RU2020114670A - Бициклические соединения для применения в качестве ингибиторов rip1 киназы - Google Patents
Бициклические соединения для применения в качестве ингибиторов rip1 киназы Download PDFInfo
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- RU2020114670A RU2020114670A RU2020114670A RU2020114670A RU2020114670A RU 2020114670 A RU2020114670 A RU 2020114670A RU 2020114670 A RU2020114670 A RU 2020114670A RU 2020114670 A RU2020114670 A RU 2020114670A RU 2020114670 A RU2020114670 A RU 2020114670A
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- fluoro
- phenyl
- pyrrolo
- dihydro
- triazole
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- 150000001875 compounds Chemical class 0.000 title claims 21
- 102100021009 Cytochrome b-c1 complex subunit Rieske, mitochondrial Human genes 0.000 title 1
- 101000643956 Homo sapiens Cytochrome b-c1 complex subunit Rieske, mitochondrial Proteins 0.000 title 1
- 101001099199 Homo sapiens RalA-binding protein 1 Proteins 0.000 title 1
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 title 1
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- -1 C 1 -C 6 alkoxy Chemical group 0.000 claims 30
- 150000003839 salts Chemical class 0.000 claims 29
- 229910052731 fluorine Inorganic materials 0.000 claims 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims 18
- 239000011737 fluorine Substances 0.000 claims 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 14
- 229910052799 carbon Inorganic materials 0.000 claims 14
- 229910052739 hydrogen Inorganic materials 0.000 claims 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 14
- 229910052801 chlorine Inorganic materials 0.000 claims 13
- 239000000460 chlorine Chemical group 0.000 claims 13
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 12
- 229910052805 deuterium Inorganic materials 0.000 claims 12
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 11
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 9
- 125000001424 substituent group Chemical group 0.000 claims 9
- 125000000623 heterocyclic group Chemical group 0.000 claims 8
- 229910052736 halogen Inorganic materials 0.000 claims 7
- 150000002367 halogens Chemical class 0.000 claims 7
- 229910052757 nitrogen Inorganic materials 0.000 claims 7
- 208000002320 spinal muscular atrophy Diseases 0.000 claims 7
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 6
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 6
- 206010003694 Atrophy Diseases 0.000 claims 6
- 230000037444 atrophy Effects 0.000 claims 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 6
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 5
- 201000010099 disease Diseases 0.000 claims 5
- 208000035475 disorder Diseases 0.000 claims 5
- 208000024827 Alzheimer disease Diseases 0.000 claims 4
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims 4
- 208000016192 Demyelinating disease Diseases 0.000 claims 4
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 4
- 206010018985 Haemorrhage intracranial Diseases 0.000 claims 4
- 208000023105 Huntington disease Diseases 0.000 claims 4
- 208000008574 Intracranial Hemorrhages Diseases 0.000 claims 4
- 208000009829 Lewy Body Disease Diseases 0.000 claims 4
- 201000002832 Lewy body dementia Diseases 0.000 claims 4
- 206010028289 Muscle atrophy Diseases 0.000 claims 4
- 208000018737 Parkinson disease Diseases 0.000 claims 4
- 208000027089 Parkinsonian disease Diseases 0.000 claims 4
- 206010034010 Parkinsonism Diseases 0.000 claims 4
- 208000032319 Primary lateral sclerosis Diseases 0.000 claims 4
- 208000006011 Stroke Diseases 0.000 claims 4
- 206010046298 Upper motor neurone lesion Diseases 0.000 claims 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 4
- 208000013044 corticobasal degeneration disease Diseases 0.000 claims 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 4
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 208000020658 intracerebral hemorrhage Diseases 0.000 claims 4
- 208000028867 ischemia Diseases 0.000 claims 4
- 201000010901 lateral sclerosis Diseases 0.000 claims 4
- 208000005264 motor neuron disease Diseases 0.000 claims 4
- 230000020763 muscle atrophy Effects 0.000 claims 4
- 201000006938 muscular dystrophy Diseases 0.000 claims 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 4
- 208000027232 peripheral nervous system disease Diseases 0.000 claims 4
- 208000033808 peripheral neuropathy Diseases 0.000 claims 4
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 4
- 208000011580 syndromic disease Diseases 0.000 claims 4
- 230000009885 systemic effect Effects 0.000 claims 4
- ALCTUKGOYARRNH-YIFXQUHMSA-N (5S,7S)-2-[(S)-cyclopropyl-deuterio-fluoromethyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound [2H][C@](F)(C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 ALCTUKGOYARRNH-YIFXQUHMSA-N 0.000 claims 3
- 206010033799 Paralysis Diseases 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 3
- 201000000585 muscular atrophy Diseases 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 201000008752 progressive muscular atrophy Diseases 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 3
- KPKUNSHYTZNQGB-STQMWFEESA-N (5S,7S)-2-(2-ethoxyethyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CCOCCC1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 KPKUNSHYTZNQGB-STQMWFEESA-N 0.000 claims 2
- IOASJLGDLUGRAU-KBPBESRZSA-N (5S,7S)-2-(cyclobutylmethyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(CC3CCC3)N=C12)C1=CC=CC=C1 IOASJLGDLUGRAU-KBPBESRZSA-N 0.000 claims 2
- ALCTUKGOYARRNH-WPNOJFKCSA-N (5S,7S)-2-(cyclopropyl-deuterio-fluoromethyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound [2H]C(F)(C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 ALCTUKGOYARRNH-WPNOJFKCSA-N 0.000 claims 2
- GDTCUGRIYFPSJN-BPXMWWTQSA-N (5S,7S)-2-[(2,2-difluorocyclopropyl)methyl]-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(CC3CC3(F)F)N=C12)C1=C(F)C=CC=C1 GDTCUGRIYFPSJN-BPXMWWTQSA-N 0.000 claims 2
- TZJYCNIDUFJHMJ-ZLHQZALHSA-N (5S,7S)-2-[cyclopropyl(deuterio)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound [2H]C(C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 TZJYCNIDUFJHMJ-ZLHQZALHSA-N 0.000 claims 2
- JEGJYXYMPWLQOO-RYUDHWBXSA-N (5S,7S)-2-[cyclopropyl(difluoro)methyl]-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)C(F)(F)C1CC1)C1=C(F)C=CC=C1 JEGJYXYMPWLQOO-RYUDHWBXSA-N 0.000 claims 2
- ALCTUKGOYARRNH-VYAYZGMFSA-N (5S,7S)-2-[cyclopropyl(fluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC(C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 ALCTUKGOYARRNH-VYAYZGMFSA-N 0.000 claims 2
- MUJRUMLHIAZTAZ-DCPRQKDISA-N (5S,7S)-7-fluoro-2-(2-methylcyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC1CC1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 MUJRUMLHIAZTAZ-DCPRQKDISA-N 0.000 claims 2
- RXUYYIANSGIRBA-STQMWFEESA-N (5S,7S)-7-fluoro-5-phenyl-2-(propan-2-yloxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC(C)OCC1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 RXUYYIANSGIRBA-STQMWFEESA-N 0.000 claims 2
- UNGACTKJXUJRLY-UHFFFAOYSA-N 7-fluoro-5-phenyl-2-(3,3,3-trifluoropropyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC1CC(c2ccccc2)n2nc(CCC(F)(F)F)nc12 UNGACTKJXUJRLY-UHFFFAOYSA-N 0.000 claims 2
- 206010010356 Congenital anomaly Diseases 0.000 claims 2
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 claims 2
- 101710138589 Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- DMAYXWLZZCHGOM-UHFFFAOYSA-N cyclopropyl-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol Chemical compound OC(C1CC1)c1nc2C(F)CC(c3ccccc3)n2n1 DMAYXWLZZCHGOM-UHFFFAOYSA-N 0.000 claims 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 230000000750 progressive effect Effects 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 201000000196 pseudobulbar palsy Diseases 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000004434 sulfur atom Chemical group 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- WDRYHJYWUJHCFD-RNJOBUHISA-N (1R,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]cyclopropane-1-carbonitrile Chemical compound F[C@H]1C[C@@H](c2ccccc2)n2nc(nc12)[C@@H]1C[C@H]1C#N WDRYHJYWUJHCFD-RNJOBUHISA-N 0.000 claims 1
- FHXFRFFNQZTYIR-IALDZJHCSA-N (1S,2S)-2-[difluoro-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl]cyclopropane-1-carbonitrile Chemical compound FC([C@@H]1[C@H](C1)C#N)(C=1N=C2N(N=1)C(CC2F)C1=CC=CC=C1)F FHXFRFFNQZTYIR-IALDZJHCSA-N 0.000 claims 1
- BKAOETZHKDXDGK-RKDXNWHRSA-N (5R,7R)-2-(difluoromethyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC(F)C1=NN2[C@H](C[C@@H](F)C2=N1)C1=CC=CC=C1 BKAOETZHKDXDGK-RKDXNWHRSA-N 0.000 claims 1
- PMUFTGWGLJZNOX-ZDUSSCGKSA-N (5S)-2-(cyclopropylmethyl)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC1=C(C=CC=C1)[C@@H]1CCC2=NC(CC3CC3)=NN12 PMUFTGWGLJZNOX-ZDUSSCGKSA-N 0.000 claims 1
- LICTZQWETXXEHP-QWRGUYRKSA-N (5S,7S)-2-(2-chloroimidazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=CN=C1Cl)C1=CC=CC=C1 LICTZQWETXXEHP-QWRGUYRKSA-N 0.000 claims 1
- CYUQVAGRGYEPQD-KBPBESRZSA-N (5S,7S)-2-(4,5-dimethylimidazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC1=C(C)N(C=N1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 CYUQVAGRGYEPQD-KBPBESRZSA-N 0.000 claims 1
- MSAYVCFDYBZMAP-QWRGUYRKSA-N (5S,7S)-2-(4-chloroimidazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=NC(Cl)=C1)C1=CC=CC=C1 MSAYVCFDYBZMAP-QWRGUYRKSA-N 0.000 claims 1
- QBKVTLIQUSUQRS-RYUDHWBXSA-N (5S,7S)-2-(4-chloropyrazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=C(Cl)C=N1)C1=CC=CC=C1 QBKVTLIQUSUQRS-RYUDHWBXSA-N 0.000 claims 1
- FLYMGQORFVCALO-GJZGRUSLSA-N (5S,7S)-2-(4-cyclopropylpyrazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=C(C=N1)C1CC1)C1=CC=CC=C1 FLYMGQORFVCALO-GJZGRUSLSA-N 0.000 claims 1
- FSNONCHUJMFFJY-KBPBESRZSA-N (5S,7S)-2-(4-ethylpyrazol-1-yl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CCC1=CN(N=C1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 FSNONCHUJMFFJY-KBPBESRZSA-N 0.000 claims 1
- HZAROVNAMRBNGP-CLJTZFLHSA-N (5S,7S)-2-[(R)-1-bicyclo[1.1.1]pentanyl(fluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound C1=CC=CC=C1[C@H]1N2C([C@H](C1)F)=NC([C@@H](C13CC(C1)C3)F)=N2 HZAROVNAMRBNGP-CLJTZFLHSA-N 0.000 claims 1
- ALCTUKGOYARRNH-RWMBFGLXSA-N (5S,7S)-2-[(R)-cyclopropyl(fluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H](C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 ALCTUKGOYARRNH-RWMBFGLXSA-N 0.000 claims 1
- HZAROVNAMRBNGP-UGLBVFMYSA-N (5S,7S)-2-[(S)-1-bicyclo[1.1.1]pentanyl(fluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound C1=CC=CC=C1[C@H]1N2C([C@@H](F)C1)=NC(=N2)[C@H](C12CC(C1)C2)F HZAROVNAMRBNGP-UGLBVFMYSA-N 0.000 claims 1
- ALCTUKGOYARRNH-AVGNSLFASA-N (5S,7S)-2-[(S)-cyclopropyl(fluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@@H](C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 ALCTUKGOYARRNH-AVGNSLFASA-N 0.000 claims 1
- UHAUTGSTWXFJTQ-YWGVVOLTSA-N (5S,7S)-2-[1-bicyclo[1.1.1]pentanyl(difluoro)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound C1=CC=CC=C1[C@H]1N2C([C@H](C1)F)=NC(C(C13CC(C1)C3)(F)F)=N2 UHAUTGSTWXFJTQ-YWGVVOLTSA-N 0.000 claims 1
- TZJYCNIDUFJHMJ-BSELDSRWSA-N (5S,7S)-2-[cyclopropyl(dideuterio)methyl]-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound [2H]C([2H])(C1CC1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 TZJYCNIDUFJHMJ-BSELDSRWSA-N 0.000 claims 1
- LTFXUKMFJNTABL-STQMWFEESA-N (5S,7S)-2-but-1-en-2-yl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CCC(=C)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 LTFXUKMFJNTABL-STQMWFEESA-N 0.000 claims 1
- NUZSTKOHEMQTRQ-QWRGUYRKSA-N (5S,7S)-2-ethenyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(C=C)N=C12)C1=CC=CC=C1 NUZSTKOHEMQTRQ-QWRGUYRKSA-N 0.000 claims 1
- KGPQVYVRXMOVKQ-RYUDHWBXSA-N (5S,7S)-7-fluoro-2-(1-methylimidazol-2-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CN1C=CN=C1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 KGPQVYVRXMOVKQ-RYUDHWBXSA-N 0.000 claims 1
- NULLQENWXKEGAA-STQMWFEESA-N (5S,7S)-7-fluoro-2-(2-methylimidazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC1=NC=CN1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 NULLQENWXKEGAA-STQMWFEESA-N 0.000 claims 1
- ZJSLXLZEVNZLOX-QWRGUYRKSA-N (5S,7S)-7-fluoro-2-(4-fluoroimidazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=NC(F)=C1)C1=CC=CC=C1 ZJSLXLZEVNZLOX-QWRGUYRKSA-N 0.000 claims 1
- PLSQSURQPYGYGM-RYUDHWBXSA-N (5S,7S)-7-fluoro-2-(4-fluoropyrazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound F[C@H]1C[C@H](N2N=C(N=C12)N1C=C(F)C=N1)C1=CC=CC=C1 PLSQSURQPYGYGM-RYUDHWBXSA-N 0.000 claims 1
- WCMWOUHEAUMMDL-STQMWFEESA-N (5S,7S)-7-fluoro-2-(4-methoxypyrazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound COC1=CN(N=C1)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 WCMWOUHEAUMMDL-STQMWFEESA-N 0.000 claims 1
- MIRIPTKIMZOSGE-RYUDHWBXSA-N (5S,7S)-7-fluoro-2-(5-methyl-1,2,4-triazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC1=NC=NN1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 MIRIPTKIMZOSGE-RYUDHWBXSA-N 0.000 claims 1
- RGTCHMJHRGZKQJ-STQMWFEESA-N (5S,7S)-7-fluoro-2-(5-methylpyrazol-1-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC1=CC=NN1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 RGTCHMJHRGZKQJ-STQMWFEESA-N 0.000 claims 1
- MUJRUMLHIAZTAZ-XEZLXBQYSA-N (5S,7S)-7-fluoro-2-[(1R,2R)-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound C[C@@H]1C[C@H]1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 MUJRUMLHIAZTAZ-XEZLXBQYSA-N 0.000 claims 1
- MUJRUMLHIAZTAZ-BQUFFADESA-N (5S,7S)-7-fluoro-2-[(1S,2S)-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound C[C@H]1C[C@@H]1C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 MUJRUMLHIAZTAZ-BQUFFADESA-N 0.000 claims 1
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- UBRCRPXDHQXFBT-UHFFFAOYSA-N 7-fluoro-5-phenyl-2-[2-(trifluoromethyl)cyclopropyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC1CC(c2ccccc2)n2nc(nc12)C1CC1C(F)(F)F UBRCRPXDHQXFBT-UHFFFAOYSA-N 0.000 claims 1
- RTVUQWXCWIYPBL-UHFFFAOYSA-N 7-fluoro-5-phenyl-2-prop-1-ynyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound CC#Cc1nc2C(F)CC(c3ccccc3)n2n1 RTVUQWXCWIYPBL-UHFFFAOYSA-N 0.000 claims 1
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- CENJBCACQPQXNX-UHFFFAOYSA-N 7-fluoro-5-phenyl-2-pyrazol-1-yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole Chemical compound FC1CC(c2ccccc2)n2nc(nc12)-n1cccn1 CENJBCACQPQXNX-UHFFFAOYSA-N 0.000 claims 1
- 206010006542 Bulbar palsy Diseases 0.000 claims 1
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- QHBDKUZEAPMVTE-QOZQQMKHSA-N FC1CC(N2N=C(N=C21)[C@](C)(CC)F)C2=CC=CC=C2 Chemical compound FC1CC(N2N=C(N=C21)[C@](C)(CC)F)C2=CC=CC=C2 QHBDKUZEAPMVTE-QOZQQMKHSA-N 0.000 claims 1
- 108091000080 Phosphotransferase Proteins 0.000 claims 1
- 208000029033 Spinal Cord disease Diseases 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 208000034799 Tauopathies Diseases 0.000 claims 1
- LXUZLYORJUIQBG-LAYINKIGSA-N [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanol Chemical compound OC([C@H]1C[C@@H]1F)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 LXUZLYORJUIQBG-LAYINKIGSA-N 0.000 claims 1
- LXUZLYORJUIQBG-BWOQGFTMSA-N [(1S,2R)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanol Chemical compound OC([C@@H]1C[C@H]1F)C1=NN2[C@@H](C[C@H](F)C2=N1)C1=CC=CC=C1 LXUZLYORJUIQBG-BWOQGFTMSA-N 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-M cyclopropanecarboxylate Chemical compound [O-]C(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-M 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 210000003205 muscle Anatomy 0.000 claims 1
- 230000003387 muscular Effects 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 230000001769 paralizing effect Effects 0.000 claims 1
- 102000020233 phosphotransferase Human genes 0.000 claims 1
- 201000002241 progressive bulbar palsy Diseases 0.000 claims 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 239000010802 sludge Substances 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201762570892P | 2017-10-11 | 2017-10-11 | |
| US62/570,892 | 2017-10-11 | ||
| PCT/EP2018/077656 WO2019072942A1 (en) | 2017-10-11 | 2018-10-10 | BICYCLIC COMPOUNDS FOR USE AS INHIBITORS OF KINASE RIP1 |
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| RU2020114670A true RU2020114670A (ru) | 2021-11-12 |
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| AU (1) | AU2018348930A1 (https=) |
| BR (1) | BR112020007067A2 (https=) |
| CA (1) | CA3078653A1 (https=) |
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| CO (1) | CO2020004977A2 (https=) |
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| PE (1) | PE20211246A1 (https=) |
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| RU (1) | RU2020114670A (https=) |
| SG (1) | SG11202003283TA (https=) |
| WO (1) | WO2019072942A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11071721B2 (en) | 2016-12-02 | 2021-07-27 | Genentech, Inc. | Bicyclic amide compounds and methods of use thereof |
| US11098058B2 (en) * | 2017-07-14 | 2021-08-24 | Genentech, Inc. | Bicyclic ketone compounds and methods of use thereof |
| SG11202002877RA (en) | 2017-10-31 | 2020-04-29 | Hoffmann La Roche | Bicyclic sulfones and sulfoxides and methods of use thereof |
| CN113302193A (zh) | 2019-01-11 | 2021-08-24 | 豪夫迈·罗氏有限公司 | 双环吡咯并三唑酮化合物及其使用方法 |
| CN114591333B (zh) * | 2020-12-04 | 2023-08-01 | 广州嘉越医药科技有限公司 | 一种吡咯并嘧啶类化合物的制备方法 |
| WO2023039795A1 (zh) * | 2021-09-16 | 2023-03-23 | 维泰瑞隆（北京）生物科技有限公司 | Rip1激酶抑制剂及其用途 |
| WO2025261418A1 (zh) * | 2024-06-19 | 2025-12-26 | 成都赜灵生物医药科技有限公司 | 并芳基类化合物及其用途 |
| WO2026001865A1 (en) * | 2024-06-24 | 2026-01-02 | Sironax Ltd. | Rip1 modulators, preparations, and uses thereof |
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| EP0102324A3 (de) | 1982-07-29 | 1984-11-07 | Ciba-Geigy Ag | Lipide und Tenside in wässriger Phase |
| US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
| HUT35524A (en) | 1983-08-02 | 1985-07-29 | Hoechst Ag | Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance |
| US5004697A (en) | 1987-08-17 | 1991-04-02 | Univ. Of Ca | Cationized antibodies for delivery through the blood-brain barrier |
| US5112596A (en) | 1990-04-23 | 1992-05-12 | Alkermes, Inc. | Method for increasing blood-brain barrier permeability by administering a bradykinin agonist of blood-brain barrier permeability |
| US5268164A (en) | 1990-04-23 | 1993-12-07 | Alkermes, Inc. | Increasing blood-brain barrier permeability with permeabilizer peptides |
| AU8405691A (en) * | 1990-09-04 | 1992-03-30 | Yamanouchi Pharmaceutical Co., Ltd. | Novel tetrahydrobenzazole derivative |
| ATE191853T1 (de) | 1992-07-27 | 2000-05-15 | Us Health | Zielgerichte liposome zur blut-hirne schranke |
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| EP1007042A4 (en) | 1997-06-13 | 2001-07-04 | Sugen Inc | NEW HETEROCYCLIC COMPOUNDS FOR MODULATING THE PROTEIN-TYROSIN-ENZYME-RELATED CELLULAR SIGNAL TRANSDUCTION |
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| JP2012051806A (ja) * | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | イミダゾリルピラジン誘導体 |
| JP2012532912A (ja) | 2009-07-15 | 2012-12-20 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | ガンマセクレターゼモジュレーターとしての置換されたトリアゾールおよびイミダゾール誘導体 |
| KR101913135B1 (ko) | 2011-07-15 | 2018-10-30 | 얀센 파마슈티칼즈, 인코포레이티드 | 감마 세크레타제 조절 인자로서의 신규의 치환 인돌 유도체 |
| EP2852584B1 (en) | 2012-05-22 | 2018-02-28 | F. Hoffmann-La Roche AG | Substituted dipyridylamines and uses thereof |
| CA2896187A1 (en) | 2013-01-18 | 2014-07-24 | F. Hoffmann-La Roche Ag | 3-substituted pyrazoles and use as dlk inhibitors |
| TWI648274B (zh) | 2013-02-15 | 2019-01-21 | 英商葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之雜環醯胺類 （二） |
| PH12019502378A1 (en) | 2013-05-01 | 2022-05-11 | Hoffmann La Roche | Biheteroaryl compounds and uses thereof |
| CA2907912A1 (en) | 2013-05-01 | 2014-11-06 | F. Hoffmann-La Roche Ag | C-linked heterocycloalkyl substituted pyrimidines and their uses |
| MX2016008110A (es) | 2013-12-20 | 2016-08-19 | Hoffmann La Roche | Derivados de pirazol como inhibidores de la cinasa de cremallera de leucina dual (dlk) y usos de los mismos. |
| RU2017109122A (ru) | 2014-08-21 | 2018-09-21 | Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед | Способы лечения с использованием гетероциклических амидов в качестве ингибиторов киназы |
| WO2016142310A1 (en) | 2015-03-09 | 2016-09-15 | F. Hoffmann-La Roche Ag | Tricyclic dlk inhibitors and uses thereof |
| TWI763630B (zh) | 2015-07-02 | 2022-05-11 | 瑞士商赫孚孟拉羅股份公司 | 雙環內醯胺及其使用方法 |
| MA44007A (fr) * | 2016-02-05 | 2018-12-19 | Denali Therapeutics Inc | Inhibiteurs du récepteur interagissant avec protéine kinase 1 |
| KR102613433B1 (ko) | 2017-10-11 | 2023-12-13 | 주식회사 대웅제약 | 신규한 페닐피리딘 유도체 및 이를 포함하는 약학 조성물 |
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| JP2020536915A (ja) | 2020-12-17 |
| SG11202003283TA (en) | 2020-05-28 |
| US20200283446A1 (en) | 2020-09-10 |
| CL2020000944A1 (es) | 2020-08-21 |
| US11673892B2 (en) | 2023-06-13 |
| MA50356A (fr) | 2021-04-21 |
| CA3078653A1 (en) | 2019-04-18 |
| EP3694858B1 (en) | 2023-01-11 |
| CR20200151A (es) | 2020-05-23 |
| IL273443A (en) | 2020-05-31 |
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| PH12020550253A1 (en) | 2021-02-22 |
| CN111201229B (zh) | 2024-08-23 |
| CO2020004977A2 (es) | 2020-05-05 |
| KR20200070297A (ko) | 2020-06-17 |
| PE20211246A1 (es) | 2021-07-13 |
| CN111201229A (zh) | 2020-05-26 |
| EP3694858A1 (en) | 2020-08-19 |
| WO2019072942A1 (en) | 2019-04-18 |
| AU2018348930A1 (en) | 2020-03-26 |
| BR112020007067A2 (pt) | 2020-10-06 |
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