JP5584778B2 - Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての２−アミノ−５，５−ジフルオロ−５，６−ジヒドロ−４ｈ−オキサジン - Google Patents

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Publication number

JP5584778B2

JP5584778B2 JP2012542481A JP2012542481A JP5584778B2 JP 5584778 B2 JP5584778 B2 JP 5584778B2 JP 2012542481 A JP2012542481 A JP 2012542481A JP 2012542481 A JP2012542481 A JP 2012542481A JP 5584778 B2 JP5584778 B2 JP 5584778B2

Authority

JP

Japan

Prior art keywords

difluoro

dihydro

amino

methyl

fluoro

Prior art date

2009-12-11

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.)

Expired - Fee Related

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• 102100021277 Beta-secretase 2 Human genes 0.000 title claims description 36
• 101000894883 Homo sapiens Beta-secretase 2 Proteins 0.000 title claims description 35
• 102100021257 Beta-secretase 1 Human genes 0.000 title claims description 33
• 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 title claims description 32
• 239000003112 inhibitor Substances 0.000 title claims description 17
• KYROKMLNDZIHAV-UHFFFAOYSA-N 5,5-difluorooxazinan-2-amine Chemical compound NN1CCC(F)(F)CO1 KYROKMLNDZIHAV-UHFFFAOYSA-N 0.000 title 1
• -1 1H-pyrazolyl Chemical group 0.000 claims description 403
• 150000001875 compounds Chemical class 0.000 claims description 332
• 125000000217 alkyl group Chemical group 0.000 claims description 224
• 229910052736 halogen Inorganic materials 0.000 claims description 174
• 150000002367 halogens Chemical class 0.000 claims description 173
• 238000000034 method Methods 0.000 claims description 125
• 125000003545 alkoxy group Chemical group 0.000 claims description 111
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 71
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 70
• 125000001424 substituent group Chemical group 0.000 claims description 66
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
• 239000001257 hydrogen Substances 0.000 claims description 34
• 229910052739 hydrogen Inorganic materials 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 30
• 125000003342 alkenyl group Chemical group 0.000 claims description 29
• 125000001072 heteroaryl group Chemical group 0.000 claims description 29
• 230000000694 effects Effects 0.000 claims description 28
• 125000004076 pyridyl group Chemical group 0.000 claims description 28
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 27
• 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 27
• 238000004519 manufacturing process Methods 0.000 claims description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 230000001225 therapeutic effect Effects 0.000 claims description 24
• 238000011321 prophylaxis Methods 0.000 claims description 21
• 125000000304 alkynyl group Chemical group 0.000 claims description 17
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• 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 125000002971 oxazolyl group Chemical group 0.000 claims description 12
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 12
• HXRMCZBDTDCCOP-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(C(F)(F)F)C=C1Cl HXRMCZBDTDCCOP-UHFFFAOYSA-N 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
• 230000008021 deposition Effects 0.000 claims description 10
• 150000002431 hydrogen Chemical class 0.000 claims description 10
• DVMUZHLUMHPCGZ-QGZVFWFLSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(=CC=2)C#N)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F DVMUZHLUMHPCGZ-QGZVFWFLSA-N 0.000 claims description 10
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
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• WDIQNOHELORDIA-GOSISDBHSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4,6,6-trimethyl-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound FC1(F)C(C)(C)OC(N)=N[C@]1(C)C1=CC(NC(=O)C=2N=CC(Cl)=CC=2)=CC=C1F WDIQNOHELORDIA-GOSISDBHSA-N 0.000 claims description 7
• SAJHJLBNBLIXLI-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3,5-dichloropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC(Cl)=CN=2)Cl)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F SAJHJLBNBLIXLI-MRXNPFEDSA-N 0.000 claims description 7
• ROPIFMKHYVUXLG-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3-chloro-5-fluoropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC(F)=CN=2)Cl)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F ROPIFMKHYVUXLG-MRXNPFEDSA-N 0.000 claims description 7
• MJNKAMVVSNDFFW-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloro-3-fluoropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC(Cl)=CN=2)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F MJNKAMVVSNDFFW-MRXNPFEDSA-N 0.000 claims description 7
• FQQAQHRJTBVECP-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(Cl)=CC=2)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F FQQAQHRJTBVECP-MRXNPFEDSA-N 0.000 claims description 7
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• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• BZFXEYAWDBWTSY-UHFFFAOYSA-N 4-chloro-1-methylpyrazole-3-carboxylic acid Chemical compound CN1C=C(Cl)C(C(O)=O)=N1 BZFXEYAWDBWTSY-UHFFFAOYSA-N 0.000 claims description 5
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• 125000003368 amide group Chemical group 0.000 claims description 5
• MWPXKDUGYVKQEK-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3,5-difluoropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC(F)=CN=2)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F MWPXKDUGYVKQEK-MRXNPFEDSA-N 0.000 claims description 5
• PMNGCQQFGJDTIA-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC=CN=2)C(F)(F)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F PMNGCQQFGJDTIA-MRXNPFEDSA-N 0.000 claims description 5
• CVPLFHPGKNAETQ-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3-chloropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC=CN=2)Cl)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F CVPLFHPGKNAETQ-MRXNPFEDSA-N 0.000 claims description 5
• XEOUKBZRMLTRTN-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-3-fluoropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2C(=CC=CN=2)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F XEOUKBZRMLTRTN-MRXNPFEDSA-N 0.000 claims description 5
• QIDZVQSSIOGZDK-QGZVFWFLSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(OCC(F)(F)F)=CC=2)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F QIDZVQSSIOGZDK-QGZVFWFLSA-N 0.000 claims description 5
• KLPOVFVWIUCTEB-OAHLLOKOSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-(trifluoromethyl)pyrazine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(=NC=2)C(F)(F)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F KLPOVFVWIUCTEB-OAHLLOKOSA-N 0.000 claims description 5
• DOWZAMREDXYADB-OAHLLOKOSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-(trifluoromethyl)pyrimidine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(=CN=2)C(F)(F)F)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F DOWZAMREDXYADB-OAHLLOKOSA-N 0.000 claims description 5
• LSQOOIQMQSYBNI-QGZVFWFLSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide Chemical compound CC1=CC(Cl)=CN=C1C(=O)NC1=CC=C(F)C([C@]2(C)C(COC(N)=N2)(F)F)=C1 LSQOOIQMQSYBNI-QGZVFWFLSA-N 0.000 claims description 5
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• CNXVOHMMAKBONG-UNTBIKODSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide;hydrochloride Chemical compound Cl.C=1C(NC(=O)C=2N=CC(=CC=2)C#N)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F CNXVOHMMAKBONG-UNTBIKODSA-N 0.000 claims description 5
• FBXUIKJIHZEJMQ-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC(F)=CC=2)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F FBXUIKJIHZEJMQ-MRXNPFEDSA-N 0.000 claims description 5
• SYEULBIUWRUKDF-MRXNPFEDSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4-methyl-6h-1,3-oxazin-4-yl]-4-fluorophenyl]pyridine-2-carboxamide Chemical compound C=1C(NC(=O)C=2N=CC=CC=2)=CC=C(F)C=1[C@@]1(C)N=C(N)OCC1(F)F SYEULBIUWRUKDF-MRXNPFEDSA-N 0.000 claims description 5
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• IFPWUATXSMOUFP-UHFFFAOYSA-N (1-chloro-3,4-dihydronaphthalen-2-yl)methanol Chemical compound C1=CC=C2CCC(CO)=C(Cl)C2=C1 IFPWUATXSMOUFP-UHFFFAOYSA-N 0.000 claims description 4
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• OTNGMPRPWYLIGH-HXUWFJFHSA-N n-[3-[(4r)-2-amino-5,5-difluoro-4,6,6-trimethyl-1,3-oxazin-4-yl]-4-fluorophenyl]-5-(2,2,3,3-tetrafluoropropoxy)pyridine-2-carboxamide Chemical compound FC1(F)C(C)(C)OC(N)=N[C@]1(C)C1=CC(NC(=O)C=2N=CC(OCC(F)(F)C(F)F)=CC=2)=CC=C1F OTNGMPRPWYLIGH-HXUWFJFHSA-N 0.000 claims description 4
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• CMUKPCIZFMTLKD-UHFFFAOYSA-N methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC(CCl)=N1 CMUKPCIZFMTLKD-UHFFFAOYSA-N 0.000 description 1
• UOXPKVPNSWDMQU-UHFFFAOYSA-N methyl 3-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate Chemical compound COC(=O)C1=NC=CC=C1OCC(F)(F)F UOXPKVPNSWDMQU-UHFFFAOYSA-N 0.000 description 1
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• DOTSWVJTIJIZIJ-UHFFFAOYSA-N methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(OCC(F)(F)F)C=N1 DOTSWVJTIJIZIJ-UHFFFAOYSA-N 0.000 description 1
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