AU2013216870B2 - Compounds for treating spinal muscular atrophy - Google Patents
Compounds for treating spinal muscular atrophy Download PDFInfo
- Publication number
- AU2013216870B2 AU2013216870B2 AU2013216870A AU2013216870A AU2013216870B2 AU 2013216870 B2 AU2013216870 B2 AU 2013216870B2 AU 2013216870 A AU2013216870 A AU 2013216870A AU 2013216870 A AU2013216870 A AU 2013216870A AU 2013216870 B2 AU2013216870 B2 AU 2013216870B2
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- Australia
- Prior art keywords
- pyrido
- pyrimidin
- pyrazin
- methyl
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 1413
- 208000002320 spinal muscular atrophy Diseases 0.000 title claims abstract description 291
- -1 dihydrochloride Chemical compound 0.000 claims description 346
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 146
- 125000000623 heterocyclic group Chemical group 0.000 claims description 135
- 125000001424 substituent group Chemical group 0.000 claims description 129
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 108
- 125000001072 heteroaryl group Chemical group 0.000 claims description 92
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 125000004076 pyridyl group Chemical group 0.000 claims description 60
- 239000008194 pharmaceutical composition Substances 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 239000003085 diluting agent Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 12
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- 125000004613 furo[2,3-c]pyridinyl group Chemical group O1C(=CC=2C1=CN=CC2)* 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- 125000005960 1,4-diazepanyl group Chemical group 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims 379
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 8
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- NOJBJWZWMDMEJO-UHFFFAOYSA-N 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C(C)C2=NC(C)=CN2C=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCNCC1 NOJBJWZWMDMEJO-UHFFFAOYSA-N 0.000 claims 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 claims 1
- IIGPDHWJNPYHKW-AWEZNQCLSA-N 2-(1-methylindazol-5-yl)-7-[(3s)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN[C@@H](C)CN1C1=CN2C(=O)C=C(C=3C=C4C=NN(C)C4=CC=3)N=C2C=C1 IIGPDHWJNPYHKW-AWEZNQCLSA-N 0.000 claims 1
- BPNJIDDZIZJYIH-UHFFFAOYSA-N 2-(2,7-dimethylindazol-5-yl)-7-(4-methylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(C)CCN1C1=CN2C(=O)C=C(C3=CC4=CN(C)N=C4C(C)=C3)N=C2C=C1 BPNJIDDZIZJYIH-UHFFFAOYSA-N 0.000 claims 1
- VKBXHPYPNYCDBH-UHFFFAOYSA-N 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(C)CCN1C1=CN2C(=O)C=C(C3=CN4C=C(C)N=C4C(C)=C3)N=C2C=C1 VKBXHPYPNYCDBH-UHFFFAOYSA-N 0.000 claims 1
- FCJFBUROMMKJRC-ZDUSSCGKSA-N 2-(2-methyl-1,3-benzothiazol-5-yl)-7-[(3s)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN[C@@H](C)CN1C1=CN2C(=O)C=C(C=3C=C4N=C(C)SC4=CC=3)N=C2C=C1 FCJFBUROMMKJRC-ZDUSSCGKSA-N 0.000 claims 1
- WIRNEEAZZNLZFV-UHFFFAOYSA-N 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2OC(C)=NC2=CC=C1C(N=C1C=C2)=CC(=O)N1C=C2C1=CCNCC1 WIRNEEAZZNLZFV-UHFFFAOYSA-N 0.000 claims 1
- QHGQLEZVCXCAHB-CYBMUJFWSA-N 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3r)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN[C@H](C)CN1C1=CN2C(=O)C=C(C=3C=C4OC(C)=NC4=CC=3)N=C2C=C1 QHGQLEZVCXCAHB-CYBMUJFWSA-N 0.000 claims 1
- QHGQLEZVCXCAHB-ZDUSSCGKSA-N 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3s)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN[C@@H](C)CN1C1=CN2C(=O)C=C(C=3C=C4OC(C)=NC4=CC=3)N=C2C=C1 QHGQLEZVCXCAHB-ZDUSSCGKSA-N 0.000 claims 1
- STBQDINWEFFVNY-UHFFFAOYSA-N 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-propylpiperidin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CCC)CCC1C1=CN2C(=O)C=C(C3=CN4C=C(C)N=C4C=C3)N=C2C=C1 STBQDINWEFFVNY-UHFFFAOYSA-N 0.000 claims 1
- UVIYXIMQVSSPSU-UHFFFAOYSA-N 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1-methylpiperidin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(C)CCC1C1=CN2C(=O)C=C(C3=CC4=NC(C)=CN4C=C3)N=C2C=C1 UVIYXIMQVSSPSU-UHFFFAOYSA-N 0.000 claims 1
- ZHHKRPADXSHSSD-UHFFFAOYSA-N 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C=1C2=NC(C)=CN2C=CC=1C(N=C1C=C2)=CC(=O)N1C=C2N1CCNCC1 ZHHKRPADXSHSSD-UHFFFAOYSA-N 0.000 claims 1
- CTRKFPRBODSBDX-UHFFFAOYSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CC)CCN1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(C)C4=C3)N=C2C=C1 CTRKFPRBODSBDX-UHFFFAOYSA-N 0.000 claims 1
- MFEJEHBIUCQMQJ-UHFFFAOYSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-piperidin-1-ylpiperidin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(C)=NC(C)=CN2N=C1C(N=C1C=C2)=CC(=O)N1C=C2N(CC1)CCC1N1CCCCC1 MFEJEHBIUCQMQJ-UHFFFAOYSA-N 0.000 claims 1
- XAQIBZIVIVBYPA-MRXNPFEDSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3r)-4-ethyl-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1[C@@H](C)N(CC)CCN1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(C)C4=C3)N=C2C=C1 XAQIBZIVIVBYPA-MRXNPFEDSA-N 0.000 claims 1
- IECPRWYSJTWAQC-ZDUSSCGKSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3s)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN[C@@H](C)CN1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(C)C4=C3)N=C2C=C1 IECPRWYSJTWAQC-ZDUSSCGKSA-N 0.000 claims 1
- LTIQUVYQSAXIKR-UHFFFAOYSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methyl-3,6-dihydro-2h-pyridin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1N(C)CCC(C2=CN3C(=O)C=C(N=C3C(C)=C2)C2=NN3C=C(C)N=C(C)C3=C2)=C1 LTIQUVYQSAXIKR-UHFFFAOYSA-N 0.000 claims 1
- ZENSDMBUHUWTPB-UHFFFAOYSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CCC)CCC1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(C)C4=C3)N=C2C(C)=C1 ZENSDMBUHUWTPB-UHFFFAOYSA-N 0.000 claims 1
- QATKMCTWUDXGKK-UHFFFAOYSA-N 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CC)CCN1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(CC)C4=C3)N=C2C(C)=C1 QATKMCTWUDXGKK-UHFFFAOYSA-N 0.000 claims 1
- FICLUJLAYRZCAR-UHFFFAOYSA-N 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(CC)=NC(C)=CN2N=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCCN(C)CC1 FICLUJLAYRZCAR-UHFFFAOYSA-N 0.000 claims 1
- ZMSVZYJNMNOYAW-UHFFFAOYSA-N 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(3-fluoropropyl)piperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(CC)=NC(C)=CN2N=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCN(CCCF)CC1 ZMSVZYJNMNOYAW-UHFFFAOYSA-N 0.000 claims 1
- QEIBZMAOAFKPSZ-UHFFFAOYSA-N 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-piperidin-4-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(CC)=NC(C)=CN2N=C1C(N=C1C=C2)=CC(=O)N1C=C2C1CCNCC1 QEIBZMAOAFKPSZ-UHFFFAOYSA-N 0.000 claims 1
- CNDGKNQXKNWKEQ-UHFFFAOYSA-N 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-piperidin-4-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(CC)=NC(C)=CN2N=C1C(N=C1C(C)=C2)=CC(=O)N1C=C2C1CCNCC1 CNDGKNQXKNWKEQ-UHFFFAOYSA-N 0.000 claims 1
- UTKYUGQUDUXQPK-UHFFFAOYSA-N 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-propyl-3,6-dihydro-2h-pyridin-4-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1N(CCC)CCC(C2=CN3C(=O)C=C(N=C3C=C2)C=2C=C3OC(C)=NC3=C(F)C=2)=C1 UTKYUGQUDUXQPK-UHFFFAOYSA-N 0.000 claims 1
- WMGIQXYMZKSCGJ-UHFFFAOYSA-N 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-propylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CCC)CCN1C1=CN2C(=O)C=C(C=3C=C4OC(C)=NC4=C(F)C=3)N=C2C=C1 WMGIQXYMZKSCGJ-UHFFFAOYSA-N 0.000 claims 1
- ZTIAVYUOJXJYMU-UHFFFAOYSA-N 2-(4-methylimidazol-1-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=NC(C)=CN1C1=CC(=O)N(C=C(C=C2)N3CCNCC3)C2=N1 ZTIAVYUOJXJYMU-UHFFFAOYSA-N 0.000 claims 1
- MVLJVTFGOOSRFQ-UHFFFAOYSA-N 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one Chemical compound O1C=2C(C)=NC(C)=CC=2C=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCN(CCO)CC1 MVLJVTFGOOSRFQ-UHFFFAOYSA-N 0.000 claims 1
- JIKCPPWCTGKHNK-UHFFFAOYSA-N 2-(5-fluoro-6-methoxypyridin-3-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C(F)C(OC)=NC=C1C1=CC(=O)N(C=C(C=C2)N3CCNCC3)C2=N1 JIKCPPWCTGKHNK-UHFFFAOYSA-N 0.000 claims 1
- ODDLPXZBSYNVIP-UHFFFAOYSA-N 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C(Cl)C2=NC(C)=CN2C=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCNCC1 ODDLPXZBSYNVIP-UHFFFAOYSA-N 0.000 claims 1
- IRBDSPQBNBCRAZ-UHFFFAOYSA-N 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-piperidin-4-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C(Cl)C2=NC(C)=CN2C=C1C(N=C1C=C2)=CC(=O)N1C=C2C1CCNCC1 IRBDSPQBNBCRAZ-UHFFFAOYSA-N 0.000 claims 1
- TYPQZWUOAZWGNP-UHFFFAOYSA-N 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-piperazin-1-ylpyrido[1,2-a]pyrimidin-4-one Chemical compound C=1N2C=C(C)N=C2C(CC)=CC=1C(N=C1C=C2)=CC(=O)N1C=C2N1CCNCC1 TYPQZWUOAZWGNP-UHFFFAOYSA-N 0.000 claims 1
- YCRUZUCJHWRHRE-UHFFFAOYSA-N 2-imidazo[1,2-a]pyridin-6-yl-7-(4-methylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(C)CCN1C1=CN2C(=O)C=C(C3=CN4C=CN=C4C=C3)N=C2C=C1 YCRUZUCJHWRHRE-UHFFFAOYSA-N 0.000 claims 1
- QTZRAEIEFLIRBX-UHFFFAOYSA-N 2-methyl-6-[7-(4-methylpiperazin-1-yl)-4-oxopyrido[1,2-a]pyrimidin-2-yl]imidazo[1,2-a]pyridine-8-carbonitrile Chemical compound C1CN(C)CCN1C1=CN2C(=O)C=C(C3=CN4C=C(C)N=C4C(C#N)=C3)N=C2C=C1 QTZRAEIEFLIRBX-UHFFFAOYSA-N 0.000 claims 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 claims 1
- ZYZWUDYTSAKYPS-UHFFFAOYSA-N 7-(1,4-diazepan-1-yl)-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C2C(CC)=NC(C)=CN2C=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCCNCC1 ZYZWUDYTSAKYPS-UHFFFAOYSA-N 0.000 claims 1
- ZIFXFWUDPJRGPU-UHFFFAOYSA-N 7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=CC2=NC(C)=CN2C=C1C(N=C1C=C2)=CC(=O)N1C=C2N1CCCNCC1 ZIFXFWUDPJRGPU-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
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- 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
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Families Citing this family (82)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10327940B2 (en) | 2008-11-09 | 2019-06-25 | 3D Systems, Inc. | Spiral brace |
| USRE47689E1 (en) | 2011-12-30 | 2019-11-05 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| PL2809322T3 (pl) | 2012-01-26 | 2019-11-29 | Ptc Therapeutics Inc | Związki do leczenia zaniku mięśni pochodzenia rdzeniowego |
| CN119528903A (zh) | 2012-02-10 | 2025-02-28 | Ptc医疗公司 | 用于治疗脊髓性肌萎缩的化合物 |
| CA2865957C (en) | 2012-03-01 | 2020-02-11 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| KR102109992B1 (ko) | 2012-03-23 | 2020-05-13 | 피티씨 테라퓨틱스, 인크. | 척수성 근위축증을 치료하기 위한 화합물 |
| US10987370B2 (en) * | 2012-12-24 | 2021-04-27 | Ramot At Tel-Aviv University Ltd. | Methods of inducing read-through of a nonsense mutation associated with ataxia telangiectasia, Rett syndrome or spinal muscular atrophy by erythromycin or azithromycin |
| BR112015032718A2 (pt) | 2013-08-19 | 2019-09-17 | Hoffmann La Roche | composto de modificação de splicing do gene foxm1, uso do composto, formulação farmacêutica e métodos de triagem de compostos |
| WO2015105657A1 (en) * | 2013-12-19 | 2015-07-16 | Ptc Therapeutics, Inc. | Methods for modulating the amount of rna transcripts |
| PL3663296T3 (pl) * | 2014-05-15 | 2023-08-07 | F. Hoffmann-La Roche Ag | Sposób wytwarzania związków użytecznych w leczeniu rdzeniowego zaniku mięśni |
| US10882868B2 (en) | 2014-05-15 | 2021-01-05 | Hoffmann-La Roche Inc. | Compounds for treating spinal muscular atrophy |
| GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
| US10436802B2 (en) | 2014-09-12 | 2019-10-08 | Biogen Ma Inc. | Methods for treating spinal muscular atrophy |
| CN107109411B (zh) | 2014-10-03 | 2022-07-01 | 冷泉港实验室 | 核基因输出的定向增加 |
| ES2879809T3 (es) * | 2014-11-01 | 2021-11-23 | Shanghai Fochon Pharmaceutical Co Ltd | Ciertos inhibidores de proteínas quinasas |
| WO2016111896A1 (en) * | 2015-01-05 | 2016-07-14 | Sikorsky Aircraft Corporation | Integrated vibration damper for additively manufactured structure and method |
| JP6749343B2 (ja) * | 2015-05-20 | 2020-09-02 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | 脊髄性筋萎縮症を処置するための化合物 |
| US10668171B2 (en) | 2015-05-30 | 2020-06-02 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
| EP3359685A1 (en) | 2015-10-09 | 2018-08-15 | University Of Southampton | Modulation of gene expression and screening for deregulated protein expression |
| CN108289959B (zh) | 2015-11-12 | 2021-07-16 | 豪夫迈·罗氏有限公司 | 用于治疗脊髓性肌萎缩的组合物 |
| KR20180081520A (ko) * | 2015-11-12 | 2018-07-16 | 에프. 호프만-라 로슈 아게 | 근위축성 측삭 경화증의 치료를 위한 화합물 |
| HRP20201522T1 (hr) | 2015-12-09 | 2020-12-11 | Cadent Therapeutics, Inc. | Heteroaromatski nmda receptor modulatori i njihove uporabe |
| EA201800367A1 (ru) | 2015-12-10 | 2019-02-28 | ПиТиСи ТЕРАПЬЮТИКС, ИНК. | Способы лечения болезни хантингтона |
| EP3386978B1 (en) | 2015-12-10 | 2021-01-27 | H. Hoffnabb-La Roche Ag | Bridged piperidine derivatives |
| US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
| US11083745B2 (en) | 2015-12-14 | 2021-08-10 | Cold Spring Harbor Laboratory | Antisense oligomers for treatment of autosomal dominant mental retardation-5 and Dravet Syndrome |
| CN108473510B (zh) * | 2016-04-28 | 2021-10-29 | 豪夫迈·罗氏有限公司 | 制备2-吡唑并[1,5-a]吡嗪-2-基吡啶并[1,2-a]嘧啶-4-酮的方法 |
| EP3471779A4 (en) | 2016-06-16 | 2020-07-08 | Ionis Pharmaceuticals, Inc. | COMBINATIONS FOR MODULATING SMN EXPRESSION |
| US11702646B2 (en) | 2016-11-28 | 2023-07-18 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
| EP3558318B1 (en) | 2016-12-22 | 2023-12-20 | Novartis AG | Nmda receptor modulators and uses thereof |
| KR20200033249A (ko) | 2017-06-05 | 2020-03-27 | 피티씨 테라퓨틱스, 인크. | 헌팅턴병 치료 화합물 |
| JP2020523365A (ja) | 2017-06-14 | 2020-08-06 | ピーティーシー セラピューティクス，インコーポレーテッド | Ｒｎａスプライシングを改変する方法 |
| CA3067591A1 (en) * | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | Methods for treating huntington's disease |
| US11395822B2 (en) | 2017-06-28 | 2022-07-26 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
| CN111499615B (zh) | 2017-08-04 | 2024-02-02 | 斯基霍克疗法公司 | 用于调节剪接的方法和组合物 |
| SMT202400071T1 (it) | 2017-08-25 | 2024-03-13 | Stoke Therapeutics Inc | Oligomeri antisenso per il trattamento di condizioni e malattie |
| MX2020002711A (es) * | 2017-09-22 | 2020-07-20 | Hoffmann La Roche | Proceso para preparacion de 7-(4,7-diazaespiro[2.5]octan-7-il)-2-( 2,8-dimetilimidazo[1,2-b]piridazin-6-il)pirido[1,2-a]pirimidin-4- ona. |
| HRP20250322T1 (hr) | 2017-10-23 | 2025-06-06 | Stoke Therapeutics, Inc. | Protusmisleni oligomeri, namijenjeni liječenju stanja i bolesti uzrokovanih raspadanjem rna posredovanim besmislenim mutacijama |
| US12103926B2 (en) | 2018-03-27 | 2024-10-01 | Ptc Therapeutics, Inc. | Compounds for treating huntington's disease |
| JP2021523227A (ja) | 2018-05-04 | 2021-09-02 | ストーク セラピューティクス，インク． | コレステリルエステル蓄積症の処置のための方法及び組成物 |
| SG11202013088YA (en) | 2018-06-27 | 2021-02-25 | Reborna Biosciences Inc | Prophylactic or therapeutic agent for spinal muscular atrophy |
| EA202092899A1 (ru) | 2018-06-27 | 2021-05-14 | ПиТиСи ТЕРАПЬЮТИКС, ИНК. | Гетероарильные соединения для лечения болезни гентингтона |
| BR112020026545A2 (pt) | 2018-06-27 | 2021-03-23 | Ptc Therapeutics, Inc. | Compostos heterocíclicos e de heteroarila para o tratamento da doença de huntington |
| EP3814360B8 (en) | 2018-06-27 | 2024-11-06 | PTC Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| CU24647B1 (es) | 2018-08-03 | 2023-02-13 | Cadent Therapeutics Inc | Moduladores del receptor nmda heteroaromático |
| KR20210042123A (ko) * | 2018-08-07 | 2021-04-16 | 더 칠드런스 호스피탈 오브 필라델피아 | 유전자 발현의 선택적 스플라이싱 조절 및 치료 방법 |
| CN114007613A (zh) | 2019-02-05 | 2022-02-01 | 斯基霍克疗法公司 | 用于调节剪接的方法和组合物 |
| JP7603595B2 (ja) | 2019-02-06 | 2024-12-20 | スカイホーク・セラピューティクス・インコーポレーテッド | スプライシングを調節するための方法および組成物 |
| US11129829B2 (en) | 2019-06-17 | 2021-09-28 | Skyhawk Therapeutics, Inc. | Methods for modulating splicing |
| US12492214B2 (en) | 2019-07-31 | 2025-12-09 | Assia Chemical Industries Ltd. | Solid state forms of Risdiplam and process for preparation thereof |
| CN110540535B (zh) * | 2019-10-23 | 2020-07-31 | 上海再启生物技术有限公司 | 适合放大制备4-(6-氨基吡啶-3-基)取代哌啶的工艺方法 |
| CN111116576A (zh) * | 2019-12-01 | 2020-05-08 | 北京师范大学 | 一种喹嗪酮类化合物及其制备方法 |
| BR112022010561A2 (pt) | 2019-12-02 | 2022-11-16 | Storm Therapeutics Ltd | Compostos poli-heterocíclicos como inibidores de mettl3 |
| MX2022009025A (es) | 2020-01-28 | 2022-10-07 | Protego Biopharma Inc | Compuestos, composiciones y métodos para estabilizar la transtiretina e inhibir el plegamiento incorrecto de la transtiretina. |
| EP4103717A4 (en) * | 2020-02-12 | 2024-02-28 | The Children's Hospital of Philadelphia | Compositions and methods for inducible alternative splicing regulation of gene expression |
| EP4110775A1 (en) | 2020-02-28 | 2023-01-04 | Remix Therapeutics Inc. | Thiophenyl derivatives useful for modulating nucleic acid splicing |
| MX2022010634A (es) | 2020-02-28 | 2023-01-19 | Remix Therapeutics Inc | Derivados de piridazina para modular el empalme de acidos nucleicos. |
| JP7446443B2 (ja) | 2020-02-28 | 2024-03-08 | アイオーニス ファーマシューティカルズ， インコーポレーテッド | Ｓｍｎ２を調節するための化合物及び方法 |
| JP7736700B2 (ja) | 2020-02-28 | 2025-09-09 | リミックス セラピューティクス インコーポレイテッド | 複素環アミド及びスプライシングを調節するためのその使用 |
| AU2021228285A1 (en) | 2020-02-28 | 2022-09-29 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| TW202208344A (zh) | 2020-04-08 | 2022-03-01 | 美商雷密克斯醫療公司 | 調節剪接之化合物及方法 |
| BR112022020418A2 (pt) | 2020-04-08 | 2023-05-02 | Remix Therapeutics Inc | Compostos e métodos para modulação de splicing |
| CA3173647A1 (en) | 2020-05-11 | 2021-11-18 | Isabel AZNAREZ | Opa1 antisense oligomers for treatment of conditions and diseases |
| WO2022006543A1 (en) | 2020-07-02 | 2022-01-06 | Remix Therapeutics Inc. | 5-[5-(piperidin-4-yl)thieno[3,2-c]pyrazol-2-yl]indazole derivatives and related compounds as modulators for splicing nucleic acids and for the treatment of proliferative diseases |
| WO2022006550A1 (en) | 2020-07-02 | 2022-01-06 | Remix Therapeutics Inc. | 2-(indazol-5-yl)-6-(piperidin-4-yl)-1,7-naphthyridine derivatives and related compounds as modulators for splicing nucleic acids and for the treatment of proliferative diseases |
| WO2022070071A1 (en) * | 2020-09-30 | 2022-04-07 | Janssen Biotech, Inc. | Dihydroorotate dehydrogenase inhibitors |
| KR20230157367A (ko) | 2021-03-17 | 2023-11-16 | 에프. 호프만-라 로슈 아게 | 신규 티아졸로피리미디논 유도체 |
| TW202321206A (zh) | 2021-07-28 | 2023-06-01 | 美商普羅泰戈生物製藥股份有限公司 | 轉甲狀腺素蛋白穩定化合物 |
| WO2023034827A1 (en) | 2021-08-30 | 2023-03-09 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| US20240400584A1 (en) | 2021-08-30 | 2024-12-05 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| PE20241764A1 (es) | 2021-08-30 | 2024-08-28 | Remix Therapeutics Inc | Compuestos y metodos para modular el empalme |
| WO2023034836A1 (en) | 2021-08-30 | 2023-03-09 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| TW202319047A (zh) | 2021-08-30 | 2023-05-16 | 美商雷密克斯醫療公司 | 調節剪接之化合物及用途 |
| EP4416141A1 (en) | 2021-10-13 | 2024-08-21 | Remix Therapeutics Inc. | Compounds and methods for modulating nucleic acid splicing |
| WO2023064879A1 (en) | 2021-10-13 | 2023-04-20 | Remix Therapeutics Inc. | Compounds and methods for modulating nucleic acid splicing |
| US20250109140A1 (en) | 2022-01-05 | 2025-04-03 | Remix Theraputics Inc. | 5-[5-(piperidin-4-yl)thieno[3,2-c]pyrazol-2-yl]indazole derivatives and related compounds as modulators for splicing nucleic acids and for the treatment of proliferative diseases |
| US20250092065A1 (en) | 2022-01-05 | 2025-03-20 | Remix Therapeutics Inc. | 2-(indazol-5-yl)-6-(piperidin-4-yl)-1,7-naphthyridine derivatives and related compounds as modulators for splicing nucleic acids and for the treatment of proliferative diseases |
| US20250326748A1 (en) | 2022-01-05 | 2025-10-23 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| WO2023240236A1 (en) | 2022-06-10 | 2023-12-14 | Voyager Therapeutics, Inc. | Compositions and methods for the treatment of spinal muscular atrophy related disorders |
| AU2024286618A1 (en) * | 2023-06-09 | 2025-10-30 | F. Hoffmann-La Roche Ag | Inducible gene expression system |
| CN117263936B (zh) * | 2023-11-21 | 2024-02-23 | 中国中医科学院医学实验中心 | 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用 |
| WO2025233837A1 (en) | 2024-05-07 | 2025-11-13 | Takeda Pharmaceutical Company Limited | 4h-pyrimido[1,2-a]pyrimidin-4-one derivatives for use as nlrp3 inflammasome inhibitors for the treatment of neurodegenerative disorder |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6977255B2 (en) * | 2000-01-24 | 2005-12-20 | Kinacia Pty. Ltd. | Therapeutic morpholino-substituted compounds |
Family Cites Families (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3558618A (en) | 1968-04-01 | 1971-01-26 | Dow Chemical Co | Novel 4h-pyrazino(1,2-a)pyrimidine-4-ones |
| US4122274A (en) * | 1977-05-25 | 1978-10-24 | Bristol-Myers Company | 3-Tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones |
| US4342870A (en) * | 1980-03-28 | 1982-08-03 | Janssen Pharmaceutica N.V. | Novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives |
| JPS56150091A (en) * | 1980-03-28 | 1981-11-20 | Janssen Pharmaceutica Nv | 3-(1-piperidinylalkyl)-4h-pyrido(1,2-a)pyrimidine- 4-one derivative and its manufacture |
| US5089633A (en) | 1987-04-28 | 1992-02-18 | Georgia Tech Research Corporation | Substituted isocoumarins |
| US5726182A (en) | 1990-05-02 | 1998-03-10 | Abbott Laboratories | Quinolizinone type compounds |
| AU4231293A (en) * | 1992-05-13 | 1993-12-13 | E.I. Du Pont De Nemours And Company | Substituted pyrido(1,2-A)pyrimidinone derivatives as fungicides |
| WO1996039407A1 (en) | 1995-06-06 | 1996-12-12 | Abbott Laboratories | Quinolizinone type compounds |
| US5869500A (en) | 1996-12-13 | 1999-02-09 | Hoffmann-La Roche Inc. | Pyridone compounds useful in treating Alzheimer's disease |
| US6630488B1 (en) * | 1998-09-21 | 2003-10-07 | Biochem Pharma, Inc. | Quinolizinones as integrin inhibitors |
| DE60024861T2 (de) * | 1999-10-28 | 2006-07-06 | Trine Pharmaceuticals, Inc., Waltham | Pumpeninhibitoren zur freisetzung von medikamenten |
| CA2445697A1 (en) | 2001-04-26 | 2002-11-07 | Daiichi Pharmaceutical Co., Ltd. | Drug efflux pump inhibitor |
| DE60236322D1 (de) | 2001-12-07 | 2010-06-17 | Vertex Pharma | Verbindungen auf pyrimidin-basis als gsk-3-hemmer |
| GB0205281D0 (en) | 2002-03-06 | 2002-04-17 | Novartis Ag | Organic compounds |
| ATE548354T1 (de) | 2002-07-24 | 2012-03-15 | Ptc Therapeutics Inc | Ureido-substituierte benzoesäureverbindungen und ihre verwendung für die nonsense-suppression und behandlung von erkrankungen |
| ATE458735T1 (de) * | 2003-06-20 | 2010-03-15 | Novartis Vaccines & Diagnostic | Pyridino[1,2-a pyrimidin-4-onverbindungen als mittel gegen krebs |
| BRPI0510560A (pt) | 2004-05-04 | 2007-11-20 | Warner Lambert Co | pirido[2,3-d] pirimidin-7-onas pirrolil substituìdas e seus derivados como agentes terapêuticos |
| CN101146798A (zh) | 2005-01-21 | 2008-03-19 | 詹森药业有限公司 | 用作雌激素受体调节剂的新的杂环苯并[c]色烯衍生物 |
| AR059339A1 (es) | 2006-02-09 | 2008-03-26 | Chugai Pharmaceutical Co Ltd | Derivados de la cumarina para trastornos proliferativos de celulas, composicion farmaceutica y agente terapeutico que los contiene |
| US8110681B2 (en) * | 2006-03-17 | 2012-02-07 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Compounds for the treatment of spinal muscular atrophy and other uses |
| WO2008013997A2 (en) | 2006-07-27 | 2008-01-31 | The Trustees Of Columbia University In The City Of New York | Fluorescent substrates for monoamine transporters as optical false neurotransmitters |
| WO2009151546A2 (en) | 2008-05-27 | 2009-12-17 | Ptc Therapeutics, Inc. | Methods for treating spinal muscular atrophy |
| EP2138493A1 (en) | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidone derivatives |
| US8932818B2 (en) | 2008-08-13 | 2015-01-13 | Ptc Therapeutics, Inc. | Screening assays for compounds that modulate programmed ribosomal frameshifting |
| WO2011050245A1 (en) * | 2009-10-23 | 2011-04-28 | Yangbo Feng | Bicyclic heteroaryls as kinase inhibitors |
| US8754220B2 (en) * | 2009-11-20 | 2014-06-17 | Merck Sharp & Dohme Corp. | Quinolizidinone carboxamide M1 receptor positive allosteric modulators |
| CA2786329A1 (en) * | 2010-01-13 | 2011-07-21 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Anti - infective pyrido (1,2-a) pyrimidines |
| USRE47689E1 (en) | 2011-12-30 | 2019-11-05 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| PL2809322T3 (pl) | 2012-01-26 | 2019-11-29 | Ptc Therapeutics Inc | Związki do leczenia zaniku mięśni pochodzenia rdzeniowego |
| CN119528903A (zh) * | 2012-02-10 | 2025-02-28 | Ptc医疗公司 | 用于治疗脊髓性肌萎缩的化合物 |
| CA2865957C (en) | 2012-03-01 | 2020-02-11 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
| KR102109992B1 (ko) | 2012-03-23 | 2020-05-13 | 피티씨 테라퓨틱스, 인크. | 척수성 근위축증을 치료하기 위한 화합물 |
| PL3663296T3 (pl) | 2014-05-15 | 2023-08-07 | F. Hoffmann-La Roche Ag | Sposób wytwarzania związków użytecznych w leczeniu rdzeniowego zaniku mięśni |
| JP6749343B2 (ja) | 2015-05-20 | 2020-09-02 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | 脊髄性筋萎縮症を処置するための化合物 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6977255B2 (en) * | 2000-01-24 | 2005-12-20 | Kinacia Pty. Ltd. | Therapeutic morpholino-substituted compounds |
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