS:m/e=392.0[M+H]+。
[D]4-[3-(2-甲氧基-2-氧代乙基)-4-氧代喹唑啉-6-基]哌啶-1-甲酸叔丁酯
在氮气气氛下,向4-[4-氨基-3-[(2-甲氧基-2-氧代乙基)氨基甲酰基]苯基]哌啶-1-甲酸叔丁酯(0.5 g,1.27 mmol)在甲醇(20 mL)中的溶液中加入原甲酸三乙酯(2 mL,12.0mmol;[CAS RN 122-51-0])并将反应混合物在由于中加热至80℃持续24h。将反应混合物冷却至室温,在减压下浓缩并且粗反应产物通过柱色谱(100-200目径硅胶),使用60%EtOAc-己烷作为洗脱剂纯化。获得标题化合物,为粘稠固体(0.30g,78%,经2个步骤)。MS:m/e=401.7[M+H]+。
[E]2-[6-(1-叔丁氧基羰基-4-哌啶基)-4-氧代喹唑啉-3-基]乙酸
向4-[3-(2-甲氧基-2-氧代乙基)-4-氧代喹唑啉-6-基]哌啶-1-甲酸叔丁酯(5.0g,12.46mmol)在THF(25mL)中的溶液中加入LiOH·H2O(0.79g,18.70mmol;[CAS RN1310-66-3])在水(2.5ml)中的水溶液。在室温将反应混合物搅拌2h之后,将溶剂在减压下蒸发。向粗反应产物中加入水(20mL),含水部分通过加入1N HCl酸化(pH约4)并且水相用在DCM中的5%MeOH(3x25mL)萃取。合并的有机相用无水Na2SO4干燥并在减压下浓缩。获得标题化合物,为灰白色固体(4.0g,83%)。MS:m/e=387.7[M+H]+。
[F]2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中
间体A-8)
向2-[6-(1-叔丁氧基羰基-4-哌啶基)-4-氧代喹唑啉-3-基]乙酸(1.5g,3.87mmol)在二烷(15mL)中的溶液中加入在二烷中的4M HCl(15mL)并将反应混合物在室温搅拌12h。将溶剂在减压下蒸发并将中间体再溶解在二烷(30mL)和10%NaHCO3水溶液(30mL)中。加入氯甲酸9-芴基甲酯(1.69g,6.53mmol;[CAS RN28920-43-6])并将反应混合物在室温搅拌2h。将粗反应混合物在减压下浓缩并在水(50mL)和EtOAc(50mL)之间分配。将有机相分离并将水相用EtOAc(2x 50mL)萃取。之后水相通过加入25%HCl酸化(pH约3)并用DCM(3x50mL)萃取。合并的有机相用无水MgSO4干燥并在减压下浓缩。获得标题化合物,为灰白色固体(0.61g,31%)。MS:m/e=510.2[M+H]+。
中间体A-9
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺
在氮气气氛下,向2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)(0.40g,0.79mmol)在DCM(8mL)中的溶液中加入TBTU(0.38g,1.18mmol;[CAS RN125700-67-6])和DIPEA(0.41mL,2.36mmol)。然后,加入2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐(实施例56,步骤A)(0.17g,0.79mmol)并将反应混合物在室温搅拌18h。加入甲胺的溶液(4.5mL,3.40g,36.1mmol;33重量%溶液,在EtOH中;[CASRN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩,重新溶解在二烷(5mL)中并用在二烷中的4M HCl(20mL)处理。将白色沉淀滤出,用TBME (40mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体,并在未经进一步纯化下直接用于连续反应步骤中(0.38g,98%)。MS:m/e=450,2[M+H]+。
实施例1
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-甲基丙酰胺
合成在流动中进行。试剂溶液A含有在DMF(280μl)中的(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸(中间体A-3)(10.2mg,0.020mmol)、TBTU(12.8mg,0.040mmol;[CAS RN 125700-67-6])和DIPEA(7.0μl,0.040mmol)并且试剂溶液B含有在DMF(300μl)中的甲胺(100μl,0.80mmol;在乙醇中的8.0M溶液;[CAS RN 74-89-5])。借助于Gilson LH 215自动取样器将两种试剂溶液(300μL各个溶液)注入到反应器样品环(各300μL,Gilson 819)中。然后,将这两种试剂流在T-型管接头处合并并将试剂混合物在10ml PFA管式反应器盘管中在100℃加热10min。粗产物流通过制备型HPLC(C18反相,乙腈/水(0.05%三乙胺)=2∶98至98∶2)在线纯化,得到标题化合物,为浅黄色固体(3.1mg,30%)。MS:m/e=525.3[M+H]+。
实施例2至8
根据对于实施例1的合成所述的程序,另外的实施例制备自(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酸(中间体A-3)和(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-[4-(三氟甲基)苯基]丙酸(中间体A-4)以及表1中指示的相应胺中间体。结果编辑在表1中并且包括实施例2至8。
表1
实施例9
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-甲基-3-(4-硝基苯基)丙酰胺
[A](3R)-N-[3-(甲基氨基)-1-(4-硝基苯基)-3-氧代丙基]氨基甲酸叔丁酯
在室温,在氮气气氛下,向3-[(2-甲基丙-2-基)氧基羰基氨基]-3-(4-硝基苯基)丙酸(0.25g,0.80mmol;[CAS RN 500770-85-4])在无水DCM(20mL)中的溶液中加入EDC·HCl(0.23g,1.20mmol)和HOBt(0.16g,1.20mmol)。然后,加入三乙胺(0.33mL,2.40mmol)并将反应混合物在室温搅拌30min,接着加入甲胺(0.5mL,1.00mmol;2.0M溶液,在THF中;[CASRN74-89-5])。在搅拌16h之后,反应混合物通过加入水(20mL)猝灭并且水相用DCM(3x50mL)萃取。合并的有机相用Na2SO4干燥并在减压下浓缩。通过柱色谱(100-200目径硅胶),使用2%甲醇-DCM作为洗脱剂纯化,得到标题化合物,为白色固体(0.20g,77%)。MS:m/e=324.3[M+H]+。
[B](3R)-3-氨基-N-甲基-3-(4-硝基苯基)丙酰胺盐酸盐
在0℃,在Ar气氛下,向(3R)-N-[3-(甲基氨基)-1-(4-硝基苯基)-3-氧代丙基]氨基甲酸叔丁酯(0.20g,0.62mmol)中加入HCl(5mL,4.0M溶液,在二烷中)。将反应混合物在室温搅拌4h,然后在减压下浓缩。将获得的固体过滤并用无水二乙醚洗涤。分离标题化合物,为水分敏感的黄色粘性液体(0.14g,87%),并在未经进一步纯化下用于连续反应步骤。MS:m/e=224.2[M+H]+。
[C](3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-
N-甲基-3-(4-硝基苯基)丙酰胺
在室温,在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(0.20g,0.60mmol)在无水DMF(5mL)中的溶液中加入EDC·HCl(0.17g,0.90mmol)和HOBt(0.12g,0.90mmol)。然后,加入DIPEA(0.31mL,1.81mmol)并将反应混合物在室温搅拌30min,接着加入(3R)-3-氨基-N-甲基-3-(4-硝基苯基)丙酰胺盐酸盐(0.14g,0.60mmol)。在搅拌16h之后,反应混合物通过加入至冰猝灭并且水相用DCM(2x 30mL)萃取。合并的有机相用水(2x 10mL)、饱和氯化钠水溶液(10mL)洗涤,用无水Na2SO4干燥并在减压下浓缩。粗反应产物用20%DCM-正戊烷研磨,得到沉淀,将其用DCM进一步洗涤。获得标题化合物,为灰白色固体(0.095g,30%)。MS:m/e=536.2[M+H]+。
实施例10
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯苯基)甲基]乙酰胺
在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(11.9mg,0.036mmol)在无水DMF(1mL)中的溶液中加入TBTU(17.3mg,0.054mmol;[CASRN 125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入(4-氯苯基)甲胺(6.1mg,0.043mmol;[CAS RN104-86-9])并将反应混合物通过微波辐照加热至100℃持续15min。加入水(1mL)并且粗反应产物通过反相制备型HPLC用乙腈-水梯度洗脱纯化。获得标题化合物,为白色固体(1.8mg,11%)。MS:m/e=454.2[M+H]+。
实施例11至27
根据对于实施例10的合成所述的程序,另外的实施例制备自2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)以及如表2中指示的相应胺中间体。备选地,酰胺形成反应可以如在实施例1((3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-甲基丙酰胺)中所述在流动中进行。结果编辑在表2并且包括实施例11至27。
表2
实施例28
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN269078-82-2])(50mg,0.098mmol)在无水DCM(2mL)中的溶液中加入TBTU(47.2mg,0.15mmol;[CASRN 125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入4-(氨基甲基)-2-氟苯甲腈(20.1mg,0.11mmol;[CAS RN368426-73-7])并将反应混合物在室温搅拌90min。加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水DMF(2mL)中。在氮气气氛下,加入DIPEA(50μL,0.29mmol)和乙酰氯(7.0μL,0.098mmol;[CAS RN 368426-73-7])并将反应混合物在室温搅拌2h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(19mg,42%)。MS:m/e=463.3[M+H]+。
实施例29至51
根据对于实施例28的合成所述的程序,另外的实施例制备自2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1)以及如表3中指示的相应胺中间体。结果编辑在表3并且包括实施例29至51。
表3
实施例52
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(3,4-二氯苯基)-N-甲基丙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN 269078-82-2])(40mg,0.078mmol)在无水DCM(2mL)中的溶液中加入TBTU(37.7mg,0.12mmol;[CASRN125700-67-6])和DIPEA(41μL,0.24mmol)。然后,加入3-氨基-3-(3,4-二氯苯基)丙酸乙酯(24.6mg,0.094mmol;[CAS RN 380842-80-8])并将反应混合物在室温搅拌90min。加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在DMF(2mL)。在氮气气氛下,加入DIPEA(41μL,0.24mmol)和乙酰氯(5.6μL,0.078mmol;[CASRN368426-73-7])并将反应混合物在室温搅拌2h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(8.4mg,19%)。MS:m/e=559.3[M+H]+。
实施例53
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]甲酯
在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(41.6mg,0.13mmol)在无水DCM(1.5mL)中的溶液中加入HATU(71.8mg,0.19mmol)和DIPEA(66μL,0.38mmol)。然后,加入3-[(3,4-二氯苯基)甲基氨基]丙酸甲酯(33mg,0.13mmol;[CAS RN4020-24-0])并将反应混合物在室温搅拌2h。反应混合物通过加入饱和碳酸氢钠水溶液(10mL)猝灭并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过MPLC(20g SiO2,Telos-筒),用0至3%甲醇-DCM梯度洗脱纯化,得到标题化合物(35mg,48%),为白色固体。MS:574.4(M+H)+。
实施例54
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸
向3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸甲酯(实施例53)(26mg,0.045mmol)在THF-水(0.5mL:1mL)中的溶液中加入LiOH·H2O(47.2mg,0.15mmol)并将反应混合物在室温搅拌1h。将反应混合物在减压下浓缩,加入1M HCl(5mL)并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(9.5mg,38%)。MS:m/e=558.4[M-H]-。
实施例55
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]-N-甲基丙酰胺
类似于用于制备3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(3,4-二氯苯基)-N-甲基丙酰胺(实施例52)所述的程序,用3-[(3,4-二氯苯基)甲基氨基]丙酸甲酯([CAS RN 4020-24-0])代替3-氨基-3-(3,4-二氯苯基)丙酸乙酯。在反应完成之后,反应混合物通过加入饱和碳酸氢钠水溶液(10mL)猝灭并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过MPLC(20g SiO2,Telos-筒),用0至3%甲醇-DCM梯度洗脱纯化,得到标题化合物(47mg,84%),浅橙色固体。MS:573.2(M+H)+。
实施例56
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺
[A]2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐
在0℃,在30min内,向4-(溴甲基)-2-氯苯甲腈(3.04g,13.2mmol;[CAS RN 83311-25-5])中逐滴加入甲胺的溶液(20mL,40.0mmol;2.0M溶液,在THF中;[CAS RN 74-89-5])。将粗反应混合物温热至室温并继续搅拌10min。将沉淀滤出,用THF(50mL)洗涤并将滤液在减压下浓缩。加入1M NaOH的溶液(50mL)并且水相用DCM(3x 50mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。将粗反应产物溶解在二烷(50mL)中并用在二烷中的4MHCl(20mL)处理。将白色沉淀滤出,用TBME(40mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体(1.33g,46%)。MS:m/e=181.1[M+H]+。
[B]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲
基]-N-甲基乙酰胺
类似于用于制备2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺(实施例28)所述的程序,用2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐代替4-(氨基甲基)-2-氟苯甲腈。在反应完成之后,反应混合物通过加入饱和碳酸氢钠水溶液(10mL)猝灭并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过MPLC(20gSiO2,Telos-筒),用0至5%甲醇-DCM梯度洗脱纯化,得到标题化合物(36mg,75%),为无色油状物。MS:492.2(M+H)+。
实施例57
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺
[A]2-氯-5-(甲基氨基甲基)苯甲腈盐酸盐
向2-氯-5-甲基苯甲腈(1.0g,6.6mmol;[CAS RN 4387-32-0])在四氯化碳(40mL)中的溶液中加入N-溴代琥珀酰亚胺;(1.17g,6.6mmol)和过氧苯甲酰(8.0mg,0.033mmol)。将反应混合物加热至回流并使用荧光灯(λ=365nm)辐照4h。将沉淀滤出并将滤液在减压下浓缩。在0℃在30min内,向粗反应产物中逐滴加入甲胺的溶液(20mL,40.0mmol;2.0M溶液,在THF中;[CAS RN 74-89-5])。将粗反应混合物温热至室温并继续搅拌10min。将沉淀滤出,用THF(50mL)洗涤并将滤液在减压下浓缩。加入1M NaOH的溶液(40mL)并且水相用DCM(3x40mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。将粗反应产物溶解在二烷(30mL)中并用在在二烷中的4M HCl(10mL)处理。将白色沉淀滤出,用TBME(30mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体(0.75g,52%)。MS:m/e=181.9[M+H]+。
[B]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲
基]-N-甲基乙酰胺
类似于用于制备2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺(实施例28)所述的程序,用2-氯-5-(甲基氨基甲基)苯甲腈盐酸盐代替4-(氨基甲基)-2-氟苯甲腈。在反应完成之后,反应混合物通过加入饱和碳酸氢钠水溶液(10mL)猝灭并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过MPLC(20gSiO2,Telos-筒),用0至5%甲醇-DCM梯度洗脱纯化,得到标题化合物(22mg,46%),为白色固体。MS:492.2(M+H)+。
实施例58
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3,5-二氟苯基)甲基]-N-甲基乙酰胺
[A]2,6-二氟-4-(甲基氨基甲基)苯甲腈
向2,6-二氟-4-甲酰基苯甲腈(0.10g,0.60mmol;[CAS RN433939-88-9])在甲醇(2mL)中的溶液中加入甲胺盐酸盐(40mg,0.60mmol;[CAS RN593-51-1])和乙酸(3.5μL,0.060mmol)。在室温将反应混合物搅拌30min之后,在10min内分批加入氰基硼氢化钠(57mg,0.90mmol;[CAS RN25895-60-7])。将反应混合物继续搅拌40min,然后将反应混合物在减压下浓缩。加入1M NaOH的溶液(50mL)并且水相用DCM(3x40mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。获得粗反应产物,为无色油状物,并在未经进一步纯化下直接用于连续反应步骤中(7mg,6%)。MS:m/e=183.1[M+H]+。
[B]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3,5-二氟苯
基)甲基]-N-甲基乙酰胺
在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(11.9mg,0.036mmol)在无水DCM(1.5mL)中的溶液中加入HATU(20.5mg,0.054mmol)和DIPEA(19μL,0.11mmol)。然后,加入2,6-二氟-4-(甲基氨基甲基)苯甲腈(7mg,0.038mmol)并将反应混合物在室温搅拌12h。加入DCM(2mL)和饱和碳酸氢钠水溶液(5mL)并且水相用DCM(3x 10mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过制备型TLC(Merck二氧化硅TLC玻璃板,20x 20cm),用甲苯-丙酮-甲醇(5∶5∶1)的混合物洗脱纯化,得到标题化合物,为微黄色固体(7mg,37%)。MS:m/e=495.3[M+H]+。
实施例59
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-甲基丁酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(15mg,0.022mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在DMF(1mL)中。在氮气气氛下,加入三乙胺(30μL,0.22mmol)和3-甲基丁酰氯(5.2mg,0.043mmol;[CAS RN 108-12-3])并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(3.6mg,32%)。MS:m/e=530.3[M+H]+。
实施例60至69
根据对于实施例59的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)和4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)以及如表4中所示的相应酰氯。结果编辑在表4并且包括实施例60至69。
表4
实施例70
2-[6-[4-(3-氨基氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(30mg,0.044mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在THF(2mL)中。在氮气气氛下,向该溶液中加入PYBOP(28.6mg,0.055mmol;[CAS RN 128625-52-5])和DIPEA(12μL,0.066mmol)。然后,加入3-氨基氧杂环丁烷-3-甲酸(6.4mg,0.055mmol;[CASRN 138650-24-5])并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为无色油状物(2.6mg,11%)。MS:m/e=545.3[M+H]+。
实施例71至81
根据对于实施例70的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)和4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)以及如表5中所示的相应羧酸。结果编辑在表5并且包括实施例71至81。
表5
实施例82
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-丙-2-基哌嗪-1-甲酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(30mg,0.044mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水THF(2mL)中。在氮气气氛下,向该溶液中加入2-异氰酸基丙烷(4.7mg,0.055mmol;[CAS RN 1795-48-8])并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(5.7mg,25%)。MS:m/e=531.2[M+H]+。
实施例83至87
根据对于实施例82的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)以及如表6中所示的相应异腈。结果编辑在表6并且包括实施例83至87。
表6
实施例88
N-[(3,4-二氯苯基)甲基]-2-[6-(4-甲基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(15mg,0.022mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水DMF(1mL)中。在氮气气氛下,加入三乙胺(30μL,0.22mmol)和甲磺酰氯(4.9mg,0.088mmol;[CAS RN 124-63-0])并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(5.6mg,50%)。MS:m/e=524.2[M+H]+。
实施例89至92
根据对于实施例88的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)和4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)以及如表7所示的相应磺酰氯。结果编辑在表7并且包括实施例89至92。
表7
实施例93
2-[4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-基]乙酸甲酯
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(58mg,0.085mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水THF(4mL)中。向该溶液中加入NaH(6.8mg,0.17mmol;60%分散液,在矿物油中)并将反应混合物在室温搅拌。在45min之后,加入2-溴乙酸甲酯(19.5mg,0.13mmol;[CAS RN 96-32-2])并将反应混合物在室温继续搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(4.6mg,10%)。MS:m/e=518.2[M+H]+。
实施例94
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-羟基乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)(30mg,0.044mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水THF(2mL)中。在氮气气氛下,向该溶液中加入2-羟基乙醛(4.0mg,0.066mmol;[CAS RN 141-46-8])和乙酸(4μL,0.066mmol)并将反应混合物在室温搅拌。在45min之后,加入氰基硼氢化钠(4.1mg,0.066mmol;[CAS RN25895-60-7])并将反应混合物在室温继续搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(2.5mg,12%)。MS:m/e=490.2[M+H]+。
实施例95至103
根据对于实施例94的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-5)以及如表8中所示的相应醛。结果编辑在表8并且包括实施例95至103。
表8
实施例104
2-[6-[4-(环丙基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)(37mg,0.054mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在乙腈(1.5mL)中。向该溶液中加入溴甲基环丙烷(11.0mg,0.081mmol;[CAS RN 7051-34-5])和碳酸钾(30mg,0.22mmol)并将反应混合物在微波辐照下加热至120℃持续15min。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(2.1mg,8%)。MS:m/e=514.3[M+H]+。
实施例105和106
根据对于实施例104的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)以及如表9中所示的相应烷基溴。结果编辑在表9并且包括实施例105和106。
表9
实施例107
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-[2-(甲基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺
向4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)(37mg,0.054mmol)在无水DMF(1mL)中的溶液中加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水DMF(1.5mL)。向该溶液中加入DIPEA(38μL,0.22mmol)和2-氯-N-甲基乙酰胺(11.6mg,0.11mmol;[CAS RN96-30-0])并将反应混合物在微波辐照下加热至100℃持续10min。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(16.4mg,57%)。MS:m/e=531.3[M+H]+。
实施例108至112
根据对于实施例107的合成所述的程序,另外的实施例制备自4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酸9H-芴-9-基甲酯(中间体A-6)以及如表10中所示的相应烷基氯。
结果编辑在表10并且包括实施例108至112。
表10
实施例113
N-[(2-氯-4-氰基苯基)甲基]-2-[6-[4-(氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN 269078-82-2])(50mg,0.098mmol)在无水DCM(2mL)中的溶液中加入TBTU(47.2mg,0.15mmol;[CASRN 125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入4-(氨基甲基)-3-氯苯甲腈(20.4mg,0.12mmol;[CAS RN 202521-97-9])并将反应混合物在室温搅拌90min。加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水DMF(2mL)中。在氮气气氛下,向该溶液中加入DIPEA(50μL,0.29mmol)、TBTU(47.2mg,0.15mmol;[CASRN125700-67-6])和氧杂环丁烷-3-甲酸(7.0μL,0.098mmol;[CAS RN114012-41-8])并将反应混合物在室温搅拌2h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为浅褐色固体(20mg,39%)。MS:m/e=521.3[M+H]+。
实施例114
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酸(中间体A-1;[CAS RN 269078-82-2])(50mg,0.098mmol)在无水DCM(2mL)中的溶液中加入TBTU(47.2mg,0.15mmol;[CASRN125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐(26.7mg,0.12mmol;实施例56,步骤A)并将反应混合物在室温搅拌90min。加入甲胺的溶液(2mL,16.0mmol;8.0M溶液,在乙醇中;[CAS RN74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在甲醇(2mL)。在氮气气氛下,向该溶液中加入氧杂环戊烷-3-甲醛(27μL,29.4mg,0.15mmol;50重量%溶液,在水中;[CAS RN 79710-86-4])和乙酸(9μL,0.15mmol)并将反应混合物在室温搅拌。在45min之后,加入氰基硼氢化钠(9.2mg,0.15mmol;[CASRN 25895-60-7])并将反应混合物在室温继续搅拌过夜。将粗反应混合物在减压下浓缩,饱和碳加入酸氢钠水溶液(20mL)并将水相用DCM(3x 20mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过柱色谱(100-200目径硅胶),用0至4%甲醇-DCM的梯度洗脱纯化并从甲醇中结晶,得到标题化合物,为白色固体(25mg,48%)。MS:m/e=535.4[M+H]+。
实施例115
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺
类似于用于制备N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺(实施例114)所述的程序,用2-氯-5-(甲基氨基甲基)苯甲腈盐酸盐(实施例57,步骤A)代替2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐。通过柱色谱(100-200目径硅胶),用0至4%甲醇-DCM的梯度洗脱纯化,得到标题化合物,为无色油状物(26mg,50%)。MS:m/e=535.3[M+H]+。
实施例116
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-乙基乙酰胺
[A]N-[(3,4-二氯苯基)甲基]乙胺盐酸盐
在氮气气氛下,向3,4-二氯苯甲醛(1.0g,5.71mmol;[CAS RN6287-38-3])和乙胺(5.71mL,11.4mmol;2.0M溶液,在THF中;[CAS RN75-04-7])在异丙醇(12mL)中的溶液中加入乙酸(0.34mL,5.71mmol)并将反应混合物在室温搅拌。在45min之后,加入氰基硼氢化钠(0.72g,5.71mmol;[CAS RN 25895-60-7])并将反应混合物在室温继续搅拌过夜。将粗反应混合物在减压下浓缩,加入EtOAc(50mL)并将有机相用0.1M HCl水溶液(3x 20mL)萃取。通过添加固体NaOH将合并的水相设置为pH 14并且水相用EtOAc(3x 100mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。将粗反应产物溶解在二烷(50mL)中并用在二烷中的4MHCl(20mL)处理。将白色沉淀滤出,用TBME(30mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体(0.95g,69%)。MS:m/e=204.0[M+H]+。
[B]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲
基]-N-乙基-乙酰胺
在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸甲酯(中间体A-7)(50mg,0.15mmol)和N-[(3,4-二氯苯基)甲基]乙胺盐酸盐(38.1mg,0.16mmol)在无水THF(2mL)中的溶液中加入二(三甲基铝)-1,4-二氮杂二环[2.2.2]辛烷加合物(44.7mg,0.17mmol;[CAS RN137203-34-0])并将反应混合物在微波辐照下加热至130℃持续1h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(7.6mg,10%)。MS:m/e=516.3[M+H]+。
实施例117
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-丙-2-基乙酰胺
[A]N-[(3,4-二氯苯基)甲基]丙-2-胺盐酸盐
类似于用于制备N-[(3,4-二氯苯基)甲基]乙胺盐酸盐(实施例116,步骤A)所述的程序,用2-丙胺代替乙胺([CAS RN 75-31-0])。获得标题化合物,为白色固体(1.10g,73%)。MS:m/e=218.1[M+H]+。
[B]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲
基]-N-异丙基-乙酰胺
类似于用于制备2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-乙基-乙酰胺(实施例116,步骤B)所述的程序,用N-[(3,4-二氯苯基)甲基]丙-2-胺盐酸盐代替N-[(3,4-二氯苯基)甲基]乙胺盐酸盐。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(7.9mg,10%)。MS:m/e=530.3[M+H]+。
实施例118
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸(如US2010/0069307A1第12页中所示制备;[CAS RN 1217190-17-2])(50mg,0.095mmol)在无水DMF(0.5mL)中的溶液中加入TBTU(45.9mg,0.14mmol;[CAS RN125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入(3,4-二氯苯基)甲胺(20.1mg,0.11mmol;[CAS RN 102-49-8])并将反应混合物在室温搅拌5h。加入甲胺的溶液(60μL,0.48mmol;8.0M溶液,在乙醇中;[CAS RN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在无水DMF(0.5mL)中。在氮气气氛下,加入DIPEA(50μL,0.29mmol)和乙酰氯(34μL,0.48mmol;[CAS RN 368426-73-7])并将反应混合物在室温搅拌16h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为浅黄色固体(17.7mg,37%)。MS:m/e=463.3[M+H]+。
实施例119至127
根据对于实施例118的合成所述的程序,另外的实施例制备自2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸(如在US2010/0069307A1第12页中所述制备;[CAS RN1217190-17-2])和2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)以及如表11中指示的相应胺中间体。结果编辑在表11并且包括实施例119至127。
表11
实施例128
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧基)苯基]甲基]-N-甲基乙酰胺
[A]1-[4-氯-3-(三氟甲氧基)苯基]-N-甲基-甲胺
向4-氯-3-(三氟甲氧基)苯甲醛(0.30g,1.34mmol;[CAS RN886499-59-8])在甲醇(3mL)中的溶液中加入甲胺(0.22mL,0.16g,1.74mmol;33重量%溶液,在EtOH中;[CAS RN74-89-5])和乙酸(0.10mL,1.74mmol)。在室温将反应混合物搅拌30min之后,在10min内分批加入氰基硼氢化钠(86mg,2.61mmol;[CAS RN 25895-60-7])。将反应混合物继续搅拌40min,然后将反应混合物在减压下浓缩。加入1M NaOH的溶液(50mL)并且水相用DCM(3x50mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。获得粗反应产物,为无色油状物,并在未经进一步纯化下直接用于连续反应步骤中(70mg,22%)。MS:m/e=240.1[M+H]+。
[B]2-[6-(1-乙酰基-4-哌啶基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧
基)苯基]甲基]-N-甲基-乙酰胺
类似于用于制备2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺(实施例118)所述的程序,分别用2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)代替2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸并且用1-[4-氯-3-(三氟甲氧基)苯基]-N-甲基-甲胺代替(3,4-二氯苯基)甲胺。通过柱色谱(100-200目径硅胶),用0至3%甲醇-DCM的梯度洗脱纯化,得到标题化合物,为白色固体(38mg,73%)。MS:m/e=551.2[M+H]+。
实施例129
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺
在氮气气氛下,向2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸(如在US2010/0069307A1第12页中所述制备;[CAS RN 1217190-17-2])(50mg,0.095mmol)在无水DMF(0.5mL)中的溶液中加入TBTU(45.9mg,0.14mmol;[CASRN 125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐(23.9mg,0.11mmol;实施例56,步骤A)并将反应混合物在室温搅拌5h。加入甲胺的溶液(60μL,0.48mmol;8.0M溶液,在乙醇中;[CASRN 74-89-5])并在室温继续搅拌过夜。将粗反应混合物在减压下浓缩并重新溶解在甲醇(2mL)。在氮气气氛下,向该溶液中加入氧杂环戊烷-3-甲醛(27μL,29.4mg,0.15mmol;50重量%溶液,在水中;[CAS RN79710-86-4])和乙酸(9μL,0.15mmol)并将反应混合物在室温搅拌。在45min之后,加入氰基硼氢化钠(9.2mg,0.15mmol;[CAS RN 25895-60-7])并将反应混合物在室温继续搅拌过夜。将粗反应混合物在减压下浓缩,加入饱和碳酸氢钠水溶液(20mL)并将水相用DCM(3x 20mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过柱色谱(100-200目径硅胶),用0至5%甲醇-DCM的梯度洗脱纯化,得到标题化合物,为无色油状物(19mg,36%)。MS:m/e=549.3[M+H]+。
实施例130
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺
类似于用于制备N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(四氢呋喃-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺(实施例129)所述的程序,用2-氯-5-(甲基氨基甲基)苯甲腈盐酸盐(实施例57,步骤A)代替2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐。通过柱色谱(100-200目径硅胶),用0至5%甲醇-DCM的梯度洗脱纯化,得到标题化合物,为无色油状物(31mg,60%)。MS:m/e=549.4[M+H]+。
实施例131
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-羟基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(27mg,0.056mmol)在无水DMF(1.5mL)中的溶液中加入TBTU(27mg,0.083mmol;[CAS RN125700-67-6])和DIPEA(50μL,0.29mmol)。然后,加入2-羟基乙酸(5.1mg,0.067mmol;[CAS RN 79-14-1])并将反应混合物在室温搅拌18h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(10.7mg,38%)。MS:m/e=508.3[M+H]+。
实施例132至142
根据对于实施例131的合成所述的程序,另外的实施例制备自N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)以及如表12中所示的相应羧酸。结果编辑在表12并且包括实施例132至142。
表12
实施例143
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺
类似于用于制备N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(四氢呋喃-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺(实施例129)所述的程序,用2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)代替2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为无色油状物(14.2mg,28%)。MS:m/e=536.4[M+H]+。
实施例144
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺
类似于用于制备N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(四氢呋喃-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺(实施例129)所述的程序,用2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)代替2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸并且用2-氯-5-(甲基氨基甲基)苯甲腈盐酸盐(实施例57,步骤A)代替2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐。通过柱色谱(100-200目径硅胶),用0至5%甲醇-DCM的梯度洗脱纯化,得到标题化合物,为无色油状物(21.3mg,42%)。MS:m/e=534.3[M+H]+。
实施例145
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-(1-甲基磺酰基哌啶-4-基)-4-氧代喹唑啉-3-基]乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(22mg,0.045mmol)在无水DMF(1.5mL)中的溶液中加入DIPEA(25μL,0.15mmol)和甲磺酰氯(6.2mg,0.054mmol;[CAS RN124-63-0])并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(12.8mg,54%)。MS:m/e=528.2[M+H]+。
实施例146
N-环丙基-N-[(3,4-二氯苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺
[A]N-[(3,4-二氯苯基)甲基]环丙胺盐酸盐
类似于用于制备N-[(3,4-二氯苯基)甲基]乙胺盐酸盐(实施例116,步骤A)所述的程序,用环丙胺([CAS RN765-30-0])代替乙胺。获得标题化合物,为白色固体(0.46g,32%)。MS:m/e=216.1[M+H]+。
[B]N-环丙基-N-[(3,4-二氯苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)-4-哌啶
基]-4-氧代喹唑啉-3-基]乙酰胺
类似于用于制备2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺(实施例118)所述的程序,分别用2-[6-[1-(9H-芴-9-基甲氧基羰基)-4-哌啶基]-4-氧代喹唑啉-3-基]乙酸(中间体A-8)代替2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸,用N-[(3,4-二氯苯基)甲基]环丙胺盐酸盐代替(3,4-二氯苯基)甲胺并且用2-甲氧基乙酰氯([CAS RN38870-89-2])代替乙酰氯。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(11.1mg,21%)。MS:m/e=557.6[M+H]+。
实施例147
2-[6-[2-乙酰基-2-氮杂二环[2.2.1]庚-5-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
类似于用于制备2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺(实施例118)所述的程序,用2-[6-[2-(9H-芴-9-基甲氧基羰基)-2-氮杂二环[2.2.1]庚-5-基]-4-氧代喹唑啉-3-基]乙酸(如在US2010/0069307A1中第19页所述制备;[CAS RN1217190-42-5])代替2-[6-[4-(9H-芴-9-基甲氧基羰基)-1,4-二氮杂环庚烷-1-基]-4-氧代喹唑啉-3-基]乙酸。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为浅黄色固体(17mg,36%)。MS:m/e=499.1[M+H]+。
实施例148
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]丙酰胺
[A]N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯
在氮气气氛下,向2-(叔丁氧基羰基氨基)丙酸(1.0g,5.3mmol;[CASRN3744-87-4])在DCM(40mL)中的溶液中加入HATU(2.4g,5.3mmol;[CAS RN 148893-10-1])和三乙胺(1.4mL,10.6mmol)。然后,加入(3,4-二氯苯基)甲胺(0.9g,5.3mmol;[CAS RN 102-49-8])并将反应混合物在室温搅拌过夜。加入1M柠檬酸溶液(20mL)并将水相用DCM(3x 20mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过柱色谱(100-200目径硅胶),用1∶20至1∶1EtOAc-石油醚的梯度洗脱纯化,得到标题化合物,为白色固体(1.6g,87%)。MS:m/e=347.1[M+H]+。
[B]2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐
将N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯(1.6g,4.6mmol)在EtOAc(10mL)中的溶液用在二烷中的4M HCl(10mL)处理并将反应混合物在室温搅拌2h。将白色沉淀滤出,用TBME(40mL)洗涤并在高真空下干燥。获得标题化合物,为白色固体,并将粗产物用于连续反应步骤(1.2g,92%)。MS:m/e=247.0[M+H]+。
[C]5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-
基]-2-硝基苯甲酰胺
在氮气气氛下,向5-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酸(中间体A-7,步骤A)(0.51g,2.1mmol)在DCM(40mL)中的溶液中加入HATU(0.78g,2.1mmol;[CAS RN 148893-10-1])和三乙胺(0.5mL,3.4mmol)。然后,加入2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐(0.50g,1.7mmol)并将反应混合物在室温搅拌过夜。加入1M柠檬酸溶液(40mL)并且水相用DCM(3x 40mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过柱色谱(100-200目径硅胶),用1∶80至1∶30甲醇-DCM的梯度洗脱纯化,得到标题化合物,为黄色固体(0.44g,50%)。MS:m/e=522.1[M+H]+。
[D]5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代
丙-2-基]苯甲酰胺
在室温,向溶解在乙醇(20mL)中的5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺(0.44g,0.84mmol)中逐滴加入氯化锡(II)二水合物(1.1g,5.05mmol)在浓HCl(2mL)中的溶液。在将反应混合物搅拌2h之后,加入10%碳酸钠的水溶液(50mL),将反应过滤并且水相用DCM(3x 40mL)萃取。合并的有机相用Na2SO4干燥压下浓缩。通过柱色谱(100-200目径硅胶),用1∶50至1∶20甲醇-DCM的梯度洗脱纯化,得到标题化合物,为浅褐色固体(0.20g,48%)。MS:m/e=492.1[M+H]+。
[E]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]
丙酰胺
向5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺(100mg,0.20mmol)在乙醇(5mL)中的溶液中加入乙酸(12μg,0.20mmol)和原甲酸三甲酯(22mg,0.20mmol;[CAS RN149-73-5])并将反应混合物加热至60℃持续12h。将粗反应混合物在减压下浓缩并且上通过反相制备型HPLC用乙腈-水梯度洗脱纯化。获得标题化合物,为白色固体(47mg,46%)。MS:m/e=502.1[M+H]+。
实施例149
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基丙酰胺
[A]N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯
类似于用于制备N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯(实施例148,步骤A)所述的程序,用1-(3,4-二氯苯基)-N-甲基-甲胺([CAS RN 5635-67-6])代替(3,4-二氯苯基)甲胺。通过柱色谱(100-200目径硅胶),用1∶10至1∶3 EtOAc-石油醚的梯度洗脱纯化,得到标题化合物,为无色油状物(1.7g,90%)。MS:m/e=362.3[M+H]+。
[B]2-氨基-N-[(3,4-二氯苯基)甲基]-N-甲基丙酰胺盐酸盐
类似于用于制备2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐(实施例148,步骤B)所述的程序,用N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯代替N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯。获得标题化合物,为白色固体并将粗产物用于连续反应步骤(1.0g,71%)。MS:m/e=261.1[M+H]+。
[C]5-(4-乙酰基哌嗪-1-基-N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-氧代丙-
2-基]-2-硝基苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺(实施例148,步骤C)所述的程序,用2-氨基-N-[(3,4-二氯苯基)甲基]-N-甲基丙酰胺盐酸盐代替2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐。通过柱色谱(100-200目径硅胶),用1∶80至1∶30甲醇-DCM的梯度洗脱纯化,得到标题化合物,为红色固体(2.0g,58%;53%纯度)。MS:m/e=536.0[M+H]+。
[D]5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-
氧代丙-2-基]苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺(实施例148,步骤D)所述的程序,用5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺代替5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺。通过柱色谱(100-200目径硅胶),用1∶30至1∶10甲醇-DCM的梯度洗脱纯化,得到标题化合物,为浅黄色油状物(0.45g,31%;65%纯度)。MS:m/e=506.0[M+H]+。
[E]2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲
基]-N-甲基丙酰胺
类似于用于制备2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]丙酰胺(实施例148,步骤E)所述的程序,用5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基-甲基氨基]-1-氧代丙-2-基]苯甲酰胺代替5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(25mg,13%)。MS:m/e=515.2[M+H]+。
实施例150
1-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]环丙烷-1-甲酰胺
[A]N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环丙基]氨基甲酸叔丁酯
类似于用于制备N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯(实施例148,步骤A)所述的程序,用1-(叔丁氧基羰基氨基)环丙烷羧酸([CAS RN88950-64-5])代替2-(叔丁氧基羰基氨基)丙酸。通过柱色谱(100-200目径硅胶),用1∶20至1∶1EtOAc-石油醚的梯度洗脱纯化,得到标题化合物,为无色油状物(2.0g,90%;66%纯度)。MS:m/e=381.0[M+H]+。
[B]1-氨基-N-[(3,4-二氯苯基)甲基]环丙烷甲酰胺盐酸盐
类似于用于制备2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐(实施例148,步骤B)所述的程序,用N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环丙基]氨基甲酸叔丁酯代替N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯。获得标题化合物,为白色固体并将粗产物用于连续反应步骤(1.0g,61%)。MS:m/e=259.1[M+H]+。
[C]5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环丙基]-
2-硝基苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺(实施例148,步骤C)所述的程序,用1-氨基-N-[(3,4-二氯苯基)甲基]环丙烷甲酰胺盐酸盐代替2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐。通过柱色谱(100-200目径硅胶),用1∶80至1∶30甲醇-DCM的梯度洗脱纯化,得到标题化合物,为红色固体(1.1g,60%)。MS:m/e=534.1[M+H]+。
[D]5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环
丙基]苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺(实施例148,步骤D)所述的程序,用5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环丙基]-2-硝基苯甲酰胺代替5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺。分离标题化合物,为浅黄色固体(0.35g,69%)。MS:m/e=557.3[M+H]+。
[E]1-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]
环丙烷-1-甲酰胺
类似于用于制备2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]丙酰胺(实施例148,步骤E)所述的程序,用5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基甲酰基]环丙基]苯甲酰胺代替5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(25mg,16%)。MS:m/e=514.0[M+H]+。
实施例151
2-[6-(4-乙酰基哌嗪-1-基)-2-甲基-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
[A]N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]氨基甲酸叔丁酯
类似于用于制备N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯(实施例148,步骤A)所述的程序,用2-(叔丁氧基羰基氨基)乙酸([CAS RN 4530-20-5])代替2-(叔丁氧基羰基氨基)丙酸。通过柱色谱(100-200目径硅胶),用1∶20至1∶1EtOAc-石油醚的梯度洗脱纯化,得到标题化合物,为白色固体(2.5g,66%)。MS:m/e=276.8[M+H-tert-Bu]+。
[B]2-氨基-N-[(3,4-二氯苯基)甲基]乙酰胺盐酸盐
类似于用于制备2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐(实施例148,步骤B)所述的程序,用N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]氨基甲酸叔丁酯代替N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]氨基甲酸叔丁酯。获得标题化合物,为白色固体并将粗产物用于连续反应步骤(1.3g,67%)。MS:m/e=233.1[M+H]+。
[C]5-(4-乙酰基哌嗪-1-基)-N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-2-
硝基苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺(实施例148,步骤C)所述的程序,用2-氨基-N-[(3,4-二氯苯基)甲基]乙酰胺盐酸盐代替2-氨基-N-[(3,4-二氯苯基)甲基]丙酰胺盐酸盐。通过柱色谱(100-200目径硅胶),用1∶100至1∶20甲醇-DCM的梯度洗脱纯化,得到标题化合物,为黄色固体(1.6g,71%)。MS:m/e=508.6[M+H]+。
[D]5-(4-乙酰基哌嗪-1-基-2-氨基-N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙
基]苯甲酰胺
类似于用于制备5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]苯甲酰胺(实施例148,步骤D)所述的程序,用5-(4-乙酰基哌嗪-1-基)-N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-2-硝基苯甲酰胺代替5-(4-乙酰基哌嗪-1-基)-N-[1-[(3,4-二氯苯基)甲基氨基]-1-氧代丙-2-基]-2-硝基苯甲酰胺。通过柱色谱(100-200目径硅胶),用1∶100至1∶20甲醇-DCM的梯度洗脱纯化,得到标题化合物,为浅褐色固体(0.9g,60%)。MS:m/e=478.1[M+H]+。
[E]2-[6-(4-乙酰基哌嗪-1-基)-2-甲基-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯
基)甲基]乙酰胺
向5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]苯甲酰胺(200mg,0.42mmol)在乙醇(10mL)中的溶液中加入乙酸(24μg,0.42mmol)和原乙酸三甲酯(50mg,0.42mmol;[CAS RN1445-45-0])并将反应混合物加热至回流过夜。将粗反应混合物在减压下浓缩并且通过反相制备型HPLC用乙腈-水梯度洗脱纯化。获得标题化合物,为白色固体(120mg,57%)。MS:m/e=502.1[M+H]+。
实施例152
2-[6-(4-乙酰基哌嗪-1-基)-2,4-二氧代-1H-喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
向5-(4-乙酰基哌嗪-1-基)-2-氨基-N-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]苯甲酰胺(实施例151,步骤D)(200mg,0.42mmol)在DCM(10mL)中的溶液中加入N,N’-羰二咪唑(102mg,0.63mmol;[CAS RN 530-62-1])并将反应混合物加热至80℃过夜。将粗反应混合物在减压下浓缩并且通过反相制备型HPLC用乙腈-水梯度洗脱纯化。获得标题化合物,为白色固体(100mg,47%)。MS:m/e=504.1[M+H]+。
实施例153
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[1-(3,4-二氯苯基)-3-甲氧基丙基]乙酰胺
在氮气气氛下,向2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酸(中间体A-2)(11.9mg,0.036mmol)在无水DMF(1mL)中的溶液中加入HATU(20.5mg,0.054mmol;[CASRN 148893-10-1])和DIPEA(50μL,0.29mmol)。然后,加入1-(3,4-二氯苯基)-3-甲氧基丙-1-胺盐酸盐(11.6mg,0.043mmol;[CAS RN 1803587-38-3])并且将反应混合物通过微波辐照加热至100℃持续10min。加入水(1mL)并且粗反应产物通过反相制备型HPLC用乙腈-水梯度洗脱纯化。获得标题化合物,为白色固体(1.4mg,7%)。MS:m/e=546.1[M+H]+。
实施例154
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-氰基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(68mg,0.15mmol)在DCM(2mL)中的溶液中加入HATU(86.2mg,0.23mmol;[CAS RN 148893-10-1])和DIPEA(79μL,0.45mmol)。然后,加入2-氰基乙酸(19.3mg,0.23mmol;[CAS RN 372-09-8])并且将反应混合物通过微波辐照加热至100℃持续10min。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为浅黄色固体(35.1mg,45%)。MS:m/e=517.2[M+H]+。
实施例155
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-氰基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(50mg,0.11mmol)在无水DMF(2mL)中的溶液中加入(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(69.4mg,0.13mmol;PyBOP;[CAS RN 128625-52-5])和DIPEA(97μL,0.56mmol)。然后,加入3-氰基丙酸(13.2mg,0.13mmol;[CAS RN16051-87-9])并将反应混合物在室温搅拌1h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(5mg,9%)。MS:m/e=531.3[M+H]+。
实施例156至159
根据对于实施例155的合成所述的程序,另外的实施例制备自N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)以及如在表13中所示的相应羧酸。结果编辑在表13并且包括实施例156至159。
表13
实施例160
4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌啶-1-甲酸甲酯
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(50mg,0.11mmol)在无水DMF(2mL)中的溶液中加入氯甲酸甲酯(10μL,0.13mmol;[CAS RN 79-22-1])和DIPEA(97μL,0.56mmol)并将反应混合物在室温搅拌1h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(40mg,70%)。MS:m/e=508.3[M+H]+。
实施例161
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[3-氯-5-(三氟甲基)苯基]甲基]乙酰胺
在氮气气氛下,向2-[6-(1-叔丁氧基羰基-4-哌啶基)-4-氧代喹唑啉-3-基]乙酸(中间体A-8,步骤E)(100mg,0.26mmol)在DCM(2mL)中的溶液中加入(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(161mg,0.31mmol;PyBOP;[CAS RN 128625-52-5])和DIPEA(225μL,1.29mmol)。然后,加入(3-氯-5-(三氟甲基)苯基)甲胺(59.5mg,0.28mmol;[CASRN400771-41-7])并将反应混合物在室温搅拌1h。将溶剂在减压下蒸发并加入在二烷中的4M HCl(2mL)。在室温搅拌15min之后,将反应混合物在减压下浓缩并将粗反应混合物重新溶解在无水DMF(2mL)中。在氮气气氛下,加入DIPEA(500μL,2.86mmol)、(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(161mg,0.31mmol;PyBOP;[CAS RN 128625-52-5])和乙酸(30μL,0.52mmol)并将反应混合物在室温搅拌1h。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(46mg,35%)。MS:m/e=521.3[M+H]+。
实施例162至164
根据对于实施例161的合成所述的程序,另外的实施例制备自2-[6-(1-叔丁氧基羰基-4-哌啶基)-4-氧代喹唑啉-3-基]乙酸(中间体A-8,步骤E)以及如在表14中所示的相应苄胺。结果编辑在表14并且包括实施例162至164。
表14
实施例165
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(2-氨磺酰基乙酰基)哌啶-4-基]喹唑啉-3-基]乙酰胺
[A]N-[(3,4-二氯苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙
酰胺
在氮气气氛下,向2-[6-(1-叔丁氧基羰基-4-哌啶基)-4-氧代喹唑啉-3-基]乙酸(中间体A-8,步骤E)(2.03g,5.23mmol)在DCM(50mL)中的溶液中加入HATU(2.98g,7.84mmol;[CAS RN 148893-10-1])和DIPEA(2.74mL,15.7mmol)。然后,加入1-(3,4-二氯苯基)-N-甲基甲胺(1.0g,5.23mmol;[CAS RN 5635-67-6])并将反应混合物在室温搅拌1h。向反应混合物中加入在二烷中的4M HCl(15mL)并在室温继续搅拌过夜。通过加入2M氢氧化钠溶液将反应混合物设置为pH 14并且水相用DCM(3×200mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩。通过MPLC(20g SiO2,Telos-筒),用0至5%甲醇-DCM梯度洗脱纯化,得到标题化合物,为浅褐色固体(0.77g,32%)。MS:459.3(M+H)+。
[B]N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(2-氨磺酰基乙酰基)哌
啶-4-基]喹唑啉-3-基]乙酰胺
在氮气气氛下,向N-[(3,4-二氯苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(50mg,0.11mmol)在无水DMF(2mL)中的溶液中加入HATU(62.1mg,0.16mmol;[CAS RN 148893-10-1])和DIPEA(150μL,0.86mmol)。然后,加入2-氨磺酰基乙酸(23.9mg,0.16mmol;[CAS RN 17551-00-7])并将反应混合物通过微波辐照加热至100℃持续10min。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为无色油状物(19mg,30%)。MS:m/e=580.1[M+H]+。
实施例166至183
根据对于实施例165的合成所述的程序,另外的实施例制备自N-[(3,4-二氯苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(实施例165,步骤A)以及如在表15中所示的相应羧酸。结果编辑在表15并且包括实施例166至183。
表15
实施例184
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺
[A]4-羟基-4-(4-氧代-3H-喹唑啉-6-基)哌啶-1-甲酸叔丁酯
在-78℃,向6-溴-3,4-二氢喹唑啉-4-酮(100mg,0.44mmol;[CAS RN32084-59-6])在THF(12.5mL)中的溶液中在5min内逐滴加入MeLi(0.2mL,0.58mmol)。在10min之后,在10min内逐滴加入在己烷中的1.6Mn-BuLi (1.8mL,1.33mmol)并在-78℃继续搅拌1h。在-78℃,在10min内逐滴加入4-氧代哌啶-1-甲酸叔丁酯(900mg,0.44mmol)在THF(2.5mL)中的溶液并继续搅拌2h。反应混合物通过加入饱和NH4Cl溶液(25mL)猝灭并且水相用EtOAc(3×10mL)萃取。合并的有机相用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用80%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为浅黄色固体(600mg,39%)。MS:346.3(M+H)+。
[B]4-羟基-4-[3-(2-甲氧基-2-氧代乙基)-4-氧代喹唑啉-6-基]哌啶-1-甲酸叔
丁酯
将4-羟基-4-(4-氧代-3H-喹唑啉-6-基)哌啶-1-甲酸叔丁酯(2.0g,5.80mmol)、K2CO3(1.60g,11.59mmol)和溴乙酸甲酯(1.15g,7.54mmol)在CH3CN(25mL)中的悬浮液在回流温度下搅拌6h。将反应混合物冷却至室温并在减压下除去挥发物。粗反应产物用EtOAc(100mL)稀释并用H2O(2×50mL)和饱和NaCl溶液(50mL)洗涤。合并的有机相用无水Na2SO4干燥并在减压下浓缩,得到标题化合物,为褐色固体(1.60g,66%),将其在未经进一步纯化下用于连续反应步骤。MS:417.9(M+H)+。
[C]2-[6-[4-羟基-1-[(2-甲基丙-2-基)氧基羰基]哌啶-4-基]-4-氧代喹唑啉-3-
基]乙酸
在0℃,在5min内向4-羟基-4-[3-(2-甲氧基-2-氧代乙基)-4-氧代喹唑啉-6-基]哌啶-1-甲酸叔丁酯(1.40g,3.36mmol)在THF(20mL)中的冷却溶液中逐滴加入LiOH·H2O(420mg,10.07mmol)在H2O(2.5mL)中的溶液,接着在室温搅拌3h。将粗反应混合物在减压下浓缩并将所获得的残余物用H2O(25mL)稀释并用二乙醚洗涤。水相通过加入1M的HCl溶液中和,然后在减压下浓缩,得到标题化合物,为褐色固体(1.20g,粗产物)。粗物料在未经进一步纯化下用于连续反应步骤。MS:404.1(M+H)+。
[D]4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-
基]-4-羟基哌啶-1-甲酸叔丁酯
在氮气气氛下,向2-[6-[4-羟基-1-[(2-甲基丙-2-基)氧基羰基]哌啶-4-基]-4-氧代喹唑啉-3-基]乙酸(1.20g,2.98mmol)和1-(3,4-二氯苯基)-N-甲基甲胺(622mg,3.28mmol;[CAS RN 5635-67-6])在DMF(20mL)中的溶液中加入TBTU(1.19g,3.72mmol;[CASRN 125700-67-6])和N-甲基吗啉(0.61mL,5.96mmol)。在将反应混合物在室温搅拌12h之后,溶剂在减压下除去并将所得残余物用EtOAc(100mL)稀释,接着用H2O(3×50mL)和饱和NaCl溶液(2×50mL)洗涤。合并的有机相用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),使用80%EtOAc-己烷作为洗脱剂纯化,得到标题化合物,为灰白色固体(800mg,42%,经过两个步骤)。MS:575.1(M+H)+.
[E]2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯
基)甲基]-N-甲基乙酰胺
在0℃,向4-[3-[2-[(3,4-二氯苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-4-羟基哌啶-1-甲酸叔丁酯(500mg,0.87mmol)在二烷(10mL)中的搅拌溶液中加入在二烷中的4M HCl(5mL)并将反应混合物在室温搅拌4h。将反应混合物在减压下浓缩并且粗物料通过与TBME(2×10mL)研磨纯化。在0℃,向沉淀中加入DCM(10mL)和Et3N(0.35mL,0.25mmol),接着在5min内逐滴加入乙酰氯(0.09mL,1.27mmol)在DCM(5mL)中的溶液。在将反应混合物在室温搅拌6h之后,加入DCM(10mL)并且有机相用H2O(10mL)和饱和NaCl溶液(10mL)洗涤。合并的有机相用无水Na2SO4干燥并在减压下浓缩。粗反应产物通过柱色谱(100-200目径硅胶),用1∶50至1∶40甲醇-EtOAc的梯度洗脱纯化,得到标题化合物,为灰白色固体(150mg,33%,经过两个步骤)。MS:517.2(M+H)+。
实施例185
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺
类似于用于制备2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺(实施例184)所述的程序,在步骤D中用2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐(实施例56,步骤A)代替1-(3,4-二氯苯基)-N-甲基甲胺[CASRN5635-67-6],制备标题化合物。通过柱色谱(100-200目径硅胶),用1∶50至1∶40甲醇-EtOAc的梯度洗脱纯化,得到标题化合物,为灰白色固体(80mg,34%,经过两个步骤)。MS:508.2(M+H)+。
实施例186
硝酸[2-[4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌啶-1-基]-2-氧代乙基]酯
[A]2-[6-[1-(2-溴乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基
苯基)甲基]-N-甲基乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-(4-氧代-6-哌啶-4-基喹唑啉-3-基)乙酰胺(中间体A-9)(25mg,0.056mmol)在DCM(2.5mL)中的溶液中加入Et3N(23μL,0.17mmol)。然后,在0℃,加入溴乙酰氯(6μL,0.084mmol)在DCM(0.5mL)中的溶液并将反应混合物搅拌1h。溶剂在减压下除去并将所得的残余物用H2O(5mL)稀释并用DCM(2×10mL)萃取。合并的有机相用无水Na2SO4干燥并在减压下浓缩。通过制备型TLC(Merck二氧化硅TLC玻璃板,20x20cm),用庚烷-EtOAc(10∶1)的混合物洗脱纯化,得到标题化合物,为灰白色固体(15mg,44%)。MS:m/e=571.0[M+H]+。
[B]硝酸[2-[4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧
代喹唑啉-6-基]哌啶-1-基]-2-氧代乙基]酯
在氮气气氛下,向2-[6-[1-(2-溴乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺(0.18g,0.30mmol)在乙腈(10mL)中的溶液中加入硝酸银(0.20g,0.11mmol)并将反应混合物在70℃搅拌24h。蒸发溶剂并通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为灰白色固体(30mg,18%)。MS:m/e=552.6[M+H]+。
实施例187
2-[6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺
[A]6-溴-8-氟-3H-喹唑啉-4-酮
将2-氨基-5-溴-3-氟苯甲酸(1.0g,4.27mmol;[CAS RN874784-14-2])和乙酸甲脒(0.89g,8.55mmol;[CAS RN 3473-63-0])在2-甲氧基乙醇(12mL)中的悬浮液在微波辐照下加热至150℃持续45min。将所形成的沉淀滤出,晶体用少量EtOH洗涤并在减压下干燥。分离标题化合物,为白色粉末(0.80g,77%)。MS:m/e=245.0[M+H]+。
[B]2-(6-溴-8-氟-4-氧代喹唑啉-3-基)乙酸甲酯
将6-溴-8-氟-3H-喹唑啉-4-酮(0.8g,3.29mmol)、2-溴乙酸甲酯(1.01g,0.61mL,6.58mmol;[CAS RN 96-32-2])和碳酸钾(1.36g,9.88mmol)在DMF(12mL)中的悬浮液在微波辐照下加热至80℃持续30min。粗反应产物通过柱色谱(100-200目径硅胶),用0∶1至1∶0EtOAc-己烷的梯度洗脱纯化,得到标题化合物,为浅黄色固体(0.67g,64%)。MS:317.0(M+H)+。
[C]2-(6-溴-8-氟-4-氧代喹唑啉-3-基)-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙
酰胺
在Ar气氛下,向2-(6-溴-8-氟-4-氧代喹唑啉-3-基)乙酸甲酯(0.65g,2.06mmol)和2-氯-4-(甲基氨基甲基)苯甲腈盐酸盐(实施例56,步骤A)(0.47g,2.17mmol)在THF(10mL)中的溶液中加入二(三甲基铝)-1,4-二氮杂二环[2.2.2]辛烷加合物(0.64g,2.48mmol;[CAS RN 137203-34-0])并将反应混合物在微波辐照下加热至130℃持续30min。粗反应产物通过柱色谱(100-200目径硅胶),用0∶1至1∶0EtOAc-己烷的梯度洗脱纯化,得到标题化合物,为浅黄色固体(0.54g,47%)。MS:465.1(M+H)+。
[D]4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-8-氟-4-氧代喹
唑啉-6-基]-3,6-二氢-2H-吡啶-1-甲酸叔丁酯
将2-(6-溴-8-氟-4-氧代喹唑啉-3-基)-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺(0.54g,0.97mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.30g,0.97mmol;[CAS RN286961-14-6])、三苯基膦(51mg,0.19mmol;CAS RN 603-35-0])和磷酸三钾(0.21g,0.97mmol;[CAS RN 7778-53-2])在水(2.5mL)和1,2-二乙氧基乙醇(10mL)的混合物中的溶液通过超声处理由Ar脱气10min。最后,在Ar气氛下,加入Pd(OAc)2(22mg,0.097mmol;[CAS RN 3375-31-3])并将反应混合物加热至90℃持续90min。将反应混合物在减压下蒸发并通过柱色谱(100-200目径硅胶),用0∶1至1∶0EtOAc-己烷的梯度洗脱纯化,得到标题化合物,为浅黄色固体(0.40g,62%)。MS:568.4(M+H)+。
[E]N-[(3-氯-4-氰基苯基)甲基]-2-(8-氟-4-氧代-6-哌啶-4-基喹唑啉-3-基)-
N-甲基乙酰胺
向4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-8-氟-4-氧代喹唑啉-6-基]-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(0.40g,0.60mmol)在MeOH(10mL)中的脱气溶液中加入20%Pd(OH)2/C(0.042g,0.060mmol;[CASRN 12135-22-7])并将反应混合物在氢气(大气压力)下、在室温搅拌2h。反应混合物通过过滤并将有机相在真空下浓缩。将残余物重新溶解在二烷(5mL)中,加入在二烷中的4M HCl(5mL)并将反应混合物在室温搅拌2h。通过加入2M氢氧化钠溶液将反应混合物设置为pH 14并且水相用DCM(3×200mL)萃取。合并的有机相用MgSO4干燥并在减压下浓缩,得到标题化合物,为浅褐色固体(0.22g,37%;48%纯度,根据LC-MS)。MS:468.3(M+H)+。
[F]2-[6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯
基)甲基]-N-甲基乙酰胺
在氮气气氛下,向N-[(3-氯-4-氰基苯基)甲基]-2-(8-氟-4-氧代-6-哌啶-4-基喹唑啉-3-基)-N-甲基乙酰胺(108mg,0.11mmol;48%纯度)在无水DMF(2mL)中的溶液中加入(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(69.4mg,0.13mmol;PyBOP;[CAS RN128625-52-5])和DIPEA(97μL,0.56mmol)。然后,加入乙酸(8.0mg,0.13mmol)并将反应混合物在室温搅拌过夜。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为灰白色固体(4.4mg,8%)。MS:m/e=510.4[M+H]+。
实施例188
N-[(3-氯-4-氰基苯基)甲基]-2-[8-氟-6-[1-(3-甲氧基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
类似于用于制备2-[6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺(实施例187)所述的程序,在步骤F用3-甲氧基丙酸([CAS RN 2544-06-1])代替乙酸,制备标题化合物。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为灰白色固体(6.6mg,11%)。MS:m/e=554.4[M+H]+。
实施例189
2-[6-(1-乙酰基哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺
类似于用于制备2-[6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺(实施例187)所述的程序,在步骤A中用5-氨基-2-溴吡啶-4-甲酸([CAS RN 1242336-80-6])代替2-氨基-5-溴-3-氟苯甲酸,制备标题化合物。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(8.1mg,15%)。MS:m/e=493.4[M+H]+。
实施例190
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-甲氧基丙酰基)哌啶-4-基]-4-氧代吡啶并[3,4-d]嘧啶-3-基]-N-甲基乙酰胺
类似于用于制备2-[6-(1-乙酰基哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺(实施例189)所述的程序,在步骤F中用3-甲氧基丙酸([CAS RN 2544-06-1])代替乙酸,制备标题化合物。通过反相制备型HPLC利用乙腈-水的梯度洗脱纯化,得到标题化合物,为白色固体(10mg,17%)。MS:m/e=537.4[M+H]+。
实施例A
式(I)的化合物可以以本身已知的方式用作活性成分用于生产以下组成的片剂:
实施例B
式(I)的化合物可以以本身已知的方式用作活性成分用于生产以下组成的胶囊:
Claims (36)
1.式(I)的化合物
R1是羟基烷基、二羟基烷基、羟基环烷基、烷氧基、卤代烷氧基、烷氧基烷氧基烷基、烷氧基烷基、卤代烷氧基烷基、烷基、卤代烷基、烷基磺酰基、卤代烷基磺酰基、氨基磺酰基烷基、氰基烷基、硝酸烷基、取代的环烷基、取代的环烷基烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷基羰基、羧基、卤素和氰基;
R2和R3独立地选自H、烷基和环烷基;
或者R2和R3与它们连接的碳一起形成环烷基;
A1是-CH-、-C(OH)-或-N-;
A2是-C(O)-、-C(O)CH2-、-CH2-、-NR11C(O)-、-NR11C(O)CH2-、-S(O)2-;
A3是-CR8-或-N-;
R4和R5中的一个是H或烷基并且另一个是H、烷氧基烷基、烷氧基羰基烷基、卤代烷氧基羰基烷基、烷基、卤代烷基、羧基烷基、环烷基或取代的氨基羰基烷基,其中取代的氨基羰基烷基在氮原子上被两个独立地选自以下各项的取代基取代:H、烷基、环烷基和取代的苯基,其中取代的苯基被一至三个独立地选自以下各项的取代基取代:H、烷基、卤代烷基和环烷基;
或者R4和R5与它们连接的氮和碳原子一起形成杂环烷基;
R6是H或烷基;
R7、R8和R9独立地是H、烷基、环烷基、卤素或氰基;
R10是取代的芳基或取代的杂芳基,其中取代的芳基或取代的杂芳基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基、卤代烷基磺酰基和五氟-λ6-硫烷基;
R11是H、烷基或环烷基;
R12和R13都是H或R12和R13一起形成-(CH2)p-;
R14是H、烷基或羟基;
n、m和p独立地为零、1或2;
或药用盐。
2.根据权利要求1的化合物,其中
R1是烷氧基、卤代烷氧基、烷氧基烷基、卤代烷氧基烷基、烷基、卤代烷基、烷基磺酰基、卤代烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷基羰基、羧基、卤素和氰基;
R2和R3独立地选自H、烷基和环烷基;
或者R2和R3与它们连接的碳一起形成环烷基;
A1是-CH-或-N-;
A2是-C(O)-、-C(O)CH2-、-CH2-、-NR11C(O)-、-NR11C(O)CH2-、-S(O)2-;
R4和R5中的一个是H或烷基并且另一个是H、烷氧基羰基烷基、卤代烷氧基羰基烷基、烷基、卤代烷基、羧基烷基、环烷基或取代的氨基羰基烷基,其中取代的氨基羰基烷基在氮原子上被两个独立地选自以下各项的取代基取代:H、烷基、环烷基和取代的苯基,其中取代的苯基被一至三个独立地选自以下各项的取代基取代:H、烷基、卤代烷基和环烷基;
或者R4和R5与它们连接的氮和碳原子一起形成杂环烷基;
R6是H或烷基;
R7、R8和R9独立地是H、烷基、环烷基、卤素或氰基;
R10是取代的芳基或取代的杂芳基,其中取代的芳基或取代的杂芳基被一至三个选自以下各项的取代基取代:H、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、氰基、烷基磺酰基、卤代烷基磺酰基和五氟-λ6-硫烷基;
R11是H、烷基或环烷基;
R12和R13都是H或R12和R13一起形成-(CH2)p-;
R14是H、烷基或羟基;
n、m和p独立地为零、1或2;
或药用盐。
3.根据权利要求1至2中任一项的化合物,其中R1是羟基烷基、二羟基烷基、羟基环烷基、烷氧基、烷氧基烷氧基烷基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、氰基、硝酸烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
4.根据权利要求1至2中任一项的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的杂芳基、取代的杂环烷基或取代的芳基,其中取代的环烷基、取代的环烷基烷基、取代的杂芳基、取代的杂环烷基和取代的芳基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
5.根据权利要求1至2中任一项的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的二烷基、取代的氮杂环丁烷基、取代的吗啉基和或取代的苯基,其中,取代的环烷基、取代的环烷基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的二烷基、取代的氮杂环丁烷基、取代的吗啉基和取代的苯基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
6.根据权利要求1至2中任一项的化合物,其中R1是烷氧基、烷氧基烷基、烷基、烷基磺酰基、氨基磺酰基烷基、取代的环烷基、取代的环烷基烷基、卤代烷基、羟基烷基、二羟基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的氮杂环丁烷基、取代的吗啉基和或取代的苯基,其中,取代的环烷基、取代的环烷基烷基、取代的呋喃基、取代的唑基、取代的异唑基、取代的咪唑基、取代的吡咯基、取代的吡啶基、取代的氧杂环丁烷基、取代的四氢呋喃基、取代的四氢吡喃基、取代的氮杂环丁烷基、取代的吗啉基和取代的苯基被一至三个选自以下各项的取代基取代:H、氨基、烷基、卤代烷基、烷氧基、烷基羰基、羧基和卤素。
7.根据权利要求1至2中任一项的化合物,其中R1是烷氧基烷基、烷基、取代的环烷基或取代的环烷基烷基,其中取代的环烷基和取代的环烷基烷基被一至三个选自以下各项的取代基取代:H、卤代烷基和卤素。
8.根据权利要求1至2中任一项的化合物,其中R1是烷氧基烷基或烷基。
9.根据权利要求1至2中任一项的化合物,其中R1是烷基。
10.根据权利要求1至2中任一项的化合物,其中A1是-CH-或-N-。
11.根据权利要求1至2中任一项的化合物,其中R2是H或烷基。
12.根据权利要求1至2中任一项的化合物,其中R3是H。
13.根据权利要求1至2中任一项的化合物,其中R2和R3是H。
14.根据权利要求1至2中任一项的化合物,其中R4是H、烷氧基羰基烷基、烷基、羧基烷基、环烷基或在氮原子上被一个H和一个烷基取代的氨基羰基烷基。
15.根据权利要求1至2中任一项的化合物,其中R5是H、烷氧基烷基、烷基、在氮原子上被两个独立地选自H和烷基的取代基取代的氨基羰基烷基。
16.根据权利要求1至2中任一项的化合物,其中R5是H、烷基、在氮原子上被两个独立地选自H和烷基的取代基取代的氨基羰基烷基。
17.根据权利要求1至2中任一项的化合物,其中R4是H或烷基和R5是H。
18.根据权利要求1至2中任一项的化合物,其中R6是H。
19.根据权利要求1至2中任一项的化合物,其中R7、R8和R9是H。
21.根据权利要求1至2中任一项的化合物,其中R10是被一至三个选自卤素和氰基的取代基取代的苯基。
22.根据权利要求1至2中任一项的化合物,其中R11是H和烷基。
23.根据权利要求1至2中任一项的化合物,其中n为1并且m为1或2。
24.根据权利要求1至2中任一项的化合物,其中n和m为1。
25.根据权利要求1至2中任一项的化合物,其中p为1。
26.根据权利要求1至2中任一项的化合物,其中R12和R13都是H。
27.根据权利要求1至2中任一项的化合物,其中R14是H。
28.根据权利要求1至2中任一项的化合物,其中A2是-C(O)-。
29.根据权利要求1至2中任一项的化合物,其中A3是-CR8-。
30.根据权利要求1的化合物,其中
R1是烷氧基烷基或烷基;
R2、R3、R5、R6、R7、R8、R9、R12、R13和R14全部是H;
A1是-CH-或-N-;
A2是-C(O)-;
R4是H或烷基;
R10是被一至三个选自卤素和氰基的取代基取代的苯基;
n和m为1;
或药用盐。
31.根据权利要求1的化合物,其选自
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-甲基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N,N-二甲基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)-N-苯基丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-甲基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N,N-二甲基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-(2-甲基丙基)-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-苯基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-苄基-3-[4-(三氟甲基)苯基]丙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-N-甲基-3-(4-硝基苯基)丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(6-氯吡啶-3-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(5-氯吡啶-2-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[1-(4-氯苯基)乙基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-(1,3-苯并二氧杂环戊烯-5-基甲基)乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[6-(三氟甲基)吡啶-3-基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(6-氰基吡啶-3-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-硝基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氟-3-(三氟甲氧基)苯基]甲基]乙酰胺;
(3R)-3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(4-氯苯基)丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2,6-二氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-2-甲氧基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氰基-2-(2,2,2-三氟乙氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氰基-2-甲基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2-氯吡啶-4-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-硝基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(五氟-λ6-硫烷基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-甲基-4-甲基磺酰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4,5-二氯吡啶-2-基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-甲基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(2,6-二氯吡啶-4-基)甲基]-N-甲基乙酰胺;
6-(4-乙酰基哌嗪-1-基)-3-[2-[2-(4-氯苯基)吡咯烷-1-基]-2-氧代乙基]喹唑啉-4-酮;
6-(4-乙酰基哌嗪-1-基)-3-[2-[(2R)-2-(4-甲基苯基)吡咯烷-1-基]-2-氧代乙基]喹唑啉-4-酮;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[2-(3,4-二氯苯基)乙基]乙酰胺;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]氨基]-3-(3,4-二氯苯基)-N-甲基丙酰胺;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸甲酯;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]丙酸;
3-[[2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰基]-[(3,4-二氯苯基)甲基]氨基]-N-甲基丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3,5-二氟苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-甲基丁酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-(4-戊酰基哌嗪-1-基)喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-甲氧基乙酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(2,2,2-三氟乙酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-[4-(环戊烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-[4-(环己烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-(4-丙酰基哌嗪-1-基)喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(2-甲基丙酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(3-氨基氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(2-氨磺酰基乙酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(4-氨磺酰基丁酰基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-氟环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3,3-二氟环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[4-[1-(三氟甲基)环丁烷羰基]哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-[4-(3-氯环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(3-甲氧基环丁烷羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(3-甲基氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(1-乙酰基氮杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-丙-2-基哌嗪-1-甲酰胺;
N-环丙基-4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酰胺;
N-环戊基-4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-甲酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-(2-甲氧基乙基)哌嗪-1-甲酰胺;
4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]-N-吡啶-3-基哌嗪-1-甲酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-(4-甲基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-(4-环戊基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-环己基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-环丙基磺酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-[4-(环丁基甲基磺酰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-基]乙酸甲酯;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-羟基乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2,3-二羟基丙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(环丁基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[(1-甲基吡咯-2-基)甲基]哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(1H-咪唑-2-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(1H-咪唑-5-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
3-[[4-[3-[2-[(3,4-二氯苯基)甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌嗪-1-基]甲基]呋喃-2-甲酸;
2-[6-[4-(环丙基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-(2-甲氧基乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(氧杂环丁烷-3-基甲基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-[2-(甲基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[2-(二甲基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[4-氧代-6-[4-[2-氧代-2-(丙-2-基氨基)乙基]哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(3,4-二氯苯基)甲基]-2-[6-[4-[2-(二乙基氨基)-2-氧代乙基]哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3,4-二氯苯基)甲基]-N-甲基-2-[6-[4-(2-吗啉-4-基-2-氧代乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[4-(2-苯胺基-2-氧代乙基)哌嗪-1-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
N-[(2-氯-4-氰基苯基)甲基]-2-[6-[4-(氧杂环丁烷-3-羰基)哌嗪-1-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)哌嗪-1-基]喹唑啉-3-基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-乙基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-丙-2-基乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[4-(三氟甲基)苯基]甲基]乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[[4-氯-3-(三氟甲氧基)苯基]甲基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[4-(氧杂环戊烷-3-基甲基)-1,4-二氮杂环庚烷-1-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-羟基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-甲氧基丙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(2-丙-2-基氧基乙酰基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(环丙烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-氟环丁烷羰基)哌啶4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3-氯环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(3,3-二氟环丁烷羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-[1-(氧杂环丁烷-2-羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-[1-(氧杂环丁烷-3-羰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(4-氯-3-氰基苯基)甲基]-N-甲基-2-[4-氧代-6-[1-(氧杂环戊烷-3-基甲基)哌啶-4-基]喹唑啉-3-基]乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-N-甲基-2-[6-(1-甲基磺酰基哌啶-4-基)-4-氧代喹唑啉-3-基]乙酰胺;
N-环丙基-N-[(3,4-二氯苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]乙酰胺;
2-[6-[2-乙酰基-2-氮杂二环[2.2.1]庚-5-基]-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]丙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基丙酰胺;
1-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]环丙烷-1-甲酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-2-甲基-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-2,4-二氧代-1H-喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]乙酰胺
及其药用盐。
32.根据权利要求1的化合物,其选自
2-(6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3(4H)-基)-N-(1-(3,4-二氯苯基)-3-甲氧基丙基)乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(2-氰基乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(3-氰基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3-氯-4-氰基苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
4-(3-(2-((3-氯-4-氰基苄基)(甲基)氨基)-2-氧代乙基)-4-氧代-3,4-二氢喹唑啉-6-基)哌啶-1-甲酸甲酯;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(3-氯-5-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(4-氟-3-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(4-氯-3-(三氟甲基)苄基)乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-(3,5-二氯苄基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(2-氨磺酰基乙酰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-(2-甲氧基乙氧基)乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-3-甲基丁酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基乙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-羟基-2-甲基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(R)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
(S)-N-(3,4-二氯苄基)-2-(6-(1-(2-羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(1-羟基环丁烷羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(2,3-二羟基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-2-(6-(1-(1-羟基环丙烷羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(四氢呋喃-2-羰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(6-(1-(2-甲基四氢呋喃-2-羰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙酰胺;
N-(3,4-二氯苄基)-N-甲基-2-(4-氧代-6-(1-(四氢呋喃-3-羰基)哌啶-4-基)喹唑啉-3(4H)-基)乙酰胺;
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-#N!-[(3,4-二氯苯基)甲基]-#N!-甲基乙酰胺;
2-[6-(1-乙酰基-4-羟基哌啶-4-基)-4-氧代喹唑啉-3-基]-#N!-[(3-氯-4-氰基苯基)甲基]-#N!-甲基乙酰胺;
硝酸[2-[4-[3-[2-[(3-氯-4-氰基苯基)甲基-甲基氨基]-2-氧代乙基]-4-氧代喹唑啉-6-基]哌啶-1-基]-2-氧代乙基]酯;
2-(6-(1-乙酰基哌啶-4-基)-8-氟-4-氧代喹唑啉-3(4H)-基)-N-(3-氯-4-氰基苄基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(8-氟-6-(1-(3-甲氧基丙酰基)哌啶-4-基)-4-氧代喹唑啉-3(4H)-基)-N-甲基乙酰胺;
2-(6-(1-乙酰基哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3(4H)-基)-N-(3-氯-4-氰基苄基)-N-甲基乙酰胺;
N-(3-氯-4-氰基苄基)-2-(6-(1-(3-甲氧基丙酰基)哌啶-4-基)-4-氧代吡啶并[3,4-d]嘧啶-3(4H)-基)-N-甲基乙酰胺;
及其药用盐。
33.根据权利要求1的化合物,其选自
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氯-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(4-氰基-3-氟苯基)甲基]乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3,4-二氯苯基)甲基]-N-甲基乙酰胺;
2-[6-(4-乙酰基哌嗪-1-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
2-[6-(1-乙酰基哌啶-4-基)-4-氧代喹唑啉-3-基]-N-[(3-氯-4-氰基苯基)甲基]-N-甲基乙酰胺;
N-[(3-氯-4-氰基苯基)甲基]-2-[6-[1-(2-甲氧基乙酰基)哌啶-4-基]-4-氧代喹唑啉-3-基]-N-甲基乙酰胺
及其药用盐。
35.一种药物组合物,所述药物组合物包含根据权利要求1至33中任一项的化合物和治疗惰性载体。
36.根据权利要求1至33中任一项的化合物用于制备药物的用途,所述药物用于治疗或预防眼病症。
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