CN112673007A - 用于治疗自身免疫性疾病的吡唑并吡啶胺化合物 - Google Patents
用于治疗自身免疫性疾病的吡唑并吡啶胺化合物 Download PDFInfo
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- CN112673007A CN112673007A CN201880097397.7A CN201880097397A CN112673007A CN 112673007 A CN112673007 A CN 112673007A CN 201880097397 A CN201880097397 A CN 201880097397A CN 112673007 A CN112673007 A CN 112673007A
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- Prior art keywords
- methyl
- diazaspiro
- morpholin
- pyridine
- pyrazolo
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- -1 Pyrazolopyridine amine compounds Chemical class 0.000 title claims description 278
- 238000011282 treatment Methods 0.000 title claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims description 95
- KIDIJBYYGAEULX-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound N#CC1=CC=CC2=CC=NN12 KIDIJBYYGAEULX-UHFFFAOYSA-N 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 31
- 125000003386 piperidinyl group Chemical group 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 21
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 19
- 125000004193 piperazinyl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 claims description 15
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 13
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 13
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 13
- 239000005557 antagonist Substances 0.000 claims description 12
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 claims description 6
- YLPCXVWMHNNQGI-UHFFFAOYSA-N 1,2-diazabicyclo[3.2.1]octane Chemical compound C1C2CCN1NCC2 YLPCXVWMHNNQGI-UHFFFAOYSA-N 0.000 claims description 6
- JGHLEANWAYIBHW-UHFFFAOYSA-N 1,2-diazabicyclo[4.2.0]octane Chemical compound N1CCCC2CCN21 JGHLEANWAYIBHW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- SXLSRHDXODSRBR-KNQAVFIVSA-N 4-[(2R,6S)-2-methyl-6-[[4-(4-methylpiperazin-1-yl)piperidin-1-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC(CC1)N1CCN(CC1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 SXLSRHDXODSRBR-KNQAVFIVSA-N 0.000 claims description 6
- NQDUSHUZWOIETE-MJGOQNOKSA-N 4-[(2S,6R)-2-(2,9-diazaspiro[5.5]undecan-2-ylmethyl)-6-methylmorpholin-4-yl]-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C1N(CCCC11CCNCC1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2F NQDUSHUZWOIETE-MJGOQNOKSA-N 0.000 claims description 6
- WWUUZADWVGXOJD-CUWFNYONSA-N 4-[(2S,6R)-2-[(2-benzyl-4-piperidin-4-ylpiperazin-1-yl)methyl]-6-methylmorpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C(C1=CC=CC=C1)C1N(CCN(C1)C1CCNCC1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 WWUUZADWVGXOJD-CUWFNYONSA-N 0.000 claims description 6
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 6
- 102000002689 Toll-like receptor Human genes 0.000 claims description 6
- 108020000411 Toll-like receptor Proteins 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003725 azepanyl group Chemical group 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- LYDKTPRIAYMOIB-UHFFFAOYSA-N 1,2-diazaspiro[2.5]octane Chemical compound C1CCCCC21NN2 LYDKTPRIAYMOIB-UHFFFAOYSA-N 0.000 claims description 4
- XVKAMJJNLSQRHR-UHFFFAOYSA-N 1,2-diazaspiro[3.4]octane Chemical compound C1NNC11CCCC1 XVKAMJJNLSQRHR-UHFFFAOYSA-N 0.000 claims description 4
- CERXGXGNTTZICX-WBVHZDCISA-N 4-[(2S,6R)-2-[[4-(2-aminoacetyl)piperazin-1-yl]methyl]-6-methylmorpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound NCC(=O)N1CCN(CC1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 CERXGXGNTTZICX-WBVHZDCISA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- QDUAMZUGVDYTDM-XZFDIXFUSA-N 4-[(2R,6R)-2-methyl-6-[(1-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1C(C2(CC1)CNCC2)=O)C=1C=2N(C(=CC=1)C#N)N=CC=2 QDUAMZUGVDYTDM-XZFDIXFUSA-N 0.000 claims description 3
- KGHQJPYPZHFNMK-ZKSQUDLQSA-N 4-[(2R,6R)-2-methyl-6-[(3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC2(CC1=O)CNCC2)C=1C=2N(C(=CC=1)C#N)N=CC=2 KGHQJPYPZHFNMK-ZKSQUDLQSA-N 0.000 claims description 3
- YUHIOIRJYWFBOB-MJGOQNOKSA-N 4-[(2R,6S)-2-methyl-6-(1-oxa-4,9-diazaspiro[5.5]undecan-4-ylmethyl)morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCOC2(C1)CCNCC2)C=1C=2N(C(=CC=1)C#N)N=CC=2 YUHIOIRJYWFBOB-MJGOQNOKSA-N 0.000 claims description 3
- JBHYXHUWWMAJGS-MJGOQNOKSA-N 4-[(2R,6S)-2-methyl-6-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC2(CNCCO2)CC1)C=1C=2N(C(=CC=1)C#N)N=CC=2 JBHYXHUWWMAJGS-MJGOQNOKSA-N 0.000 claims description 3
- NNFVFBFYRMESMT-AGERRDQYSA-N 4-[(2R,6S)-2-methyl-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1C2COCC1CNC2)C=1C=2N(C(=CC=1)C#N)N=CC=2 NNFVFBFYRMESMT-AGERRDQYSA-N 0.000 claims description 3
- VIPFGMONMGPQMS-ZBFHGGJFSA-N 4-[(2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCNCC1)C=1C=2N(C(=CC=1)C#N)N=CC=2 VIPFGMONMGPQMS-ZBFHGGJFSA-N 0.000 claims description 3
- HOLJRXMQIIVMNS-LBVBGPOBSA-N 4-[(2R,6S)-2-methyl-6-[(2-methylpiperazin-1-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1C(CNCC1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 HOLJRXMQIIVMNS-LBVBGPOBSA-N 0.000 claims description 3
- YSMMVQUTOCRLHJ-LBVBGPOBSA-N 4-[(2R,6S)-2-methyl-6-[(3-methylpiperazin-1-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC(NCC1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 YSMMVQUTOCRLHJ-LBVBGPOBSA-N 0.000 claims description 3
- ZYWRUDKVPVCYHH-WBVHZDCISA-N 4-[(2R,6S)-2-methyl-6-[(4-methylpiperazin-1-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCN(CC1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 ZYWRUDKVPVCYHH-WBVHZDCISA-N 0.000 claims description 3
- FHCBDNQRSQOPNO-NQIIRXRSSA-N 4-[(2R,6S)-2-methyl-6-[(4-piperazin-1-ylpiperidin-1-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC(CC1)N1CCNCC1)C=1C=2N(C(=CC=1)C#N)N=CC=2 FHCBDNQRSQOPNO-NQIIRXRSSA-N 0.000 claims description 3
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- SPXZSKZYRFGFJU-NQIIRXRSSA-N 4-[(2R,6S)-2-methyl-6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CCC(CC1)N1CCCC1)C=1C=2N(C(=CC=1)C#N)N=CC=2 SPXZSKZYRFGFJU-NQIIRXRSSA-N 0.000 claims description 3
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- CFLALZCTHKPKDL-GDBMZVCRSA-N 4-[(2S,6R)-2-(1,6-diazaspiro[3.3]heptan-1-ylmethyl)-6-methylmorpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound N1(CCC11CNC1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 CFLALZCTHKPKDL-GDBMZVCRSA-N 0.000 claims description 3
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- PJWOHYVOPBJJAI-CKYAKLRSSA-N 4-[(2S,6R)-2-(2,7-diazaspiro[4.5]decan-7-ylmethyl)-6-methylmorpholin-4-yl]-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound FC=1C=NN2C=1C(=CC=C2C#N)N1C[C@@H](O[C@@H](C1)C)CN1CC2(CCNC2)CCC1 PJWOHYVOPBJJAI-CKYAKLRSSA-N 0.000 claims description 3
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- OGAFPCPHUIPWEO-UHFFFAOYSA-N tert-butyl 2,9-diazaspiro[4.5]decane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC21CNCCC2 OGAFPCPHUIPWEO-UHFFFAOYSA-N 0.000 description 1
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- VGJOEEIXDPWTAZ-UHFFFAOYSA-N tert-butyl 4,7-diazabicyclo[4.2.0]octane-4-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2CNC21 VGJOEEIXDPWTAZ-UHFFFAOYSA-N 0.000 description 1
- TUIAJQPTVCSWOB-UHFFFAOYSA-N tert-butyl 4,8-diazabicyclo[4.2.0]octane-4-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2NCC21 TUIAJQPTVCSWOB-UHFFFAOYSA-N 0.000 description 1
- WWQRKRDWYBRFAA-UHFFFAOYSA-N tert-butyl 4,8-diazabicyclo[4.2.0]octane-8-carboxylate Chemical compound C1NCCC2N(C(=O)OC(C)(C)C)CC21 WWQRKRDWYBRFAA-UHFFFAOYSA-N 0.000 description 1
- IZUZIVIUDTZPFE-UHFFFAOYSA-N tert-butyl decanoate Chemical compound CCCCCCCCCC(=O)OC(C)(C)C IZUZIVIUDTZPFE-UHFFFAOYSA-N 0.000 description 1
- CBYPCXLWNJUVLF-UHFFFAOYSA-N tert-butyl n-(2-azaspiro[3.3]heptan-6-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC11CNC1 CBYPCXLWNJUVLF-UHFFFAOYSA-N 0.000 description 1
- HHYUNZXSGVNMOY-UHFFFAOYSA-N tert-butyl n-(3-azabicyclo[3.2.1]octan-8-yl)carbamate Chemical compound C1NCC2CCC1C2NC(=O)OC(C)(C)C HHYUNZXSGVNMOY-UHFFFAOYSA-N 0.000 description 1
- AYPWPGOPAZUJDF-UHFFFAOYSA-N tert-butyl n-(4,4-difluoropyrrolidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CNCC1(F)F AYPWPGOPAZUJDF-UHFFFAOYSA-N 0.000 description 1
- UUHPKKKRSZBQIG-UHFFFAOYSA-N tert-butyl n-(8-azabicyclo[3.2.1]octan-3-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC2CCC1N2 UUHPKKKRSZBQIG-UHFFFAOYSA-N 0.000 description 1
- VHYXAWLOJGIJPC-UHFFFAOYSA-N tert-butyl n-(piperidin-4-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCNCC1 VHYXAWLOJGIJPC-UHFFFAOYSA-N 0.000 description 1
- LHSNRJGZDUFKQT-RKDXNWHRSA-N tert-butyl n-[(3r,4r)-3-methylpiperidin-4-yl]carbamate Chemical compound C[C@@H]1CNCC[C@H]1NC(=O)OC(C)(C)C LHSNRJGZDUFKQT-RKDXNWHRSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
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- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
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Classifications
-
- 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
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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,尤其涉及用于治疗系统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
自身免疫性结缔组织病(CTD)包括典型的自身免疫综合征,例如系统性红斑狼疮(SLE)、原发性干燥综合征(pSjS)、混合性结缔组织病(MCTD)、皮肌炎/多发性肌炎(DM/PM)、类风湿关节炎(RA)和系统性硬化症(SSc)。除RA以外,患者没有真正有效、安全的疗法。SLE代表典型的CTD,其发病率为20-150/100,000,并在不同器官引起广泛的炎症和组织损伤,从皮肤和关节的常见症状到肾、肺或心力衰竭。传统上,SLE已经用非特异性抗炎或免疫抑制药物治疗。但是,长期使用免疫抑制药物(例如皮质类固醇)仅部分有效,并伴有不良的毒性和副作用。贝利木单抗是过去50年中唯一获得FDA批准的用于狼疮的药物,即使其仅对部分SLE患者具有适度且延迟的疗效(Navarra,S.V.等人.Lancet 2011,377,721.)。其他生物制剂,例如抗CD20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、8和9作为天然的宿主防御传感器,可识别源自病毒、细菌的核酸,具体地,TLR7/8和TLR9分别识别单链RNA(ssRNA)和单链CpG-DNA。然而,TRL7/8/9的异常核酸传感被认为是广泛的自身免疫和自身炎症性疾病的关键节点(Krieg,A.M.等人,Immunol.Rev.2007,220,251.Jiménez-Dalmaroni,M.J.等人,Autoimmun Rev.2016,15,1.Chen,J.Q.等人,Clinical Reviews in Allergy&Immunology 2016,50,1.)因此,TLR7/8/9代表用于自身免疫性疾病和自身炎症性疾病的新治疗靶点,针对这些疾病,不存在有效的不含类固醇和无细胞毒性的口服药物,并且从非常上游抑制这些途径可能会带来令人满意的治疗效果。从安全性的角度来看,由于有多种核酸传感途径(例如其他TLR、cGAS/STING),此类冗余性应仍然允许在TLR7/8/9抑制存在的情况下对感染作出响应。因此,我们提出并发明了靶向并抑制TLR7/8/9的口服化合物,以用于治疗自身免疫性疾病和自身炎症性疾病。
发明内容
本发明涉及具有式(I)的新型化合物,
其中
R1为氰基、C1-6烷基、卤素、卤代C1-6烷基或硝基;
R2为杂环基或杂环基氨基;
R3为C1-6烷基或卤代C1-6烷基;
R4为H或卤素;
X为O或CH2;
或其药用盐、对映体或非对映体。
本发明的另一个目的涉及式(I)的新型化合物、其制造、基于根据本发明化合物的药物和其生产以及式(I)化合物作为TLR7和/或TLR8和/或TLR9拮抗剂的用途,及用于系统性红斑狼疮或狼疮肾炎治疗或预防的用途。式(I)化合物示出优异的TLR7和/或TLR8和/或TLR9拮抗活性。另外,式(I)化合物还显示出良好的细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
具体实施方式
定义
术语“C1-6烷基”表示含有1至6个,特别是1至4个碳原子的饱和、直链或支链烷基,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”表示烷基,其中烷基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-或三氟代的-甲基、-乙基或-丙基、例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基、二氟甲基、三氟甲基和三氟乙基。
术语“卤代哌啶基”表示一种哌啶基基团,其中哌啶基基团的氢原子中的至少一个已由相同或不同的卤素原子,特别是由氟原子取代。卤代哌啶基的示例包括氟吡咯烷基和二氟哌啶基。
术语“杂环基”表示3至12个环原子的单价饱和或部分不饱和的单环或双环体系,其包含1、2或3个选自N、O和S的环杂原子,剩余的环原子为碳。在特定的实施例中,杂环基是4至10个环原子的单价饱和的单环体系,其包含1、2或3个选自N、O和S的环杂原子,剩余的环原子为碳。单环饱和杂环基的示例为氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚烷基、二氮杂环庚烷基、高哌嗪基或氧氮杂环庚烷基。杂环基可完全或部分饱和。双环饱和杂环基的示例为(3,4,4a,5,6,7,8,8a-八氢-2H-萘啶基;3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶基;1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶基;1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶基;3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯基;氮杂双环[3.2.1]辛烷基;氮杂双环[3.3.1]壬烷基;氮杂螺[3.3]庚烷基;氧杂氮杂双环[3.3.1]壬烷基;氧杂二氮杂螺[4.5]癸烷基;二氮杂双环[2.2.2]辛烷基;二氮杂双环[3.2.1]辛烷基;二氮杂双环[4.2.0]辛烷基;二氮杂螺[2.5]辛烷基;二氮杂螺[3.3]庚烷基;二氮杂螺[3.4]辛烷基;二氮杂螺[3.5]壬烷基;二氮杂螺[3.6]癸烷基;二氮杂螺[4.4]壬烷基;二氮杂螺[4.5]癸烷基;二氮杂螺[5.5]十一烷基;氧杂二氮杂双环[3.3.1]壬烷基;氧杂二氮杂螺[5.5]十一烷基;和氧代二氮杂螺[4.4]壬烷基。部分饱和杂环基的示例为二氢呋喃基、咪唑啉基、二氢噁唑基、四氢吡啶基和二氢吡喃基。单环或双环杂环基可进一步由卤素、羟基、氨基、氨基C1-6烷基、氨基C1-6烷基羰基、C1-6烷基羰基氨基、(C1-6烷基)2氨基、氨基甲酰基、C1-6烷基、卤代C1-6烷基、苯基、苯基C1-6烷基或杂环基取代。
术语“对映体”表示化合物的两种立体异构体,它们是彼此不可重叠的镜像。
术语“非对映体”表示具有两个或更多个手性中心并且其分子并非彼此镜像的立体异构体。非对映体具有不同的物理性质,例如熔点、沸点、光谱特性和反应性。
术语“药用盐”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排泄的方式。然而,在某些情况下,药物代谢是治疗效果所必需的。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,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
R1为氰基、C1-6烷基、卤素、卤代C1-6烷基或硝基;
R2为杂环基或杂环基氨基;
R3为C1-6烷基或卤代C1-6烷基;
R4为H或卤素;
X为O或CH2;
或其药用盐、对映体或非对映体。
本发明的进一步实施例为(ii),其为根据(i)所述的式(I)化合物,其中
R1为氰基;
R2为(3,4,4a,5,6,7,8,8a-八氢-2H-萘啶基;
(C1-6烷基)2氨基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯基;
1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶基;
1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶基;
1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶基;
3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氮杂双环[3.3.1]壬烷基;
氨基氮杂螺[3.3]庚烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
C1-6烷基氧杂二氮杂螺[4.5]癸烷基;
C1-6烷基哌啶基氨基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[2.5]辛烷基;
二氮杂螺[3.3]庚烷基;
二氮杂螺[3.4]辛烷基;
二氮杂螺[3.5]壬烷基;
二氮杂螺[3.6]癸烷基;
二氮杂螺[4.4]壬烷基;
二氮杂螺[4.5]癸烷基;
二氮杂螺[5.5]十一烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧杂二氮杂螺[5.5]十一烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:C1-6烷基、苯基、苯基C1-6烷基、氨基C1-6烷基羰基和哌啶基;
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、氨基C1-6烷基、氮杂环庚烷基、C1-6烷基、C1-6烷基羰基氨基、C1-6烷基哌嗪基、氨基甲酰基、卤素、苯基、哌嗪基、哌啶基和吡咯烷基;或
吡咯烷基,所述吡咯烷基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基和卤素;
R3为C1-6烷基;
R4为H或卤素;
X为O;
或其药用盐、对映体或非对映体。
本发明的进一步实施例为(iii),其为根据(ii)所述的式(I)化合物,其中
R1为氰基;
R2为(3,4,4a,5,6,7,8,8a-八氢-2H-萘啶基;
2,2-二甲基丙酰氨基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯基;
1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶基;
1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶基;
1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶基;
3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氮杂双环[3.3.1]壬烷基;
氨基氮杂螺[3.3]庚烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
甲基氧杂二氮杂螺[4.5]癸烷基;
甲基哌啶基氨基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[2.5]辛烷基;
二氮杂螺[3.3]庚烷基;
二氮杂螺[3.4]辛烷基;
二氮杂螺[3.5]壬烷基;
二氮杂螺[3.6]癸烷基;
二氮杂螺[4.4]壬烷基;
二氮杂螺[4.5]癸烷基;
二氮杂螺[5.5]十一烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧杂二氮杂螺[5.5]十一烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:甲基、苯基、苄基、氨基乙酰基和哌啶基;
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、氨基甲基、氨基乙基、氮杂环庚烷基、甲基、2,2-二甲基丙酰氨基、甲基哌嗪基、氨基甲酰基、氟、苯基、哌嗪基、哌啶基和吡咯烷基;或
吡咯烷基,所述吡咯烷基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基和氟;
R3为甲基;
R4为H或氟;
X为O;
或其药用盐、对映体或非对映体。
本发明的进一步实施例为(iv),其为根据(iii)所述的式(I)化合物,其中R2为(3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-4-基;1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-基、1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-基;1,6-二氮杂螺[3.3]庚烷-1-基;1,7-二氮杂螺[3.5]壬烷-7-基;1,8-二氮杂螺[4.5]癸烷-8-基;1,9-二氮杂螺[5.5]十一烷-9-基、1-甲基-4-哌啶基氨基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基;1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;2-(3-氨基甲酰基)-1-哌啶基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-基;2,5-二氮杂双环[2.2.2]辛烷-2-基;2,6-二氮杂螺[3.3]庚烷-2-基;2,6-二氮杂螺[3.5]壬烷-6-基;2,6-二氮杂螺[4.5]癸烷-2-基;2,7-二氮杂螺[3.4]辛烷-2-基;2,7-二氮杂螺[3.5]壬烷-2-基;2,7-二氮杂螺[3.5]壬烷-7-基;2,7-二氮杂螺[4.4]壬烷-2-基;2,7-二氮杂螺[4.5]癸烷-7-基;2,8-二氮杂螺[3.5]壬烷-2-基;2,8-二氮杂螺[3.6]癸烷-2-基;2,8-二氮杂螺[4.5]癸烷-2-基;2,8-二氮杂螺[4.5]癸烷-8-基;2,8-二氮杂螺[5.5]十一烷-2-基;2,9-二氮杂螺[4.5]癸烷-2-基;2,9-二氮杂螺[5.5]十一烷-2-基;2,9-二氮杂螺[5.5]十一烷-9-基;2-苄基-4-(4-哌啶基)哌嗪-1-基;2-苄基哌嗪-1-基;2-甲基哌嗪-1-基;3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯-1-基;3,7-二氮杂双环[4.2.0]辛烷-3-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3,8-二氮杂双环[3.2.1]辛烷-8-基;3,8-二氮杂双环[4.2.0]辛烷-8-基;3,9-二氮杂螺[5.5]十一烷-3-基;3-氨基-8-氮杂双环[3.2.1]辛烷-8-基;3-氨基-9-氮杂双环[3.3.1]壬烷-9-基;3-甲基哌嗪-1-基;3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基;3-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;3-苯基哌嗪-1-基;4-(1-哌啶基)-1-哌啶基;4-(2,2-二甲基丙酰氨基)-1-哌啶基;4-(2-氨基乙酰基)哌嗪基;4-(2-氨基乙基)-1-哌啶基;4-(4-甲基哌嗪-1-基)-1-哌啶基;4-(氨基甲基)-1-哌啶基;4-(氮杂环庚烷-1-基)-1-哌啶基;4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基;4,7-二氮杂螺[2.5]辛烷-7-基;4-氨基-1-哌啶基;4-氨基-2-甲基-1-哌啶基;4-氨基-3,3-二氟-1-哌啶基;4-氨基-3,3-二氟-吡咯烷-1-基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;4-氨基-4-苯基-1-哌啶基;4-甲基哌嗪基;4-哌嗪-1-基-1-哌啶基;4-吡咯烷-1-基-1-哌啶基;6-氨基-2-氮杂螺[3.3]庚烷-2-基;7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基;8-氨基-3-氮杂双环[3.2.1]辛烷-3-基;9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷-2-基或哌嗪基。
本发明的进一步实施例为(v),其为根据(iv)所述的式(I)化合物,其中R2为
1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[4.5]癸烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由C1-6烷基或苯基C1-6烷基所取代;或
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、C1-6烷基、C1-6烷基哌嗪基和卤素。
本发明的进一步实施例为(vi),其为根据(v)所述的式(I)化合物,其中R2为1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;氨基氮杂双环[3.2.1]辛烷基;氨基氧杂氮杂双环[3.3.1]壬烷基;二氮杂双环[2.2.2]辛烷基;二氮杂双环[3.2.1]辛烷基;二氮杂双环[4.2.0]辛烷基;二氮杂螺[4.5]癸烷基;氧杂二氮杂双环[3.3.1]壬烷基;氧代二氮杂螺[4.4]壬烷基;哌嗪基、甲基哌嗪基;苄基哌嗪基;甲基哌嗪基哌啶基;氨基哌啶基;氨基(C1-6烷基)哌啶基或氨基卤代哌啶基。
本发明的进一步实施例为(vii),其为根据(vi)所述的式(I)化合物,其中R2为4-(4-甲基哌嗪-1-基)-1-哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,5-二氮杂双环[2.2.2]辛烷-2-基;2,6-二氮杂螺[4.5]癸烷-2-基;2-苄基哌嗪-1-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3,8-二氮杂双环[3.2.1]辛烷-8-基;3-甲基哌嗪-1-基;3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基;4-氨基-1-哌啶基;4-氨基-3,3-二氟-1-哌啶基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基;8-氨基-3-氮杂双环[3.2.1]辛烷-3-基或哌嗪基。
本发明的进一步实施例为(viii),其为根据(v)或(vi)所述的式(I)化合物,其中R2为C1-6烷基哌嗪基哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;氧杂二氮杂螺[5.5]十一烷基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;二氮杂螺[4.5]癸烷基;二氮杂双环[4.2.0]辛烷基;氨基哌啶基;氨基(C1-6烷基)哌啶基。
本发明的进一步实施例为(ix),其为根据(viii)所述的式(I)化合物,其中R2为4-(4-甲基哌嗪-1-基)-1-哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,9-二氮杂螺[4.5]癸烷-2-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;4-氨基-1-哌啶基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基。
本发明的进一步实施例为(x),其为根据(viii)所述的式(I)化合物,其中R2为二氮杂螺[4.5]癸烷基。
本发明的进一步实施例为(xi),其为根据(x)所述的式(I)化合物,其中R2为2,9-二氮杂螺[4.5]癸烷-2-基。
本发明的另一实施例为(xii),其为以下项的式(I)的特定化合物:
4-[(2R,6S)-2-甲基-6-[[4-(4-甲基哌嗪-1-基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
N-[1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]-4-哌啶基]-2,2-二甲基-丙酰胺;
4-[(2S,6R)-2-(3,9-二氮杂螺[5.5]十一烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(氮杂环庚烷-1-基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(哌嗪-1-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[4.4]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[(1-甲基-4-哌啶基)氨基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[3.3]庚烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.4]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(6-氨基-2-氮杂螺[3.3]庚烷-2-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(氨基甲基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(2-氨基乙基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(2-氨基乙酰基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[4-(1-哌啶基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6R)-2-甲基-6-[(3-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6R)-2-甲基-6-[(1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(3-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-4-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,5-二氮杂双环[2.2.2]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[3.5]壬烷-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-吡咯烷-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(8-氨基-3-氮杂双环[3.2.1]辛烷-3-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(3-氨基-8-氮杂双环[3.2.1]辛烷-8-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[(3R)-3-苯基哌嗪-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-哌嗪-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(4,7-二氮杂螺[2.5]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[3.6]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(2-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-2-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-吡咯烷-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,6-二氮杂螺[3.3]庚烷-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[4.2.0]辛烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(2-苄基哌嗪-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[顺式-(3aR,6aR)-3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[顺式-(3aS,7aS)-1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-4-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
内型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
外型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-腈;
3-氟-4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
3-氟-4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]哌啶-3-甲酰胺;
4-[(2S,6R)-2-[(4-氨基-4-苯基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并
[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[(3R,4S)-4-氨基-3-甲基-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;和
4-[(2S,6R)-2-[[2-苄基-4-(4-哌啶基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
或其药用盐、对映体或非对映体。
合成
本发明的化合物可以通过任何常规方法制备。在以下方案和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。
用于制备式(I)或式(II)的化合物的一般合成路线如下所示。
方案1
其中R为Ms、Ts或Tf。R5和R6独立地选自H和杂环基,或者R5和R6与它们所连接的氮一起形成杂环基。Y为卤素。
式(III)化合物与卤化物(IV)的偶联可通过在碱(诸如DIPEA和K2CO3)的存在下或在Buchwald-Hartwig胺化条件(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)下,使用催化剂(诸如Ruphos Pd-G2)和碱(诸如Cs2CO3)直接偶联而实现,以提供式(V)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(V)化合物的羟基基团转变为离去基团(诸如–OTf、–OTs或–OMs)。在碱(诸如K2CO3、DIPEA或Cs2CO3)存在下,将式(VI)化合物进一步与胺(VII)偶联,以获得式(II)化合物。在一些实施例中,式(VI)化合物和胺(VII)的偶联可得到源自胺(VII)的含有保护基团(例如Boc)的产物,其将在获得最终的式(II)化合物之前加以去除。
本发明还涉及用于制备式(I)化合物的方法,该方法包括以下步骤的任一项:
a)式(VI)化合物,
与胺(VII)在碱的存在下反应;
在步骤a)和d)中,碱可为例如K2CO3、DIPEA或Cs2CO3;
根据上述方法生产的式(I)或式(II)的化合物也是本发明的目的。
本发明的化合物可以以非对映体或对映体的混合物形式获得,它们可以通过本领域熟知的方法分离,例如(手性)HPLC或SFC。
适应症和治疗方法
本发明提供了可用作TLR7和/或TLR8和/或TLR9拮抗剂的化合物,其抑制通过TLR7和/或TLR8和/或TLR9的途径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,所述化合物可用作系统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系统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系统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
DIPEA: N,N-二异丙基乙胺
EtOAc: 乙酸乙酯
FA: 甲酸
HATU: 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡
啶鎓3-氧化六氟磷酸盐
IC50: 半抑制浓度
IPA: 异丙醇
LCMS 液相色谱-质谱
L-DATA: 二-对-茴香酰基-L-酒石酸
MS: 质谱
Ms: 甲磺酰基
NCS: N-氯代琥珀酰亚胺
NIS: N-碘代琥珀酰亚胺
Prep-HPLC: 制备型高效液相色谱
PPh3: 三苯膦
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
SelectFluor: 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷双(四氟硼
酸酯)
TEA: 三乙胺
TEMPO: 四甲基哌啶氧化物
Tf: 三氟甲磺酰基
TFA: 三氟乙酸
THF: 四氢呋喃
Ts 对甲苯磺酰基
v/v: 体积比
DDI: 药物相互作用
LYSA: 冻干溶解度测定
HLM: 人肝微粒体
一般实验条件
使用以下仪器之一通过快速色谱法纯化中间体和最终化合物:i)Biotage SP1系统和Quad 12/25 Cartridge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在反相色谱柱上通过制备性HPLC,使用XBridgeTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱,SunFireTMPrep-C18(5μm,OBDTM 30×100mm)色谱柱,Phenomenex Synergi-C18(10μm,25×150mm)或Phenomenex Gemini-C18(10μm,25×150mm)纯化。Waters自动纯化系统(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纯化系统(泵322,检测器:UV 156,溶剂体系:乙腈和0.05%氢氧化铵的水溶液;乙腈和0.225%的FA的水溶液;乙腈和0.05%HCl的水溶液;乙腈和0.075%TFA的水溶液;或乙腈和水)。
对于SFC手性分离,使用Mettler Toledo Multigram III系统SFC,Waters 80Q制备型SFC或Thar 80制备型SFC,通过手性柱(Daicel chiralpak IC,5vm,30×250mm),AS(10μm,30×250mm)或AD(10μm,30×250mm)分离中间体,溶剂系统为:CO2和IPA(0.5%TEA的IPA溶液)或CO2和MeOH(0.1%NH3H2O的MeOH溶液),背压100bar,在254或220nm下检测UV。
使用LC/MS(WatersTM Alliance 2795-Micromass ZQ,Shimadzu 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的水溶液;B:0.1%TFA的乙腈溶液
酸性条件II:A:0.0375%TFA的水溶液;B:0.01875%TFA的乙腈溶液
碱性条件I:A:0.1%NH3·H2O的水溶液;B:乙腈
碱性条件II:A:0.025%NH3·H2O的水溶液;B:乙腈
中性条件:A:水;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:
实例1
4-[(2R,6S)-2-甲基-6-[[4-(4-甲基哌嗪-1-基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
根据以下方案合成标题化合物:
步骤1:[(2R,6R)-6-甲基吗啉-2-基]甲醇(化合物1a)的制备
向(2R,6R)-2-(苄氧基甲基)-6-甲基-吗啉-4-羧酸叔丁酯(参考文献:US20150105370 A1)(22.0g,68.4mmol)的EtOH(500mL)溶液中加入Pd/C(7.28mg,10%潮湿)并且在H2气氛下于30℃搅拌48小时。然后过滤溶液,并且浓缩滤液以得到中间体(15g),其为无色油状物。在0℃下向此中间体(231mg,1.0mmol)的DCM(2mL)溶液中加入TFA(1mL)。将反应混合物在室温下搅拌2小时,然后浓缩以得到粗制化合物1a(250mg),将该粗制化合物直接用于下一步骤。MS:计算的132(MH+),测得的132(MH+)。
步骤2:4-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(化合物1c)的制备
向粗制[(2R,6R)-6-甲基吗啉-2-基]甲醇(化合物1a,250mg,约1.0mmol)、4-氯吡唑并[1,5-a]吡啶-7-腈(CAS:1268520-74-6,Pharmablock)(化合物1b,450mg,2.5mmol)和Cs2CO3(3.3g,10.1mmol)的二噁烷(5mL)溶液中加入Ruphos Pd G2(98mg,0.13mmol)。将反应混合物脱气并在90℃下加热(油浴)3小时,然后冷却至室温,用EtOAc(10mL)稀释并且通过硅藻土过滤。浓缩滤液以得到棕色油状物,将该棕色油状物通过柱层析法纯化以得到化合物1c(521mg),其为微黄色油状物。MS:计算的273(MH+),测得的273(MH+)。
步骤3:[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(化合物1d)的制备
在0℃下,向4-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(化合物1c,190mg,0.70mmol)和2,6-二甲基吡啶(150mg,1.4mmol)的DCM(4mL)溶液中逐滴加入三氟甲磺酸酐(295mg,1.05mmol)。将混合物在0℃下搅拌1小时。然后将混合物用DCM稀释,用饱和NH4Cl和盐水洗涤,经Na2SO4干燥并且浓缩以得到粗产物,将该粗产物通过柱层析法纯化以得到化合物1d(166mg),其为白色固体。MS:计算的405(MH+),测得的405(MH+)。
步骤4:4-[(2R,6S)-2-甲基-6-[[4-(4-甲基哌嗪-1-基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(实例1)的制备
在室温下,向[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(化合物1d,41mg,0.10mmol)和1-甲基-4-(哌啶-4-基)哌嗪盐酸盐(33mg,0.15mmol)的ACN(4mL)溶液中加入K2CO3(56mg,0.41mmol)。反应混合物回流6小时后。将混合物用ACN稀释,并且通过硅藻土过滤。浓缩滤液以得到黄色固体,将该黄色固体通过制备型HPLC纯化以得到实例1(7mg),其为白色固体。MS:计算的438(MH+),测得的438(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.4Hz,1H),7.46(d,J=7.9Hz,1H),6.86(d,J=2.4Hz,1H),6.58(d,J=7.9Hz,1H),4.04-3.86(m,2H),3.81(br d,J=12.3Hz,1H),3.77-3.68(m,1H),3.16(br d,J=11.9Hz,1H),3.01(br s,1H),2.77-2.58(m,5H),2.58-2.36(m,6H),2.28(s,3H),2.28-2.17(m,2H),2.17-2.02(m,2H),1.90(br d,J=10.4Hz,2H),1.64-1.51(m,2H),1.25(d,J=6.2Hz,3H)。
实例2
N-[1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]-4-哌啶基]-2,2-二甲基-丙酰胺
类似于实例1的制备,通过使用2,2-二甲基-N-(4-哌啶基)丙酰胺代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例2(11mg),其为白色粉末。MS:计算的439(MH+),测得的439(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.47(d,J=8.1Hz,1H),6.86(d,J=2.4Hz,1H),6.59(d,J=8.1Hz,1H),4.03-3.96(m,1H),3.96-3.86(m,1H),3.81(br d,J=12.3Hz,1H),3.77-3.71(m,1H),3.71-3.63(m,1H),3.10(br d,J=12.0Hz,1H),2.98(br d,J=11.7Hz,1H),2.65(td,J=10.1,12.1Hz,2H),2.60-2.46(m,2H),2.29-2.13(m,2H),1.80(br d,J=12.2Hz,2H),1.68-1.54(m,2H),1.26(d,J=6.2Hz,3H),1.17(s,9H)。
实例3
4-[(2S,6R)-2-(3,9-二氮杂螺[5.5]十一烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
在室温下,向[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(化合物1d,41mg,0.10mmol)和3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(39mg,0.15mmol)的ACN(4mL)溶液中加入K2CO3(56mg,0.41mmol)。反应混合物回流6小时后。将混合物用ACN稀释,并且通过硅藻土过滤。浓缩滤液以得到以得到黄色固体。然后将粗产物溶于DCM(2mL)中,用TFA(1mL)处理。将反应混合物在室温下搅拌1小时,然后浓缩以得到黄色油状物,将该黄色油状物通过制备型HPLC纯化以得到实例3(22mg),其为淡黄色固体。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.3Hz,1H),7.46(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.61(d,J=8.1Hz,1H),4.32(br t,J=10.0Hz,1H),4.08-3.95(m,1H),3.78(br t,J=11.9Hz,2H),3.69-3.51(m,2H),3.43-3.33(m,2H),3.29-3.17(m,6H),2.80-2.65(m,2H),2.09-1.89(m,4H),1.89-1.66(m,4H),1.30(d,J=6.2Hz,3H)。
实例4
4-[(2S,6R)-2-[[4-(氮杂环庚烷-1-基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用1-(4-哌啶基)氮杂环庚烷盐酸盐代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例4(13mg),其为白色粉末。MS:计算的437(MH+),测得的437(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.60(d,J=7.9Hz,1H),4.14-4.05(m,1H),4.01-3.91(m,1H),3.79(br t,J=14.1Hz,2H),3.44-3.34(m,7H),2.77(br d,J=5.6Hz,2H),2.75-2.69(m,1H),2.69-2.62(m,1H),2.49(q,J=12.6Hz,2H),2.21-2.11(m,2H),2.03-1.86(m,6H),1.81-1.70(m,4H),1.28(d,J=6.1Hz,3H)。
实例5
4-[(2R,6S)-2-甲基-6-(哌嗪-1-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用哌嗪-1-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例5(21mg),其为白色粉末。MS:计算的341(MH+),测得的341(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.4Hz,1H),7.46(d,J=8.1Hz,1H),6.85(d,J=2.4Hz,1H),6.58(d,J=8.1Hz,1H),4.06-3.96(m,1H),3.95-3.85(m,1H),3.81(br d,J=12.3Hz,1H),3.74(dd,J=2.0,12.3Hz,1H),2.92(t,J=4.9Hz,4H),2.73-2.60(m,4H),2.59-2.47(m,4H),1.25(d,J=6.2Hz,3H)。
实例6
4-[(2S,6R)-2-(2,7-二氮杂螺[4.4]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例6(27mg),其为淡黄色油状物。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.2Hz,1H),7.45(d,J=7.9Hz,1H),6.89-6.84(m,1H),6.59(d,J=7.9Hz,1H),4.16-4.07(m,1H),4.02-3.91(m,1H),3.78(br dd,J=12.6,18.6Hz,2H),3.39(br t,J=7.2Hz,2H),3.36-3.31(m,2H),3.30-3.19(m,3H),3.19-3.09(m,2H),3.09-2.99(m,1H),2.77-2.61(m,J=11.0,11.0,17.8Hz,2H),2.21-2.01(m,4H),1.29(d,J=6.2Hz,3H)。
实例7
4-[(2R,6S)-2-甲基-6-[[(1-甲基-4-哌啶基)氨基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用1-甲基哌啶-4-胺盐酸盐代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例7(22mg),其为淡棕色固体。MS:计算的369(MH+),测得的369(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.1Hz,1H),7.51-7.43(m,1H),6.93-6.86(m,1H),6.60(d,J=7.9Hz,1H),4.61-4.45(m,1H),4.13-4.02(m,1H),4.02-3.93(m,1H),3.92-3.70(m,3H),3.70-3.54(m,1H),3.54-3.44(m,1H),3.43-3.33(m,2H),3.22-3.11(m,1H),3.08-2.98(m,1H),2.88-2.73(m,2H),2.73-2.65(m,3H),2.30-2.15(m,2H),1.88-1.71(m,1H),1.35-1.24(m,3H)。
实例8
4-[(2S,6R)-2-(2,6-二氮杂螺[3.3]庚烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,6-二氮杂螺并[3.3]庚烷-2-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例8(14mg),其为白色粉末。MS:计算的353(MH+),测得的353(MH+)。1H NMR(400MHz,甲醇-d4)δ8.05(d,J=2.3Hz,1H),7.49(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.60(d,J=7.9Hz,1H),3.97-3.78(m,6H),3.79-3.67(m,2H),3.53-3.45(m,4H),2.72-2.57(m,4H),1.26(d,J=6.2Hz,3H)。
实例9
4-[(2S,6R)-2-(2,7-二氮杂螺[3.4]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,6-二氮杂螺[3.4]辛烷-6-羧酸叔丁酯(CAS:885270-86-0,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例9(18mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.47-4.30(m,4H),4.19-4.08(m,1H),4.02-3.91(m,1H),3.76(brd,J=12.0Hz,2H),3.61(br s,2H),3.56-3.50(m,1H),3.48-3.41(m,1H),3.41-3.34(m,1H),3.41-3.34(m,1H),2.78-2.63(m,2H),2.51-2.38(m,2H),1.29(d,J=6.2Hz,3H)。
实例10
4-[(2S,6R)-2-(2,8-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,6-二氮杂螺[3.5]壬烷-6-羧酸叔丁酯(CAS:885272-17-3,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例10(25mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.45-4.04(m,5H),4.03-3.89(m,1H),3.76(br d,J=12.8Hz,2H),3.58-3.39(m,4H),3.14(t,J=5.6Hz,2H),2.78-2.63(m,2H),2.08(br s,2H),1.87(br s,2H),1.29(d,J=6.2Hz,3H)。
实例11
4-[(2S,6R)-2-[(6-氨基-2-氮杂螺[3.3]庚烷-2-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(2-氮杂螺[3.3]庚烷-6-基)氨基甲酸叔丁酯(CAS:1118786-85-8,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例11(24mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1HNMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.61(d,J=8.1Hz,1H),4.50-4.20(m,4H),4.13-4.04(m,1H),4.00-3.90(m,1H),3.81-3.69(m,3H),3.47-3.41(m,1H),3.38-3.33(m,1H),2.85(br s,1H),2.69(ddd,J=10.5,12.5,16.6Hz,3H),2.47(br s,2H),1.29(d,J=6.2Hz,3H)。
实例12
4-[(2S,6R)-2-[[4-(氨基甲基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(4-哌啶基甲基)氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例12(10mg),其为淡棕色固体。MS:计算的369(MH+),测得的369(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.49(d,J=7.9Hz,1H),6.90(d,J=2.4Hz,1H),6.63(d,J=8.1Hz,1H),4.33(br t,J=9.0Hz,1H),4.07-3.97(m,1H),3.86-3.70(m,4H),3.40-3.32(m,1H),3.30-3.22(m,1H),3.18-3.07(m,J=6.5Hz,2H),2.93(br d,J=6.5Hz,2H),2.79-2.67(m,2H),2.16-1.94(m,3H),1.76-1.55(m,2H),1.31(d,J=6.2Hz,3H)。
实例13
4-[(2S,6R)-2-[[4-(2-氨基乙基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-[2-(4-哌啶基)乙基]氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例13(15mg),其为淡棕色固体。MS:计算的383(MH+),测得的383(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.62(d,J=7.9Hz,1H),4.32(br t,J=9.8Hz,1H),4.06-3.97(m,1H),3.85-3.66(m,4H),3.45-3.32(m,1H),3.29-3.23(m,1H),3.12-2.95(m,4H),2.79-2.66(m,2H),2.09-1.93(m,2H),1.73(br s,1H),1.71-1.59(m,3H),1.59-1.49(m,1H),1.31(d,J=6.4Hz,3H)。
实例14
4-[(2S,6R)-2-[[4-(2-氨基乙酰基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
根据以下方案制备标题化合物:
步骤1:N-(2-氧代-2-哌嗪-1-基-乙基)氨基甲酸叔丁酯的制备
向Boc-Ala-OH(398mg,2.3mmol)、哌嗪-1-羧酸苄酯(500mg,2.3mmol)和DIPEA(587mg,0.79mL,4.5mmol)的DCM(10mL)溶液中加入HATU(1.29g,3.4mmol)。将反应混合物在室温下搅拌过夜,然后用DCM稀释,用饱和NH4Cl和盐水洗涤,经Na2SO4干燥并且浓缩以得到油状物,将该油状物通过柱层析法纯化以得到产物(900mg),其为无色油状物。向上述产物(200mg,0.53mmol)的MeOH(20mL)溶液中加入Pd(OH)2(20%碳载,潮湿,30mg)。将反应混合物用H2囊充气并且在室温下搅拌2小时,然后通过硅藻土过滤,并且浓缩滤液以得到化合物14a(100mg),其为油状物。MS:计算的244(MH+),测得的244(MH+)。
步骤2:4-[(2S,6R)-2-[[4-(2-氨基乙酰基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈的制备
类似于实例3的制备,通过使用N-(2-氧代-2-哌嗪-1-基-乙基)氨基甲酸叔丁酯(化合物14a)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例14(14mg),其为淡黄色粉末。MS:计算的398(MH+),测得的398(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.49(d,J=7.9Hz,1H),6.90(d,J=2.4Hz,1H),6.63(d,J=8.1Hz,1H),4.34(br t,J=9.8Hz,1H),4.10-3.97(m,3H),3.88-3.70(m,J=13.6,13.6Hz,5H),3.60-3.32(m,7H),2.79-2.67(m,2H),1.32(d,J=6.2Hz,3H)。
实例15
4-[(2R,6S)-2-甲基-6-[(4-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用1-甲基哌嗪代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例15(18mg),其为淡棕色固体。MS:计算的355(MH+),测得的355(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.46(d,J=8.1Hz,1H),6.87(d,J=2.4Hz,1H),6.60(d,J=7.9Hz,1H),4.18-4.09(m,1H),4.00-3.91(m,1H),3.83-3.77(m,1H),3.75(dd,J=2.0,12.3Hz,1H),3.42(br s,4H),3.29-3.07(m,4H),2.99-2.94(m,2H),2.91(s,3H),2.74(dd,J=10.6,12.2Hz,1H),2.67(dd,J=10.5,12.4Hz,1H),1.27(d,J=6.2Hz,3H)。
实例16
4-[(2R,6S)-2-甲基-6-[[4-(1-哌啶基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用1-(4-哌啶基)哌啶代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例16(15mg),其为淡棕色固体。MS:计算的423(MH+),测得的423(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04-7.99(m,1H),7.49-7.44(m,1H),6.91-6.86(m,1H),6.64-6.59(m,1H),4.33(br t,J=10.0Hz,1H),4.07-3.97(m,1H),3.96-3.89(m,1H),3.88-3.78(m,2H),3.75(br d,J=12.3Hz,1H),3.64-3.50(m,3H),3.48-3.37(m,1H),3.36-3.32(m,J=9.9Hz,1H),3.28-3.16(m,2H),3.06(br t,J=11.8Hz,2H),2.72(td,J=10.1,12.1Hz,2H),2.47-2.34(m,2H),2.30-2.11(m,2H),2.07-1.74(m,5H),1.62-1.46(m,1H),1.31(d,J=6.2Hz,3H)。
实例17
4-[(2S,6R)-2-[(4-氨基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(4-哌啶基)氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例17(6mg),其为淡棕色固体。MS:计算的355(MH+),测得的355(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.32(br t,J=10.0Hz,1H),4.07-3.96(m,1H),3.95-3.64(m,J=12.9,12.9Hz,4H),3.49(br t,J=11.3Hz,1H),3.45-3.32(m,2H),3.29-3.15(m,2H),2.78-2.65(m,2H),2.35-2.22(m,2H),2.16-1.95(m,2H),1.31(d,J=6.2Hz,3H)。
实例18
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,8-二氮杂螺[4.5]癸烷-8-羧酸叔丁酯(CAS:236406-39-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例18(7mg),其为淡棕色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.2Hz,1H),7.47(d,J=7.9Hz,1H),6.87(d,J=2.3Hz,1H),6.60(d,J=8.1Hz,1H),4.16-4.07(m,1H),4.02-3.92(m,1H),3.81(br d,J=12.1Hz,1H),3.75(br d,J=12.2Hz,1H),3.27-3.15(m,6H),3.15-2.94(m,4H),2.75-2.61(m,2H),1.95(br t,J=7.0Hz,2H),1.88(br s,4H),1.29(d,J=6.2Hz,3H)。
实例19
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(CAS:1180509-95-8,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例19(9mg),其为淡棕色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.47(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.33(br t,J=10.0Hz,1H),4.10-3.97(m,1H),3.84-3.58(m,4H),3.49-3.32(m,5H),3.26-3.11(m,3H),2.79-2.73(m,1H),2.72-2.65(m,1H),2.17-1.90(m,6H),1.31(d,J=6.4Hz,3H)。
实例20
4-[(2R,6R)-2-甲基-6-[(3-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用8-氧代-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(CAS:1251009-03-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例20(6mg),其为淡黄色固体。MS:计算的395(MH+),测得的395(MH+)。1HNMR(400MHz,甲醇-d4)δ8.02(d,J=2.4Hz,1H),7.45(d,J=7.9Hz,1H),6.87(d,J=2.3Hz,1H),6.58(d,J=7.9Hz,1H),4.06-3.98(m,1H),3.95-3.86(m,1H),3.79-3.70(m,2H),3.69-3.63(m,2H),3.57-3.39(m,4H),3.34(s,2H),2.74-2.62(m,2H),2.62-2.48(m,2H),2.23-2.07(m,2H),1.26(d,J=6.2Hz,3H)。
实例21
4-[(2R,6R)-2-甲基-6-[(1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1-氧代-2,7-二氮杂螺[4.4]壬烷-7-羧酸叔丁酯(CAS:1194376-44-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例21(4mg),其为黄色粉末。MS:计算的395(MH+),测得的395(MH+)。1HNMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.60(d,J=8.1Hz,1H),4.07-3.99(m,1H),3.95-3.85(m,1H),3.78(br d,J=12.2Hz,1H),3.75-3.58(m,3H),3.57-3.44(m,4H),3.44-3.37(m,1H),3.25(dd,J=2.0,12.0Hz,1H),2.73-2.61(m,2H),2.29-2.18(m,3H),2.18-2.06(m,1H),1.25(dd,J=2.9,6.2Hz,3H)。
实例22
4-[(2S,6R)-2-(2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-羧酸叔丁酯(CAS:141449-85-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例22(12mg),其为黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(d,J=2.4Hz,1H),7.50(d,J=7.9Hz,1H),6.91(d,J=2.4Hz,1H),6.65(d,J=8.1Hz,1H),4.25(br t,J=10.0Hz,1H),4.09-3.98(m,1H),3.97-3.68(m,4H),3.61-3.35(m,10H),2.78-2.68(m,2H),1.33(d,J=6.2Hz,3H)。
实例23
4-[(2S,6R)-2-(2,8-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,8-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(CAS:189333-03-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例23(8mg),其为淡棕色固体。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06-8.01(m,1H),7.48(d,J=7.9Hz,1H),6.92-6.86(m,1H),6.66-6.60(m,1H),4.36(br t,J=10.0Hz,1H),4.13-3.98(m,1H),3.89-3.69(m,3H),3.56(br s,1H),3.42-3.32(m,2H),3.30-3.21(m,J=13.6Hz,2H),3.21-2.85(m,4H),2.80-2.68(m,2H),2.21-1.77(m,6H),1.76-1.40(m,2H),1.36-1.27(m,3H)。
实例24
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(CAS:896464-16-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例24(13mg),其为淡棕色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.47(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.61(d,J=8.1Hz,1H),4.36-4.05(m,5H),4.01-3.91(m,1H),3.76(tdd,J=2.0,4.1,10.4Hz,2H),3.58-3.51(m,1H),3.48-3.40(m,1H),3.22(br s,4H),2.77-2.64(m,2H),2.16(br s,4H),1.30(d,J=6.2Hz,3H)。
实例25
4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,7-二氮杂螺[4.5]癸烷-7-羧酸叔丁酯(CAS:236406-61-4,Wuxi AppTech)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例25(1.3mg),其为淡黄色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.05(d,J=2.4Hz,1H),7.50(d,J=7.9Hz,1H),6.90(dd,J=1.1,2.3Hz,1H),6.64(d,J=8.1Hz,1H),4.24(br t,J=9.9Hz,1H),4.08-3.97(m,1H),3.79(brt,J=10.8Hz,4H),3.54-3.37(m,3H),3.30-3.07(m,5H),2.78-2.66(m,2H),2.31-1.98(m,2H),1.88(br s,4H),1.33(dd,J=1.2,6.2Hz,3H)。
实例26
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(CAS:236406-55-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例26(1.3mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.88(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.36-4.26(m,1H),4.11-3.85(m,5H),3.77(td,J=2.5,12.6Hz,2H),3.74-3.54(m,2H),3.39-3.32(m,1H),3.30-3.24(m,1H),3.23-3.02(m,2H),2.78-2.64(m,2H),2.41-1.98(m,4H),1.31(d,J=6.2Hz,3H)。
实例27
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(CAS:189333-03-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例27(13mg),其为黄色固体。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.63(d,J=8.1Hz,1H),4.32(br t,J=9.8Hz,1H),4.08-3.97(m,1H),3.84-3.73(m,2H),3.72-3.50(m,2H),3.44-3.33(m,2H),3.30-3.11(m,5H),3.02(br s,1H),2.79-2.66(m,2H),2.14-1.57(m,8H),1.31(d,J=6.2Hz,3H)。
实例28
4-[(2R,6S)-2-甲基-6-[(3-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2-甲基哌嗪-1-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例28(19mg),其为淡黄色固体。MS:计算的355(MH+),测得的355(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=8.1Hz,1H),6.87(dd,J=1.0,2.3Hz,1H),6.60(d,J=8.1Hz,1H),4.22-4.12(m,1H),4.02-3.92(m,1H),3.81(br d,J=12.2Hz,1H),3.75(br d,J=12.3Hz,1H),3.64-3.44(m,4H),3.42-3.33(m,1H),3.07-2.85(m,3H),2.80-2.63(m,3H),1.37(d,J=6.6Hz,3H),1.28(d,J=6.2Hz,3H)
实例29
4-[(2S,6R)-2-[(4-氨基-4-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2-甲基哌嗪-1-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例29(19mg),其为淡黄色固体。MS:计算的369(MH+),测得的369(MH+)。1H NMR(400MHz,甲醇-d4)δ 8.04(d,J=2.4Hz,1H),7.48(d,J=8.1Hz,1H),6.90(d,J=2.4Hz,1H),6.63(d,J=7.9Hz,1H),4.38-4.29(m,1H),4.08-3.97(m,1H),3.79(br t,J=13.9Hz,2H),3.75-3.52(m,2H),3.50-3.33(m,4H),2.79-2.67(m,2H),2.33-2.17(m,2H),2.17-2.06(m,2H),1.55(s,3H),1.31(d,J=6.2Hz,3H)。
实例30
4-[(2S,6R)-2-(2,5-二氮杂双环[2.2.2]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯(CAS:858671-91-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例30(24mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.08-8.02(m,1H),7.49(d,J=7.9Hz,1H),6.90(t,J=2.4Hz,1H),6.63(d,J=7.9Hz,1H),4.27-4.16(m,1H),4.04-3.93(m,1H),3.89-3.71(m,5H),3.70-3.53(m,2H),3.48(ddd,J=1.9,6.5,13.4Hz,1H),3.43-3.33(m,2H),2.81-2.65(m,2H),2.49-2.33(m,1H),2.25-2.12(m,1H),2.11-1.91(m,2H),1.30(dd,J=1.1,6.2Hz,3H)。
实例31
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(CAS:149771-44-8,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例30(18mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.47(d,J=8.1Hz,1H),6.85(d,J=2.4Hz,1H),6.60(d,J=8.1Hz,1H),4.05-3.97(m,3H),3.92(ddd,J=2.3,6.3,10.3Hz,1H),3.88-3.81(m,1H),3.75-3.68(m,1H),3.16-3.08(m,1H),3.04(br d,J=11.2Hz,1H),2.78-2.71(m,2H),2.70-2.63(m,4H),2.22-2.09(m,2H),2.09-1.97(m,2H),1.25(d,J=6.2Hz,3H)。
实例32
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯(CAS:1023595-19-8,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例32(24mg),其为淡黄色固体。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.48(d,J=8.1Hz,1H),6.88(d,J=2.4Hz,1H),6.63(d,J=7.9Hz,1H),4.40(br t,J=10.0Hz,1H),4.12-3.98(m,1H),3.85-3.74(m,2H),3.74-3.60(m,1H),3.59-3.48(m,1H),3.45-3.34(m,1H),3.30-3.19(m,5H),3.15-2.87(m,2H),2.79-2.68(m,2H),2.20-1.89(m,5H),1.84-1.63(m,2H),1.63-1.38(m,1H),1.31(d,J=6.2Hz,3H)。
实例33
4-[(2S,6R)-2-(2,6-二氮杂螺[3.5]壬烷-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,8-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(CAS:1086394-57-1,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例33(13mg),其为淡棕色半固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=8.1Hz,1H),6.83(d,J=2.4Hz,1H),6.59(d,J=8.1Hz,1H),4.07-3.89(m,2H),3.88-3.70(m,6H),2.82-2.51(m,7H),2.51-2.32(m,1H),1.82-1.66(m,2H),1.66-1.55(m,2H),1.27(d,J=6.2Hz,3H)。
实例34
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(3,3-二氟-4-哌啶基)氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例34(9mg),其为淡黄色固体。MS:计算的391(MH+),测得的391(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(t,J=2.2Hz,1H),7.47(d,J=7.9Hz,1H),6.85(d,J=1.7Hz,1H),6.58(dd,J=1.3,8.1Hz,1H),4.04-3.96(m,1H),3.95-3.80(m,2H),3.72(br t,J=12.2Hz,1H),3.50-3.33(m,2H),3.15-2.95(m,1H),2.77-2.53(m,5H),2.53-2.33(m,1H),2.07-1.95(m,1H),1.84-1.71(m,1H),1.25(d,J=6.2Hz,3H)。
实例35
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-吡咯烷-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(4,4-二氟吡咯烷-3-基)氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例35(14mg),其为淡黄色固体。MS:计算的377(MH+),测得的377(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.3Hz,1H),7.46(d,J=7.9Hz,1H),6.85(t,J=2.1Hz,1H),6.59(d,J=7.9Hz,1H),4.02-3.86(m,2H),3.81-3.72(m,2H),3.70-3.55(m,1H),3.29-3.17(m,2H),3.04(qd,J=12.1,16.5Hz,1H),2.79-2.55(m,5H),1.26(d,J=6.2Hz,3H)
实例36
4-[(2S,6R)-2-[(8-氨基-3-氮杂双环[3.2.1]辛烷-3-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(CAS:198210-17-2,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例36(13mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1HNMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.86(d,J=2.4Hz,1H),6.62(d,J=7.9Hz,1H),4.31(br t,J=9.6Hz,1H),4.05-3.95(m,1H),3.77(br dd,J=12.2,19.6Hz,2H),3.63(br d,J=14.1Hz,1H),3.53-3.32(m,6H),2.80-2.66(m,2H),2.58(br s,2H),2.18-2.00(m,3H),1.96-1.86(m,1H),1.29(d,J=6.2Hz,3H)。
实例37
4-[(2S,6R)-2-[(3-氨基-8-氮杂双环[3.2.1]辛烷-8-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(8-氮杂双环[3.2.1]辛烷-3-基)氨基甲酸叔丁酯(CAS:287114-25-4,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例37(13mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1HNMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.88(d,J=2.3Hz,1H),6.60(d,J=7.9Hz,1H),4.10(br s,1H),4.00-3.92(m,1H),3.89(br d,J=12.1Hz,1H),3.84(br s,1H),3.74(br d,J=12.3Hz,1H),3.69(br s,1H),3.56-3.45(m,1H),2.97-2.87(m,1H),2.87-2.78(m,1H),2.76-2.62(m,2H),2.25-2.10(m,2H),2.02-1.90(m,4H),1.86-1.76(m,2H),1.27(d,J=6.2Hz,3H)。
实例38
4-[(2R,6S)-2-甲基-6-[[(3R)-3-苯基哌嗪-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用(2R)-2-苯基哌嗪-1-羧酸叔丁酯(CAS:859518-32-4,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例38(18mg),其为淡黄色固体。MS:计算的417(MH+),测得的417(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.51-7.38(m,6H),6.86(d,J=2.4Hz,1H),6.60(d,J=8.1Hz,1H),4.29(dd,J=3.0,10.9Hz,1H),4.09-4.00(m,1H),3.97-3.87(m,1H),3.82(br d,J=12.3Hz,1H),3.75(br d,J=12.2Hz,1H),3.38-3.31(m,2H),3.28-3.25(m,1H),3.19(br d,J=12.7Hz,1H),2.80-2.73(m,1H),2.73-2.68(m,2H),2.68-2.63(m,1H),2.63-2.54(m,2H),1.23(d,J=6.2Hz,3H)。
实例39
4-[(2R,6S)-2-甲基-6-[(4-哌嗪-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用4-(4-哌啶基)哌嗪-1-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例39(13mg),其为淡黄色固体。MS:计算的424(MH+),测得的424(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.26(br t,J=9.6Hz,1H),4.05-3.95(m,1H),3.78(br t,J=12.2Hz,2H),3.69-3.52(m,2H),3.28-3.13(m,6H),3.11-2.97(m,2H),2.88-2.78(m,4H),2.77-2.62(m,3H),2.14-2.00(m,2H),1.98-1.79(m,2H),1.30(d,J=6.2Hz,3H)
实例40
4-[(2S,6R)-2-(4,7-二氮杂螺[2.5]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例40(12mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.86(d,J=2.4Hz,1H),6.59(d,J=8.1Hz,1H),4.11-4.02(m,1H),3.98-3.88(m,1H),3.82(br d,J=12.3Hz,1H),3.74(br d,J=12.2Hz,1H),3.29-3.24(m,2H),3.07-2.96(m,1H),2.95-2.88(m,1H),2.88-2.80(m,1H),2.79-2.69(m,4H),2.66(dd,J=10.5,12.3Hz,1H),1.26(d,J=6.2Hz,3H),0.99-0.91(m,2H),0.90-0.82(m,2H)。
实例41
4-[(2S,6R)-2-(1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,3,3a,4,5,6,7,7a-八氢吡咯并[3,2-c]吡啶-1-羧酸叔丁酯(CAS:1147422-00-1,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例41(14mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=8.1Hz,1H),6.91-6.83(m,1H),6.61(d,J=8.1Hz,1H),4.31-4.16(m,1H),4.04-3.93(m,1H),3.91-3.79(m,2H),3.75(td,J=2.0,12.4Hz,1H),3.58-3.47(m,1H),3.46-3.33(m,2H),3.29-2.99(m,5H),2.82-2.65(m,3H),2.33-2.20(m,2H),2.19-2.07(m,2H),1.33-1.26(m,3H)。
实例42
4-[(2S,6R)-2-(2,6-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,6-二氮杂螺[4.5]癸烷-6-羧酸叔丁酯(CAS:960294-16-0,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例42(10mg),其为淡黄色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.2Hz,1H),7.46(d,J=7.9Hz,1H),6.85(d,J=2.3Hz,1H),6.59(d,J=7.9Hz,1H),4.05-3.90(m,2H),3.77(br d,J=12.7Hz,2H),3.30-3.13(m,4H),2.84-2.72(m,3H),2.71-2.56(m,3H),2.17-1.99(m,2H),1.89-1.82(m,2H),1.82-1.66(m,4H),1.27(dd,J=3.8,6.2Hz,3H)。
实例43
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-8-基甲基)-6-甲基-吗啉-4基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例43(5mg),其为淡黄色固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.87(d,J=2.3Hz,1H),6.60(d,J=8.1Hz,1H),4.00-3.85(m,3H),3.78-3.69(m,1H),3.66-3.58(m,1H),3.55-3.49(m,1H),3.29-3.21(m,2H),3.14-3.04(m,2H),2.76(dd,J=10.5,12.2Hz,1H),2.71-2.62(m,2H),2.60-2.53(m,1H),2.30-2.14(m,2H),1.93-1.84(m,2H),1.26(d,J=6.2Hz,3H)。
实例44
4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,9-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(CAS:885268-42-8,Wuxi AppTech)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例44(12mg),其为淡棕色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.83(dd,J=2.3,5.7Hz,1H),6.60(dd,J=2.6,8.1Hz,1H),4.01-3.82(m,3H),3.74(br t,J=11.9Hz,1H),3.36-3.33(m,3H),3.28-3.18(m,1H),3.11-3.03(m,1H),2.75-2.59(m,3H),2.58-2.44(m,3H),2.38-2.28(m,1H),2.05-1.91(m,1H),1.87-1.77(m,1H),1.75-1.55(m,3H),1.54-1.43(m,1H),1.25(d,J=6.2Hz,3H)。
实例45
4-[(2S,6R)-2-(1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-羧酸叔丁酯(CAS:159877-36-8,Accela)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例45(12mg),其为淡棕色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(d,J=2.3Hz,1H),7.50(d,J=8.1Hz,1H),6.91-6.87(m,1H),6.63(d,J=8.1Hz,1H),4.08-3.91(m,2H),3.86-3.75(m,2H),3.64(q,J=4.5Hz,1H),3.30-3.23(m,1H),3.11-2.61(m,10H),1.88-1.73(m,4H),1.30(t,J=6.7Hz,3H)。
实例46
4-[(2S,6R)-2-(2,8-二氮杂螺[3.6]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用2,8-二氮杂螺[3.6]癸烷-8-羧酸叔丁酯(CAS:270257-46-0,Wuxi AppTech)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例46(13mg),其为淡棕色固体。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.87(d,J=2.4Hz,1H),6.60(d,J=7.9Hz,1H),4.01-3.89(m,2H),3.81(br d,J=12.5Hz,1H),3.76(br d,J=12.3Hz,1H),3.58-3.46(m,2H),3.30-3.21(m,3H),3.19-3.14(m,1H),2.85-2.77(m,4H),2.77-2.70(m,1H),2.66(dd,J=10.5,12.2Hz,1H),2.15-2.01(m,2H),2.00-1.89(m,2H),1.80-1.66(m,2H),1.27(d,J=6.2Hz,3H)。
实例47
4-[(2S,6R)-2-(1,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,9-二氮杂螺[5.5]十一烷-1-羧酸叔丁酯(CAS:1158750-00-5,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例47(13mg),其为淡棕色固体。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.48(d,J=8.1Hz,1H),6.85(d,J=2.6Hz,1H),6.59(d,J=8.1Hz,1H),4.06-3.97(m,1H),3.96-3.87(m,1H),3.82(br d,J=12.3Hz,1H),3.74(br d,J=12.2Hz,1H),3.17(t,J=5.7Hz,2H),2.99-2.91(m,1H),2.90-2.80(m,1H),2.73-2.58(m,4H),2.57-2.45(m,2H),2.06-1.97(m,2H),1.91-1.81(m,4H),1.80-1.69(m,4H),1.26(d,J=6.2Hz,3H)
实例48
4-[(2S,6R)-2-(1,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,7-二氮杂螺[3.5]壬烷-1-羧酸叔丁酯(CAS:1216936-29-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例47(13mg),其为淡棕色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.05(d,J=2.3Hz,1H),7.49(d,J=7.9Hz,1H),6.87(d,J=2.4Hz,1H),6.61(d,J=7.9Hz,1H),4.04-3.90(m,4H),3.82(br d,J=12.2Hz,1H),3.77(br d,J=12.3Hz,1H),2.81-2.48(m,8H),2.48-2.40(m,2H),2.20-2.07(m,4H),1.27(d,J=6.2Hz,3H)
实例49
4-[(2S,6R)-2-(1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,2,3,3a,4,6,7,7a-八氢吡咯并[3,4-c]吡啶-5-羧酸叔丁酯(CAS:351370-99-5,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例49(17mg),其为淡黄色固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.2Hz,1H),7.46(d,J=7.9Hz,1H),6.87(d,J=2.0Hz,1H),6.59(d,J=7.9Hz,1H),4.18-4.07(m,1H),4.04-3.91(m,1H),3.86-3.71(m,2H),3.49-3.33(m,3H),3.30-3.09(m,7H),2.77-2.60(m,4H),2.10-1.98(m,1H),1.96-1.83(m,1H),1.29(d,J=6.2Hz,3H)。
实例50
4-[(2R,6S)-2-甲基-6-[(2-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用(3S)-3-甲基哌嗪-1-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。通过制备型HPLC获得实例50A(8mg)和实例50B(7mg),其为淡黄色粉末。
实例50A:MS:计算的355(MH+),测得的355(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.3Hz,1H),7.45(d,J=7.9Hz,1H),6.84(d,J=2.4Hz,1H),6.58(d,J=8.1Hz,1H),4.03-3.94(m,1H),3.94-3.85(m,1H),3.76(br d,J=12.0Hz,2H),3.29-3.17(m,3H),3.16-3.06(m,1H),2.97(dd,J=7.0,14.2Hz,1H),2.88-2.70(m,4H),2.63(dd,J=10.6,12.3Hz,1H),2.55(dd,J=4.2,14.2Hz,1H),1.26(d,J=6.2Hz,3H),1.18(d,J=5.7Hz,3H)。
实例50B:MS:计算的355(MH+),测得的355(MH+)。1H NMR(400MHz,甲醇-d4)δ8.01(d,J=2.3Hz,1H),7.44(d,J=7.9Hz,1H),6.82(d,J=2.4Hz,1H),6.57(d,J=7.9Hz,1H),4.05-3.96(m,1H),3.96-3.86(m,1H),3.81(br d,J=12.2Hz,1H),3.75(br d,J=12.3Hz,1H),3.30-3.20(m,3H),3.11(dt,J=2.9,11.8Hz,1H),2.90(dd,J=5.6,13.8Hz,1H),2.86-2.73(m,2H),2.70-2.60(m,3H),2.59-2.54(m,1H),1.24(d,J=6.2Hz,3H),1.18(d,J=5.9Hz,3H)。
实例51
4-[(2S,6R)-2-[(4-氨基-2-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3-甲基哌嗪-1-羧酸叔丁酯(CAS:1281674-64-3,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例51(21mg),其为淡黄色粉末。MS:计算的369(MH+),测得的369(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.2Hz,1H),7.48(br d,J=7.8Hz,1H),6.95-6.86(m,1H),6.62(br d,J=7.9Hz,1H),4.31(br t,J=9.2Hz,1H),4.10-3.65(m,4H),3.64-3.36(m,3H),3.32-3.14(m,2H),2.84-2.66(m,2H),2.34-1.77(m,4H),1.53-1.45(m,3H),1.36-1.28(m,3H)。
实例52
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,7-二氮杂双环[4.2.0]辛烷-3-羧酸叔丁酯(CAS:885271-67-0,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例52(24mg),其为淡黄色粉末。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.2Hz,1H),7.47(d,J=7.9Hz,1H),6.88(d,J=1.8Hz,1H),6.61(d,J=7.9Hz,1H),4.57(br s,1H),4.21-3.90(m,4H),3.83-3.72(m,2H),3.72-3.63(m,1H),3.56-3.35(m,4H),3.31-3.19(m,1H),3.12(br s,1H),2.81-2.65(m,2H),2.52-2.30(m,1H),2.30-2.17(m,1H),1.29(dd,J=2.1,6.2Hz,3H)。
实例53
4-[(2S,6R)-2-(1,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,8-二氮杂螺[4.5]癸烷-1-羧酸叔丁酯(CAS:885279-92-5,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例53(24mg),其为淡黄色粉末。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.90(d,J=2.4Hz,1H),6.63(d,J=8.1Hz,1H),4.31(br t,J=9.7Hz,1H),4.07-3.98(m,1H),3.85-3.70(m,2H),3.70-3.51(m,2H),3.44(t,J=7.0Hz,2H),3.32-3.22(m,4H),2.73(dt,J=10.5,12.9Hz,2H),2.38-2.25(m,2H),2.25-2.11(m,6H),1.32(d,J=6.2Hz,3H)。
实例54
4-[(2R,6S)-2-甲基-6-[(4-吡咯烷-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用4-吡咯烷-1-基哌啶代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例54(14mg),其为淡黄色粘性油状物。MS:计算的409(MH+),测得的409(MH+)。1H NMR(400MHz,甲醇-d4)δ8.05(d,J=2.3Hz,1H),7.50(d,J=8.1Hz,1H),6.87(d,J=2.4Hz,1H),6.62(d,J=7.9Hz,1H),4.07-4.00(m,1H),3.99-3.89(m,1H),3.83(br d,J=12.2Hz,1H),3.76(br d,J=12.2Hz,1H),3.45-3.34(m,4H),3.30-3.24(m,1H),3.21-3.07(m,2H),2.74-2.57(m,4H),2.37-2.23(m,2H),2.22-2.14(m,2H),2.13-2.05(m,4H),1.83-1.69(m,2H),1.28(d,J=6.2Hz,3H)。
实例55
4-[(2S,6R)-2-(1,6-二氮杂螺[3.3]庚烷-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,6-二氮杂螺[3.3]庚烷-6-羧酸叔丁酯半草酸酯(CAS:1272412-72-2,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例55(10mg),其为淡黄色半固体。MS:计算的353(MH+),测得的353(MH+)。1H NMR(400MHz,甲醇-d4)δ8.05(d,J=2.4Hz,1H),7.50(d,J=8.1Hz,1H),6.87(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.50-4.43(m,2H),4.05-3.85(m,4H),3.82-3.74(m,2H),3.32-3.29(m,2H),2.84(d,J=5.6Hz,2H),2.82-2.76(m,1H),2.68(dd,J=10.4,12.5Hz,1H),2.49(t,J=6.9Hz,2H),1.31(d,J=6.2Hz,3H)。
实例56
4-[(2S,6R)-2-(3,8-二氮杂双环[4.2.0]辛烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,8-二氮杂双环[4.2.0]辛烷-3-羧酸叔丁酯(CAS:928754-14-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例56(18mg),其为淡黄色半固体。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(t,J=2.0Hz,1H),7.48(d,J=7.9Hz,1H),6.87(dd,J=0.9,2.4Hz,1H),6.62(dd,J=1.2,7.9Hz,1H),4.87-4.80(m,2H),4.35-4.16(m,2H),4.03-3.94(m,2H),3.81-3.71(m,2H),3.61-3.50(m,3H),3.50-3.35(m,1H),3.09-2.92(m,2H),2.80-2.66(m,2H),2.42(ddd,J=3.1,8.7,15.1Hz,1H),2.30-2.13(m,1H),1.30(dd,J=6.4,7.6Hz,3H)。
实例57
4-[(2R,6S)-2-甲基-6-(3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-7-羧酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例57(14mg),其为淡棕色半固体。MS:计算的383(MH+),测得的383(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.47(d,J=8.1Hz,1H),6.85(d,J=2.3Hz,1H),6.59(d,J=8.1Hz,1H),4.13-4.05(m,2H),4.01-3.86(m,5H),3.73(br d,J=12.2Hz,1H),3.58-3.48(m,2H),3.37(s,1H),3.35-3.32(m,1H),3.13(dd,J=5.4,13.6Hz,1H),3.01(br d,J=13.8Hz,2H),2.86(dd,J=5.4,13.6Hz,1H),2.78(dd,J=10.5,12.0Hz,1H),2.66(dd,J=10.4,12.2Hz,1H),1.24(d,J=6.2Hz,3H)。
实例58
4-[(2S,6R)-2-[(7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)氨基甲酸叔丁酯(CAS:198211-13-1,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例58(16mg),其为淡黄色粉末。MS:计算的397(MH+),测得的397(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=8.1Hz,1H),6.84(d,J=2.4Hz,1H),6.58(d,J=7.9Hz,1H),4.35-4.24(m,1H),3.97(br d,J=12.3Hz,1H),3.94-3.85(m,4H),3.84-3.76(m,2H),3.71(br d,J=12.2Hz,1H),3.10-3.02(m,2H),2.96(br s,1H),2.73(dd,J=10.5,12.3Hz,1H),2.70-2.62(m,2H),2.09-1.99(m,1H),1.98-1.90(m,3H),1.24(d,J=6.2Hz,3H)。
实例59
4-[(2S,6R)-2-[(2-苄基哌嗪-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3-苄基哌嗪-1-羧酸叔丁酯(CAS:502649-29-8,Bepharm)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例59(15mg),其为白色粉末。MS:计算的431(MH+),测得的431(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(d,J=2.3Hz,1H),7.50(dd,J=1.5,7.9Hz,1H),7.37-7.20(m,5H),6.88(dd,J=2.4,5.3Hz,1H),6.60(t,J=8.4Hz,1H),4.18-3.91(m,2H),3.83-3.69(m,2H),3.52-3.36(m,2H),3.31-3.11(m,4H),3.11-2.99(m,2H),2.99-2.81(m,2H),2.79-2.56(m,3H),1.31(dd,J=6.2,12.2Hz,3H)。
实例60
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-羧酸叔丁酯(CAS:1023595-11-0,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例60(18mg),其为淡黄色固体。MS:计算的411(MH+),测得的411(MH+)。1HNMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.90(d,J=2.4Hz,1H),6.62(d,J=8.1Hz,1H),4.33(br t,J=9.5Hz,1H),4.08-3.99(m,1H),3.99-3.91(m,2H),3.85-3.72(m,2H),3.68-3.52(m,2H),3.44-3.32(m,3H),3.30-3.13(m,5H),2.79-2.66(m,2H),2.34(br d,J=10.0Hz,2H),2.22-1.87(m,2H),1.31(d,J=6.2Hz,3H)。
实例61
4-[(2S,6R)-2-(2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-羧酸叔丁酯(CAS:186203-81-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例61(19mg),其为淡黄色粉末。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(dd,J=1.1,2.2Hz,1H),7.48(d,J=7.9Hz,1H),6.89(dd,J=2.4,4.4Hz,1H),6.62(dd,J=1.5,8.0Hz,1H),4.30-4.13(m,1H),4.05-3.93(m,1H),3.93-3.84(m,1H),3.84-3.68(m,3H),3.63-3.50(m,1H),3.49-3.36(m,3H),3.27-2.90(m,3H),2.80-2.63(m,3H),1.99-1.70(m,4H),1.29(dd,J=2.6,6.2Hz,3H)。
实例62
4-[(2R,6S)-2-甲基-6-[[顺式-(3aR,6aR)-3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用顺式-(3aR,6aR)-2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-b]吡咯-5-羧酸叔丁酯(CAS:370882-39-6,Accela)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例62(23mg),其为淡黄色粉末。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ7.91(t,J=2.9Hz,1H),7.33(dd,J=1.2,7.9Hz,1H),6.77(t,J=2.4Hz,1H),6.49(d,J=8.1Hz,1H),4.41(br s,1H),4.25-4.10(m,1H),3.97-3.55(m,6H),3.52-3.23(m,6H),2.70-2.56(m,2H),2.45-2.32(m,1H),1.98-1.77(m,1H),1.20(t,J=5.8Hz,3H)。
实例63
4-[(2R,6S)-2-甲基-6-[[顺式-(3aS,7aS)-1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-4-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用顺式-(3aS,7aS)-2,3,3a,4,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-1-羧酸叔丁酯(CAS:1251010-63-5,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例63(13mg),其为淡黄色半固体。MS:计算的381(MH+),测得的381(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.3Hz,1H),7.46(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.61(d,J=8.0Hz,1H),4.31-4.16(m,1H),4.05-3.82(m,3H),3.82-3.72(m,2H),3.70-3.54(m,1H),3.50-3.34(m,2H),3.29-3.18(m,1H),3.17-2.98(m,2H),2.79-2.64(m,2H),2.60-2.47(m,1H),2.45-2.31(m,1H),2.12-1.79(m,4H),1.28(dd,J=2.2,6.2Hz,3H)。
实例64
4-[(2S,6R)-2-(3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-羧酸叔丁酯(CAS:1000931-58-7,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例64(13mg),其为淡黄色粉末。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.3Hz,1H),7.48(d,J=7.9Hz,1H),6.89(dd,J=2.4,5.5Hz,1H),6.62(d,J=7.9Hz,1H),4.37-4.17(m,1H),4.06-3.67(m,4H),3.39-3.32(m,2H),3.30-3.15(m,5H),2.77-2.64(m,2H),2.39-1.85(m,7H),1.84-1.69(m,1H),1.29(t,J=5.6Hz,3H)。
实例65
内型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用内型-N-(9-氮杂双环[3.3.1]壬烷-3-基)氨基甲酸叔丁酯(CAS:155560-04-6,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例65(25mg),其为淡黄色粉末。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ7.93(d,J=2.4Hz,1H),7.38(d,J=7.9Hz,1H),6.78(d,J=2.4Hz,1H),6.52(d,J=8.1Hz,1H),4.21(br t,J=9.5Hz,1H),4.03-3.94(m,1H),3.93-3.68(m,4H),3.64(br d,J=12.5Hz,1H),3.54-3.40(m,1H),3.40-3.29(m,1H),2.71-2.56(m,4H),2.26-2.04(m,2H),2.02-1.84(m,1H),1.80-1.60(m,3H),1.60-1.42(m,2H),1.19(d,J=6.2Hz,3H)。
实例66
外型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用外型-N-(9-氮杂双环[3.3.1]壬烷-3-基)氨基甲酸叔丁酯(CAS:599165-35-2,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例66(24mg),其为淡黄色粉末。MS:计算的395(MH+),测得的395(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.4Hz,1H),7.48(d,J=7.9Hz,1H),6.89(d,J=2.2Hz,1H),6.63(d,J=7.9Hz,1H),4.34(br t,J=9.7Hz,1H),4.27-4.13(m,1H),4.13-3.94(m,2H),3.94-3.80(m,2H),3.80-3.71(m,1H),3.69-3.59(m,1H),3.57-3.50(m,1H),2.82-2.67(m,2H),2.59-2.14(m,6H),2.14-1.99(m,1H),1.99-1.69(m,3H),1.28(d,J=6.2Hz,3H)。
实例67
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-腈
根据以下方案制备标题化合物:
步骤1:4-氯-3-氟-吡唑并[1,5-a]吡啶-7-腈(化合物67a)的制备
向4-氯吡唑并[1,5-a]吡啶-7-腈(化合物1b,600mg,3.38mmol)的ACN(50mL)溶液中加入选择性氟试剂(Selectfluor)(2.39g,6.76mmol)。将反应混合物在室温下搅拌24小时后,LCMS指示产物形成。然后浓缩反应混合物以去除大部分ACN,用水(30mL)稀释,用DCM萃取。有机层用饱和NH4Cl和盐水洗涤,经Na2SO4干燥,并且浓缩以得到粗产物,将该粗产物通过柱层析法纯化以得到化合物67a(419mg),其为淡黄色粉末。MS:计算的196(MH+),测得的196(MH+)。
步骤2:3-氟-4-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(化合物67b)的制备
在N2下,向4-氯-3-氟吡唑并[1,5-a]吡啶-7-腈(化合物67a,419mg,2.14mmol)、(2R,6R)-6-甲基吗啉-2-基]甲醇三氟乙酸盐(化合物1a,526mg,2.14mmol)和Cs2CO3(2.79g,8.57mmol)的二噁烷(10mL)溶液中加入RuPhos Pd G2(116mg,0.15mmol)。将反应混合物在90℃下加热(油浴)2小时,然后冷却至室温,用EtOAc稀释并且通过硅藻土过滤,浓缩滤液以得到棕色油状物,将该棕色油状物通过柱层析法纯化以得到化合物67b(325mg),其为黄色油状物。MS:计算的291(MH+),测得的291(MH+)。
步骤3:(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(化合物67c)的制备
在室温下,向3-氟-4-[(2R,6R)-2-(羟甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(化合物67b,325mg,1.12mmol)的DCM(3mL)溶液中加入2,6-二甲基吡啶(240mg,258μl,2.24mmol)和Tf2O(474mg,284μl,1.68mmol)。将反应混合物在室温下搅拌1.5小时后,LCMS指示产物形成。然后将混合物用DCM稀释,用饱和NH4Cl和盐水洗涤。有机层经Na2SO4干燥并且浓缩以得到粗产物,将该粗产物通过柱层析法纯化以得到化合物67c(180mg),其为黄色固体。MS:计算的423(MH+),测得的423(MH+)。
步骤4:4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-腈(实例67)的制备
向(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(化合物67c,30mg,71mmol)、2,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯(27mg,0.11mmol)的ACN(4mL)溶液中加入K2CO3(20mg,0.14mmol)。在室温下搅拌3小时后,将反应混合物用ACN稀释并且通过硅藻土过滤。浓缩滤液以得到以得到黄色固体。将固体溶于DCM(2mL)中,并且逐滴加入TFA(1mL)。将反应混合物在室温下搅拌1.5小时,然后浓缩以得到粗产物,将该粗产物通过制备型HPLC纯化以获得实例67(34mg),其为淡黄色粉末。MS:计算的427(MH+),测得的427(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=3.5Hz,1H),7.45(d,J=7.8Hz,1H),6.56(d,J=7.9Hz,1H),4.39(br t,J=9.4Hz,1H),4.14-3.98(m,1H),3.81-3.52(m,4H),3.43-3.35(m,1H),3.32-3.23(m,5H),3.14-2.86(m,2H),2.81-2.63(m,2H),2.20-1.62(m,7H),1.57-1.39(m,1H),1.31(d,J=6.2Hz,3H)。
实例68
3-氟-4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例67的制备,通过使用2,9-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯代替2,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯来制备标题化合物。获得实例68(34mg),其为淡黄色粉末。MS:计算的413(MH+),测得的413(MH+)。1H NMR(400MHz,甲醇-d4)δ8.00(d,J=3.7Hz,1H),7.43(d,J=7.9Hz,1H),6.54(d,J=7.9Hz,1H),4.39-4.27(m,1H),4.10-3.96(m,1H),3.77-3.32(m,8H),3.30-2.92(m,4H),2.80-2.63(m,2H),2.24-1.59(m,6H),1.29(d,J=6.2Hz,3H)。
实例69
3-氟-4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例67的制备,通过使用2,7-二氮杂螺[4.5]癸烷-7-羧酸叔丁酯代替2,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯来制备标题化合物。获得实例69(19mg),其为淡黄色粉末。MS:计算的413(MH+),测得的413(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=3.5Hz,1H),7.45(d,J=7.8Hz,1H),6.56(d,J=7.9Hz,1H),4.22(br t,J=9.8Hz,1H),4.07-3.96(m,1H),3.94-3.77(m,1H),3.65-3.52(m,3H),3.51-3.38(m,3H),3.32-3.18(m,4H),3.18-3.09(m,1H),2.83-2.62(m,2H),2.36-2.00(m,2H),1.99-1.82(m,4H),1.32(dd,J=1.3,6.2Hz,3H)。
实例70
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用3,7-二氮杂双环[4.2.0]辛烷-7-羧酸叔丁酯(CAS:885271-73-8,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例70(19mg),其为淡黄色粉末。MS:计算的367(MH+),测得的367(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(d,J=2.3Hz,1H),7.50(d,J=7.9Hz,1H),6.92(d,J=2.4Hz,1H),6.65(d,J=7.9Hz,1H),4.78-4.69(m,1H),4.40-4.31(m,1H),4.29-4.20(m,1H),4.11-3.97(m,2H),3.84(br d,J=12.2Hz,1H),3.78(br dd,J=2.0,12.4Hz,1H),3.74-3.52(m,3H),3.51-3.34(m,4H),2.81-2.69(m,2H),2.57-2.38(m,2H),1.32(dd,J=1.6,6.2Hz,3H)。
实例71
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-羧酸叔丁酯(CAS:930785-40-3,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例71(16mg),其为白色粉末。MS:计算的411(MH+),测得的411(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(d,J=2.4Hz,1H),7.50(d,J=8.1Hz,1H),6.89(d,J=2.4Hz,1H),6.64(d,J=8.1Hz,1H),4.38-4.30(m,1H),4.08-3.96(m,3H),3.83(br d,J=12.2Hz,1H),3.77(br d,J=12.5Hz,1H),3.49-3.34(m,2H),3.32-3.16(m,8H),2.80-2.69(m,2H),2.47(br s,1H),2.22(br s,1H),1.95-1.76(m,2H),1.32(d,J=6.4Hz,3H)。
实例72
1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]哌啶-3-甲酰胺
类似于实例1的制备,通过使用哌啶-3-甲酰胺代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例72(11mg),其为白色粉末。MS:计算的383(MH+),测得的383(MH+)。1H NMR(400MHz,甲醇-d4)δ8.04(d,J=2.2Hz,1H),7.48(d,J=7.9Hz,1H),6.90(d,J=2.3Hz,1H),6.63(d,J=7.9Hz,1H),4.39-4.28(m,1H),4.10-3.98(m,1H),3.91-3.50(m,4H),3.41-3.34(m,1H),3.30-3.06(m,3H),3.05-2.94(m,1H),2.81-2.65(m,2H),2.17-1.84(m,4H),1.31(d,J=6.2Hz,3H)。
实例73
4-[(2S,6R)-2-[(4-氨基-4-苯基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-(4-苯基-4-哌啶基)氨基甲酸叔丁酯代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例73(24mg),其为白色粉末。MS:计算的431(MH+),测得的431(MH+)。1H NMR(400MHz,甲醇-d4)δ8.02(d,J=2.3Hz,1H),7.73-7.68(m,2H),7.62(t,J=7.5Hz,2H),7.58-7.53(m,1H),7.47(d,J=8.1Hz,1H),6.86(d,J=2.4Hz,1H),6.60(d,J=8.1Hz,1H),4.27(br t,J=10.3Hz,1H),4.02-3.91(m,1H),3.84-3.68(m,4H),3.30-3.21(m,2H),3.20-2.91(m,4H),2.68(br t,J=11.4Hz,2H),2.63-2.48(m,2H),1.26(d,J=6.2Hz,3H)。
实例74
4-[(2S,6R)-2-[[(3R,4S)-4-氨基-3-甲基-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例3的制备,通过使用N-[(3R,4S)-3-甲基-4-哌啶基]氨基甲酸叔丁酯(CAS:473839-06-4,PharmaBlock)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例74(16mg),其为白色粉末。MS:计算的369(MH+),测得的369(MH+)。1H NMR(400MHz,甲醇-d4)δ8.06(dd,J=1.2,2.3Hz,1H),7.50(d,J=7.9Hz,1H),6.91(d,J=2.4Hz,1H),6.65(dd,J=0.8,8.0Hz,1H),4.42-4.30(m,1H),4.11-4.00(m,1H),3.86-3.75(m,2H),3.75-3.61(m,2H),3.52-3.34(m,4H),3.32-3.18(m,1H),2.80-2.69(m,2H),2.65-2.47(m,1H),2.43-2.10(m,2H),1.33(dd,J=3.8,5.7Hz,3H),1.23(br s,3H)。
实例75
4-[(2S,6R)-2-[[4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(在*所指示位置处的外消旋混合物)
根据以下方案制备标题化合物:
步骤1:(3aR,4R,6aS)-N,N-二甲基-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-4-胺(化合物75a)的制备
向甲醛(37%水溶液,1.09g,1mL,13.4mmol)和rac-(3aR,4R,6aS)-4-氨基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-羧酸叔丁酯(CAS:1251012-14-2,WuxiAppTech)(350mg,1.55mmol)的MeOH(20mL)溶液中加入NaBH(OAc)3(1.97g,9.28mmol)。然后将反应混合物在50℃下搅拌4小时。浓缩反应混合物,倒入饱和NaHCO3中,并且用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,并且浓缩以得到粗产物(388mg)。向此粗产物(20mg,0.080mmol)的DCM(2mL)溶液中加入TFA(1mL)。将反应混合物在室温下搅拌1小时,然后浓缩以得到粗制化合物75a(24mg),将该粗制化合物直接用于下一步骤。MS:计算的155(MH+),测得的155(MH+)。
步骤2:4-[(2S,6R)-2-[[4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(实例75)的制备
类似于实例3的制备,通过使用(3aR,4R,6aS)-N,N-二甲基-1,2,3,3a,4,5,6,6a-八氢环戊二烯并[c]吡咯-4-胺(化合物75a)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例75(12mg),其为淡黄色油状物。MS:计算的409(MH+),测得的409(MH+)。
1H NMR(400MHz,甲醇-d4)δ8.04(dd,J=2.4,4.0Hz,1H),7.51-7.45(m,1H),6.90(t,J=2.6Hz,1H),6.63(d,J=8.1Hz,1H),4.26(br t,J=10.0Hz,1H),4.12-3.95(m,3H),3.87-3.74(m,2H),3.70(td,J=5.9,12.1Hz,1H),3.57-3.38(m,3H),3.28-3.07(m,2H),3.02(d,J=3.2Hz,6H),3.00-2.90(m,1H),2.79-2.66(m,2H),2.29(td,J=5.9,11.9Hz,1H),2.18-2.04(m,1H),2.02-1.88(m,1H),1.86-1.75(m,1H),1.33(d,J=6.2Hz,3H)。
实例76
4-[(2R,6S)-2-甲基-6-[(9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
类似于实例1的制备,通过使用9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷(CAS:151097-02-8,PharmaBlock)代替1-甲基-4-(哌啶-4-基)哌嗪盐酸盐来制备标题化合物。获得实例76(11mg),其为油状物。MS:计算的411(MH+),测得的411(MH+)。1H NMR(400MHz,甲醇-d4)δ8.03(d,J=2.3Hz,1H),7.47(d,J=7.9Hz,1H),6.88(t,J=2.3Hz,1H),6.61(d,J=8.1Hz,1H),4.29-4.18(m,1H),4.10-3.96(m,3H),3.90-3.59(m,5H),3.58-3.31(m,7H),2.94(s,3H),2.78-2.65(m,2H),2.62-2.14(m,2H),1.32(dd,J=2.7,6.2Hz,3H)。
实例77
4-[(2S,6R)-2-[[2-苄基-4-(4-哌啶基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈
根据以下方案制备标题化合物:
步骤1:2-苄基哌嗪-1-羧酸苄酯(化合物77a)的制备
向3-苄基哌嗪-1-羧酸叔丁酯(300mg,1.09mmol)的DCM(10mL)溶液中加入TEA(330mg,0.45mL,3.26mmol)和CbzCl(278mg,0.23mL,1.63mmol)。然后将反应混合物在室温下搅拌2小时后。将混合物用水稀释,并且用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥并且浓缩以得到粗产物,将该粗产物通过柱层析法纯化以得到产物(368mg),其为油状物。将油状物溶于DCM(2mL)中,然后加入TFA(124mg,84μL,1.09mmol)。将反应混合物在室温下搅拌过夜,然后浓缩以得到粗制化合物77a(385mg),其为油状物,将该粗制化合物直接用于下一步骤。MS:计算的311(MH+),测得的311(MH+)。
步骤2:4-(3-苄基哌嗪-1-基)哌啶-1-羧酸叔丁酯(化合物77b)的制备
向2-苄基哌嗪-1-羧酸苄酯(化合物77a,84mg,0.27mmol)和4-氧代哌啶-1-羧酸叔丁酯(65mg,0.32mmol)的ACN/MeOH(5mL,v/v=4/1)溶液中。将反应混合物在80℃下搅拌24小时,加入另一部分4-氧代哌啶-1-羧酸叔丁酯(65mg,0.32mmol)和NaBH(OAc)3(114mg,0.54mmol)。将反应混合物在80℃下搅拌2天,然后冷却至室温,用水稀释,并且用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥并且浓缩以得到粗产物,将该粗产物通过柱层析法纯化以得到纯产物(264mg),其为油状物。然后将油状物溶于MeOH(4mL)中,加入Pd(OH)2/C(26mg,20%潮湿)。将反应混合物用H2囊充气并且在室温下搅拌2小时,然后通过硅藻土过滤。浓缩滤液以得到粗制化合物77b(100mg),其为油状物,将该粗制化合物直接用于下一步骤。MS:计算的360(MH+),测得的360(MH+)。
步骤3:4-[(2S,6R)-2-[[2-苄基-4-(4-哌啶基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈(实例77)的制备
类似于实例3的制备,通过使用4-(3-苄基哌嗪-1-基)哌啶-1-羧酸叔丁酯(化合物77b)代替3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯来制备标题化合物。获得实例77(6mg),其为淡黄色固体。MS:计算的514(MH+),测得的514(MH+)。1H NMR(400MHz,甲醇-d4)δ8.07(s,1H),7.52(d,J=7.8Hz,1H),7.43-7.36(m,2H),7.35-7.27(m,3H),6.93(dd,J=2.4,4.3Hz,1H),6.66(dd,J=4.0,8.1Hz,1H),4.40-4.28(m,1H),4.12-4.01(m,1H),3.90-3.77(m,3H),3.76-3.58(m,2H),3.53-3.37(m,5H),3.15-2.91(m,5H),2.90-2.59(m,5H),2.11-1.99(m,2H),1.65(br d,J=10.6Hz,2H),1.36(dd,J=3.1,6.1Hz,3H)。
实例81
为了确定式(I)化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行以下检测。
HEK293-Blue-hTLR-7细胞测定:
稳定的HEK293-Blue-hTLR-7细胞系购自InvivoGen(目录号:hkb-htlr7,圣地亚哥,加利福尼亚,美国)。这些细胞最初设计用于通过监测NF-κB的活化来研究人类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℃下孵育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活化的信号传导途径已被广泛接受,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℃下孵育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活化的信号传导途径已被广泛接受,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。
HEK293-Blue-hTLR9细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco′s Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20μMODN2006的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在处读取吸光度。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)化合物具有人TLR7和/或TLR8抑制活性(IC50值)<1μM,特别是<0.1μM。此外,一些化合物还具有人TLR9抑制活性<1μM,特别是<0.3μM。表1中示出了本发明化合物的活性数据。
表1:本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
Claims (23)
2.根据权利要求1所述的化合物,其中
R1为氰基;
R2为(3,4,4a,5,6,7,8,8a-八氢-2H-萘啶基;
(C1-6烷基)2氨基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯基;
1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶基;
1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶基;
1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶基;
3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氮杂双环[3.3.1]壬烷基;
氨基氮杂螺[3.3]庚烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
C1-6烷基氧杂二氮杂螺[4.5]癸烷基;
C1-6烷基哌啶基氨基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[2.5]辛烷基;
二氮杂螺[3.3]庚烷基;
二氮杂螺[3.4]辛烷基;
二氮杂螺[3.5]壬烷基;
二氮杂螺[3.6]癸烷基;
二氮杂螺[4.4]壬烷基;
二氮杂螺[4.5]癸烷基;
二氮杂螺[5.5]十一烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧杂二氮杂螺[5.5]十一烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:C1-6烷基、苯基、苯基C1-6烷基、氨基C1-6烷基羰基和哌啶基;
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、氨基C1-6烷基、氮杂环庚烷基、C1-6烷基、C1-6烷基羰基氨基、C1-6烷基哌嗪基、氨基甲酰基、卤素、苯基、哌嗪基、哌啶基和吡咯烷基;或
吡咯烷基,所述吡咯烷基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基和卤素;
R3为C1-6烷基;
R4为H或卤素;
X为O;
或其药用盐、对映体或非对映体。
3.根据权利要求2所述的化合物,其中
R1为氰基;
R2为(3,4,4a,5,6,7,8,8a-八氢-2H-萘啶基;
2,2-二甲基丙酰氨基-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯基;
1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶基;
1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶基;
1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶基;
3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氮杂双环[3.3.1]壬烷基;
氨基氮杂螺[3.3]庚烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
甲基氧杂二氮杂螺[4.5]癸烷基;
甲基哌啶基氨基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[2.5]辛烷基;
二氮杂螺[3.3]庚烷基;
二氮杂螺[3.4]辛烷基;
二氮杂螺[3.5]壬烷基;
二氮杂螺[3.6]癸烷基;
二氮杂螺[4.4]壬烷基;
二氮杂螺[4.5]癸烷基;
二氮杂螺[5.5]十一烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧杂二氮杂螺[5.5]十一烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:甲基、苯基、苄基、氨基乙酰基和哌啶基;
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、氨基甲基、氨基乙基、氮杂环庚烷基、甲基、2,2-二甲基丙酰氨基、甲基哌嗪基、氨基甲酰基、氟、苯基、哌嗪基、哌啶基和吡咯烷基;或
吡咯烷基,所述吡咯烷基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基和氟;
R3为甲基;
R4为H或氟;
X为O;
或其药用盐、对映体或非对映体。
4.根据权利要求3所述的化合物,其中R2为(3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-4-基;1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-基、1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-基;1,6-二氮杂螺[3.3]庚烷-1-基;1,7-二氮杂螺[3.5]壬烷-7-基;1,8-二氮杂螺[4.5]癸烷-8-基;1,9-二氮杂螺[5.5]十一烷-9-基、1-甲基-4-哌啶基氨基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基;1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;2-(3-氨基甲酰基)-1-哌啶基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-基;2,5-二氮杂双环[2.2.2]辛烷-2-基;2,6-二氮杂螺[3.3]庚烷-2-基;2,6-二氮杂螺[3.5]壬烷-6-基;2,6-二氮杂螺[4.5]癸烷-2-基;2,7-二氮杂螺[3.4]辛烷-2-基;2,7-二氮杂螺[3.5]壬烷-2-基;2,7-二氮杂螺[3.5]壬烷-7-基;2,7-二氮杂螺[4.4]壬烷-2-基;2,7-二氮杂螺[4.5]癸烷-7-基;2,8-二氮杂螺[3.5]壬烷-2-基;2,8-二氮杂螺[3.6]癸烷-2-基;2,8-二氮杂螺[4.5]癸烷-2-基;2,8-二氮杂螺[4.5]癸烷-8-基;2,8-二氮杂螺[5.5]十一烷-2-基;2,9-二氮杂螺[4.5]癸烷-2-基;2,9-二氮杂螺[5.5]十一烷-2-基;2,9-二氮杂螺[5.5]十一烷-9-基;2-苄基-4-(4-哌啶基)哌嗪-1-基;2-苄基哌嗪-1-基;2-甲基哌嗪-1-基;3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯-1-基;3,7-二氮杂双环[4.2.0]辛烷-3-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3,8-二氮杂双环[3.2.1]辛烷-8-基;3,8-二氮杂双环[4.2.0]辛烷-8-基;3,9-二氮杂螺[5.5]十一烷-3-基;3-氨基-8-氮杂双环[3.2.1]辛烷-8-基;3-氨基-9-氮杂双环[3.3.1]壬烷-9-基;3-甲基哌嗪-1-基;3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基;3-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;3-苯基哌嗪-1-基;4-(1-哌啶基)-1-哌啶基;4-(2,2-二甲基丙酰氨基)-1-哌啶基;4-(2-氨基乙酰基)哌嗪基;4-(2-氨基乙基)-1-哌啶基;4-(4-甲基哌嗪-1-基)-1-哌啶基;4-(氨基甲基)-1-哌啶基;4-(氮杂环庚烷-1-基)-1-哌啶基;4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基;4,7-二氮杂螺[2.5]辛烷-7-基;4-氨基-1-哌啶基;4-氨基-2-甲基-1-哌啶基;4-氨基-3,3-二氟-1-哌啶基;4-氨基-3,3-二氟-吡咯烷-1-基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;4-氨基-4-苯基-1-哌啶基;4-甲基哌嗪基;4-哌嗪-1-基-1-哌啶基;4-吡咯烷-1-基-1-哌啶基;6-氨基-2-氮杂螺[3.3]庚烷-2-基;7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基;8-氨基-3-氮杂双环[3.2.1]辛烷-3-基;9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷-2-基或哌嗪基。
5.根据权利要求2所述的化合物,其中
R2为1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;
2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;
氨基氮杂双环[3.2.1]辛烷基;
氨基氧杂氮杂双环[3.3.1]壬烷基;
二氮杂双环[2.2.2]辛烷基;
二氮杂双环[3.2.1]辛烷基;
二氮杂双环[4.2.0]辛烷基;
二氮杂螺[4.5]癸烷基;
氧杂二氮杂双环[3.3.1]壬烷基;
氧代二氮杂螺[4.4]壬烷基;
哌嗪基,所述哌嗪基未被取代或由C1-6烷基或苯基C1-6烷基所取代;或
哌啶基,所述哌啶基未被取代或由独立地选自以下项的一个、两个或三个取代基所取代:氨基、C1-6烷基、C1-6烷基哌嗪基和卤素。
6.根据权利要求5所述的化合物,其中R2为1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;氨基氮杂双环[3.2.1]辛烷基;氨基氧杂氮杂双环[3.3.1]壬烷基;二氮杂双环[2.2.2]辛烷基;二氮杂双环[3.2.1]辛烷基;二氮杂双环[4.2.0]辛烷基;二氮杂螺[4.5]癸烷基;氧杂二氮杂双环[3.3.1]壬烷基;氧代二氮杂螺[4.4]壬烷基;哌嗪基、甲基哌嗪基;苄基哌嗪基;甲基哌嗪基哌啶基;氨基哌啶基;氨基(C1-6烷基)哌啶基或氨基卤代哌啶基。
7.根据权利要求6所述的化合物,其中R2为4-(4-甲基哌嗪-1-基)-1-哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,5-二氮杂双环[2.2.2]辛烷-2-基;2,6-二氮杂螺[4.5]癸烷-2-基;2-苄基哌嗪-1-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3,8-二氮杂双环[3.2.1]辛烷-8-基;3-甲基哌嗪-1-基;3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基;4-氨基-1-哌啶基;4-氨基-3,3-二氟-1-哌啶基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基;8-氨基-3-氮杂双环[3.2.1]辛烷-3-基或哌嗪基。
8.根据权利要求5或6所述的化合物,其中R2为C1-6烷基哌嗪基哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶基;氧杂二氮杂螺[5.5]十一烷基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯基;二氮杂螺[4.5]癸烷基;二氮杂双环[4.2.0]辛烷基;氨基哌啶基;氨基(C1-6烷基)哌啶基。
9.根据权利要求8所述的化合物,其中R2为4-(4-甲基哌嗪-1-基)-1-哌啶基;1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基;1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基;2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基;2,9-二氮杂螺[4.5]癸烷-2-基;3,7-二氮杂双环[4.2.0]辛烷-7-基;4-氨基-1-哌啶基;4-氨基-3-甲基-1-哌啶基;4-氨基-4-甲基-1-哌啶基。
10.根据权利要求8所述的化合物,其中R2为二氮杂螺[4.5]癸烷基。
11.根据权利要求10所述的化合物,其中R2为2,9-二氮杂螺[4.5]癸烷-2-基。
12.根据权利要求2所述的化合物,其选自:
4-[(2R,6S)-2-甲基-6-[[4-(4-甲基哌嗪-1-基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
N-[1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]-4-哌啶基]-2,2-二甲基-丙酰胺;
4-[(2S,6R)-2-(3,9-二氮杂螺[5.5]十一烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(氮杂环庚烷-1-基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(哌嗪-1-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[4.4]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[(1-甲基-4-哌啶基)氨基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[3.3]庚烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.4]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(6-氨基-2-氮杂螺[3.3]庚烷-2-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(氨基甲基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(2-氨基乙基)-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(2-氨基乙酰基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[4-(1-哌啶基)-1-哌啶基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6R)-2-甲基-6-[(3-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6R)-2-甲基-6-[(1-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,3,3a,4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(3-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-4-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,5-二氮杂双环[2.2.2]辛烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[3.5]壬烷-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-3,3-二氟-吡咯烷-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(8-氨基-3-氮杂双环[3.2.1]辛烷-3-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(3-氨基-8-氮杂双环[3.2.1]辛烷-8-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[(3R)-3-苯基哌嗪-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-哌嗪-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(4,7-二氮杂螺[2.5]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,2,3,3a,4,6,7,7a-八氢吡咯并[3,2-c]吡啶-5-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,6-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[3.2.1]辛烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,2,3,4,4a,5,7,7a-八氢吡咯并[3,4-b]吡啶-6-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,8-二氮杂螺[3.6]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,9-二氮杂螺[5.5]十一烷-9-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,7-二氮杂螺[3.5]壬烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(2-甲基哌嗪-1-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(4-氨基-2-甲基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,8-二氮杂螺[4.5]癸烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(4-吡咯烷-1-基-1-哌啶基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(1,6-二氮杂螺[3.3]庚烷-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,8-二氮杂双环[4.2.0]辛烷-8-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(7-氨基-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[(2-苄基哌嗪-1-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,3,4,4a,5,6,7,7a-八氢吡咯并[3,4-b]吡啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[顺式-(3aR,6aR)-3,3a,4,5,6,6a-六氢-2H-吡咯并[3,4-b]吡咯-1-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[[顺式-(3aS,7aS)-1,2,3,3a,5,6,7,7a-八氢吡咯并[3,2-b]吡啶-4-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,4,4a,5,6,7,8,8a-八氢-2H-1,5-萘啶-1-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
内型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
外型-4-[(2S,6R)-2-[(3-氨基-9-氮杂双环[3.3.1]壬烷-9-基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(2,9-二氮杂螺[5.5]十一烷-2-基甲基)-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-腈;
3-氟-4-[(2S,6R)-2-(2,7-二氮杂螺[4.5]癸烷-7-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
3-氟-4-[(2S,6R)-2-(2,9-二氮杂螺[4.5]癸烷-2-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-(3,7-二氮杂双环[4.2.0]辛烷-3-基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-(1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-基甲基)吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
1-[[(2S,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]哌啶-3-甲酰胺;
4-[(2S,6R)-2-[(4-氨基-4-苯基-1-哌啶基)甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[(3R,4S)-4-氨基-3-甲基-1-哌啶基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2S,6R)-2-[[4-(二甲基氨基)-3,3a,4,5,6,6a-六氢-1H-环戊二烯并[c]吡咯-2-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
4-[(2R,6S)-2-甲基-6-[(9-甲基-6-氧杂-2,9-二氮杂螺[4.5]癸烷-2-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;和
4-[(2S,6R)-2-[[2-苄基-4-(4-哌啶基)哌嗪-1-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-腈;
或其药用盐、对映体或非对映体。
14.一种根据权利要求1至12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。
15.一种药物组合物,其包含根据权利要求1至12中任一项所述的化合物以及治疗惰性载体。
16.根据权利要求1至12中任一项所述的化合物用于治疗或预防系统性红斑狼疮或狼疮肾炎的用途。
17.根据权利要求1至12中任一项所述的化合物用于制备治疗或预防系统性红斑狼疮或狼疮肾炎的药物的用途。
18.根据权利要求1至12中任一项所述的化合物作为TLR7或TLR8或TLR9拮抗剂的用途。
19.根据权利要求1至12中任一项所述的化合物作为TLR7和TLR8拮抗剂的用途。
20.一种根据权利要求1至12中任一项所述的化合物或药用盐、对映体或非对映体,其用于治疗或预防系统性红斑狼疮或狼疮肾炎。
21.一种根据权利要求1至12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13所述的方法制造。
22.一种用于治疗或预防系统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12中任一项所定义的化合物。
23.如前所述的本发明。
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PCT/EP2018/074463 WO2020052738A1 (en) | 2018-09-11 | 2018-09-11 | Pyrazolopyridine amine compounds for the treatment of autoimmune disease |
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EP (1) | EP3849974A1 (zh) |
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CN105061422A (zh) * | 2007-03-22 | 2015-11-18 | 吉恩基奥泰克斯股份有限公司 | 吡唑并吡啶衍生物及其用途 |
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 |
WO2017106607A1 (en) * | 2015-12-17 | 2017-06-22 | Merck Patent Gmbh | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
CN112313228A (zh) * | 2018-06-12 | 2021-02-02 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的新型杂芳基杂环基化合物 |
CN112585134A (zh) * | 2018-06-13 | 2021-03-30 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的吡啶基杂环基化合物 |
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SI2694484T1 (sl) * | 2011-04-08 | 2018-10-30 | Janssen Sciences Ireland Uc | Derivati pirimidina za zdravljenje virusnih okužb |
-
2018
- 2018-09-11 WO PCT/EP2018/074463 patent/WO2020052738A1/en unknown
- 2018-09-11 US US17/275,498 patent/US20220112187A1/en not_active Abandoned
- 2018-09-11 CN CN201880097397.7A patent/CN112673007A/zh active Pending
- 2018-09-11 EP EP18773112.0A patent/EP3849974A1/en not_active Withdrawn
- 2018-09-11 JP JP2021537478A patent/JP2022502480A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061422A (zh) * | 2007-03-22 | 2015-11-18 | 吉恩基奥泰克斯股份有限公司 | 吡唑并吡啶衍生物及其用途 |
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 |
WO2017106607A1 (en) * | 2015-12-17 | 2017-06-22 | Merck Patent Gmbh | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
CN112313228A (zh) * | 2018-06-12 | 2021-02-02 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的新型杂芳基杂环基化合物 |
CN112585134A (zh) * | 2018-06-13 | 2021-03-30 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的吡啶基杂环基化合物 |
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EP3849974A1 (en) | 2021-07-21 |
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