CN114599653A - 作为造血祖细胞激酶1(hpk1)抑制剂的吲唑及其使用方法 - Google Patents
作为造血祖细胞激酶1(hpk1)抑制剂的吲唑及其使用方法 Download PDFInfo
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- CN114599653A CN114599653A CN202180003294.1A CN202180003294A CN114599653A CN 114599653 A CN114599653 A CN 114599653A CN 202180003294 A CN202180003294 A CN 202180003294A CN 114599653 A CN114599653 A CN 114599653A
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- Prior art keywords
- fluoro
- indazol
- imidazo
- carboxamide
- pyrazin
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- HGBIXXKSAQAUPE-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-hydroxypropan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(CO)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F HGBIXXKSAQAUPE-SNZBGZMYSA-N 0.000 claims 2
- URRAQCREYRUNMN-ZNVNOEFISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-imidazol-1-ylethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1C=NC=C1 URRAQCREYRUNMN-ZNVNOEFISA-N 0.000 claims 2
- MMOPNUXKKXWAQQ-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methylsulfanylethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)SC MMOPNUXKKXWAQQ-SNZBGZMYSA-N 0.000 claims 2
- IJGZGKUVGUPURU-AOSPTPAASA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-fluorocyclopropyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C(C3)C3F)C(F)=C2Cl)N=C2)C2=N1 IJGZGKUVGUPURU-AOSPTPAASA-N 0.000 claims 2
- UGXDIKBOCXRLSV-VYMOZUCKSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-hydroxycyclopentyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(CCC1)C1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F UGXDIKBOCXRLSV-VYMOZUCKSA-N 0.000 claims 2
- WHQPCNXCGODLTJ-MXYZKLHESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methoxycyclopentyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound COC(CCC1)C1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F WHQPCNXCGODLTJ-MXYZKLHESA-N 0.000 claims 2
- CIGJDHMPZWXQDZ-MFKMUULPSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methylprop-1-enyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)=CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F CIGJDHMPZWXQDZ-MFKMUULPSA-N 0.000 claims 2
- OQMHYWNADCZIOJ-MFKMUULPSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methylpropyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F OQMHYWNADCZIOJ-MFKMUULPSA-N 0.000 claims 2
- DIFIRGRGDZZULA-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methylpyrazol-3-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN1N=CC=C1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F DIFIRGRGDZZULA-KOLCDFICSA-N 0.000 claims 2
- ASHGUNGHEFPUPT-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methylpyrrol-1-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=CC=CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ASHGUNGHEFPUPT-YPMHNXCESA-N 0.000 claims 2
- WJAOWWNYOPOPIK-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C=C(C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F WJAOWWNYOPOPIK-SCZZXKLOSA-N 0.000 claims 2
- ZYTDATCWOCLXKD-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-methylbut-1-en-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)C(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=C ZYTDATCWOCLXKD-YPMHNXCESA-N 0.000 claims 2
- LMGAIDISQFOEFH-KCJUWKMLSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(methylsulfanylmethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSCC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LMGAIDISQFOEFH-KCJUWKMLSA-N 0.000 claims 2
- IGFIUDDUTIXHMH-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(oxolan-3-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3COCC3)C(F)=C2Cl)N=C2)C2=N1 IGFIUDDUTIXHMH-YWTFCRFGSA-N 0.000 claims 2
- PVMMCPPFLXTCOS-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(prop-2-ynylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C#CCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PVMMCPPFLXTCOS-KOLCDFICSA-N 0.000 claims 2
- LOCQDPAQBWMVMF-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(propan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LOCQDPAQBWMVMF-KOLCDFICSA-N 0.000 claims 2
- ITLLPDKAFUALEK-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(propylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ITLLPDKAFUALEK-KOLCDFICSA-N 0.000 claims 2
- FQEGIKCNABRYEY-KKZNHRDASA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1R)-1-(tetrazol-2-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=NC=N1 FQEGIKCNABRYEY-KKZNHRDASA-N 0.000 claims 2
- MWRXOSAUHAOOPD-NGZCFLSTSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1S)-1-(tetrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=NN=C1 MWRXOSAUHAOOPD-NGZCFLSTSA-N 0.000 claims 2
- VBNPSNFKPUJIHN-MRTMQBJTSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2R)-1,1,1-trifluoropropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VBNPSNFKPUJIHN-MRTMQBJTSA-N 0.000 claims 2
- VBNPSNFKPUJIHN-XKSSXDPKSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VBNPSNFKPUJIHN-XKSSXDPKSA-N 0.000 claims 2
- QEXJMUHFHMDBLU-FOGDFJRCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2S)-1-methoxypropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](COC)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F QEXJMUHFHMDBLU-FOGDFJRCSA-N 0.000 claims 2
- NZCMKEZXZFGODE-RISCZKNCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(4-methylpyrazol-1-yl)methyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=CN(CC2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)N=C1 NZCMKEZXZFGODE-RISCZKNCSA-N 0.000 claims 2
- IQJUIUMBNZYNOA-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(4-methylimidazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1C=NC(C)=C1 IQJUIUMBNZYNOA-AOUZGSJDSA-N 0.000 claims 2
- XREYTABGTXMKAJ-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(methanesulfonamido)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NS(C)(=O)=O XREYTABGTXMKAJ-SNZBGZMYSA-N 0.000 claims 2
- NNWGVHLYRWBOOJ-VWHDNNRLSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-[(2,2,2-trifluoroacetyl)amino]ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)(F)F)=O NNWGVHLYRWBOOJ-VWHDNNRLSA-N 0.000 claims 2
- OGGZRWZTORSMPY-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(propan-2-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F OGGZRWZTORSMPY-PWSUYJOCSA-N 0.000 claims 2
- WQYPPFVSSQFASZ-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl-(2-methylpyrazol-3-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=CC=NN1C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F WQYPPFVSSQFASZ-PWSUYJOCSA-N 0.000 claims 2
- WVIVJKDAOPZHBJ-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-7-(1,1-difluoroprop-1-en-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=C(F)F WVIVJKDAOPZHBJ-SCZZXKLOSA-N 0.000 claims 2
- UCNFEEWWUNACBT-VWHDNNRLSA-N (1S,2S)-N-[6-[5-chloro-7-(1,1-difluoropropan-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F UCNFEEWWUNACBT-VWHDNNRLSA-N 0.000 claims 2
- BDUGRPFJHXYYTG-PPHWZAGGSA-N (1S,2S)-N-[6-[5-chloro-7-(1,4-dioxan-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3OCCOC3)C(F)=C2Cl)N=C2)C2=N1 BDUGRPFJHXYYTG-PPHWZAGGSA-N 0.000 claims 2
- YWBTXAGMERBJOH-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-7-(1-cyanoethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)C#N YWBTXAGMERBJOH-SNZBGZMYSA-N 0.000 claims 2
- AKENPIWZWRAQMQ-APPZFPTMSA-N (1S,2S)-N-[6-[5-chloro-7-(2,2-difluoroethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NCC(F)F)N=C2)C2=N1 AKENPIWZWRAQMQ-APPZFPTMSA-N 0.000 claims 2
- LTKXRMYSLVONST-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-(cyclobutylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2CCC2)N=C2)C2=N1 LTKXRMYSLVONST-PWSUYJOCSA-N 0.000 claims 2
- WHHNMKYHDCOSNZ-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-(cyclopropylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2CC2)N=C2)C2=N1 WHHNMKYHDCOSNZ-KOLCDFICSA-N 0.000 claims 2
- NPZUWHORWVARFS-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-(cyclopropylmethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NCC2CC2)N=C2)C2=N1 NPZUWHORWVARFS-PWSUYJOCSA-N 0.000 claims 2
- AKTUDXMFMCXAJL-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F AKTUDXMFMCXAJL-SCZZXKLOSA-N 0.000 claims 2
- GRQDHBMNIXROEX-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-7-(ethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GRQDHBMNIXROEX-SCZZXKLOSA-N 0.000 claims 2
- QMKHBGYZDQMHPZ-VWHDNNRLSA-N (1S,2S)-N-[6-[5-chloro-7-[1-[(2,2-difluoroacetyl)amino]ethyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)F)=O QMKHBGYZDQMHPZ-VWHDNNRLSA-N 0.000 claims 2
- NEHXGWXIAMYAIT-IKZKJGMZSA-N (1S,2S)-N-[6-[5-chloro-7-[cyano-[(2,2,2-trifluoroacetyl)amino]methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)(F)F)=O NEHXGWXIAMYAIT-IKZKJGMZSA-N 0.000 claims 2
- QGMHAELSTOVJFV-QICSLXPLSA-N (1S,2S)-N-[6-[5-chloro-7-[cyano-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC([C@H](C1)[C@H]1F)=O QGMHAELSTOVJFV-QICSLXPLSA-N 0.000 claims 2
- JUHWPXTXXBCDJS-JTWFHRJASA-N (1S,2S)-N-[6-[5-chloro-7-[cyclopropyl(hydroxy)methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(C1CC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F JUHWPXTXXBCDJS-JTWFHRJASA-N 0.000 claims 2
- WHXVADORTTUIIS-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-[cyclopropyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1CC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F WHXVADORTTUIIS-PWSUYJOCSA-N 0.000 claims 2
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- COAHKJCYTXJZMI-OCCSQVGLSA-N (1S,2S)-N-[6-[5-ethyl-6-fluoro-7-(propan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1NC(C)C)=C1F COAHKJCYTXJZMI-OCCSQVGLSA-N 0.000 claims 2
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- FUZYLAVLRYDZTG-PWSUYJOCSA-N (1S,2S)-N-[6-(5-chloro-6-fluoro-7-prop-2-ynyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C#CCC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F FUZYLAVLRYDZTG-PWSUYJOCSA-N 0.000 claims 1
- CGTPRAWFRNHNMZ-KOLCDFICSA-N (1S,2S)-N-[6-(5-chloro-7-ethenyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C=CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F CGTPRAWFRNHNMZ-KOLCDFICSA-N 0.000 claims 1
- DVQYGSKGJGQZKB-SCZZXKLOSA-N (1S,2S)-N-[6-(5-chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(NN=C1)=C1C(C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C1Cl)=C1F DVQYGSKGJGQZKB-SCZZXKLOSA-N 0.000 claims 1
- HXFHFIJXZFGBKJ-KOLCDFICSA-N (1S,2S)-N-[6-(5-ethoxy-6-fluoro-7-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1SC)=C1F HXFHFIJXZFGBKJ-KOLCDFICSA-N 0.000 claims 1
- LSHANDUEKTVYEM-KOLCDFICSA-N (1S,2S)-N-[6-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1F)=C1F LSHANDUEKTVYEM-KOLCDFICSA-N 0.000 claims 1
- CKQUTXAQPVZKGJ-KOLCDFICSA-N (1S,2S)-N-[6-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(F)=C(C1=C2C=NN1)F)=C2C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 CKQUTXAQPVZKGJ-KOLCDFICSA-N 0.000 claims 1
- NMWSMWRTLFGRBO-PWSUYJOCSA-N (1S,2S)-N-[6-(5-ethyl-6-fluoro-7-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1SC)=C1F NMWSMWRTLFGRBO-PWSUYJOCSA-N 0.000 claims 1
- SSSUELPFBHXWCD-OCCSQVGLSA-N (1S,2S)-N-[6-(5-ethyl-6-fluoro-7-propan-2-yl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1C(C)C)=C1F SSSUELPFBHXWCD-OCCSQVGLSA-N 0.000 claims 1
- LXDGWHBTCQECNG-SCZZXKLOSA-N (1S,2S)-N-[6-(6,7-difluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1F)=C1F LXDGWHBTCQECNG-SCZZXKLOSA-N 0.000 claims 1
- IGKNMWCGRSZZGS-SCZZXKLOSA-N (1S,2S)-N-[6-(6,7-difluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)=C(C1=C2C=NN1)F)=C2C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 IGKNMWCGRSZZGS-SCZZXKLOSA-N 0.000 claims 1
- LOANMTOYZYENDZ-APPZFPTMSA-N (1S,2S)-N-[6-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C(C=NN1)C1=C1F)=C1F LOANMTOYZYENDZ-APPZFPTMSA-N 0.000 claims 1
- OZMBNYSKFNSTPQ-APPZFPTMSA-N (1S,2S)-N-[6-(6,7-difluoro-5-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CSC(C(F)=C(C1=C2C=NN1)F)=C2C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 OZMBNYSKFNSTPQ-APPZFPTMSA-N 0.000 claims 1
- YJYSYRJSJFPHNH-SCZZXKLOSA-N (1S,2S)-N-[6-(7-acetyl-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O YJYSYRJSJFPHNH-SCZZXKLOSA-N 0.000 claims 1
- DIMDVFPOSBWXLH-SVRRBLITSA-N (1S,2S)-N-[6-(7-amino-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F DIMDVFPOSBWXLH-SVRRBLITSA-N 0.000 claims 1
- RKSFCYACAKQGKA-PWSUYJOCSA-N (1S,2S)-N-[6-(7-ethoxy-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(F)=C1C)=C2NN=CC2=C1C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 RKSFCYACAKQGKA-PWSUYJOCSA-N 0.000 claims 1
- QJHSCCDABCLVOC-PWSUYJOCSA-N (1S,2S)-N-[6-(7-ethoxy-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(NN=C1)=C1C(C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C1C)=C1F QJHSCCDABCLVOC-PWSUYJOCSA-N 0.000 claims 1
- BBVKKNCONISCAR-KOLCDFICSA-N (1S,2S)-N-[6-(7-ethoxy-6-fluoro-5-methylsulfanyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(SC)=C1F BBVKKNCONISCAR-KOLCDFICSA-N 0.000 claims 1
- FQKINZZIZNLMSM-VWHDNNRLSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-fluoroethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)F FQKINZZIZNLMSM-VWHDNNRLSA-N 0.000 claims 1
- ODAYHWXBXXQKDK-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-fluoropropan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(CF)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ODAYHWXBXXQKDK-SNZBGZMYSA-N 0.000 claims 1
- SEPWQJIVFXOHPE-JZHZUCMVSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-hydroxy-3-trimethylsilylprop-2-ynyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[Si](C)(C)C#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)O SEPWQJIVFXOHPE-JZHZUCMVSA-N 0.000 claims 1
- GDFFCHGWXAPMHJ-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-hydroxycyclopentyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC1(CCCC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GDFFCHGWXAPMHJ-PWSUYJOCSA-N 0.000 claims 1
- RMEPXTXBQTXCRA-RWPGAEDHSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-hydroxyprop-2-ynyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)O RMEPXTXBQTXCRA-RWPGAEDHSA-N 0.000 claims 1
- VIJDHQYDUAYARN-QUXRYKJESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methoxy-2-methylpropyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)C(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)OC VIJDHQYDUAYARN-QUXRYKJESA-N 0.000 claims 1
- WHMSNBSXPHTSCW-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methoxyethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)OC WHMSNBSXPHTSCW-SNZBGZMYSA-N 0.000 claims 1
- QEXJMUHFHMDBLU-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methoxypropan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(COC)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F QEXJMUHFHMDBLU-YWTFCRFGSA-N 0.000 claims 1
- VRBXORURVMMULP-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methoxypropan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(COC)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VRBXORURVMMULP-YWTFCRFGSA-N 0.000 claims 1
- GYUZABNCRWIVNQ-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methylpyrrol-3-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C=C1)C=C1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GYUZABNCRWIVNQ-YPMHNXCESA-N 0.000 claims 1
- MKFYTZGNKZHDHF-GWNVKBESSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-methylsulfinylethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)S(C)=O MKFYTZGNKZHDHF-GWNVKBESSA-N 0.000 claims 1
- HRKDKYLXGFRAQZ-ZNVNOEFISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1-pyrazol-1-ylethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC=C1 HRKDKYLXGFRAQZ-ZNVNOEFISA-N 0.000 claims 1
- VTTVFASUUWIQMQ-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1H-pyrazol-5-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2=CC=NN2)N=C2)C2=N1 VTTVFASUUWIQMQ-SCZZXKLOSA-N 0.000 claims 1
- BEHKPLZAYSQJFC-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(1H-pyrrol-3-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3=CNC=C3)C(F)=C2Cl)N=C2)C2=N1 BEHKPLZAYSQJFC-PWSUYJOCSA-N 0.000 claims 1
- JEFPTCHRYAAFQP-HLYRCDQVSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F JEFPTCHRYAAFQP-HLYRCDQVSA-N 0.000 claims 1
- NJTGCASTUJMSTN-WZKUZMHBSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound COC(C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NJTGCASTUJMSTN-WZKUZMHBSA-N 0.000 claims 1
- GQDKPRQPCZZYJC-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-fluoropropan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)F GQDKPRQPCZZYJC-SCZZXKLOSA-N 0.000 claims 1
- RKBVGHYHUFSBLL-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-hydroxyethylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F RKBVGHYHUFSBLL-SCZZXKLOSA-N 0.000 claims 1
- QHUXNLWVUUXHAP-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-hydroxypropan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)O QHUXNLWVUUXHAP-SCZZXKLOSA-N 0.000 claims 1
- BOHJGJBJDNHHAU-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methyl-1H-imidazol-5-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=NC=C(C2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)N1 BOHJGJBJDNHHAU-KOLCDFICSA-N 0.000 claims 1
- KTGQINUIORANMD-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(2-methylpropanoyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)C(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O KTGQINUIORANMD-KOLCDFICSA-N 0.000 claims 1
- VWOIZQSAQATFQT-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-fluoropyrrolidin-1-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2N(CC2)CC2F)N=C2)C2=N1 VWOIZQSAQATFQT-YWTFCRFGSA-N 0.000 claims 1
- MAPOAVJTMMFTPW-PTFDWCFRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-hydroxybutan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(C)O)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F MAPOAVJTMMFTPW-PTFDWCFRSA-N 0.000 claims 1
- YYADGKKJFLWCEE-ZNVNOEFISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-hydroxycyclopenten-1-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(CC1)C=C1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F YYADGKKJFLWCEE-ZNVNOEFISA-N 0.000 claims 1
- GYIKJTWPYIIQTQ-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-hydroxyprop-1-ynyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCC#CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GYIKJTWPYIIQTQ-PWSUYJOCSA-N 0.000 claims 1
- OOAJUYKREZEZRA-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-hydroxypropylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCCCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F OOAJUYKREZEZRA-KOLCDFICSA-N 0.000 claims 1
- PZQICGNFTCJPSE-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(3-hydroxypyrrolidin-1-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OC(CC1)CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PZQICGNFTCJPSE-YWTFCRFGSA-N 0.000 claims 1
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- KTODKKZSKSFAMG-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(furan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3=CC=CO3)C(F)=C2Cl)N=C2)C2=N1 KTODKKZSKSFAMG-KOLCDFICSA-N 0.000 claims 1
- NEQLLPJLJHARRJ-MFKMUULPSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(imidazol-1-ylmethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(CN3C=NC=C3)C(F)=C2Cl)N=C2)C2=N1 NEQLLPJLJHARRJ-MFKMUULPSA-N 0.000 claims 1
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- BZCGZZIQAZMXSN-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(morpholin-4-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NN2CCOCC2)N=C2)C2=N1 BZCGZZIQAZMXSN-PWSUYJOCSA-N 0.000 claims 1
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- ADTLLHXZZYRVEX-PPHWZAGGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(oxolan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3OCCC3)C(F)=C2Cl)N=C2)C2=N1 ADTLLHXZZYRVEX-PPHWZAGGSA-N 0.000 claims 1
- PKILGWBYBPHKEU-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(oxolan-3-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2COCC2)N=C2)C2=N1 PKILGWBYBPHKEU-YWTFCRFGSA-N 0.000 claims 1
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- BWPKGWKKQPSKKH-RISCZKNCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(pyrrol-1-ylmethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(CN3C=CC=C3)C(F)=C2Cl)N=C2)C2=N1 BWPKGWKKQPSKKH-RISCZKNCSA-N 0.000 claims 1
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- YYIKKXHNFJNHGW-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1-hydroxy-2-methylpropan-2-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(CO)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F YYIKKXHNFJNHGW-KOLCDFICSA-N 0.000 claims 1
- MWRXOSAUHAOOPD-KKZNHRDASA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1R)-1-(tetrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=NN=C1 MWRXOSAUHAOOPD-KKZNHRDASA-N 0.000 claims 1
- FQEGIKCNABRYEY-NGZCFLSTSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(1S)-1-(tetrazol-2-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=NC=N1 FQEGIKCNABRYEY-NGZCFLSTSA-N 0.000 claims 1
- NXAIBNKDKAESPV-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2-methylpyrazol-3-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN1N=CC=C1NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NXAIBNKDKAESPV-KOLCDFICSA-N 0.000 claims 1
- RQYZBWPLXGLHQX-DOMZBBRYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2-methylpyrrol-1-yl)methyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=CC=CN1CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F RQYZBWPLXGLHQX-DOMZBBRYSA-N 0.000 claims 1
- QEXJMUHFHMDBLU-UMNHJUIQSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(2R)-1-methoxypropan-2-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@@H](COC)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F QEXJMUHFHMDBLU-UMNHJUIQSA-N 0.000 claims 1
- SMNGHXNFBPXHKS-PTFDWCFRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(3-fluorocyclobutyl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC(C2)CC2F)N=C2)C2=N1 SMNGHXNFBPXHKS-PTFDWCFRSA-N 0.000 claims 1
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- CTIYKKAJLOUIBY-WZRBSPASSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(3R)-3-methoxypyrrolidin-1-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CO[C@H](CC1)CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F CTIYKKAJLOUIBY-WZRBSPASSA-N 0.000 claims 1
- PZQICGNFTCJPSE-UMNHJUIQSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O[C@@H](CC1)CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PZQICGNFTCJPSE-UMNHJUIQSA-N 0.000 claims 1
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- VXUVZQDSCOUZGN-FEHORCSSSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(E)-3-triethylsilylprop-1-enyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC[Si](CC)(CC)C/C=C/C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F VXUVZQDSCOUZGN-FEHORCSSSA-N 0.000 claims 1
- KHRQPSUJLDOZRB-RLDWSQPBSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(E)-4-hydroxybut-1-enyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound OCC/C=C/C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F KHRQPSUJLDOZRB-RLDWSQPBSA-N 0.000 claims 1
- ILZXBINLSXJZJZ-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(1,2,4-triazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CN=C1 ILZXBINLSXJZJZ-YWTFCRFGSA-N 0.000 claims 1
- XQMHVBBHFWTREI-VOHIISRTSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(2-methylimidazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1C(C)=NC=C1 XQMHVBBHFWTREI-VOHIISRTSA-N 0.000 claims 1
- UWGNMVNFWANSEC-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(3-methylpyrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=C(C)C=C1 UWGNMVNFWANSEC-AOUZGSJDSA-N 0.000 claims 1
- JAHNKHRKGLHUPP-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(4-methylpyrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC(C)=C1 JAHNKHRKGLHUPP-AOUZGSJDSA-N 0.000 claims 1
- RWBDIIYSDJZLQO-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(5-methylpyrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC=C1C RWBDIIYSDJZLQO-AOUZGSJDSA-N 0.000 claims 1
- FCUWLVTYJWOHAX-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(propanoylamino)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCC(NC(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O FCUWLVTYJWOHAX-YWTFCRFGSA-N 0.000 claims 1
- XEKOZEKLRINBIP-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(triazol-2-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC=N1 XEKOZEKLRINBIP-YWTFCRFGSA-N 0.000 claims 1
- SPUGTHIKXGYGNT-CZXHOFHRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[[(1R,3S)-3-hydroxycyclopentyl]-methylamino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN([C@H](CC1)C[C@H]1O)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F SPUGTHIKXGYGNT-CZXHOFHRSA-N 0.000 claims 1
- KHJSYOJYUXWIRG-WGBDABJCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[[(1S,3R)-3-hydroxycyclopentyl]amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O[C@H](CC1)C[C@H]1NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F KHJSYOJYUXWIRG-WGBDABJCSA-N 0.000 claims 1
- KHRCNLLSSCKKIV-BYNQJWBRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[[(2R,3R)-3-methoxybutan-2-yl]-methylamino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H]([C@@H](C)OC)N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F KHRCNLLSSCKKIV-BYNQJWBRSA-N 0.000 claims 1
- KQPNTIBMWVHEDR-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(1H-pyrazol-5-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=CC=NN1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F KQPNTIBMWVHEDR-KOLCDFICSA-N 0.000 claims 1
- GELXMLGWJNUSKL-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(methylcarbamoyl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CNC(N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O GELXMLGWJNUSKL-SCZZXKLOSA-N 0.000 claims 1
- LAAGAFUKQVIJQA-ZNVNOEFISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(oxolan-3-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1COCC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LAAGAFUKQVIJQA-ZNVNOEFISA-N 0.000 claims 1
- GJMIZUNZLLSKLW-WBVHZDCISA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=CC=NN1COCC[Si](C)(C)C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GJMIZUNZLLSKLW-WBVHZDCISA-N 0.000 claims 1
- IAPKMOREAFOZOM-WPLSFSDESA-N (1S,2S)-N-[6-[5-chloro-7-(1-cyclopropylethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1CC1)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F IAPKMOREAFOZOM-WPLSFSDESA-N 0.000 claims 1
- ZRRRAWZAIYRGGI-VRCHLBOPSA-N (1S,2S)-N-[6-[5-chloro-7-(1-ethoxy-2,2,2-trifluoroethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ZRRRAWZAIYRGGI-VRCHLBOPSA-N 0.000 claims 1
- JVPQYMMARFJNGD-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-(2,3-dihydro-1,4-dioxin-5-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3=COCCO3)C(F)=C2Cl)N=C2)C2=N1 JVPQYMMARFJNGD-KOLCDFICSA-N 0.000 claims 1
- ZICIEQHLOJCTJT-PPHWZAGGSA-N (1S,2S)-N-[6-[5-chloro-7-(2,5-dihydrofuran-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3OCC=C3)C(F)=C2Cl)N=C2)C2=N1 ZICIEQHLOJCTJT-PPHWZAGGSA-N 0.000 claims 1
- VWPGDNCTVIJLCN-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-(2-cyanopropan-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)C#N VWPGDNCTVIJLCN-KOLCDFICSA-N 0.000 claims 1
- VZJQGLRTXZFFBD-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-7-(3,3-difluoroazetidin-1-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2N(C2)CC2(F)F)N=C2)C2=N1 VZJQGLRTXZFFBD-SCZZXKLOSA-N 0.000 claims 1
- LMFOEJQDEPZGTQ-ZNVNOEFISA-N (1S,2S)-N-[6-[5-chloro-7-(5,5-dimethyloxolan-3-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)(C1)OCC1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LMFOEJQDEPZGTQ-ZNVNOEFISA-N 0.000 claims 1
- VHOMQEUAMIQYAM-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2N2CC(C3)(CC3(F)F)C2)N=C2)C2=N1 VHOMQEUAMIQYAM-PWSUYJOCSA-N 0.000 claims 1
- NMTOAMHIEUWIHO-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-(cyanomethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CCC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F NMTOAMHIEUWIHO-KOLCDFICSA-N 0.000 claims 1
- URXREUDKCZZMMF-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-7-(cyclopentylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2CCCC2)N=C2)C2=N1 URXREUDKCZZMMF-YPMHNXCESA-N 0.000 claims 1
- PLTXDJYJERJABK-SVRRBLITSA-N (1S,2S)-N-[6-[5-chloro-7-(difluoromethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C(F)F)C(F)=C2Cl)N=C2)C2=N1 PLTXDJYJERJABK-SVRRBLITSA-N 0.000 claims 1
- HACQIIMLQKSKPF-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C(C(NN=C1)=C1C(C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C1Cl)=C1F HACQIIMLQKSKPF-SCZZXKLOSA-N 0.000 claims 1
- FKBBGYQVIRNYKK-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-[(1,3-dihydroxy-2-methylpropan-2-yl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(CO)(CO)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F FKBBGYQVIRNYKK-KOLCDFICSA-N 0.000 claims 1
- HJAPFTCQFLTTDY-AZMKCTDRSA-N (1S,2S)-N-[6-[5-chloro-7-[(1S,2R)-1,2-dihydroxypropyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H]([C@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)O)O HJAPFTCQFLTTDY-AZMKCTDRSA-N 0.000 claims 1
- HJVIORPKFYSGNR-FTGZGXTLSA-N (1S,2S)-N-[6-[5-chloro-7-[(1S,2R)-1,2-dimethoxypropyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C[C@H]([C@H](C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)OC)OC HJVIORPKFYSGNR-FTGZGXTLSA-N 0.000 claims 1
- KBTBLROZWNRMGI-UKWYHXRUSA-N (1S,2S)-N-[6-[5-chloro-7-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O[C@@H](CN(C1)C2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)[C@H]1O KBTBLROZWNRMGI-UKWYHXRUSA-N 0.000 claims 1
- XGSKNJGZEJBOLY-WCUVEOEZSA-N (1S,2S)-N-[6-[5-chloro-7-[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CO[C@@H](CN(C1)C2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)[C@H]1OC XGSKNJGZEJBOLY-WCUVEOEZSA-N 0.000 claims 1
- XOCRANZZQJQCLP-SKDRFNHKSA-N (1S,2S)-N-[6-[5-chloro-7-[(dimethylamino)methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F XOCRANZZQJQCLP-SKDRFNHKSA-N 0.000 claims 1
- MXYRBULCJMPPJO-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-7-[1,1-difluoropropan-2-yl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)F)N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F MXYRBULCJMPPJO-SNZBGZMYSA-N 0.000 claims 1
- PNIRACXDKFFUBC-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-7-[1-(dimethylamino)-1-oxopropan-2-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(N(C)C)=O)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PNIRACXDKFFUBC-YWTFCRFGSA-N 0.000 claims 1
- CTYXIGQVUPSAHZ-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-7-[1-(ethylamino)-1-oxopropan-2-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCNC(C(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O CTYXIGQVUPSAHZ-YWTFCRFGSA-N 0.000 claims 1
- GKVSEJIXJNSQMW-SKDRFNHKSA-N (1S,2S)-N-[6-[5-chloro-7-[2-(dimethylamino)-2-oxoethyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C(CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O GKVSEJIXJNSQMW-SKDRFNHKSA-N 0.000 claims 1
- XIFNQHSVPLXVKJ-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-[2-(dimethylamino)-2-oxoethyl]sulfanyl-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C)C(CSC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O XIFNQHSVPLXVKJ-KOLCDFICSA-N 0.000 claims 1
- WEFDKNORNZTQLG-IKZKJGMZSA-N (1S,2S)-N-[6-[5-chloro-7-[cyano(fluoro)methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)F WEFDKNORNZTQLG-IKZKJGMZSA-N 0.000 claims 1
- ICUYMSZRUDOHDX-HTDYCOQPSA-N (1S,2S)-N-[6-[5-chloro-7-[cyano(hydroxy)methyl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound N#CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)O ICUYMSZRUDOHDX-HTDYCOQPSA-N 0.000 claims 1
- JSYIFGTTZPDGRN-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-7-[ethyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C(C(NN=C1)=C1C(C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2)=C1Cl)=C1F JSYIFGTTZPDGRN-KOLCDFICSA-N 0.000 claims 1
- CQNGXTYKDGLXHT-XCBNKYQSSA-N (1S,2S)-N-[6-[7-(2-amino-2-oxoethyl)-5-chloro-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound NC(CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O CQNGXTYKDGLXHT-XCBNKYQSSA-N 0.000 claims 1
- VVMXMHMHSWRCRY-HXXSPTRESA-N (1S,2S)-N-[6-[7-(2-bromo-2-fluorocyclopropyl)-5-chloro-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C(C3)C3(F)Br)C(F)=C2Cl)N=C2)C2=N1 VVMXMHMHSWRCRY-HXXSPTRESA-N 0.000 claims 1
- JULJNNZFPPBTNB-KOLCDFICSA-N (1S,2S)-N-[6-[7-(azetidin-1-yl)-5-chloro-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2N2CCC2)N=C2)C2=N1 JULJNNZFPPBTNB-KOLCDFICSA-N 0.000 claims 1
- ZUQRELGNPZTQMX-PWSUYJOCSA-N (1S,2S)-N-[6-[7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C(F)=C(C1=C2C=NN1)N(C)C)=C2C(C=C1)=NN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 ZUQRELGNPZTQMX-PWSUYJOCSA-N 0.000 claims 1
- GKNFCDVXRBXMMT-WTQORWENSA-N (1S,2S)-N-[6-[7-[(1E)-buta-1,3-dienyl]-5-chloro-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C=C/C=C/C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F GKNFCDVXRBXMMT-WTQORWENSA-N 0.000 claims 1
- NIPDHCDTVBZHBM-YPMHNXCESA-N (1S,2S)-N-[6-[7-[ethyl(methyl)amino]-6-fluoro-5-methyl-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCN(C)C(C(F)=C1C)=C2NN=CC2=C1C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 NIPDHCDTVBZHBM-YPMHNXCESA-N 0.000 claims 1
- UOJNEESMDPEBQV-OCCSQVGLSA-N 1-[5-chloro-6-fluoro-4-[2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]imidazo[1,2-a]pyrazin-6-yl]-1H-indazol-7-yl]-N,N-dimethylpyrrole-3-carboxamide Chemical compound CN(C)C(C(C=C1)=CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O UOJNEESMDPEBQV-OCCSQVGLSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- FJAKJLVOBUNDSO-PWSUYJOCSA-N C=C=CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound C=C=CC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F FJAKJLVOBUNDSO-PWSUYJOCSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
本公开提供了式(I)化合物或其药学上可接受的盐、含有所述化合物的组合物、使用所述化合物治疗与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2020年9月28日提交的美国临时专利申请号63/084,059的权益和优先权。在本段落中确定的该申请的全部公开内容通过引用并入本文。
技术领域
本公开涉及造血祖细胞激酶1(HPK1)的抑制剂、含有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帮助对抗癌症和其他疾病的治疗方法。近年来,这种相对新的方法在治疗多种肿瘤类型方面取得了显著的临床成功,尤其是在免疫检查点抑制剂的治疗和嵌合抗原T细胞疗法方面。研究最多的检查点抑制剂包括CTLA4、PD-1或PD-L1抑制剂,其通过克服肿瘤位点的免疫抑制机制已显示出显著的抗肿瘤活性。
造血祖细胞激酶1(HPK1,MAP4K1)是一种丝氨酸/苏氨酸激酶,是MAP4K的成员。HPK1在造血细胞谱系的亚群中显著表达。HPK1是一种新发现的T淋巴细胞和树突状细胞活化中的关键负调节因子。最近已经证明,HPK1的激酶活性作为一种新的细胞内检查点分子在抗癌免疫中的重要作用,以及与现有检查点方案联合治疗的潜在优势。HPK1抑制有望具有双重功能,1、延长T细胞活化;2、通过树突状细胞增强APC功能。这种双重靶向可能协同工作用于肿瘤微环境中有效的免疫应答。因此,HPK1已被证实为抗癌免疫治疗的新靶点。使用本公开的化合物治疗的癌症的实例包括但不限于上皮癌、黑色素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病的所有形式,包括但不限于膀胱癌、脑肿瘤、乳腺癌、宫颈癌、结直肠癌、食道癌、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、急性髓性白血病、室管膜瘤、尤文氏肉瘤、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(威尔姆氏瘤)。
用小分子抑制剂抑制HPK1具有治疗癌症和其他疾病的潜力[Hernandez,S.,et.al.,(2018)Cell Reports 25,80-94]。
发明内容
本公开提供了作为有效的HPK1抑制剂和T细胞和树突细胞的双重激活剂的新型吲唑化合物和药学上可接受的盐。
本发明的一种实施方式是式(I)的化合物:
或其药学上可接受的盐、水合物、溶剂化物,其中,R1、R2、R3、R4、R5、Het、M和L如具体实施方式中所定义。
在另一种实施方式中,提供了一种药物组合物,其含有药学上可接受的载体或稀释剂和式(I)的化合物或其药学上可接受的盐。
在又一种实施方式中,提供了治疗患有与HPK1调节相关的疾病或病症的受试者的方法,包括:向受试者给药治疗有效量的式(I)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示例性的,并不旨在限制本公开、应用或用途。
定义
为清楚起见,本文定义了本公开中使用的通用术语。
本说明书交替使用术语“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的直链或支链烃基,即碳-碳sp2双键。在一种实施方式中,烯基具有2-12个碳原子。在一些实施方式中,烯基是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”是ROC(O)—,其中,R是本文定义的烷基。在各种实施方式中,R是C1-C10烷基或C1-C6烷基。
如本文所用,术语“烷基”是指直链或支链烃基。在一种实施方式中,烷基具有1-12个碳原子。在一些实施方式中,烷基是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1-6。例如,C1-C6烷基是指碳原子数为1-6的任意整数的烷基。
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基团是如本文所定义的烷基并且相同或不同。在各种实施方式中,R是C1-C10烷基或C1-C6烷基。烷氨基的实例包括甲氨基、乙氨基、丙氨基、丁氨基、二甲氨基、二乙氨基和甲乙氨基。
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的直链或支链碳链基团,即碳-碳sp三键。在一种实施方式中,炔基具有2-12个碳原子。在一些实施方式中,炔基是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”是指每个环中最多7个原子的任意单环或双环碳环,其中,至少一个环是芳香环,或包括与5或6元环烷基融合的碳环芳香基的5-14个碳原子的芳香环体系。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。碳环芳香基可以是未取代的或任选取代的。
如本文所用,术语“环烷基”是含有至少一个饱和的或部分不饱和的环结构并经由环碳连接的烃基。在各种实施方式中,它是指饱和的或部分不饱和的C3-C12环状部分,其实例包括环丙基、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“卤族”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基取代的烷氧基,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基取代的烷基部分。卤代烷基的实例包括—CF3和—CHF2。
如本文所用,术语“杂烷基”是指链中具有2-14个碳(在一些实施方式中,2-10个碳)的直链或支链烷基,其中一个或多个已被杂原子替代,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2-14个环碳原子并且除了环碳原子之外还有1-4个杂原子的饱和或部分不饱和的单环、双环或三环基团,杂原子选自P、N、O和S。在各种实施方式中,杂环基团通过碳或通过杂原子连接到另一部分,并且任选地在碳或杂原子上被取代。杂环基的实例包括氮杂环丁烷基、苯并咪唑基、苯并呋喃基、苯并呋喃唑基、苯并吡唑基、苯并三唑基、苯并苯硫基、苯并恶唑基、咔唑基、咔啉基、肉桂基、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、四氢噻喃基、四氢异喹啉基、四唑基、四唑吡啶基、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、六氢氮杂蒎基、哌嗪基、哌啶基、吡啶-2-酮基、吡咯烷基、吗啉基、硫吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并苯硫基、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-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由N、O和S组成的组的杂原子。3-或4-元杂环基的非限制性实例包括氮丙啶基、2H-氮丙啶基、环氧乙烷基、硫杂环丙烷基、氮杂环丁烷基、2,3-二氢氮杂环丁二烯基、氮杂环丁二烯基、1,3-二氮杂环丁烷基、氧杂环丁基、2H-氧杂基、硫杂环丁烷基和2H-硫杂基。
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该环中含有1-4个选自由N、O和S组成的组的杂原子。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、二苯并苯硫基、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、噻吩基和吡嗪基。杂芳基的连接可以通过芳香环发生,或者,如果杂芳基是双环或三环并且其中一个环不是芳香环或不含杂原子,则通过非芳香环或不含杂原子的环连接。“杂芳基”还应理解为包括任意含氮杂芳基的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。羟基烷氧基的一个实例是羟基乙氧基。
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,对于这种用途通常认为是安全的,国家或州政府的监管机构正式批准用于这种用途,或被列入美国药典或其他公认的用于动物尤其是人类的药典。
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的化合物一起给药的其他成分。
如本文所用,术语“药学上可接受的盐”是指可增强所期望的药理活性的盐。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,有机酸例如乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(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-羟基乙磺酸、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]oct-2-烯-1-羧酸、葡糖庚酸、4,4'-亚甲基双(3-羟基-2-萘甲基)酸、3-苯基丙酸、三甲基乙酸、叔丁乙酸、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、铁和锌离子形成的盐。胺盐的实例包括与氨和有机含氮碱形成的盐,其强度足以与羧酸形成盐。
如本文所用,术语“取代的”是指任意上述基团(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。在一种实施方式中,被取代基团的每个碳原子被不超过两个取代基取代。在另一种实施方式中,被取代基团的每个碳原子被不超过一个取代基取代。在酮取代基的情况下,两个氢原子被通过双键连接到碳上的氧取代。除非特别定义,取代基包括卤素、羟基、(低级)烷基、卤代烷基、单或二烷基氨基、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(例如,硫亚胺)和-SRa,其中,Ra和Rb相同或不同,并且独立地为-H、卤素、氨基、烷基、卤代烷基、芳基或杂环,或其中,Ra和Rb与它们所连接的氮原子一起形成杂环。基于所连接的原子,Ra和Rb可以是复数形式。
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、减缓或延迟疾病进展或疾病状态、或病症或疾病的症状。在一种实施方式中,本发明的方法提供了用于化合物组合的给药。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生物效应的量。
如本文所用,本文所用的术语“治疗(treatment)”或“治疗(treating)”是指改善或逆转疾病或病症的进展或严重性,或改善或逆转这种疾病或病症的一种或多种症状或副作用。如本文所用,“治疗(treatment)”或“治疗(treating)”还指抑制或阻断疾病或病症的体系、症状或状态的进展,如延迟、阻滞、约束、妨碍或阻碍。为了本发明的目的,“治疗(treatment)”或“治疗(treating)”进一步指获得有益的或期望的临床结果的方法,其中,“有益的或期望的临床结果”包括但不限于症状的减轻、病症或疾病程度的减少,稳定(即,不恶化)疾病或病症状态,疾病或病症状态的延迟或减缓,疾病或病症状态的改善或缓和,以及疾病或病症的缓解,部分或全部。
化合物
本公开提供了式(I)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为O或S;
L为键、-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地选自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、卤素、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R10和R11与它们所连接的氮原子一起形成任选被一个或多个基团取代的4-12元杂环基,基团选自由卤素、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组成的组;
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任选被一个或多个基团取代的4-8元杂环基,基团选自由卤素、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组成的组;
Het选自由以下组成的组:
Ra、Rb和Rc各自独立地为-H、-D、卤素、-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、卤素、羟基、-CD2OH、-CN、-NO2、卤代烷基、三甲基甲硅烷基乙氧基甲基、-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、杂芳基或杂环基任选地被一个或多个基团取代,基团选自由卤素、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组成的组;
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为键、-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、卤素、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基团取代,基团选自由卤素、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组成的组;并且
R5为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、羟基、-CH2OH、-CD2OH、-CN或卤代烷基。
在一些实施方式中,L为键,并且R1为环烷基,其任选地被一个或多个基团取代,基团选自由C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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组成的组。
在一些实施方式中,R2和R3各自独立地为-H、卤素、烷硫基、卤代烷基或烷基。
在一些实施方式中,M为键、-O-或-NR6-;并且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、卤素、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一个或多个基团取代,基团选自由卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-CD3、-NR10R11、-NR10S(O)2R9和-NR10C(=O)R9组成的组。
在另一种实施方式中,提供了式(II)的化合物:
其中,R1、R2、R3、R4、R5、Ra、Rb、M和L如上式(I)所定义。
在一些实施方式中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。非限制性的示例性的式(II)化合物包括表1的实施例1和2。
在另一种实施方式中,提供了式(III)的化合物:
其中,R1、R2、R3、R4、R5、Ra、Rb、M和L如上式(I)所定义。
在一些实施方式中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。非限制性的示例性的式(III)化合物包括表1的实施例3和23。
在另一种实施方式中,提供了式(IV)的化合物:
其中,R1、R2、R3、R4、R5、Ra、Rb、M和L如上式(I)所定义。非限制性的示例性的式(IV)化合物包括表1的实施例24和307。
在一些实施方式中,L为键,并且R1为环烷基,其任选地被一个或多个基团取代,基团选自由C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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组成的组。
在一些实施方式中,L为键;R1为环烷基,其任选被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组。在特定实施方式中,环烷基选自环丙基、环丁基和环戊基。
在一些实施方式中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤代烷基或卤素;R3为-H、烷基或卤素;M为键、-O-或-NR6-;R4为-H、卤素、烷基、单烷基氨基或二烷基氨基;R5为-H、烷基或卤素。在特定实施方式中,L为键;Ra为-H;Rb为-H;R1为被氯、氟、C1-C3烷基、C1-C3羟烷基或C1-C3卤代烷基取代的环丙基;R2为-H、烷基、氯或氟;R3为-H、烷基、氯或氟;M为键或-NH-;R4为-H、氯、氟、甲基、乙基、丙基、异丙基、丁基、甲氨基或二甲氨基;并且R5为-H或烷基。在特定实施方式中,L为键;Ra为-H;Rb为-H;R1为被氯或氟取代的环丙基;R2为-H、氯或氟;R3为-H、氯或氟;M为键或-NH-;R4为-H、氯、氟、甲基、乙基、丙基或异丙基;并且R5为-H。具有这种取代基的非限制性示例性化合物包括表1的实施例61、64、84、85、86、155、156和157。
在一些实施方式中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、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氨基;并且R5为-H、烷基或卤素。具有这种取代基的非限制性示例性化合物包括表1的实施例33、39、40、46、82、102、141、166、228和286。
在一些实施方式中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。具有这种取代基的非限制性示例性化合物包括表1的实施例26、27、34、38、41-44、50、58、62、63、66、68、73、77、79、80、83、87、88、90-92、94、96、101、105、107、110、113、116、118-120、128、130、131、133、134、136、141、153、160、162、166-168、170、173-176、179、181、183、186、188、190、191、194、208、210、213、215-219、221、223、226、228、232、235、237、248、250、252、257、261、262、264、266、268、269、272、273、284-290、295、300和302-305。
在一种实施方式中,提供了一种药物组合物,其含有药学上可接受的载体或稀释剂和式(I)的化合物或其药学上可接受的盐。
使用该化合物的医疗用途和治疗方法
本公开提供了治疗患有与HPK1调节相关的疾病或病症的受试者的方法,包括:向需要其的受试者给药治疗有效量的式(I)化合物或其药学上可接受的盐。在一些实施方式中,与HPK1的调节相关的疾病或病症为癌症、转移、炎症或包括自身免疫疾病的免疫疾病。
在一些其他实施方式中,疾病为癌症、转移、炎症或自身免疫疾病。在特定的实施方式中,癌症选自由上皮癌、黑色素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病组成的组,包括但不限于膀胱癌、脑肿瘤、乳腺癌、宫颈癌、结直肠癌、食道癌、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、急性髓性白血病、室管膜瘤、尤文氏肉瘤、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(威尔姆氏瘤)。
在一些实施方式中,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、伯杰氏病、大疱性类天疱疮、心肌病、乳糜泻、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、原发性混合性冷球蛋白血症、格雷夫斯病、格林-巴利综合征、桥本甲状腺炎、甲状腺功能减退症、自身免疫性淋巴综合征(ALPS)、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、幼年关节炎、扁平苔藓、红斑狼疮、梅尼埃病、混合性结缔组织病、多发性硬化症、重症肌无力、寻常型天疱疮、恶性贫血、多软骨炎、自身免疫性多腺体综合征、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、银屑病关节炎、雷诺氏现象、瑞特综合征、风湿热、类风湿关节炎、结节病、硬皮病、干燥综合征、僵人综合症、高安动脉炎、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。
在另一种实施方式中,提供了式(I)化合物或其药学上可接受的盐的用途,以制备药物用于抑制需要抑制HPK1活性的受试者的HPK1活性。在一些实施方式中,该用途包括治疗癌症或自身免疫疾病。
根据本公开的待治疗的合适受试者包括哺乳动物受试者。根据本公开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、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。在一种实施方式中,根据本公开的待治疗的合适受试者是人。
本公开的化合物通常以治疗有效量给药。本公开的化合物可以通过任何合适的途径以适于这种途径的药物组合物的形式并且以对预期治疗有效的剂量给药。有效剂量通常在约0.01-约1000mg/kg体重/天的范围内,优选约0.01-约500mg/kg/天,以单次或分次剂量。根据年龄、物种和所治疗的疾病或病症,低于该范围下限的剂量水平可能是合适的。在其他情况下,可以使用更大的剂量而没有有害的副作用。较大的剂量也可以分成几个较小的剂量,用于全天给药。确定合适剂量的方法在本公开所属的领域中是众所周知的。例如,雷明顿:可以使用The Science and Practice of Pharmacy,Mack Publishing Co.,20thed.,2000。
药物组合物、剂型和给药途径
为了治疗上述提及的疾病或病症,本文所述的化合物或其药学上可接受的盐可以如下给药:
口服给药
本公开的化合物可以口服给药,包括通过吞咽,使得化合物进入胃肠道,或直接从口腔吸收到血流中(例如,颊侧或舌下给药)。适合口服给药的组合物包括固体、液体、凝胶或粉末制剂,并具有诸如片剂、含片、胶囊、颗粒剂或粉末的剂型。用于口服给药的组合物可配制成立即释放或改性释放,包括延迟释放或缓释,任选地带有肠溶衣。液体制剂可包括溶液、糖浆和悬浮液,可用于软胶囊或硬胶囊。这种制剂可包括药学上可接受的载体,例如水、乙醇、聚乙二醇、纤维素或油。制剂还可包括一种或多种乳化剂和/或悬浮剂。
在片剂剂型中,按剂型的重量计,存在的药物量可为重量的约0.05%至约95%,更通常为约2%至约50%。另外,片剂可含有崩解剂,按重量计,含有约0.5%至约35%,更通常为剂型的约2%至约25%。崩解剂的实例包括但不限于乳糖、淀粉、羟基乙酸淀粉钠、交联聚维酮、交联羧甲基纤维素钠、麦芽糖糊精或其混合物。
用于片剂的合适润滑剂,按重量计,可为约0.1%至约5%,并且包括但不限于滑石、二氧化硅、硬脂酸、硬脂酸钙、硬脂酸锌或硬脂酸镁、富马酸硬脂酸钠等。
用于片剂的合适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。
用于片剂的合适增溶剂,按重量计,可为约0.1%至约3%,并且包括但不限于聚山梨醇酯、月桂基硫酸钠、十二烷基硫酸钠、碳酸丙烯酯、二甘醇单乙醚、異山梨醇二甲醚、蓖麻油聚乙二醇(天然或氢化)、HCORTM(Nikkol)、油基酯、GelucireTM、辛酸/辛酸单/双甘油酯、山梨醇酐脂肪酸酯和Solutol HSTM。
肠胃外给药
本公开的化合物可直接给药到血流、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。肠胃外给药的合适装置包括注射器(包括针式和无针式注射器)和输注方法。
用于肠胃外给药的组合物可配制成立即释放或改性释放,包括延迟释放或缓释。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载体一起使用,诸如无菌水。溶解度增强剂也可用于制备肠胃外溶液。
经皮给药
本公开的化合物可局部给药至皮肤或经皮给药。用于这种局部给药的制剂可包括乳液、溶液、乳膏、凝胶、水凝胶、软膏、泡沫、植入物、贴片等。用于局部给药制剂的药学上可接受的载体可包括水、醇、矿物油、甘油、聚乙二醇等。局部或经皮给药也可通过电穿孔、离子电渗疗法、声渗疗法等进行。用于局部给药的组合物可配制成立即释放或改性释放,包括延迟释放或缓释。
联合疗法
根据本公开的药物组合物可含有一种或多种附加治疗剂,例如,以增加疗效或减少副作用。因此,在一些实施方式中,药物组合物进一步含有一种或多种附加治疗剂,附加治疗剂选自用于治疗或抑制由HPK1直接或间接介导的疾病的活性成分。这种活性成分的实例是但不限于治疗癌症、转移、炎症或自身免疫发病机制的药剂。在一些实施方式中,式(I)化合物与抗PD-1剂、抗PD-L1剂或抗CTLA4剂一起给药。
制备药物组合物的参考文献
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公开所属领域中众所周知的。例如,根据Handbook of Pharmaceutical Excipients(7th ed.)、Remington:TheScience and Practice of Pharmacy(20th ed.)、Encyclopedia of PharmaceuticalTechnology(3rd ed.)或Sustained and Controlled Release Drug Delivery Systems(1978),可选择药学上可接受的赋形剂、载体、添加剂等,然后与本公开的化合物混合用于制成药物组合物。
本公开提供通过抑制HPK1活性而具有多种药理作用的化合物、具有该化合物作为有效药剂的药物组合物、医疗用途,特别是用于治疗由HPK1调节的疾病或病症,以及治疗或预防方法,包括向需要这种治疗或预防的受试者给药该化合物。本公开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,因此作为药物表现出优异的性质。
化合物制备
以下制备实施例说明可用于制备式(I)化合物的中间体化合物的制备。本文所述的新型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了本发明的实施方式。
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)的AcOH(100mL)溶液中加入N-氯琥珀酰亚胺(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。合并的有机层用饱和NaHCO3 200mL洗涤,经Na2SO4干燥,过滤并在减压下浓缩以得到残余物。获得呈黑色油状的粗产物(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)的AcOH(1.96L,0.05M)、H2O(0.065L,1.5M)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并用二氯甲烷(1L*2)萃取残余物。合并的有机层用饱和NaHCO3(1L)洗涤,经Na2SO4干燥,过滤并在减压下浓缩以得到残余物。获得呈棕色固体的粗产物(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)的THP(40mL)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。用乙酸乙酯萃取反应混合物并经MgSO4干燥。有机残余物通过柱色谱法(硅胶,己烷:乙酸乙酯=1:0-4:1)纯化。获得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)的硫酸(1.7mL)溶液中分批加入N-碘代琥珀酰亚胺(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,并用固体NaOH猝灭,然后用二氯甲烷萃取。真空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)的THP(40mL)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。用乙酸乙酯萃取反应混合物并经MgSO4干燥。有机残余物通过柱色谱法(硅胶,己烷:乙酸乙酯=1:0-4:1)纯化。获得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
向在0℃下搅拌的HNO3(12.63g,200.43mmol,9.02mL,5eq)的H2SO4(50mL)混合物中缓慢加入4-溴-5-氯-6-氟-1H-吲唑(10g,40.09mmol,1eq)。加入后将混合物在0℃下搅拌2小时。TLC(石油醚:乙酸乙酯=3:1)表明所有反应物都被消耗,并出现了一个新的主要点。将混合物倒入冰水中,用乙酸乙酯(50mL*3)萃取,合并的有机相经Na2SO4干燥,过滤并浓缩滤液获得呈黄色固体的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)的THF(40mL)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。用乙酸乙酯萃取反应混合物并经MgSO4干燥。有机残余物通过柱色谱法(硅胶,己烷:乙酸乙酯=1:0-4:1)纯化。获得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)的EtOH(5mL)和H2O(5mL)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,然后有机层经Na2SO4干燥,过滤并减压浓缩至得到残余物。通过prep-TLC(SiO2,石油醚/乙酸乙酯=1:1)纯化残余物。获得呈黄色油状的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)。
中间体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)的H2SO4(10mL)(98%纯度)的溶液中逐滴加入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,过滤并减压浓缩至得到残余物。获得呈黄色固体的4-溴-5-氯-6-氟-7-硝基-1H-吲唑(900mg,粗品)。
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)(粗品)的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NaHCO3(15mL*2)的饱和水溶液洗涤混合物,有机层经Na2SO4干燥,过滤并减压浓缩至得到残余物。残余物通过柱色谱法(SiO2,石油醚/乙酸乙酯=40/1-25:1,4-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。获得呈棕色固体的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)。获得呈黄色固体的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
1H NMR(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)的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,并将滤液浓缩以除去EtOH,然后用乙酸乙酯(20mL)稀释混合物,用水(20mL*2)洗涤混合物,然后有机层经Na2SO4干燥,过滤并减压浓缩至得到残余物。获得呈黄色固体的4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺(140mg,粗品)。
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N2下在0℃下向4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-胺(120mg,344.24umol,1eq)的THF(5mL)的溶液中分批加入NaH(34.42mg,860.59umol,60%纯度,2.5eq),然后将混合物在N2下在0℃下搅拌30分钟,然后逐滴加入MeI(293.16mg,2.06mmol,128.58uL,6eq),并将反应混合物在N2下在20℃下搅拌12小时。将反应混合物倒入NH4Cl的饱和水溶液(20mL)中,然后用乙酸乙酯(20mL*2)萃取混合物,合并的有机层经Na2SO4干燥,过滤并减压浓缩至得到残余物。通过prep-TLC(SiO2,石油醚/乙酸乙酯=5:1)纯化残余物。获得呈黄色油状的中间体1E(30mg,78.06umol,22.68%产率,98%纯度)。
中间体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)的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N2吹扫3次,然后加入丙-2-胺(0.19mL,2.18mmol,10eq)。将混合物在密封管中在90℃下搅拌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,过滤并在真空下浓缩滤液至得到残余物。通过硅胶色谱法(产物在己烷/乙酸乙酯=10/1时出现)纯化残余物以提供呈米色固体的中间体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)的甲醇(7.7mL)溶液中加入甲醛(0.572mL,7.68mmol,5.0eq)和乙酸(88μL,1.54mmol,1.0eq)。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。用H2O淬灭反应混合物并用乙酸乙酯(150mL*3)萃取。合并的有机层经Na2SO4干燥,过滤并在真空下浓缩滤液至得到残余物。通过硅胶色谱法(产物在己烷/乙酸乙酯=100/4时出现)纯化残余物以提供呈棕色油状的中间体1F(292mg,0.722mmol,47%产率)。
1H NMR(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,2H),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)的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。通过硅藻土滤饼过滤反应混合物,浓缩滤液以得到粗产物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1-3/1)纯化残余物。获得呈黄色固体的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)的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。残余物通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1-4/1)纯化以获得呈黄色固体的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N2下在0℃下向LAH(520.00mg,13.70mmol,1.5eq)的THF(50mL)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)的THF(100mL)溶液,加入后,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品。残余物通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1-2/1)纯化以获得呈黄色固体的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)的MeOH(50mL)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。残余物通过柱色谱法(SiO2,石油醚/乙酸乙酯=50/1-5/1)纯化以获得呈白色固体的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)的THF(10mL)的溶液中逐滴加入LDA(2M,1.87mL,2.5eq)。加入后,将混合物在该温度下搅拌2.5小时,然后在-78℃下逐滴加入MeI(319.12mg,2.25mmol,139.97uL,1.5eq)。并将所得混合物在20℃下搅拌16小时。将混合物倒入饱和的NH4Cl中并用EA20mL萃取。浓缩有机层。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1-10/1)纯化残余物。我们得到期望的产物,获得呈白色固体的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)。
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)的H2SO4(80mL)(98%纯度)溶液中分批加入KNO3(4.70g,46.51mmol,1eq),然后在0℃下将混合物搅拌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,合并的有机层用饱和NaHCO3水溶液(100mL*2)和盐水(100mL)洗涤,经Na2SO4干燥,过滤并减压浓缩至得到残余物。残余物经硅胶色谱(200-300目硅胶,石油醚/乙酸乙酯=15/1-1/1,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,以得到呈黄色固体的4-溴-6-氟-7-硝基-1H-吲唑(2.7g,10.38mmol,22.32%产率)和粗产物。通过MPLC(石油醚/乙酸乙酯)纯化粗产物,以得到呈黄色固体的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)的H2SO4(30mL)溶液中加入NIS(7.01g,31.15mmol,3eq)。将反应混合物在50℃下搅拌16小时。用冰水(50mL)淬灭反应混合物。然后用乙酸乙酯(50mL*3)萃取混合物。合并的有机层用Na2SO3水溶液(20mL*2)、NaHCO3水溶液(20mL*2)和盐水(20mL)洗涤,经硫酸钠干燥,过滤并在真空下浓缩滤液以得到呈黄色固体的4-溴-6-氟-5-碘-7-硝基-1H-吲唑(3.4g,8.81mmol,84.85%产率)。
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)的EtOH(50mL)和H2O(25mL)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。反应混合物趁热通过硅藻土过滤。然后在真空下浓缩滤液以除去EtOH。用乙酸乙酯(50mL*2)萃取所得水相。合并的有机层用盐水(50mL)洗涤,经硫酸钠干燥,过滤并在真空下浓缩滤液,以得到残余物。残余物经硅胶色谱(MPLC,石油醚/乙酸乙酯=5/1-2/1,产物在石油醚/乙酸乙酯=2/1时出现)纯化,以得到呈灰色固体的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)的MeOH(50mL)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。悬浮液在25℃下搅拌16小时。将反应混合物倒入水(50mL)中,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,并且合并的有机层用盐水(50mL)洗涤,经硫酸钠干燥,过滤并减压浓缩至得到残余物。残余物经硅胶色谱(200-300目硅胶,石油醚/乙酸乙酯=15/1-8/1,产物在石油醚/乙酸乙酯=8/1时出现)纯化,以得到呈灰白色固体的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
向配备磁力搅拌棒的100mL瓶中依次加入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)。将瓶子抽真空并用氮气回填。然后将混合物在氮气气氛下在90℃下搅拌16小时。残余物经硅胶色谱(200-300目硅胶,石油醚/乙酸乙酯=20/1-8/1,产物在石油醚/乙酸乙酯=10/1时出现)纯化,以得到呈橙色固体的4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺(540mg,1.78mmol,56.81%产率)。
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)和甲基2,2-二氟-2-(氟磺酰基)乙酸酯(1.00g,5.22mmol,664.45uL,2eq)的DMF(10mL)溶液中加入CuI(994.63mg,5.22mmol,2eq)。将混合物在N2气氛下在100℃下搅拌6小时。过滤反应混合物,并用水50mL稀释滤液并用乙酸乙酯(50mL*2)萃取。合并的有机层用盐水(50mL*3)洗涤,经无水Na2SO4干燥,过滤并减压浓缩滤液至得到残余物。通过硅胶柱色谱法(石油醚:乙酸乙酯=1:0-10:1)纯化残余物。获得呈黄色固体的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N2气氛下,在-78℃下,向二异丙胺(132.75mg,1.31mmol,185.41uL,1.2eq)的THF(5mL)溶液中缓慢加入正丁基锂(2.5M,481.04uL,1.1eq)0.5小时。然后将4-溴-6-氟-2-三苯基-2H-吲唑(500mg,1.09mmol,1eq)的THF(2mL)溶液逐滴加入到溶液中。将混合物在-78℃下搅拌0.5小时后,将EtI(204.62mg,1.31mmol,104.93uL,1.2eq)的THF(2mL)溶液加入混合物中,并将溶液加热至15℃并在N2气氛下搅拌2小时。通过在15℃下加入3mL饱和NH4Cl水溶液来淬灭反应混合物,用水20mL稀释并用乙酸乙酯(30mL*2)萃取。合并的有机层用盐水(30mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩滤液至得到残余物。获得呈黄色固体的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)的DCM(6mL)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的pH值调节至7,并将混合物用二氯甲烷(30mL*2)萃取。合并的有机层用盐水(30mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩滤液至得到残余物。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%,10分钟)纯化。将分液减压浓缩至除去ACN,用饱和NaHCO3水溶液将水溶液的pH值调节至7。用乙酸乙酯(10mL*2)萃取水溶液。合并的有机层用盐水(10mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩滤液至得到残余物。获得呈黄色固体的4-溴-5-乙基-6-氟-1H-吲唑(70mg,287.98umol,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)的H2SO4(30mL)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,合并的有机层经Na2SO4干燥,过滤并减压浓缩,获得呈黄色固体的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)的DCM(50mL)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NaHCO3的饱和溶液(100mL)中,然后用二氯甲烷(50mL*2)萃取混合物,合并的有机层经Na2SO4干燥,过滤并减压浓缩至得到残余物。残余物通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1-15:1)纯化,获得呈黄色固体的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)的MeOH(30mL)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H2(15Psi)下在15℃下搅拌4小时。过滤反应混合物,并减压浓缩滤液至得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=15/1-8:1)纯化残余物。获得呈砖红色固体的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/z236.1(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)的MeCN(10mL)溶液中分批加入NBS(1.21g,6.80mmol,1.2eq)。并将混合物在0℃下搅拌2小时。浓缩反应混合物以得到残余物。然后将残余物溶解在乙酸乙酯(30mL)中,混合物用盐水(15mL*2)洗涤,有机层经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1)纯化残余物。获得呈棕色固体的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)。
中间体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
在N2下,在-78℃下,向中间体1A(3g,8.99mmol,1eq)的THF(60mL)混合物中逐滴加入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HCO2Et(3.17g,35.97mmol,3.52mL,4eq)的THF(8mL)溶液,然后将混合物在-78℃下搅拌2小时。在-78℃下,通过加入饱和NH4Cl溶液(20mL)来淬灭反应混合物,然后用EA(30mL*3)萃取。合并的有机层用盐水(30mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=30/1-20/1)纯化残余物。获得呈灰白色固体的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)丁-3-烯-1-醇
在N2下,在0℃下,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)的THF(60mL)混合物中逐滴加入烯丙基溴化镁(1M,9.13mL,1.5eq)。在0℃下搅拌混合物2小时。在0℃下通过加入饱和NH4Cl溶液(20mL)来淬灭反应混合物,然后用EA(30mL*3)萃取。合并的有机层用盐水(30mL*2)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1-5/1)纯化残余物。获得呈无色油状的1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)丁-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N2下,在-20℃下,向1-(4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-7-基)丁-3-烯-1-醇(2g,4.95mmol,1eq)的DCM(20mL)混合物中逐滴加入Br2(1.19g,7.43mmol,383.11uL,1.5eq)的DCM(2mL)混合物。混合物在-10℃下搅拌3小时。通过加入Na2SO3溶液(30mL)淬灭混合物,然后用DCM(30mL)稀释。有机层用Na2SO3溶液(30mL*2)洗涤,经无水Na2SO4干燥,过滤并浓缩以获得残余物。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。加入水(20mL)淬灭反应,用EA(30mL*3)萃取,经Na2SO4干燥,过滤并浓缩以获得残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1-3:1)纯化残余物。通过反相HPLC(0.1%FA条件)纯化粗产物。获得呈白色固体的4-溴-7-(3-溴环戊基)-5-氯-6-氟-1H-吲唑(300mg,752.91umol,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N2下,在20℃下,向4-溴-7-(3-溴环戊基)-5-氯-6-氟-1H-吲唑(100mg,250.97μmol,1eq)的DMSO(2mL)混合物中加入一份KOAc(73.89mg,752.91μmol,3eq)。然后将混合物加热至70℃并搅拌3小时。加入水(15mL)淬灭反应,然后用EA(20mL*3)萃取,合并的有机层用盐水(20mL*2)洗涤,经Na2SO4干燥,过滤并浓缩以得到残余物。3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊基乙酸酯(100mg,粗品,棕色油状)不经进一步纯化直接用于下一步。
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N2下,在20℃下,向3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊基乙酸酯(80mg,211.87umol,1eq)的MeOH(4mL)和H2O(0.8mL)混合物中加入一份K2CO3(442.15mg,3.20mmol,15.1eq)。在20℃下搅拌混合物2小时。在20℃下通过加入水(15mL)来淬灭反应混合物,然后用乙酸乙酯(20mL*3)萃取。合并的有机层用盐水(20mL*1)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=3/1-1/2)纯化残余物。获得呈白色固体的3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)环戊烷-1-醇(50mg,149.01umol,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)的MeCN(40mL)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H2O(100mL)稀释反应混合物,并用EtOAc(100mL*3)萃取。合并的有机层经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈棕色油状的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硼烷(8.82g,29.51mmol,9.82mL,42%纯度,1.5eq)的DME(60mL)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。减压浓缩反应混合物以提供残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=5/1-3/1,石油醚/乙酸乙酯=2:1,Rf=0.3)纯化残余物。获得呈黄色油状的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)的AcOH(15mL)溶液中加入NaNO2(357.25mg,5.18mmol,1eq)和H2O(3mL),然后将反应混合物在15℃下搅拌2小时。通过在20℃下加入H2O(60mL)淬灭反应,并用EtOAc(50mL*3)萃取所得混合物。合并的有机层用H2O(50mL*3)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱(SiO2,石油醚/乙酸乙酯=10/1-5/1,石油醚/乙酸乙酯=3:1,Rf=0.5)纯化残余物。获得呈黄色固体的6-氟-5-(三氟甲基)-1H-吲唑(500mg,2.45mmol,47.31%产率)。
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)的H2SO4(5mL,95%纯度)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。合并的有机层用饱和碳酸氢钠溶液处理至pH=7,经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈黄色固体的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)的THF(10mL)溶液中加入PPTS(50.44mg,200.71umol,0.1eq)和DHP(844.13mg,10.04mmol,917.53uL,5eq),然后在60℃下将反应混合物搅拌15小时。用溶剂H2O(50mL)稀释反应混合物,并用EtOAc(50mL*3)萃取。合并的有机层用H2O(50mL*3)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈黄色油状的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)的EtOH(10mL)溶液中加入NH4Cl(642.08mg,12.00mmol,5eq)和Fe(268.13mg,4.80mmol,2eq),然后将反应混合物在60℃下搅拌1小时。用H2O(20mL)稀释反应混合物,并用EtOAc(20mL*3)萃取。合并的有机层用H2O(30mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=10/1-5/1,石油醚:乙酸乙酯=3:1,Rf=0.3)纯化残余物。获得呈黄色固体的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)的DMF(1mL)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。合并的有机层用H2O(10mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈黄色固体的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,335.53umol,1eq)的MeOH(1mL)溶液中加入AcOH(40.30mg,671.06umol,38.38uL,2eq)和丙酮(97.44mg,1.68mmol,123.34uL,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,将丙酮(97.44mg,1.68mmol,123.34uL,5eq)、NaBH3CN(105.43mg,1.68mmol,5eq)和AcOH(60.45mg,1.01mmol,57.57uL,3eq)加入到混合物中,并在20℃下搅拌反应混合物20小时。用H2O(10mL)稀释反应混合物,并用EtOAc(10mL*3)萃取。合并的有机层用H2O(10mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过prep-TLC(石油醚/乙酸乙酯=3:1,Rf=0.4)纯化残余物。获得呈白色固体的4-溴-6-氟-N-异丙基-5-(三氟甲基)-1H-吲唑-7-胺(60mg,165.83umol,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)的THF(1mL)溶液中加入PPTS(3.69mg,14.70umol,0.1eq)和DHP(61.83mg,735.05umol,67.21uL,5eq),然后在60℃下将反应混合物搅拌2小时。用H2O(50mL)稀释反应混合物,并用EtOAc(50mL*3)萃取。合并的有机层用H2O(50mL*3)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过prep-TLC(石油醚:乙酸乙酯=5:1,Rf=0.6)纯化残余物。获得呈黄色油状的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,117.86umol,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)的EtOH(80mL)和H2O(80mL)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除去EtOH。所得混合物用DCM(50mL*3)萃取。合并的有机相用盐水(50mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物以得到呈黄色液体的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)的CH3CN(150mL)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显示残留化合物2,并且也检测到期望的量。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期望量的主峰。用饱和Na2SO3(200mL)淬灭混合物并用EtOAc(50mL*3)萃取所得混合物。合并的有机相用盐水(50mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。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,以得到呈棕色固体的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
在0℃下,向3-溴-5-氟-4-碘-2-甲基苯胺(22g,66.68mmol,1eq)的CH3COOH(200mL)混合物中加入溶解水(40mL)的NaNO2(5.52g,80.02mmol,1.2eq)。将混合物在30℃下搅拌16小时。将混合物倒入饱和NaHCO3(1000mL)中并用EtOAc(200mL*3)萃取所得混合物。合并的有机相用盐水(100mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物经硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=15/1、5/1)纯化,以得到呈棕色固体的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,1eq)和4-甲基苯磺酸水合物(418.47mg,2.20mmol,0.1eq)的DCM(100mL)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。混合物用饱和NaHCO3(30mL*3)和盐水(30mL*3)洗涤。有机相经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物经硅胶色谱法(1000目硅胶,石油醚/乙酸乙酯=100/1、50/1)纯化,以得到呈黄色固体的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)和环丙基硼酸(303.14mg,3.53mmol,1eq)的二恶烷(10mL)和H2O(2.5mL)的混合物中加入Na2CO3(748.10mg,7.06mmol,2eq)和Pd(dppf)Cl2(258.23mg,352.91μmol,0.1eq)。将混合物在80℃下搅拌16小时。减压浓缩混合物以得到残余物。残余物通过prep-TLC(石油醚:乙酸乙酯=20:1)纯化以得到呈无色油状的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)和三氟(异丙烯基)硼氫化钾(626.67mg,4.23mmol,1.2eq)的二恶烷(10mL)和H2O(2mL)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。减压浓缩混合物以得到残余物。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))纯化以得到0.9g的黄色油。这种油通过prep-TLC(石油醚:乙酸乙酯=20:1)纯化以得到呈黄色油状的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)的MeOH(10mL)溶液中加入PtO2。将悬浮液在真空下脱气并用H2吹扫数次。将混合物在H2(15Psi)下在30℃下搅拌2.5小时。过滤混合物并减压浓缩滤液以得到残余物。残余物通过硅胶色谱法(300-400目硅胶,石油醚/乙酸乙酯=50/1)纯化以得到呈无色油状的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)的DCM(1mL)溶液中加入TFA(2.30g,20.14mmol,1.49mL,22.91eq)。将混合物在30℃下搅拌0.5小时。减压浓缩混合物以得到残余物。残余物用DCM(10mL)稀释并用TEA将所得混合物调节pH至约8。减压浓缩混合物以得到残余物。残余物经硅胶色谱法(300-400目硅胶,石油醚/乙酸乙酯=30/1、5/1)纯化以得到呈无色油状的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)。
中间体1Q。4-溴-6-氟-5-甲氧基-1H-吲唑
步骤1)2-溴-4-氟-3-甲氧基-1-甲基苯
向2-溴-6-氟-3-甲基苯酚(4.8g,23.41mmol,1eq)的丙酮(50mL)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1小时。浓缩反应混合物以得到残余物。将残余物溶于乙酸乙酯(50mL)中,并过滤混合物,并浓缩滤液以得到呈黄色油状的残余物(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-甲基苯(4.4g,20.09mmol,1eq)的H2SO4(40mL)(98%)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,合并的有机层经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈棕色油状的3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯(4.6g,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)的EtOH(30mL)和H2O(30mL)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,并将滤液浓缩以除去EtOH,然后用EA(50mL)稀释混合物,并用水(20mL*2)洗涤混合物,然后有机层经Na2SO4干燥,过滤并减压浓缩以得到残余物。获得呈棕色油状的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)的AcOH(20mL)混合物中逐滴加入NaNO2(1.24g,17.94mmol,1.2eq)的H2O(4mL)溶液,然后将混合物在25℃下搅拌12小时。将反应混合物用冰水(100mL)稀释,并通过使用KOH将混合物调节至pH7,然后用EA(100mL*2)萃取混合物,合并的有机层用盐水(50mL*2)洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(SiO2,石油醚/乙酸乙酯=20/1-15:1)纯化残余物。获得呈棕色固体的4-溴-6-氟-5-甲氧基-1H-吲唑(600mg,2.45mmol,16.37%产率)。
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)化合物的合成
使用合成方法A-F制备以下化合物。下文描述了本公开的一些化合物的说明性合成实例,并且其他化合物可以通过与下文所述方法类似的方法用不同的起始或反应材料制备。
合成方法A
实施例1(1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-基)
环丙烷-1-甲酰胺
步骤1)5-氨基-1-(3-甲氧基-3-氧代丙-1-烯-1-基)-1H-吡唑-3-羧酸甲酯
向化合物1(9.1g,64.48mmol,1eq)的EtOH(700mL)溶液中加入丙炔酸甲酯(27.11g,322.40mmol,26.84mL,5eq)。将混合物在90℃下搅拌16小时。减压浓缩反应混合物直至所有固体沉淀出来,过滤并减压浓缩以得到粗产物。获得呈黄色固体的化合物2(7.8g,粗品)。
1H NMR(400MHz,DMSO-d6)δ8.09(d,J=14.8Hz,1H),7.05(s,1H),6.68(br s,2H),6.63(d,J=14.8Hz,1H),3.88(s,3H),3.76(s,3H)。
步骤2)5-氧代-4,5-二氢吡唑并[1,5-a]嘧啶-2-羧酸乙酯
向化合物2(3.9g,17.32mmol,1eq)的EtOH(15mL)中加入EtONa(1.77g,25.98mmol,1.5eq)。将混合物在90℃下搅拌16小时。减压浓缩反应混合物以得到残余物。用水200mL稀释残余物并用乙酸乙酯(200mL*2)萃取。过滤水层,并减压浓缩所得滤饼,以得到呈黄色固体的化合物3(5.4g,粗品)。
1H NMR(400MHz,DMSO-d6)δ12.62(br s,1H),7.99(d,J=7.5Hz,1H),6.58(s,1H),5.82(d,J=7.5Hz,1H),4.35(q,J=7.1Hz,2H),1.34(t,J=7.2Hz,3H)。
步骤3)5-氯吡唑并[1,5-a]嘧啶-2-羧酸乙酯
在N2气氛下,向化合物3(1g,4.83mmol,1eq)的MeCN(5mL)溶液中加入N,N-二甲基苯胺(1.17g,9.65mmol,1.22mL,2eq)、氯化苄基(三乙基)銨(5.50g,24.13mmol,5eq)和POCl3(7.40g,48.27mmol,4.49mL,10eq)。在N2气氛下,将反应混合物在100℃下搅拌16小时。减压浓缩反应混合物。残余物用水(100mL)淬灭并用饱和碳酸氢钠溶液处理直至pH=7。然后用乙酸乙酯(100mL*2)萃取混合物。合并的有机层用盐水100mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物通过柱色谱法(硅胶,石油醚:乙酸乙酯=1:0-1:1)纯化。获得呈黄色固体的化合物4(900mg,3.99mmol,82.64%产率)。
1H NMR(400MHz,DMSO-d6)δ8.63(d,J=4.5Hz,1H),7.61(d,J=4.5Hz,1H),7.36(s,1H),4.40(d,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
步骤4)5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-羧酸乙酯
在N2气氛下,向化合物4(900mg,3.99mmol,1eq)、(5-甲基-1H-吲唑-4-基)硼酸(701.95mg,3.99mmol,1eq)和Na2CO3(845.55mg,7.98mmol,2eq)的二恶烷(5mL)和H2O(1mL)的混合物中加入Pd(dppf)Cl2(145.93mg,199.44umol,0.05eq)。在N2气氛下,将混合物在80℃下搅拌16小时。用水100mL稀释反应混合物并用乙酸乙酯(50mL*2)萃取。合并的有机层用盐水50mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物通过柱色谱法(硅胶,石油醚:乙酸乙酯=1:0-0:1)纯化。获得呈黄色固体的化合物5(450mg,1.40mmol,35.10%产率)。
1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),8.81-8.78(m,1H),7.71(d,J=8.5Hz,1H),7.66(s,1H),7.44(d,J=8.5Hz,1H),7.34(d,J=4.1Hz,1H),7.31(s,1H),4.30(q,J=7.1Hz,2H),2.14(s,3H),1.27(t,J=7.1Hz,3H)。
步骤5)5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-羧酸
向化合物5(450mg,1.40mmol,1eq)的THF(5mL)和H2O(5mL)溶液中加入LiOH·H2O(117.53mg,2.80mmol,2eq)。将混合物在45℃下搅拌2小时。用水100mL稀释反应混合物并用乙酸乙酯(100mL*2)萃取。合并的水层用HCl(1M)处理直至pH4,搅拌直至所有固体沉淀出来,过滤并减压浓缩以得到残余物。获得呈黄色固体的化合物6(330mg,粗品)。
1H NMR(400MHz,DMSO-d6)δ13.51-13.06(m,1H),8.77(d,J=4.2Hz,1H),7.71(d,J=8.6Hz,1H),7.66(d,J=0.9Hz,1H),7.43(d,J=8.7Hz,1H),7.31(d,J=4.2Hz,1H),7.24(s,1H),2.14(s,3H)。
步骤6)5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-胺
在N2气氛下,向化合物6(230mg,784.23umol,1eq)的甲苯(2mL)溶液中加入TEA(87.29mg,862.66umol,120.07uL,1.1eq)和DPPA(237.40mg,862.66umol,186.93uL,1.1eq)。将混合物在110℃下搅拌16小时。在N2气氛下,将H2O(1.00g,55.51mmol,1mL,70.78eq)加入到混合物中。在N2气氛下,将混合物在110℃下搅拌3小时。用水50mL稀释反应混合物并用乙酸乙酯(50mL*2)萃取。合并的有机层用盐水50mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物通过prep-TLC(石油醚:乙酸乙酯=0:1)纯化。获得呈黄色固体的化合物7(70mg,264.87umol,33.77%产率)。
1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),8.32(d,J=4.3Hz,1H),7.63-7.59(m,2H),7.35(d,J=8.6Hz,1H),6.71(d,J=4.4Hz,1H),5.79(s,1H),5.71-5.63(m,2H),2.15(s,3H)。
步骤7)(1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-基)环丙烷-1-甲酰胺
在N2气氛下,在0℃下,向化合物7(70mg,264.87umol,1eq)、(1S,2S)-2-氟环丙烷甲酸(33.08mg,317.84umol,1.2eq)和3-甲基吡啶(123.33mg,1.32mmol,128.95uL,5eq)的MeCN(2mL)溶液中加入MsCl(45.51mg,397.30umol,30.75uL,1.5eq)。在N2气氛下,将混合物在25℃下搅拌16小时。将反应混合物逐滴加入到水20mL中并用乙酸乙酯(20mL*2)萃取。合并的有机层用盐水20mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物通过prep-TLC(石油醚:乙酸乙酯=0:1)纯化。然后残余物通过prep-HPLC(柱:Phenomenex lunaC18150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:%-%,10分钟)纯化并冻干。获得呈黄色固体的实施例1(4.3mg,12.27umol,4.63%产率,100%纯度)。
1H NMR(400MHz,METHANOL-d4)δ8.57(d,J=4.3Hz,1H),7.66(d,J=8.6Hz,1H),7.64(d,J=2.3Hz,1H),7.44(d,J=8.8Hz,1H),7.13(s,1H),7.04(d,J=4.3Hz,1H),4.75-4.61(m,1H),2.26(s,3H),1.98-1.90(m,1H),1.83-1.72(m,1H),1.19-1.11(m,1H)。
合成方法B
实施例3(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)
环丙烷-1-甲酰胺
步骤1)N-(6-氯哒嗪-3-基)-4-甲基苯磺酰胺
向化合物8(25g,192.98mmol,1eq)的吡啶(300mL)溶液中加入TsCl(40.47g,212.28mmol,1.1eq),然后将混合物在90℃下于N2中搅拌6小时。将水(100mL)倒入混合物中,并用乙酸乙酯(50mL*3)萃取混合物,然后有机相用无水硫酸钠(Na2SO4)干燥,过滤并在真空下浓缩以获得呈灰色固体的化合物9(56.5g,粗品)。
1H NMR(400MHz,DMSO-d6)δ8.67-8.59(m,1H),7.82-7.77(m,2H),7.61-7.54(m,1H),7.52-7.46(m,1H),7.38(d,J=8.3Hz,2H),2.35(s,3H)。
步骤2)(E)-2-(3-氯-6-(甲苯磺醯亞胺基)哒嗪-1(6H)-基)乙酰胺
向化合物9(53g,186.79mmol,1eq)的DMF(300mL)溶液中加入DIPEA(26.56g,205.47mmol,35.79mL,1.1eq)和2-溴乙酰胺(28.35g,205.47mmol,1.1eq),然后将混合物在25℃下搅拌20小时。向混合物中加入水(1000mL)并过滤混合物,收集滤饼并真空浓缩以得到呈棕色固体的化合物10(40g,117.38mmol,62.84%产率)。
1H NMR(400MHz,DMSO-d6)δ8.00(d,J=9.8Hz,1H),7.79(d,J=9.8Hz,1H),7.70(brd,J=7.1Hz,3H),7.38(br s,1H),7.32(br d,J=7.8Hz,2H),4.88-4.77(m,2H),2.40-2.30(m,3H)。
步骤3)N-(6-氯咪唑并[1,2-b]哒嗪-2-基)-2,2,2-三氟乙酰胺
向化合物10(35g,102.70mmol,1eq)的DCE(250mL)溶液中加入TFAA(258.85g,1.23mol,171.43mL,12eq),然后将混合物在60℃下搅拌3小时。向混合物中加入水(1000mL),然后向混合物中加入足量的NaHCO3以调节pH值为8,然后将混合物过滤并收集滤饼,然后用水(500mL)和乙酸乙酯(500mL)萃取,然后有机相用Na2SO4干燥并真空浓缩以获得呈白色固体的化合物11(21g,79.37mmol,77.28%产率)。
1H NMR(400MHz,DMSO-d6)δ12.88-12.57(m,1H),8.41(s,1H),8.19(d,J=9.4Hz,1H),7.43(d,J=9.4Hz,1H)。
步骤4)6-氯咪唑并[1,2-b]哒嗪-2-胺
向化合物11(21g,79.37mmol,1eq)的MeOH(200mL)和H2O(200mL)的溶液中加入K2CO3(54.85g,396.84mmol,5eq),然后将混合物在75℃下搅拌3小时。将水(100mL)倒入混合物中,并用乙酸乙酯(50mL*3)萃取混合物,然后有机相用Na2SO4干燥,过滤并在真空下浓缩以获得化合物60(13.5g,粗品)。
1H NMR(400MHz,DMSO-d6)δ7.68(d,J=9.2Hz,1H),7.36(s,1H),7.03(d,J=9.2Hz,1H),5.65(s,2H)。
步骤5)(1S,2S)-N-(6-氯咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺
向化合物12(2g,11.86mmol,1eq)、(1S,2S)-2-氟环丙烷羧酸(1.56g,14.24mmol,1.2eq)的DCM(50mL)溶液中加入EDCI(3.41g,17.80mmol,1.5eq),然后将混合物在25℃下搅拌16小时。真空浓缩混合物以得到残余物。然后将水(100mL)倒入混合物中,并用乙酸乙酯(50mL*3)萃取混合物,然后有机相用Na2SO4干燥,过滤并在真空下浓缩以得到呈白色固体的化合物13(3.8g,粗品)。
1H NMR(400MHz,DMSO-d6)δ11.37-11.22(m,1H),8.32-8.23(m,1H),8.07(d,J=9.4Hz,1H),7.72-7.64(m,1H),5.07-4.80(m,1H),2.21-2.12(m,1H),1.73-1.61(m,1H),1.13-1.05(m,1H)。
步骤6)(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)环丙烷-1-甲酰胺。2TFA
向化合物13(170mg,667.59umol,1eq)、Na2CO3(141.51mg,1.34mmol,2eq)的二恶烷(6mL)和H2O(2mL)的溶液中加入(5-甲基-1H-吲唑-4-基)硼酸(117.48mg,667.59umol,1eq)和Pd(dppf)Cl2(48.85mg,66.76umol,0.1eq),然后将混合物在90℃下于N2中搅拌16小时。反应混合物通过prep-HPLC(柱:Phenomenex luna C18 150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:19%-49%,10分钟)纯化以获得呈淡黄色固体的实施例3(56.8mg,93.88umol,14.06%产率,95.6%纯度,2TFA)。
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.31(s,1H),8.10(d,J=9.3Hz,1H),7.84(d,J=0.9Hz,1H),7.58(d,J=8.4Hz,1H),7.38(dd,J=8.9,16.1Hz,2H),5.08-4.82(m,1H),2.38(s,3H),2.23-2.14(m,1H),1.77-1.62(m,1H),1.23-1.12(m,1H)。
合成方法C
实施例24(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-
基)环丙烷甲酰胺。2TFA
步骤1)(1S,2S)-N-(6-溴咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷甲酰胺
向(1S,2S)-2-氟环丙烷甲酸(537.41mg,5.16mmol,1.1eq)和化合物14(1g,4.69mmol,1eq)的NMP(20mL)的溶液中加入T3P(2.99g,9.39mmol,2.79mL,2eq)和DIPEA(1.42g,11.03mmol,1.92mL,2.35eq)。将反应混合物在25℃下搅拌16小时。加入水(15mL),并用EtOAc(10mL*2)萃取水相。合并的有机相用饱和盐水(10mL*2)洗涤,并真空浓缩。粗产物通过反向闪蒸(MeCN/H2O.0.05%TFA)纯化,以得到呈浅黄色固体的化合物15(750mg,2.51mmol,53.42%产率)。
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.93(d,J=1.2Hz,1H),8.75(s,1H),8.29(s,1H),5.17-4.76(m,1H),2.23-2.11(m,1H),1.67(tdd,J=3.3,6.9,19.9Hz,1H),1.25-1.13(m,1H)。
步骤2)(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙甲酰胺。2TFA
在N2下,向(5-甲基-1H-吲唑-4-基)硼酸(58.84mg,334.34umol,1eq)的二恶烷/H2O(3mL)的溶液中加入Pd(dppf)Cl2(12.23mg,16.72umol,0.05eq)、化合物15(100mg,334.34umol,1eq)和Na2CO3(70.87mg,668.67umol,2eq)。将混合物在90℃下搅拌3小时。加入水(10mL)并用EtOAc(10mL*2)萃取水相。合并的有机相用饱和盐水(10mL*2)洗涤并真空浓缩。粗产物通过prep-HPLC(柱:Phenomenex luna C18 150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:13%-43%,10分钟)纯化以得到呈淡黄色固体的实施例24(38.2mg,62.74umol,18.77%产率,95%纯度,2TFA)。
1H NMR(400MHz,DMSO-d6)δ11.48-11.28(m,1H),9.06(s,1H),8.83(d,J=1.3Hz,1H),8.36(s,1H),7.91(d,J=0.9Hz,1H),7.52(d,J=8.3Hz,1H),7.33(d,J=8.6Hz,1H),5.15-4.79(m,1H),2.43-2.35(m,3H),2.26-2.14(m,1H),1.78-1.62(m,1H),1.37-1.06(m,1H)。
合成方法D
实施例25(1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-
基)-2-氟环丙烷甲酰胺。2TFA
步骤1)(1S,2S)-2-氟-N-(6-(三丁基甲锡烷基)咪唑并[1,2-a]吡嗪-2-基)环丙烷甲酰胺。
在N2下,向三丁基(三丁基甲锡烷基)锡烷(1.16g,2.01mmol,1.00mL,3eq)和化合物16(200mg,668.67umol,1eq)的二恶烷(3mL)的溶液中加入Pd(PPh3)4(38.63mg,33.43umol,0.05eq)和TBAI(246.99mg,668.67umol,1eq)。将反应混合物在110℃下搅拌32小时。过滤反应并浓缩滤液以得到产物。粗产物通过prep-TLC(石油醚:乙酸乙酯=1:1)纯化以得到呈白色固体的化合物17(130mg,255.28umol,38.18%产率)。
步骤2)(1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷甲酰胺。2TFA
在N2下,向4-溴-5-乙基-6-氟-1H-吲唑(40mg,164.56umol,1eq)和化合物17(92.18mg,181.01umol,1.1eq)的EtOH(2mL)溶液中加入Ad2n-BuP-Pd-G3(11.98mg,16.46umol,0.1eq)。将反应混合物在90℃下搅拌16小时。真空浓缩反应混合物。粗产物通过prep-HPLC(柱:Phenomenex Luna C18 150*25mm*10um;流动相:[水(0.1%TFA)-ACN];B%:24%-54%,10分钟)纯化以得到呈白色固体的实施例25(10mg,16.22umol,9.86%产率,99%纯度,2TFA)。
1H NMR(400MHz METHANOL-d4)δ8.99(s,1H),8.71(s,1H),8.42(s,1H),7.83(s,1H),7.36(d,J=10.4Hz,1H),5.00-4.97(m,1H),2.76-2.72(m,2H),2.16-2.15(m,1H),1.86-1.79(m,1H),1.26-1.24(m,1H),1.19-1.16(m,3H)。
合成方法E
实施例61(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,
2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺
向化合物17(456mg,0.896mmol,1.3eq)和中间体1E(269mg,0.689mmol)的EtOH(3.44mL)溶液中加入Ad2nBuP-Pd-G3(50mg,0.0689mmol,0.1eq)。将混合物脱气并用N2吹扫3次,然后在N2气氛下在90℃下搅拌16小时。真空浓缩反应混合物。粗产物通过硅胶色谱法(产物在乙酸乙酯时出现)纯化以提供呈黄色固体的实施例61(86mg,0.162mmol,24%产率)。
合成方法F
实施例64(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡 嗪-2-基)-2-氟环丙烷-1-甲酰胺
步骤1)4-溴-5-氯-6-氟-7-(丙-1-烯-2-基)-2-(四氢-2H-吡喃-2-基)-2H-吲唑
在N2气氛下,向中间体1B(2g,4.35mmol,1eq)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧硼烷(877.73mg,5.22mmol,1.2eq)的二恶烷(0.4mL)和H2O(0.1mL)的溶液中加入Na2CO3(922.69mg,8.71mmol,2eq)和Pd(dppf)Cl2(159.25mg,217.64μmol,0.05eq)。在N2气氛下,将混合物在80℃下搅拌16小时。用水100mL稀释反应混合物并用乙酸乙酯(100mL*2)萃取。合并的有机层用盐水100mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。通过柱色谱法(硅胶,石油醚:乙酸乙酯=1:0-20:1)纯化残余物。获得呈黄色油状的化合物18(870mg,2.33mmol,53.49%产率)。
步骤2)4-溴-5-氯-6-氟-7-异丙基-1H-吲唑
在N2下,向化合物18(400mg,1.07mmol,1eq)的MeOH(0.5mL)溶液中加入PtO2(40.00mg,176.15umol,1.65e-1eq)。将悬浮液在真空下脱气并用H2吹扫数次。将混合物在H2(15psi)下在25℃下搅拌1小时。过滤反应混合物并减压浓缩以得到残余物。通过柱色谱法(硅胶,石油醚:乙酸乙酯=1:0-4:1)纯化残余物。获得呈黄色固体的化合物19(240mg,823.19umol,76.90%产率)。
1H NMR(400MHz,DMSO-d6)δ13.73(br s,1H),8.09(s,1H),3.59-3.49(m,1H),1.39(d,J=6.9Hz,6H)。
步骤3)(1S,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺
在N2气氛下,向化合物19(70mg,240.10umol,1eq)、化合物17(134.50mg,264.11umol,1.1eq)的EtOH(1mL)溶液中加入Ad2nBuP-Pd-G3(17.49mg,24.01umol,0.1eq)。在N2气氛下,将混合物在80℃下搅拌12小时。加入5mL饱和KF水溶液以淬灭反应混合物。将混合物溶解于水(20mL)中并用乙酸乙酯(20mL*2)萃取。合并的有机层用盐水20mL洗涤,经Na2SO4干燥,过滤并减压浓缩以得到残余物。残余物通过prep-HPLC(柱:Unisil 3-100C18Ultra 150*50mm*3um;流动相:[水(0.225%FA)-ACN];B%:40%-60%,10分钟)纯化并冻干。获得呈白色固体的实施例64(15mg,34.12umol,14.21%产率,98%纯度)。
1H NMR(400MHz,DMSO-d6)δ13.52(br s,1H),11.40(s,1H),9.14-8.87(m,2H),8.38(s,1H),8.04(br s,1H),5.17-4.75(m,1H),3.66-3.59(m,1H),2.19(td,J=7.0,13.6Hz,1H),1.75-1.62(m,1H),1.45(br d,J=7.0Hz,6H),1.20(tdd,J=6.3,8.9,12.3Hz,1H);LCMS(电喷雾)m/z 431.2(M+H+)。
下表1显示了实施例的化合物以及用于制备该化合物的一般合成方法和表征数据。
表1.实施例的化合物
化合物的评价
HPK1激酶检测
通过Promega的ADP-GloTM激酶检测来测量HPK1激酶活性。在该检测中,将5ng的重组人HPK1(signalchem)与5μL的化合物(0.5%DMSO)、5μL的MBP(0.5μg/μl)和5μL的ATP(25μM)缓冲液(40mM Tris,7.5;20mM MgCl2;0.1mg/ml BSA;50μM DTT。)一起培养。通过将反应混合物在96孔板中在30℃下培养40分钟来开始检测。培养后,加入25uL ADP-Glo试剂,并在室温下培养反应40分钟以停止反应并降解残余的ATP。然后通过在每孔中加入50uL的检测试剂将ADP产物转化为ATP。用Molecular device I3X读板器在室温下培养30分钟后检测到冷光。使用GraphPad Prism 7软件和SigmaPlot13.0中执行的软件程序,从抑制剂浓度范围内确定的一系列抑制百分比值计算IC50值。
表2显示了本发明化合物的IC50值,其中+表示为>1000nM,++为501-1000nM,+++为101-500nM,++++为<100nM。
表2.针对HPK1数据的体外活性
人外周泛T细胞的IFNγ和IL-2分析
人外周血泛T细胞购自STEMCELLTM Technologies Inc.。将人外周血泛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8X104T细胞接种在96孔板中,并与不同浓度的化合物和100nM前列腺素E2培养1小时。用Dynabeads人T-激活剂CD3/CD28(Life Technologies)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人细胞因子试剂盒在刺激后24小时后测量细胞因子分泌。用MESO Quickplex SQ120(Mesoscale Discovery)分析数据。
在表3中,值+表示为>1000nM,++为200-1,000nM,+++为<200nM和–为未測定。
表3.本发明化合物在人外周血泛T细胞中的IFNγ和IL-2分泌
Claims (29)
1.一种式(I)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为O或S;
L为键、-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地选自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、卤素、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R10和R11与它们所连接的氮原子一起形成任选被一个或多个基团取代的4-12元杂环基,基团选自由卤素、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组成的组;
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任选被一个或多个基团取代的4-8元杂环基,基团选自由卤素、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组成的组;
Het选自由以下组成的组:
Ra、Rb和Rc各自独立地为-H、-D、卤素、-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、卤素、羟基、-CD2OH、-CN、-NO2、卤代烷基、三甲基甲硅烷基乙氧基甲基、-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、杂芳基或杂环基任选地被一个或多个基团取代,基团选自由卤素、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组成的组;
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为键、-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、卤素、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基团取代,基团选自由卤素、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组成的组;并且
R5为-H、-D、-CD3、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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,其中,L为键,并且R1为环烷基,其任选地被一个或多个基团取代,基团选自由C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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组成的组。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中,R2和R3各自独立地为-H、卤素、烷硫基、卤代烷基或烷基。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中,M为键、-O-或-NR6-;并且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、卤素、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一个或多个基团取代,基团选自由卤素、羟基、烷基、烯基、炔基、卤代烷基、羟烷基、-CN、-CD3、-NR10R11、-NR10S(O)2R9和-NR10C(=O)R9组成的组。
6.根据权利要求5所述的化合物或其药学上可接受的盐,其中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。
7.根据权利要求5所述的化合物或其药学上可接受的盐,其为
(1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-基)环丙烷-1-甲酰胺;或
(1S,2S)-N-(5-(5-乙基-6,7-二氟-1H-吲唑-4-基)吡唑并[1,5-a]嘧啶-2-基)-2-氟环丙烷-1-甲酰胺。
9.根据权利要求8所述的化合物或其药学上可接受的盐,其中,L为键,并且R1为环烷基,其任选地被一个或多个基团取代,基团选自由C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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组成的组。
10.根据权利要求8所述的化合物或其药学上可接受的盐,其中,R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。
11.根据权利要求8所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氨基-6-氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺。
12.根据权利要求8所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-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)咪唑并[1,2-b]哒嗪-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-b]哒嗪-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,其中,L为键,并且R1为环烷基,其任选地被一个或多个基团取代,基团选自由C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素、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组成的组。
15.根据权利要求13所述的化合物或其药学上可接受的盐,其中,L为键;R1为环烷基,其任选地被一个或多个基团取代,基团选自由卤素、C1-3烷基、C1-3羟烷基和C1-3卤代烷基组成的组。
16.根据权利要求13所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-溴-6,7-二氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-溴-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(哌啶-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((3-羟丙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(氮杂环丁烷-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-硫吗啉-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基(甲基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-氨基-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-羟基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-乙烯基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-乙酰基-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-环丙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(2-乙氧基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(叔丁氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-氟吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-N,N-二甲基-1H-吡咯-3-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丁氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((E)-丙-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(3R,4S)-4-甲基四氢呋喃-3-基(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)氨基甲酸酯;
(1S,2S)-N-(6-(5-氯-7-(2-(二甲氨基)-2-氧乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((2-(二甲氨基)-2-氧乙基)硫代)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3,3,3-三氟丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((甲氨基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((二甲氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-羟基-2-甲基丙烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-叔戊酰-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
4-甲基四氢呋喃-3-基(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)氨基甲酸酯;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-羟乙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丁氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环戊氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲氧基乙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-羟基丙烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲氧基丙烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R,3S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)环丙烷-1-甲酰胺;
(1S,2S,3S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环戊-1-烯-1-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((1H-咪唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(吗啉氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(2-氨基-2-氧乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基丙-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((2,2-二氟乙基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(2-溴-2-氟环丙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(烯丙氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基哌嗪-1-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-氟乙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1,3-二羟基-2-甲基丙烷-2-基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲基-1H-吡唑-5-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-羟基丁烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2R,3S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)环丙烷-1-甲酰胺;
(1S,2S,3S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((1H-吡咯-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((1H-吡唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-羟基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-羟基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-氧代环戊-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(N-甲基乙酰氨基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(羟基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((1H-吡唑-5-基)氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1H-吡唑-5-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑-5-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-甲基-1H-吡唑-5-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丁酰-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基-2-甲基丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3R)-3-羟基环戊基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基环戊基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丁基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基-2-甲基丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟-2-甲基丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲氧基丁烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((3-氟环丁基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(甲氧基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((E)-丁-2-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(丁-3-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(仲丁氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-羟基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((四氢呋喃-3-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基环戊基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3S)-3-羟基环戊基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(二甲氨基)-1-氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((R)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-氰乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((R)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-氨基-1-氧丙烷-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-氟丙烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异恶唑-4-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羟基环戊基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-羟基环戊烷-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((3-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(四氢呋喃-3-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(2H-1,2,3-三唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(1H-1,2,4-三唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二羟基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1-环丙基乙基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((3,3-二氟环丁基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基丙-2-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-乙酰氨基乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(2-氰基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-2-基)-2H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((E)-丁烷-1,3-二烯-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-乙氧基-2,2,2-三氟乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二甲氧基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1,2-二烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(羟基(四氢-2H-吡喃-3-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(5,6-二氢-1,4-二恶英-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(1H-吡唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羟基环戊基)(甲基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(丙-1-烯-2-基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-羟基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(四氢呋喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(4-羟基四氢呋喃-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(3,3-二甲基氮杂环丁烷-1-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((3-氯-2,2-二甲基丙基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(5-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(3-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(3,3-二氟氮杂环丁烷-1-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(2,5-二氢呋喃-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙酰氨基乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-6-氟-7-(3-羟基丙酰氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲酰氨基乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((E)-4-羟基丁-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-(三甲基甲硅烷基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺。1甲酸;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基-3-(三甲基甲硅烷基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((3-羟基丁烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(5,5-二甲基四氢呋喃-3-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(1H-咪唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((E)-3-(三乙基甲硅烷基)丙-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(仲丁基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,4-二恶烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(四氢-2H-吡喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰氟甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙酰氨基(氰基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(6,6-二氟-2-氮杂螺环[3.3]庚烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺酰氨基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙-1-烯-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二羟基丙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙酰氨基甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-甲酰基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-羧酸乙酯;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3R)-3-甲氧基丁烷-2-基)(甲基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3S)-3-甲氧基丁烷-2-基)(甲基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-((1-氰基环丙基)氨基)乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙酸乙酯;
(9H-芴-9-基)甲基(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)氨基甲酸酯;
(1S,2S)-N-(6-(5-氯-7-(二氟甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(羟基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙基)环丁烷甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟环丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(四氢呋喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((甲基亚磺酰基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((甲基磺酰基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,3-二甲基脲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二甲氧基丙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙酰氨基)乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-咪唑-5-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺酰基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基亚磺酰基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(乙基氨基)-1-氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(2,2,2-三氟乙酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-3-(环丁氨基)-3-氧代丙酸甲酯;
(1S,2S)-N-((5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)(氰基)甲基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(环丙甲酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(2,2-二氟乙酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((丙烷-2-基-1,1,1,3,3,3-d6)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-乙氧基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺。
17.根据权利要求13所述的化合物或其药学上可接受的盐,其中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤代烷基或卤素;R3为-H、烷基或卤素;M为键、-O-或-NR6-;R4为-H、卤素、烷基、单烷基氨基或二烷基氨基;并且R5为-H、烷基或卤素。
18.根据权利要求13所述的化合物或其药学上可接受的盐,其中,L为键;Ra为-H;Rb为-H;R1为被氯、氟、C1-C3烷基、C1-C3羟烷基或C1-C3卤代烷基取代的环丙基;R2为-H、烷基、氯或氟;R3为-H、烷基、氯或氟;M为键或-NH-;R4为-H、氯、氟、甲基、乙基、丙基、异丙基、丁基、甲氨基或二甲氨基;并且R5为-H或烷基。
19.根据权利要求13所述的化合物或其药学上可接受的盐,其中,L为键;Ra为-H;Rb为-H;R1为被氯或氟取代的环丙基;R2为-H、氯或氟;R3为-H、氯或氟;M为键或-NH-;R4为-H、氯、氟、甲基、乙基、丙基或异丙基;并且R5为-H。
20.根据权利要求17所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2R)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;和
(1R,2S)-N-(6-(5-氯-6-氟-7-异丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺。
21.根据权利要求13所述的化合物或其药学上可接受的盐,其中,L为键;R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、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氨基;并且R5为-H、烷基或卤素。
22.根据权利要求21所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-N-(6-(5-氯-7-(二甲氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-甲基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;和
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺。
23.根据权利要求13所述的化合物或其药学上可接受的盐,其中,R1为环丙基,其任选地被一个或多个基团取代,基团选自由卤素、C1-C3烷基、C1-C3羟烷基和C1-C3卤代烷基组成的组;R2为-H、烷基、卤素、卤代烷基或烷硫基;R3为-H、烷基或卤素;M为键、-O-、-S-或-NR6-;R4为-H、卤素、烷基、羟烷基、卤代烷基、卤代烯基、环烷基、氰基烷基、氨基羰基烷基、乙酰氨基乙基、丙酰氨基乙基、甲酰氨基乙基、环烷基烷基、环烷基(羟基)烷基、羟基环烷基、甲氧基环烷基、环烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺酰氨基乙基、咪唑基乙基、二恶烷基、环丁基羰基氨基乙基、二氟乙酰氨基乙基、三氟乙酰氨基乙基、甲硫甲基、甲硫乙基、环丙基羰基氨基(氰基)甲基、氰基(二氟乙酰氨基)甲基、丙基-1,1,1,3,3,3-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;并且R5为–H、烷基或卤素。
24.根据权利要求23所述的化合物或其药学上可接受的盐,其选自由以下组成的组:
(1S,2S)-N-(6-(7-(二甲氨基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙基(甲基)氨基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异丙基(甲基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-环丙基-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-丙基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3,3,3-三氟丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-乙基-6-氟-7-(异丙基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丁氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲氧基乙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((1-羟基丙烷-2-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基丙-1-烯-1-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-((2,2-二氟乙基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(烯丙氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((2-氟乙基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(羟基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-甲基-1H-吡唑-5-基)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-羟基-2-甲基丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-异丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-异丁基-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟-2-甲基丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(环丙基(甲氧基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((E)-丁-2-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(丁-3-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(仲丁氨基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基环戊基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-((R)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-氰乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-氨基-1-氧丙烷-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(异恶唑-4-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2S)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-乙酰氨基乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1R,2R)-N-(6-(5-氯-7-(环丙基(甲基)氨基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(甲硫基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(丙-1-烯-2-基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙酰氨基乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲酰氨基乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-1-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(1-(1H-咪唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(仲丁基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,4-二恶烷-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(7-(乙酰氨基(氰基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺酰氨基)乙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙-1-烯-2-基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁烷-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙基)环丁烷甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟环丙基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-2-氟-N-(6-(6-氟-7-(异丙氨基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-6-氟-7-(四氢呋喃-3-基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-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)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙酰氨基)乙基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(2,2,2-三氟乙酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-((5-氯-6-氟-4-(2-((1S,2S)-2-氟环丙烷-1-甲酰氨基)咪唑并[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)(氰基)甲基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(环丙甲酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;
(1S,2S)-N-(6-(5-氯-7-(氰基(2,2-二氟乙酰氨基)甲基)-6-氟-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺;和
(1S,2S)-N-(6-(5-氯-6-氟-7-((丙烷-2-基-1,1,1,3,3,3-d6)氨基)-1H-吲唑-4-基)咪唑并[1,2-a]吡嗪-2-基)-2-氟环丙烷-1-甲酰胺。
25.一种药物组合物,所述药物组合物含有药学上可接受的载体或稀释剂和权利要求1所述的化合物或其药学上可接受的盐。
26.一种治疗患有与HPK1调节相关的疾病或病症的受试者的方法,所述方法包括:
向需要其的受试者给药治疗有效量的权利要求1所述的化合物或其药学上可接受的盐。
27.根据权利要求26所述的方法,其中,所述疾病为癌症,其中,权利要求1所述的化合物与抗PD-1剂、抗PD-L1剂或抗CTLA4剂一起给药。
28.根据权利要求26所述的方法,其中,所述疾病为癌症、转移、炎症或自身免疫疾病。
29.根据权利要求28所述的方法,其中,所述癌症选自由上皮癌、黑色素瘤、母细胞瘤、肉瘤、淋巴瘤和白血病组成的组,包括但不限于膀胱癌、脑肿瘤、乳腺癌、宫颈癌、结直肠癌、食道癌、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、急性髓性白血病、室管膜瘤、尤文氏肉瘤、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(威尔姆氏瘤)。
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US20220098219A1 (en) | 2022-03-31 |
TW202220999A (zh) | 2022-06-01 |
WO2022064458A1 (en) | 2022-03-31 |
MX2023003631A (es) | 2023-04-11 |
US20220098193A1 (en) | 2022-03-31 |
IL301244A (en) | 2023-05-01 |
US11834467B2 (en) | 2023-12-05 |
JP2023542724A (ja) | 2023-10-11 |
CN114599651A (zh) | 2022-06-07 |
WO2022064459A1 (en) | 2022-03-31 |
EP4217358A1 (en) | 2023-08-02 |
US11649255B2 (en) | 2023-05-16 |
KR20230104143A (ko) | 2023-07-07 |
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CA3193865A1 (en) | 2022-03-31 |
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