JP2018515489A5 - - Google Patents

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Publication number

JP2018515489A5

JP2018515489A5 JP2017557324A JP2017557324A JP2018515489A5 JP 2018515489 A5 JP2018515489 A5 JP 2018515489A5 JP 2017557324 A JP2017557324 A JP 2017557324A JP 2017557324 A JP2017557324 A JP 2017557324A JP 2018515489 A5 JP2018515489 A5 JP 2018515489A5

Authority

JP

Japan

Prior art keywords

pharmaceutically acceptable

acceptable salt

membered

compound according

alkyl

Prior art date

2016-05-06

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.)

Granted

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• -1 3-phenylazetidin-1-yl Chemical group 0.000 claims description 107
• 150000001875 compounds Chemical class 0.000 claims description 100
• 150000003839 salts Chemical class 0.000 claims description 93
• 125000001424 substituent group Chemical group 0.000 claims description 81
• 229910052757 nitrogen Inorganic materials 0.000 claims description 67
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 59
• 125000005843 halogen group Chemical group 0.000 claims description 56
• 125000003118 aryl group Chemical group 0.000 claims description 52
• 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 51
• 125000001072 heteroaryl group Chemical group 0.000 claims description 41
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 20
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 20
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
• 238000000034 method Methods 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 12
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 12
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 230000003287 optical effect Effects 0.000 claims description 8
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000001188 haloalkyl group Chemical group 0.000 claims description 6
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
• 102000003964 Histone deacetylase Human genes 0.000 claims description 5
• 108090000353 Histone deacetylase Proteins 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000000203 mixture Substances 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 208000023105 Huntington disease Diseases 0.000 claims description 3
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
• 125000001627 3 membered heterocyclic group Chemical group 0.000 claims description 2
• 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 2
• 102100021454 Histone deacetylase 4 Human genes 0.000 claims description 2
• 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 claims description 2
• 230000005764 inhibitory process Effects 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• 230000000626 neurodegenerative effect Effects 0.000 claims description 2
• 230000007170 pathology Effects 0.000 claims description 2
• 108010033040 Histones Proteins 0.000 claims 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
• VZNPNWZRFNGPCD-DHXVBOOMSA-N 3-fluoro-N-[(2R)-1-[(2S)-2-methylpyrrolidin-1-ium-1-yl]propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide formate Chemical compound [O-]C=O.C[C@H](C[NH+]1CCC[C@@H]1C)NC(=O)c1ccc(-c2noc(n2)C(F)(F)F)c(F)c1 VZNPNWZRFNGPCD-DHXVBOOMSA-N 0.000 description 1
• UHNTVGGNBPFNBL-HNNXBMFYSA-N N-[(1R)-1-cyclopropyl-2-pyrrolidin-1-ylethyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound C1(CC1)[C@H](CN1CCCC1)NC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O UHNTVGGNBPFNBL-HNNXBMFYSA-N 0.000 description 1
• UHNTVGGNBPFNBL-OAHLLOKOSA-N N-[(1S)-1-cyclopropyl-2-pyrrolidin-1-ylethyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound C1(CC1)[C@@H](CN1CCCC1)NC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O UHNTVGGNBPFNBL-OAHLLOKOSA-N 0.000 description 1
• FJDBAYCKADCQBQ-XNOZTZMFSA-N N-[(2R)-1-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-2-ium-2-yl)propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide formate Chemical compound [O-]C=O.C[C@H](C[NH+]1CC2CCCC2C1)NC(=O)c1ccc(cc1)-c1noc(n1)C(F)(F)F FJDBAYCKADCQBQ-XNOZTZMFSA-N 0.000 description 1
• ZHVSKKPOSCSUPK-CYBMUJFWSA-N N-[(2R)-1-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound C1N(CCC2=CC=NC=C12)C[C@@H](C)NC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O ZHVSKKPOSCSUPK-CYBMUJFWSA-N 0.000 description 1
• IPGUFGHVOXYGBE-VCANKDNSSA-N N-[(2R)-1-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound CC1(C2CN(CC12)C[C@@H](C)NC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O)C IPGUFGHVOXYGBE-VCANKDNSSA-N 0.000 description 1
• IZFWXPXCTQFPQU-CYBMUJFWSA-N N-[(2R)-1-(azepan-1-yl)propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound N1(CCCCCC1)C[C@@H](C)NC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O IZFWXPXCTQFPQU-CYBMUJFWSA-N 0.000 description 1
• HMUGKBRTVPNJFM-UHFFFAOYSA-N N-[2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound C12CN(CC(CC1)C2)CCNC(C1=CC=C(C=C1)C1=NOC(=N1)C(F)(F)F)=O HMUGKBRTVPNJFM-UHFFFAOYSA-N 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• XAXGLDHLTLQVOD-UHFFFAOYSA-N pyrrolidin-1-ium;formate Chemical compound [O-]C=O.C1CC[NH2+]C1 XAXGLDHLTLQVOD-UHFFFAOYSA-N 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
• 238000006467 substitution reaction Methods 0.000 description 1