JP2015514073A5 - - Google Patents
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- 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
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- 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
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- 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
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- 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
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- 150000003573 thiols Chemical group 0.000 claims description 2
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- 125000004438 haloalkoxy group Chemical group 0.000 claims 2
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- 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
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| 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 |
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| US8637504B2 (en) | 2008-06-13 | 2014-01-28 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
| RU2012129168A (ru) | 2009-12-11 | 2014-01-20 | Сионоги Энд Ко. Лтд. | Производные оксазина |
| JP2016501827A (ja) * | 2012-10-24 | 2016-01-21 | 塩野義製薬株式会社 | Ｂａｃｅ１阻害作用を有するジヒドロオキサジンまたはオキサゼピン誘導体 |
| AU2014223334C1 (en) * | 2013-03-01 | 2018-10-18 | Amgen Inc. | Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
| EP2964644B1 (en) | 2013-03-08 | 2018-12-26 | Amgen, Inc. | Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
| US20170066741A1 (en) | 2014-02-19 | 2017-03-09 | H. Lundbeck A/S | 2-Amino-3,5,5-Trifluoro-3,4,5,6-Tetrahydropyridines as BACE1 Inhibitors for Treatment of Alzheimer's Disease |
| WO2016001266A1 (en) | 2014-07-04 | 2016-01-07 | F. Hoffmann-La Roche Ag | Fluoro-[1,3]oxazines as bace1 inhibitors |
| MX381482B (es) | 2014-08-08 | 2025-03-12 | Amgen Inc | Compuestos de tiazin-2-amina fusionados con ciclopropilo como inhibidores de beta-secretasa y metodos de uso. |
| 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 |
| 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 |
| 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 |
| RU2018104868A (ru) | 2015-08-12 | 2019-09-13 | Х. Лундбекк А/С | 2-амино-3-фтор-3-(фторметил)-6-метил-6-фенил-3,4,5,6-тетрагидропиридины в качестве ингибиторов bace1 |
| AU2017376441B2 (en) * | 2016-12-15 | 2021-10-14 | Amgen Inc. | Oxazine derivatives as beta-secretase inhibitors and methods of use |
| MX386618B (es) | 2016-12-15 | 2025-03-19 | Amgen Inc | Derivados de tiazina condensados con ciclopropilo como inhibidores de beta-secretasa y métodos de uso. |
| 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. |
| AU2017376445B2 (en) | 2016-12-15 | 2021-09-30 | Amgen Inc. | Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use |
| MX388697B (es) | 2016-12-15 | 2025-03-20 | Amgen Inc | Derivados de tiazina como inhibidores de beta-secretasa y metodos de uso. |
| 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 |
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| US5744346A (en) | 1995-06-07 | 1998-04-28 | Athena Neurosciences, Inc. | β-secretase |
| JPH11507538A (ja) | 1995-06-07 | 1999-07-06 | アテナ ニューロサイエンシズ インコーポレイティド | β−セクレターゼ、β−セクレターゼに対する抗体、及びβ−セクレターゼ阻害を検出するためのアッセイ |
| CA2624904A1 (en) | 2005-10-12 | 2007-04-26 | Elan Pharmaceuticals, Inc. | Methods of treating amyloidosis using aryl-cyclopropyl derivative aspartyl protease inhibitors |
| ES2537898T3 (es) | 2005-10-25 | 2015-06-15 | Shionogi & Co., Ltd. | Derivados de aminotiazolidina y aminotetrahidrotiazepina como inhibidores de BACE 1 |
| EP1971598A1 (en) * | 2005-11-21 | 2008-09-24 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
| AU2008245082B8 (en) | 2007-04-24 | 2012-09-13 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
| US8450308B2 (en) * | 2008-08-19 | 2013-05-28 | 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 |
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2013
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- 2013-03-20 CA CA2867851A patent/CA2867851A1/en not_active Abandoned
- 2013-03-20 EP EP13764741.8A patent/EP2827857A4/en not_active Withdrawn
- 2013-03-20 BR BR112014023384A patent/BR112014023384A8/pt not_active Application Discontinuation
- 2013-03-20 WO PCT/US2013/033177 patent/WO2013142613A1/en not_active Ceased
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- 2013-03-20 JP JP2015501888A patent/JP2015514073A/ja active Pending
- 2013-03-20 AU AU2013235117A patent/AU2013235117A1/en not_active Abandoned
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2014
- 2014-12-01 US US14/556,914 patent/US20150087826A1/en not_active Abandoned
- 2014-12-01 US US14/556,895 patent/US20150087825A1/en not_active Abandoned
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2016
- 2016-06-01 US US15/169,978 patent/US20160272654A1/en not_active Abandoned
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