CN114599651A - 作为造血祖细胞激酶1(hpk1)抑制剂的吲唑类药物及其使用方法 - Google Patents
作为造血祖细胞激酶1(hpk1)抑制剂的吲唑类药物及其使用方法 Download PDFInfo
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- CN114599651A CN114599651A CN202180003282.9A CN202180003282A CN114599651A CN 114599651 A CN114599651 A CN 114599651A CN 202180003282 A CN202180003282 A CN 202180003282A CN 114599651 A CN114599651 A CN 114599651A
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- Prior art keywords
- fluoro
- carboxamide
- indazol
- pyridin
- fluorocyclopropane
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- FOYXSSOAOWTSII-MFKMUULPSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(methylsulfanylmethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSCC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F FOYXSSOAOWTSII-MFKMUULPSA-N 0.000 claims 2
- FGPXEVXPNAJUJL-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(trifluoromethoxy)-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C=C2)C(C(Cl)=C3F)=C(C=NN4)C4=C3OC(F)(F)F)C2=N1 FGPXEVXPNAJUJL-SCZZXKLOSA-N 0.000 claims 2
- VUXNJCFAGHRLTM-NDMJEZRESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1S)-1-(tetrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=NN=C1 VUXNJCFAGHRLTM-NDMJEZRESA-N 0.000 claims 2
- VPGGUKJWLLPGPY-SUHUHFCYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2R)-1-methoxypropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](COC)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VPGGUKJWLLPGPY-SUHUHFCYSA-N 0.000 claims 2
- VPGGUKJWLLPGPY-QKCSRTOESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2S)-1-methoxypropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](COC)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VPGGUKJWLLPGPY-QKCSRTOESA-N 0.000 claims 2
- NVKQFHYHFHDAMF-WBVHZDCISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(pyridin-3-ylmethyl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(CC1=CC=CN=C1)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NVKQFHYHFHDAMF-WBVHZDCISA-N 0.000 claims 2
- CTVGMLOUDWOFCX-WBVHZDCISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(pyridin-4-ylmethyl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(CC1=CC=NC=C1)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F CTVGMLOUDWOFCX-WBVHZDCISA-N 0.000 claims 2
- NTRLFLULDSRDMO-FVIPRIBZSA-N (1S,2S)-N-[6-[5-chloro-7-(1,1-difluoropropan-2-ylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)F)NC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NTRLFLULDSRDMO-FVIPRIBZSA-N 0.000 claims 2
- LSJGADXTFOUEFI-WPLSFSDESA-N (1S,2S)-N-[6-[5-chloro-7-(1-cyanoethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C#N)NC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LSJGADXTFOUEFI-WPLSFSDESA-N 0.000 claims 2
- VKDHDCAZISQCBH-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-(cyanomethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CCNC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VKDHDCAZISQCBH-PWSUYJOCSA-N 0.000 claims 2
- DPRGJVNQEWICNS-RISCZKNCSA-N (1S,2S)-N-[6-[5-chloro-7-(ethoxymethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOCC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F DPRGJVNQEWICNS-RISCZKNCSA-N 0.000 claims 2
- FOTGZKKQQZKCFC-VOHIISRTSA-N (1S,2S)-N-[6-[5-chloro-7-[1-(ethylamino)-1-oxopropan-2-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCNC(C(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O FOTGZKKQQZKCFC-VOHIISRTSA-N 0.000 claims 2
- MFJYZUHVRYGGTR-FVIPRIBZSA-N (1S,2S)-N-[6-[5-chloro-7-[1-[(2,2-difluoroacetyl)amino]ethyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)F)=O MFJYZUHVRYGGTR-FVIPRIBZSA-N 0.000 claims 2
- CFTQVQGOMHRLBZ-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-7-[ethyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F CFTQVQGOMHRLBZ-YPMHNXCESA-N 0.000 claims 2
- VMHSRQRMNXLMIM-HIFRSBDPSA-N (1S,2S)-N-[6-[7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C(C=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1N(C)C)=C1F VMHSRQRMNXLMIM-HIFRSBDPSA-N 0.000 claims 2
- IURZKPAKWHZSRN-HIFRSBDPSA-N (1S,2S)-N-[6-[7-[ethyl(methyl)amino]-6-fluoro-5-methyl-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C(C(F)=C1C)=C2NN=CC2=C1C(C=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 IURZKPAKWHZSRN-HIFRSBDPSA-N 0.000 claims 2
- WYNDECZMZJKBSQ-OCCSQVGLSA-N (1S,2S)-N-[6-[7-[ethyl(methyl)amino]-6-fluoro-5-methylsulfanyl-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(SC)=C1F WYNDECZMZJKBSQ-OCCSQVGLSA-N 0.000 claims 2
- QVRKYRDOARNWAJ-YPMHNXCESA-N 5-chloro-N-ethyl-6-fluoro-4-[2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-1H-indazole-7-carboxamide Chemical compound CCN(C)C(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O QVRKYRDOARNWAJ-YPMHNXCESA-N 0.000 claims 2
- IQFWWPXJXLBBGX-WPLSFSDESA-N CC(C(NC)=O)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound CC(C(NC)=O)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F IQFWWPXJXLBBGX-WPLSFSDESA-N 0.000 claims 2
- KYBKPLSRLJFDOC-FVIPRIBZSA-N CC(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)(F)F)=O Chemical compound CC(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)(F)F)=O KYBKPLSRLJFDOC-FVIPRIBZSA-N 0.000 claims 2
- RKKVUYGAGLNPDO-YJTDSAHGSA-N CC(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C)=O Chemical compound CC(C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C)=O RKKVUYGAGLNPDO-YJTDSAHGSA-N 0.000 claims 2
- ZMXSWXHNIZWGCQ-HIFRSBDPSA-N CCC(C(C(C=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1OCC)=C1F Chemical compound CCC(C(C(C=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1OCC)=C1F ZMXSWXHNIZWGCQ-HIFRSBDPSA-N 0.000 claims 2
- GCJUYLADQBVIKD-PWSUYJOCSA-N CCNC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound CCNC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GCJUYLADQBVIKD-PWSUYJOCSA-N 0.000 claims 2
- NDTWGGCDEASITD-PWSUYJOCSA-N CCOC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound CCOC1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NDTWGGCDEASITD-PWSUYJOCSA-N 0.000 claims 2
- ASOPCWUXMCPADQ-UHFFFAOYSA-N N-[6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC(C2CC2)=O)=C3)C(Cl)=C1F ASOPCWUXMCPADQ-UHFFFAOYSA-N 0.000 claims 2
- BWJVTNHRVGTTOM-CMPLNLGQSA-N (1R,2R)-N-[5-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(C1=CC2=CC(NC([C@@H](C3)[C@@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1F)=C1F BWJVTNHRVGTTOM-CMPLNLGQSA-N 0.000 claims 1
- BWJVTNHRVGTTOM-JQWIXIFHSA-N (1R,2S)-N-[5-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(C1=CC2=CC(NC([C@@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1F)=C1F BWJVTNHRVGTTOM-JQWIXIFHSA-N 0.000 claims 1
- MQVHACCBIAQZPF-JQWIXIFHSA-N (1R,2S)-N-[6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F MQVHACCBIAQZPF-JQWIXIFHSA-N 0.000 claims 1
- BWJVTNHRVGTTOM-ZYHUDNBSSA-N (1S,2R)-N-[5-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(C1=CC2=CC(NC([C@H](C3)[C@@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1F)=C1F BWJVTNHRVGTTOM-ZYHUDNBSSA-N 0.000 claims 1
- MQVHACCBIAQZPF-ZYHUDNBSSA-N (1S,2R)-N-[6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C(C=C2)=CN3C2=NC(NC([C@H](C2)[C@@H]2F)=O)=C3)C(Cl)=C1F MQVHACCBIAQZPF-ZYHUDNBSSA-N 0.000 claims 1
- KZQUMOYORVGRHD-OCCSQVGLSA-N (1S,2S)-2-fluoro-N-[5-(6-fluoro-7-methoxy-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1OC)=C1F KZQUMOYORVGRHD-OCCSQVGLSA-N 0.000 claims 1
- VXLMPLIGADFNRB-YPMHNXCESA-N (1S,2S)-2-fluoro-N-[5-[6-fluoro-5-methyl-7-(trifluoromethoxy)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1OC(F)(F)F)=C1F VXLMPLIGADFNRB-YPMHNXCESA-N 0.000 claims 1
- ATBAPHRLLXWACB-HIFRSBDPSA-N (1S,2S)-2-fluoro-N-[5-[6-fluoro-7-(2-hydroxyethoxy)-5-methyl-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1OCCO)=C1F ATBAPHRLLXWACB-HIFRSBDPSA-N 0.000 claims 1
- AKHBTPPGMIXBCG-YPMHNXCESA-N (1S,2S)-2-fluoro-N-[6-(6-fluoro-7-methoxy-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C(C(C=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1OC)=C1F AKHBTPPGMIXBCG-YPMHNXCESA-N 0.000 claims 1
- HYMVGQPVKLEXEG-KOLCDFICSA-N (1S,2S)-N-[5-(5,7-dichloro-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C(Cl)=C2F)=C(C=NN3)C3=C2Cl)=C2)C2=C1 HYMVGQPVKLEXEG-KOLCDFICSA-N 0.000 claims 1
- KBFZTZXTCVCYRK-PWSUYJOCSA-N (1S,2S)-N-[5-(5-bromo-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C2=C(C=NN3)C3=CC(F)=C2Br)=C2)C2=C1 KBFZTZXTCVCYRK-PWSUYJOCSA-N 0.000 claims 1
- GWWLJYQSXRFHQQ-PWSUYJOCSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-methoxy-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound COC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F GWWLJYQSXRFHQQ-PWSUYJOCSA-N 0.000 claims 1
- SPSDZRKWLRJXEJ-PWSUYJOCSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F SPSDZRKWLRJXEJ-PWSUYJOCSA-N 0.000 claims 1
- MKVZWAYFLAPTTK-OCCSQVGLSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-prop-1-en-2-yl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F)=C MKVZWAYFLAPTTK-OCCSQVGLSA-N 0.000 claims 1
- WODJBHVEIOCMHB-OCCSQVGLSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-propan-2-yl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)C(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F WODJBHVEIOCMHB-OCCSQVGLSA-N 0.000 claims 1
- SFZUAQICZMTBPP-OCCSQVGLSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-propan-2-yloxy-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)OC(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F SFZUAQICZMTBPP-OCCSQVGLSA-N 0.000 claims 1
- BBDJXLFNIUZGOX-HIFRSBDPSA-N (1S,2S)-N-[5-(5-chloro-6-fluoro-7-pyrrol-1-yl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C2=C(C(N3C=CC=C3)=C3F)NN=C2)=C3Cl)=C2)C2=C1 BBDJXLFNIUZGOX-HIFRSBDPSA-N 0.000 claims 1
- OHCAUCLMNKROGV-MFKMUULPSA-N (1S,2S)-N-[5-(5-chloro-7-cyano-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F OHCAUCLMNKROGV-MFKMUULPSA-N 0.000 claims 1
- BPIAAPGGXBSVTP-ZBFHGGJFSA-N (1S,2S)-N-[5-(5-chloro-7-cyclopentyl-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C2=C(C(C3CCCC3)=C3F)NN=C2)=C3Cl)=C2)C2=C1 BPIAAPGGXBSVTP-ZBFHGGJFSA-N 0.000 claims 1
- PVXCSQZITJQSSL-YPMHNXCESA-N (1S,2S)-N-[5-(5-chloro-7-ethylsulfanyl-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCSC(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F PVXCSQZITJQSSL-YPMHNXCESA-N 0.000 claims 1
- KGXYABJZEPWDAS-OCCSQVGLSA-N (1S,2S)-N-[5-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1F)=C1F KGXYABJZEPWDAS-OCCSQVGLSA-N 0.000 claims 1
- XAKDNWSYBONUOQ-KOLCDFICSA-N (1S,2S)-N-[5-(5-ethyl-6-fluoro-1H-indazol-4-yl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC=C2N=C(NC([C@H](C3)[C@H]3F)=O)SC2=N1)=C(C=NN1)C1=C1)=C1F XAKDNWSYBONUOQ-KOLCDFICSA-N 0.000 claims 1
- APRSJKQFAPWMEO-HIFRSBDPSA-N (1S,2S)-N-[5-(5-ethyl-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1)=C1F APRSJKQFAPWMEO-HIFRSBDPSA-N 0.000 claims 1
- BWJVTNHRVGTTOM-PWSUYJOCSA-N (1S,2S)-N-[5-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1F)=C1F BWJVTNHRVGTTOM-PWSUYJOCSA-N 0.000 claims 1
- SDJFQKSHJYLFNR-KOLCDFICSA-N (1S,2S)-N-[5-(7-bromo-5-chloro-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C(Cl)=C2F)=C(C=NN3)C3=C2Br)=C2)C2=C1 SDJFQKSHJYLFNR-KOLCDFICSA-N 0.000 claims 1
- FYKAZLONEKGYME-YPMHNXCESA-N (1S,2S)-N-[5-(7-bromo-6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1Br)=C1F FYKAZLONEKGYME-YPMHNXCESA-N 0.000 claims 1
- VVBNDBFPEWEVOP-PWSUYJOCSA-N (1S,2S)-N-[5-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC=C2N=C(NC([C@H](C3)[C@H]3F)=O)SC2=N1)=C(C=NN1)C1=C1OCC)=C1F VVBNDBFPEWEVOP-PWSUYJOCSA-N 0.000 claims 1
- AGPJQHDLYYEYIC-ZBFHGGJFSA-N (1S,2S)-N-[5-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1OCC)=C1F AGPJQHDLYYEYIC-ZBFHGGJFSA-N 0.000 claims 1
- JIZWCAABFOOSPN-KOLCDFICSA-N (1S,2S)-N-[5-(7-ethoxy-6-fluoro-5-methyl-1H-indazol-4-yl)-[1,3]thiazolo[5,4-b]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(NN=C1)=C1C(C(C=C1)=NC2=C1N=C(NC([C@H](C1)[C@H]1F)=O)S2)=C1C)=C1F JIZWCAABFOOSPN-KOLCDFICSA-N 0.000 claims 1
- SSIHFQROZFYIPJ-OCCSQVGLSA-N (1S,2S)-N-[5-(7-ethoxy-6-fluoro-5-methylsulfanyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(SC)=C1F SSIHFQROZFYIPJ-OCCSQVGLSA-N 0.000 claims 1
- SJPHEYWUPSYPSL-HLNONWOFSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(C(F)(F)F)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F SJPHEYWUPSYPSL-HLNONWOFSA-N 0.000 claims 1
- ZXFARUZAXQHRRY-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(2-hydroxyethylsulfanyl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCCSC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F ZXFARUZAXQHRRY-YPMHNXCESA-N 0.000 claims 1
- UKSBECQHYUHDDD-ZBFHGGJFSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(2-methylpyrrol-1-yl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=CC=CN1C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F UKSBECQHYUHDDD-ZBFHGGJFSA-N 0.000 claims 1
- FXETZCNPBTYULM-ICSQTIAXSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(3-fluoropyrrolidin-1-yl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C(Cl)=C2F)=C(C=NN3)C3=C2N(CC2)CC2F)=C2)C2=C1 FXETZCNPBTYULM-ICSQTIAXSA-N 0.000 claims 1
- AZDAACKCQATEFP-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(3-methyl-2-oxoimidazolidin-1-yl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(CCN1C2=C3NN=CC3=C(C3=CC4=CC(NC([C@H](C5)[C@H]5F)=O)=NN4C=C3)C(Cl)=C2F)C1=O AZDAACKCQATEFP-OCCSQVGLSA-N 0.000 claims 1
- PFQRSWMHDTYZFN-MFKMUULPSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(fluoromethyl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C2=C(C=NN3)C3=C(CF)C(F)=C2Cl)=C2)C2=C1 PFQRSWMHDTYZFN-MFKMUULPSA-N 0.000 claims 1
- QQKAJVPVZWKFRE-MFKMUULPSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(hydroxymethyl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F QQKAJVPVZWKFRE-MFKMUULPSA-N 0.000 claims 1
- LBRNUONFZBPONR-PWSUYJOCSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(methylamino)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CNC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F LBRNUONFZBPONR-PWSUYJOCSA-N 0.000 claims 1
- KCZWTCPMKQMEGA-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(propan-2-ylamino)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)NC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F KCZWTCPMKQMEGA-OCCSQVGLSA-N 0.000 claims 1
- AKDQWTJKSHMQTK-KOLCDFICSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-(trifluoromethoxy)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C(C(Cl)=C2F)=C(C=NN3)C3=C2OC(F)(F)F)=C2)C2=C1 AKDQWTJKSHMQTK-KOLCDFICSA-N 0.000 claims 1
- VDSKDKMJLRJXPK-YVLXSGLVSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[(2S)-1-methoxypropan-2-yl]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](COC)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F VDSKDKMJLRJXPK-YVLXSGLVSA-N 0.000 claims 1
- LHYIBWNKHXPEJS-YFRQPTDVSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[(3-hydroxycyclobutyl)-methylamino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C(C1)CC1O)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F LHYIBWNKHXPEJS-YFRQPTDVSA-N 0.000 claims 1
- KAQPOXXFNUQQPF-SPMVYCQMSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[(4-hydroxycyclohexyl)-methylamino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C(CC1)CCC1O)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F KAQPOXXFNUQQPF-SPMVYCQMSA-N 0.000 claims 1
- QYNFLGVDJUJQQM-AFGDWVFNSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[1-(propanoylamino)ethyl]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(NC(C)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)=O QYNFLGVDJUJQQM-AFGDWVFNSA-N 0.000 claims 1
- KWAUCMZDLCMKGW-KQBUEYNVSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[1-[(2,2,2-trifluoroacetyl)amino]ethyl]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)NC(C(F)(F)F)=O KWAUCMZDLCMKGW-KQBUEYNVSA-N 0.000 claims 1
- PHHYGRZJCAODNW-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[methyl(1,2,4-triazin-3-yl)amino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)C1=NC=CN=N1 PHHYGRZJCAODNW-OCCSQVGLSA-N 0.000 claims 1
- TZZKWZXIIZLRSA-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[methyl(1,3,5-triazin-2-yl)amino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)C1=NC=NC=N1 TZZKWZXIIZLRSA-OCCSQVGLSA-N 0.000 claims 1
- BPWAKDHTUXMHEA-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[methyl(methylcarbamoyl)amino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CNC(N(C)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)=O BPWAKDHTUXMHEA-YPMHNXCESA-N 0.000 claims 1
- HYRMWWJSPZALAO-HIFRSBDPSA-N (1S,2S)-N-[5-[5-chloro-6-fluoro-7-[methyl(pyrimidin-2-yl)amino]-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)C1=NC=CC=N1 HYRMWWJSPZALAO-HIFRSBDPSA-N 0.000 claims 1
- ZLHVGCXPCRUSQL-KQBUEYNVSA-N (1S,2S)-N-[5-[5-chloro-7-(1,1-difluoropropan-2-ylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)F)NC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F ZLHVGCXPCRUSQL-KQBUEYNVSA-N 0.000 claims 1
- AXUWEZLDHQMDRA-YJTDSAHGSA-N (1S,2S)-N-[5-[5-chloro-7-(1-cyanoethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C#N)NC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F AXUWEZLDHQMDRA-YJTDSAHGSA-N 0.000 claims 1
- AZIPXRKCTWOLLX-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-7-(2-cyanopropan-2-ylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(C#N)NC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F AZIPXRKCTWOLLX-OCCSQVGLSA-N 0.000 claims 1
- ANJXEAJBZODOON-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-7-(cyanomethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CCNC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F ANJXEAJBZODOON-YPMHNXCESA-N 0.000 claims 1
- ZAAIQNJCBZIQTN-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-7-(cyanomethylsulfanyl)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CCSC1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F ZAAIQNJCBZIQTN-YPMHNXCESA-N 0.000 claims 1
- FTIXSLGTHQREPE-HIFRSBDPSA-N (1S,2S)-N-[5-[5-chloro-7-(diethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(CC)C(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F FTIXSLGTHQREPE-HIFRSBDPSA-N 0.000 claims 1
- SYGNDVBDUBBOBV-KOLCDFICSA-N (1S,2S)-N-[5-[5-chloro-7-(difluoromethyl)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=NN(C=CC(C2=C(C=NN3)C3=C(C(F)F)C(F)=C2Cl)=C2)C2=C1 SYGNDVBDUBBOBV-KOLCDFICSA-N 0.000 claims 1
- FNHNAGDZQDJXLF-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F FNHNAGDZQDJXLF-YPMHNXCESA-N 0.000 claims 1
- ANOOOFJOAFVNEK-YPMHNXCESA-N (1S,2S)-N-[5-[5-chloro-7-(ethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCNC(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F ANOOOFJOAFVNEK-YPMHNXCESA-N 0.000 claims 1
- SCOZAKFHWMKHGF-KQBUEYNVSA-N (1S,2S)-N-[5-[5-chloro-7-[1-[(2,2-difluoroacetyl)amino]ethyl]-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F)NC(C(F)F)=O SCOZAKFHWMKHGF-KQBUEYNVSA-N 0.000 claims 1
- RMQBDHZFGZIONQ-CCJHYTBNSA-N (1S,2S)-N-[5-[5-chloro-7-[[4-(dimethylamino)cyclohexyl]-methylamino]-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C(CC1)CCC1N(C)C(C(NN=C1)=C1C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C1Cl)=C1F RMQBDHZFGZIONQ-CCJHYTBNSA-N 0.000 claims 1
- YACRXAQISOZVHO-HIFRSBDPSA-N (1S,2S)-N-[5-[5-chloro-7-[cyclopropyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1CC1)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F YACRXAQISOZVHO-HIFRSBDPSA-N 0.000 claims 1
- AMDDYXDIHSKSHO-OCCSQVGLSA-N (1S,2S)-N-[5-[5-chloro-7-[ethyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C1=C2NN=CC2=C(C2=CC3=CC(NC([C@H](C4)[C@H]4F)=O)=NN3C=C2)C(Cl)=C1F AMDDYXDIHSKSHO-OCCSQVGLSA-N 0.000 claims 1
- VGFAYYBSPPPODC-OCCSQVGLSA-N (1S,2S)-N-[5-[5-ethyl-6-fluoro-7-(trifluoromethyl)-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1C(F)(F)F)=C1F VGFAYYBSPPPODC-OCCSQVGLSA-N 0.000 claims 1
- PGESPHPIOPNCGZ-ZBFHGGJFSA-N (1S,2S)-N-[5-[5-ethyl-7-(ethylamino)-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(F)=C(C1=C2C=NN1)NCC)=C2C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1 PGESPHPIOPNCGZ-ZBFHGGJFSA-N 0.000 claims 1
- INYNXPFJZFECDS-WBVHZDCISA-N (1S,2S)-N-[5-[5-ethyl-7-[ethyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1N(C)CC)=C1F INYNXPFJZFECDS-WBVHZDCISA-N 0.000 claims 1
- WCMWHVJLWVBMSH-ZBQDIEFISA-N (1S,2S)-N-[5-[7-(1-cyanoethylsulfanyl)-5-ethyl-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1SC(C)C#N)=C1F WCMWHVJLWVBMSH-ZBQDIEFISA-N 0.000 claims 1
- TXXOPBREMIESND-ZBFHGGJFSA-N (1S,2S)-N-[5-[7-(cyanomethylsulfanyl)-5-ethyl-6-fluoro-1H-indazol-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C1=CC2=CC(NC([C@H](C3)[C@H]3F)=O)=NN2C=C1)=C(C=NN1)C1=C1SCC#N)=C1F TXXOPBREMIESND-ZBFHGGJFSA-N 0.000 claims 1
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Abstract
本发明提供式(I)所示化合物或其药学上可接受的盐、包含该化合物的组合物、使用该化合物治疗与HPK1相关的各种疾病的方法以及制备这些化合物的方法。
Description
相关申请的交叉引用
本申请要求于2020年9月28日提交的美国临时专利申请No.63/084059的优先权。在本段中指定的申请的全部公开内容通过引用并入本文。
技术领域
本发明涉及造血祖细胞激酶1(HPK1)抑制剂、包含该抑制剂的药物组合物、使用该抑制剂治疗与HPK1相关的各种疾病的方法以及制备这些化合物的方法。
背景技术
免疫疗法是一种利用人体自身免疫系统来对抗癌症和其他疾病的治疗方法。近年来,这种相对较新的方法,特别是结合免疫检查点抑制剂治疗和嵌合抗原T细胞疗法的联合应用下,在临床治疗多种肿瘤方面取得了很大的成功。研究最多的检查点抑制剂,包括CTLA4、PD-1或PD-L1抑制剂,通过克服肿瘤部位的免疫抑制机制,显示出显著的抗肿瘤活性。
造血祖细胞激酶1(HPK1,MAP4K1)是丝氨酸/苏氨酸激酶,是MAP4K的成员。HPK1在造血细胞系的亚群中显著表达。最新发现HPK1是T淋巴细胞和树突状细胞活化的关键负调节因子。最近的研究表明,HPK1激酶活性在抗癌免疫中作为新细胞内检查点分子扮演重要的角色,以及与现有检查点方案联合疗法的潜在优势。HPK1抑制预期具有双重功能,1.长期激活T细胞;2.树突状细胞增强APC功能。这种双重靶向可协同工作,以在肿瘤微环境中达到有效的免疫反应。因此,HPK1已被证实为抗癌免疫治疗的新靶点。可使用本发明化合物治疗的癌症示例包括但不限于所有形式的癌症、黑素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病,包括但不限于膀胱癌、脑瘤、乳腺癌、宫颈癌、结直肠癌、食管癌、子宫内膜癌、肝细胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰腺癌、前列腺癌、肾癌和甲状腺癌、急性淋巴细胞白血病、急性髓系白血病、室管膜瘤、尤因肉瘤、胶质母细胞瘤、髓母细胞瘤、神经母细胞瘤、骨肉瘤、横纹肌肉瘤、横纹肌样癌和肾母细胞瘤。
用小分子抑制剂抑制HPK1可用于治疗癌症和其他疾病[Hernandez,S.,et.al.(2018)Cell Reports 2580-94]。
发明内容
本发明提供了新型吲唑化合物和药学上可接受的盐作为有效的HPK1抑制剂和T细胞和树突状细胞的双重激活剂。
本发明的一个实施方案是由式(I)所示的化合物:
或其药学上可接受的盐、水合物、溶剂化物,其中R1、R1、R3、R4、R5、Het、M和L如具体实施方式中所定义。
在另一实施方案中,提供了一种药物组合物,其包含药学上可接受的载体或稀释剂和式(I)所示化合物或其药学上可接受的盐。
在另一实施方案中,提供了一种治疗患有与HPK1调节相关的疾病或病症的受试者的方法,包括:向受试者施用治疗有效量的式(I)所示化合物或其药学上可接受的盐。
具体实施方式
以下描述本质上仅是范例,并且无意于限制本发明,应用或用途。
定义
为了清楚起见,本文中定义了本发明中使用的通用术语。
本说明书可互换地使用术语“取代基”、“自由基”、“基团”、“部分”和“片段”。
如本文所用,术语“烯基”是指具有至少一个不饱和位点,即碳-碳,sp2双键的直链或支链的烃基。在一个实施方案中,烯基具有2至12个碳原子。在一些实施方案中,烯基为C2-C10烯基或C2-C6烯基。烯基的实例包括但不限于乙烯或乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、环戊烯基(-C5H7)和5-己烯基(-CH2CH2CH2CH2CH=CH2)。
如本文所用,术语“烷氧基”是RO-其中R是烷基。烷氧基的非限制性实例包括甲氧基、乙氧基和丙氧基。
如本文所用,术语“烷氧基烷基”是指被烷氧基取代的烷基部分。烷氧基烷基的实例包括甲氧基甲基、甲氧基乙基、甲氧基丙基和乙氧基乙基。
如本文所用,术语“烷氧羰基”为ROC(O)-,其中R为如本发明所定义的烷基。在各种实施方案中,R为C1-C10烷基或C1-C6烷基。
如本文所用,术语“烷基”是指直链或支链的烃基。在一个实施方案中,烷基具有1至12个碳原子。在一些实施方案中,烷基为C1-C10烷基或C1-C6烷基。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基和癸基。“低级烷基”是指具有1-4个碳原子的烷基。
如本文所用,如果使用术语“C1-C6”,则表示碳原子数为1到6。例如,C1-C6烷基表示碳数为1到6的任何整数的烷基。
如本文所用,术语“烷基氨基”是指被一个或多个烷基取代的氨基。“N-(烷基)氨基”是RNH-,并且“N,N-(烷基)2氨基”是R2N-,其中R基团是本文所定义的烷基并且相同或不同。在各种实施方案中,R为C1-C10烷基或C1-C6烷基。烷基氨基的实例包括甲基氨基、乙基氨基、丙基氨基、丁基氨基、二甲基氨基、二乙基氨基和甲基乙基氨基。
如本文所用,术语“烷基氨基烷基”是指被烷基氨基取代的烷基部分,其中烷基氨基如本文所定义。烷基氨基烷基的实例包括甲基氨基甲基和乙基氨基甲基。
如本文所用,术语“炔基”是指具有至少一个不饱和位点即碳-碳-sp三键的直链或支链碳链基团。在一个实施方案中,炔基具有2至12个碳原子。在一些实施方案中,炔基为C2-C10炔基或C2-C6炔基。炔基的实例包括炔基(-C≡CH)和炔丙基(-CH2C≡CH)。
如本文所用,术语“芳基”是指每个环中至多7个原子的任何单环或双环碳环,其中至少一个环是芳族的,或5至14个碳原子的芳环体系,该芳环体系包括与5或6元环烷基稠合的碳环芳族基团。芳基的代表性实例包括但不限于苯基、甲苯基、二甲苯基、萘基、四氢萘基、蒽基、芴基、茚基、薁基和茚满基。碳环芳族基团可以是未取代的或任选取代的。
如本文所用,术语“环烷基”是包含至少一个饱和或部分不饱和的环结构并且经由环碳连接的烃基。在各种实施方案中,它是指饱和或部分不饱和的C3-C12环状部分,饱和或部分不饱和的C3-C12环状部分的实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。“环烷氧基”是RO-,其中R是环烷基。
如本文所用,术语“卤素”和“卤代”是指氯(-Cl)、溴(-Br)、氟(-F)或碘(-I)。“卤代烷氧基”是指被一个或多个卤素基团取代的烷氧基,并且卤代烷氧基的实例包括但不限于-OCF3、-OCHF2和-OCH2F。“卤代烷氧基烷基”是指被卤代烷氧基取代的烷基部分,其中卤代烷氧基如本文所定义。卤代烷氧基烷基的实例包括三氟甲氧基甲基、三氟乙氧基甲基和三氟甲氧基乙基。“卤代烷基”是指被一个或多个卤素基团取代的烷基部分。卤代烷基的实例包括-CF3和-CHF2。
如本文所用,术语“杂烷基”是指在链中具有2至14个碳(在一些实施方案中为2至10个碳)的直链或支链烷基,其中一个或多个已被杂原子取代,该杂原子选自S、O、P和N。示例性的杂烷基包括烷基醚、仲和叔烷基胺、酰胺、烷基硫化物等。
如本文所用,术语“杂环基”包括以下定义的杂芳基,并且是指具有2至14个环碳原子的饱和或部分不饱和的单环、双环或三环基团,除了环碳原子外,还有1-4个选自P、N、O和S的杂原子。在各个实施方案中,杂环基通过碳或通过杂原子连接至另一部分,并且任选地被碳或杂原子取代。杂环基的实例包括氮杂环丁烷基、苯并咪唑基、苯并呋喃基、苯并呋喃氮基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并恶唑基、咔唑基、咔啉基、肉桂啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲哚嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、萘吡啶基、恶二唑基、恶唑基、恶唑啉、异恶唑啉、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氢吡喃基、四氢硫吡喃基、四氢异喹啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮杂环丁烷基、1,4-二恶烷基、六氢氮杂吡啶基、哌嗪基、哌啶基、吡啶-2-基、吡咯烷基、吗啉基、硫代吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并恶唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基二氢异恶唑基、二氢异噻唑基、二氢恶二唑基、二氢恶唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基和四氢噻吩基及其N-氧化物。“杂环基氧基”是RO-,其中R是杂环基。“杂环硫基”是RS-,其中R是杂环基。
如本文所用,术语“3元或4元杂环基”是指具有3或4个环原子的单环,其中至少一个环原子是选自N、O和S的杂原子。3-或4-元杂环基的非限制性实例包括吖丙啶基、2H-吖啶基、氧杂环烷基、噻喃基、氮杂环丁烷基、2、3-二乙酰氮、氮杂基、1、3-二氮杂环丁烷基、氧杂环丁烷基、2H-氧杂环丁烷基、硫杂环丁烷基和2H-噻吩基。
如本文所用,术语“杂芳基”是指在每个环中具有至多7个原子的单环、双环或三环,其中至少一个环是芳族的并且在环中包含1-4个选自N、O和S的杂原子。杂芳基的非限制性实例包括吡啶基、噻吩基、呋喃基、嘧啶基、咪唑基、吡喃基、吡唑基、噻唑基、噻二唑基、异噻唑基、恶唑基、异恶唑基、吡咯基、哒嗪基、吡嗪基、喹啉基、异喹啉基、苯并呋喃基、二苯并呋喃基、二苯并噻吩基、苯并噻吩基、吲哚基、苯并噻唑基、苯并恶唑基、苯并咪唑基、异吲哚基、苯并三唑基、嘌呤基、硫杂茚基和吡嗪基。杂芳基的连接可以通过芳环发生,或者,如果杂芳基是双环或三环并且其中一个环不是芳族的或不包含杂原子,则可以通过非芳族环或不包含杂原子的环进行连接。“杂芳基”也应理解为包括任何含氮杂芳基的N-氧化物衍生物。“杂芳氧基”是RO-,其中R是杂芳基。
如本文所用,术语“羟基烷氧基”是指被羟基(-OH)取代的烷氧基,其中烷氧基如本文所定义。羟基烷氧基的实例是羟基乙氧基。
如本文所用,术语“羟烷基”是指被至少一个羟基取代的直链或支链的单价C1-C10烃基,并且羟烷基的实例包括但不限于羟甲基、羟乙基、羟丙基和羟丁基。
如本文所用,术语“药学上可接受的”是指适用于药物制剂中,通常认为对于这种用途而言是安全的,已经由国家或州政府的监管机构正式批准用于该用途,或列在《美国药典》或其他公认的药典中,供动物,尤其是人类使用。
如本文所用,术语“药学上可接受的载体”是指稀释剂、佐剂、赋形剂或载体,或药学上可接受的并且与本发明化合物一起施用的其他成分。
如本文所用,术语“药学上可接受的盐”是指可以增强所需药理活性的盐。药学上可接受的盐的实例包括与无机或有机酸形成的酸加成盐、金属盐和胺盐。与无机酸形成的酸加成盐的实例包括与盐酸、氢溴酸、硫酸、硝酸和磷酸形成的盐。与有机酸形成的酸加成盐的实例包括乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、邻-(4-羟基-苯甲酰基)-苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟乙磺酸、苯磺酸、对氯苯磺酸、2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基-双环[2.2.2]辛-2-烯-1-羧酸、葡萄糖庚酸、4,4'-亚甲基双(3-羟基-2-萘)酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸和粘康酸。金属盐的实例包括与钠、钾、钙、镁、铝、铁和锌离子的盐。胺盐的实例包括与氨的盐和足够坚固以与羧酸形成盐的有机含氮碱。
如本文所用,术语“被取代”指上述任何基团(即烷基、芳基、杂芳基、杂环或环烷基),其中被取代部分的至少一个氢原子被取代基取代。在一个实施方案中,被取代的基团的每个碳原子被不超过两个取代基取代。在另一实施方案中,被取代的基团的每个碳原子被不多于一个取代基取代。在酮取代基的情况下,两个氢原子被氧取代,氧通过双键连接到碳上。除非特别规定,否则取代基包括卤代、羟基、(低级)烷基、卤代烷基、单烷基或二烷基氨基、芳基、杂环、-NO2、B(OH)2、BPin、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-NRaSO2Rb、-ORa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa、-OC(=O)NRaRb、-NRaSO2Rb、-PO3Ra、-PO(ORa)(ORb)、-SO2Ra、-S(O)Ra、-SO(N)Ra(例如,亚砜亚胺),-(Ra)S=NRb(e.g.,烃基硫亚胺)和-SRa,其中Ra和Rb相同或不同且独立-H、卤代、氨基、烷基、卤代烷基、芳基或杂环,或者其中Ra和Rb与它们所连接的氮原子一起形成杂环。Ra和Rb可以是基于它们所连接的原子的复数形式。
如本文所用,术语“治疗有效量”是指当应用于本发明的化合物时旨在表示足以改善、减轻、稳定、逆转、减慢或延迟病症或疾病状态,或病症或疾病的症状发展的化合物的量。在一个实施方案中,本发明的方法提供化合物的组合的施用。在这种情况下,“治疗有效量”是本发明化合物在组合中足以引起预期的生物学效应的量。
如本文所用,术语“治疗”是指改善或逆转疾病或病症的进展或严重程度,或改善或逆转此类疾病或病症的一种或多种症状或副作用。如本文所用,“治疗”还意指抑制或阻断,如延迟、阻滞、约束、妨碍或阻碍,疾病或病症的体系、症状或状态的进展。为了实现本发明的目的,“治疗”进一步意指获得有益或期望的临床结果的方法,其中“有益或期望的临床结果”包括但不限于减轻症状,减轻疾病或疾病的程度,稳定(即不恶化)的疾病或病症状态,疾病或病症状态的延迟或减慢,疾病或病症状态的改善或缓解以及部分或全部疾病或病症的缓解。
化合物
本发明提供了式(I)所示的化合物:
或其药学上可接受的盐、水合物或溶剂化物,其中:
X是O或S;
L是键,-O-,-S-,或-NR6-;
R1为烷基、环烷基、芳基、杂芳基或杂环基,其中R1任选地被一个或多个独立选自R7的取代基取代;
R6为-H或C1-6烷基;
R7为C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氧代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-SR9、-S(O)R9、-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9、-N(R6)C(O)NR10R11、-N(R6)S(O)2R9、-N(R6)S(O)2NR10R11,或-P(O)R12R13;
R9为-H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基或杂环基;
每个R10和R11独立地为-H、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基或杂环基,或者R10和R11与它们所连接的氮原子一起形成4-到12-员杂环基,杂环基任选地被一个或多个以下基团所取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN,-NO2,-NR10R11,-NR10C(=O)R9,-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9,-C(=O)NR10R11,-OC(=O)R9,-OC(=O)OR9,和-OC(=O)NR10R11;
每个R12和R13独立地为C1-6烷基,C1-6烷氧基、C3-8环烷基、芳基、杂芳基、杂环基,或R12和R13与它们所连接的磷原子一起形成4-到8-元杂环基,杂环基任选地被一个或多个以下基团所取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN,-NO2,-NR10R11,-NR10C(=O)R9,-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9,-C(=O)NR10R11,-OC(=O)R9,-OC(=O)OR9,和-OC(=O)NR10R11;
Het选自以下基团:
Ra、Rb和Rc各自独立地为-H、-D、卤代、CF3、CF2H、CH2F、CN、OR9或NR10R11;
R2为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、羟基、-CD2OH、-CN、-NO2、卤代烷基、三甲基硅氧基甲基,-C(O)R9,-C(O)OR9,-C(O)NR10R11,-OR9,-OC(O)R9,-OC(O)N R10R11,-SR9,-S(O)R9,-S(O)2R9,-S(O)(=NH)R10,-S(O)2NR10R11,-NR10R11,-N(R6)NR10R11,-N(R6)OR9,-N(R6)C(O)R9,-N(R6)C(O)R9,-N(R6)C(O)OR9,-N(R6)C(O)NR10R11,-N(R6)S(O)2R9,-N(R6)S(O)2NR10R11,或-P(O)R12R13,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基可选地被以下一个或多个基团所取代,卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-NO2、-NR10R11、-NR10C(=O)R9、-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9、-C(=O)NR10R11、-OC(=O)R9,、-OC(=O)OR9、和-OC(=O)NR10R11;
R3为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氰基、羟基、-CH2OH、-CD2OH、-OH、-CN、-NO2、卤代烷基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9,-OC(O)R9,-OC(O)NR10R11、-SR9,-S(O)R9,-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11、-NR10R11、-N(R6)NR10R11,-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9、-N(R6)C(O)NR10R11、-N(R6)S(O)2R9、-N(R6)S(O)2NR10R11,或-P(O)R12R13;
M是一个键,-O-,-S-,或-NR6-;
R6为-H或C1-6烷基;
R4为-H、-D、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基,杂芳基、杂环基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11,或-P(O)R12R13,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基,或杂环基任选地被一个或多个选自以下的基团取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-CD3、-NO2、-NR10R11、-NR10C(=O)R9、-NR10C(=O)NR10R11、-NR10C(=O)OR9、-NR10S(O)2R9、-OR9、-C(=O)R9、-C(=O)OR9、-C(=O)NR10R11、-OC(=O)R9、-OC(=O)OR9,和-OC(=O)NR10R11;和
R5为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、羟基、-CH2OH、-CD2OH、-CN或卤代烷基。
在各种实施方案中,L为键,R1为环烷基,其任选地被一个或多个选自以下的基团所取代:C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)R10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9和-N(R6)C(O)NR10R11。
在各种实施方案中,R2和R3中的每一个独立地为-H、卤代、烷基硫基、卤代烷基或烷基。在各种实施方案中,M是键、-O-或-NR6-;R4为-H、-D、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氰基、羟基、-C(O)R9、-C(O)NR10R11、-S(O)2R9、-S(O)(=NH)R10或-S(O)2NR10R11,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基,或杂环基任选地被选自卤代、羟基、烷基、烯基、炔基、卤代烷基、羟基烷基、-CN、-CD3、-NR10R11、-NR10S(O)2R9和-NR10C(=O)R9的一个或多个基团取代。
在另一实施方案中,提供了由式(II)所示的化合物:
其中R1、R2、R3、R4、R5、Ra、Rb、M和L如上文公式(I)所定义。
在各种实施方案中,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基硫基、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M是键,-O-、-S-或-NR6-;
R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙胺四乙酸乙酯、丙胺基乙基、甲氨基乙基、氨基烷基、甲氨基羰基甲基、烷氧基烷基、氮杂环丁烯基或氮杂环丁烯基甲基;R5为–H、烷基或卤代。
式(II)所示的非限制性示例化合物包括表1示例1-145的化合物。在特定实施方案中,该化合物选自以下组:实施例58、80、82、85、87、92、94、97、98、110、111、118、123、125、129和134的化合物。
在另一实施方案中,提供了由式(III)所示的化合物:
其中R1、R2、R3、R4、R5、Ra、Rb、M和L如上文公式(I)所定义。
在一些实施方案中,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙胺乙基或烷氧基烷基;R5为–H、烷基或卤代。
式(III)所示的非限制性示例化合物包括表1示例146-218的化合物。在特定实施方案中,化合物选自149、152、156、159、161-163、167、169、170、172-175、178、184、193、194、196、199和218的化合物。
在另一个实施方案中,提供了由式(IV)所示的化合物:
其中R1、R2、R3、R4、R5、Ra、Rb、M和L如上文公式(I)所定义。
在一些实施方案中,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙酰胺基乙基、丙胺基乙基、甲氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰胺基乙基、咪唑啉基乙基、二氧芳基、环丁基羰基氨基乙基、二氟乙酰胺基乙基、三氟乙酰胺基乙基、甲基硫代甲基、甲基硫代乙基、氮杂环丁烯基、氮杂环丁烯基甲基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰胺基)甲基、丙基-1,1,3,3,3-d6)氨基、四氢呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、异恶唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;R5为–H、烷基或卤代。
式(IV)的非限制性示例化合物包括表1的实施例219和220的化合物。
在另一个实施方案中,提供了一种由式(V)所示的化合物:
其中R1、R2、R3、R4、R5、Ra、Rb、M和L如上式(I)所定义。
在一些实施方案中,L为键,R1为环烷基,其任选地被选自C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9,和-N(R6)C(O)NR10R11中的一个或多个基团取代。在一些其他实施方案中,R1为环烷基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代。
式(V)所示的非限制性示例化合物包括表1示例221-445的化合物。
在一些实施方案中,R1为环丙基,其任选地被选自卤代、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基的一个或多个基团取代;R2为–H、烷基、烷基硫基、卤代烷基或卤代;R3为–H、烷基或卤代;M为键、-O-或-NR6-;R4为–H、卤代、烷基、单烷基氨基或二烷基氨基;R5为–H、烷基或卤代。非限制性示例化合物包括以下一种:
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;以及
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
在一些实施方案中,R1为环丙基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、单烷基氨基或二烷基胺基;以及R5为–H、烷基或卤代。非限制性示例化合物包括一种选自以下组的化合物:实施例258、261、265、266、269、272、275、280、288、291、293、296、297、300、304、306、310、318、320、324、327、329、330、332、334、336、341、345、349、353、356、358、359、361、366、371、372、374、390、391、393、404、405、408、410、414、417、419、422、423、425、426、428、430、433、434、436、439、441和445。
在一些实施方案中,R1为环丙基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键、-O-、-S-或-NR6-;R4为–H、卤代、烷基、烷基羰基、二烷基氨基碳基、氧吡咯烷基、羟基烷基、卤代烷基、卤代烯基、环烷基、吡啶基、单烷基氨基或二烷基氨基;R5为–H、烷基或卤代。非限制性示例化合物包括从实施例258、261、265、266、268、269、271-273 275、280、281、288、290、291、293、296-298、300、304、306、307、310、316、318、320、324、326、327、329、330-334、336、339、341、345、346、349、353、356、358、359、361-363、365-367、370-374、377-379、383、388、390、391、393、398、401、404-406、408-410、414、415、417、419、421-426、428、430、433、434、436、439、441和445。
在另一实施方案中,提供了由式(VI)所示的化合物:
其中R1、R2、R3、R4、R5、Ra、Rb、M和L如式(I)所定义。
在一些实施方案中,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键、-O-、-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烷基氨基烷基、卤代烷基羰基氨基烷基、烷基氨基烷基、羟基卤代烷基、卤代烯基、环烷基、氰基、氰基烷基、二甲氨基、二甲氨基乙基、甲氨基羰基、二甲氨基羰基、甲氨基氧乙基、氨基羰基、乙胺乙基、二烷基氨基环烷基,氨基环烷基、甲氨基环烷基、环烷基烷基、环烷基(羟基)烷基、环烷基酰胺烷基、环烷基氨基羰基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基羰基、烷基羰基、烷基酰胺烷基、烷氧基烷基、烯基、甲基磺酰胺基乙基、咪唑基乙基、二氧基、氮杂环丁烯基、氮杂环丁烯基甲基、四氢呋喃基、呋喃基、嘧啶基、吡啶基、吡咯基、卤代吡咯烷基、吡咯烷基、甲基吡咯基、异恶唑基、四唑烷基、三嗪基、甲基吡唑基或甲基吡唑基甲基;R5为–H、烷基或卤代。
(VI)所示的非限制性示例化合物包括表1实施例446-666的化合物。在特定实施方案中,该化合物选自实施例464、466、467、476、477、480、484、485、487、488、490-494、496、497、502-505、509、513、514、519-521、523-525、529-532、534、541、543、548、550、552、556-558、561-565、568-574、577、579、581、585、586、588、592、596-600、602、607、612、615、617-619、621、623、625、629、634、636-642、644、646、650-652、655-657和659-665。
在一个实施方案中,提供了一种药物组合物,其包含药学上可接受的载体或稀释剂和式(I)所示化合物或其药学上可接受的盐。
化合物的医疗用途以及使用该化合物进行治疗的方法
本发明提供了一种治疗患有与HPK1调节相关的疾病或病症的受试者的方法,包括:向有需要的受试者施用与治疗有效量的如权利要求1所述的化合物或其药学上可接受的盐。在一些实施方案中,与HPK1调节相关的疾病或病症是癌症、转移、炎症或包括自身免疫疾病的免疫疾病。
在一些其他实施方案中,该疾病为癌症、转移、炎症或自身免疫疾病。在特定实施方案中,癌症选自肿瘤癌、黑色素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病,包括但不限于膀胱癌、脑瘤、乳腺癌、宫颈癌、结直肠癌、食管癌、子宫内膜癌、肝细胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰腺癌、前列腺癌、肾癌和甲状腺癌、急性淋巴细胞白血病、急性髓系白血病、室管膜瘤、尤因肉瘤、胶质母细胞瘤、髓母细胞瘤、神经母细胞瘤、骨肉瘤、横纹肌肉瘤、横纹肌样癌和肾母细胞瘤。
在一些实施方案中,自身免疫疾病是炎症性肠病、艾迪生病、斑秃、强直性脊柱炎、抗磷脂综合征、溶血性贫血、自身免疫性肝炎、白塞氏病、伯杰病、大疱性类天疱疮、心肌病、腹腔积液、慢性疲劳免疫功能障碍综合征(CFIDS)、慢性炎性脱髓鞘性多发性神经病、Churg-Strauss综合征、瘢痕性类天疱疮、冷凝集素病、1型糖尿病、盘状狼疮、原发性混合冷球蛋白血症、Graves病、格林-巴利综合征、桥本甲状腺炎、甲状腺功能减退、自身免疫性淋巴增生综合征(ALPS)、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、青少年关节炎、扁平苔藓、红斑狼疮、梅尼埃病、混合结缔组织病、多发性硬化、重症肌无力、寻常天疱疮、恶性贫血、多软骨炎、自身免疫性多发性红斑综合征、风湿性多肌痛、多发性肌炎、皮肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、雷诺现象、雷特综合征、风湿热、类风湿性关节炎、结节病、硬皮病、干燥综合征、僵硬人综合征、大动脉炎、巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、或肉芽肿伴多血管炎。
在另一个实施方案中,提供了式(I)所示的化合物或其药学上可接受的盐用于制备用于在需要抑制HPK1活性的受试者中抑制HPK1活性的药物的用途。在一些实施方案中,所述用途包括癌症的治疗。
根据本发明的待治疗的合适的受试者包括哺乳动物受试者。根据本发明的哺乳动物包括但不限于人、犬、猫、牛、山羊、马、绵羊、猪、啮齿动物、兔类动物、灵长类等,并且包括子宫内的哺乳动物。受试者可以是任何性别,也可以处于任何发育阶段。在一实施方案中,根据本发明的待治疗的合适受试者是人。
本发明的化合物通常以治疗有效量施用。本发明的化合物可以通过任何适合的途径以适合于该途径的药物组合物的形式,并且以对于预期治疗有效的剂量来施用。有效剂量通常为单剂量或分剂量的每千克体重每天约0.001至约100mg,优选约0.01至约50mg/kg/天。根据治疗对象的年龄、种类和疾病或病症,低于该范围下限的剂量水平可能是合适的。在其他情况下,可以使用更大剂量而无有害副作用。大剂量也可以分为几个小剂量,以便全天服用。确定合适剂量的方法是本发明所属领域中所公知的。例如,可以使用《雷明顿:药学的科学与实践》,Mack Publishing Co.,第20版,2000年。
药物组合物、剂型和给药途径
为了治疗上述疾病或病症,本发明所述的化合物或其药学上可接受的盐可以如下方式施用:
口服给药
本发明的化合物可以口服给药,包括通过吞咽给药,使得该化合物进入胃肠道,或直接从口腔吸收到血流中(例如,颊或舌下给药)。用于口服的合适的组合物包括固体、液体、凝胶或粉末制剂,并且具有剂型,例如片剂、锭剂、胶囊、颗粒或粉末。用于口服的组合物可以配制成立即释放或调节释放,包括延迟释放或持续释放,任选地具有肠溶衣。液体制剂可以包括溶液、糖浆和悬浮液,它们可以用于软胶囊或硬胶囊中。这样的制剂可以包含药学上可接受的载体,例如水、乙醇、聚乙二醇、纤维素或油。该制剂还可以包含一种或多种乳化剂和/或助悬剂。
在片剂剂型中,存在的药物的量可以为剂型重量的约0.05%至约95%,更通常为约2%至约50%。另外,片剂可包含崩解剂,其占剂型重量的约0.5%至约35%,更通常为约2%至约25%。崩解剂的实例包括但不限于乳糖、淀粉、淀粉羟乙酸钠、交聚维酮、交联羧甲基纤维素钠、麦芽糊精或其混合物。
用于片剂的合适的润滑剂的量按重量计约0.1%至约5%,并且包括但不限于滑石、二氧化硅、硬脂酸、钙、锌或硬脂酸镁、硬脂富马酸钠等。
用于片剂的合适的粘合剂包括但不限于明胶、聚乙二醇、糖、树胶、淀粉、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素等。用于片剂的合适的稀释剂包括但不限于甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇、微晶纤维素和淀粉。
用于片剂中的合适的增溶剂的量按重量计可约0.1%至约3%,并且包括但不限于聚山梨酯、月桂基硫酸钠、十二烷基硫酸钠、碳酸亚丙酯、二甘醇单乙醚、二甲基异山梨醇酯、聚乙二醇(天然或氢化)蓖麻油、HCORTM(Nikkol)、油酸酯、GelucireTM、辛酸/辛酸甘油单酯/甘油二酯、山梨糖醇酐脂肪酸酯和Solutol HSTM。
肠胃外给药
本发明的化合物可以直接施用到血流,肌肉或内部器官中。肠胃外给药的合适方式包括静脉内,肌肉内,皮下动脉内,腹膜内,鞘内,颅内等。用于肠胃外给药的合适装置包括注射器(包括针头和无针头注射器)和输液方法。
用于肠胃外给药的组合物可以配制成立即或调节释放,包括延迟或持续释放。大多数肠胃外制剂是含有赋形剂的水溶液,包括盐、缓冲剂和等渗剂。肠胃外制剂也可以以脱水形式(例如通过冻干)或作为无菌非水溶液制备。这些制剂可以与合适的媒介物例如无菌水一起使用。增溶剂也可以用于制备肠胃外溶液。
经皮给药
本发明的化合物可以局部施用于皮肤或经皮地施用。用于该局部给药的制剂可以包括洗剂、溶液、乳膏、凝胶、水凝胶、软膏、泡沫、植入物、贴剂等。用于局部给药制剂的药学上可接受的载体可以包括水、酒精、矿物油、甘油、聚乙二醇等。局部或经皮给药也可以通过电穿孔、离子电渗疗法、超声透入疗法等进行。用于局部给药的组合物可以配制成立即释放或调释,包括延迟释放或持续释放。
联合疗法
根据本发明的药物组合物可以包含一种或多种另外的治疗剂,例如,以提高功效或减少副作用。因此,在一些实施方案中,药物组合物还包含一种或多种选自活性成分的其他治疗剂,所述活性成分可用于治疗或抑制直接或间接由HPK1介导的疾病。此类活性成分的示例包括但不限于治疗癌症、转移、炎症或自身免疫发病机制的药物。在一些实施方案中,使用抗PD-1剂、抗PD-L1剂或抗CTLA4剂施用式(I)所示化合物。
制备药物组合物的参考文献
用于制备用于治疗或预防疾病或病症的药物组合物的方法是本发明所属领域中众所周知的。例如,根据《药物赋形剂手册》(第7版)、《雷明顿:药学的科学与实践》(第20版)、《药学技术百科全书》(第3版)或《缓释控释药物输送系统》(1978年)可以选择药学上可接受的赋形剂、载体、添加剂等,然后将其与本发明的化合物混合以制备药物组合物。
本发明提供了一种通过抑制HPK1活性而具有各种药理作用的化合物,一种将该化合物作为有效剂的药物组合物,以及该化合物的医疗用途,特别是用于治疗由HPK1调节的疾病或病症,以及一种治疗或预防方法,该方法包括将所述化合物施用于需要这种治疗或预防的受试者。本发明的化合物及其药学上可接受的盐具有良好的安全性和对HPK1的高选择性,因此表现出作为药物的优异性能。
化合物制备
以下制备实施例说明了用于制备式(I)所示化合物的中间体化合物的制备。本文所述的新中间体化合物以及用于制备中间体化合物的合成方法代表本发明的实施方案。
中间体1A。1-(四氢-2H-吡喃-2-基)-5-(噻吩-2-基)-1H-吲唑-4-基三氟甲基磺酸盐
步骤1)3-溴-4-氯-5-氟-2-甲基苯胺
向3-溴-5-氟-2-甲基苯胺(50g,245mmol,1eq)在AcOH(100mL)的溶液中加入N-氯丁二酰亚胺(36g,270mmol,1.1eq)。将混合物在25℃下搅拌16小时。在真空下浓缩混合物,并用二氯甲烷(200mL*2)萃取残余物。用200mL饱和NaHCO3洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。得到为黑油的粗产物(66g,粗品)。
步骤2)4-溴-5-氯-6-氟-1H-吲唑
向3-溴-4-氯-5-氟-2-甲基苯胺(25.8g,108mmol,1eq)在AcOH(1.96L,0.05M),H2O(0.065L,1.5M)中的溶液中加入亚硝酸钠(8.96g,130mmol,1.2eq)。将混合物在25℃下搅拌16小时。在真空下浓缩混合物,用二氯甲烷(1L*2)萃取残余物。用饱和NaHCO3(1L)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。得到为棕色固体的粗产物(23.6g,粗品)。
步骤3)4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑
向4-溴-5-氯-6-氟-1H-吲唑(1.98g,7.97mmol,1eq)在THP(40mL)的溶液中加入3,4-二氢-2H-吡喃(2.18mL,23.9mmol,3eq)和对甲苯磺酸一水合物(300mg,1.59mmol,0.2eq)。将反应混合物在70℃下搅拌14小时。反应混合物用乙酸乙酯萃取并经硫酸镁干燥。通过柱色谱法(硅胶,Hex:乙酸乙酯=1:0至4:1)纯化有机残余物。得到4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑(1.51g,4.54mmol,57%产率)。
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.00(dd,J=9.3,1.1Hz,1H),5.85(dd,J=9.6,2.5Hz,1H),3.87(d,J=12.6Hz,1H),3.79-3.72(m,1H),2.38-2.30(m,1H),2.04-1.94(m,2H),1.77-1.55(m,3H)。
中间体1B。4-溴-5-氯-6-氟-7-碘-2-(四氢-2H-吡喃-2-基)-2H吲唑
步骤1)4-溴-5-氯-6-氟-7-碘-1H-吲唑
向4-溴-5-氯-6-氟-1H-吲唑(2g,8.02mmol)在硫酸(1.7mL)中的溶液中按比例加入N-碘代丁二酰亚胺(2.7g,12.03mmol)。将混合物在0℃下搅拌3小时。反应完成后,将混合物倒入冰水中,用固体NaOH淬火,然后用二氯甲烷萃取。在真空下浓缩合并的有机残余物。(2.99g,粗品)。
1H NMR(400MHz,DMSO-d6)δ13.91(s,1H),8.27(d,J=1.6Hz,1H)。
步骤2)4-溴-5-氯-6-氟-7-碘-2-(四氢-2H-吡喃-2-基)-2H吲唑
向4-溴-5-氯-6-氟-7-碘-1H-吲唑(2.99g,7.97mmol,1eq)在THF(40mL)的溶液中加入3,4-二氢-2H-吡喃(2.18mL,23.9mmol,3eq)和对甲苯磺酸一水合物(300mg,1.59mmol,0.2eq)。将反应混合物在60℃下搅拌16小时。反应混合物用乙酸乙酯萃取并经硫酸镁干燥。通过柱色谱法(硅胶,Hex:乙酸乙酯=1:0至4:1)纯化有机残余物。得到4-溴-5-氯-6-氟-7-碘-2-(四氢-2H-吡喃-2-基)-2H吲唑(1.64g,7.97mmol,60.7%产率)。
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),5.80(dd,J=9.9,2.7Hz,1H),5.66(s,1H),4.02(t,J=6.6Hz,1H),3.85-3.70(m,1H),2.33-2.21(m,1H),2.08-1.91(m,2H),1.79-1.45(m,4H).
中间体1C。4-溴-5-氯-6-氟-2-(四氢-2H-吡喃-2-基)-2H-吲唑-7-胺
步骤1)4-溴-5-氯-6-氟-7-硝基-1H-吲唑
向HNO3(12.63g,200.43mmol,9.02mL,5eq)在H2SO4(50mL)中的混合物中在0℃下慢慢搅拌加入4-溴-5-氯-6-氟-1H-吲唑(10g,40.09mmol,1eq)。添加完成后,将混合物在0℃下搅拌2小时。TLC(石油醚:乙酸乙酯=3:1)显示所有反应物均已消耗,并出现一个新的主要点。将混合物倒入冰水中,用乙酸乙酯(50mL*3)萃取混合物,合并的有机相经Na2SO4干燥,过滤,滤液浓缩,得到为黄色固体的4-溴-5-氯-6-氟-7-硝基-1H-吲唑(12g,粗品)。
步骤2)4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(2.34g,7.97mmol,1eq)在THF(40mL)的溶液中加入3,4-二氢-2H-吡喃(2.18mL,23.9mmol,3eq)和对甲苯磺酸一水合物(300mg,1.59mmol,0.2eq)。将反应混合物在60℃下搅拌14小时。反应混合物用乙酸乙酯萃取并经硫酸镁干燥。通过柱色谱法(硅胶,Hex:乙酸乙酯=1:0至4:1)纯化有机残余物。得到4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑(1.65g,4.35mmol,54.7%产率)。
步骤3)4-溴-5-氯-6-氟-2-(四氢-2H-吡喃-2-基)-2H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑(600mg,1.58mmol,1eq)在EtOh(5mL)和H2O(5mL)中的溶液中加入NH4Cl(508.66mg,9.51mmol,6eq)和Fe(531.04mg,9.51mmol,6eq),然后将反应混合物在80℃下搅拌1小时。过滤反应混合物,用乙酸乙酯(20mL)稀释滤液,用水(20mL*2)洗涤混合物,然后有机层Na2SO4干燥,减压过滤和浓缩,得到残余物。通过prep-TLC(SiO2,石油醚/乙酸乙酯=1:1)纯化残余物。得到为黄色油的4-溴-5-氯-6-氟-2-(四氢-2H-吡喃-2-基)-2H-吲唑-7-胺(390mg,1.12mmol,70.59%产率)。
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),5.85(br s,2H),5.71(br d,J=8.0Hz,1H),4.00(br d,J=11.3Hz,1H),3.77-3.59(m,1H),2.29-2.17(m,1H),2.10-1.91(m,2H),1.78-1.54(m,3H)。
中间1D。4-溴-5-氯-6-氟-N,N-二甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺
步骤1)4-溴-5-氯-6-氟-7-硝基-1H-吲唑
在-15℃下,向中间体1A(900mg,3.61mmol,1eq)在H2SO4(10mL)(98%纯度)中的溶液逐滴加入HNO3(419.69mg,4.33mmol,299.78uL,1.2eq)(65%纯度),然后将反应混合物在0℃下搅拌2小时。将反应混合物缓慢倒入冰水(20mL)中,然后使用饱和NaOH水溶液将混合物的pH值调节至pH=7,然后用乙酸乙酯(30mL*2)萃取混合物,合并的有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。得到为黄色固体的4-溴-5-氯-6-氟-7-硝基-1H-吲唑(900mg,未加工)。
1H NMR(400MHz,DMSO-d6)δ14.36(br s,1H),8.37(br s,1H)。
步骤2)4-溴-5-氯-6-氟-7-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(900mg,3.06mmol,1eq)(未加工)在DCM(10mL)的溶液中加入TsOH.H2O(58.14mg,305.64umol,0.1eq)和DHP(771.27mg,9.17mmol,838.34uL,3eq),然后将反应混合物在20℃下搅拌2小时。用二氯甲烷(20mL)稀释反应混合物,并用饱和NaHCO3水溶液(15mL*2)洗涤混合物,有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=40/1至25:1,4-溴-5-氯-6-氟-7-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑在石油醚/乙酸乙酯=40/1时出现,4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑在石油醚/乙酸乙酯=25/1时出现)纯化残余物。得到为棕色固体的4-溴-5-氯-6-氟-7-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑(200mg,528.29umol,17.28%产率)。得到为黄色固体的4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑(600mg,1.58mmol,51.85%产率)。
4-溴-5-氯-6-氟-7-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑
1HNMR(400MHz,DMSO-d6)δ8.43(s,1H),5.50(dd,J=2.8,7.8Hz,1H),3.45-3.38(m,2H),2.35-2.27(m,1H),2.23-2.14(m,1H),1.92(td,J=4.6,13.6Hz,1H),1.68(ddt,J=4.0,10.1,13.9Hz,1H),1.59-1.36(m,2H)。
4-溴-5-氯-6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-2H吲唑
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),5.86(dd,J=2.7,9.7Hz,1H),4.08-3.96(m,1H),3.81-3.68(m,1H),2.28-2.14(m,1H),2.14-2.02(m,1H),2.02-1.89(m,1H),1.78-1.67(m,1H),1.64-1.56(m,2H)。
步骤3)4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑(200mg,528.29umol,1eq)在EtOH(5mL)和H2O(5mL)的溶液中加入NH4Cl(169.55mg,3.17mmol,6eq)和Fe(177.03mg,3.17mmol,6eq),然后将反应混合物在80℃下搅拌2小时。过滤反应混合物,浓缩滤液以去除EtOH,然后用乙酸乙酯(20mL)稀释混合物,用水(20mL*2)洗涤混合物,然后经Na2SO4干燥有机层,有机层减压过滤和浓缩,得到残余物。得到为黄色固体的4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺(140mg,未加工)。
步骤4)4-溴-5-氯-6-氟-N,N-二甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺
在0℃下在N2下,向4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺(120mg,344.24μmol,1eq)在THF(5mL)的溶液中按比例加入NaH(34.42mg,860.59μmol,60%纯度,2.5eq),然后将混合物在0℃下在N2下搅拌30分钟,然后逐滴加入MeI(293.16mg,2.06mmol,128.58uL,6eq),然后反应混合物在N2下在20℃下搅拌12小时。将反应混合物倒入饱和NH4Cl水溶液(20mL),然后用乙酸乙酯(20mL*2)萃取混合物,将合并的有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。通过prep-TLC(SiO2,石油醚/乙酸乙酯=5:1)纯化残余物。得到为黄色油的中间体1E(30mg,78.06μmol,22.68%产率,98%纯度)。
中间1E。4-溴-5-氯-6-氟-N-异丙基-2-(四氢-2H-吡喃-2-基)-2H-吲唑-7-胺
向中间体1B(100mg,0.218mmol,1eq)在2-甲基-2-丁醇(1.09mL)的溶液中加入Xantphos Pd G3(21mg,21.8μmol,0.1eq)和Cs2CO3(142mg,0.436mmol,2.0eq)。将混合物脱气并用氮气吹扫3次,接着加入丙烷-2-胺(0.19mL,2.18mmol,10eq)。将混合物在90℃下在密封管中搅拌3小时。用H2O(40mL)稀释反应混合物,然后用DCM(50mL*3)萃取混合物。合并的有机层经Na2SO4干燥,过滤,滤液在真空中浓缩,得到残余物。残余物通过硅胶色谱法纯化(产物以己烷/乙酸乙酯=10/1的浓度产生)纯化残余物,得到为米色固体的中间体1E(47mg,0.120mmol,55%产率)。
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),5.74(dd,J=9.6,2.5Hz,1H),5.29(dd,J=9.9,3.3Hz,1H),4.63-4.57(m,1H),3.99(d,J=11.0Hz,1H),3.74-3.68(m,1H),2.23-2.17(m,1H),2.05-1.95(m,2H),1.74-1.57(m,3H),1.23-1.18(m,6H)。
中间体1F。4-溴-5-氯-6-氟-N-异丙基-N-甲基-2-(四氢-2H-吡喃-2-基)-2H-吲唑-7-胺
向中间体1E(600mg,1.54mmol,1.0eq)在甲醇(7.7mL)的溶液中加入甲醛(0.572mL,7.68mmol,5.0eq)和乙酸(88μL,1.54mmol,1.0eq)。将混合物在室温下搅拌10分钟。加入氰基硼氢化钠(290mg,4.61mmol,3.0eq),然后将混合物在室温下搅拌16小时。反应混合物用H2O淬火,并用乙酸乙酯(150mL*3)萃取。合并的有机层经Na2SO4干燥,过滤,滤液在真空中浓缩,得到残余物。通过硅胶色谱法(产物在己烷/乙酸乙酯=100/4时产生)纯化残余物,得到为棕色油的中间体1F(292mg,0.722mmol,47%产率)。
1HNMR(400MHz,DMSO-d6)δ8.51(s,1H),5.75(dd,J=9.3,2.7Hz,1H),4.14-4.05(m,1H),4.00-3.93(m,1H),3.78-3.67(m,1H),2.92(d,J=4.4Hz,3H),2.23-2.20(m,1H),2.05-1.95(m,3H),1.75-1.60(m,3H),1.17(d,J=6,6Hz,6H)。
中间体1G。4-溴-5-氯-N-乙基-6-氟-N-甲基-1H-吲唑-7-胺
步骤1)4-溴-5-氯-6-氟-1H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(12g,40.75mmol,1eq)在EtOH(100mL)和H2O(40mL)的溶液中加入Fe(6.83g,122.26mmol,3eq)和NH4Cl(6.54g,122.26mmol,3eq)。将反应混合物加热至80℃并反应2小时。反应混合物通过硅藻土滤饼过滤,滤液浓缩得到粗产物。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=20/1至3/1)纯化残余物。得到为黄色固体的4-溴-5-氯-6-氟-1H-吲唑-7-胺(5g,18.90mmol,46.39%产率)。
步骤2)N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酰胺
向4-溴-5-氯-6-氟-1H-吲唑-7-胺(3g,11.34mmol,1eq)在AcOH(30mL)的溶液中加入Ac2O(1.39g,13.61mmol,1.27mL,1.2eq),将反应混合物加热至80℃并反应3小时。在真空下除去溶剂。通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1至4/1)纯化残余物,得到为黄色固体的N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酰胺(3g,9.79mmol,86.29%产率)。
步骤3)4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺
在0℃的N2下,向LAH(520mg,13.70mmol,1.5eq)在THF(50mL)的溶液中逐滴加入N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酰胺(2.8g,9.13mmol,1eq)THF,添加完成后,使反应混合物升温至25℃,并反应16小时。将混合物倒入水(500mL)中,用乙酸乙酯(100mL*2)萃取,合并的有机相经Na2SO4干燥,过滤并浓缩滤液以得到粗产物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1至2/1)纯化残余物,得到为黄色固体的4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺(1g,3.42mmol,37.42%产率)。
步骤4)4-溴-5-氯-N-乙基-6-氟-N-甲基-1H-吲唑-7-胺
向4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺(1.4g,4.79mmol,1eq)和HCHO(718.48mg,23.93mmol,659.16uL,5eq)在甲醇(50mL)中的溶液中加入NaBH3CN(902.21mg,14.36mmol,3eq)和AcOH(287.38mg,4.79mmol,273.70uL,1eq)。将反应混合物在25℃下搅拌16小时。在真空下除去溶剂。通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1至5/1)纯化残余物,得到为白色固体的4-溴-5-氯-N-乙基-6-氟-N-甲基-1H-吲唑-7-胺(1.4g,4.57mmol,95.42%产率)。
中间体1H。4-溴-5-氯-6-氟-7-甲基-1-(四氢-2H-吡喃-2-基)-1H吲唑
在-78℃下,向4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.5g,1.50mmol,1eq)在THF(10mL)的溶液中逐滴加入LDA(2M,1.87mL,2.5eq)。添加后,将混合物在-78℃下搅拌2个半小时,然后在-78℃下逐滴加入MeI(319.12mg,2.25mmol,139.97uL,1.5eq)。将所得混合物在20℃下搅拌16小时。将混合物倒入饱和NH4Cl中,并用EA20mL萃取。浓缩有机层。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=20/1至10/1)纯化残余物。我们得到了所需的产物4-溴-5-氯-6-氟-7-甲基-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.38g,1.09mmol,72.93%产率),所得产物为白色固体。
中间体1I。4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺
步骤1)4-溴-6-氟-7-硝基-1H-吲唑
在0℃下向4-溴-6-氟-1H-吲唑(10g,46.51mmol,1eq)在H2SO4(80mL)(98%纯度)的溶液中分批加入KNO3(4.70g,46.51mmol,1eq),然后将混合物在0℃下搅拌1小时。然后将反应混合物倒入冰水(200ml)中,并用乙酸乙酯(100ml*2)萃取混合物,用饱和NaHCO3水溶液(100ml*2)和盐水(100ml)洗涤合并的有机层,有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。通过硅胶色谱法(200-300目硅胶,石油醚/乙酸乙酯=15/1至1/1,产物4-溴-6-氟-7-硝基-1H-吲唑在石油醚/乙酸乙酯=8/1时出现)纯化残余物,得到为黄色固体和粗品4-溴-6-氟-7-硝基-1H-吲唑(2.7g,10.38mmol,22.32%)。通过MPLC(石油醚/乙酸乙酯)纯化粗产物,得到为黄色固体的4-溴-6-氟-7-硝基-1H-吲唑(3.57g,13.73mmol,29.52%产率)。
步骤2)4-溴-6-氟-5-碘-7-硝基-1H-吲唑
在25℃下,向4-溴-6-氟-7-硝基-1H-吲唑(2.7g,10.38mmol,1eq)在H2SO4(30mL)的溶液中加入NIS(7.01g,31.15mmol,3eq)。将混合物在50℃下搅拌反应16小时。反应混合物用冰水(50mL)淬火。然后用乙酸乙酯(50mL*3)萃取混合物。用Na2SO3水溶液(20mL*2)、NaHCO3水溶液(20mL*2)和盐水(20mL)洗涤合并的有机层,合并的有机层用硫酸钠干燥,过滤,滤液在真空中浓缩,得到为黄色固体的4-溴-6-氟-5-碘-7-硝基-1H-吲唑(3.4g,8.81mmol,84.85%)。
1H NMR(400MHz,DMSO-d6)δ14.28(br s,1H),8.30(s,1H)。
步骤3)4-溴-6-氟-5-碘-1H-吲唑-7-胺
向4-溴-6-氟-5-碘-7-硝基-1H-吲唑(3.4g,8.81mmol,1eq)在EtOH(50mL)和水(25mL)的溶液中加入NH4Cl(2.83g,52.86mmol,6eq),然后在60℃下分批加入Fe(2.95g,52.86mmol,6eq)。将混合物在80℃下搅拌1小时。反应混合物在仍热时通过硅藻土过滤。然后滤液在真空中浓缩以去除EtOH。所得水相用乙酸乙酯(50mL*2)萃取。用盐水(50mL)冲洗合并的有机层,经硫酸钠干燥,过滤,滤液在真空中浓缩,得到残余物。通过硅胶色谱法(MPLC,石油醚/乙酸乙酯=5/1至2/1,在石油醚/乙酸乙酯=2/1时产生产物)纯化残余物,得到为灰色固体的4-溴-6-氟-5-碘-1H-吲唑-7-胺(2.2g,6.18mmol,70.16%产率)。
1H NMR(400MHz,DMSO-d6)δ13.09(br s,1H),7.86(d,J=1.7Hz,1H),5.62(s,2H)。
步骤4)4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺
向4-溴-6-氟-5-碘-1H-吲唑-7-胺(2.2g,6.18mmol,1eq)在MeOH(50mL)的溶液中加入AcOH(1.11g,18.54mmol,1.06mL,3eq)、HCHO(5.02g,61.81mmol,4.60mL,10eq),然后在40℃下分批加入NaBH3CN(3.88g,61.81mmol,10eq)。释放气体并升高温度。将悬浮液在25℃下搅拌16小时。将反应混合物倒入水中(50mL),然后将混合物浓缩以除去MeOH,然后用乙酸乙酯(50mL*2)萃取混合物,并用盐水(50mL)洗涤合并的有机层,合并的有机层经硫酸钠干燥,过滤并减压浓缩,得到残余物。通过硅胶色谱法(200-300目硅胶,石油醚/乙酸乙酯=15/1至8/1,产物在石油醚/乙酸乙酯=8/1时产生)纯化残余物,得到为灰白色固体的4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺(2.05g,5.34mmol,86.37%产率)。
步骤5)4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺
将4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺(1.2g,3.13mmol,1eq),NaSMe(328.56mg,4.69mmol,1.5eq),Xantphos(361.65mg,625.02umol,0.2eq),K2CO3(1.30g,9.38mmol,3eq),二恶烷(20mL)和Pd2(dba)3(286.17mg,312.51umol,0.1eq)依次加入到装有磁性搅拌棒的100mL瓶中。将瓶子排空并用氮气回填。然后将混合物在氮气气氛下在90℃下搅拌16小时。通过硅胶色谱法(200-300目硅胶,石油醚/乙酸乙酯=20/1至8/1,产物在石油醚/乙酸乙酯=10/1时产生)纯化残余物,得到为橙色固体的4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺(540mg,1.78mmol,56.81%)。
1H NMR(400MHz,DMSO-d6)δ13.59(br s,1H),8.00(d,J=1.6Hz,1H),2.91(d,J=2.4Hz,6H),2.39(s,3H)。
中间体1J。4-溴-6-氟-N,N-二甲基-5-(三氟甲基)-1H-吲唑-7-胺
向4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺(1.0g,2.61mmol,1eq)和2,2-二氟-2-(氟磺酰基)乙酸甲酯(1.00g,5.22mmol,664.45uL,2eq)在DMF(10mL)的溶液中加入CuI(994.63mg,5.22mmol,2eq)。在氮气气氛下,将混合物在100℃下搅拌6小时。过滤反应混合物,用50mL水稀释滤液,并用乙酸乙酯(50mL*2)萃取。用盐水(50mL*3)洗涤合并的有机层,经无水Na2SO4干燥,过滤,并减压浓缩滤液,得到残余物。通过硅胶柱色谱法(石油醚:乙酸乙酯=1:0至10:1)纯化残余物。得到为黄色固体的4-溴-6-氟-N,N-二甲基-5-(三氟甲基)-1H-吲唑-7-胺(502mg,1.54mmol,58.91%产率)。
中间体1K。4-溴-5-乙基-6-氟-1H-吲唑
步骤1)4-溴-5-乙基-6-氟-2-三苯基-2H-吲唑
在-78℃下在N2气氛下,向二异丙胺(132.75mg,1.31mmol,185.41uL,1.2eq)在THF(5mL)的溶液中缓慢加入n-BuLi(2.5M,481.04uL,1.1eq),然后将4-溴-6-氟-2-三苯基-2H-吲唑(500mg,1.09mmol,1eq)在THF(2mL)溶液逐滴加入到该溶液中。将混合物在-78℃下搅拌半小时后,向混合物中加入THF(2mL)中的EtI(204.62mg,1.31mmol,104.93uL,1.2eq)溶液,并将溶液加热至15℃并在N2气氛下搅拌2小时。通过在15℃下添加3mL饱和NH4Cl水溶液使反应混合物淬火,用20mL水稀释混合物并用乙酸乙酯(30mL*2)萃取。用盐水(30ml*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤,并减压浓缩滤液,得到残余物。得到为黄色固体的4-溴-5-乙基-6-氟-2-三苯基-2H-吲唑(500mg,粗品)。
步骤2)4-溴-5-乙基-6-氟-1H-吲唑
向4-溴-5-乙基-6-氟-2-三苯基-2H-吲唑(500mg,1.03mmol,1eq)在DCM(6mL)的溶液中加入TFA(3.08g,27.01mmol,2.00mL,26.22eq)。将混合物在15℃下搅拌4小时。用饱和NaHCO3水溶液将反应混合物pH调节至7,并用二氯甲烷(30mL*2)萃取混合物。用盐水(30ml*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤,并减压浓缩滤液,得到残余物。通过prep HPLC(柱:Phenomenex luna C18 150*40mm*15um;流动相:[水(0.1%TFA)-ACN];B%:40%-70%,10min)纯化残余物。在减压下浓缩该部分以去除ACN,用饱和NaHCO3水溶液将水溶液pH调节至7。水溶液用乙酸乙酯(10ml*2)萃取。用盐水(10mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤,并减压浓缩滤液,得到产物。得到为黄色固体的4-溴-5-乙基-6-氟-1H-吲唑(70mg,287.98μmol,27.96%产率)。
1H NMR(400MHz,DMSO-d6)δ13.39(br s,1H),8.01-7.98(m,1H),7.41(d,J=9.9Hz,1H),2.83(dq,J=2.4,7.5Hz,2H),1.14(t,J=7.5Hz,3H)。
中间体1L。4-溴-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺
步骤1)6-氟-5-硝基-1H-吲唑
在-15℃下,向6-氟-1H-吲唑(4.4g,32.32mmol,1eq)在H2SO4(30mL)的溶液中逐滴加入HNO3(2.44g,38.79mmol,1.75mL,1.2eq),将反应混合物在0℃下搅拌2小时。将反应混合物缓慢倒入冰水(100mL)中,然后用乙酸乙酯(100mL*2)萃取混合物,将合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到为黄色固体的6-氟-5-硝基-1H-吲唑(5.4g,粗品)。
步骤2)6-氟-5-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑
向6-氟-5-硝基-1H-吲唑(4.9g,27.05mmol,1eq)(粗品)在DCM(50mL)的混合物中加入DHP(6.83g,81.16mmol,7.42mL,3eq)和TsOH.H2O(514.60mg,2.71mmol,0.1eq),并将反应混合物在15℃下搅拌1小时。将反应混合物倒入饱和NaHCO3溶液(100mL),然后用二氯甲烷(50mL*2)萃取混合物,将合并的有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1至15:1)纯化残余物。得到为黄色固体的6-氟-5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(3g,11.31mmol,41.81%产率)。
1H NMR(400MHz,DMSO-d6)δ8.78(d,J=7.3Hz,1H),8.41(s,1H),7.97(d,J=12.1Hz,1H),5.90(dd,J=2.1,9.7Hz,1H),3.94-3.85(m,1H),3.82-3.72(m,1H),2.43-2.28(m,1H),2.10-1.93(m,2H),1.82-1.34(m,3H)。
步骤3)6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺
在N2气氛下,向6-氟-5-硝基-1-(四氢-2H-吡喃-2-基)-1H吲唑(2.9g,10.93mmol,1eq)在MeOH(30mL)的溶液中加入湿Pd/C(300mg,10%纯度)。将悬浮液脱气并用H2吹扫3次。将混合物在15℃下在H2(15Psi)下搅拌4小时。过滤反应混合物,并减压浓缩滤液,得到残余物。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=15/1至8:1)纯化残余物。得到为砖红色固体的6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺(1.5g,5.87mmol,53.65%产率,92%纯度)。
1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.43(d,J=11.6Hz,1H),6.98(d,J=8.6Hz,1H),5.66(dd,J=2.3,9.7Hz,1H),4.91(s,2H),3.85(br d,J=12.1Hz,1H),3.77-3.62(m,1H),2.42-2.27(m,1H),2.07-1.96(m,1H),1.95-1.86(m,1H),1.76-1.63(m,1H),1.59-1.51(m,2H);LCMS(电喷雾)m/z 236.1(M+H)+。
步骤4)4-溴-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺
在0℃下,向6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺(1.45g,5.67mmol,1eq)在MeCN(10mL)的溶液中分批加入NBS(1.21g,6.80mmol,1.2eq),将混合物在0℃下搅拌2小时。将反应混合物浓缩得到残余物。然后将残余物溶解在乙酸乙酯(30ml)中,并用盐水(15ml*2)洗涤混合物,有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=20/1)纯化残余物。得到为棕色固体的4-溴-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-胺(1.3g,4.14mmol,72.98%产率)。
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.60(d,J=10.6Hz,1H),5.71(dd,J=2.5,9.6Hz,1H),5.15(s,2H),3.88-3.82(m,1H),3.76-3.68(m,1H),2.36-2.27(m,1H),2.02(brdd,J=4.6,8.5Hz,1H),1.96-1.90(m,1H),1.76-1.65(m,1H),1.60-1.52(m,2H)。
中间1M。3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊烷-1-醇
步骤1)4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-碳醛
向中间体1A(3g,8.99mmol,1eq)的THF(60mL)的混合物中,在-78℃的氮气条件下逐滴加入LDA(2M,17.99mL,4eq)。将混合物在-78℃下搅拌1小时。然后,在-78℃下逐滴加入THF(8mL)中的HCO2Et(3.17g,35.97mmol,3.52mL,4eq),然后将混合物在-78℃下搅拌2小时。通过在-78℃下添加饱和NH4Cl溶液(20mL)使反应混合物淬火,然后用EA(30mL*3)萃取。用盐水(30ml*2)清洗合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=30/1至20/1)纯化残余物。得到为灰白色固体的4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-碳醛(2.78g,7.69mmol,85.49%产率)。
1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.35(s,1H),6.09(dd,J=2.6,8.9Hz,1H),3.71-3.63(m,1H),3.63-3.52(m,1H),2.42-2.30(m,1H),2.21-2.10(m,1H),2.07-1.95(m,1H),1.77-1.63(m,2H),1.60-1.40(m,2H);LCMS(电喷雾)m/z 278.9(M+H)+。
步骤2)1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)但-3-烯-1-醇
向4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-碳醛(2.2g,6.08mmol,1eq)在THF(60mL)的混合物中,在0℃下N2下逐滴加入烯丙基溴化镁(1M,9.13mL,1.5eq)。将混合物在0℃下搅拌2小时。通过在0℃下添加饱和NH4Cl溶液(20mL)使反应混合物淬火,然后用EA(30mL*3)萃取。用盐水(30ml*2)清洗合并的有机层,合并的有机层经无水Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1至5/1)纯化残余物。得到为无色油的1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)但-3-烯-1-醇(2g,4.95mmol,81.43%产率)。
1H NMR(400MHz,DMSO-d6)δ8.25-8.21(m,1H),8.20-8.18(m,1H),6.61(br d,J=9.0Hz,1H),6.23(d,J=4.0Hz,1H),6.18(br d,J=8.3Hz,1H),5.95(d,J=5.0Hz,1H),5.90-5.75(m,2H),5.36(dt,J=4.3,7.5Hz,1H),5.30(td,J=5.9,7.9Hz,1H),5.10-4.97(m,4H),3.97(br d,J=11.5Hz,1H),3.89(br d,J=11.3Hz,1H),3.69-3.55(m,2H),2.87-2.74(m,2H),2.70-2.55(m,4H),2.06(br d,J=10.8Hz,3H),1.96-1.87(m,1H),0.90-0.78(m,1H);LCMS(电喷雾)m/z 302.9(M+H)+。
步骤3)4-溴-7-(3-溴环戊基)-5-氯-6-氟-1H-吲唑
在-20℃下,在氮气下,向1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)但-3-烯-1-醇(2g,4.95mmol,1eq)在DCM(20mL)的混合物中加入Br2(1.19g,7.43mmol,383.11ul,1.5eq)。将混合物在-10℃下搅拌3小时。通过添加Na2SO3溶液(30mL)使混合物淬火,然后用DCM(30mL)稀释。用Na2SO3溶液(30mL*2)清洗有机层,有机层经无水Na2SO4干燥,过滤并浓缩,得到残余物残。将残余物溶解在MeOH(15mL)中,然后加入K2CO3(2.05g,14.86mmol,3eq),并将所得混合物在20℃下搅拌16小时。通过添加水(20mL)使反应停止,并用EA(30mL*3)萃取,经Na2SO4干燥,过滤和浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1至3:1)纯化残余物。粗产物通过反相高效液相色谱(0.1%FA条件)纯化。得到为白色固体的4-溴-7-(3-溴环戊基)-5-氯-6-氟-1H-吲唑(300mg,752.91μmol,15.20%产率)。
1H NMR(400MHz,DMSO-d6)δ13.44-13.37(m,2H),8.14-8.11(m,2H),5.71-5.67(m,1H),5.44(dt,J=1.2,7.5Hz,1H),4.97(s,1H),4.83-4.76(m,2H),4.47(dd,J=3.7,10.1Hz,1H),4.22(dd,J=5.5,10.1Hz,1H),4.15(dd,J=2.3,10.6Hz,1H),3.20-3.13(m,1H),2.69-2.64(m,1H),2.34-2.27(m,2H);LCMS(电喷雾)m/z 398.8(M+H)+.
步骤4)3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊基乙酸酯
在20℃下,在氮气下,向4-溴-7-(3-溴环戊基)-5-氯-6-氟-1H-吲唑(100mg,250.97umol,1eq)在DMSO(2mL)的混合物中一次加入KOAc(73.89mg,752.91umol,3eq)。然后将混合物加热至70℃并搅拌3小时。通过添加水(15ml)使反应停止,然后用EA(20ml*3)萃取,用盐水(20ml*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并浓缩,得到残余物。3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊基乙酸酯(100mg,粗品,棕色油)无需进一步纯化便可直接用于下一步中。
LCMS(电喷雾)m/z 378.8(m+H)+。
步骤5)3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊烷-1-醇
在20℃下,在氮气下,向3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊基乙酸酯(80mg,211.87umol,1eq)在MeOH(4mL)和水(0.8mL)的混合物中一次加入K2CO3(442.15mg,3.20mmol,15.1eq)。将混合物在20℃下搅拌2小时。通过在20℃下加入水(15mL)使反应混合物停止,然后用乙酸乙酯(20mL*3)萃取。用盐水(20mL*1)清洗合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=3/1至1/2)纯化残余物。得到白色固体的3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊烷-1-醇(50mg,149.01μmol,70.33%产率)。
LCMS(电喷雾)m/z 336.9(m+H)+。
中间体1N。4-溴-6-氟-N-异丙基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
步骤1)5-氟-2-碘-4-(三氟甲基)苯胺
在15℃下,向3-氟-4-(三氟甲基)苯胺(4g,22.33mmol,1eq)在MeCN(40mL)的溶液中加入NIS(5.53g,24.57mmol,1.1eq),然后将反应混合物在15℃下搅拌15小时。用水(100mL)稀释反应混合物,并用EtOAc(100mL*3)萃取混合物。合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。得到为棕色油的5-氟-2-碘-4-(三氟甲基)苯胺(5.6g,粗品)。
LCMS(电喷雾)m/z 305.9(m+H)+。
步骤2)5-氟-2-甲基-4-(三氟甲基)苯胺
在15℃下,向5-氟-2-碘-4-(三氟甲基)苯胺(6.0g,19.67mmol,1eq)和2,4,6-三甲基-1,3,5,2,4,6-三氧杂核糖烷(8.82g,29.51mmol,9.82mL,42%纯度,1.5eq)在DME(60mL)的溶液中加入Pd(PPh3)4(1.14g,983.57umol,0.05eq)和K2CO3(8.16g,59.01mmol,3eq),然后将反应混合物在100℃下搅拌60小时。反应混合物在减压下浓缩以提供残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=5/1至3/1,石油醚/乙酸乙酯=2:1,Rf=0.3)纯化残余物。得到为黄色油的5-氟-2-甲基-4-(三氟甲基)苯胺(1.6g,4.06mmol,20.64%产率,49%纯度)。
LCMS(电喷雾)m/z 194.1.9(m+H)+。
步骤3)6-氟-5-(三氟甲基)-1H吲唑
在0℃下,向5-氟-2-甲基-4-(三氟甲基)苯胺(1g,5.18mmol,1eq)在AcOH(15ml)的溶液中加入NaNO2(357.25mg,5.18mmol,1eq)和水(3ml),然后将反应混合物在15℃下搅拌2小时。通过在20℃下加入水(60mL)使反应停止,并使用EtOAc(50mL*3)萃取所得混合物。用水(50mL*3)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1至5/1,石油醚/乙酸乙酯=3:1,Rf=0.5)纯化残余物。得到为黄色固体的6-氟-5-(三氟甲基)-1H吲唑(500mg,2.45mmol,产率47.31%)。
LCMS(电喷雾)m/z 205.2(m+H)+。
步骤4)6-氟-7-硝基-5-(三氟甲基)-1H吲唑
在0℃下,向6-氟-5-(三氟甲基)-1H吲唑(500mg,2.45mmol,1eq)在H2SO4(5mL,95%纯度)的溶液中加入KNO3(249mg,2.46mmol,1.01eq),然后将反应混合物在15℃下搅拌15小时。用水(100mL)稀释反应混合物,并用乙酸乙酯(50mL*2)萃取。用饱和碳酸氢钠溶液处理合并的有机层,直到pH=7,经Na2SO4干燥,减压过滤和浓缩,得到残余物。得到黄色固体的6-氟-7-硝基-5-(三氟甲基)-1H吲唑(500mg)。
LCMS(电喷雾)m/z 250.2(m+H)+。
步骤5)6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H吲唑
在0℃下,向6-氟-7-硝基-5-(三氟甲基)-1H吲唑(500mg,2.01mmol,1eq)在THF(10mL)的溶液中加入PPTS(50.44mg,200.71umol,0.1eq)和DHP(844.13mg,10.04mmol,917.53uL,5eq)。然后将反应混合物在60℃下搅拌15小时。用溶剂H2O(50mL)稀释反应混合物,并用EtOAc(50mL*3)萃取。用H2O(50mL*3)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。得到为黄色油的6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H吲唑(1g,粗品)。
步骤6)6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在0℃下,向6-氟-7-硝基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H吲唑(800mg,2.40mmol,1eq)和H2O(2mL)在EtOH(10mL)的溶液中加入NH4Cl(642.08mg,12.00mmol,5eq)和Fe(268.13mg,4.80mmol,2eq),然后在60℃下搅拌反应混合物1小时。用H2O(20mL)稀释反应混合物,并用EtOAc(20mL*3)萃取。用H2O(30mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1至5/1,石油醚:乙酸乙酯=3:1,Rf=0.3)纯化残余物。得到为黄色固体的6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(500mg,1.65mmol,68.68%产率)。
LCMS(电喷雾)m/z 220.2(m+H)+。
步骤7)4-溴-6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在20℃下,向6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(200mg,659.51umol,1eq)在DMF(1mL)的溶液中加入NBS(129.12mg,725.46umol,1.1eq),然后将反应混合物在20℃下搅拌2小时。用H2O(10mL)稀释反应混合物,并用EtOAc(10mL*3)萃取混合物。用H2O(10mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。得到为黄色固体的4-溴-6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(120mg,粗品)。
LCMS(电喷雾)m/z 297.9(m+H)+。
步骤8)4-溴-6-氟-N-异丙基-5-(三氟甲基)-1H-吲唑-7-胺
在20℃下,向4-溴-6-氟-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(100mg,335.53μmol,1eq)在MeOH(1mL)的溶液中加入AcOH(40.30mg,671.06μmol,38.38μl,2eq)和丙酮(97.44mg,1.68mmol,123.34μl,5eq),然后加入NaBH3CN(105.42mg,1.68mmol,5eq),并将反应混合物在20℃下搅拌2小时。然后,向混合物中加入丙酮(97.44mg,1.68mmol,123.34uL,5eq)、NaBH3CN(105.43mg,1.68mmol,5eq)和AcOH(60.45mg,1.01mmol,57.57uL,3eq),并将反应混合物在20℃下搅拌20小时。用H2O(10mL)稀释反应混合物,并用EtOAc(10mL*3)萃取。用H2O(10mL*2)洗涤合并的有机层,经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过prep-TLC(石油醚:乙酸乙酯=3:1,Rf=0.4)纯化残余物。得到为白色固体的4-溴-6-氟-N-异丙基-5-(三氟甲基)-1H-吲唑-7-胺(60mg,165.83μmol,49.42%产率,94%纯度)。
LCMS(电喷雾)m/z 340.1(m+H)+。
步骤9)4-溴-6-氟-N-异丙基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在0℃下,向4-溴-6-氟-N-异丙基-5-(三氟甲基)-1H-吲唑-7-胺(50mg,147.01umol,1eq)在THF(1mL)的溶液中加入PPTS(3.69mg,14.70umol,0.1eq)和DHP(61.83mg,735.05umol,67.21uL,5eq),然后将反应混合物在60℃下搅拌2小时。用H2O(50mL)稀释反应混合物,并用EtOAc(50mL*3)萃取。用H2O(50mL*3)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过prep-TLC(石油醚:乙酸乙酯=5:1,Rf=0.6)纯化残余物。得到黄色油的4-溴-6-氟-N-异丙基-2-(四氢-2H-吡喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(50mg,117.86μmol,80.17%产率)。
LCMS(电喷雾)m/z 424.1(m+H)+。
中间体1O。4-溴-5-环丙基-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑
步骤1)3-溴-5-氟-2-甲基苯胺
向1-溴-5-氟-2-甲基-3-硝基苯(23g,98.28mmol,1eq)在EtOH(80mL)和水(80mL)中的混合物中加入Fe(27.44g,491.41mmol,5eq)和NH4Cl(26.29g,491.41mmol,5eq)。将混合物在100℃下搅拌3小时。过滤混合物,并减压浓缩滤液以去除乙醇。所得混合物用DCM(50mL*3)提取。用盐水(50mL*2)洗涤合并的有机相,经Na2SO4干燥,过滤并减压浓缩,得到残余物,得到为黄色液体3-溴-5-氟-2-甲基苯胺(20.6g,粗品)。
1H NMR(400MHz,DMSO-d6)δ6.59(br d,J=8.4Hz,1H),6.42(br d,J=11.2Hz,1H),5.51(br s,2H),2.09(s,3H)。
步骤2)3-溴-5-氟-4-碘-2-甲基苯胺
在0℃下,向3-溴-5-氟-2-甲基苯胺(18g,88.22mmol,1eq)(粗品)在CH3CN(150mL)的混合物中分批加入NIS(19.85g,88.22mmol,1eq)。将混合物在30℃下搅拌3小时。3小时后,LCMS显示化合物2残留,并检测到所需质量。然后将混合物在30℃下再搅拌12小时。LCMS显示没有化合物2残留,并且检测到一个具有所需质量的主峰。使用饱和Na2SO3(200mL)对混合物进行淬火,并使用EtOAc(50mL*3)提取所得混合物。用盐水(50mL*2)洗涤合并的有机相,经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=50/1,30/1;TLC(石油醚:乙酸乙酯=10:1;Rf=0.28))纯化残余物,得到为棕色固体的3-溴-5-氟-4-碘-2-甲基苯胺(22g,66.68mmol,75.58%产率)。
1H NMR(400MHz,DMSO-d6)δ6.55(d,J=10.5Hz,1H),5.67(s,2H),2.25(d,J=0.8Hz,3H)。
步骤3)4-溴-6-氟-5-碘-1H-吲唑
向3-溴-5-氟-4-碘-2-甲基苯胺(22g,66.68mmol,1eq)在CH3COOH(200mL)的混合物中加入NaNO2(5.52g,80.02mmol,1.2eq),该混合物在0℃下溶解在水(40mL)中。将该混合物在30℃下搅拌16小时。将混合物倒入饱和NaHCO3(1000mL)中,所得混合物用EtOAc(200mL*3)萃取。用盐水(100mL*2)洗涤合并的有机相,经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=15/1,5/1)纯化残余物,得到为棕色固体的4-溴-6-氟-5-碘-1H-吲唑(7.5g,22.00mmol,32.99%产率)。
1H NMR(400MHz,DMSO-d6)δ13.58(br s,1H),8.00(s,1H),7.51(d,J=8.1Hz,1H),3.32(s,1H)。
步骤4)4-溴-6-氟-5-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑
向4-溴-6-氟-5-碘-1H-吲唑(7.5g,22.00mmol,1当量)和4-甲苯磺酸;水合物(418.47mg,2.20mmol,0.1eq)在DCM(100mL)中的混合物中缓慢加入DHP(5.55g,66.00mmol,6.03mL,3eq)。将混合物在30℃下搅拌1小时。用饱和NaHCO3(30mL*3)和盐水(30mL*3)洗涤混合物。有机相经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=100/1,50/1)纯化残余物,得到为黄色固体的4-溴-6-氟-5-碘-1-(四氢-2H-吡喃-2-基)-1H吲唑(7.4g,17.41mmol,79.14%产率)。
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.80(dd,J=0.7,8.4Hz,1H),5.83(dd,J=2.4,9.6Hz,1H),3.88-3.85(m,1H),3.80-3.70(m,2H),2.40-2.27(m,1H),2.07-1.94(m,2H),1.81-1.63(m,2H),1.62-1.53(m,2H)。
步骤5)4-溴-5-环丙基-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑
在氮气下,向4-溴-6-氟-5-碘-1-(四氢-2H-吡喃-2-基)-1H吲唑(1.5g,3.53mmol,1eq)和环丙基硼酸(303.14mg,3.53mmol,1eq)在二恶烷(10ml)和H2O(2.5ml)中的混合物中加入Na2CO3(748.10mg,7.06mmol,2eq)和Pd(dppf)Cl2(258.23mg,352.91umol,0.1eq)。将混合物在80℃下搅拌16小时。在减压下浓缩混合物,得到残余物。通过prep-TLC(石油醚:乙酸乙酯=20:1)纯化残余物,得到为无色油的4-溴-5-环丙基-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.21g,619.10umol,17.54%产率)。
1H NMR(400MHz,CDCl3)δ7.98(d,J=0.6Hz,1H),7.20(d,J=10.4Hz,1H),5.61(dd,J=2.8,9.1Hz,1H),4.03-3.94(m,1H),3.76-3.69(m,1H),2.55-2.42(m,1H),2.19-2.06(m,2H),1.91-1.86(m,1H),1.81-1.64(m,3H),1.12-1.05(m,2H),0.87-0.81(m,2H)。
中间体1P。4-溴-6-氟-5-异丙基-1H-吲唑
步骤1)4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氢-2H-吡喃-2-基)-1H吲唑
在N2下,向4-溴-6-氟-5-碘-1-(四氢-2H-吡喃-2-基)-1H吲唑(1.5g,3.53mmol,1eq)和钾;三氟(异丙烯基)硼酰化物(626.67mg,4.23mmol,1.2eq)在二恶烷(10mL)和H20(2mL)中的混合物中加入Pd(dppf)Cl2(258.23mg,352.91umol,0.1eq)和Na2CO3(748.10mg,7.06mmol,2eq)。将混合物在80℃下搅拌16小时。减压浓缩混合物,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=100/1,50/1;TLC(石油醚:乙酸乙酯=10:1;Rf=0.61))纯化残余物,得到0.9g黄色油。通过prep-TLC(石油醚:乙酸乙酯=20:1)纯化油,得到为黄色油的4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.55g,1.62mmol,45.94%产率)。
1H NMR(400MHz,CDCl3)δ8.00(d,J=0.6Hz,1H),7.28(d,J=0.9Hz,0.5H),7.26(d,J=0.7Hz,0.5H),5.64(dd,J=2.8,9.0Hz,1H),5.46(t,J=1.6Hz,1H),5.01(s,1H),4.05-3.97(m,1H),3.80-3.69(m,1H),2.57-2.42(m,1H),2.19-2.09(m,2H),2.07(s,3H),1.81-1.66(m,4H)。
步骤2)4-溴-6-氟-5-异丙基-1-(四氢-2H-吡喃-2-基)-1H吲唑
在N2下,向4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.4g,1.18mmol,1eq)在MeOH(10mL)的溶液中加入PtO2。悬浮液在真空下脱气,并用H2吹扫数次。将混合物在30℃下在H2(15Psi)下搅拌2个半小时。过滤混合物,并减压浓缩滤液,得到残余物。通过硅胶色谱法(300-400目硅胶,石油醚/乙酸乙酯=50/1)纯化残余物,得到为无色油状的4-溴-6-氟-5-异丙基-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.3g,879.20umol,74.56%产率)。
步骤3)4-溴-6-氟-5-异丙基-1H-吲唑
向4-溴-6-氟-5-异丙基-1-(四氢-2H-吡喃-2-基)-1H吲唑(0.3g,879.20umol,1eq)在DCM(1mL)的溶液中加入TFA(2.30g,20.14mmol,1.49mL,22.91eq)。将该混合物在30℃下搅拌半个小时。减压浓缩混合物,得到残余物。用DCM(10mL)稀释残余物,并用TEA将所得混合物的pH值调节至约8。减压浓缩混合物,得到残余物。通过硅胶色谱法(300-400目硅胶,石油醚/乙酸乙酯=30/1,5/1)纯化残余物,得到为无色油状的4-溴-6-氟-5-异丙基-1H-吲唑(0.2g,777.90umol,88.48%产率)。
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.11(d,J=11.2Hz,1H),3.75-3.63(m,1H),1.38(dd,J=1.7,7.1Hz,6H)。
中间1Q。4-溴-6-氟-5-甲氧基-1H-吲唑
步骤1)2-溴-4-氟-3-甲氧基-1-甲苯
向2-溴-6-氟-3-甲基苯酚(4.8g,23.41mmol,1eq)在丙酮(50mL)的溶液中加入K2CO3(6.47g,46.82mmol,2eq)和碘甲烷(9.97g,70.24mmol,4.37mL,3eq),并将混合物在25℃下搅拌混合物1小时。将反应混合物浓缩得到残余物。将残余物溶解在乙酸乙酯(50mL)中,过滤混合物,并浓缩滤液,得到黄色油状残余物(4.6g,21.00mmol,89.70%产率)。
1H NMR(400MHz,CHLOROFORM-d)δ7.05-6.85(m,2H),3.95(d,J=1.2Hz,3H),2.38(s,3H)。
步骤2)3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯
在0℃下,向2-溴-4-氟-3-甲氧基-1-甲苯(4.4g,20.09mmol,1eq)在H2SO4(40mL)(98%)中的溶液中分批加入KNO3(2.23g,22.10mmol,1.1eq),并将混合物在25℃下搅拌1小时。将反应混合物缓慢倒入冰水(200ml)中,然后用乙酸乙酯(200ml*2)萃取混合物,将合并的有机层经Na2SO4干燥,减压过滤和浓缩,到残余物。得到棕色油状的3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯(4.6克,粗品)。
1H NMR(400MHz,CHLOROFORM-d)δ7.70(d,J=10.9Hz,1H),4.08(d,J=2.7Hz,3H),2.61(d,J=1.1Hz,3H)。
步骤3)3-溴-5-氟-4-甲氧基-2-甲基苯胺
向3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯(4.6g,17.42mmol,1eq)在EtOH(30mL)和水(30mL)中的溶液中加入Fe(5.84g,104.53mmol,6eq)和NH4Cl(5.59g,104.53mmol,6eq),并将混合物在80℃下搅拌2小时。过滤反应混合物,浓缩滤液以去除EtOH,然后用EA(50mL)稀释混合物,用水(20mL*2)洗涤混合物,然后有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。得到为棕色油状的3-溴-5-氟-4-甲氧基-2-甲基苯胺(3.5g,粗品)。
1H NMR(400MHz,CHLOROFORM-d)δ6.44(d,J=11.9Hz,1H),3.83(s,3H),3.76-3.48(m,2H),2.24(d,J=1.0Hz,3H)。
步骤4)4-溴-6-氟-5-甲氧基-1H-吲唑
在0℃下,向3-溴-5-氟-4-甲氧基-2-甲基苯胺(3.5g,14.95mmol,1eq)(粗品)在AcOH(20mL)的混合物中逐滴加入NaNO2(1.24g,17.94mmol,1.2eq)在水(4mL)中的溶液。然后将混合物在25℃下搅拌12小时。用冰水(100mL)稀释反应混合物,并使用KOH将混合物调节至pH 7,然后用EA(100mL*2)萃取混合物,用盐水(50mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,减压过滤和浓缩,得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1至15:1)纯化残余物。得到为棕色固体的4-溴-6-氟-5-甲氧基-1H-吲唑(600mg,2.45mmol,产率16.37%)。
1H NMR(400MHz,DMSO-d6)δ13.44(br s,1H),8.00(s,1H),7.52(br d,J=10.4Hz,1H),3.84(s,3H)。
式(I)所示化合物的合成
合成方法A到J用于制备以下化合物。以下描述了本发明的一些化合物的示例性合成实例,并且可以通过与以下所述的方法相似的方法,使用不同的起始或反应材料来制备其他化合物。
合成方法A
实施例2。(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)苯并[d]噻唑-2-基)环丙
烷-1-甲酰胺
向化合物1(0.2g,0.462mmol,1eq)(5-甲基-1H-吲唑-4-基)硼酸(0.081g,0.462mmol,1eq)在二恶烷(4mL)和H2O(1mL)中的溶液中加入Na2CO3(0.146g,1.38mmol,3eq)和Pd(dppf)Cl2(33mg,0.046mmol,0.1eq)。将混合物在110℃下搅拌16小时。将反应混合物用水(10ml)稀释,并用乙酸乙酯(10ml x 2)萃取。合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过柱层析纯化残余物,获得为黄色固体的实施例2(135mg,0.369mmol,80%产率)。
1H NMR(400MHz,DMSO-d6)δ13.04(s,NH),12.76(s,CONH),8.05(s,1H),7.86(d,J=8.0Hz,1H),7.63(s,2H),7.49-7.44(m,2H),7.31(d,J=8.4Hz,1H),5.05(td,J12=3.3Hz,J13=65.7Hz,1H),2.24(s,3H),2.23-2.24(m,1H),1.78-1.73(m,1H),1.31-1.23(m,1H);LCMS(电喷雾)m/z 367.1(M+H)+。
合成方法B
实施例58(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-
2-基)-2-氟环丙烷-1-甲酰胺。2TFA
步骤1)(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-2-(四氢-2H-吡喃-2-基)-2H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺
在N2下,向化合物3(4.4g,11.59mmol,1eq)在二恶烷(100mL)和H2O(20mL)的溶液中加入化合物2(4.20g,11.59mmol,1eq)、Pd(dppf)Cl2(847.97mg,1.16mmol,0.1eq)和Na2CO3(2.46g,23.18mmol,2eq)。将反应混合物在90℃下搅拌12小时。加入水(100mL),并用EA(200mL*2)萃取水相。用饱和盐水(200ml*2)洗涤合并的有机相,并在真空中浓缩。通过硅胶柱色谱法(石油醚:乙酸乙酯=10:1至1:1)纯化混合物,获得为淡黄色固体的化合物4(3.9g,7.29mmol,62.90%产率)。
1H NMR(400MHz,DMSO-d6)δ8.00-7.95(m,2H),7.92-7.85(m,1H),7.59(dd,J=1.8,8.4Hz,1H),5.70(dd,J=2.5,9.5Hz,1H),5.07-4.79(m,1H),3.82-3.63(m,1H),2.72(d,J=0.9Hz,3H),2.35-2.23(m,1H),2.04-1.94(m,2H),1.81-1.48(m,4H),1.46-1.33(m,2H)。
步骤2)(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺。2TFA盐
在N2下,向化合物4(3.80g,7.10mmol,1eq)在DCM(100mL)的溶液中加入TFA(9.86g,86.51mmol,6.41mL,12.18eq)。将反应混合物在20℃下搅拌4小时。加入DCM(10ml),然后缓慢添加MeOH(200ml)。将反应混合物在20℃下搅拌半小时。过滤反应混合物并浓缩滤饼以得到产物。滤液在真空中浓缩得到产物。然后将粗产物冻干,得到为淡黄色固体的实施例58(3.1g,4.26mmol,59.98%产率,2TFA)。
1H NMR(400MHz,DMSO-d6)δ13.76(br s,1H),12.82(br s,1H),8.19(d,J=1.7Hz,1H),7.96-7.82(m,2H),7.59(dd,J=1.8,8.4Hz,1H),5.26-4.85(m,1H),2.57(s,3H),2.30-2.19(m,1H),1.84-1.69(m,1H),1.33(tdd,J=6.4,9.0,12.9Hz,1H);LCMS(电喷雾)m/z450.8(M+H)+。
合成方法C
实施例149。(1S,2S)-N-(5-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)噻唑并[5,4-b]
吡啶-2-基)-2-氟环丙烷-1-甲酰胺。2TFA
步骤1)(1S,2S)-2-氟-N-(5-(三丁基三苯基)噻唑并[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺
向化合物5(2.5g,7.91mmol,1eq)在二恶烷(30mL)的溶液中加入(SnBu3)2(6.88g,11.86mmol,5.93mL,1.5eq),Pd(PPh3)4(913.78mg,790.77umol,0.1eq)和LiCl(1.01g,23.72mmol,485.85uL,3eq)。将反应混合物在N2下在110℃下搅拌16小时。过滤反应混合物,并减压浓缩滤液,得到残余物。通过柱色谱法(硅胶,石油醚:乙酸乙酯=10:1至3:1)纯化残余物。获得为黄色油状的化合物6(1.3g,2.47mmol,31.24%产率)。
步骤2)(1S,2S)-N-(5-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。2TFA
向4-溴-5-氯-7-乙氧基-6-氟-1H-吲唑(100mg,264.81umol,1eq)在二恶烷(2mL)的溶液中加入化合物6(167.24mg,317.77umol,1.2eq)、Pd(PPh3)4(30.60mg,26.48umol,0.1eq)和LiCl(33.68mg,794.42umol,16.27uL,3eq)。将混合物在140℃下在微波下搅拌2小时。然后,向反应混合物中添加10mL饱和K2CO3水溶液,并在20℃下搅拌15分钟。用10mL水稀释混合物,并用乙酸乙酯(20mL*2)萃取。用盐水(20mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过prep-TLC(硅胶板,石油醚:乙酸乙酯=1:2)纯化残余物,得到粗产物。通过prep HPLC(柱:Phenomenex luna C18 150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:55%-85%,10min)纯化粗产物。得到为黄色油状的实施例149(60mg,112.36μmol,42.43%产率)。
1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),8.28(d,J=8.4Hz,1H),7.95(s,1H),7.81(d,J=8.4Hz,1H),6.12-6.06(m,1H),5.20-4.96(m,1H),4.46-4.34(q,J=7.0Hz,2H),3.97(m,1H),3.73-3.61(m,1H),2.47-2.40(m,1H),2.32-2.22(m,1H),2.04(m,2H),1.83-1.69(m,2H),1.57(m,2H),1.49(t,J=7.0Hz,3H),1.41-1.28(m,1H)。
合成方法D
实施例152。(1S,2S)-N-(5-(5-乙基-6-氟-1H-吲唑-4-基)噻唑并[5,4-b]吡啶-2-
基)-2-氟环丙烷-1-甲酰胺
向中间体1K(45mg,185.13umol,1eq)在EtOH(2mL)的溶液中加入化合物6(116.92mg,222.15umol,1.2eq)和Ad2nBuP-Pd-G3(13.48mg,18.51umol,0.1eq)。然后将反应混合物在N2气氛下在80℃下搅拌16小时。将反应混合物用水20mL稀释,并用乙酸乙酯(20mL*2)萃取。用盐水(20mL*2)洗涤合并的有机层,合并的有机层经Na2SO4干燥,过滤,并在减压下浓缩滤液,得到残余物。通过prep HPLC(色谱柱:Phenomenex luna C18 150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:33%-63%,10min)纯化残余物,得到粗产物。粗产物通过prep TLC(硅胶板,石油醚:乙酸乙酯=1:1)提纯。得到白色固体的实施例152(9.7mg,24.29umol,13.12%产率,100%纯度)。
1H NMR(400MHz,DMSO-d6)δ13.18(br s,1H),12.94(br s,1H),8.26(d,J=8.2Hz,1H),7.72(s,1H),7.68(d,J=8.3Hz,1H),7.42(d,J=10.1Hz,1H),5.20-4.95(m,1H),2.65(dq,J=2.4,7.2Hz,2H),2.27(m,1H),1.85-1.69(m,1H),1.34(m,1H),1.11(t,J=7.0Hz,3H);LCMS(电喷雾)m/z 400.4(M+H)+。
合成方法E
实施例221。(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-
基)环丙烷-1-甲酰胺
步骤1)(1S,2S)-2-氟-N-(6-碘代咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺
在室温下用N,N-二异丙基乙胺(2.376mL,13.642mmol)处理二氯甲烷(100mL)中化合物7(5.890g,22.737mmol),(1S,2S)-2-氟环丙烷-1-羧酸(3.076g,29.558mmol)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(EDC HCl,6.538g,34.105mmol)的混合物,在相同温度下搅拌40小时。通过过滤收集沉淀物,用二氯甲烷洗涤,并干燥,得为米黄色固体的化合物8(3.870g,49.3%)。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.87(s,1H),8.02(s,1H),7.36~7.23(m,2H),4.97~4.77(m,1H),2.09~2.07(m,1H),1.65~1.57(m,1H),1.16~1.09(m,1H)。
步骤2)(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺
化合物8(0.750g,2.173mmol),(5-甲基-1H-吲唑-4-基)硼酸(0.459g,2.608mmol),[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)(Pd(dppf)Cl2,0.159g,0.217mmol)和碳酸铯(1.416g,4.346mmol)在四氢呋喃(15mL)/水中(4mL)在室温下混合,然后在微波下在120℃下加热1小时,冷却至室温,通过硅藻土垫过滤以去除固体,并在乙酸乙酯和饱和碳酸氢钠水溶液之间分离。用饱和氯化钠水溶液清洗有机层,有机层被分离、干燥(无水硫酸镁)、过滤,并在真空中浓缩。对残余物进行色谱分析(SiO2,30g筒;乙酸乙酯/己烷=100%),得到粗产物,在室温下使用乙醚(5mL)使粗产物结晶。过滤所得沉淀物,用乙醚洗涤并干燥沉淀物,得到为淡黄色固体的实施例221(0.550g,72.4%)。
1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),9.70(s,1H),9.00(s,1H),8.66(d,J=9.2Hz,1H),8.59(s,1H),8.55(d,J=9.2Hz,1H),8.33(d,J=8.0Hz,1H),8.14(d,J=8.8Hz,1H),5.91~5.71(m,1H),3.11(s,3H),3.05~3.00(m,1H),2.54~2.48(m,1H),2.07~2.03(m,1H);LCMS(电喷雾)m/z 350.0(M+H)+。
合成方法F
实施例223。N-(6-(5-氯-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷甲酰胺盐
酸
步骤1)(2-氨基-6-碘代咪唑[1,2-a]吡啶-3-基)(环丙基)甲酮
向环丙烷羧酸(3.17g,36.78mmol,2.91mL,1.3eq)在DCM(50mL)的溶液中加入EDCI(6.51g,33.95mmol,1.2eq),HOBt(4.59g,33.95mmol,1.2eq)和TEA(8.59g,84.89mmol,11.82mL,3eq)。将混合物在20℃下搅拌1小时。然后添加化合物7(6g,28.30mmol,1eq)。最终将混合物在20℃下搅拌18小时。将混合物倒入H2O(200mL)中,用乙酸乙酯(300mL*3)萃取,用盐水(500mL*2)洗涤有机相,经无水硫酸钠(Na2SO4)干燥,过滤并在真空中浓缩。残余物用乙酸乙酯(50mL)研磨提纯,过滤并浓缩滤饼,得到为黄色固体的化合物9(1.9g,6.78mmol,23.96%产率)。
1H NMR(400MHz,DMSO-d6)δ9.70(d,J=1.2Hz,1H),7.60(dd,J=2.1,9.3Hz,1H),7.32(d,J=9.3Hz,1H),6.62(s,2H),2.46-2.37(m,1H),1.02-0.90(m,4H)。
步骤2)(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲哚-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺二盐酸盐
向化合物9(10.22g,31.27mmol,1eq)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,3,2-二氧苯甲醛(11.12g,43.78mmol,1.4eq)在二恶烷(100mL)的溶液中加入KOAc(9.21g,93.82mmol,3eq)和Pd(dppf)Cl2(1.14g,1.56mmol,0.05eq)。将混合物加热至90℃ 3小时。将残余物倒入水(200mL)中。用乙酸乙酯(200ml*2)萃取水相。用盐水(300mL)洗涤合并的有机相,有机相经无水Na2SO4干燥,过滤并在真空中浓缩。TLC(石油醚/乙酸乙酯=0:1)显示一个主要斑点。通过硅胶色谱法纯化残余物,用石油醚/乙酸乙酯=0:1洗脱。得到化合物10(11g,粗品),其为黄色固体。用石油醚(20ml)和乙酸乙酯(4ml)研磨纯化粗产物,过滤并浓缩滤饼。得到为白色固体的化合物10(6.3g,19.26mmol,产率48.46%)。
步骤3)N-(6-(5-氯-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷甲酰胺。二盐酸盐
向化合物10(100mg,305.64umol,1eq)和4-溴-5-氯-1H-吲唑(84.90mg,366.76umol,1.2eq)在二恶烷(3mL)和H2O(1mL)的溶液中加入Na2CO3(97.18mg,916.91umol,3eq)和Pd(dppf)Cl2(11.18mg,15.28umol,0.05eq)。将混合物在90℃下搅拌10小时。将混合物倒入石油醚(10mL)中,用硅胶过滤,滤液在真空中浓缩。通过prep-HPLC(柱:PhenomenexSynergi C18 150*25*10um;流动相:[水(0.05%HCl)-ACN];B%:14%-34%,9min)纯化残余物,然后进行冻干。获得为白色固体的实施例223(36.8mg,85.95μmol,28.12%产率,99.2%纯度,2HCl)。
1H NMR(400MHz,METHANOL-d4)δ8.92(s,1H),8.13(s,1H),7.99-7.91(m,3H),7.68(dd,J=1.0,8.9Hz,1H),7.58(d,J=8.9Hz,1H),1.95-1.87(m,1H),1.12-1.07(m,2H),1.05-0.98(m,2H);LCMS(电喷雾)m/z 352.0(M+H)+。
合成方法G
实施例231。N-(6-(5-溴-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷甲
酰胺2 TFA盐
CuBr(137.29mg,957.04umol,29.15uL,1eq)和t-BuONO(98.69mg,957.04umol,113.83uL,1eq)在MeCN(5mL)中的混合物在0℃下搅拌30分钟,然后加入实施例27(662mg,957.04umol,1eq)在MeCN(1mL)中的溶液,并将混合物在20℃下搅拌2小时,然后加入CuBr(137.29mg,957.04umol,29.15uL,1eq)和t-BuONO(98.69mg,957.04umol,113.83uL,1eq),接着将混合物在20℃下再搅拌12小时。将反应混合物浓缩以得到残余物,然后将残余物溶解在乙酸乙酯(50mL)中,然后用稀释的氢氧化铵(3%,20mL*2]洗涤混合物,用盐水(20mL)洗涤有机层,经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过prep-HPLC纯化(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:20%-50%,9分钟)残余物。得到为黄色固体的实施例231(14mg,22.01umol,2.3%产率,2TFA)。
1H NMR(400MHz,DMSO-d6)δ13.49(br s,1H),11.05(s,1H),8.78(s,1H),8.14(s,1H),7.92(s,1H),7.64(d,J=8.7Hz,1H),7.57(d,J=9.2Hz,1H),7.32(dd,J=1.7,9.2Hz,1H),2.05-1.86(m,1H),0.85-0.79(m,4H);LCMS(电喷雾)m/z 414.1(M+H)+。
合成方法H
实施例258。(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-
a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
步骤1)(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
向中间体1D(30mg,78.06umol,1eq)和化合物11(32.33mg,93.67umol,1.2eq)在二恶烷(1mL)和H2O(0.2mL)中的溶液中加入Pd(dppf)Cl2(5.71mg,7.81umol,0.1eq)和Na2CO3(24.82mg,234.17umol,3eq),然后将混合物在80℃下在N2下搅拌12小时。将反应混合物浓缩得到残余物。通过prep-TLC(SiO2,二氯甲烷:甲醇=10:1)纯化残余物。得到为黄油状的化合物12(34mg,57.44umol,73.59%产率,87%纯度)。
步骤2)(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
向化合物12(34mg,57.44umol,1eq)在二恶烷(1mL)的溶液中加入HCl/二恶烷(4M,1ml,69.64eq),然后将混合物在20℃下在N2下搅拌2小时。用乙酸乙酯(20mL)稀释反应混合物,并用饱和NaHCO3水溶液(15mL*2)洗涤混合物,经Na2SO4干燥有机层,过滤并减压浓缩,得到残余物。通过prep HPLC(色谱柱:Phenomenex luna C18 150*25 10u;流动相:[水(0.1%TFA)-ACN];B%:23%-53%,10分钟)纯化残余物。得到为白色固体的实施例258(8.7mg,13.05μmol,22.72%产率,2TFA)。
1H NMR(400MHz,DMSO-d6)δ13.55(br s,1H),11.21(s,1H),8.80(s,1H),8.17(s,1H),7.95(s,1H),7.62(d,J=9.2Hz,1H),7.43(d,J=9.2Hz,1H),5.08-4.77(m,1H),3.01(s,3H),3.00(s,3H),2.16(td,J=7.0,13.8Hz,1H),1.76-1.57(m,1H),1.27-1.11(m,1H);LCMS(电喷雾)m/z 431.2(M+H)+。
合成方法I
实施例393。(1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-
基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
步骤1)1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)乙烷-1-酮
将中间体1A(3.29g,9.86mmol,1eq)在THF(49mL)中的溶液冷却至-78℃,然后将LDA(7.39mL,14.7mmol,1.5eq)缓慢添加到反应混合物中,将混合物在相同温度下搅拌30分钟。然后逐滴添加醋酸酐(1.11mL,11.8mmol,1.2eq),并在rt下搅拌反应混合物2小时。消耗中间体1A后,用水淬火并用DCM萃取,分离,经无水MgSO4干燥,过滤,并在真空中浓缩。通过硅胶色谱法纯化残余物(产物在己烷/乙酸乙酯=10/1时产生),得到为橙色固体的化合物13(1.86g,4.95mmol,50.2%产率)。
步骤2)1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)乙烷-1-醇
将化合物13(1.86mg,4.95mmol,1eq)在MeOH(24mL)中的溶液冷却至0℃,然后按比例添加硼氢化钠(375mg,9.90mmol,2eq)。将反应混合物在室温下搅拌2小时。消耗化合物13后,浓缩反应混合物并用DCM萃取,用水洗涤,分离,经无水MgSO4干燥,过滤,并在真空中浓缩。通过硅胶色谱法纯化残余物(产物在己烷/乙酸乙酯=7/3时产生),得到为象牙色固体的化合物14(615mg,1.62mmol,32%产率)。
步骤3)7-(1-(2H-四唑-2-基)乙基)-4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H吲唑
向化合物14(100mg,0.265mmol,1.0eq)在THF(1.33mL)中的溶液中加入1H四唑(0.89mL,0.398mmol,1.5eq)和PPh3(104mg,0.398mmol,1.5eq)。将混合物冷却至0℃,并在0℃下缓慢加入DEAD(0.181mL,0.398mmol,1.5eq)。将混合物在室温下搅拌1小时。用DCM(30mL*3)萃取反应混合物。合并的有机层经Na2SO4干燥,过滤,在真空中浓缩滤液。通过硅胶色谱法(产物在己烷/乙酸乙酯=10/2时产生)纯化粗产物,得到为白色固体的化合物15(62mg,0.144mmol,54%产率)。
步骤4)(1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
向化合物15(62mg,0.144mmol,1eq)在1,4-二恶烷(0.577mL)/H2O(0.144mL)中的溶液中加入化合物11(54mg,0.159mmol,1.1eq)、Pd(dppf)Cl2(5mg,0.007mmol,0.05eq)、Na2CO3(30mg,0.289mmol,2eq)。将混合物脱气并用氮气清洗3次。将混合物在微波反应器中于120℃搅拌30分钟。反应混合物通过硅藻土过滤,滤液用DCM萃取。合并的有机层经Na2SO4干燥,过滤,滤液在真空中浓缩,得到残余物。通过硅胶色谱法纯化残余物(产物在己烷/乙酸乙酯=2/8时产生),得到为黄色固体的化合物16(68mg,0.120mmol,83%)。
步骤5)(1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
向化合物16(66mg,0.116mmol,1eq)在乙酸乙酯(0.6mL)中的溶液中加入1N HClEA溶液(1.16mL,1.16mmol,10eq)中。将混合物在室温下搅拌1小时。反应混合物用饱和NaHCO3淬火,用EA萃取,经Na2SO4干燥,过滤,滤液在真空中浓缩。通过硅胶色谱法纯化粗产物(产物在DCM/MeOH=10/1时产生),得到为象牙色固体的实施例393(4mg,0.008mmol,7%)。
1H NMR(400MHz,DMSO-d6)δ13.77(s,1H),11.07(s,1H),8.99(s,1H),8.80(s,1H),8.14-8.04(m,2H),7.58-7.54(m,1H),7.35(dd,J=9.3,1.6Hz,1H),6.74(q,J=7.1Hz,1H),5.00-4.79(m,1H),2.23(d,J=7.2Hz,3H),2.16-2.09(m,1H),1.68-1.57(m,1H),1.18-1.09(m,1H));LCMS(电喷雾)m/z 485.10(M+H)+。
合成方法J
实施例446。(1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-
基)环丙烷甲酰胺
步骤1)(1S,2S)-N-(5-溴吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺
在N2下于0℃下,向化合物17(3.1g,14.62mmol,1eq)和(1S,2S)-2-氟环丙烷羧酸(1.67g,16.08mmol,1.1eq)在CH3CN(40mL)中的混合物中缓慢加入MsCl(3.35g,29.24mmol,2.26mL,2eq)和3-甲基吡啶(6.81g,73.10mmol,7.12mL,5eq)。将混合物在30℃下搅拌3小时。减压浓缩混合物。用乙酸乙酯(200mL)溶解残余物,所得混合物用10%柠檬酸(30mL*2)、饱和Na2CO3(30mL*2)、盐水(30mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=5/1,3/1)纯化残余物,得到为白色固体的化合物18(2.3g,7.72mmol,52.81%产率)。
步骤2)(1S,2S)-2-氟-N-(5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)吡唑并[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺
将化合物18(0.345g,1.159mmol),4,4,4',4',5,5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧苯甲醛,0.588g,2.318mmol),[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(Pd(dppf)Cl2,0.084g,0.115mmol)和醋酸钾(0.398g,4.056mmol)在室温下在DMSO(10mL)中混合,然后将该混合物在90℃下搅拌18小时,冷却至室温,通过硅藻土垫过滤以去除固体,并在乙酸乙酯和水之间分离。用饱和氯化钠水溶液清洗有机层、分离,经无水硫酸镁干燥,过滤,真空浓缩。对残余物进行色谱分析(SiO2,12g筒;乙酸乙酯/己烷=0%至100%),得到为棕色固体的化合物19(0.289g,72.3%)。
步骤3)(1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷甲酰胺
在N2下,向化合物19(6g*,17.34mmol,1eq)和4-溴-5-甲基-1H-吲唑(3.6g,17.34mmol,1eq)在二恶烷(120mL)和H2O(24mL)中的混合物中加入Na2CO3(3.67g,34.68mmol,2eq)和Pd(dppf)Cl2(1.28g,1.73mmol,0.1eq)。将该混合物在90℃下搅拌4小时。减压浓缩混合物,得到残余物。通过硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=5/1,1/1;TLC(石油醚:乙酸乙酯=1:1;Rf=0.08)纯化残余物,得到2.5g黄色固体。该固体用CH3CN(10mL)研磨两次。过滤混合物并收集过滤滤饼。用H2O/CH3CN(5:1;10mL)分散滤饼,并将所得混合物冻干第三次,得到为灰白色固体的实施例446(1.53g,4.37mmol,25.20%产率,96.98%纯度)。
1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),11.13(s,1H),8.61(d,J=7.1Hz,1H),7.74(s,1H),7.63(d,J=0.9Hz,1H),7.49(d,J=8.6Hz,1H),7.32(d,J=8.6Hz,1H),6.91(s,1H),6.86(dd,J=1.9,7.0Hz,1H),5.06-4.98(m,1H),4.88-4.84(m,1H),2.34(s,3H),2.15(td,J=6.9,13.8Hz,1H),1.74-1.61(m,1H),1.21-1.13(m,1H);LCMS(电喷雾)m/z350.1(M+H)+。
下表1显示了实施例的化合物以及用于制备化合物的一般合成方法和表征数据。
表1.实施例化合物
化合物的评价
HPK1激酶试验
通过Promega的ADP GloTM激酶试验测定HPK1激酶活性。在测定过程中,将5ng重组人HPK1(signalchem)与5μL化合物(0.5%DMSO)、5μL MBP(0.5μg/μL)和5μL ATP(25μM)在缓冲液(40mM Tris,7.5;20mM MgCl2;0.1mg/ml BSA;50μM DTT)中一起孵育。检测的第一步是通过将反应混合物在96孔板中于30℃培养40分钟。孵育后,添加25μL ADP-Glo试剂,并将反应在室温下孵育40分钟以终止反应并降解残留的ATP。然后通过每孔添加50μL检测试剂将ADP产物转化为ATP。在室温下,用酶标仪I3X读板仪温育30分钟后检测到发光。使用在GraphPad Prism 7软件或SigmaPlot 13.0中实施的软件例程,根据一系列抑制百分比值计算IC50值,该抑制百分比值是在一定的抑制剂浓度范围内测定的。
表2示出了本发明化合物的IC50值,其中+表示>1000nM,++表示501-1000nM,+++表示101-500nM,++++表示<100nM。
表2就HPK1数据方面的体外活性
人外周血pan T细胞的IFNγ和IL-2分析
人外周血pan T细胞购自STEMCELLTM Technologies Inc.。人外周血pan T细胞解冻并悬浮在DMEM培养基(10%FBS和1%青霉素/链霉素)中。将8X104个T细胞接种于96孔板中,并与不同浓度的化合物和100nM前列腺素E2孵育1小时。使用Dynabeads人T-激活剂CD3/CD28(美国生命技术公司)以1:3的细胞/珠比例刺激T细胞。按照制造商的建议,使用MSD V-PLEX人类细胞因子试剂盒在刺激后24小时测量细胞因子分泌。数据采用中尺度发现(MESOQuickplex SQ120)进行分析。
在表3中,+表示>1000nM,++表示200-1000nM,+++表示<200nM,-表示未确定。
表3本发明化合物在人外周血pan T细胞中的IFNγ和IL-2分泌
Claims (34)
1.一种式(I)所示的化合物:
或其药学上可接受的盐、水合物或溶剂化物,其中:
X是O或S;
L是键,-O-,-S-,或-NR6-;
R1为烷基、环烷基、芳基、杂芳基或杂环基,其中R1任选地被一个或多个独立选自R7的取代基取代;
R6为-H或C1-6烷基;
R7为C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氧代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-SR9、-S(O)R9、-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9、-N(R6)C(O)NR10R11、-N(R6)S(O)2R9、-N(R6)S(O)2NR10R11,或-P(O)R12R13;R9为-H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基或杂环基;每个R10和R11独立地为-H、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基或杂环基,或者R10和R11与它们所连接的氮原子一起形成4-到12-员杂环基,杂环基任选地被一个或多个以下基团所取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN,-NO2,-NR10R11,-NR10C(=O)R9,-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9,-C(=O)NR10R11,-OC(=O)R9,-OC(=O)OR9,和-OC(=O)NR10R11;
每个R12和R13独立地为C1-6烷基,C1-6烷氧基、C3-8环烷基、芳基、杂芳基、杂环基,或R12和R13与它们所连接的磷原子一起形成4-到8-元杂环基,杂环基任选地被一个或多个以下基团所取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN,-NO2,-NR10R11,-NR10C(=O)R9,-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9,-C(=O)NR10R11,-OC(=O)R9,-OC(=O)OR9,和-OC(=O)NR10R11;
Het选自以下基团:
Ra、Rb和Rc各自独立地为-H、-D、卤代、CF3、CF2H、CH2F、CN、OR9或NR10R11;
R2为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、羟基、-CD2OH、-CN、-NO2、卤代烷基、三甲基硅氧基甲基,-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-SR9、-S(O)R9、-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)R9、-N(R6)C(O)OR9、-N(R6)C(O)NR10R11、-N(R6)S(O)2R9、-N(R6)S(O)2NR10R11,或-P(O)R12R13,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、或杂环基可选地被以下一个或多个基团所取代,卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-NO2、-NR10R11、-NR10C(=O)R9、-NR10C(=O)NR10R11、-NR10C(=O)OR9、-OR9、-C(=O)R9、-C(=O)OR9、-C(=O)NR10R11、-OC(=O)R9、-OC(=O)OR9,和-OC(O=)NR10R11;
R3为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氰基、羟基、-CH2OH、-CD2OH、-OH、-CN、-NO2、卤代烷基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9,-OC(O)R9,-OC(O)NR10R11、-SR9,-S(O)R9,-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11、-NR10R11、-N(R6)NR10R11,-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9、-N(R6)C(O)NR10R11、-N(R6)S(O)2R9、-N(R6)S(O)2NR10R11,或-P(O)R12R13;
M是一个键,-O-,-S-,或-NR6-;
R6为-H或C1-6烷基;
R4为-H、-D、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基,杂芳基、杂环基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-S(O)2R9、-S(O)(=NH)R10、-S(O)2NR10R11,或-P(O)R12R13,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基,或杂环基任选地被一个或多个选自以下的基团取代:卤代、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-CD3、-NO2、-NR10R11、-NR10C(=O)R9、-NR10C(=O)NR10R11、-NR10C(=O)OR9、-NR10S(O)2R9、-OR9、-C(=O)R9、-C(=O)OR9、-C(=O)NR10R11、-OC(=O)R9、-OC(=O)OR9,和-OC(=O)NR10R11;和
R5为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、羟基、-CH2OH、-CD2OH、-CN或卤代烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环烷基,其任选地被一个或多个选自以下的基团所取代:C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)R10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、-N(R6)C(O)OR9和-N(R6)C(O)NR10R11。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐,其特征在于,R2和R3中的每一个独立地为-H、卤代、烷基硫基、卤代烷基或烷基。
4.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐,其特征在于,M是键、-O-或-NR6-;R4为-H、-D、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基、杂环基、卤代、氰基、羟基、-C(O)R9、-C(O)NR10R11、-S(O)2R9、-S(O)(=NH)R10或-S(O)2NR10R11,其中C1-6烷基、C2-6烯基、C2-6炔基、环烷基、芳基、杂芳基,或杂环基任选地被选自卤代、羟基、烷基、烯基、炔基、卤代烷基、羟基烷基、-CN、-CD3、-NR10R11、-NR10S(O)2R9和-NR10C(=O)R9的一个或多个基团取代。
6.根据权利要求5所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基硫基、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M是键,-O-、-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙胺四乙酸乙酯、丙胺基乙基、甲氨基乙基、氨基烷基、甲氨基羰基甲基、烷氧基烷基、氮杂环丁烯基或氮杂环丁烯基甲基;R5为–H、烷基或卤代。
7.根据权利要求5或6所述的化合物或其药学上可接受的盐,其特征在于,其选自由表1中的实施例1-145的化合物。
8.根据权利要求5至7中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-甲氧基-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((2-氨基乙基)(甲基)氨基)-5-氯-6-氟-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((2-(二甲氨基)乙基)(甲基)氨基)-6-氟-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-(甲氨基)-2-氧乙基)硫代)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(2-(甲氨基)乙基)氨基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((氮杂环丁烯-3-基甲基)(甲基)氨基)-5-氯-6-氟-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-甲氧基-5-甲基-1H-吲唑-4-基)苯并[d]噻唑-2-基)环丙烷甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5,7-双(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(N-甲基乙酰胺)-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)苯并[d]噻唑-6-基)-N,N-二甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(6-(7-(氮杂环丁烯-3-基(甲基)氨基)-5-氯-6-氟-1H-吲唑-4-基)苯并[d]噻唑-2-基)-2-氟环丙烷-1-甲酰胺;和
6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)苯并[d]噻唑-6-基)-N,N,5-三甲基-1H-吲唑-7-甲酰胺。
10.根据权利要求9所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙胺乙基或烷氧基烷基;R5为–H、烷基或卤代。
11.根据权利要求9或10所述的化合物或其药学上可接受的盐,其特征在于,其选自表1中实施例146-218的化合物。
12.根据权利要求9至11中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(5-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)噻唑并[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-1H-吲唑-4-基)噻唑并[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(乙氨基)-6-氟-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-5-乙基-6-氟-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-7-((2-羟乙基)硫代)-5-甲基-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-7-((2-(甲氨基)-2-氧乙基)硫代)-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-6-氟-5-甲基-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5,7-双(甲硫基)-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)噻唑并[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)噻唑并[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)噻唑基[5,4-b]吡啶-5-基)-N,N-二甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5,7-二甲基-1H-吲唑-4-基)噻唑基[5,4-b]吡啶-2-基)环丙烷-1-甲酰胺;和
(1S,2S)-N-(5-(7-(乙基(甲基)氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)噻唑[5,4-b]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
14.根据权利要求13所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、二甲氨基、二甲氨基乙基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙酰胺基乙基、丙胺基乙基、甲氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰胺基乙基、咪唑啉基乙基、二氧芳基、环丁基羰基氨基乙基、二氟乙酰胺基乙基、三氟乙酰胺基乙基、甲基硫代甲基、甲基硫代乙基、氮杂环丁烯基、氮杂环丁烯基甲基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰胺基)甲基、丙基-1,1,3,3,3-d6)氨基、四氢呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、异恶唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;R5为–H、烷基或卤代。
15.根据权利要求13或14所述的化合物或其药学上可接受的盐,其特征在于,其选自表1中的实施例219及220的化合物。
17.根据权利要求16所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环烷基,其任选地被选自C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤代、氰基、羟基、-C(O)R9、-C(O)OR9、-C(O)NR10R11、-OR9、-OC(O)R9、-OC(O)NR10R11、-NR10R11、-N(R6)NR10R11、-N(R6)OR9、-N(R6)C(O)R9、--N(R6)C(O)OR9,和-N(R6)C(O)NR10R11中的一个或多个基团取代。
18.根据权利要求16或17所述的化合物或其药学上可接受的盐,其特征在于,R1为环烷基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代。
19.根据权利要求16至18中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自表1中的实施例221-445的化合物。
20.根据权利要求16所述的化合物或其药学上可接受的盐,其特征在于,R1为环丙基,其任选地被选自卤代、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基的一个或多个基团取代;R2为–H、烷基、烷基硫基、卤代烷基或卤代;R3为–H、烷基或卤代;M为键、-O-或-NR6-;R4为–H、卤代、烷基、单烷基氨基或二烷基氨基;R5为–H、烷基或卤代。
21.根据权利要求16至20中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
22.根据权利要求16-19中任一项所述的化合物或其药学上可接受的盐,其特征在于,R1为环丙基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键,-O-,-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、单烷基氨基或二烷基胺基;以及R5为–H、烷基或卤代。
23.根据权利要求16至19及22中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-溴-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-甲氧基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5,7-双(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)咪唑[1,2-a]吡啶-6-基)-N,N-二甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷甲酰胺;
6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)咪唑[1,2-a]吡啶-6-基)-N,N,5-三甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-氧吡咯烷-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-N-乙基-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)咪唑[1,2-a]吡啶-6-基)-N-甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(三氟甲氧基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(吡啶-3-基甲基)氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(吡啶-4-基甲基)氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(三氟甲氧基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基-2-氧代咪唑啉-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((氰甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1-氰乙基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲氧基甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙氧基甲基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙氧基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((S)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-羟基环戊基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((S)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-乙酰胺乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1,2,2,2-四氟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲酰胺乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2,2,2-三氟乙酰氨基)乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)咪唑[1,2-a]吡啶-6-基)-1H-吲唑-7-基)乙基)环丁烷甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲氨基)-1-氧丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((甲硫基)甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲硫基)乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(甲酰胺)甲基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙酰胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-氯-7-(1-(乙氨基)-1-氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
24.根据权利要求16至19中任一权利要求所述的化合物或其药学上可接受的盐,其特征在于,R1为环丙基,其任选地被选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的一个或多个基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键、-O-、-S-或-NR6-;R4为–H、卤代、烷基、烷基羰基、二烷基氨基碳基、氧吡咯烷基、羟基烷基、卤代烷基、卤代烯基、环烷基、吡啶基、单烷基氨基或二烷基氨基;以及R5为–H、烷基或卤代。
25.根据权利要求16至19及24中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-溴-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-溴-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-甲氧基-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-甲氧基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(二乙氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-羟乙基)硫代)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5,7-双(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6,7-二氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(二甲氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(N-甲基乙酰胺)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)咪唑[1,2-a]吡啶-6-基)-N,N-二甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷甲酰胺;
6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)咪唑[1,2-a]吡啶-6-基)-N,N,5-三甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(二氟甲基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-氧吡咯烷-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(三氟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-N-乙基-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)咪唑[1,2-a]吡啶-6-基)-N-甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(三氟甲氧基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(嘧啶-2-基)氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(吡啶-3-基甲基)氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(吡啶-4-基甲基)氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(三氟甲氧基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基-2-氧代咪唑啉-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(羟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(氟甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((氰甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(仲丁胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1-氰乙基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡唑-5-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((2H-四唑-2-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((2H-1,2,3-三唑-2-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-吡咯-1-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲氧基甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(乙氧基甲基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-环丙氧基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙氧基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-环戊基-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((S)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-羟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-羟基环戊基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((S)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-甲氧基乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-乙酰胺乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1,2,2,2-四氟乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((环丙基甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙酰胺基乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)氨基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲酰胺乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2,2,2-三氟乙酰氨基)乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)咪唑[1,2-a]吡啶-6-基)-1H-吲唑-7-基)乙基)环丁烷甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲氨基)-1-氧丙烷-2-基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((甲硫基)甲基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲硫基)乙基)-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(甲酰胺)甲基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙酰胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;及
(1S,2S)-N-(6-(5-氯-7-(1-(乙氨基)-1-氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑[1,2-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
27.根据权利要求26所述的化合物或其药学上可接受的盐,其特征在于,L为键,R1为环丙基,其任选地被一个或多个选自卤代、C1-3烷基、C1-3羟烷基和C1-3卤代烷基的基团取代;R2为–H、烷基、卤代、卤代烷基或烷基硫基;R3为–H、烷基或卤代;M为键、-O-、-S-或-NR6-;R4为–H、卤代、烷基、羟烷基、卤代烷基、卤代烷基氨基烷基、卤代烷基羰基氨基烷基、烷基氨基烷基、羟基卤代烷基、卤代烯基、环烷基、氰基、氰基烷基、二甲氨基、二甲氨基乙基、甲氨基羰基、二甲氨基羰基、甲氨基氧乙基、氨基羰基烷基、乙酰胺乙基、二烷基氨基环烷基,氨基环烷基、甲氨基环烷基、环烷基烷基、环烷基(羟基)烷基、环烷基酰胺烷基、环烷基氨基羰基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基羰基、烷基羰基、烷基酰胺烷基、烷氧基烷基、烯基、甲基磺酰胺基乙基、咪唑基乙基、二恶烷基、氮杂环丁烯基、氮杂环丁烯基甲基、四氢呋喃基、呋喃基、嘧啶基、吡啶基、吡咯基、卤代吡咯烷基、吡咯烷基、甲基吡咯基、异恶唑基、四唑烷基、三嗪基、甲基吡唑基或甲基吡唑基甲基;R5为–H、烷基或卤代。
28.根据权利要求26或27所述的化合物或其药学上可接受的盐,其特征在于,其选自表1中的实施例446-666的化合物。
29.根据权利要求26至28中任一项所述的化合物或其药学上可接受的盐,其特征在于,其选自:
(1S,2S)-N-(5-(5-溴-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-甲氧基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5,7-二氯-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5,7-二甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-溴-5-氯-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-溴-6-氟-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-6-氟-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-7-甲氧基-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-甲氧基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(乙氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(二乙氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((4-(二甲氨基)环己基)(甲基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-((4-羟基环己基)(甲基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲基((1R,4R)-4-(甲氨基)环己基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲基((1S,4S)-4-(甲氨基)环己基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺二盐酸盐;
(1S,2S)-N-(5-(7-((4-氨基环己基)(甲基)氨基)-5-氯-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-5-乙基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-((2-羟乙基)硫代)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-7-((2-(甲氨基)-2-氧乙基)硫代)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺双(2,2,2-三氟乙酸);
(1S,2S)-2-氟-N-(5-(6-氟-7-((2-羟乙基)硫代)-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-7-(乙基氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5,7-双(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6,7-二氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-7-(2-羟基乙氧基)-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
甲基6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)吡唑[1,5-a]吡啶-5-基)-5-甲基-1H-吲唑-7-羧酸盐;
(1S,2S)-2-氟-N-(5-(6-氟-5-甲基-7-(N-甲基乙酰胺)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(N-甲基乙酰胺)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)吡唑[1,5-a]吡啶-5-基)-N,N-二甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-7-((2-羟乙基)(甲基)氨基)-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-((3-羟基环丁基)(甲基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(5-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷甲酰胺;
(1S,2S)-N-(5-(7-(乙基(甲基)氨基)-6-氟-5-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(乙基(甲基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(二甲氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-2-氟-N-(5-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷甲酰胺;
6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)吡唑[1,5-a]吡啶-5-基)-N,N,5-三甲基-1H-吲唑-7-甲酰胺;
(1R,2S)-2-氟-N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2R)-2-氟-N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1R,2R)-2-氟-N-(5-(6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1R,2R)-2-氟-N-(5-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(乙基(甲基)氨基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-甲基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(二氟甲基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-乙基-6-氟-7-(三氟甲基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-氰基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-((氰甲基)硫代)-5-乙基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(5-(6-氟-5-甲基-7-(三氟甲氧基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲基(嘧啶-2-基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((氰甲基)硫代)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(5-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(5-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(5-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-((1-氰乙基)硫代)-5-乙基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(三氟甲氧基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
5-氯-N-(氰甲基)-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺基)吡唑[1,5-a]吡啶-5-基)-N-甲基-1H-吲唑-7-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(N-(氰甲基)乙酰胺)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲基(1,3,5-三嗪-2-基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(甲基(1,2,4-三嗪-3-基)氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(乙硫基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(3-甲基-2-氧代咪唑啉-1-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(羟甲基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(氟甲基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((氰甲基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(1H-吡咯-1-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((2-氰基丙烷-2-基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((1-氰乙基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(3-氟吡咯烷-1-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(2-甲基-1H-吡咯-1-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R,3S)-N-(5-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-异丙氧基-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-环戊基-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(2,2,2-三氟-1-羟乙基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-((1,1-二氟丙烷-2-基)氨基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(1-甲酰胺乙基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(1-丙酰胺基乙基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰胺)吡唑[1,5-a]吡啶-5-基)-1H-吲唑-7-基)乙基)环丁烷甲酰胺;
(1S,2S)-N-(5-(5-氯-6-氟-7-(1-(2,2,2-三氟乙酰氨基)乙基)-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(7-(1-乙酰胺乙基)-5-氯-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(5-(5-氯-7-(1,3-二甲基脲基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(5-(5-氯-7-(1-(2,2-二氟乙酰胺基)乙基)-6-氟-1H-吲唑-4-基)吡唑[1,5-a]吡啶-2-基)-2-氟环丙烷-1-甲酰胺。
30.一种药物组合物,其包含药学上可接受的载体或稀释剂和如权利要求1-29中任一项所述的化合物或其药学上可接受的盐。
31.一种治疗患有与HPK1调节相关的疾病或病症的受试者的方法,包括:
向需要的受试者施用治疗有效量的如权利要求1至29中任一项所述的化合物或其药学上可接受的盐。
32.根据权利要求31所述的方法,其特征在于,所述疾病为癌症,其中如权利要求1所述的化合物与抗PD-1剂、抗PD-L1剂或抗CTLA4剂一起施用。
33.根据权利要求32所述的方法,其特征在于,所述疾病是癌症、转移、炎症或自身免疫疾病。
34.根据权利要求33所述的方法,其特征在于,所述癌症选自肿瘤癌、黑色素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病,包括但不限于膀胱癌、脑瘤、乳腺癌、宫颈癌、结直肠癌、食管癌、子宫内膜癌、肝细胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰腺癌、前列腺癌、肾癌和甲状腺癌、急性淋巴细胞白血病、急性髓系白血病、室管膜瘤、尤因肉瘤、胶质母细胞瘤、髓母细胞瘤、神经母细胞瘤、骨肉瘤、横纹肌肉瘤、横纹肌样癌和肾母细胞瘤(威尔姆氏肿瘤)。
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WO2023180976A1 (en) * | 2022-03-25 | 2023-09-28 | 1ST Biotherapeutics, Inc. | Indazoles as hematopoietic progenitor kinase 1 (hpk1) inhibitors and methods for using same |
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PE20070978A1 (es) * | 2006-02-14 | 2007-11-15 | Novartis Ag | COMPUESTOS HETEROCICLICOS COMO INHIBIDORES DE FOSFATIDILINOSITOL 3-QUINASAS (PI3Ks) |
ES2401557T3 (es) | 2007-08-02 | 2013-04-22 | Amgen, Inc | Moduladores de Pl3 cinasas y métodos de uso |
WO2009114874A2 (en) * | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
US20110178070A1 (en) * | 2008-06-24 | 2011-07-21 | Takeda Pharmaceutical Company Limited | PI3K/mTOR INHIBITORS |
US8450321B2 (en) | 2008-12-08 | 2013-05-28 | Gilead Connecticut, Inc. | 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor |
EP3123864A1 (en) | 2008-12-08 | 2017-02-01 | Gilead Connecticut, Inc. | Imidazopyrazine syk inhibitors |
WO2010100144A1 (en) | 2009-03-04 | 2010-09-10 | Merck Serono S.A. | Fused bicyclic compounds as inhibitors for pi3 kinase |
WO2010119264A1 (en) | 2009-04-16 | 2010-10-21 | Centro Nacional De Investigaciones Oncólogicas (Cnio) | Imidazopyrazines for use as kinase inhibitors |
CA2787714C (en) | 2010-01-22 | 2019-04-09 | Joaquin Pastor Fernandez | Inhibitors of pi3 kinase |
WO2012052745A1 (en) * | 2010-10-21 | 2012-04-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Combinations of pi3k inhibitors with a second anti -tumor agent |
AR086042A1 (es) | 2011-04-28 | 2013-11-13 | Galapagos Nv | Compuesto util para el tratamiento de enfermedades degenerativas e inflamatorias y composicion farmaceutica |
WO2013130855A1 (en) | 2012-03-02 | 2013-09-06 | Takeda Pharmaceutical Company Limited | Indazole derivatives |
PL236355B1 (pl) | 2015-04-02 | 2021-01-11 | Celon Pharma Spolka Akcyjna | Pochodne 7-(morfolin-4-ylo)pirazolo[1,5-α]pirymidyny jako inhibitory kinazy PI3 |
KR20200051832A (ko) * | 2017-10-02 | 2020-05-13 | (주)퍼스트바이오 테라퓨틱스 | 벤조티아졸 화합물 및 신경퇴행성 질환을 치료하기 위한 그의 사용 방법 |
CN109721620B (zh) | 2017-10-27 | 2022-05-13 | 药捷安康(南京)科技股份有限公司 | Hpk1抑制剂及其用途 |
WO2020170206A1 (en) | 2019-02-22 | 2020-08-27 | 1ST Biotherapeutics, Inc. | Imidazopyridinyl compounds and use thereof for treatment of proliferative disorders |
TW202220999A (zh) * | 2020-09-28 | 2022-06-01 | 南韓商福斯特生物股份有限公司 | 作為造血前驅細胞激酶1(hpk1)抑制劑的吲唑及其使用方法 |
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CA3193865A1 (en) | 2022-03-31 |
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US11834467B2 (en) | 2023-12-05 |
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