CN113039185A - 5-[6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈衍生物和类似化合物作为tlr7-9拮抗剂用于治疗***性红斑狼疮 - Google Patents
5-[6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈衍生物和类似化合物作为tlr7-9拮抗剂用于治疗***性红斑狼疮 Download PDFInfo
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- CN113039185A CN113039185A CN201980073844.XA CN201980073844A CN113039185A CN 113039185 A CN113039185 A CN 113039185A CN 201980073844 A CN201980073844 A CN 201980073844A CN 113039185 A CN113039185 A CN 113039185A
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- CN
- China
- Prior art keywords
- methyl
- tetrahydropyrazolo
- morpholin
- quinoline
- carbonitrile
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 171
- 201000000596 systemic lupus erythematosus Diseases 0.000 title claims abstract description 21
- 239000005557 antagonist Substances 0.000 title claims abstract description 19
- 238000011282 treatment Methods 0.000 title claims abstract description 14
- SVFAPZKGXABADZ-UHFFFAOYSA-N 5-[2-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical class N1(N=CC=2CNCCC=21)C1CN(C1)CC1OCCN(C1)C1=C2C=CC=NC2=C(C=C1)C#N SVFAPZKGXABADZ-UHFFFAOYSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims abstract description 37
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims abstract description 35
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims abstract description 35
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims abstract description 35
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims abstract description 30
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 30
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000002393 azetidinyl group Chemical group 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- 208000005777 Lupus Nephritis Diseases 0.000 claims abstract description 11
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- -1 5, 6-dihydro-4H-pyrrolo [3,4-c ] pyrazolyl Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 102000002689 Toll-like receptor Human genes 0.000 claims description 9
- 108020000411 Toll-like receptor Proteins 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- NJPHNBYMDRVKHL-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC=2CNCCC=21)C1=C2C=CC=NC2=C(C=C1)C#N NJPHNBYMDRVKHL-UTKZUKDTSA-N 0.000 claims description 7
- BTYJQKDIALPOBT-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CNCC2)=C1)C1=C2C=CC=NC2=C(C=C1)C#N BTYJQKDIALPOBT-UTKZUKDTSA-N 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- YBNFBNPUBCOAII-GCJKJVERSA-N 5-[(2R,6S)-2-methyl-6-[[3-(6-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CN(CCC2=C1)C)C1=C2C=CC=NC2=C(C=C1)C#N YBNFBNPUBCOAII-GCJKJVERSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ZZKACNWEAVWJEO-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(3-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C(C2=C1CNCC2)C)C1=C2C=CC=NC2=C(C=C1)C#N ZZKACNWEAVWJEO-UTKZUKDTSA-N 0.000 claims description 3
- AVOLBQOLAYPTKV-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(3-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CNCCC2=C1C)C1=C2C=CC=NC2=C(C=C1)C#N AVOLBQOLAYPTKV-UTKZUKDTSA-N 0.000 claims description 3
- YIRBVVLGTYPMBV-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(3-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C(C=2CNCCC=21)C)C1=C2C=CC=NC2=C(C=C1)C#N YIRBVVLGTYPMBV-UTKZUKDTSA-N 0.000 claims description 3
- JERWJPDVRLHUBI-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(3-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CNCC2)=C1C)C1=C2C=CC=NC2=C(C=C1)C#N JERWJPDVRLHUBI-UTKZUKDTSA-N 0.000 claims description 3
- XIYZEDMMVHOYNK-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC2=C1CNCC2)C1=C2C=CC=NC2=C(C=C1)C#N XIYZEDMMVHOYNK-UTKZUKDTSA-N 0.000 claims description 3
- SLFPBDPLYAMHTK-UTKZUKDTSA-N 5-[(2R,6S)-2-methyl-6-[[3-(4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CNCCC2=C1)C1=C2C=CC=NC2=C(C=C1)C#N SLFPBDPLYAMHTK-UTKZUKDTSA-N 0.000 claims description 3
- FOAHBXYEJJGYPM-YKSBVNFPSA-N 5-[(2R,6S)-2-methyl-6-[[3-(6-propan-2-yl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C(C)(C)N1CC2=C(CC1)C=NN2C1CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=C2C=CC=NC2=C(C=C1)C#N FOAHBXYEJJGYPM-YKSBVNFPSA-N 0.000 claims description 3
- MWMJMIHHMKWABZ-YKSBVNFPSA-N 5-[(2R,6S)-2-methyl-6-[[3-(6-propan-2-yl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-2-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C(C)(C)N1CC=2C(CC1)=CN(N=2)C1CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=C2C=CC=NC2=C(C=C1)C#N MWMJMIHHMKWABZ-YKSBVNFPSA-N 0.000 claims description 3
- MMAXWUFLORODOH-OPYAIIAOSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(4R)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC=2[C@H](NCCC=21)C)C1=C2C=CC=NC2=C(C=C1)C#N MMAXWUFLORODOH-OPYAIIAOSA-N 0.000 claims description 3
- MMAXWUFLORODOH-LQWHRVPQSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(4S)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC=2[C@@H](NCCC=21)C)C1=C2C=CC=NC2=C(C=C1)C#N MMAXWUFLORODOH-LQWHRVPQSA-N 0.000 claims description 3
- UFXODFZGPWZVKQ-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(5R)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC2=C1CN[C@@H](C2)C)C1=C2C=CC=NC2=C(C=C1)C#N UFXODFZGPWZVKQ-HMFYCAOWSA-N 0.000 claims description 3
- GXMCBSITZKGVLQ-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(5R)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CN[C@@H](CC2=C1)C)C1=C2C=CC=NC2=C(C=C1)C#N GXMCBSITZKGVLQ-HMFYCAOWSA-N 0.000 claims description 3
- UFXODFZGPWZVKQ-SVMVAKDDSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(5S)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC2=C1CN[C@H](C2)C)C1=C2C=CC=NC2=C(C=C1)C#N UFXODFZGPWZVKQ-SVMVAKDDSA-N 0.000 claims description 3
- GXMCBSITZKGVLQ-SVMVAKDDSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(5S)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CN[C@H](CC2=C1)C)C1=C2C=CC=NC2=C(C=C1)C#N GXMCBSITZKGVLQ-SVMVAKDDSA-N 0.000 claims description 3
- LMWPZUCKGRDNKH-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(6R)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC=2CN[C@@H](CC=21)C)C1=C2C=CC=NC2=C(C=C1)C#N LMWPZUCKGRDNKH-HMFYCAOWSA-N 0.000 claims description 3
- FZDOSRHRPUTHLB-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(6R)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CN[C@@H](C2)C)=C1)C1=C2C=CC=NC2=C(C=C1)C#N FZDOSRHRPUTHLB-HMFYCAOWSA-N 0.000 claims description 3
- LMWPZUCKGRDNKH-SVMVAKDDSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC=2CN[C@H](CC=21)C)C1=C2C=CC=NC2=C(C=C1)C#N LMWPZUCKGRDNKH-SVMVAKDDSA-N 0.000 claims description 3
- FZDOSRHRPUTHLB-SVMVAKDDSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CN[C@H](C2)C)=C1)C1=C2C=CC=NC2=C(C=C1)C#N FZDOSRHRPUTHLB-SVMVAKDDSA-N 0.000 claims description 3
- RZLGDAZQCBGDKC-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7R)-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC2=C1[C@H](NCC2)C)C1=C2C=CC=NC2=C(C=C1)C#N RZLGDAZQCBGDKC-HMFYCAOWSA-N 0.000 claims description 3
- CAINYLVIIWIXSR-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7R)-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2[C@H](NCCC2=C1)C)C1=C2C=CC=NC2=C(C=C1)C#N CAINYLVIIWIXSR-HMFYCAOWSA-N 0.000 claims description 3
- BINPAIPGOFZKRR-HMFYCAOWSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7R)-7-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CNC[C@H]2C)=C1)C1=C2C=CC=NC2=C(C=C1)C#N BINPAIPGOFZKRR-HMFYCAOWSA-N 0.000 claims description 3
- RZLGDAZQCBGDKC-FGSXEWAUSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7S)-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=CC2=C1[C@@H](NCC2)C)C1=C2C=CC=NC2=C(C=C1)C#N RZLGDAZQCBGDKC-FGSXEWAUSA-N 0.000 claims description 3
- CAINYLVIIWIXSR-FGSXEWAUSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7S)-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2[C@@H](NCCC2=C1)C)C1=C2C=CC=NC2=C(C=C1)C#N CAINYLVIIWIXSR-FGSXEWAUSA-N 0.000 claims description 3
- BINPAIPGOFZKRR-SVMVAKDDSA-N 5-[(2R,6S)-2-methyl-6-[[3-[(7S)-7-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2C(CNC[C@@H]2C)=C1)C1=C2C=CC=NC2=C(C=C1)C#N BINPAIPGOFZKRR-SVMVAKDDSA-N 0.000 claims description 3
- BQGAGMFDIHWKHF-APWZRJJASA-N 5-[(2R,6S)-2-methyl-6-[[3-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C(C2=C1CNCC2)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BQGAGMFDIHWKHF-APWZRJJASA-N 0.000 claims description 3
- QYRCCCIPMIQGLG-APWZRJJASA-N 5-[(2R,6S)-2-methyl-6-[[3-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(C1)N1N=C2CNCCC2=C1C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N QYRCCCIPMIQGLG-APWZRJJASA-N 0.000 claims description 3
- CPYZXWJMQFFVNF-XXBNENTESA-N 5-[(2R,6S)-2-methyl-6-[[4-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC(CC1)N1N=CC=2CNCCC=21)C1=C2C=CC=NC2=C(C=C1)C#N CPYZXWJMQFFVNF-XXBNENTESA-N 0.000 claims description 3
- CNTVPWSEIBFAHI-XXBNENTESA-N 5-[(2R,6S)-2-methyl-6-[[4-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)piperidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC(CC1)N1N=C2C(CNCC2)=C1)C1=C2C=CC=NC2=C(C=C1)C#N CNTVPWSEIBFAHI-XXBNENTESA-N 0.000 claims description 3
- YXHKWJCKFKBXMT-GCJKJVERSA-N 5-[(2S,6R)-2-[[3-(3,5-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]-6-methylmorpholin-4-yl]quinoline-8-carbonitrile Chemical compound CC1=NN(C2=C1CN(CC2)C)C1CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=C2C=CC=NC2=C(C=C1)C#N YXHKWJCKFKBXMT-GCJKJVERSA-N 0.000 claims description 3
- MOXWKCKRNDZZLF-GCJKJVERSA-N 5-[(2S,6R)-2-[[3-(3,5-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-2-yl)azetidin-1-yl]methyl]-6-methylmorpholin-4-yl]quinoline-8-carbonitrile Chemical compound CC=1N(N=C2C=1CN(CC2)C)C1CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=C2C=CC=NC2=C(C=C1)C#N MOXWKCKRNDZZLF-GCJKJVERSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Description
本发明涉及用于哺乳动物的治疗和/或预防的有机化合物,尤其涉及用于治疗***性红斑狼疮或狼疮肾炎的TLR7和/或TLR8和/或TLR9的拮抗剂。
技术领域
自身免疫性***病(CTD)包括典型的自身免疫综合征,例如***性红斑狼疮(SLE)、原发性干燥综合征(pSjS)、混合性***病(MCTD)、皮肌炎/多发性肌炎(DM/PM)、类风湿关节炎(RA)和***性硬化症(SSc)。除RA以外,患者没有真正有效、安全的疗法。SLE代表典型的CTD,其发病率为20-150/100,000,并在不同器官引起广泛的炎症和组织损伤,从皮肤和关节的常见症状到肾、肺或心力衰竭。传统上,SLE已经用非特异性抗炎或免疫抑制药物治疗。但是,长期使用免疫抑制药物(例如皮质类固醇)仅部分有效,并伴有不良的毒性和副作用。贝利木单抗是过去50年中唯一获得FDA批准的用于狼疮的药物,即使其仅对部分SLE患者具有适度且延迟的疗效(Navarra,S.V.等人.Lancet 2011,377,721.)。其他生物制剂,例如抗CD20单克隆抗体(抗特定细胞因子的单克隆抗体或可溶性受体的单克隆抗体),已在大多数临床研究中失败。因此,需要新型的疗法,其在更大比例的患者组中提供持续的改善,并且对于在许多自身免疫以及自身炎症性疾病中的长期使用而言更安全。
Toll样受体(TLR)是模式识别受体(PRR)的重要家族,其可以在多种免疫细胞中引发广泛的免疫应答。内体TLR7、TLR8和TLR9作为天然的宿主防御传感器,可识别源自病毒、细菌的核酸,具体地,TLR7/TLR8和TLR9分别识别单链RNA(ssRNA)和单链CpG-DNA。然而,TLR7、TLR8、TLR9的异常核酸传感被认为是广泛的自身免疫性和自身炎性疾病的关键节点(Krieg,A.M.等人,Immunol.Rev.2007,220,251.Jiménez-Dalmaroni,M.J.等人,AutoimmunRev.2016,15,1.Chen,J.Q.等人Clinical Reviews in Allergy&Immunology 2016,50,1)。抗RNA和抗DNA抗体是SLE的公认诊断标志物,这些抗体可以将自身RNA和自身DNA传递至核内体。自身RNA复合物可以被TLR7和TLR8识别,而自身DNA复合物可以触发TLR9活化。实际上,在SLE(Systemic Lupus Erythematosus,***性红斑狼疮)患者中,自身RNA和自身DNA从血液和/或组织的清除缺陷明显。已有报道表明TLR7和TLR9在SLE组织中被上调,并分别与狼疮肾炎的长期性和活性有关。在SLE患者的B细胞中,TLR7表达与抗RNP抗体产生相关,而TLR9表达与IL-6和抗dsDNA抗体水平相关。同样地,在狼疮小鼠模型中,抗RNA抗体需要TLR7,而抗核小体抗体则需要TLR9。另一方面,小鼠中TLR7或人TLR8的过度表达促进自身免疫和自身炎症。此外,TLR8活化特别有助于mDC/巨噬细胞的炎性细胞因子分泌、嗜中性粒细胞胞外捕网过程(NETosis)、Th17细胞的诱导和Treg细胞的抑制。除了所述的TLR9在促进B细胞自身抗体产生中的作用外,pDC中自身DNA导致的TLR9活化还导致诱导I型IFN和其他炎症细胞因子。考虑到pDC和B细胞中TLR9的这些作用,二者均是自身免疫性疾病发病机理的关键因素,并且在许多自身免疫性疾病患者中广泛存在的自身DNA复合物可以很容易地活化TLR9,因此在抑制TLR7和TLR8通路的基础上,这对于进一步阻断自身DNA介导的TLR9通路可能具有额外益处。总而言之,TLR7、TLR8和TLR9通路代表了治疗自身免疫性疾病和自身炎症性疾病的新治疗靶点,对于这些疾病,尚无有效的不含类固醇和无细胞毒性的口服药物,并且从最上游抑制所有这些通路可能会产生令人满意的治疗效果。同样的,我们发明了靶向和抑制TLR7、TLR8和TLR9的口服化合物,用于治疗自身免疫性疾病和自身炎症性疾病。
发明内容
本发明涉及式(I)或式(Ia)的新型化合物,
其中
R2为未被取代或被C1-6烷基或卤代C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;
未被取代或被C1-6烷基取代一次或两次的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;或
5,6-二氢-4H-吡咯并[3,4-c]吡唑基;
R3为C1-6烷基;
L为氮杂环丁烷基或哌啶基;
或其药用盐。
本发明的另一目的涉及式(I)或式(Ia)的新型化合物、其生产、基于根据本发明化合物的药物及其制备以及式(I)或式(Ia)的化合物作为TLR7和/或TLR8和/或TLR9拮抗剂的用途,及用于治疗或预防***性红斑狼疮或狼疮肾炎的用途。式(I)或式(Ia)的化合物显示出优异的TLR7和/或TLR8和/或TLR9拮抗活性。另外,式(I)或式(Ia)的化合物还显示出良好的细胞毒性、溶解性、hPBMC、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
具体实施方式
定义
术语“C1-6烷基”表示含有1至6个,特别是1至4个碳原子的饱和、直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。特别的“C1-6烷基”基团是甲基、乙基和正丙基。
术语“卤素”和“卤代”在本文可互换使用,表示氟、氯、溴或碘。
术语“卤代C1-6烷基”表示C1-6烷基基团,其中C1-6烷基基团的至少一个氢原子已被相同或不同的卤素原子,特别是氟原子取代。卤代C1-6烷基的示例包括单氟-、二氟-或三氟-甲基、-乙基或-丙基、例如3,3,3-三氟丙基、2-氟乙基、三氟乙基、氟甲基、二氟甲基、二氟乙基或三氟甲基。
术语“LG”表示离去基团,其为在杂合键断裂中与一对电子分开的分子片段。离去基团可为阴离子或中性分子,但是在任一种情况下,至关重要的是离去基团能够稳定由于键异裂而产生的额外电子密度。常见的阴离子离去基团为卤化物和诸如OTf、OTs和OMs的磺酸酯。
术语“PG”表示保护基团,该保护基团通过官能团的化学修饰引入分子中,以在随后的化学反应中获得化学选择性。典型的保护基团为Boc、Cbz和Bn。
术语“非对映体”表示具有两个或更多个手性中心并且其分子并非彼此镜像的立体异构体。非对映体具有不同的物理性质,例如熔点、沸点、光谱特性和反应性。
术语“药用盐”表示在生物学上或其他方面不是不期望的盐。“药用盐”包括酸加成盐和碱加成盐。
“药用酸加成盐”是指与无机酸和有机酸形成的那些药用盐,所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可以选自脂肪族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,诸如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸、和水杨酸等。
术语“药用碱加成盐”表示与有机或无机碱形成的那些药用盐。可接受的无机碱的示例包括钠、钾、铵、钙、镁、铁、锌、铜、锰和铝盐。衍生自药用有机无毒碱的盐包括伯胺、仲胺和叔胺,取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、氨丁三醇、二环己胺,赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶和多胺树脂)的盐。
术语“药物活性代谢物”表示通过特定化合物或其盐在体内代谢产生的药理活性产物。进入人体后,大多数药物都是化学反应的底物,这些化学反应可能会改变其物理性质和生物学效应。这些通常影响本发明化合物极性的代谢转化改变了药物在体内分布和从体内***的方式。然而,在某些情况下,药物代谢是治疗效果所必需的。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,给药途径和形式,主治医学或兽医的判断和其他因素。
术语“药物组合物”表示包含治疗有效量的活性药物成分和一起施用于有此需要的哺乳动物(例如人)的药用赋形剂的混合物或溶液。
TLR7和/或TLR8和/或TLR9的拮抗剂
本发明涉及式(I)化合物,
其中
R2为未被取代或被C1-6烷基或卤代C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;
未被取代或被C1-6烷基取代一次或两次的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;或
5,6-二氢-4H-吡咯并[3,4-c]吡唑基;
R3为C1-6烷基;
L为氮杂环丁烷基或哌啶基;
或其药用盐。
本发明的另一个实施例是(ii),其为式(Ia)化合物,
其中
R2为未被取代或被C1-6烷基或卤代C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;
未被取代或被C1-6烷基取代一次或两次的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;或
5,6-二氢-4H-吡咯并[3,4-c]吡唑基;
R3为C1-6烷基;
L为氮杂环丁烷基或哌啶基;
或其药用盐。
本发明的进一步实施例是(iii),其为根据(i)或(ii)的式(I)或式(Ia)的化合物,其中
R2为未被取代或被甲基、乙基、异丙基或三氟甲基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;
未被取代或被甲基取代一次或两次的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;或
5,6-二氢-4H-吡咯并[3,4-c]吡唑基;
R3为甲基;
L为氮杂环丁烷基或哌啶基;
或其药用盐。
本发明的进一步实施例是(v),其为根据(i)至(v)中任一项的式(I)或式(Ia)的化合物或其药用盐,其中L为氮杂环丁烷基。
本发明的进一步实施例是(vi),其为根据(i)至(v)中任一项的式(I)或式(Ia)的化合物或其药用盐,其中R2为被C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被C1-6烷基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基。
本发明的进一步实施例是(vii),其为根据(i)至(vi)中任一项的式(I)或式(Ia)的化合物或其药用盐,其中R2为被甲基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被甲基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基。
本发明的另一实施例是(viii),其为根据(i)或(ii)的式(I)或式(Ia)的化合物,其中
R2为被C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被C1-6烷基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;
R3为C1-6烷基;
L为氮杂环丁烷基;
或其药用盐。
本发明的进一步实施例是(ix),其为根据(viii)的式(I)或式(Ia)的化合物,其中
R2为被甲基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被甲基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基;
R3为甲基;
L为氮杂环丁烷基;
或其药用盐。
本发明的另一实施例是(x),其为选自以下项的式(I)或式(Ia)的化合物:
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(6-甲基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(7,7-二甲基-5,6-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;和
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
或其药用盐、对映体或非对映体。
专利US20150105370中公开了多种用作本文参比的化合物,其显示了表1中汇总的TLR7和TLR9效能数据(未获得TLR8数据)。表1中的所有化合物均在末端位置具有芳香环(苯基或吡啶基)。然而,根据公开的效能数据,表1中仅一些化合物显示出良好的TLR7效能,而所有这些化合物均缺乏TLR9效能。US20150105370中公开的具有相同结构特征的更多实例证实了这种趋势,这表明末端芳基/杂芳基环不利于TLR9活性。
同时,合成了US20150105370中公开的化合物的更多类似物,诸如在末端芳基环上带有一些取代基的化合物R1、化合物R2,以确认SAR(结构-活性-关系)。但是根据表2所示的效能数据,末端芳基环上的取代基不一定能提高TLR9的效能。因此,本领域技术人员不会从US20150105370公开的信息中获得任何启发来进一步优化这种化学结构。
令人惊讶地,本发明的化合物显著改善了TLR9效能(与ER-888286相比>8倍),同时保持了优异的TLR7和TLR8效能。在另一实施例中,与来自US20150105370的参考化合物以及本文合成的参考化合物R1和R2相比,hERG特征和安全性比大大提高(参见表3)。式(I)或式(Ia)的化合物还显示出良好hPBMC、细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
表1.US20150105370中公开的化合物的TLR7和TLR9效能
合成
本发明的化合物可以通过任何常规方法制备。在以下方案和示例中提供了合成这些化合物及其原料的合适方法。除非另有说明,否则所有取代基,特别是R1至R4如上所定义。此外,除非另有明确说明,否则所有反应、反应条件、缩写和符号均具有有机化学领域普通技术人员众所周知的含义。
制备式(I)或式(Ia)的化合物的一般合成路线如下所示。
方案1
其中LG为离去基团,诸如卤素、OTf、OTs和OMs;PG为保护基团,诸如Boc和Cbz。
式(II)化合物与R1-X的偶联可以通过在高温下,在碱(诸如DIPEA或K2CO3)的存在下或在Buchwald-Hartwig胺化条件下(参见:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in Current Chemistry,2002,219,131-209;和其中引用的参考文献),使用催化剂(诸如RuPhos Pd G2)和碱(诸如Cs2CO3或K2CO3)而直接偶联实现,以提供式(IV)化合物。随后,在碱性条件(诸如DIPEA、TEA、K2CO3或2,6-二甲基吡啶)下使用Tf2O、TsCl或MsCl,将式(IV)化合物的羟基转变为离去基团(诸如OTf、OTs或OMs)。式(VI)化合物与式(VII)化合物的偶联可通过在高温,在碱(诸如NaH或Cs2CO3)的存在下直接偶联来实现,以得到式(VIII)化合物。式(VIII)化合物的保护基团可在高温或在酸性条件(诸如TFA)下,或在氢化条件下,使用催化剂(诸如Pd/C或Pd(OH)2/C)除去。在碱(诸如K2CO3、DIPEA或Cs2CO3)的存在下,将式(IX)化合物进一步与式(V)化合物偶联,以得到式(I)化合物。在一些实施例中,式(IX)化合物和式(V)化合物的偶联可得到含有源自(IX)的保护基团(例如Boc或Cbz)的产物,该保护基团将在获得最终的式(I)化合物之前除去。并且在另一个实施例中,具有末端仲胺的式(I)或式(Ia)的化合物通过在还原条件(诸如NaBH3CN或NaBH(OAc)3与甲醛、乙醛或丙酮)下的还原胺化反应进一步引入有烷基基团,诸如甲基、乙基或异丙基,以得到最终的式(I)或式(Ia)的化合物。
本发明的化合物可以以非对映体或对映体的混合物形式获得,它们可以通过本领域熟知的方法分离,例如(手性)HPLC或SFC。
本发明还涉及制备式(I)或式(Ia)的化合物的方法,所述方法包括以下步骤:
a)将式(V)化合物,
与式(IX)化合物,H-L-R2(IX),在碱的存在下偶联;
其中
在步骤a)中,碱可以是,例如,K2CO3、DIPEA或Cs2CO3。
根据上述方法生产的式(I)或式(Ia)的化合物也是本发明的目的。
适应症和治疗方法
本发明提供了可用作TLR7和/或TLR8和/或TLR9拮抗剂的化合物,其抑制通过TLR7和/或TLR8和/或TLR9的通路活化以及相应的下游生物学事件,所述下游生物学事件包括但不限于通过产生所有类型的细胞因子和所有形式的自身抗体介导的先天性和适应性免疫应答。因此,本发明的化合物可用于在表达此类受体的所有类型的细胞中阻断TLR7和/或TLR8和/或TLR9,所述细胞包括但不限于浆细胞样树突细胞、B细胞、T细胞、巨噬细胞、单核细胞、嗜中性粒细胞、角质形成细胞、上皮细胞。这样,所述化合物可用作***性红斑狼疮和狼疮肾炎的治疗剂或预防剂。
本发明提供在有需要的患者中治疗或预防***性红斑狼疮和狼疮肾炎的方法。
另一个实施例包括在需要这种治疗的哺乳动物中治疗或预防***性红斑狼疮和狼疮肾炎的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式(I)化合物、立体异构体、互变异构体、前药或其药用盐。
实例
通过参考以下实例将更充分地理解本发明。但是,它们不应被解释为限制本发明的范围。
缩写
通过参考以下实例将更充分地理解本发明。但是,它们不应被解释为限制本发明的范围。
本文使用的缩写如下:
ACN: 乙腈
Boc2O: 二碳酸二叔丁酯
CbzCl: 氯甲酸苄酯
DCM: 二氯甲烷
DEA: 二乙胺
DIPEA: N,N-二异丙基乙胺
DMA: 二甲基乙酰胺
DMF: N,N-二甲基甲酰胺
DMFDMA: N,N-二甲基甲酰胺二甲基缩醛
EtOAc or EA: 乙酸乙酯
FA: 甲酸
HLM 人肝微粒体
IC50: 半抑制浓度
LCMS 液相色谱-质谱
MS: 质谱
PE: 石油醚
Prep-HPLC: 制备型高效液相色谱
rt: 室温
RuPhos Pd G2: 氯(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)第2代
SFC: 超临界流体色谱
TEA: 三甲胺
TFA: 三氟乙酸
Tf2O: 三氟甲磺酸酐
THF: 四氢呋喃
v/v: 体积比
一般实验条件
使用以下仪器之一通过快速色谱法纯化中间体和最终化合物:i)Biotage SP1***和Quad 12/25Cartridge模块。ii)ISCO combi-flash色谱仪。硅胶品牌和孔径:i)KP-SIL粒径:40-60μm;ii)CAS登录号:硅胶:63231-67-4,粒径:47-60微米硅胶;iii)青岛海洋化学有限公司的ZCX,孔:200-300或300-400。
中间体和最终化合物使用XBridgeTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱、SunFireTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱、Phenomenex Synergi-C18(10μm,25×150mm)或Phenomenex Gemini-C18(10μm,25×150mm)在反相色谱柱上通过制备型HPLC纯化。Waters自动纯化***(样品管理器2767,泵2525,检测器:微量物质ZQ和UV 2487,溶剂体系:乙腈和0.1%氢氧化铵的水溶液;乙腈和0.1%FA的水溶液,或乙腈和0.1%TFA的水溶液)。或Gilson-281纯化***(泵322,检测器:UV 156,溶剂体系:乙腈和0.05%氢氧化铵的水溶液;乙腈和0.225%的FA的水溶液;乙腈和0.05%HCl的水溶液;乙腈和0.075%TFA的水溶液;或乙腈和水)。
对于SFC手性分离,使用Mettler Toledo Multigram III***SFC,Waters 80Q制备型SFC或Thar 80制备型SFC,通过手性柱(Daicel chiralpak IC,5μm,30×250mm),AS(10μm,30×250mm)或AD(10μm,30×250mm)分离中间体,溶剂***为:CO2和IPA(0.5%TEA在IPA中的溶液)或CO2和MeOH(0.1%NH3·H2O在MeOH中的溶液),背压100bar,检测UV@254或220nm。
使用LC/MS(WatersTM Alliance 2795-Micromass ZQ,Shimadzu Alliance 2020-Micromass ZQ或Agilent Alliance 6110-Micromass Zq)获得化合物的LC/MS光谱,LC/MS条件如下(运行时间3或1.5分钟):
酸性条件I:A:0.1%TFA的H2O溶液;B:0.1%TFA的乙腈溶液;
酸性条件II:A:0.0375%TFA的H2O溶液;B:0.01875%TFA的乙腈溶液;
碱性条件I:A:0.1%NH3·H2O的H2O溶液;B:乙腈;
碱性条件II:A:0.025%NH3·H2O的H2O溶液;B:乙腈;
中性条件:A:H2O;B:乙腈。
质谱(MS):通常只报告指示母体质量的离子,除非另有说明,否则所引用的质量离子为正质量离子(MH)+。
使用Bruker Avance 400MHz获得NMR光谱。
微波辅助反应在Biotage Initiator Sixty微波合成仪中进行。所有涉及空气敏感试剂的反应均在氩气或氮气气氛下进行。除非另有说明,否则试剂按原样购自商业供应商,未经进一步纯化。
制备实例
以下实例旨在说明本发明的含义,但绝不代表本发明含义的限制:
中间体A
[(2R,6R)-4-(8-氰基-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯
根据以下方案制备标题化合物:
步骤1:制备[(2R,6R)-6-甲基吗啉-2-基]甲醇;2,2,2-三氟乙酸(化合物A1)
向(2R,6R)-2-(羟甲基)-6-甲基吗啉-4-甲酸叔丁酯(CAS:1700609-48-8,供应商:WuXi Apptec,1.35g,5.84mmol)的DCM(10mL)溶液中加入2,2,2-三氟乙酸(2.66g,23.30mmol)。将反应混合物在rt搅拌3h,然后在真空中浓缩,以得到粗产物化合物A1(1.43g),其直接用于下一步。MS:calc’d 132(MH+),测量值132(MH+)。
步骤2:制备5-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]喹啉-8-腈(化合物A3)
将5-溴喹啉-8-腈(化合物A2,CAS:507476-70-2,供应商:BePharm,1.50g,6.42mmol)、[(2R,6R)-6-甲基吗啉-2-基]甲醇;2,2,2-三氟乙酸(化合物A1,1.43g,5.83mmol)、RuPhos Pd G2(136mg,175μmol)和Cs2CO3(5.70g,17.50mmol)在1,4-二噁烷(10mL)中的混合物在N2下加热至90℃过夜。冷却后,将固体滤出并用EA(10mL)洗涤两次。浓缩合并的有机物,将残余物通过快速色谱柱纯化,以EA/PE(0至100%)梯度洗脱,以得到化合物A3(0.71g),其为淡黄色固体。MS:calc’d 284(MH+),测量值284(MH+)。
步骤3:制备[(2R,6R)-4-(8-氰基-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体A)
向烧瓶中加入5-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]喹啉-8-腈(化合物A3,0.71g,2.50mmol)、DCM(10mL)和2,6-二甲基吡啶(0.54g,577μL,5.00mmol)。然后将反应混合物用冰浴冷却,并逐滴加入三氟甲磺酸酐(1.06g,634μL,3.75mmol)。搅拌2h后,将混合物浓缩并通过快速色谱柱(EA/PE=0至40%)纯化,以得到产物中间体A(0.72g),其为黄色固体。MS:calc’d 416(MH+),测量值416(MH+)。
中间体B
[(2R,6R)-4-(8-羟基喹喔啉-5-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯
与中间体A的制备类似,标题化合物通过使用8-溴喹啉-5-腈(合成参考US20170174653 A1)代替5-溴喹啉-8-腈(化合物A2)进行制备。获得中间体B(825mg),其为灰白色固体。MS:calc’d 417(MH+),测量值417(MH+)。
中间体C
5-甲基-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯
根据以下方案制备标题化合物:
步骤1:制备4-(二甲基氨基亚甲基)-2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C2)
向2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C1,CAS:362704-66-3,供应商:Pharmablock,5.00g,23.44mmol)的DMF(30mL)溶液中加入N,N-二甲基甲酰胺二甲基乙缩醛(5.58g,46.88mmol)。在90℃加热18h后,将混合物冷却并浓缩,以得到化合物C2(6.29g),其为橘红色液体,直接用于下一步而不经进一步纯化。MS:calc’d 269(MH+),测量值269(MH+)。
步骤2:制备5-甲基-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯(中间体C)
向4-(二甲基氨基亚甲基)-2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C2,6.29g,23.44mmol)的乙醇(30mL)溶液中加入水合肼(1.76g,35.16mmol)。在50℃搅拌2h后,将混合物冷却并用水(100mL)稀释。将混合物用EA(100mL)萃取三次。合并的有机相经Na2SO4干燥,过滤并浓缩。将残余物通过快速色谱柱(EA/PE=0至60%)纯化,以得到中间体C(1.80g),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体D
7-甲基-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯
与中间体C的制备类似,标题化合物是通过使用2-甲基-3-氧代-哌啶-1-甲酸叔丁酯(CAS:741737-30-4,供应商:Bide)代替2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C1)来制备的。获得中间体D(2.70g),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体E
7-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
与中间体C的制备类似,标题化合物是通过使用3-甲基-4-氧代-哌啶-1-甲酸叔丁酯(CAS:181269-69-2,供应商:Pharmablock)代替2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C1)来制备的。获得中间体E(3.50g),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体F
(6R)-6-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
中间体G
(4R)-4-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
与中间体C的制备类似,中间体F和中间体G是通过使用(2R)-2-甲基-4-氧代-哌啶-1-甲酸叔丁酯(CAS:790667-43-5,供应商:Pharmablock)代替2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C1)来制备的。中间体F(较慢洗脱)和中间体G(较快洗脱)通过手性SFC(梯度:20%MeOH在CO2中,色谱柱:ChiralPak AD,300×50mm I.D.,10μm)分离。获得中间体F(700mg),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。获得中间体G(580mg),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体H
(6S)-6-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
中间体I
(4S)-4-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
与中间体C的制备类似,中间体H和中间体I是通过使用(2S)-2-甲基-4-氧代-哌啶-1-甲酸叔丁酯(CAS:790667-49-1,供应商:Pharmablock)代替2-甲基-5-氧代-哌啶-1-甲酸叔丁酯(化合物C1)来制备的。中间体H(较慢洗脱)和中间体I(较快洗脱)通过手性SFC(梯度:5-40%MeOH(0.05%DEA)在CO2中,色谱柱:ChiralPak AY,150×4.6mm I.D.,3μm)分离。获得中间体H(430mg),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。获得中间体I(450mg),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体J
3-甲基-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯
根据以下方案制备标题化合物:
步骤1:制备4-乙酰基-3-氧代-哌啶-1-甲酸叔丁酯(化合物J2)
向3-氧代哌啶-1-甲酸叔丁酯(化合物J1,CAS:98977-36-7,供应商:Accela,8.00g,40.14mmol)的THF(30mL)溶液(-78℃)加入LiHMDS(40mL,1.2M在THF中,48.00mmol)。在-78℃搅拌0.5h后,加入乙酰氯(4.73g,60.20mmol),并将混合物缓慢温热至rt,然后在rt搅拌2h。通过添加饱和NH4Cl溶液(30mL)淬灭后,将混合物用EA(30mL)萃取三次。合并的有机相经Na2SO4干燥,过滤并浓缩,以得到中间体J2(9.65g),其为橘红色油状物,直接用于下一步而不经进一步纯化。MS:calc’d 242(MH+),测量值142(MH+-Boc)。
步骤2:制备3-甲基-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯(中间体J)
向4-乙酰基-3-氧代-哌啶-1-甲酸叔丁酯(化合物J2,9.65g,40.14mmol)的乙醇(30mL)溶液中加入水合肼(3.00g,60.00mmol)。在50℃搅拌2h后,将混合物冷却并用水(100mL)稀释。将混合物用EA(100mL)萃取三次。合并的有机相经Na2SO4干燥,过滤并浓缩。将残余物通过快速色谱柱(EA/PE=0至60%)纯化,然后通过手性SFC处理,以得到中间体J(2.00g),其为黄色油状物。MS:calc’d 238(MH+),测量值238(MH+)。
中间体K
3-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
根据以下方案制备标题化合物:
步骤1:制备3-甲基-2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯
在冰浴下,向含有3-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶(化合物K1,CAS:740061-36-3,供应商:BePharm,300mg,2.19mmol)、TEA(332mg,457μL,3.28mmol)和DCM(6mL)的烧瓶中加入Boc2O(501mg,2.30mmol)。在rt搅拌1h后,将混合物浓缩并通过快速色谱柱(EA/PE=0至100%)纯化,以得到所需产物中间体K(490mg),其为白色泡沫。MS:calc’d238(MH+),测量值238(MH+)。
中间体L
1,4,6,7-四氢咪唑并[4,5-c]吡啶-5-甲酸叔丁酯
与中间体K的制备类似,标题化合物是通过使用4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶二盐酸盐(CAS:62002-31-7,供应商:Accela)代替3-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶(化合物K1)来制备的。获得中间体L(273mg),其为白色泡沫。MS:calc’d 224(MH+),测量值224(MH+)。
参比化合物R1
5-[(2S,6R)-2-[[4-(4-甲氧基苯基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
根据以下方案制备标题化合物:
向烧瓶中加入[(2R,6R)-4-(8-氰基-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体A,30mg,72μmol)、1-(4-甲氧基苯基)哌嗪(CAS:38212-30-5,供应商:Accela,21mg,108μmol)、碳酸钾(30mg,217μmol)和乙腈(4mL)。在85℃搅拌2小时后,将混合物通过硅藻土过滤,并通过制备型HPLC纯化,得到化合物R1(22mg),为黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.7,4.2Hz,1H),8.67(dd,J=1.7,8.6Hz,1H),8.18(d,J=8.1Hz,1H),7.66(dd,J=4.3,8.6Hz,1H),7.30(d,J=7.9Hz,1H),7.05-6.98(m,2H),6.93-6.85(m,2H),4.55-4.46(m,1H),4.26-4.16(m,1H),3.89-3.56(m,7H),3.50-3.37(m,6H),3.25-3.00(m,2H),2.84-2.71(m,2H),1.33(d,J=6.2Hz,3H)。
参比化合物R2
5-[(2S,6R)-2-[[4-(4-氯苯基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与化合物R1的制备类似,标题化合物通过使用1-(4-氯苯基)哌嗪(CAS:38212-33-8,供应商:BePharm)代替1-(4-甲氧基苯基)哌嗪进行制备。获得化合物R2(24mg),为黄色固体。MS:calc’d 462(MH+),测量值462(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.6,4.3Hz,1H),8.67(dd,J=1.7,8.6Hz,1H),8.17(d,J=8.1Hz,1H),7.66(dd,J=4.3,8.6Hz,1H),7.34-7.26(m,3H),7.07-6.98(m,2H),4.55-4.47(m,1H),4.25-4.15(m,1H),3.99-3.55(m,3H),3.55-3.32(m,7H),3.28-3.04(m,2H),2.85-2.71(m,2H),1.33(d,J=6.2Hz,3H)。
实例1
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例2
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
根据以下方案制备标题化合物:
步骤1:制备1-(1-苄氧基羰基氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1c)和2-(1-苄氧基羰基氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物2c)
向烧瓶中加入2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a,CAS:230301-11-8,供应商:BePharm,200mg,896μmol)和DMF(2mL),将悬浮液用N2鼓泡5min,然后添加NaH(60%在矿物油中,107mg,2.69mmol)。将混合物在rt搅拌0.5h后,加入3-碘氮杂环丁烷-1-甲酸苄酯(化合物1b,CAS:939759-26-9,供应商:PharmaBlock,284mg,896μmol),并将混合物在60℃搅拌2h。冷却后,通过加水(10mL)淬灭反应。将混合物用EA(10mL)萃取3次,并且有机相用盐水(20mL)洗涤两次,经Na2SO4干燥,过滤并浓缩,以得到淡黄色油状物,其通过快速色谱柱(EA/PE=0至70%)纯化,以得到化合物1c和化合物2c的混合物(65mg),其为黄色油状物。MS:calc’d 413(MH+),测量值413(MH+)。
步骤2:制备1-(氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1d)和2-(氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物2d)
向含有1-(1-苄氧基羰基氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1c)和2-(1-苄氧基羰基氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物2c)(65mg,79μmol)的烧瓶中加入MeOH(5mL)和Pd(OH)2/C(10wt.%,6mg,39μmol)。在rt在氢气囊下搅拌2h后,将反应混合物过滤并浓缩,以得到化合物1d和化合物2d的混合物(44mg),其为淡黄色油状物,直接用于下一步而不经进一步纯化。MS:calc’d 279(MH+),测量值279(MH+)。
步骤3:制备5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈(实例1)和5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈(实例2)
向管中加入[(2R,6R)-4-(8-氰基-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体A,65mg,156μmol)、1-(氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1d)和2-(氮杂环丁烷-3-基)-6,7-二氢-4H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物2d)(44mg,79μmol)、碳酸钾(65mg,469μmol)和ACN(5mL),将混合物在55℃搅拌2h。冷却后,将混合物通过硅藻土过滤并浓缩,以得到黄色油状物,其在DCM(5mL)和TFA(1mL)中溶解。将混合物在rt搅拌2h,然后浓缩,以得到油状物,其通过制备型HPLC(梯度:10%-25%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)纯化,以得到淡黄色固体的实例1(较慢洗脱,16mg)和淡黄色固体的实例2(较快洗脱,21mg)。两种产物均通过核欧佛豪瑟效应频谱(NOESY)确定。
实例1:MS:calc’d 444(MH+),测量值444(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.02(dd,J=1.6,4.2Hz,1H),8.68(dd,J=1.6,8.6Hz,1H),8.20(d,J=7.9Hz,1H),7.73-7.57(m,2H),7.31(d,J=8.1Hz,1H),5.44-5.32(m,1H),4.85-4.78(m,2H),4.77-4.60(m,2H),4.42-4.32(m,1H),4.28(s,2H),4.21-4.10(m,1H),3.79-3.60(m,2H),3.56(t,J=6.2Hz,2H),3.48-3.40(m,2H),3.07(br t,J=6.5Hz,2H),2.88-2.68(m,2H),1.31(d,J=6.2Hz,3H)。NOESY显示H1’与H2’相关,并且H5’与H4’相关。
实例2:MS:calc’d 444(MH+),测量值444(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.02(dd,J=1.6,4.3Hz,1H),8.68(dd,J=1.5,8.6Hz,1H),8.19(d,J=8.1Hz,1H),7.70(s,1H),7.67(dd,J=4.3,8.6Hz,1H),7.31(d,J=7.9Hz,1H),5.44(quin,J=7.3Hz,1H),4.85-4.75(m,2H),4.74-4.57(m,2H),4.36(br t,J=9.9Hz,1H),4.31(s,2H),4.21-4.10(m,1H),3.74-3.54(m,4H),3.44(br d,J=12.5Hz,2H),3.12(br t,J=6.1Hz,2H),2.87-2.78(m,1H),2.73(dd,J=10.3,12.2Hz,1H),1.31(d,J=6.2Hz,3H)。NOESY显示H1’与H2’和H5’相关。
实例3
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例4
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯(CAS:871726-73-7,供应商:BePharm)代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的。实例3和实例4通过制备型HPLC(梯度:20-65%ACN的水溶液(0.1%NH3),色谱柱:Waters X-Bridge C18,30×100mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例3(较快洗脱,18mg),其为淡黄色固体。MS:calc’d 444(MH+),测量值444(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.87(dd,J=1.7,4.2Hz,1H),8.54(dd,J=1.6,8.6Hz,1H),8.05(d,J=7.9Hz,1H),7.54(dd,J=4.3,8.6Hz,1H),7.26(s,1H),7.15(d,J=8.1Hz,1H),4.74-4.67(m,1H),4.02-3.87(m,2H),3.84-3.71(m,4H),3.55(q,J=7.8Hz,2H),3.27(br d,J=11.1Hz,2H),2.85(t,J=5.8Hz,2H),2.75-2.68(m,2H),2.67-2.59(m,1H),2.54(dd,J=10.3,11.9Hz,1H),2.47(t,J=5.7Hz,2H),1.14(d,J=6.2Hz,3H)。
获得实例4(较慢洗脱,60mg),其为淡黄色固体。MS:calc’d 444(MH+),测量值444(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(d,J=4.2Hz,1H),8.65(d,J=8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.65(dd,J=4.2,8.5Hz,1H),7.52(s,1H),7.26(d,J=8.1Hz,1H),5.02-4.94(m,1H),4.13-3.99(m,2H),3.98-3.83(m,4H),3.62(dt,J=3.7,7.5Hz,2H),3.39(br d,J=12.1Hz,2H),3.01(t,J=5.9Hz,2H),2.80(d,J=6.1Hz,2H),2.78-2.70(m,1H),2.70-2.58(m,3H),1.25(d,J=6.2Hz,3H)。
实例5
5-[(2R,6S)-2-甲基-6-[[3-(6-甲基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
根据以下方案制备标题化合物:
步骤1:制备5-[(2R,6S)-2-甲基-6-[[3-(6-甲基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈(实例5)
向含有5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈(实例4,30mg,68μmol)和MeOH(2mL)的烧瓶中加入甲醛(37%在水中,25μL,340μmol)。将混合物在rt搅拌10min后,加入NaBH3CN(13mg,204μmol)。再搅拌1小时后,将混合物通过制备型HPLC直接纯化,以得到实例5(19mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(dd,J=1.6,4.3Hz,1H),8.66(dd,J=1.6,8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.65(dd,J=4.2,8.6Hz,1H),7.53(s,1H),7.26(d,J=8.1Hz,1H),5.02-4.95(m,1H),4.13-3.99(m,2H),3.96-3.82(m,2H),3.62(dt,J=4.0,7.5Hz,2H),3.56(s,2H),3.43-3.36(m,2H),2.84-2.76(m,2H),2.76-2.62(m,6H),2.50(s,3H),1.25(d,J=6.2Hz,3H)。
实例6
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
实例7
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与实例5的制备类似,标题化合物是通过使用实例3和实例4的混合物代替单独的实例4,使用乙醛(5M在THF中)代替甲醛(37%在水中)来制备的。实例6和实例7通过制备型HPLC(梯度:5%-25%ACN的水溶液(0.1%FA),色谱柱:Waters CSH C18,30×100mm,5μm)分离。
获得实例6(较慢洗脱,20mg),其为黄色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(d,J=4.2Hz,1H),8.66(dd,J=1.6,8.6Hz,1H),8.17(d,J=8.1Hz,1H),7.69-7.60(m,2H),7.29(d,J=7.9Hz,1H),5.35-5.22(m,1H),4.69-4.54(m,4H),4.53-4.39(m,2H),4.37-4.28(m,1H),4.18-4.07(m,1H),3.70-3.49(m,3H),3.46-3.32(m,5H),2.95(br s,2H),2.84-2.67(m,2H),1.48-1.40(m,3H),1.28(d,J=6.2Hz,3H)。
获得实例7(较快洗脱,58mg),其为黄色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.96(dd,J=1.5,4.2Hz,1H),8.63(dd,J=1.5,8.6Hz,1H),8.13(d,J=7.9Hz,1H),7.73-7.58(m,2H),7.25(d,J=8.1Hz,1H),5.44(quin,J=7.3Hz,1H),4.83-4.74(m,2H),4.67(br s,3H),4.42-4.23(m,2H),4.19-4.06(m,1H),3.92-3.51(m,3H),3.48-3.34(m,5H),3.09-2.91(m,2H),2.84-2.61(m,2H),1.45(t,J=7.3Hz,3H),1.28(d,J=6.2Hz,3H)。
实例8
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
实例9
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与实例6和实例7的制备类似,标题化合物是通过使用丙酮代替乙醛(5M在THF中),将反应温度从rt变为50℃,并且将反应时间从1h变为过夜来制备的。实例8和实例9通过制备型HPLC(梯度:5%-25%ACN的水溶液(0.1%FA),色谱柱:Waters CSH C18,30×100mm,5μm)分离。
获得实例8(较慢洗脱,11mg),其为黄色固体。MS:calc’d 486(MH+),测量值486(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.98(dd,J=1.6,4.3Hz,1H),8.66(dd,J=1.6,8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.65(dd,J=4.3,8.6Hz,1H),7.57(s,1H),7.27(d,J=7.9Hz,1H),5.26-5.14(m,1H),4.55-4.47(m,2H),4.43-4.31(m,4H),4.29-4.19(m,1H),4.16-4.06(m,1H),3.65(td,J=6.6,13.2Hz,1H),3.46-3.33(m,6H),2.90(t,J=5.9Hz,2H),2.83-2.64(m,2H),1.41(d,J=6.7Hz,6H),1.27(d,J=6.2Hz,3H)。
获得实例9(较快洗脱,61mg),其为黄色固体。MS:calc’d 486(MH+),测量值486(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.95(br s,1H),8.61(br d,J=8.2Hz,1H),8.18-8.00(m,1H),7.74-7.57(m,2H),7.31-7.14(m,1H),5.22(br d,J=5.4Hz,1H),4.37(s,4H),4.24-4.01(m,4H),3.70(td,J=6.3,12.8Hz,1H),3.49(br t,J=5.7Hz,2H),3.43-3.34(m,2H),3.27-3.12(m,2H),2.98(br t,J=5.7Hz,2H),2.81-2.59(m,2H),1.44(d,J=6.6Hz,6H),1.25(d,J=6.1Hz,3H)。
实例10
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
实例11
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用4,6-二氢-2H-吡咯并[3,4-c]吡唑-5-甲酸叔丁酯(CAS:1280210-79-8,供应商:Pharmablock)代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的。实例10和实例11通过制备型HPLC(梯度:20-65%ACN的水溶液(0.1%NH3),色谱柱:Waters X-Bridge C18,30×100mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例10(较快洗脱,19mg),其为淡黄色固体。MS:calc’d430(MH+),测量值430(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.7,4.2Hz,1H),8.66(dd,J=1.6,8.6Hz,1H),8.17(d,J=7.9Hz,1H),7.72-7.58(m,1H),7.31(s,1H),7.27(d,J=8.1Hz,1H),4.95-4.91(m,1H),4.23(s,2H),4.10-3.98(m,4H),3.95-3.82(m,2H),3.65-3.56(m,2H),3.43-3.36(m,2H),2.85-2.71(m,3H),2.71-2.61(m,1H),1.26(d,J=6.2Hz,3H)。
获得实例11(较慢洗脱,55mg),其为淡黄色固体。MS:calc’d430(MH+),测量值430(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.87(dd,J=1.6,4.3Hz,1H),8.54(dd,J=1.6,8.6Hz,1H),8.04(d,J=8.1Hz,1H),7.53(dd,J=4.3,8.6Hz,1H),7.37(s,1H),7.14(d,J=8.1Hz,1H),4.93-4.84(m,1H),3.99-3.73(m,8H),3.54(dt,J=4.7,7.5Hz,2H),3.28(br d,J=12.2Hz,2H),2.72-2.59(m,3H),2.54(dd,J=10.3,12.0Hz,1H),1.14(d,J=6.2Hz,3H)。
实例12
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例13
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用中间体K代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的。实例12和实例13通过制备型HPLC(梯度:10%-25%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例12(较慢洗脱,60mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.6,4.3Hz,1H),8.67(dd,J=1.3,8.6Hz,1H),8.18(d,J=8.1Hz,1H),7.67(dd,J=4.2,8.6Hz,1H),7.30(d,J=8.1Hz,1H),5.39-5.25(m,1H),5.05-4.94(m,2H),4.73-4.58(m,2H),4.43-4.32(m,1H),4.27-4.09(m,3H),3.79-3.57(m,2H),3.53(t,J=6.2Hz,2H),3.49-3.39(m,2H),3.03(br t,J=6.0Hz,2H),2.89-2.78(m,1H),2.73(dd,J=10.5,12.0Hz,1H),2.27(s,3H),1.31(d,J=6.2Hz,3H)。
获得实例13(较快洗脱,40mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99-8.81(m,1H),8.55(d,J=8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.54(dd,J=4.3,8.6Hz,1H),7.17(d,J=7.9Hz,1H),5.33(quin,J=7.1Hz,1H),4.85(br s,2H),4.64-4.45(m,2H),4.32-4.20(m,1H),4.10(s,2H),4.08-3.97(m,1H),3.68-3.48(m,2H),3.43(br t,J=6.3Hz,2H),3.38-3.27(m,2H),2.95(br t,J=6.1Hz,2H),2.76-2.66(m,1H),2.61(dd,J=10.5,12.0Hz,1H),2.15(s,3H),1.18(d,J=6.2Hz,3H)。
实例14
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
实例15
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与实例5的制备类似,标题化合物是通过使用实例12和实例13的混合物代替实例4来制备的。实例14和实例15通过制备型HPLC(梯度:10%-30%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。
获得实例14(较慢洗脱,18mg),其为黄色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.6,4.3Hz,1H),8.66(dd,J=1.5,8.6Hz,1H),8.17(d,J=7.9Hz,1H),7.65(dd,J=4.3,8.6Hz,1H),7.29(d,J=8.1Hz,1H),5.34-5.20(m,1H),4.82-4.72(m,2H),4.72-4.58(m,2H),4.50-4.30(m,2H),4.24-4.03(m,2H),3.77-3.55(m,3H),3.42(br dd,J=1.7,12.2Hz,3H),3.09(br t,J=5.8Hz,2H),3.05(s,3H),2.85-2.76(m,1H),2.72(dd,J=10.4,12.1Hz,1H),2.25(s,3H),1.29(d,J=6.2Hz,3H)。
获得实例15(较快洗脱,12mg),其为黄色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(dd,J=1.6,4.2Hz,1H),8.65(dd,J=1.5,8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.65(dd,J=4.3,8.6Hz,1H),7.28(d,J=8.1Hz,1H),5.42(quin,J=7.2Hz,1H),4.84-4.74(m,2H),4.73-4.56(m,2H),4.53-4.40(m,1H),4.39-4.29(m,1H),4.18-4.04(m,2H),3.87-3.53(m,3H),3.50-3.37(m,3H),3.19-3.07(m,2H),3.05(s,3H),2.80(dd,J=10.5,11.7Hz,1H),2.71(dd,J=10.3,12.2Hz,1H),2.24(s,3H),1.28(d,J=6.2Hz,3H)。
实例16
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例17
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用中间体F代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的,不同之处在于步骤1的反应条件是通过将碱和溶剂从NaH和DMF变为Cs2CO3和ACN,以及将反应温度和反应时间从60℃和2h变为回流和过夜来改进的。实例16和实例17通过手性SFC(梯度:45%异丙醇(0.1%NH3H2O)在CO2中,色谱柱:Daicel chiralcel OD 250×30mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例16(较快洗脱,21mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.88(dd,J=1.6,4.3Hz,1H),8.54(dd,J=1.6,8.6Hz,1H),8.05(d,J=7.9Hz,1H),7.54(dd,J=4.3,8.6Hz,1H),7.43(s,1H),7.15(d,J=7.9Hz,1H),4.97-4.84(m,1H),4.20-4.03(m,2H),4.03-3.86(m,4H),3.73(br s,2H),3.56-3.44(m,1H),3.28(br d,J=11.1Hz,2H),3.06(dd,J=4.9,16.8Hz,1H),2.82(br d,J=5.6Hz,2H),2.70-2.50(m,3H),1.39(d,J=6.5Hz,3H),1.15(d,J=6.4Hz,3H)。
获得实例17(较慢洗脱,20mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.87(dd,J=1.6,4.3Hz,1H),8.53(dd,J=1.6,8.6Hz,1H),8.04(d,J=8.1Hz,1H),7.53(dd,J=4.2,8.6Hz,1H),7.50(s,1H),7.14(d,J=8.1Hz,1H),4.93-4.85(m,1H),4.06-3.86(m,4H),3.85-3.73(m,2H),3.61-3.47(m,2H),3.27(br d,J=12.0Hz,2H),3.20-3.15(m,1H),2.85(br dd,J=4.3,16.3Hz,1H),2.69(brd,J=5.6Hz,2H),2.67-2.59(m,1H),2.58-2.40(m,2H),1.28(d,J=6.5Hz,3H),1.13(d,J=6.2Hz,3H)。
实例18
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例19
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物是通过使用中间体H代替中间体F来制备的。实例18和实例19通过制备型HPLC(梯度:5%-25%ACN的水溶液(0.1%TFA),色谱柱:Waters X-Bridge C8,30×100mm,5μm)分离。
获得实例18(较慢洗脱,10mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.5,4.3Hz,1H),8.67(dd,J=1.5,8.6Hz,1H),8.17(d,J=7.9Hz,1H),7.72-7.59(m,2H),7.29(d,J=8.1Hz,1H),5.38(quin,J=7.3Hz,1H),4.87-4.77(m,2H),4.69(br s,2H),4.45-4.20(m,3H),4.19-4.07(m,1H),3.81-3.55(m,3H),3.44(br t,J=10.9Hz,2H),3.20(br dd,J=4.5,16.9Hz,1H),2.90-2.64(m,3H),1.54(d,J=6.6Hz,3H),1.30(d,J=6.2Hz,3H)。
获得实例19(较快洗脱,12mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.6,4.3Hz,1H),8.67(dd,J=1.5,8.6Hz,1H),8.18(d,J=8.1Hz,1H),7.71(s,1H),7.67(dd,J=4.2,8.6Hz,1H),7.30(d,J=8.1Hz,1H),5.45(quin,J=7.5Hz,1H),4.85-4.75(m,2H),4.69(br d,J=6.5Hz,2H),4.42-4.31(m,2H),4.31-4.23(m,1H),4.20-4.10(m,1H),3.78-3.54(m,3H),3.49-3.39(m,2H),3.21(dd,J=4.6,16.9Hz,1H),2.90-2.77(m,2H),2.73(dd,J=10.3,12.2Hz,1H),1.54(d,J=6.5Hz,3H),1.30(d,J=6.2Hz,3H)。
实例20
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例21
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物是通过使用中间体G代替中间体F来制备的。实例20和实例21通过制备型HPLC(梯度:10%-25%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。
获得实例20(较慢洗脱,29mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.5,4.2Hz,1H),8.68(dd,J=1.5,8.6Hz,1H),8.19(d,J=7.9Hz,1H),7.73(s,1H),7.67(dd,J=4.3,8.6Hz,1H),7.31(d,J=8.1Hz,1H),5.38(td,J=7.3,14.5Hz,1H),4.86-4.80(m,2H),4.71(br s,2H),4.55(q,J=6.6Hz,1H),4.42-4.33(m,1H),4.21-4.11(m,1H),3.79-3.55(m,3H),3.49-3.39(m,3H),3.13-3.03(m,2H),2.87-2.79(m,1H),2.73(dd,J=10.3,12.2Hz,1H),1.65(d,J=6.7Hz,3H),1.31(d,J=6.2Hz,3H)。
获得实例21(较快洗脱,48mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.02(dd,J=1.6,4.2Hz,1H),8.68(dd,J=1.5,8.6Hz,1H),8.19(d,J=7.9Hz,1H),7.78(s,1H),7.67(dd,J=4.3,8.6Hz,1H),7.31(d,J=8.1Hz,1H),5.44(quin,J=7.4Hz,1H),4.98-4.94(m,2H),4.75-4.62(m,2H),4.57(q,J=6.4Hz,1H),4.40-4.31(m,1H),4.20-4.09(m,1H),3.79-3.55(m,3H),3.49-3.40(m,3H),3.10(br dd,J=4.0,6.9Hz,2H),2.82(t,J=11.1Hz,1H),2.73(dd,J=10.5,12.1Hz,1H),1.63(d,J=6.7Hz,3H),1.31(d,J=6.2Hz,3H)。
实例22
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例23
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物是通过使用中间体I代替中间体F来制备的。实例22和实例23通过制备型HPLC(梯度:10%-25%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。
获得实例22(较慢洗脱,40mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.07-8.96(m,1H),8.68(d,J=7.7Hz,1H),8.20(d,J=8.1Hz,1H),7.73(s,1H),7.68(dd,J=4.3,8.6Hz,1H),7.31(d,J=8.1Hz,1H),5.42-5.33(m,1H),4.84-4.79(m,2H),4.74-4.61(m,2H),4.59-4.50(m,1H),4.37(dt,J=2.3,9.9Hz,1H),4.20-4.11(m,1H),3.79-3.56(m,3H),3.49-3.40(m,3H),3.12-3.00(m,2H),2.83(t,J=11.1Hz,1H),2.78-2.68(m,1H),1.65(d,J=6.7Hz,3H),1.31(d,J=6.2Hz,3H)。
获得实例23(较快洗脱,48mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(dd,J=1.7,4.2Hz,1H),8.66(dd,J=1.6,8.7Hz,1H),8.16(d,J=7.9Hz,1H),7.78(s,1H),7.65(dd,J=4.3,8.6Hz,1H),7.28(d,J=8.1Hz,1H),5.45(quin,J=7.4Hz,1H),4.86-4.77(m,2H),4.69(br s,2H),4.57(q,J=6.6Hz,1H),4.43-4.31(m,1H),4.21-4.09(m,1H),3.81-3.54(m,3H),3.51-3.38(m,3H),3.15-3.05(m,2H),2.82(dd,J=10.5,11.7Hz,1H),2.72(dd,J=10.3,12.2Hz,1H),1.63(d,J=6.7Hz,3H),1.30(d,J=6.2Hz,3H)。
实例24
5-[(2S,6R)-2-[[3-(7,7-二甲基-5,6-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈
与实例2的制备类似,标题化合物是通过使用7,7-二甲基-4,6-二氢-2H-吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(CAS:635712-88-8,供应商:Accela)代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的。获得实例24(108mg),其为淡黄色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(dd,J=1.7,4.2Hz,1H),8.66(dd,J=1.7,8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.69(s,1H),7.66(dd,J=4.3,8.6Hz,1H),7.28(d,J=8.1Hz,1H),5.27(quin,J=7.2Hz,1H),4.42(q,J=8.7Hz,2H),4.33-4.18(m,5H),4.18-4.06(m,1H),3.46-3.38(m,2H),3.37-3.33(m,2H),3.32-3.22(m,2H),2.79(dd,J=10.5,11.8Hz,1H),2.70(dd,J=10.3,12.1Hz,1H),1.47(s,6H),1.29(d,J=6.2Hz,3H)。
实例25和实例26
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈和5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例17的制备类似,标题化合物实例25和实例26的混合物是通过使用中间体E代替中间体F来制备的。实例25和实例26通过手性SFC(梯度:50%异丙醇(0.1%NH3H2O)在CO2中,色谱柱:ID,250×20mm I.D.,5μm)分离。
获得实例25(较快洗脱,12mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.6,4.2Hz,1H),8.67(d,J=8.3Hz,1H),8.17(d,J=7.8Hz,1H),7.66(dd,J=4.6,8.7Hz,1H),7.53(s,1H),7.27(d,J=8.3Hz,1H),5.00-4.94(m,1H),4.11-4.01(m,2H),3.96-3.78(m,3H),3.63(br t,J=7.3Hz,2H),3.43-3.37(m,2H),3.01-2.93(m,2H),2.86-2.72(m,4H),2.70-2.59(m,2H),1.29(d,J=7.0Hz,3H),1.26(d,J=6.2Hz,3H)。
获得实例26(较慢洗脱,7mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(d,J=3.1Hz,1H),8.66(d,J=8.6Hz,1H),8.17(d,J=8.2Hz,1H),7.66(dd,J=4.5,8.6Hz,1H),7.53(s,1H),7.27(d,J=8.1Hz,1H),5.00-4.94(m,1H),4.12-4.00(m,2H),3.95-3.82(m,3H),3.66-3.58(m,2H),3.43-3.37(m,2H),2.99-2.91(m,2H),2.84-2.71(m,4H),2.70-2.57(m,2H),1.29(d,J=7.1Hz,3H),1.26(d,J=6.2Hz,3H)。
实例27和实例28
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈和5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例29和实例30
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈和5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物实例27和实例28的混合物以及标题化合物实例29和实例30的混合物是通过使用中间体C代替中间体F来制备的。实例27和实例28的混合物以及实例29和实例30的混合物通过步骤1中的快速色谱柱分离。实例27和实例28通过手性SFC(梯度:35%异丙醇(0.1%NH3H2O)在CO2中,色谱柱:AS,250×20mm I.D.,5μm)分离。实例29和实例30通过手性SFC(梯度:40%异丙醇(0.1%NH3H2O)在CO2中,色谱柱:Daicel chiralcel AD 250×30mm,5μm)分离。
获得实例27(较快洗脱,9mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01-8.94(m,1H),8.64(d,J=7.0Hz,1H),8.15(d,J=8.1Hz,1H),7.64(dd,J=4.0,8.7Hz,1H),7.32(s,1H),7.25(d,J=8.1Hz,1H),5.27-5.10(m,1H),4.09-3.94(m,3H),3.92-3.81(m,3H),3.65(br t,J=7.7Hz,2H),3.41-3.34(m,2H),2.93-2.83(m,1H),2.81-2.77(m,2H),2.77-2.69(m,1H),2.67-2.57(m,2H),2.28-2.18(m,1H),1.23(dd,J=2.0,6.3Hz,6H)。
获得实例28(较慢洗脱,9mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.97(dd,J=1.7,4.2Hz,1H),8.64(dd,J=1.8,8.6Hz,1H),8.15(d,J=8.1Hz,1H),7.64(dd,J=4.2,8.6Hz,1H),7.33(s,1H),7.25(d,J=8.1Hz,1H),5.23-5.14(m,1H),4.09-3.94(m,3H),3.94-3.81(m,3H),3.71-3.60(m,2H),3.41-3.35(m,2H),2.93-2.83(m,1H),2.82-2.69(m,3H),2.67-2.57(m,2H),2.29-2.18(m,1H),1.24(dd,J=2.8,6.2Hz,6H)。
获得实例29(较慢洗脱,21mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.87(dd,J=1.3,4.1Hz,1H),8.53(d,J=8.6Hz,1H),8.03(d,J=8.1Hz,1H),7.53(dd,J=4.2,8.6Hz,1H),7.39(s,1H),7.13(d,J=8.1Hz,1H),4.90-4.80(m,1H),4.01-3.71(m,6H),3.50(dt,J=3.5,7.5Hz,2H),3.27(br d,J=12.2Hz,2H),2.94-2.79(m,1H),2.72-2.48(m,5H),2.20(dd,J=10.5,15.3Hz,1H),1.15(dd,J=6.3,9.5Hz,6H)。
获得实例30(较快洗脱,19mg),其为淡黄色固体。MS:calc’d458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.87(dd,J=1.7,4.2Hz,1H),8.54(dd,J=1.7,8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.54(dd,J=4.3,8.6Hz,1H),7.38(s,1H),7.14(d,J=8.1Hz,1H),4.89-4.80(m,1H),4.00-3.71(m,6H),3.50(dt,J=3.5,7.5Hz,2H),3.32-3.24(m,2H),2.88-2.77(m,1H),2.73-2.47(m,5H),2.18(dd,J=10.4,15.3Hz,1H),1.14(t,J=5.9Hz,6H)。
实例31和实例32
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈和5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例33和实例34
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈和5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物实例31和实例32的混合物以及标题化合物实例33和实例34的混合物是通过使用中间体D代替中间体F来制备的。实例31和实例32的混合物(较慢洗脱)以及实例33和实例34的混合物(较快洗脱)通过制备型HPLC(梯度:10%-30%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。实例31和实例32通过手性SFC(梯度:30%甲醇(0.1%NH3H2O)在CO2中,色谱柱:AD,250×20mm I.D.,5μm)分离。实例33和实例34通过手性SFC(梯度:45%异丙醇(0.1%NH3H2O)在CO2中,色谱柱:ID,250×20mm I.D.,5μm)分离。
获得实例31(较快洗脱,6mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.97(dd,J=1.6,4.3Hz,1H),8.64(dd,J=1.7,8.6Hz,1H),8.15(d,J=8.1Hz,1H),7.63(dd,J=4.3,8.7Hz,1H),7.35(s,1H),7.25(d,J=8.1Hz,1H),4.95-4.88(m,1H),4.15(q,J=6.8Hz,1H),4.09-3.97(m,2H),3.92-3.83(m,2H),3.82-3.74(m,1H),3.58(t,J=7.9Hz,1H),3.41-3.35(m,2H),3.05-2.97(m,1H),2.93-2.70(m,4H),2.64(dd,J=10.2,11.9Hz,1H),2.53(t,J=5.8Hz,2H),1.38(d,J=6.7Hz,3H),1.23(d,J=6.2Hz,3H)。
获得实例32(较慢洗脱,6mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.97(dd,J=1.7,4.2Hz,1H),8.64(dd,J=1.7,8.6Hz,1H),8.15(d,J=7.9Hz,1H),7.64(dd,J=4.3,8.6Hz,1H),7.35(s,1H),7.25(d,J=8.1Hz,1H),4.95-4.87(m,1H),4.15(q,J=6.6Hz,1H),4.09-3.97(m,2H),3.92(dt,J=2.2,7.3Hz,1H),3.84(dt,J=2.0,7.3Hz,1H),3.79-3.71(m,1H),3.60(t,J=7.8Hz,1H),3.41-3.35(m,2H),3.08-2.95(m,1H),2.94-2.84(m,1H),2.84-2.77(m,2H),2.74(dd,J=10.6,11.8Hz,1H),2.64(dd,J=10.2,12.0Hz,1H),2.53(t,J=5.7Hz,2H),1.38(d,J=6.8Hz,3H),1.23(d,J=6.2Hz,3H)。
获得实例33(较慢洗脱,12mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.97(dd,J=1.7,4.2Hz,1H),8.64(dd,J=1.7,8.6Hz,1H),8.15(d,J=7.9Hz,1H),7.63(dd,J=4.3,8.7Hz,1H),7.50(s,1H),7.24(d,J=8.1Hz,1H),4.99-4.90(m,1H),4.09-3.81(m,5H),3.60(t,J=7.5Hz,2H),3.41-3.34(m,2H),3.18(ddd,J=3.4,5.3,12.6Hz,1H),2.88-2.52(m,7H),1.44(d,J=6.7Hz,3H),1.24(d,J=6.2Hz,3H)。
获得实例34(较快洗脱,12mg),其为淡黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.97(dd,J=1.7,4.2Hz,1H),8.64(dd,J=1.7,8.6Hz,1H),8.15(d,J=7.9Hz,1H),7.64(dd,J=4.3,8.6Hz,1H),7.50(s,1H),7.25(d,J=8.1Hz,1H),4.99-4.91(m,1H),4.08-3.82(m,5H),3.60(q,J=7.3Hz,2H),3.40-3.34(m,2H),3.22-3.10(m,1H),2.87-2.70(m,4H),2.68-2.53(m,3H),1.44(d,J=6.6Hz,3H),1.24(d,J=6.2Hz,3H)。
实例35
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈
实例36
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用4-溴哌啶-1-甲酸苄酯(CAS:166953-64-6,供应商:Bide)代替3-碘氮杂环丁烷-1-甲酸苄酯(化合物1b)来制备的。实例35和实例36通过制备型HPLC(梯度:25-70%ACN的水溶液(0.1%NH3),色谱柱:WatersRPC18,30×100mm,5μm)分离。
获得实例35(较快洗脱,20mg),其为粉色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=8.99(dd,J=1.6,4.3Hz,1H),8.67(dd,J=1.6,8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.65(dd,J=4.2,8.6Hz,1H),7.32-7.20(m,2H),4.24-4.14(m,1H),4.13-4.03(m,2H),3.79(s,2H),3.50(br d,J=11.9Hz,1H),3.40(br d,J=11.9Hz,1H),3.26(br d,J=10.9Hz,1H),3.09(br t,J=5.8Hz,3H),2.79-2.51(m,6H),2.43-2.13(m,4H),1.94-1.82(m,2H),1.27(d,J=6.2Hz,3H)。
获得实例36(较慢洗脱,28mg),其为粉色固体。MS:calc’d 472(MH+),测量值472(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.00(dd,J=1.6,4.2Hz,1H),8.67(dd,J=1.6,8.6Hz,1H),8.17(d,J=8.1Hz,1H),7.66(dd,J=4.2,8.6Hz,1H),7.43(s,1H),7.27(d,J=8.1Hz,1H),4.24-4.15(m,1H),4.14-4.03(m,2H),3.84(s,2H),3.52-3.37(m,2H),3.24(brd,J=13.2Hz,1H),3.09(br t,J=5.9Hz,3H),2.78-2.50(m,6H),2.42-2.25(m,2H),2.12-1.97(m,4H),1.27(d,J=6.2Hz,3H)。
实例37
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例38
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例1和实例2的制备类似,标题化合物是通过使用3-(三氟甲基)-2,4,5,7-四氢吡唑并[3,4-c]吡啶-6-甲酸叔丁酯(CAS:733757-89-6,供应商:Shuya)代替2,4,6,7-四氢吡唑并[4,3-c]吡啶-5-甲酸叔丁酯(化合物1a)来制备的。实例37和实例38通过制备型HPLC(梯度:15%-35%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例37(较慢洗脱,57mg),其为黄色固体。MS:calc’d 512(MH+),测量值512(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.6,4.2Hz,1H),8.67(dd,J=1.6,8.6Hz,1H),8.18(d,J=8.1Hz,1H),7.67(dd,J=4.2,8.6Hz,1H),7.30(d,J=8.1Hz,1H),5.45(quin,J=7.1Hz,1H),5.05-4.95(m,2H),4.81-4.65(m,2H),4.52(s,2H),4.39(br t,J=9.8Hz,1H),4.24-4.08(m,1H),3.74-3.56(m,2H),3.52(t,J=6.2Hz,2H),3.48-3.39(m,2H),3.01(br t,J=5.9Hz,2H),2.83(dd,J=10.5,11.8Hz,1H),2.74(dd,J=10.4,12.1Hz,1H),1.30(d,J=6.2Hz,3H)。
获得实例38(较快洗脱,12mg),其为黄色固体。MS:calc’d 512(MH+),测量值512(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.7,4.2Hz,1H),8.67(dd,J=1.6,8.6Hz,1H),8.18(d,J=7.9Hz,1H),7.67(dd,J=4.3,8.6Hz,1H),7.30(d,J=8.1Hz,1H),5.68-5.53(m,1H),5.02-4.77(m,4H),4.47(s,2H),4.42-4.31(m,1H),4.21-4.08(m,1H),3.72-3.58(m,2H),3.55(t,J=6.2Hz,2H),3.44(br d,J=12.5Hz,2H),3.08(br t,J=5.6Hz,2H),2.87-2.78(m,1H),2.73(dd,J=10.4,12.2Hz,1H),1.30(d,J=6.2Hz,3H)。
实例42
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
实例43
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈
与实例16和实例17的制备类似,标题化合物是通过使用中间体J代替中间体F来制备的。实例42和实例43通过制备型HPLC(梯度:10%-30%ACN的水溶液(0.1%TFA),色谱柱:Waters SunFire C18,30×100mm,5μm)分离。与实例1和实例2类似,这两种产物也是通过NOESY确认的。
获得实例42(较慢洗脱,23mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.01(dd,J=1.6,4.3Hz,1H),8.68(dd,J=1.5,8.6Hz,1H),8.19(d,J=8.1Hz,1H),7.67(dd,J=4.3,8.6Hz,1H),7.31(d,J=8.1Hz,1H),5.32-5.18(m,1H),5.00-4.84(m,2H),4.74-4.57(m,2H),4.47-4.32(m,3H),4.22-4.08(m,1H),3.81-3.55(m,2H),3.53-3.40(m,4H),2.89-2.78(m,3H),2.74(dd,J=10.4,12.1Hz,1H),2.28(s,3H),1.31(d,J=6.2Hz,3H)。
获得实例43(较快洗脱,24mg),其为黄色固体。MS:calc’d 458(MH+),测量值458(MH+)。1H NMR(400MHz,METHANOL-d4)δ=9.02(dd,J=1.6,4.3Hz,1H),8.68(dd,J=1.5,8.6Hz,1H),8.19(d,J=7.9Hz,1H),7.67(dd,J=4.2,8.6Hz,1H),7.31(d,J=8.1Hz,1H),5.54-5.39(m,1H),4.99-4.79(m,2H),4.75-4.55(m,2H),4.45-4.29(m,3H),4.23-4.05(m,1H),3.78-3.55(m,2H),3.50(t,J=6.2Hz,2H),3.47-3.41(m,2H),2.90-2.78(m,3H),2.73(dd,J=10.3,12.2Hz,1H),2.27(s,3H),1.31(d,J=6.2Hz,3H)。
实例44
为了确定式(I)和式(Ia)的化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行以下检测。
HEK293-Blue-hTLR-7细胞测定:
稳定的HEK293-Blue-hTLR-7细胞系购自InvivoGen(目录号:hkb-htlr7,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的活化来研究人类TLR7的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR7配体刺激HEK-Blue hTLR7细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如R848(瑞喹莫德)的刺激下,孵育20小时后,TLR7拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
HEK293-Blue-hTLR7细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20μMR848的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在处读取吸光度。TLR7活化导致下游NF-κB活化的信号传导通路已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR7拮抗剂。
HEK293-Blue-hTLR-8细胞测定:
稳定的HEK293-Blue-hTLR-8细胞系购自InvivoGen(目录号:hkb-htlr8,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的活化来研究人类TLR8的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR8配体刺激HEK-Blue hTLR8细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如R848的刺激下,孵育20小时后,TLR8拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
HEK293-Blue-hTLR8细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的60μMR848的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在处读取吸光度。TLR8活化导致下游NF-κB活化的信号传导通路已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR8拮抗剂。
HEK293-Blue-hTLR-9细胞测定:
稳定的HEK293-Blue-hTLR-9细胞系购自InvivoGen(目录号:hkb-htlr9,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的活化来研究人类TLR9的刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR9配体刺激HEK-Blue hTLR9细胞激活NF-κB和AP-1来诱导SEAP。因此,在配体诸如ODN2006(Resiquimod)(目录号:tlrl-2006-1,Invivogen,圣地亚哥,加利福尼亚,美国)的刺激下,孵育20小时后,TLR9拮抗剂使报告基因表达下降。使用QUANTI-BlueTM试剂盒(目录号:rep-qb1,Invivogen,圣地亚哥,加利福尼亚,美国)在640nm波长,在碱性磷酸酶存在下会变成紫色或蓝色的检测介质下,测定细胞培养上清液SEAP报告基因的活性。
在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)的96孔板中以170μL的体积将HEK293-Blue-hTLR9细胞以250,000~450,000个细胞/mL的密度孵育,在上述DMEM中,在最终DMSO中以1%的最终稀释度添加20μL供试化合物和10μL的20uMODN2006,在37℃的CO2培养箱中进行20小时的培养。然后将每个孔中的20μL上清液与180μLQuanti-blue底物溶液在37℃孵育2小时,并使用分光光度计在下读取吸光度。TLR9活化导致下游NF-κB活化的信号传导通路已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR9拮抗剂。
式(I)或式(Ia)的化合物具有人TLR7和/或TLR8抑制活性(IC50值)<0.5μM。此外,某些化合物还具有人TLR9抑制活性<0.5μM。表2中示出了本发明化合物的活性数据。
表2.本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
实例45
hERG通道抑制测定:
hERG通道抑制测定是一种高度灵敏的测量方法,可鉴定显示出与体内心脏毒性相关的hERG抑制作用的化合物。将hERG K+通道克隆到人体内,并在CHO(中国仓鼠卵巢)细胞系中稳定表达。CHOhERG细胞用于膜片钳(电压钳、全细胞)实验。电压模式刺激细胞活化hERG通道并传导IKhERG电流(hERG通道的快速延迟向外整流钾电流)。细胞稳定几分钟后,以0.1Hz(6bpm)的刺激频率记录IKhERG的振幅和动力学。此后,将供试化合物以递增浓度加入制剂中。对于每种浓度,均尝试达到稳态效果,通常在3-10分钟内达到此效果,然后再施加下一个最高浓度。记录IKhERG的振幅和动力学,并将其与对照值(取100%)进行比较。(参考文献:Redfern WS,Carlsson L,Davis AS,Lynch WG,MacKenzie I,Palethorpe S,Siegl PK,Strang I,Sullivan AT,Wallis R,Camm AJ,Hammond TG.2003;Relationships betweenpreclinical cardiac electrophysiology,clinical QT interval prolongation andtorsade de pointes for a broad range of drugs:evidence for aprovisionalsafety margin in drug development.Cardiovasc.Res.58:32-45,Sanguinetti MC,Tristani-Firouzi M.2006;hERG potassium channels and cardiac arrhythmia.Nature440:463-469,Webster R,Leishman D,Walker D.2002;Towards a drug concentrationeffect relationship for QT prolongation and torsades depointes.Curr.Opin.Drug Discov.Devel.5:116-26)。
hERG的结果如表3所示。安全比(hERG IC20/EC50)>30表示通过抑制TLR7/8/9通路与潜在的hERG相关心脏毒性来区分药理学的充分窗口。根据hERG IC20/TLR7/8/9IC50的计算(以下作为评估hERG责任的早期选择性指标),显然参比化合物ER-887258、ER-888285、ER-888286、R1和R2与本发明的化合物相比,具有更窄的安全窗。
表3.hERG和安全比结果
实例46
可预期这些化合物具有最小DDI(药物-药物相互作用)倾向。因此,确定式(I)或式(Ia)的化合物对CYP2D6的作用。
CYP抑制测定
这是一种高通量筛选试验,用于评估早期发现阶段人肝微粒体(HLM)中供试化合物对CYP2D6活性的可逆抑制。
表4.CYP抑制测定中使用的化学品和材料
程序
将供试化合物的10mM DMSO储备溶液在DMSO中稀释,以生成2mM中间储备溶液。将250nL中间储备溶液一式两份转移到3个单独的384孔微量滴定板(待测板)中。制备HLM和每种底物的混合物。然后将45μL HLM底物混合物转移到待测板的每个孔中并混合。阴性(溶剂)和阳性对照(CYP 2D6的标准抑制剂)包括在每个待测板中。将待测板在培养箱中温热至37℃放置10分钟。向每个培养孔中加入5μL预热的NADPH再生***以开始反应。最终孵育体积为50μL。然后将测定板放回37℃的培养箱中。孵育10分钟后,通过添加50μL含内标(20ng/mL D3右啡烷)的100%乙腈淬灭孵育物。收集上清液用于RapidFire/MS/MS分析。
使用RapidFire在线固相萃取/样品进样***(Agilent)偶联API4000三重四极杆质谱仪(AB Sciex)进行样品分析。流动相由乙腈和补充0.1%甲酸的水组成。使用C4固相萃取柱体进行样品分离。MS检测在阳离子MRM模式下完成。
数据分析
使用RapidFire积分器软件(版本3.6.12009.12296)确定底物、代谢物和内标的峰面积。然后计算代谢物和内标(稳定标记的代谢物)的峰面积比(PAR)。然后定义每个实验的测量窗:
PAR(0%活性)=含有浓缩抑制剂的所有孵育的平均PAR;
PAR(100%活性)=不包含抑制剂的所有孵育的平均PAR(DMSO对照);
活性%(供试抑制剂)
=[PAR(供试抑制剂)-PAR(0%活性)]/[PAR(100%活性)-PAR(0%活性)];
抑制%(供试抑制剂)=100-活性%(供试抑制剂)。
发现在上述测定中确定的本发明化合物对CYP2D6具有低CYP抑制作用。
表5.本发明化合物对CYP2D6的CYP抑制作用
*抑制百分比<0:非抑制剂或弱抑制剂
实例47
基于人PBMC细胞的测定
与HEK报告细胞系不同,人外周血单核细胞(PBMC)代表血液中的主要人免疫细胞,其主要由淋巴细胞、单核细胞和树突状细胞组成。这些细胞表达TLR7、TLR8或TLR9,并因此是对各自配体刺激的自然应答者。这些TLR一经活化,PBMC在体外和体内都会分泌相似的细胞因子和趋化因子,因此,TLR7/TLR8/TLR9拮抗剂在人PBMC中的体外效能可很容易地转化为其在体内的药效学应答。
通过密度梯度(Ficoll-PaqueTM PLUS,GE Healthcare life Sciences)从新鲜抽取的肝素化锂(锂肝素加采血管(Lithium Heparin Plus blood Collection tube),BD)健康供体全血中分离人外周血单核细胞(PBMC)。简而言之,在带有多孔屏障的50mL锥形管(Leucosep管,Greiner bio-one)中,用25mL PBS(不含Ca2+、Mg2+)稀释50mL血液,其中15.5mL Ficoll-Paque在旋转后置于下层。在制动器处于关闭位置的情况下,将试管在800×g(1946rpm)离心20分钟,然后从血沉棕黄层中收集PBMC。然后将细胞在PBS中洗涤两次,并通过在室温将其悬浮于2mL(红细胞裂解缓冲液,Alfa Aesar)中5-10分钟来裂解红细胞。在PBS中进行最终洗涤后,将PBMC以2×106细胞/mL的最终浓度重悬浮于补充有10%胎牛血清(Sigma)的含GlutaMAXTM(Gibco)的RPMI-1640培养基中,并以150μL/孔(3×105细胞/孔)在组织培养物处理的圆底96孔板(Corning Incorporated)中接种。
将在100%DMSO中溶解并连续稀释的拮抗剂化合物(本发明的化合物)以重复添加到细胞中,以得到1%DMSO(v/v)的最终浓度。将PBMC用拮抗剂化合物在37℃,5%CO2下孵育30分钟,然后按如下方式(指示最终浓度)在每孔48μL完全培养基中添加各种TLR激动剂:对于TLR9为1μM的CpG ODN 2216(InvivoGen),对于TLR8为1μg/mL的ORN06/LyoVec(InvivoGen),以及对于TLR7和TLR8为1μg/mL的R848(InvivoGen)。将PBMC在37℃用5%CO2孵育过夜。收集细胞培养上清液,并根据制造商推荐的方案(eBioscience,ThermoFisherScientific)通过Luminex测定(ProcartaPlexTM Multiplex Immunoassay,Invitrogen)或ELISA程序评估各种人类细胞因子的水平。另用细胞活力测定(CellTiterLuminescent Cell Viability Assay,Promega)检查细胞的活力。
表6.hPBMC结果
实例48
人微粒体稳定性测定
人微粒体稳定性测定用于早期评估人肝微粒体中供试化合物的代谢稳定性。
将人肝微粒体(化合物编号:452117,Corning,USA;化合物编号:H2610,Xenotech,USA)在37℃于100mM磷酸钾缓冲液(pH 7.4)中预孵育10分钟。通过添加NADPH再生***来起始反应。最终的孵育混合物在100mM磷酸钾缓冲液(pH 7.4)中含1μM供试化合物、0.5mg/mL肝微粒体蛋白、1mM MgCl2、1mM NADP、1单位/mL异柠檬酸脱氢酶和6mM异柠檬酸。在37℃孵育0、3、6、9、15和30分钟后,将300μL冷乙腈(包括内标)添加到100μL孵育混合物中以终止反应。沉淀和离心后,通过LC-MS/MS测定样品中残留的化合物量。还制备并分析了零和30分钟无NADPH再生***的对照。通过上述测定进行检测,本发明的化合物显示出良好的人肝微粒体稳定性,结果示如下表7所示。
表7.人肝微粒体对本发明化合物的稳定性
*检测极限
Claims (21)
5.根据权利要求4所述的化合物或其药用盐,其中L为氮杂环丁烷基。
6.根据权利要求5所述的化合物或其药用盐,其中R2为被C1-6烷基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被C1-6烷基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基。
7.根据权利要求6所述的化合物或其药用盐,其中R2为被甲基取代的4,5,6,7-四氢吡唑并[3,4-c]吡啶基;或被甲基取代的4,5,6,7-四氢吡唑并[4,3-c]吡啶基。
10.一种化合物,其选自:
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(6-甲基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-乙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(6-异丙基-5,7-二氢-4H-吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(5,6-二氢-4H-吡咯并[3,4-c]吡唑-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(3,5-二甲基-6,7-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6R)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(6S)-6-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4R)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(4S)-4-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2S,6R)-2-[[3-(7,7-二甲基-5,6-二氢-4H-吡唑并[4,3-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]-6-甲基-吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5S)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(5R)-5-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7R)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[(7S)-7-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-1-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[4-(4,5,6,7-四氢吡唑并[4,3-c]吡啶-2-基)-1-哌啶基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-[3-(三氟甲基)-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基]氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-1-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;和
5-[(2R,6S)-2-甲基-6-[[3-(3-甲基-4,5,6,7-四氢吡唑并[3,4-c]吡啶-2-基)氮杂环丁烷-1-基]甲基]吗啉-4-基]喹啉-8-腈;
或其药用盐。
12.一种根据权利要求1至10中任一项所述的化合物或药用盐、对映体或非对映体,其用作治疗活性物质。
13.一种药物组合物,其包含根据权利要求1至10中任一项所述的化合物以及治疗惰性载体。
14.根据权利要求1至10中任一项所述的化合物用于治疗或预防***性红斑狼疮或狼疮肾炎的用途。
15.根据权利要求1至10中任一项所述的化合物用于制备治疗或预防***性红斑狼疮或狼疮肾炎的药物的用途。
16.根据权利要求1至10中任一项所述的化合物作为TLR7或TLR8或TLR9拮抗剂的用途。
17.根据权利要求1至10中任一项所述的化合物作为TLR7和TLR8拮抗剂的用途。
18.根据权利要求1至10中任一项所述的化合物在制备用于TLR7和TLR8和TLR9拮抗剂的药物中的用途。
19.一种根据权利要求1至10中任一项所述的化合物或药用盐、对映体或非对映体,其用于治疗或预防***性红斑狼疮或狼疮肾炎。
20.一种根据权利要求1至10中任一项所述的化合物或药用盐、对映体或非对映体,其根据权利要求11所述的方法制造。
21.一种用于治疗或预防***性红斑狼疮或狼疮肾炎的方法,所述方法包括施用治疗有效量的如权利要求1至10中任一项所定义的化合物。
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CN2018114856 | 2018-11-09 | ||
PCT/EP2019/080454 WO2020094749A1 (en) | 2018-11-09 | 2019-11-07 | 5-[6-[[3-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile derivatives and similar compounds as tlr7-9 antagonists for treating systemic lupus erythematosus |
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WO2020048583A1 (en) | 2018-09-04 | 2020-03-12 | F. Hoffmann-La Roche Ag | Benzothiazole compounds for the treatment of autoimmune diseases |
EP3847170B1 (en) | 2018-09-06 | 2022-06-22 | F. Hoffmann-La Roche AG | Novel cyclic amidine compounds for the treatment of autoimmune disease |
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CN104507939A (zh) * | 2012-05-31 | 2015-04-08 | 卫材R&D管理有限公司 | 四氢吡唑并嘧啶化合物 |
CN106414432A (zh) * | 2013-10-14 | 2017-02-15 | 卫材R&D管理有限公司 | 选择性取代的喹啉化合物 |
CN108699032A (zh) * | 2015-12-17 | 2018-10-23 | 默克专利有限公司 | 多环tlr7/8拮抗剂及其在治疗免疫失调中的用途 |
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CN104507939A (zh) * | 2012-05-31 | 2015-04-08 | 卫材R&D管理有限公司 | 四氢吡唑并嘧啶化合物 |
CN106414432A (zh) * | 2013-10-14 | 2017-02-15 | 卫材R&D管理有限公司 | 选择性取代的喹啉化合物 |
CN108699032A (zh) * | 2015-12-17 | 2018-10-23 | 默克专利有限公司 | 多环tlr7/8拮抗剂及其在治疗免疫失调中的用途 |
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