JP2015514073A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2015514073A5 JP2015514073A5 JP2015501888A JP2015501888A JP2015514073A5 JP 2015514073 A5 JP2015514073 A5 JP 2015514073A5 JP 2015501888 A JP2015501888 A JP 2015501888A JP 2015501888 A JP2015501888 A JP 2015501888A JP 2015514073 A5 JP2015514073 A5 JP 2015514073A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- azaspiro
- amino
- fluoro
- oxa
- 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.)
- Pending
Links
- 125000001153 fluoro group Chemical group F* 0.000 claims description 148
- 125000000217 alkyl group Chemical group 0.000 claims description 141
- -1 carbon ring compound Chemical class 0.000 claims description 107
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 102
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 97
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 95
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 58
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000002950 monocyclic group Chemical group 0.000 claims description 27
- 125000001624 naphthyl group Chemical group 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000002837 carbocyclic group Chemical group 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 14
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 208000024827 Alzheimer disease Diseases 0.000 claims description 11
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- IYSTXDMECKBGJF-UHFFFAOYSA-N undec-2-en-2-amine Chemical compound CCCCCCCCC=C(C)N IYSTXDMECKBGJF-UHFFFAOYSA-N 0.000 claims description 6
- IENIEGOFAFHDMV-FQEVSTJZSA-N (4s)-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)[C@@]2(C)N=C(N)OC3(CCOCC3)C2)=C1 IENIEGOFAFHDMV-FQEVSTJZSA-N 0.000 claims description 4
- KFRODYATXDEEIY-NRFANRHFSA-N (4s)-4-methyl-4-[5-methyl-4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C2=C(SC(=C2)[C@@]2(C)N=C(N)OC3(CCOCC3)C2)C)=C1 KFRODYATXDEEIY-NRFANRHFSA-N 0.000 claims description 4
- ZYYNOJVIIKFFMO-ZZTDINLMSA-N (4s)-9,9-difluoro-4-[2-fluoro-5-[(e)-2-(4-fluorophenyl)ethenyl]phenyl]-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(\C=C\C=3C=CC(F)=CC=3)C=2)F)C21CCC(F)(F)CC2 ZYYNOJVIIKFFMO-ZZTDINLMSA-N 0.000 claims description 4
- ZSHQGPMKXVXTGN-FQEVSTJZSA-N (4s)-9,9-difluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)[C@@]2(C)N=C(N)OC3(CCC(F)(F)CC3)C2)=C1 ZSHQGPMKXVXTGN-FQEVSTJZSA-N 0.000 claims description 4
- CBEJGKXHBBTFCC-NRFANRHFSA-N (8s)-8-[2-fluoro-5-(5-prop-1-ynylpyridin-3-yl)phenyl]-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(C(F)=CC=2)[C@@]2(C)N=C(N)OC3(CCC3)C2)=C1 CBEJGKXHBBTFCC-NRFANRHFSA-N 0.000 claims description 4
- FZYKTQJILMMPKF-SHTLVRLNSA-N (8s)-8-[5-[(e)-2-(4-chlorophenyl)ethenyl]-2-fluorophenyl]-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(\C=C\C=3C=CC(Cl)=CC=3)C=2)F)C21CCC2 FZYKTQJILMMPKF-SHTLVRLNSA-N 0.000 claims description 4
- QMRAZGWOELYWAV-UHFFFAOYSA-N 4-(2-fluoro-5-pyrimidin-5-ylphenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(C=2)C=2C=NC=NC=2)F)CC21CCOCC2 QMRAZGWOELYWAV-UHFFFAOYSA-N 0.000 claims description 4
- IENIEGOFAFHDMV-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CCOCC3)C2)=C1 IENIEGOFAFHDMV-UHFFFAOYSA-N 0.000 claims description 4
- XJNRSWJNEVQPTB-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CCOCC3)C2)=C1 XJNRSWJNEVQPTB-UHFFFAOYSA-N 0.000 claims description 4
- ZYZJNCZGGMOBBG-UHFFFAOYSA-N 8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(COC3)C2)=C1 ZYZJNCZGGMOBBG-UHFFFAOYSA-N 0.000 claims description 4
- ZSHQGPMKXVXTGN-UHFFFAOYSA-N 9,9-difluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CCC(F)(F)CC3)C2)=C1 ZSHQGPMKXVXTGN-UHFFFAOYSA-N 0.000 claims description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 230000007850 degeneration Effects 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- OLJSZTMAURBGCT-UHFFFAOYSA-N n-[3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)CC21CCOCC2 OLJSZTMAURBGCT-UHFFFAOYSA-N 0.000 claims description 4
- MFBURPNLOUCMDK-UHFFFAOYSA-N n-[3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(=CC=3)C#N)C=2)F)CC21CCOCC2 MFBURPNLOUCMDK-UHFFFAOYSA-N 0.000 claims description 4
- NDXPUJMEQANHCF-UHFFFAOYSA-N n-[3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CCOCC2 NDXPUJMEQANHCF-UHFFFAOYSA-N 0.000 claims description 4
- OMPMOZDPEPBZRX-UHFFFAOYSA-N n-[3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CCCCC2 OMPMOZDPEPBZRX-UHFFFAOYSA-N 0.000 claims description 4
- ICLVFRMEZOPZEF-UHFFFAOYSA-N n-[3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)N=C(N)OC21CCOCC2 ICLVFRMEZOPZEF-UHFFFAOYSA-N 0.000 claims description 4
- PFDHUXDXZOAIGY-UHFFFAOYSA-N n-[3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CCOCC2 PFDHUXDXZOAIGY-UHFFFAOYSA-N 0.000 claims description 4
- PQQKYZNYRAUDFD-UHFFFAOYSA-N n-[3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-2-methyl-1,3-oxazole-4-carboxamide Chemical compound O1C(C)=NC(C(=O)NC=2C=C(C(F)=CC=2)C2(C)C(C3(CCC3)OC(N)=N2)(F)F)=C1 PQQKYZNYRAUDFD-UHFFFAOYSA-N 0.000 claims description 4
- CUMPDZBALDTLJS-UHFFFAOYSA-N n-[3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)N=C(N)OC21CCC2 CUMPDZBALDTLJS-UHFFFAOYSA-N 0.000 claims description 4
- JJZKNPLOOQSUEC-UHFFFAOYSA-N n-[3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(=CC=3)C#N)C=2)F)N=C(N)OC21CCC2 JJZKNPLOOQSUEC-UHFFFAOYSA-N 0.000 claims description 4
- UTHJWWGOXFMAOM-UHFFFAOYSA-N n-[3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CCC2 UTHJWWGOXFMAOM-UHFFFAOYSA-N 0.000 claims description 4
- FARQUNPWROAOKH-UHFFFAOYSA-N n-[3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C(C2(C)C(C3(CCC3)OC(N)=N2)(F)F)=C1 FARQUNPWROAOKH-UHFFFAOYSA-N 0.000 claims description 4
- PFDHUXDXZOAIGY-LJQANCHMSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound N([C@](C1(F)F)(C)C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)=C(N)OC21CCOCC2 PFDHUXDXZOAIGY-LJQANCHMSA-N 0.000 claims description 4
- OLJSZTMAURBGCT-FQEVSTJZSA-N n-[3-[(4s)-2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)C21CCOCC2 OLJSZTMAURBGCT-FQEVSTJZSA-N 0.000 claims description 4
- NDXPUJMEQANHCF-FQEVSTJZSA-N n-[3-[(4s)-2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)C21CCOCC2 NDXPUJMEQANHCF-FQEVSTJZSA-N 0.000 claims description 4
- ZWZJMWYISQSTIX-FQEVSTJZSA-N n-[3-[(4s)-2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)S1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)C21CCOCC2 ZWZJMWYISQSTIX-FQEVSTJZSA-N 0.000 claims description 4
- KVRCNBWUIVTIAP-FQEVSTJZSA-N n-[3-[(4s)-2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)S1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)C21CCOCC2 KVRCNBWUIVTIAP-FQEVSTJZSA-N 0.000 claims description 4
- ZJDNACZRPYKHGK-FQEVSTJZSA-N n-[3-[(4s)-2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]2(C)N=C(N)SC3(CCOCC3)C2)=C1 ZJDNACZRPYKHGK-FQEVSTJZSA-N 0.000 claims description 4
- GOEDFUNVQLUUNN-FQEVSTJZSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-bromopyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(Br)=CC=3)C=2)F)C21CCC(F)(F)CC2 GOEDFUNVQLUUNN-FQEVSTJZSA-N 0.000 claims description 4
- HRWNLDZIHXSYEL-FQEVSTJZSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-chloro-3-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3C(=CC(Cl)=CN=3)F)C=2)F)C21CCC(F)(F)CC2 HRWNLDZIHXSYEL-FQEVSTJZSA-N 0.000 claims description 4
- SRUBXASONBMVNN-QHCPKHFHSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-cyclopropylpyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(=CC=3)C3CC3)C=2)F)C21CCC(F)(F)CC2 SRUBXASONBMVNN-QHCPKHFHSA-N 0.000 claims description 4
- SFEWUCSGCBOCLB-FQEVSTJZSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)C21CCC(F)(F)CC2 SFEWUCSGCBOCLB-FQEVSTJZSA-N 0.000 claims description 4
- XCPISCAUTOOVPQ-SFHVURJKSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]cyclopropanecarboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C3CC3)C=2)F)C21CCC(F)(F)CC2 XCPISCAUTOOVPQ-SFHVURJKSA-N 0.000 claims description 4
- JJZKNPLOOQSUEC-LJQANCHMSA-N n-[3-[(8r)-6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound N([C@](C1(F)F)(C)C=2C(=CC=C(NC(=O)C=3N=CC(=CC=3)C#N)C=2)F)=C(N)OC21CCC2 JJZKNPLOOQSUEC-LJQANCHMSA-N 0.000 claims description 4
- ZBEMTFMMGYRMGE-SFHVURJKSA-N n-[3-[(8s)-6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)S1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)C21COC2 ZBEMTFMMGYRMGE-SFHVURJKSA-N 0.000 claims description 4
- MZAMAFVHYGFSRH-NRFANRHFSA-N n-[3-[(8s)-6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl]-4-fluorophenyl]-4-chloro-2-methoxybenzamide Chemical compound COC1=CC(Cl)=CC=C1C(=O)NC1=CC=C(F)C([C@@]2(C)N=C(N)OC3(CCC3)C2)=C1 MZAMAFVHYGFSRH-NRFANRHFSA-N 0.000 claims description 4
- MYVNXXFZPZMOFC-IBGZPJMESA-N n-[3-[(8s)-6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl]-4-fluorophenyl]-5-chloro-3-fluoropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3C(=CC(Cl)=CN=3)F)C=2)F)C21CCC2 MYVNXXFZPZMOFC-IBGZPJMESA-N 0.000 claims description 4
- 238000006384 oligomerization reaction Methods 0.000 claims description 4
- 230000007505 plaque formation Effects 0.000 claims description 4
- PPTZAPQAZMYOMX-FQEVSTJZSA-N (4s)-4-[2-fluoro-5-[(3-methoxypyridin-2-yl)amino]phenyl]-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound COC1=CC=CN=C1NC1=CC=C(F)C([C@@]2(C)N=C(N)SC3(CCOCC3)C2)=C1 PPTZAPQAZMYOMX-FQEVSTJZSA-N 0.000 claims description 3
- 201000010374 Down Syndrome Diseases 0.000 claims description 3
- 208000028389 Nerve injury Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010044688 Trisomy 21 Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 230000008764 nerve damage Effects 0.000 claims description 3
- 230000006919 peptide aggregation Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- XCQPXNJVSOBJBE-FQEVSTJZSA-N (4s)-4-methyl-4-[1-(5-prop-1-ynylpyridin-3-yl)pyrazol-4-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(N2N=CC(=C2)[C@@]2(C)N=C(N)SC3(CCCCC3)C2)=C1 XCQPXNJVSOBJBE-FQEVSTJZSA-N 0.000 claims description 2
- HOWMDVSSALLUFB-NRFANRHFSA-N (4s)-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)[C@@]2(C)N=C(N)SC3(CCCCC3)C2)=C1 HOWMDVSSALLUFB-NRFANRHFSA-N 0.000 claims description 2
- PXTQCLIDWWNRHL-SHTLVRLNSA-N (8s)-8-[2-fluoro-5-[(e)-2-(4-fluorophenyl)ethenyl]phenyl]-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(\C=C\C=3C=CC(F)=CC=3)C=2)F)C21CCC2 PXTQCLIDWWNRHL-SHTLVRLNSA-N 0.000 claims description 2
- HJAHSACWSZCZBD-FQEVSTJZSA-N (9s)-9-methyl-9-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-6-thia-8-azaspiro[4.5]dec-7-en-7-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)[C@@]2(C)N=C(N)SC3(CCCC3)C2)=C1 HJAHSACWSZCZBD-FQEVSTJZSA-N 0.000 claims description 2
- DXHRRCVFMGUVMS-UHFFFAOYSA-N 1-[6-amino-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-oxa-7-azaspiro[3.5]non-6-en-2-yl]ethanone Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CC(C3)C(C)=O)C2)=C1 DXHRRCVFMGUVMS-UHFFFAOYSA-N 0.000 claims description 2
- HTYMTMSUQBNMTH-UHFFFAOYSA-N 1-[6-amino-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-thia-7-azaspiro[3.5]non-6-en-2-yl]ethanone Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CC(C3)C(C)=O)C2)=C1 HTYMTMSUQBNMTH-UHFFFAOYSA-N 0.000 claims description 2
- VDOVJVQBHHJLFF-UHFFFAOYSA-N 10,10-difluoro-9-methyl-9-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-6-thia-8-azaspiro[4.5]dec-7-en-7-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CCCC3)SC(N)=N2)(F)F)=C1 VDOVJVQBHHJLFF-UHFFFAOYSA-N 0.000 claims description 2
- ZYNVARVKQYNHQG-UHFFFAOYSA-N 2,2,9,9-tetrafluoro-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-thia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CC(F)(F)C3)SC(N)=N2)(F)F)=C1 ZYNVARVKQYNHQG-UHFFFAOYSA-N 0.000 claims description 2
- DIQCXFBKOSDFSU-UHFFFAOYSA-N 2,2-difluoro-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-oxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CC(F)(F)C3)C2)=C1 DIQCXFBKOSDFSU-UHFFFAOYSA-N 0.000 claims description 2
- QJRIEDSLNLRRBW-UHFFFAOYSA-N 2,2-difluoro-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-thia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CC(F)(F)C3)C2)=C1 QJRIEDSLNLRRBW-UHFFFAOYSA-N 0.000 claims description 2
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 2
- KCNALOPYVQBFDB-UHFFFAOYSA-N 3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-n-(5-fluoropyridin-2-yl)benzamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(C=2)C(=O)NC=2N=CC(F)=CC=2)F)CC21CCC2 KCNALOPYVQBFDB-UHFFFAOYSA-N 0.000 claims description 2
- OJGLSPKMXPXONI-UHFFFAOYSA-N 3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-n-(5-fluoropyridin-2-yl)benzamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(C=2)C(=O)NC=2N=CC(F)=CC=2)F)CC21CCC2 OJGLSPKMXPXONI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- IROJBRGTSLGGFW-UHFFFAOYSA-N 4-[1-(5-bromopyridin-3-yl)pyrazol-4-yl]-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound S1C(N)=NC(C)(C2=CN(N=C2)C=2C=C(Br)C=NC=2)CC21CCCCC2 IROJBRGTSLGGFW-UHFFFAOYSA-N 0.000 claims description 2
- SVSNSXPCVUFVMM-UHFFFAOYSA-N 4-[3-chloro-5-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2SC(=C(Cl)C=2)C2(C)N=C(N)SC3(CCCCC3)C2)=C1 SVSNSXPCVUFVMM-UHFFFAOYSA-N 0.000 claims description 2
- XCQPXNJVSOBJBE-UHFFFAOYSA-N 4-methyl-4-[1-(5-prop-1-ynylpyridin-3-yl)pyrazol-4-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(N2N=CC(=C2)C2(C)N=C(N)SC3(CCCCC3)C2)=C1 XCQPXNJVSOBJBE-UHFFFAOYSA-N 0.000 claims description 2
- PUUWEKPXSFPKFZ-UHFFFAOYSA-N 4-methyl-4-[2-methyl-5-(5-prop-1-ynylpyridin-3-yl)pyrazol-3-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C2=NN(C)C(=C2)C2(C)N=C(N)SC3(CCCCC3)C2)=C1 PUUWEKPXSFPKFZ-UHFFFAOYSA-N 0.000 claims description 2
- CQHKAYWOMDJWNM-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,8-dioxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(COCCC3)C2)=C1 CQHKAYWOMDJWNM-UHFFFAOYSA-N 0.000 claims description 2
- PTAKMVJOBCLAPJ-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CCCCC3)C2)=C1 PTAKMVJOBCLAPJ-UHFFFAOYSA-N 0.000 claims description 2
- HOWMDVSSALLUFB-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CCCCC3)C2)=C1 HOWMDVSSALLUFB-UHFFFAOYSA-N 0.000 claims description 2
- OQPHRBGVOWHHJO-UHFFFAOYSA-N 4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-8-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(COCCC3)C2)=C1 OQPHRBGVOWHHJO-UHFFFAOYSA-N 0.000 claims description 2
- MZUQKOAHOYDRSO-UHFFFAOYSA-N 4-methyl-8,8-dioxo-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,8$l^{6}-dithia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CS(=O)(=O)CCC3)C2)=C1 MZUQKOAHOYDRSO-UHFFFAOYSA-N 0.000 claims description 2
- QCQVOCAAOVXXGN-UHFFFAOYSA-N 4-methyl-8,8-dioxo-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-oxa-8$l^{6}-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CS(=O)(=O)CCC3)C2)=C1 QCQVOCAAOVXXGN-UHFFFAOYSA-N 0.000 claims description 2
- ULIGZJOLXWXBSC-UHFFFAOYSA-N 4-methyl-9,9-dioxo-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1,9$l^{6}-dithia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CCS(=O)(=O)CC3)C2)=C1 ULIGZJOLXWXBSC-UHFFFAOYSA-N 0.000 claims description 2
- AOHABPUIZCINNS-UHFFFAOYSA-N 4-methyl-9,9-dioxo-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-oxa-9$l^{6}-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CCS(=O)(=O)CC3)C2)=C1 AOHABPUIZCINNS-UHFFFAOYSA-N 0.000 claims description 2
- JIHGAHVZNYWLNS-UHFFFAOYSA-N 5,5,9,9-tetrafluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CCC(F)(F)CC3)SC(N)=N2)(F)F)=C1 JIHGAHVZNYWLNS-UHFFFAOYSA-N 0.000 claims description 2
- FYJZIBZFEVLDHH-UHFFFAOYSA-N 5,5-difluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CCCCC3)SC(N)=N2)(F)F)=C1 FYJZIBZFEVLDHH-UHFFFAOYSA-N 0.000 claims description 2
- RTBHORPYDRAPOF-UHFFFAOYSA-N 5,5-difluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CCOCC3)SC(N)=N2)(F)F)=C1 RTBHORPYDRAPOF-UHFFFAOYSA-N 0.000 claims description 2
- OTPUCSLNENGTDL-UHFFFAOYSA-N 5-[5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-chlorothiophen-2-yl]pyridine-3-carbonitrile Chemical compound S1C(N)=NC(C)(C2=C(C=C(S2)C=2C=C(C=NC=2)C#N)Cl)CC21CCCCC2 OTPUCSLNENGTDL-UHFFFAOYSA-N 0.000 claims description 2
- GYSHMIRTKLHFNA-UHFFFAOYSA-N 5-[5-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-chlorothiophen-2-yl]pyridine-3-carbonitrile Chemical compound S1C(N)=NC(C)(C2=C(C=C(S2)C=2C=C(C=NC=2)C#N)Cl)CC21CC2 GYSHMIRTKLHFNA-UHFFFAOYSA-N 0.000 claims description 2
- YASVDQLALSFKCO-UHFFFAOYSA-N 5-[5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl]pyridine-3-carbonitrile Chemical compound O1C(N)=NC(C)(C2=C(C=C(S2)C=2C=C(C=NC=2)C#N)Cl)CC21COC2 YASVDQLALSFKCO-UHFFFAOYSA-N 0.000 claims description 2
- ZJLJKBJUODCVKJ-UHFFFAOYSA-N 5-[5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl]pyridine-3-carbonitrile Chemical compound O1C(N)=NC(C)(C=2SC=C(C=2)C=2C=C(C=NC=2)C#N)CC21COC2 ZJLJKBJUODCVKJ-UHFFFAOYSA-N 0.000 claims description 2
- IPEAQHGHUQJEMF-UHFFFAOYSA-N 5-[5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl]pyridine-3-carbonitrile Chemical compound S1C(N)=NC(C)(C2=C(C=C(S2)C=2C=C(C=NC=2)C#N)Cl)CC21COC2 IPEAQHGHUQJEMF-UHFFFAOYSA-N 0.000 claims description 2
- MTJSOCIMUGJRIR-UHFFFAOYSA-N 5-[5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl]pyridine-3-carbonitrile Chemical compound S1C(N)=NC(C)(C=2SC=C(C=2)C=2C=C(C=NC=2)C#N)CC21COC2 MTJSOCIMUGJRIR-UHFFFAOYSA-N 0.000 claims description 2
- AWYNVOFRUWMBKK-LJQANCHMSA-N 5-[5-[(4r)-2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl]thiophen-3-yl]pyridine-3-carbonitrile Chemical compound C([C@](N=C(N)S1)(C)C=2SC=C(C=2)C=2C=C(C=NC=2)C#N)C21CCCCC2 AWYNVOFRUWMBKK-LJQANCHMSA-N 0.000 claims description 2
- OTPUCSLNENGTDL-IBGZPJMESA-N 5-[5-[(4s)-2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl]-4-chlorothiophen-2-yl]pyridine-3-carbonitrile Chemical compound C([C@@](N=C(N)S1)(C)C2=C(C=C(S2)C=2C=C(C=NC=2)C#N)Cl)C21CCCCC2 OTPUCSLNENGTDL-IBGZPJMESA-N 0.000 claims description 2
- KIKIERZOQWXXJX-UHFFFAOYSA-N 7-methyl-7-[1-(5-prop-1-ynylpyridin-3-yl)pyrazol-4-yl]-4-thia-6-azaspiro[2.5]oct-5-en-5-amine Chemical compound CC#CC1=CN=CC(N2N=CC(=C2)C2(C)N=C(N)SC3(CC3)C2)=C1 KIKIERZOQWXXJX-UHFFFAOYSA-N 0.000 claims description 2
- SPENRMWFIYZFRR-UHFFFAOYSA-N 8-[4-[5-(2-cyclopropylethynyl)pyridin-3-yl]thiophen-2-yl]-8-methyl-2,2-dioxo-2$l^{6},5-dithia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound S1C(N)=NC(C)(C=2SC=C(C=2)C=2C=C(C=NC=2)C#CC2CC2)CC21CS(=O)(=O)C2 SPENRMWFIYZFRR-UHFFFAOYSA-N 0.000 claims description 2
- AKJOLZFYNYHRDM-UHFFFAOYSA-N 8-[4-[5-(2-cyclopropylethynyl)pyridin-3-yl]thiophen-2-yl]-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound O1C(N)=NC(C)(C=2SC=C(C=2)C=2C=C(C=NC=2)C#CC2CC2)CC21COC2 AKJOLZFYNYHRDM-UHFFFAOYSA-N 0.000 claims description 2
- VEEQSAHTVDLZAK-UHFFFAOYSA-N 8-methyl-2,2-dioxo-8-[1-(5-prop-1-ynylpyridin-3-yl)pyrazol-4-yl]-2$l^{6},5-dithia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(N2N=CC(=C2)C2(C)N=C(N)SC3(CS(=O)(=O)C3)C2)=C1 VEEQSAHTVDLZAK-UHFFFAOYSA-N 0.000 claims description 2
- YJLHLZJRAXXJLT-UHFFFAOYSA-N 8-methyl-2,2-dioxo-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-oxa-2$l^{6}-thia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CS(=O)(=O)C3)C2)=C1 YJLHLZJRAXXJLT-UHFFFAOYSA-N 0.000 claims description 2
- JADYZNMEEQSWJH-UHFFFAOYSA-N 8-methyl-8-[1-(5-prop-1-ynylpyridin-3-yl)pyrazol-4-yl]-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(N2N=CC(=C2)C2(C)N=C(N)OC3(COC3)C2)=C1 JADYZNMEEQSWJH-UHFFFAOYSA-N 0.000 claims description 2
- LEMSGJHTNVBLRC-UHFFFAOYSA-N 8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-oxa-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)OC3(CCC3)C2)=C1 LEMSGJHTNVBLRC-UHFFFAOYSA-N 0.000 claims description 2
- ZOIFCXQBGBZFIZ-UHFFFAOYSA-N 9,9-difluoro-4-methyl-4-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-1-thia-3-azaspiro[5.5]undec-2-en-2-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CCC(F)(F)CC3)C2)=C1 ZOIFCXQBGBZFIZ-UHFFFAOYSA-N 0.000 claims description 2
- UGZCVMBMGBSOQN-UHFFFAOYSA-N 9,9-difluoro-8-methyl-8-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-5-thia-7-azaspiro[3.5]non-6-en-6-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)C(C3(CCC3)SC(N)=N2)(F)F)=C1 UGZCVMBMGBSOQN-UHFFFAOYSA-N 0.000 claims description 2
- WVKCXNMVKIEYQY-UHFFFAOYSA-N 9-methyl-9-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-4-pyrrolidin-1-yl-6-thia-8-azaspiro[4.5]dec-7-en-7-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(C(CCC3)N3CCCC3)C2)=C1 WVKCXNMVKIEYQY-UHFFFAOYSA-N 0.000 claims description 2
- HJAHSACWSZCZBD-UHFFFAOYSA-N 9-methyl-9-[4-(5-prop-1-ynylpyridin-3-yl)thiophen-2-yl]-6-thia-8-azaspiro[4.5]dec-7-en-7-amine Chemical compound CC#CC1=CN=CC(C=2C=C(SC=2)C2(C)N=C(N)SC3(CCCC3)C2)=C1 HJAHSACWSZCZBD-UHFFFAOYSA-N 0.000 claims description 2
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 2
- 208000009829 Lewy Body Disease Diseases 0.000 claims description 2
- 201000002832 Lewy body dementia Diseases 0.000 claims description 2
- 206010034010 Parkinsonism Diseases 0.000 claims description 2
- 206010036631 Presenile dementia Diseases 0.000 claims description 2
- 206010039966 Senile dementia Diseases 0.000 claims description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 208000025698 brain inflammatory disease Diseases 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 230000001054 cortical effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 206010014599 encephalitis Diseases 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 210000004558 lewy body Anatomy 0.000 claims description 2
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 2
- MZQUNSZGFUOMBN-UHFFFAOYSA-N n-[3-(2-amino-5,5,9,9-tetrafluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CCC(F)(F)CC2 MZQUNSZGFUOMBN-UHFFFAOYSA-N 0.000 claims description 2
- VQHWTGLGTYATFO-UHFFFAOYSA-N n-[3-(2-amino-5,5-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CCCCC2 VQHWTGLGTYATFO-UHFFFAOYSA-N 0.000 claims description 2
- SFEWUCSGCBOCLB-UHFFFAOYSA-N n-[3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CCC(F)(F)CC2 SFEWUCSGCBOCLB-UHFFFAOYSA-N 0.000 claims description 2
- RPCBXBVWGXDEFA-UHFFFAOYSA-N n-[3-(2-amino-9,9-difluoro-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CCC(F)(F)CC2 RPCBXBVWGXDEFA-UHFFFAOYSA-N 0.000 claims description 2
- BBSQPQLQPNSXDE-UHFFFAOYSA-N n-[3-(5-amino-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CC2 BBSQPQLQPNSXDE-UHFFFAOYSA-N 0.000 claims description 2
- HNTCLDXXIGMPTD-UHFFFAOYSA-N n-[3-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CC2 HNTCLDXXIGMPTD-UHFFFAOYSA-N 0.000 claims description 2
- NNFDUGXKTVBZOV-UHFFFAOYSA-N n-[3-(6-amino-2,2,9,9-tetrafluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CC(F)(F)C2 NNFDUGXKTVBZOV-UHFFFAOYSA-N 0.000 claims description 2
- JQHDPUWTXMTSET-UHFFFAOYSA-N n-[3-(6-amino-2,2-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound O1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CC(F)(F)C2 JQHDPUWTXMTSET-UHFFFAOYSA-N 0.000 claims description 2
- SHSAPUGHZAJKNM-UHFFFAOYSA-N n-[3-(6-amino-2,2-difluoro-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CC(F)(F)C2 SHSAPUGHZAJKNM-UHFFFAOYSA-N 0.000 claims description 2
- YQDYJAFKEDTYIX-UHFFFAOYSA-N n-[3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound S1C(N)=NC(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)CC21CCC2 YQDYJAFKEDTYIX-UHFFFAOYSA-N 0.000 claims description 2
- WIKWLLQYOYSIKL-UHFFFAOYSA-N n-[3-(7-amino-10,10-difluoro-9-methyl-6-oxa-8-azaspiro[4.5]dec-7-en-9-yl)-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C=2C(=CC=C(NC(=O)C=3N=CC(F)=CC=3)C=2)F)N=C(N)OC21CCCC2 WIKWLLQYOYSIKL-UHFFFAOYSA-N 0.000 claims description 2
- VMUQVOVWLSNPNK-FQEVSTJZSA-N n-[3-[(4s)-2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C([C@@](N=C(N)O1)(C)C=2C(=CC=C(NC(=O)C=3N=CC(Cl)=CC=3)C=2)F)C21CCC(F)(F)CC2 VMUQVOVWLSNPNK-FQEVSTJZSA-N 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- UWXZIVLHDQQGGA-UHFFFAOYSA-N non-3-en-4-amine Chemical compound CCCCCC(N)=CCC UWXZIVLHDQQGGA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 208000020431 spinal cord injury Diseases 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000003573 thiols Chemical group 0.000 claims description 2
- 230000009529 traumatic brain injury Effects 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims 2
- 125000001769 aryl amino group Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 238000000034 method Methods 0.000 description 8
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- 0 C[C@](CC1)C(N)=NC1(C)C1(C)CCC*(*)C(*C2CCC(*)CCCC2)CCC1 Chemical compound C[C@](CC1)C(N)=NC1(C)C1(C)CCC*(*)C(*C2CCC(*)CCCC2)CCC1 0.000 description 3
- 102100021257 Beta-secretase 1 Human genes 0.000 description 2
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 206010059245 Angiopathy Diseases 0.000 description 1
- 102100021277 Beta-secretase 2 Human genes 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 101000894883 Homo sapiens Beta-secretase 2 Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000008319 inclusion body myositis Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261613377P | 2012-03-20 | 2012-03-20 | |
| US61/613,377 | 2012-03-20 | ||
| US201261727248P | 2012-11-16 | 2012-11-16 | |
| US61/727,248 | 2012-11-16 | ||
| PCT/US2013/033177 WO2013142613A1 (en) | 2012-03-20 | 2013-03-20 | Spirocyclic dihydro-thiazine and dihydro-oxazine bace inhibitors, and compositions and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2015514073A JP2015514073A (ja) | 2015-05-18 |
| JP2015514073A5 true JP2015514073A5 (enExample) | 2016-04-21 |
Family
ID=49223329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015501888A Pending JP2015514073A (ja) | 2012-03-20 | 2013-03-20 | スピロ環式ジヒドロ−チアジンおよびジヒドロ−オキサジンｂａｃｅ阻害剤、ならびにその組成物および使用 |
Country Status (8)
| Country | Link |
|---|---|
| US (4) | US9493485B2 (enExample) |
| EP (1) | EP2827857A4 (enExample) |
| JP (1) | JP2015514073A (enExample) |
| AU (1) | AU2013235117A1 (enExample) |
| BR (1) | BR112014023384A8 (enExample) |
| CA (1) | CA2867851A1 (enExample) |
| HK (1) | HK1206597A1 (enExample) |
| WO (1) | WO2013142613A1 (enExample) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2009258496B8 (en) | 2008-06-13 | 2014-06-26 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity |
| UA110467C2 (uk) | 2009-12-11 | 2016-01-12 | Шионогі Енд Ко., Лтд. | Похідні оксазину |
| EP2912035A4 (en) | 2012-10-24 | 2016-06-15 | Shionogi & Co | DERIVATIVES OF DIHYDROOXAZINE OR OXAZEPINE HAVING BACE1 INHIBITING ACTIVITY |
| WO2014134341A1 (en) * | 2013-03-01 | 2014-09-04 | Amgen Inc. | Perfluorinated 5,6-dihydro-4h-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
| AP2015008716A0 (en) | 2013-03-08 | 2015-09-30 | Amgen Inc | Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
| JP6483146B2 (ja) | 2014-02-19 | 2019-03-13 | ハー・ルンドベック・アクチエゼルスカベット | アルツハイマー病治療用のｂａｃｅ１阻害剤としての２−アミノ−３，５，５−トリフルオロ−３，４，５，６−テトラヒドロピリジン |
| WO2016001266A1 (en) | 2014-07-04 | 2016-01-07 | F. Hoffmann-La Roche Ag | Fluoro-[1,3]oxazines as bace1 inhibitors |
| JP6576433B2 (ja) | 2014-08-08 | 2019-09-18 | アムジエン・インコーポレーテツド | β−セクレターゼ阻害剤としてのシクロプロピル縮合チアジン−２−アミン化合物及び使用方法 |
| MA40941A (fr) | 2014-11-10 | 2017-09-19 | H Lundbeck As | 2-amino-5,5-difluoro-6-(fluorométhyl)-6-phényl-3,4,5,6-tétrahydropyridines comme inhibiteurs de bace1 |
| JO3458B1 (ar) | 2014-11-10 | 2020-07-05 | H Lundbeck As | 2- أمينو-6- (دايفلوروميثيل) – 5، 5- ديفلورو-6-فينيل-3،4، 5، 6-تيتراهيدروبيريدين كمثبطات bace1 |
| CR20170187A (es) | 2014-11-10 | 2018-02-01 | H Lundbeck As | 2-Amino-3,5-difluoro-6-metil-6-fenil-3,4,5,6-tetrahidropiridinas en calidad de inhibidores de BACE1 para el tratamiento de la enfermedad de Alzheimer |
| TW201717948A (zh) | 2015-08-10 | 2017-06-01 | Ｈ 朗德貝克公司 | 包括給予２－胺基－３，５，５－三氟－３，４，５，６－四氫吡啶的聯合治療 |
| HK1253372A1 (zh) | 2015-08-12 | 2019-06-14 | H‧隆德贝克有限公司 | 作为bace1抑制剂的2-氨基-3-氟-3-(氟甲基)-6-甲基-6-苯基-3，4，5，6-四氢吡啶 |
| US10947223B2 (en) | 2016-12-15 | 2021-03-16 | Amgen Inc. | Substituted oxazines as beta-secretase inhibitors |
| WO2018112083A1 (en) | 2016-12-15 | 2018-06-21 | Amgen Inc. | Thiazine derivatives as beta-secretase inhibitors and methods of use |
| MX387729B (es) | 2016-12-15 | 2025-03-18 | Amgen Inc | Derivados de dióxido de 1,4-tiazina y dióxido 1,2,4-tiadiazina como inhibidores de beta-secretasa y métodos de uso. |
| JP7148518B2 (ja) | 2016-12-15 | 2022-10-05 | アムジエン・インコーポレーテツド | β－セクレターゼ阻害剤としての二環式チアジンおよびオキサジン誘導体ならびに使用方法 |
| CA3047287A1 (en) | 2016-12-15 | 2018-06-21 | Amgen Inc. | Cyclopropyl fused thiazine derivatives as beta-secretase inhibitors and methods of use |
| CN109776295B (zh) * | 2019-02-18 | 2021-10-01 | 浙江师范大学 | 一种邻位含二氟亚甲基的芳基碘化合物及制备方法 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5744346A (en) | 1995-06-07 | 1998-04-28 | Athena Neurosciences, Inc. | β-secretase |
| AU6383396A (en) | 1995-06-07 | 1996-12-30 | Athena Neurosciences, Inc. | Beta-secretase, antibodies to beta-secretase, and assays for detecting beta-secretase inhibition |
| JP2009511589A (ja) | 2005-10-12 | 2009-03-19 | エラン ファーマシューティカルズ，インコーポレイテッド | アリール−シクロプロピル誘導体のアスパルチルプロテアーゼ阻害剤を使用してアミロイドーシスを治療する方法 |
| AU2006307314C1 (en) | 2005-10-25 | 2011-08-25 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivative |
| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
| AU2006316620B2 (en) | 2005-11-21 | 2011-03-03 | Amgen Inc. | Beta-secretase modulators and methods of use |
| ES2476605T3 (es) | 2007-04-24 | 2014-07-15 | Shionogi & Co., Ltd. | Derivados de aminohidrotiazina sustituidos con grupos cíclicos |
| EP2324032B1 (en) * | 2008-08-19 | 2014-10-01 | Vitae Pharmaceuticals, Inc. | Inhibitors of beta-secretase |
| US20110065695A1 (en) | 2009-09-11 | 2011-03-17 | Jeremy Beauchamp | Use of aminodihydrothiazines for the treatment or prevention of diabetes |
| US7964594B1 (en) * | 2009-12-10 | 2011-06-21 | Hoffmann-La Roche Inc. | Amino oxazine derivatives |
| UA103272C2 (uk) | 2009-12-11 | 2013-09-25 | Ф. Хоффманн-Ля Рош Аг | 2-аміно-5,5-дифтор-5,6-дигідро-4h-оксазини як інгібітори bace1 і/або bace2 |
-
2013
- 2013-03-20 HK HK15107058.7A patent/HK1206597A1/xx unknown
- 2013-03-20 CA CA2867851A patent/CA2867851A1/en not_active Abandoned
- 2013-03-20 BR BR112014023384A patent/BR112014023384A8/pt not_active Application Discontinuation
- 2013-03-20 US US14/386,722 patent/US9493485B2/en not_active Expired - Fee Related
- 2013-03-20 WO PCT/US2013/033177 patent/WO2013142613A1/en not_active Ceased
- 2013-03-20 JP JP2015501888A patent/JP2015514073A/ja active Pending
- 2013-03-20 EP EP13764741.8A patent/EP2827857A4/en not_active Withdrawn
- 2013-03-20 AU AU2013235117A patent/AU2013235117A1/en not_active Abandoned
-
2014
- 2014-12-01 US US14/556,895 patent/US20150087825A1/en not_active Abandoned
- 2014-12-01 US US14/556,914 patent/US20150087826A1/en not_active Abandoned
-
2016
- 2016-06-01 US US15/169,978 patent/US20160272654A1/en not_active Abandoned
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2015514073A5 (enExample) | ||
| HRP20210344T1 (hr) | Pripravci i postupci liječenja poremećaja cns | |
| RU2017101829A (ru) | Пиразоловые соединения в качестве модуляторов fshr и пути их применения | |
| JP2006515858A5 (enExample) | ||
| RU2005113168A (ru) | Производные 2-пиридона в качестве ингибитора нейтрофильной эластазы | |
| RU2013138834A (ru) | N-[3-(5-амино-3,3а,7,7а-тетрагидро-1н-2,4-диокса-6-аза-инден-7-ил)-фенил]-амиды в качестве ингибиторов васе1 и(или) васе2 | |
| JP2018522823A5 (enExample) | ||
| RU2012116877A (ru) | Соединения 2-пиридона, применяемые в качестве ингибиторов нейтрофильной эластазы | |
| RU2013138717A (ru) | Конденсированные производные аминодигидротиазина, пригодные в качестве ингибиторов васе | |
| RU2009138600A (ru) | Амиды диазабициклоалканов, селективные в отношении ацетилхолинового подтипа никотиновых рецепторов | |
| RU2006135111A (ru) | Производные тиазола | |
| JP2018502891A5 (enExample) | ||
| JP2017537940A5 (enExample) | ||
| JP2010510999A5 (enExample) | ||
| RU2017145650A (ru) | Ингибиторы тирозинкиназы брутона | |
| HRP20201216T1 (hr) | PRIPRAVCI I POSTUPCI ZA LIJEČENJE POREMEĆAJA CNS-a | |
| RU2002134487A (ru) | Бензофены как ингибиторы il-1бета и tnf-альфа | |
| RU2007108861A (ru) | Трифтометилзамещенные бензамиды в качестве ингибиторов киназ | |
| RU2017116196A (ru) | 2-амино-6-(дифторметил)-5,5-дифтор-6-фенил-3,4,5,6-тетрагидропиридины как ингибиторы васе1 | |
| RU2016141646A (ru) | Ингибиторы trka киназы, основанные на них композиции и способы | |
| HRP20230633T1 (hr) | Supstituirani 2-azabicikli i njihova uporaba kao modulatora receptora oreksina | |
| RU2003121307A (ru) | (диазоло-пиридинил)-пиримидины для применения в лечении нарушений центральной нервной системы и диабета | |
| JP2009526830A5 (enExample) | ||
| JP2013509392A5 (enExample) | ||
| RU2004102397A (ru) | Применение антагонистов рецептора nk-1 для лечения черепно-мозговой и спинномозговой травмы или повреждения нервной ткани |