CN110946865A - 用于治疗亨廷顿病的方法 - Google Patents
用于治疗亨廷顿病的方法 Download PDFInfo
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- CN110946865A CN110946865A CN201911286032.1A CN201911286032A CN110946865A CN 110946865 A CN110946865 A CN 110946865A CN 201911286032 A CN201911286032 A CN 201911286032A CN 110946865 A CN110946865 A CN 110946865A
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- CN
- China
- Prior art keywords
- pyridazin
- amino
- tetramethylpiperidin
- methyl
- pyrazol
- 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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- 238000000034 method Methods 0.000 title claims abstract description 127
- 208000023105 Huntington disease Diseases 0.000 title abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 359
- -1 hydroxy-imino Chemical group 0.000 claims description 355
- 125000001424 substituent group Chemical group 0.000 claims description 120
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 150000003839 salts Chemical group 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 125000002950 monocyclic group Chemical group 0.000 claims description 33
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 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 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000002619 bicyclic group Chemical group 0.000 claims description 22
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 125000004122 cyclic group Chemical group 0.000 claims description 17
- 150000001721 carbon Chemical group 0.000 claims description 15
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- QENGLJMQIDETFL-XYPWUTKMSA-N 2-[6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound [C@H]12CC(C[C@H](CC1)N2)NC1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC=1)O QENGLJMQIDETFL-XYPWUTKMSA-N 0.000 claims description 4
- QPFAWLFEYLIQQL-UHFFFAOYSA-N 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc(F)c(cc1F)-c1cn[nH]c1 QPFAWLFEYLIQQL-UHFFFAOYSA-N 0.000 claims description 4
- SRURHKKUYVJODD-UHFFFAOYSA-N 6-[2-methoxy-4-(4-nitropyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound COC1=C(C=CC(=C1)N1N=CC(=C1)[N+](=O)[O-])C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C SRURHKKUYVJODD-UHFFFAOYSA-N 0.000 claims description 4
- RHGRVUDHJLINSP-UHFFFAOYSA-N 2-[6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound CN1CCC(=CC1)C1=CC=C(N=N1)C1=C(O)C=C(C=C1)C1=CNN=C1 RHGRVUDHJLINSP-UHFFFAOYSA-N 0.000 claims description 3
- TXAIKBCUPDAFPS-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(4-nitropyrazol-1-yl)phenol Chemical compound CN(C1=CC=C(N=N1)C1=C(C=C(C=C1)N1N=CC(=C1)[N+](=O)[O-])O)C1CC(NC(C1)(C)C)(C)C TXAIKBCUPDAFPS-UHFFFAOYSA-N 0.000 claims description 3
- HFKDPHNPRXDFKV-UHFFFAOYSA-N 5-(5-methyl-1H-pyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound CC1=C(C=NN1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)N(C1CC(NC(C1)(C)C)(C)C)C HFKDPHNPRXDFKV-UHFFFAOYSA-N 0.000 claims description 3
- RTGHSQJOZNUIIB-UHFFFAOYSA-N 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound FC1=C(C=CC(=C1F)C=1C=NNC=1)C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C RTGHSQJOZNUIIB-UHFFFAOYSA-N 0.000 claims description 3
- JLUFJVZFZXTNFL-UHFFFAOYSA-N 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1ccc(-c2cn[nH]c2)c(F)c1F JLUFJVZFZXTNFL-UHFFFAOYSA-N 0.000 claims description 3
- YVFTVBWATCWOFA-UHFFFAOYSA-N 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound FC(C1=C(C=CC(=C1)C=1C=NNC=1)C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C)F YVFTVBWATCWOFA-UHFFFAOYSA-N 0.000 claims description 3
- YKXHMDYGLSZUHE-UHFFFAOYSA-N 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound ClC1=C(C=CC(=C1)C=1C=NNC=1)C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C YKXHMDYGLSZUHE-UHFFFAOYSA-N 0.000 claims description 3
- WQIVAGNKCKRCHE-UHFFFAOYSA-N 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound COc1nc(ccc1-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1)-c1cn[nH]c1 WQIVAGNKCKRCHE-UHFFFAOYSA-N 0.000 claims description 3
- LSHRYGPFYDODIL-UHFFFAOYSA-N 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride Chemical compound Cl.COc1nc(ccc1-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1)-c1cn[nH]c1 LSHRYGPFYDODIL-UHFFFAOYSA-N 0.000 claims description 3
- SWWALUDFCGBFQQ-UHFFFAOYSA-N Cl.Cl.Cl.N1N=CC(=C1)C=1C=CC(=C(C1)O)C=1N=NC(=CC1)C=1CCNCC1 Chemical compound Cl.Cl.Cl.N1N=CC(=C1)C=1C=CC(=C(C1)O)C=1N=NC(=CC1)C=1CCNCC1 SWWALUDFCGBFQQ-UHFFFAOYSA-N 0.000 claims description 3
- MNZKDRXBLJHDHS-UHFFFAOYSA-N 2-[6-(1-ethyl-3,6-dihydro-2H-pyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound CCN1CCC(=CC1)C1=CC=C(N=N1)C1=C(O)C=C(C=C1)C1=CNN=C1 MNZKDRXBLJHDHS-UHFFFAOYSA-N 0.000 claims description 2
- KTNPZTHAQQGORV-SJPCQFCGSA-N 2-[6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]-methylamino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound [C@H]12CC(C[C@H](CC1)N2)N(C1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC=1)O)C KTNPZTHAQQGORV-SJPCQFCGSA-N 0.000 claims description 2
- RSXIJYDYGUVXBN-XYPWUTKMSA-N 2-[6-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]oxy]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound [C@H]12CC(C[C@H](CC1)N2)OC1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC=1)O RSXIJYDYGUVXBN-XYPWUTKMSA-N 0.000 claims description 2
- BYHCBCPZWJTUQN-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(4-nitropyrazol-1-yl)phenol dihydrochloride Chemical compound Cl.Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1ccc(cc1O)-n1cc(cn1)[N+]([O-])=O BYHCBCPZWJTUQN-UHFFFAOYSA-N 0.000 claims description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 2
- RQVWREGUACKLLJ-UHFFFAOYSA-N 5-(1H-pyrazol-4-yl)-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound N1N=CC(=C1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)NC1CC(NC(C1)(C)C)(C)C RQVWREGUACKLLJ-UHFFFAOYSA-N 0.000 claims description 2
- CWFZRTMZWXTTPI-UHFFFAOYSA-N N-methyl-5-[3-(1H-pyrazol-4-yl)phenoxy]-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)C1=NN=C(OC2=CC(=CC=C2)C2=CNN=C2)S1 CWFZRTMZWXTTPI-UHFFFAOYSA-N 0.000 claims description 2
- PGTLXYFBCASJFE-UHFFFAOYSA-N N-methyl-5-[4-(1H-pyrazol-4-yl)phenoxy]-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)C1=NN=C(OC2=CC=C(C=C2)C2=CNN=C2)S1 PGTLXYFBCASJFE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- NVNDCCFRVLZBFB-UHFFFAOYSA-N 1-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]pyrazole-4-carboxamide Chemical compound C=1C=C(C=2C(=CC(=CC=2)N2N=CC(=C2)C(N)=O)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 NVNDCCFRVLZBFB-UHFFFAOYSA-N 0.000 claims 2
- MVAJLWOOSUIQJE-UHFFFAOYSA-N 1-bromo-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalene-2,7-diol Chemical compound C=1C=C(C=2C(=CC3=C(Br)C(O)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 MVAJLWOOSUIQJE-UHFFFAOYSA-N 0.000 claims 2
- YLIHSEAYNQDGCV-UHFFFAOYSA-N 1-chloro-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalene-2,7-diol Chemical compound C=1C=C(C=2C(=CC3=C(Cl)C(O)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 YLIHSEAYNQDGCV-UHFFFAOYSA-N 0.000 claims 2
- XJIULVYTRRMRCE-UHFFFAOYSA-N 1-cyclopropyl-4-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]pyridin-2-one Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CC(=O)N(C3CC3)C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 XJIULVYTRRMRCE-UHFFFAOYSA-N 0.000 claims 2
- RUWHANZNZSVTCO-UHFFFAOYSA-N 2-(1H-pyrazol-4-yl)-4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]pyrimidin-5-amine Chemical compound N1N=CC(=C1)C1=NC=C(C(=N1)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C)N RUWHANZNZSVTCO-UHFFFAOYSA-N 0.000 claims 2
- ITTHQEAYIOMTMZ-ZFWWWQNUSA-N 2-[6-[(2S,4S)-2-methylpiperidin-4-yl]oxypyridazin-3-yl]-5-pyrazol-1-ylphenol Chemical compound C1CN[C@@H](C)C[C@H]1OC1=CC=C(C=2C(=CC(=CC=2)N2N=CC=C2)O)N=N1 ITTHQEAYIOMTMZ-ZFWWWQNUSA-N 0.000 claims 2
- XXWQHTSVCLUWTG-SXUUOERCSA-N 2-[6-[(6S)-6-[(1S)-1-hydroxyethyl]-2,2-dimethylpiperidin-4-yl]oxypyridazin-3-yl]-5-pyrazol-1-ylphenol Chemical compound C1C(C)(C)N[C@H]([C@@H](O)C)CC1OC1=CC=C(C=2C(=CC(=CC=2)N2N=CC=C2)O)N=N1 XXWQHTSVCLUWTG-SXUUOERCSA-N 0.000 claims 2
- NDWPRYMFMWQCKE-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenol Chemical compound C=1C=C(C=2C(=CC=C(C=2)C2=C3CNCCN3N=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 NDWPRYMFMWQCKE-UHFFFAOYSA-N 0.000 claims 2
- PAZBJKYQEXRFLQ-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-4-(trifluoromethyl)phenol hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc(ccc1O)C(F)(F)F PAZBJKYQEXRFLQ-UHFFFAOYSA-N 0.000 claims 2
- AVIFYJPKJRAGBK-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-4-pyrazol-1-ylphenol Chemical compound C=1C=C(C=2C(=CC=C(C=2)N2N=CC=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 AVIFYJPKJRAGBK-UHFFFAOYSA-N 0.000 claims 2
- JNWGUISJPHOLKM-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2CCNCC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 JNWGUISJPHOLKM-UHFFFAOYSA-N 0.000 claims 2
- XDPNSCZCUOUYNZ-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CNN=C2)OC(F)(F)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 XDPNSCZCUOUYNZ-UHFFFAOYSA-N 0.000 claims 2
- RJVGWKITANOUKO-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)benzene-1,3-diol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CNN=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 RJVGWKITANOUKO-UHFFFAOYSA-N 0.000 claims 2
- XSBJQWNBBMWICJ-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CNN=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 XSBJQWNBBMWICJ-UHFFFAOYSA-N 0.000 claims 2
- PWZLQIQPYLVLOO-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N3CCNCC3=NC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 PWZLQIQPYLVLOO-UHFFFAOYSA-N 0.000 claims 2
- PTABTOYJMFUJEA-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(5-nitro-1H-imidazol-2-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2NC=C(N=2)[N+]([O-])=O)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 PTABTOYJMFUJEA-UHFFFAOYSA-N 0.000 claims 2
- OUPPKUCVERNQRZ-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CN(CCN3CCOCC3)N=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 OUPPKUCVERNQRZ-UHFFFAOYSA-N 0.000 claims 2
- GOIMHWBHMVIAKF-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-pyrimidin-5-ylphenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2C=NC=NC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 GOIMHWBHMVIAKF-UHFFFAOYSA-N 0.000 claims 2
- LJZSSBHFGHVWKD-UHFFFAOYSA-N 2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridin-3-yl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenol Chemical compound CN(C1=CC=C(C=N1)C1=C(C=CC(=C1)C=1C=NN2C=1CCCC2)O)C1CC(NC(C1)(C)C)(C)C LJZSSBHFGHVWKD-UHFFFAOYSA-N 0.000 claims 2
- UQNPGLMPJUMGBM-UHFFFAOYSA-N 3-(2-methoxy-4-pyrazol-1-ylphenyl)-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound COc1cc(ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1)-n1cccn1 UQNPGLMPJUMGBM-UHFFFAOYSA-N 0.000 claims 2
- IZARNFISRUVNGA-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-oxazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C=2OC(C)=CN=2)OCC2CC2)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 IZARNFISRUVNGA-UHFFFAOYSA-N 0.000 claims 2
- GIKAIOXRCNRCRS-UHFFFAOYSA-N 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound CC1(C)CC(CC(C)(C)N1)Oc1ccc(nn1)-c1c(F)cc(cc1F)-c1cn[nH]c1 GIKAIOXRCNRCRS-UHFFFAOYSA-N 0.000 claims 2
- QJIPJXOVVIBPGU-UHFFFAOYSA-N 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound FC(C1=C(C=CC(=C1)C=1C=NNC=1)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C)F QJIPJXOVVIBPGU-UHFFFAOYSA-N 0.000 claims 2
- WYVFHWXBJHOCSU-UHFFFAOYSA-N 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine hydrochloride Chemical compound Cl.CC1(C)CC(CC(C)(C)N1)Oc1ccc(nn1)-c1ccc(cc1C(F)F)-c1cn[nH]c1 WYVFHWXBJHOCSU-UHFFFAOYSA-N 0.000 claims 2
- DURZOJZMESDOEE-UHFFFAOYSA-N 3-[2-methoxy-4-(4-nitropyrazol-1-yl)phenyl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound COC1=C(C=CC(=C1)N1N=CC(=C1)[N+](=O)[O-])C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C DURZOJZMESDOEE-UHFFFAOYSA-N 0.000 claims 2
- HMALDDGOAJDKGE-UHFFFAOYSA-N 3-[4-(1-methylpyrazol-4-yl)thiophen-2-yl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound Cn1cc(cn1)-c1csc(c1)-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1 HMALDDGOAJDKGE-UHFFFAOYSA-N 0.000 claims 2
- WFKRHIDAMKDAKE-UHFFFAOYSA-N 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine hydrochloride Chemical compound Cl.CC1(C)CC(CC(C)(C)N1)Oc1ccc(nn1)-c1cc(cs1)-c1cn[nH]c1 WFKRHIDAMKDAKE-UHFFFAOYSA-N 0.000 claims 2
- RPLLPNJKQPGJFN-UHFFFAOYSA-N 3-[5-(1-methylpyrazol-4-yl)thiophen-2-yl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound Cn1cc(cn1)-c1ccc(s1)-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1 RPLLPNJKQPGJFN-UHFFFAOYSA-N 0.000 claims 2
- PHWNEVZIHSTDNJ-UHFFFAOYSA-N 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine Chemical compound CC1(C)CC(CC(C)(C)N1)Oc1ccc(nn1)-c1ccc(s1)-c1cn[nH]c1 PHWNEVZIHSTDNJ-UHFFFAOYSA-N 0.000 claims 2
- PIXDXXYQWGLTSX-UHFFFAOYSA-N 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine hydrochloride Chemical compound Cl.CC1(C)CC(CC(C)(C)N1)Oc1ccc(nn1)-c1ccc(s1)-c1cn[nH]c1 PIXDXXYQWGLTSX-UHFFFAOYSA-N 0.000 claims 2
- PGDMWBUMXYKTQH-UHFFFAOYSA-N 3-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]-1H-quinolin-2-one Chemical compound N=1N=C(C=2C(=NC3=CC=CC=C3C=2)O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 PGDMWBUMXYKTQH-UHFFFAOYSA-N 0.000 claims 2
- DEDYBGPCPUYDOK-UHFFFAOYSA-N 3-[6-(azetidin-3-ylamino)pyridazin-3-yl]naphthalen-2-ol Chemical class OC1=CC2=CC=CC=C2C=C1C(N=N1)=CC=C1NC1CNC1 DEDYBGPCPUYDOK-UHFFFAOYSA-N 0.000 claims 2
- KRNIFKQMQJNJPC-UHFFFAOYSA-N 3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-7-(oxan-4-yl)naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(=CC=C3C=2)C2CCOCC2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 KRNIFKQMQJNJPC-UHFFFAOYSA-N 0.000 claims 2
- XFUCCDHUVHJSHG-UHFFFAOYSA-N 3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-7-(piperidin-1-ylmethyl)naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(CN4CCCCC4)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 XFUCCDHUVHJSHG-UHFFFAOYSA-N 0.000 claims 2
- WBMDSHNHDDZLLQ-UHFFFAOYSA-N 3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-7-(pyrrolidin-1-ylmethyl)naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(CN4CCCC4)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 WBMDSHNHDDZLLQ-UHFFFAOYSA-N 0.000 claims 2
- KRSXOTMKEVSFBK-UHFFFAOYSA-N 3-ethoxy-5-(5-methyl-1,3-oxazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound CCOC1=CC(C=2OC(C)=CN=2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 KRSXOTMKEVSFBK-UHFFFAOYSA-N 0.000 claims 2
- ZXEHOMBJSLISHU-UHFFFAOYSA-N 3-fluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CNN=C2)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ZXEHOMBJSLISHU-UHFFFAOYSA-N 0.000 claims 2
- PNVVUFYACYMHEY-UHFFFAOYSA-N 3-fluoro-5-(1-methylpyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CN(C)N=C2)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 PNVVUFYACYMHEY-UHFFFAOYSA-N 0.000 claims 2
- CSYUCFDMNATXLM-UHFFFAOYSA-N 3-fluoro-5-(1-methylpyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol hydrochloride Chemical compound Cl.C=1C=C(C=2C(=CC(=CC=2O)C2=CN(C)N=C2)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 CSYUCFDMNATXLM-UHFFFAOYSA-N 0.000 claims 2
- MMOMXFQLECVNNA-UHFFFAOYSA-N 3-fluoro-5-(1H-pyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound CC1(C)CC(CC(C)(C)N1)OC1=NN=C(C=C1)C1=C(F)C=C(C=C1O)C1=CNN=C1 MMOMXFQLECVNNA-UHFFFAOYSA-N 0.000 claims 2
- ZPIQOPDDEXWDPB-UHFFFAOYSA-N 3-hydroxyimino-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-1,2-dihydroinden-5-ol Chemical compound OC1=C(C=C2CCC(C2=C1)=NO)C=1N=NC(=CC=1)N(C1CC(NC(C1)(C)C)(C)C)C ZPIQOPDDEXWDPB-UHFFFAOYSA-N 0.000 claims 2
- JBTBMEMPRMBGMQ-UHFFFAOYSA-N 3-hydroxyimino-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-1,2-dihydroinden-5-ol hydrochloride Chemical compound Cl.C=1C=C(C=2C(=CC=3C(=NO)CCC=3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 JBTBMEMPRMBGMQ-UHFFFAOYSA-N 0.000 claims 2
- SNUFINWSPWMYDU-UHFFFAOYSA-N 3-methoxy-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound COC1=CC(C2=CNN=C2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 SNUFINWSPWMYDU-UHFFFAOYSA-N 0.000 claims 2
- VJWSHVJALKMVIO-UHFFFAOYSA-N 3-methoxy-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenol Chemical compound COC1=CC(C=2N3CCCCC3=NC=2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 VJWSHVJALKMVIO-UHFFFAOYSA-N 0.000 claims 2
- SBRJDRZFWMSODE-UHFFFAOYSA-N 3-methoxy-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-pyridin-3-ylphenol Chemical compound COC1=CC(C=2C=NC=CC=2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 SBRJDRZFWMSODE-UHFFFAOYSA-N 0.000 claims 2
- FWONNRIYJPNLSZ-UHFFFAOYSA-N 3-methoxy-4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound COC=1C=C(C=CC=1C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C)O FWONNRIYJPNLSZ-UHFFFAOYSA-N 0.000 claims 2
- KEGQTVHNBCOAFF-UHFFFAOYSA-N 3-methoxy-5-(1-methylpyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound COC1=CC(C2=CN(C)N=C2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 KEGQTVHNBCOAFF-UHFFFAOYSA-N 0.000 claims 2
- UCRLUFAENGRCCZ-UHFFFAOYSA-N 3-methoxy-5-(5-methyl-1,3-oxazol-2-yl)-2-[6-[methyl-(2,2,6-trimethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound COC1=CC(C=2OC(C)=CN=2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)NC(C)(C)C1 UCRLUFAENGRCCZ-UHFFFAOYSA-N 0.000 claims 2
- LZZQALNTNFKKFE-UHFFFAOYSA-N 4-(1H-indol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC=C(C=2)C=2NC3=CC=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 LZZQALNTNFKKFE-UHFFFAOYSA-N 0.000 claims 2
- NXOLRRXZUVZVHE-UHFFFAOYSA-N 4-[3-fluoro-5-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1c(O)cc(cc1F)-c1ccn(C)c(=O)c1 NXOLRRXZUVZVHE-UHFFFAOYSA-N 0.000 claims 2
- NFJJBFCCSBQNOM-UHFFFAOYSA-N 4-[3-fluoro-5-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one hydrochloride Chemical compound Cl.C=1C=C(C=2C(=CC(=CC=2O)C2=CC(=O)N(C)C=C2)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 NFJJBFCCSBQNOM-UHFFFAOYSA-N 0.000 claims 2
- NAIXKVMLMVRZGO-UHFFFAOYSA-N 4-[3-fluoro-5-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1H-pyridin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)C1=CC=C(N=N1)C1=C(F)C=C(C=C1O)C1=CC(=O)NC=C1 NAIXKVMLMVRZGO-UHFFFAOYSA-N 0.000 claims 2
- ZBQGLKVFUHLVDL-UHFFFAOYSA-N 4-[3-hydroxy-4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound O=C1N(C)C=CC(C=2C=C(O)C(=CC=2)C=2N=NC(OC3CC(C)(C)NC(C)(C)C3)=CC=2)=C1 ZBQGLKVFUHLVDL-UHFFFAOYSA-N 0.000 claims 2
- LBBBRWUUNXGXNH-UHFFFAOYSA-N 4-[3-hydroxy-4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenyl]-1H-pyridin-2-one Chemical compound C1C(C)(C)NC(C)(C)CC1OC1=CC=C(C=2C(=CC(=CC=2)C=2C=C(O)N=CC=2)O)N=N1 LBBBRWUUNXGXNH-UHFFFAOYSA-N 0.000 claims 2
- UGIRVEPLXZTENQ-UHFFFAOYSA-N 4-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(trifluoromethoxy)phenyl]-1-methylpyridin-2-one Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CC(=O)N(C)C=C2)OC(F)(F)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 UGIRVEPLXZTENQ-UHFFFAOYSA-N 0.000 claims 2
- YAIFZJWCWFEAGV-UHFFFAOYSA-N 4-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CC(=O)N(C)C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 YAIFZJWCWFEAGV-UHFFFAOYSA-N 0.000 claims 2
- WDLQKLSLKQZIGM-UHFFFAOYSA-N 4-[4-hydroxy-3-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound O=C1N(C)C=CC(C=2C=C(C(O)=CC=2)C=2N=NC(OC3CC(C)(C)NC(C)(C)C3)=CC=2)=C1 WDLQKLSLKQZIGM-UHFFFAOYSA-N 0.000 claims 2
- SPMFCWSTENIEHA-UHFFFAOYSA-N 4-[4-hydroxy-3-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenyl]-1H-pyridin-2-one Chemical compound C1C(C)(C)NC(C)(C)CC1OC1=CC=C(C=2C(=CC=C(C=2)C=2C=C(O)N=CC=2)O)N=N1 SPMFCWSTENIEHA-UHFFFAOYSA-N 0.000 claims 2
- REFNDDJYUWBXSD-UHFFFAOYSA-N 4-[4-hydroxy-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1H-pyridin-2-one Chemical compound C=1C=C(C=2C(=CC=C(C=2)C=2C=C(O)N=CC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 REFNDDJYUWBXSD-UHFFFAOYSA-N 0.000 claims 2
- GQXCNXSLEFZVDT-UHFFFAOYSA-N 4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]benzene-1,3-diol Chemical compound CC1(C)CC(CC(C)(C)N1)OC1=CC=C(N=N1)C1=C(O)C=C(O)C=C1 GQXCNXSLEFZVDT-UHFFFAOYSA-N 0.000 claims 2
- SHYMDIOVKHXAQT-UHFFFAOYSA-N 4-chloro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=C(Cl)C=2)C2=CNN=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 SHYMDIOVKHXAQT-UHFFFAOYSA-N 0.000 claims 2
- MPZJVUYQTMFGPV-UHFFFAOYSA-N 4-fluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(=C(F)C=2)C2=CNN=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 MPZJVUYQTMFGPV-UHFFFAOYSA-N 0.000 claims 2
- JRIKZSMHEJYXMO-UHFFFAOYSA-N 5-(1,2-dimethylimidazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N=C(C)N(C)C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 JRIKZSMHEJYXMO-UHFFFAOYSA-N 0.000 claims 2
- JBBKLCLKNOLIQA-UHFFFAOYSA-N 5-(1-cyclopentylpyrazol-4-yl)-3-methoxy-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound COC1=CC(C2=CN(N=C2)C2CCCC2)=CC(O)=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 JBBKLCLKNOLIQA-UHFFFAOYSA-N 0.000 claims 2
- JLKVTILTOIMFHY-UHFFFAOYSA-N 5-(1-methylimidazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N=CN(C)C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 JLKVTILTOIMFHY-UHFFFAOYSA-N 0.000 claims 2
- QDJSUINZGZTJHS-UHFFFAOYSA-N 5-(1-methylpyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound CN1N=CC(=C1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C QDJSUINZGZTJHS-UHFFFAOYSA-N 0.000 claims 2
- RODHQKHCTMVAHC-UHFFFAOYSA-N 5-(1-methylpyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-(trifluoromethoxy)phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C2=CN(C)N=C2)OC(F)(F)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 RODHQKHCTMVAHC-UHFFFAOYSA-N 0.000 claims 2
- AUAALGSREBBOGE-UHFFFAOYSA-N 5-(1-methylpyrazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CN(C)N=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 AUAALGSREBBOGE-UHFFFAOYSA-N 0.000 claims 2
- SNQFDNKTYIUFTF-UHFFFAOYSA-N 5-(1H-imidazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2NC=CN=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 SNQFDNKTYIUFTF-UHFFFAOYSA-N 0.000 claims 2
- LZDFZRBFZPIDKS-UHFFFAOYSA-N 5-(1H-indazol-7-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2C=3NN=CC=3C=CC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 LZDFZRBFZPIDKS-UHFFFAOYSA-N 0.000 claims 2
- GZRHGDAVNTTXCB-UHFFFAOYSA-N 5-(1H-pyrazol-4-yl)-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-(trifluoromethoxy)phenol Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=CC=C(C=2C(=CC(=CC=2O)C2=CNN=C2)OC(F)(F)F)N=N1 GZRHGDAVNTTXCB-UHFFFAOYSA-N 0.000 claims 2
- SJIRMWMHWILMPD-UHFFFAOYSA-N 5-(1H-pyrazol-4-yl)-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)methyl]pyridazin-3-yl]phenol Chemical compound C1C(C)(C)NC(C)(C)CC1CC1=CC=C(C=2C(=CC(=CC=2)C2=CNN=C2)O)N=N1 SJIRMWMHWILMPD-UHFFFAOYSA-N 0.000 claims 2
- BTVCRRRVVUFTJY-UHFFFAOYSA-N 5-(2-methoxypyridin-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C1=NC(OC)=CC(C=2C=C(O)C(=CC=2)C=2N=NC(=CC=2)N(C)C2CC(C)(C)NC(C)(C)C2)=C1 BTVCRRRVVUFTJY-UHFFFAOYSA-N 0.000 claims 2
- PEFNHEZQRCJROL-UHFFFAOYSA-N 5-(2-methyl-1H-imidazol-5-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N=C(C)NC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 PEFNHEZQRCJROL-UHFFFAOYSA-N 0.000 claims 2
- JPIMHUKSESFYHC-UHFFFAOYSA-N 5-(2-methylpyridin-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2C=C(C)N=CC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 JPIMHUKSESFYHC-UHFFFAOYSA-N 0.000 claims 2
- OJILERHFIVFGHS-UHFFFAOYSA-N 5-(3,6-dihydro-2H-pyran-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2CCOCC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 OJILERHFIVFGHS-UHFFFAOYSA-N 0.000 claims 2
- IUQMBINWIGHFMS-UHFFFAOYSA-N 5-(3-aminopyrazol-1-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)N2N=C(N)C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 IUQMBINWIGHFMS-UHFFFAOYSA-N 0.000 claims 2
- LPBNAFZMWLAOIH-UHFFFAOYSA-N 5-(3-methylimidazol-4-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N(C=NC=2)C)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 LPBNAFZMWLAOIH-UHFFFAOYSA-N 0.000 claims 2
- XNXRTUMHNRBXHU-UHFFFAOYSA-N 5-(4-aminopyrazol-1-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound NC=1C=NN(C=1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C XNXRTUMHNRBXHU-UHFFFAOYSA-N 0.000 claims 2
- RKQKQOUFFCTTHP-UHFFFAOYSA-N 5-(4-aminopyrazol-1-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)N2N=CC(N)=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 RKQKQOUFFCTTHP-UHFFFAOYSA-N 0.000 claims 2
- IRVDBDHRBPWBHH-UHFFFAOYSA-N 5-(5-aminopyrazol-1-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)N2C(=CC=N2)N)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 IRVDBDHRBPWBHH-UHFFFAOYSA-N 0.000 claims 2
- YYOIUNRNNMJTPE-UHFFFAOYSA-N 5-(5-methoxypyridin-3-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound COC1=CN=CC(C=2C=C(O)C(=CC=2)C=2N=NC(=CC=2)N(C)C2CC(C)(C)NC(C)(C)C2)=C1 YYOIUNRNNMJTPE-UHFFFAOYSA-N 0.000 claims 2
- NUYRCRJTWOXXJZ-UHFFFAOYSA-N 5-(5-methyl-1,3-oxazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-phenylmethoxyphenol Chemical compound C=1C=C(C=2C(=CC(=CC=2O)C=2OC(C)=CN=2)OCC=2C=CC=CC=2)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 NUYRCRJTWOXXJZ-UHFFFAOYSA-N 0.000 claims 2
- LWRBTOHOMHYHQA-UHFFFAOYSA-N 5-(5-methyl-1,3-oxazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2OC(C)=CN=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 LWRBTOHOMHYHQA-UHFFFAOYSA-N 0.000 claims 2
- BTPHRHOSNPXTDZ-UHFFFAOYSA-N 5-(5-methyl-1H-imidazol-2-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2NC=C(C)N=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 BTPHRHOSNPXTDZ-UHFFFAOYSA-N 0.000 claims 2
- WNBBPPWVOLZYFH-UHFFFAOYSA-N 5-(5-methyl-1H-pyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound CC1=C(C=NN1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C WNBBPPWVOLZYFH-UHFFFAOYSA-N 0.000 claims 2
- IHUPSFRJOLYAAG-UHFFFAOYSA-N 5-(cyclopenten-1-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2CCCC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 IHUPSFRJOLYAAG-UHFFFAOYSA-N 0.000 claims 2
- AGWPKOGFWSGFBW-UHFFFAOYSA-N 5-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C2=CN(C)N=C2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 AGWPKOGFWSGFBW-UHFFFAOYSA-N 0.000 claims 2
- SAHINCITBDZACY-UHFFFAOYSA-N 5-[2-methoxy-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C2=CNN=C2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 SAHINCITBDZACY-UHFFFAOYSA-N 0.000 claims 2
- LNAHTDGMASCHIQ-UHFFFAOYSA-N 5-[3-fluoro-5-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1c(O)cc(cc1F)-c1ccc(=O)n(C)c1 LNAHTDGMASCHIQ-UHFFFAOYSA-N 0.000 claims 2
- GXYYEVIRHXTYLE-UHFFFAOYSA-N 5-[3-fluoro-5-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one hydrochloride Chemical compound Cl.C=1C=C(C=2C(=CC(=CC=2O)C2=CN(C)C(=O)C=C2)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 GXYYEVIRHXTYLE-UHFFFAOYSA-N 0.000 claims 2
- GSMOWTQPMMDROF-UHFFFAOYSA-N 5-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CN(C)C(=O)C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 GSMOWTQPMMDROF-UHFFFAOYSA-N 0.000 claims 2
- BBGPMLVIXOSLLE-UHFFFAOYSA-N 5-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]-3-(trifluoromethyl)-1H-pyridin-2-one Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2C=C(C(O)=NC=2)C(F)(F)F)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 BBGPMLVIXOSLLE-UHFFFAOYSA-N 0.000 claims 2
- ONKFJCFOMPLYSG-UHFFFAOYSA-N 5-[3-hydroxy-4-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenyl]pyridin-3-ol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2C=C(O)C=NC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ONKFJCFOMPLYSG-UHFFFAOYSA-N 0.000 claims 2
- FPXORASNBIQUNS-UHFFFAOYSA-N 5-[6-(dimethylamino)pyridin-3-yl]-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C1=NC(N(C)C)=CC=C1C1=CC=C(C=2N=NC(=CC=2)N(C)C2CC(C)(C)NC(C)(C)C2)C(O)=C1 FPXORASNBIQUNS-UHFFFAOYSA-N 0.000 claims 2
- DZIBEFMTGVGQPX-UHFFFAOYSA-N 5-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-2,3-dihydro-1H-indene-1,6-diol Chemical compound C=1C=C(C=2C(=CC=3C(O)CCC=3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 DZIBEFMTGVGQPX-UHFFFAOYSA-N 0.000 claims 2
- MAWZHKOLEMMOGH-UHFFFAOYSA-N 5-chloro-3-fluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(Cl)=CC=2O)F)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 MAWZHKOLEMMOGH-UHFFFAOYSA-N 0.000 claims 2
- ITBRQEHNXUDHNM-UHFFFAOYSA-N 5-fluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-4-(1H-pyrazol-4-yl)phenol Chemical compound C=1C=C(C=2C(=CC(F)=C(C3=CNN=C3)C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ITBRQEHNXUDHNM-UHFFFAOYSA-N 0.000 claims 2
- OPBNAPCFRMFDQW-UHFFFAOYSA-N 5-fluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-4-(1H-pyrazol-5-yl)phenol Chemical compound C=1C=C(C=2C(=CC(F)=C(C=3NN=CC=3)C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 OPBNAPCFRMFDQW-UHFFFAOYSA-N 0.000 claims 2
- ORHJIVWCOIJZAC-UHFFFAOYSA-N 5-fluoro-4-(1H-imidazol-5-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(F)=C(C=3N=CNC=3)C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ORHJIVWCOIJZAC-UHFFFAOYSA-N 0.000 claims 2
- LBRZOCGHUNTIKK-UHFFFAOYSA-N 5-imidazo[1,2-a]pyrazin-3-yl-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N3C=CN=CC3=NC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 LBRZOCGHUNTIKK-UHFFFAOYSA-N 0.000 claims 2
- NYQIFRZCUVHESB-UHFFFAOYSA-N 5-imidazo[1,2-a]pyridin-7-yl-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CC3=NC=CN3C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 NYQIFRZCUVHESB-UHFFFAOYSA-N 0.000 claims 2
- VBHKFHJQPZTSCA-UHFFFAOYSA-N 5-imidazo[1,5-a]pyridin-7-yl-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C2=CC3=CN=CN3C=C2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 VBHKFHJQPZTSCA-UHFFFAOYSA-N 0.000 claims 2
- OXMHKILMRZRSLF-UHFFFAOYSA-N 5-imidazol-1-yl-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound N1(C=NC=C1)C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C OXMHKILMRZRSLF-UHFFFAOYSA-N 0.000 claims 2
- JCXLDEBPXAHIOD-UHFFFAOYSA-N 5-pyrazol-1-yl-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)methyl]pyridazin-3-yl]phenol Chemical compound C1C(C)(C)NC(C)(C)CC1CC1=CC=C(C=2C(=CC(=CC=2)N2N=CC=C2)O)N=N1 JCXLDEBPXAHIOD-UHFFFAOYSA-N 0.000 claims 2
- PKUNXGFSTVGBKN-UHFFFAOYSA-N 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1ccc(cc1C(F)F)-c1cn[nH]c1 PKUNXGFSTVGBKN-UHFFFAOYSA-N 0.000 claims 2
- NXKCEMNZJUHUDK-UHFFFAOYSA-N 6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1ccc(cc1F)-c1cn[nH]c1 NXKCEMNZJUHUDK-UHFFFAOYSA-N 0.000 claims 2
- YREDGQQPSBDNHK-UHFFFAOYSA-N 6-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]imidazo[1,2-a]pyridine Chemical compound CC1(C)CC(CC(C)(C)N1)OC1=CC=C(N=N1)C1=CN2C=CN=C2C=C1 YREDGQQPSBDNHK-UHFFFAOYSA-N 0.000 claims 2
- XJMXYHSLTQIUAX-UHFFFAOYSA-N 6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-propan-2-ylquinolin-7-ol Chemical compound CC(C)c1cnc2cc(O)c(cc2c1)-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1 XJMXYHSLTQIUAX-UHFFFAOYSA-N 0.000 claims 2
- KHRDKCVDWMPGNR-UHFFFAOYSA-N 6-hydroxy-5-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-2,3-dihydroinden-1-one Chemical compound C=1C=C(C=2C(=CC=3C(=O)CCC=3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 KHRDKCVDWMPGNR-UHFFFAOYSA-N 0.000 claims 2
- CGEBJFQIPRJAQR-UHFFFAOYSA-N 6-quinolin-3-yl-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Chemical class C1C(C)(C)NC(C)(C)CC1NC1=CC=C(C=2C=C3C=CC=CC3=NC=2)N=N1 CGEBJFQIPRJAQR-UHFFFAOYSA-N 0.000 claims 2
- VXVHAHKCXFCPAM-UHFFFAOYSA-N 7-(3-aminopropoxy)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(OCCCN)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 VXVHAHKCXFCPAM-UHFFFAOYSA-N 0.000 claims 2
- ADNBSVXKADLTAE-UHFFFAOYSA-N 7-(3-hydroxy-3-methylbutoxy)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(OCCC(C)(C)O)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ADNBSVXKADLTAE-UHFFFAOYSA-N 0.000 claims 2
- SNBAIZPWLNETCQ-UHFFFAOYSA-N 7-(3-hydroxypropoxy)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(OCCCO)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 SNBAIZPWLNETCQ-UHFFFAOYSA-N 0.000 claims 2
- HMXDQRRMUALXRR-UHFFFAOYSA-N 7-(3-methoxypropoxy)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound OC1=CC2=CC(OCCCOC)=CC=C2C=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 HMXDQRRMUALXRR-UHFFFAOYSA-N 0.000 claims 2
- OGADZPJVAAZJTB-UHFFFAOYSA-N 7-(4-hydroxy-2-methylbutan-2-yl)oxy-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(OC(C)(C)CCO)=CC=C3C=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 OGADZPJVAAZJTB-UHFFFAOYSA-N 0.000 claims 2
- ZFMREKFGWZZCPD-UHFFFAOYSA-N 7-(difluoromethyl)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(=CC=C3C=2)C(F)F)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ZFMREKFGWZZCPD-UHFFFAOYSA-N 0.000 claims 2
- AZZWNVJXIUWPPS-UHFFFAOYSA-N 7-methoxy-3-[6-[methyl-(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound OC1=CC2=CC(OC)=CC=C2C=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)N(C)C(C)(C)C1 AZZWNVJXIUWPPS-UHFFFAOYSA-N 0.000 claims 2
- BCRSNYZJXWMFBJ-UHFFFAOYSA-N 7-methoxy-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound OC1=CC2=CC(OC)=CC=C2C=C1C(N=N1)=CC=C1N(C)C1CC(C)(C)NC(C)(C)C1 BCRSNYZJXWMFBJ-UHFFFAOYSA-N 0.000 claims 2
- DADQMRWOCWEGCZ-UHFFFAOYSA-N CC1(N)CCN(CC1)c1ccc(nn1)-c1ccc(cc1O)-n1cccn1.CN(C)C1CCCN(C1)c1ccc(nn1)-c1ccc(cc1O)-n1cccn1 Chemical compound CC1(N)CCN(CC1)c1ccc(nn1)-c1ccc(cc1O)-n1cccn1.CN(C)C1CCCN(C1)c1ccc(nn1)-c1ccc(cc1O)-n1cccn1 DADQMRWOCWEGCZ-UHFFFAOYSA-N 0.000 claims 2
- SBRLAMYYXRFTER-UHFFFAOYSA-N CN(C1=CC=C(N=N1)C1=CC2=C(S1)C=CC(=C2)C#N)C2CC(NC(C2)(C)C)(C)C.CC2(NC(CC(C2)NC2=CC=C(N=N2)C2=C(C=CC=C2)O)(C)C)C Chemical compound CN(C1=CC=C(N=N1)C1=CC2=C(S1)C=CC(=C2)C#N)C2CC(NC(C2)(C)C)(C)C.CC2(NC(CC(C2)NC2=CC=C(N=N2)C2=C(C=CC=C2)O)(C)C)C SBRLAMYYXRFTER-UHFFFAOYSA-N 0.000 claims 2
- NGICJOIOCLFNMA-UHFFFAOYSA-N Cl.Cl.Cl.C(C)N1CCC(=CC1)C1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC1)O Chemical compound Cl.Cl.Cl.C(C)N1CCC(=CC1)C1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC1)O NGICJOIOCLFNMA-UHFFFAOYSA-N 0.000 claims 2
- NDGSLDASONCIHU-UHFFFAOYSA-N Cl.Cl.Cl.CN1CCC(=CC1)C1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC1)O Chemical compound Cl.Cl.Cl.CN1CCC(=CC1)C1=CC=C(N=N1)C1=C(C=C(C=C1)C=1C=NNC1)O NDGSLDASONCIHU-UHFFFAOYSA-N 0.000 claims 2
- NRVIYHHDFFSWAC-UHFFFAOYSA-N Cl.Cl.Cl.ClC1=C(C=CC(=C1)C=1C=NNC1)C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C Chemical compound Cl.Cl.Cl.ClC1=C(C=CC(=C1)C=1C=NNC1)C1=CC=C(N=N1)N(C1CC(NC(C1)(C)C)(C)C)C NRVIYHHDFFSWAC-UHFFFAOYSA-N 0.000 claims 2
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
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- CHONZYXZXGYIEV-UHFFFAOYSA-N 3-chloro-5-(1-methylpyrazol-4-yl)-2-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenol Chemical compound N=1N=C(C=2C(=CC(=CC=2O)C2=CN(C)N=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 CHONZYXZXGYIEV-UHFFFAOYSA-N 0.000 claims 1
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- LNCLQDJLRSOWFL-UHFFFAOYSA-N 3-methyl-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-6-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ncc(C)cc2cc1O LNCLQDJLRSOWFL-UHFFFAOYSA-N 0.000 claims 1
- PDYFYSDCGYKJQR-UHFFFAOYSA-N 3-methyl-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoxalin-6-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ncc(C)nc2cc1O PDYFYSDCGYKJQR-UHFFFAOYSA-N 0.000 claims 1
- WPSDNASDRCTPJI-UHFFFAOYSA-N 4,5-difluoro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol 5-methoxy-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound COc1ccc(c(O)c1)-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc(F)c(F)cc1O WPSDNASDRCTPJI-UHFFFAOYSA-N 0.000 claims 1
- IHDALGOXWIOXAJ-UHFFFAOYSA-N 4-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(cc(C)nc2cc1O)C1=CCOCC1 IHDALGOXWIOXAJ-UHFFFAOYSA-N 0.000 claims 1
- UNVXBEOUVQQKAZ-UHFFFAOYSA-N 4-(cyclopenten-1-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC=C(C=2)C=2CCCC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 UNVXBEOUVQQKAZ-UHFFFAOYSA-N 0.000 claims 1
- VETATRCRXDLNCU-UHFFFAOYSA-N 4-(dimethylamino)-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound CN(C)c1cc(C)nc2cc(O)c(cc12)-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1 VETATRCRXDLNCU-UHFFFAOYSA-N 0.000 claims 1
- GPAJYJLFDSHYCB-UHFFFAOYSA-N 4-(dimethylamino)-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound CN(C1=CC=NC2=CC(=C(C=C12)C=1N=NC(=CC=1)N(C1CC(NC(C1)(C)C)(C)C)C)O)C GPAJYJLFDSHYCB-UHFFFAOYSA-N 0.000 claims 1
- OMVBQFOBLCPUTF-UHFFFAOYSA-N 4-[3-chloro-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1-methylpyridin-2-one Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CC(=O)N(C)C=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 OMVBQFOBLCPUTF-UHFFFAOYSA-N 0.000 claims 1
- BTMLDCDCXQYLGP-UHFFFAOYSA-N 4-[3-hydroxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]-5-(trifluoromethoxy)phenyl]-1-methylpyridin-2-one Chemical compound N=1N=C(C=2C(=CC(=CC=2O)C2=CC(=O)N(C)C=C2)OC(F)(F)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 BTMLDCDCXQYLGP-UHFFFAOYSA-N 0.000 claims 1
- LOWKFXOPCMUOQB-UHFFFAOYSA-N 4-[3-hydroxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1-methylpyridin-2-one Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CC(=O)N(C)C=C2)O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 LOWKFXOPCMUOQB-UHFFFAOYSA-N 0.000 claims 1
- PBHVAJUUBUHBNI-UHFFFAOYSA-N 4-[3-hydroxy-4-[6-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)pyridazin-3-yl]phenyl]-1-methylpyridin-2-one Chemical compound C1C2CN(C)CC2CN1C(N=N1)=CC=C1C(C(=C1)O)=CC=C1C=1C=CN(C)C(=O)C=1 PBHVAJUUBUHBNI-UHFFFAOYSA-N 0.000 claims 1
- QHUUPDDQEYKXNY-UHFFFAOYSA-N 4-[3-methoxy-4-[5-(2,2,6,6-tetramethylpiperidin-4-yl)oxy-1,3,4-thiadiazol-2-yl]phenyl]-1-methylpyridin-2-one Chemical compound COC1=CC(C2=CC(=O)N(C)C=C2)=CC=C1C(S1)=NN=C1OC1CC(C)(C)NC(C)(C)C1 QHUUPDDQEYKXNY-UHFFFAOYSA-N 0.000 claims 1
- SVRNXKIGAMVESM-UHFFFAOYSA-N 4-[3-methoxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1-methylpyridin-2-one Chemical compound COC1=CC(C2=CC(=O)N(C)C=C2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 SVRNXKIGAMVESM-UHFFFAOYSA-N 0.000 claims 1
- MKLYKVHHQXMLLP-XLIONFOSSA-N 4-[4-[6-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]pyridazin-3-yl]-3-hydroxyphenyl]-1-methylpyridin-2-one Chemical compound C([C@H]1CCN([C@H]1C1)C)N1C(N=N1)=CC=C1C(C(=C1)O)=CC=C1C=1C=CN(C)C(=O)C=1 MKLYKVHHQXMLLP-XLIONFOSSA-N 0.000 claims 1
- NYPPBHDATRBQNF-UHFFFAOYSA-N 4-chloro-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(Cl)cc(C)nc2cc1O NYPPBHDATRBQNF-UHFFFAOYSA-N 0.000 claims 1
- UEQRZGKZFNDJOM-UHFFFAOYSA-N 4-cyclopropyl-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(cc(C)nc2cc1O)C1CC1 UEQRZGKZFNDJOM-UHFFFAOYSA-N 0.000 claims 1
- DDLLOLGACFZYDU-UHFFFAOYSA-N 4-ethoxy-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound C(C)OC1=CC(=NC2=CC(=C(C=C12)C=1N=NC(=CC=1)N(C1CC(NC(C1)(C)C)(C)C)C)O)C DDLLOLGACFZYDU-UHFFFAOYSA-N 0.000 claims 1
- XGVJFFSPCYBCEY-UHFFFAOYSA-N 4-hydroxy-1-methyl-3-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]quinolin-2-one Chemical compound N=1N=C(C=2C(N(C)C3=CC=CC=C3C=2O)=O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 XGVJFFSPCYBCEY-UHFFFAOYSA-N 0.000 claims 1
- TZWUSNWOPZLLMJ-UHFFFAOYSA-N 4-methoxy-1-methyl-3-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]quinolin-2-one Chemical compound O=C1N(C)C2=CC=CC=C2C(OC)=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 TZWUSNWOPZLLMJ-UHFFFAOYSA-N 0.000 claims 1
- XERDUDXIDOFDTR-UHFFFAOYSA-N 4-methoxy-2-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound COc1cc(C)nc2cc(O)c(cc12)-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1 XERDUDXIDOFDTR-UHFFFAOYSA-N 0.000 claims 1
- MLOYTJQIAFNFIJ-UHFFFAOYSA-N 4-methoxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-7-ol Chemical compound COc1ccnc2cc(O)c(cc12)-c1ccc(nn1)N(C)C1CC(C)(C)NC(C)(C)C1 MLOYTJQIAFNFIJ-UHFFFAOYSA-N 0.000 claims 1
- PVHWCWKXWSRHQA-UHFFFAOYSA-N 5-(1H-imidazol-5-yl)-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(=CC=2)C=2N=CNC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 PVHWCWKXWSRHQA-UHFFFAOYSA-N 0.000 claims 1
- CLCNBKDQIBTIFA-UHFFFAOYSA-N 5-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound CC1(NC(CC(C1)C1=NN=C(S1)N)(C)C)C CLCNBKDQIBTIFA-UHFFFAOYSA-N 0.000 claims 1
- JVCQFMFPMGNYME-UHFFFAOYSA-N 5-(2-chloro-4-imidazol-1-ylphenyl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2C=NC=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 JVCQFMFPMGNYME-UHFFFAOYSA-N 0.000 claims 1
- JFFNTQOZAUYEGP-UHFFFAOYSA-N 5-(2-chloro-4-pyrazol-1-ylphenyl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2N=CC=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 JFFNTQOZAUYEGP-UHFFFAOYSA-N 0.000 claims 1
- AZVPBTNBKTUART-UHFFFAOYSA-N 5-(2-fluoro-4-imidazol-1-ylphenyl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2C=NC=C2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 AZVPBTNBKTUART-UHFFFAOYSA-N 0.000 claims 1
- VZZNBOBELRBXEK-UHFFFAOYSA-N 5-(2-methoxy-4-pyrazol-1-ylphenyl)-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(N2N=CC=C2)=CC=C1C(S1)=NN=C1NC1CC(C)(C)N(C)C(C)(C)C1 VZZNBOBELRBXEK-UHFFFAOYSA-N 0.000 claims 1
- JJQIYOBEPRMVMA-UHFFFAOYSA-N 5-(2-methoxy-4-pyrazol-1-ylphenyl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(N2N=CC=C2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 JJQIYOBEPRMVMA-UHFFFAOYSA-N 0.000 claims 1
- MVJWUCCVYLGVMG-UHFFFAOYSA-N 5-(2-methoxy-4-pyridin-3-ylphenyl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C=2C=NC=CC=2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 MVJWUCCVYLGVMG-UHFFFAOYSA-N 0.000 claims 1
- PVDCXFBKBFGGMM-UHFFFAOYSA-N 5-(2-methoxyquinolin-3-yl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=NC2=CC=CC=C2C=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 PVDCXFBKBFGGMM-UHFFFAOYSA-N 0.000 claims 1
- USDMNDUZPBXDBG-UHFFFAOYSA-N 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound CC1=NNC(=C1C=1C=CC(=C(C=1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C)C USDMNDUZPBXDBG-UHFFFAOYSA-N 0.000 claims 1
- YXPOHURHHMFKFM-UHFFFAOYSA-N 5-(3-chloro-1-benzothiophen-2-yl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C2=C(C3=CC=CC=C3S2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 YXPOHURHHMFKFM-UHFFFAOYSA-N 0.000 claims 1
- HLDFZPRBTCSXDB-UHFFFAOYSA-N 5-(3-methoxynaphthalen-2-yl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC2=CC=CC=C2C=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 HLDFZPRBTCSXDB-UHFFFAOYSA-N 0.000 claims 1
- HPJQWGSAALUTNI-UHFFFAOYSA-N 5-(7-methoxyquinolin-6-yl)-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC2=NC=CC=C2C=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 HPJQWGSAALUTNI-UHFFFAOYSA-N 0.000 claims 1
- BFZCDCQYEVZVQV-UHFFFAOYSA-N 5-[2,3-difluoro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=C(F)C(C3=CNN=C3)=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 BFZCDCQYEVZVQV-UHFFFAOYSA-N 0.000 claims 1
- MWKDYUMCWZLGCR-UHFFFAOYSA-N 5-[2,3-difluoro-4-(1h-pyrazol-5-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=C(F)C(C=3NN=CC=3)=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 MWKDYUMCWZLGCR-UHFFFAOYSA-N 0.000 claims 1
- LKCHRHPPECYRLS-UHFFFAOYSA-N 5-[2,3-difluoro-6-methoxy-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound FC=1C(F)=C(C=2SC(=NN=2)N(C)C2CC(C)(C)NC(C)(C)C2)C(OC)=CC=1C=1C=NNC=1 LKCHRHPPECYRLS-UHFFFAOYSA-N 0.000 claims 1
- GZARVUMZGRLOAK-UHFFFAOYSA-N 5-[2,5-difluoro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=C(F)C=2)C2=CNN=C2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 GZARVUMZGRLOAK-UHFFFAOYSA-N 0.000 claims 1
- JGBYJSGAJGAXFK-UHFFFAOYSA-N 5-[2,5-difluoro-4-(1h-pyrazol-5-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=C(F)C=2)C=2NN=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 JGBYJSGAJGAXFK-UHFFFAOYSA-N 0.000 claims 1
- WZCMWRMVUKJEHS-UHFFFAOYSA-N 5-[2,6-difluoro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2F)C2=CNN=C2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 WZCMWRMVUKJEHS-UHFFFAOYSA-N 0.000 claims 1
- WLKFMWSBPGFNTH-UHFFFAOYSA-N 5-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound C1=NN(C)C=C1C(C=C1Cl)=CC=C1C(S1)=NN=C1NC1CC(C)(C)NC(C)(C)C1 WLKFMWSBPGFNTH-UHFFFAOYSA-N 0.000 claims 1
- SAPDEQZYYBINDW-UHFFFAOYSA-N 5-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CN(C)N=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 SAPDEQZYYBINDW-UHFFFAOYSA-N 0.000 claims 1
- FCGQTUMHJLHUHS-UHFFFAOYSA-N 5-[2-chloro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CNN=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 FCGQTUMHJLHUHS-UHFFFAOYSA-N 0.000 claims 1
- FVTOVLLCKDXLCP-UHFFFAOYSA-N 5-[2-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=C3CCCCN3N=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 FVTOVLLCKDXLCP-UHFFFAOYSA-N 0.000 claims 1
- ZNQGJEVYMUDGCM-UHFFFAOYSA-N 5-[2-chloro-4-(triazol-1-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2N=NC=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 ZNQGJEVYMUDGCM-UHFFFAOYSA-N 0.000 claims 1
- ZCKCIMXPDJVSFK-UHFFFAOYSA-N 5-[2-chloro-4-(triazol-2-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2N=CC=N2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 ZCKCIMXPDJVSFK-UHFFFAOYSA-N 0.000 claims 1
- RQJFZFNQJGTLFP-UHFFFAOYSA-N 5-[2-chloro-5-fluoro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=C(F)C=2)C2=CNN=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 RQJFZFNQJGTLFP-UHFFFAOYSA-N 0.000 claims 1
- KTOQTIKPYTXNEY-UHFFFAOYSA-N 5-[2-fluoro-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CNN=C2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 KTOQTIKPYTXNEY-UHFFFAOYSA-N 0.000 claims 1
- RBSMUNYTNAEUOO-UHFFFAOYSA-N 5-[2-fluoro-4-(1h-pyrazol-5-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C=2NN=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 RBSMUNYTNAEUOO-UHFFFAOYSA-N 0.000 claims 1
- LAQSXMAXRZEMPU-UHFFFAOYSA-N 5-[2-fluoro-4-(5-methyl-1h-pyrazol-3-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C=2NN=C(C)C=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 LAQSXMAXRZEMPU-UHFFFAOYSA-N 0.000 claims 1
- UUCKAIQWJKJJRP-UHFFFAOYSA-N 5-[2-fluoro-6-methoxy-4-(1h-pyrazol-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C2=CNN=C2)=CC(F)=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 UUCKAIQWJKJJRP-UHFFFAOYSA-N 0.000 claims 1
- QSNICOPYMVUVGJ-UHFFFAOYSA-N 5-[2-methoxy-4-(1h-pyrazol-5-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C=2NN=CC=2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 QSNICOPYMVUVGJ-UHFFFAOYSA-N 0.000 claims 1
- HAHOZWCTNLYMIQ-UHFFFAOYSA-N 5-[2-methoxy-4-(2-methoxypyridin-4-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound C1=NC(OC)=CC(C=2C=C(OC)C(C=3SC(=NN=3)N(C)C3CC(C)(C)NC(C)(C)C3)=CC=2)=C1 HAHOZWCTNLYMIQ-UHFFFAOYSA-N 0.000 claims 1
- GMHQKJQXUANNSL-UHFFFAOYSA-N 5-[2-methoxy-4-(6-methoxypyridin-3-yl)phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound C1=NC(OC)=CC=C1C(C=C1OC)=CC=C1C1=NN=C(N(C)C2CC(C)(C)NC(C)(C)C2)S1 GMHQKJQXUANNSL-UHFFFAOYSA-N 0.000 claims 1
- LEJYTPZVDZOAIO-UHFFFAOYSA-N 5-[2-methoxy-4-[3-(methylamino)pyrazol-1-yl]phenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N1=C(NC)C=CN1C(C=C1OC)=CC=C1C1=NN=C(N(C)C2CC(C)(C)NC(C)(C)C2)S1 LEJYTPZVDZOAIO-UHFFFAOYSA-N 0.000 claims 1
- PRFBKAMNCMSQHK-UHFFFAOYSA-N 5-[3-(methylamino)pyrazol-1-yl]-2-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenol Chemical compound N1=C(NC)C=CN1C(C=C1O)=CC=C1C1=NN=C(N(C)C2CC(C)(C)NC(C)(C)C2)S1 PRFBKAMNCMSQHK-UHFFFAOYSA-N 0.000 claims 1
- SCPBYYHFHFKPOH-UHFFFAOYSA-N 5-[3-chloro-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1h-pyridin-2-one Chemical compound N=1N=C(C=2C(=CC(=CC=2)C2=CNC(=O)C=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 SCPBYYHFHFKPOH-UHFFFAOYSA-N 0.000 claims 1
- PAUCXNXSTWSQFR-UHFFFAOYSA-N 5-[3-fluoro-5-(1h-pyrazol-4-yl)pyridin-2-yl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CN=2)C2=CNN=C2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 PAUCXNXSTWSQFR-UHFFFAOYSA-N 0.000 claims 1
- FSNHYXABDAOVTP-UHFFFAOYSA-N 5-[3-hydroxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1H-pyridin-2-one Chemical compound N=1N=C(C=2C(=CC(=CC=2)C=2C=NC(O)=CC=2)O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 FSNHYXABDAOVTP-UHFFFAOYSA-N 0.000 claims 1
- RGNCVINLKFCTCA-UHFFFAOYSA-N 5-[3-methoxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1-methylpyridin-2-one Chemical compound COC1=CC(C2=CN(C)C(=O)C=C2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 RGNCVINLKFCTCA-UHFFFAOYSA-N 0.000 claims 1
- LCLGAHTXGGYYIR-UHFFFAOYSA-N 5-[3-methoxy-4-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]phenyl]-1h-pyridin-2-one Chemical compound COC1=CC(C=2C=NC(O)=CC=2)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 LCLGAHTXGGYYIR-UHFFFAOYSA-N 0.000 claims 1
- NOQAKKHHUXIVHD-UHFFFAOYSA-N 5-[4-(2,4-dimethyl-1,3-thiazol-5-yl)-2,3-difluorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=C(F)C(C3=C(N=C(C)S3)C)=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 NOQAKKHHUXIVHD-UHFFFAOYSA-N 0.000 claims 1
- YMLSFYVHWLXQPG-UHFFFAOYSA-N 5-[4-(2,4-dimethyl-1,3-thiazol-5-yl)-2,5-difluorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=C(F)C=2)C2=C(N=C(C)S2)C)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 YMLSFYVHWLXQPG-UHFFFAOYSA-N 0.000 claims 1
- SODRXGYTXJEHKC-UHFFFAOYSA-N 5-[4-(2,4-dimethyl-1,3-thiazol-5-yl)-2-methoxyphenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C2=C(N=C(C)S2)C)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 SODRXGYTXJEHKC-UHFFFAOYSA-N 0.000 claims 1
- BUQDYPYTZXKQDL-UHFFFAOYSA-N 5-[4-(2-aminopyrimidin-4-yl)-2-chlorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C=2N=C(N)N=CC=2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 BUQDYPYTZXKQDL-UHFFFAOYSA-N 0.000 claims 1
- QESYJCLGUQWEOE-UHFFFAOYSA-N 5-[4-(3,5-dimethyl-1h-pyrazol-4-yl)-2-methoxyphenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound COC1=CC(C2=C(NN=C2C)C)=CC=C1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 QESYJCLGUQWEOE-UHFFFAOYSA-N 0.000 claims 1
- PJOZZCGUUWYGDP-UHFFFAOYSA-N 5-[4-(3-aminopyrazol-1-yl)-2-chlorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)N2N=C(N)C=C2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 PJOZZCGUUWYGDP-UHFFFAOYSA-N 0.000 claims 1
- FOLBFCRSSWXMAT-UHFFFAOYSA-N 5-[4-(6-aminopyridin-3-yl)-2-fluorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC(=CC=2)C=2C=NC(N)=CC=2)F)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 FOLBFCRSSWXMAT-UHFFFAOYSA-N 0.000 claims 1
- FBRDQMOWXKBTGE-UHFFFAOYSA-N 5-[5-(2-aminopyrimidin-4-yl)-2-chlorophenyl]-n-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine Chemical compound N=1N=C(C=2C(=CC=C(C=2)C=2N=C(N)N=CC=2)Cl)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 FBRDQMOWXKBTGE-UHFFFAOYSA-N 0.000 claims 1
- ZFLHXUXUQRZZPS-UHFFFAOYSA-N 5-bromo-3-methyl-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-6-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ncc(C)cc2c(Br)c1O ZFLHXUXUQRZZPS-UHFFFAOYSA-N 0.000 claims 1
- ILEUZWGZQQBNKD-UHFFFAOYSA-N 5-chloro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound C=1C=C(C=2C(=CC(Cl)=CC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 ILEUZWGZQQBNKD-UHFFFAOYSA-N 0.000 claims 1
- WVJWWQCGIFQOSL-UHFFFAOYSA-N 5-chloro-2-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol 5-pyrazol-1-yl-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]phenol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1ccc(Cl)cc1O.CC1(C)CC(CC(C)(C)N1)Nc1ccc(nn1)-c1ccc(cc1O)-n1cccn1 WVJWWQCGIFQOSL-UHFFFAOYSA-N 0.000 claims 1
- ISJRIKSOXSOHTC-UHFFFAOYSA-N 6-(1H-pyrazol-4-yl)-3-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]-1H-pyridin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C(=N1)O)C=1N=NC(=CC=1)OC1CC(NC(C1)(C)C)(C)C ISJRIKSOXSOHTC-UHFFFAOYSA-N 0.000 claims 1
- DPTCXHOZHUVICD-UHFFFAOYSA-N 6-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]naphthalen-2-ol Chemical compound N=1N=C(C=2C=C3C=CC(O)=CC3=CC=2)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 DPTCXHOZHUVICD-UHFFFAOYSA-N 0.000 claims 1
- JNSAMIBWPAHBCP-UHFFFAOYSA-N 6-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]quinolin-7-ol Chemical compound N=1N=C(C=2C(=CC3=NC=CC=C3C=2)O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 JNSAMIBWPAHBCP-UHFFFAOYSA-N 0.000 claims 1
- ZGLNAKXVXDWBKZ-GASCZTMLSA-N 6-[6-[(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]pyridazin-3-yl]quinolin-7-ol Chemical compound CN1C[C@H]2CN(C[C@H]2C1)c1ccc(nn1)-c1cc2cccnc2cc1O ZGLNAKXVXDWBKZ-GASCZTMLSA-N 0.000 claims 1
- NTQWLOKZEYZZMK-UHFFFAOYSA-N 6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-(oxan-4-yl)quinolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2cc(cnc2cc1O)C1CCOCC1 NTQWLOKZEYZZMK-UHFFFAOYSA-N 0.000 claims 1
- QBEHYLSWZSIVSK-UHFFFAOYSA-N 6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccncc2cc1O QBEHYLSWZSIVSK-UHFFFAOYSA-N 0.000 claims 1
- BMGVHYDWFZRANN-UHFFFAOYSA-N 6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinazolin-7-ol Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2cncnc2cc1O BMGVHYDWFZRANN-UHFFFAOYSA-N 0.000 claims 1
- FQYMBNRXODZMMG-UHFFFAOYSA-N 6-hydroxy-1-methyl-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-4-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2n(C)ccc(=O)c2cc1O FQYMBNRXODZMMG-UHFFFAOYSA-N 0.000 claims 1
- WNRKHLOKYPEHBS-UHFFFAOYSA-N 6-hydroxy-2-methyl-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinolin-1-one hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(ccn(C)c2=O)cc1O WNRKHLOKYPEHBS-UHFFFAOYSA-N 0.000 claims 1
- DJEOAKFFVMPMMH-UHFFFAOYSA-N 6-hydroxy-5-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]-2,3-dihydroinden-1-one Chemical compound N=1N=C(C=2C(=CC=3C(=O)CCC=3C=2)O)SC=1N(C)C1CC(C)(C)NC(C)(C)C1 DJEOAKFFVMPMMH-UHFFFAOYSA-N 0.000 claims 1
- IIFPGIOUUVZHGZ-UHFFFAOYSA-N 6-hydroxy-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-2H-isoquinolin-1-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(O)nccc2cc1O IIFPGIOUUVZHGZ-UHFFFAOYSA-N 0.000 claims 1
- VWOUEHXDNKMWCV-UHFFFAOYSA-N 6-hydroxy-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinoline-1-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(nccc2cc1O)C#N VWOUEHXDNKMWCV-UHFFFAOYSA-N 0.000 claims 1
- AEKJAPJUDBOCEP-UHFFFAOYSA-N 6-hydroxy-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinoline-1-carboxamide Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(nccc2cc1O)C(N)=O AEKJAPJUDBOCEP-UHFFFAOYSA-N 0.000 claims 1
- DPISPNALPFPKAB-UHFFFAOYSA-N 6-hydroxy-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoline-2-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2nc(ccc2cc1O)C#N DPISPNALPFPKAB-UHFFFAOYSA-N 0.000 claims 1
- STWQJDCKXMIKCQ-UHFFFAOYSA-N 6-hydroxy-7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoline-2-carboxamide Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2nc(ccc2cc1O)C(N)=O STWQJDCKXMIKCQ-UHFFFAOYSA-N 0.000 claims 1
- SINPNDJNHQMGCS-UHFFFAOYSA-N 6-methoxy-2-[5-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl]-3,4-dihydroisoquinolin-1-one Chemical compound C1CC2=CC(OC)=CC=C2C(=O)N1C(S1)=NN=C1N(C)C1CC(C)(C)NC(C)(C)C1 SINPNDJNHQMGCS-UHFFFAOYSA-N 0.000 claims 1
- QJWDPPRZKLNALT-UHFFFAOYSA-N 7-(3,6-dihydro-2H-pyran-4-yl)-3-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]naphthalen-2-ol Chemical compound C=1C=C(C=2C(=CC3=CC(=CC=C3C=2)C=2CCOCC=2)O)N=NC=1N(C)C1CC(C)(C)NC(C)(C)C1 QJWDPPRZKLNALT-UHFFFAOYSA-N 0.000 claims 1
- ICJSKNBGLXEESJ-IYBDPMFKSA-N 7-[6-[(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]pyridazin-3-yl]isoquinolin-6-ol Chemical compound CN1C[C@H]2CN(C[C@H]2C1)c1ccc(nn1)-c1cc2cnccc2cc1O ICJSKNBGLXEESJ-IYBDPMFKSA-N 0.000 claims 1
- DFBCSZAWLKXZKN-UHFFFAOYSA-N 7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-phenylisoquinolin-6-ol Chemical compound CN(C1=CC=C(N=N1)C1=C(C=C2C=C(N=CC2=C1)C1=CC=CC=C1)O)C1CC(NC(C1)(C)C)(C)C DFBCSZAWLKXZKN-UHFFFAOYSA-N 0.000 claims 1
- MVSUKLWYCKKYGF-UHFFFAOYSA-N 7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3-propan-2-ylisoquinolin-6-ol Chemical compound C(C)(C)C=1N=CC2=CC(=C(C=C2C=1)O)C=1N=NC(=CC=1)N(C1CC(NC(C1)(C)C)(C)C)C MVSUKLWYCKKYGF-UHFFFAOYSA-N 0.000 claims 1
- KAUTUNCDUJLDTJ-UHFFFAOYSA-N 7-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoxalin-6-ol hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2nccnc2cc1O KAUTUNCDUJLDTJ-UHFFFAOYSA-N 0.000 claims 1
- FBSRBPSSIDGSEB-UHFFFAOYSA-N 7-hydroxy-1,3-dimethyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinazoline-2,4-dione Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(cc1O)n(C)c(=O)n(C)c2=O FBSRBPSSIDGSEB-UHFFFAOYSA-N 0.000 claims 1
- DRVYAHOGFDSAJR-UHFFFAOYSA-N 7-hydroxy-1-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3,4-dihydroquinolin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2CCC(=O)N(C)c2cc1O DRVYAHOGFDSAJR-UHFFFAOYSA-N 0.000 claims 1
- BPWKBWPEQGLJFW-UHFFFAOYSA-N 7-hydroxy-1-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccc(=O)n(C)c2cc1O BPWKBWPEQGLJFW-UHFFFAOYSA-N 0.000 claims 1
- IZPBAJNYUBZFLY-UHFFFAOYSA-N 7-hydroxy-1-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinolin-2-one hydrochloride Chemical compound Cl.CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccc(=O)n(C)c2cc1O IZPBAJNYUBZFLY-UHFFFAOYSA-N 0.000 claims 1
- IDCZPELYVBFAJI-UHFFFAOYSA-N 7-hydroxy-3-methyl-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinoline-1-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2cc(C)nc(C#N)c2cc1O IDCZPELYVBFAJI-UHFFFAOYSA-N 0.000 claims 1
- XEFPZKYCESWBHF-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-1H-quinolin-2-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccc(=O)[nH]c2cc1O XEFPZKYCESWBHF-UHFFFAOYSA-N 0.000 claims 1
- AXDQJGREOXEECG-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]-3H-quinazolin-4-one Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2c(cc1O)[nH]cnc2=O AXDQJGREOXEECG-UHFFFAOYSA-N 0.000 claims 1
- YBVOKIUNQQDJBQ-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]isoquinoline-1-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccnc(C#N)c2cc1O YBVOKIUNQQDJBQ-UHFFFAOYSA-N 0.000 claims 1
- QHDMPFUVTSHHJN-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoline-2-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccc(nc2cc1O)C#N QHDMPFUVTSHHJN-UHFFFAOYSA-N 0.000 claims 1
- VUQIMGRMLSRSQM-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoline-2-carboxamide Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2ccc(nc2cc1O)C(N)=O VUQIMGRMLSRSQM-UHFFFAOYSA-N 0.000 claims 1
- XJFOQYPVXKHCDR-UHFFFAOYSA-N 7-hydroxy-6-[6-[methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl]quinoline-3-carbonitrile Chemical compound CN(C1CC(C)(C)NC(C)(C)C1)c1ccc(nn1)-c1cc2cc(cnc2cc1O)C#N XJFOQYPVXKHCDR-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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Abstract
本发明涉及用于治疗亨廷顿病的方法。本发明公开了一种用于治疗或改善有此需要的对象中的HD的方法,所述方法包括给所述对象施用有效量的式(Ia)化合物或其形式。
Description
本申请是申请日为2016年12月11日、申请号为201680081666.1、发明名称为“用于治疗亨廷顿病的方法”的发明专利申请的分案申请。
技术领域
本发明涉及化合物、其形式及其药物组合物以及使用这些化合物、其形式或其组合物用于治疗或改善亨廷顿病的方法。具体地,本发明涉及经取代的单环杂芳基化合物、其形式及其药物组合物以及使用这些化合物、其形式或其组合物用于治疗或改善亨廷顿病的方法。
背景技术
亨廷顿病(HD)是脑部的进行性、常染色体显性神经退行性疾病,具有特征为不自主运动、认知障碍和精神衰退的症状。在症状发作13年至15年后通常发生死亡(通常由肺炎或冠状动脉疾病引起)。在西欧血统的群体中,HD的患病率为每100000人中3个人至7个人。在北美,预计30000人患有HD,同时另外的200000人有从患病的亲代遗传该疾病的风险。该疾病是由“突变的”亨廷顿(Htt)基因中的不间断三核苷酸CAG重复的扩增而引起的,导致产生具有扩增的多聚谷氨酰胺(polyQ)序列(stretch)(也称为“CAG重复”序列)的HTT(Htt蛋白)。目前没有针对该疾病的根本原因的小分子疗法,留下对可以用于治疗或改善HD的药物的高度未满足的需求。因此,仍然需要确定和提供用于治疗或改善HD的小分子化合物。
本文援引的所有其他文献都如同本文充分阐述的那样通过引用并入到本申请中。
发明内容
本发明涉及用于治疗或改善有此需要的对象中的HD的方法,所述方法包括给对象施用有效量的式(I)化合物、或其形式及其组合物:
其中,W、X、A和B如本文所定义。
特别地,本发明涉及式(I)化合物或其形式或其组合物在用于治疗或改善有此需要的对象中的HD的方法中的用途,所述用途包括给对象施用有效量的化合物或其形式或其组合物。
本发明还涉及式(I)化合物或其形式与具有附加活性或协同活性的药剂组合的用途,从而提供用于治疗HD的组合产品。
具体实施方式
本发明涉及化合物用于治疗或改善有此需要的对象中的HD的方法或用途,所述方法或用途包括给对象施用有效量的式(I)化合物、或其形式:
其中
W是CH=CH或S;
X是CH2、CH(C1-4烷基)、C(C1-4烷基)2、CH=CH、O、NR5、或键;
A是芳基、杂芳基、杂环基、或C9-10环烷基,
其中,芳基选自苯基和萘基,各自任选地被1个、2个、3个、或4个取代基取代,每个取代基选自R1,
其中,杂芳基是单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,每个芳香族碳原子环结构基团任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R1,
其中,杂环基是饱和或部分不饱和的单环、二环或三环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R2,和
其中,C9-10环烷基是饱和或部分不饱和的二环环系,每个环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R2;
B是杂环基,
其中,杂环基是饱和或部分不饱和的单环、二环或多环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R4;
R1是卤素、羟基、氰基、C1-4烷基、卤代C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,
其中,杂芳基是单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,
其中,杂环基是饱和或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
其中,苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个取代基选自R3;
R2是卤素、羟基、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基、或杂环基-C1-4烷基,
其中,杂环基是饱和或部分不饱和的单环或二环环系,具有1个、2个或3个选自N、O和S的杂原子环成员,和
其中,杂环基的每个实例任选地被1个或2个取代基取代,每个取代基选自R3;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4-烷基、C1-4烷基-羰基-氨基,C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;
R4独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;和
R5是氢、C1-4烷基、或羟基-C1-4烷基;
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的实施方式还涉及化合物用于治疗或改善有此需要的对象中的HD的方法或用途,所述方法或用途包括给对象施用有效量的式(I)化合物或其形式,该式(I)化合物选自式(Ia)和式(Ib)的化合物:
其中
X是CH2、CH(C1-4烷基)、C(C1-4烷基)2、CH=CH、O、NR5、或键;
A是芳基、杂芳基、杂环基、或C9-10环烷基,
其中,芳基选自苯基和萘基,各自任选地被1个、2个、3个、或4个取代基取代,每个取代基选自R1,
其中,杂芳基是单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,每个芳香族碳原子环结构基团任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R1,
其中,杂环基是饱和或部分不饱和的单环、二环或三环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R2,和
其中,C9-10环烷基是饱和或部分不饱和的二环环系,每个二环环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R2;
B是杂环基,
其中,杂环基是饱和或部分不饱和的单环、二环或多环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个环系任选地被1个、2个、3个、4个、或5个取代基取代,每个取代基选自R4;
R1是卤素、羟基、氰基、C1-4烷基、卤代C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,
其中,杂芳基是饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,
其中,杂环基是饱和或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
其中,苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个取代基选自R3;
R2是卤素、羟基、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基或杂环基-C1-4烷基;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;
R4独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;和
R5是氢、C1-4烷基、或羟基-C1-4烷基;
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的另一实施方式还涉及用于治疗或改善有此需要的对象中的HD的方法,所述方法包括给对象施用有效量的式(I)化合物或其形式,该式(I)化合物选自式(Ia)和式(Ib)的化合物:
其中
X是O、NH、N(CH3)或键;
A是芳基、杂芳基或杂环基,
其中,芳基选自由以下组成的组:
其中,杂芳基选自由以下组成的组:
其中杂环基选自由以下组成的组:
B是选自由以下组成的组的杂环基:
在可获得的化合价允许的情况下,R1a、R1b和R1c各自是分别选自以下的一个或多个取代基:卤素、羟基、氰基、C1-4烷基、卤代C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,
其中,杂芳基是单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,
其中,杂环基是饱和或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
其中,苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个取代基选自R3;
在可获得的化合价允许的情况下,R2a、R2b和R2c各自是分别选自以下的一个或多个取代基:卤素、羟基、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基、或杂环基-C1-4烷基,
其中,杂环基是饱和或部分不饱和的单环或二环环系,具有1个、2个或3个选自N、O和S的杂原子环成员,和
其中,杂环基的每个实例任选地被1个或2个取代基取代,每个取代基选自R3;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;和
R4a、R4b、R4c、R4d、R4e、R4f和R4g独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的另一方面涉及式(I)化合物或其形式,该式(I)化合物选自式(Ia11)化合物、式(Ia15)化合物、式(Ia18)化合物或式(Ib1)化合物:
其中(当存在时),
X选自O、NR5或键;
A选自苯基、噻吩基、吲唑基、吡啶基、嘧啶基或苯氧基,其中,苯基和苯氧基各自任选地被1个、2个或3个取代基取代,每个取代基选自R1a,
其中,噻吩基、吲唑基、吡啶基、嘧啶基各自任选地被1个或2个取代基取代,每个取代基选自R1a,
B选自1H-吡唑基、哌啶基、1,2,3,6-四氢吡啶基、(IR,5S)-8-氮杂二环[3.2.1]辛基、8-氮杂二环[3.2.1]辛-2-烯基、2,6-二氮杂螺[3.4]辛基、或2,7-二氮杂螺[3.5]壬基,各自任选地被1个或2个取代基取代,每个取代基选自R4a;
R1a选自卤素、羟基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷氧基或杂芳基,
其中,杂芳基是单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,每个芳香族碳原子环结构基团任选地被1个或2个取代基取代,每个取代基选自R3a;
R3a选自硝基或C1-4烷基;和,
R4a是C1-4烷基;
R5a是氢、C1-4烷基、或羟基-C1-4烷基;
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的另一方面涉及式(I)化合物或其形式,该式(I)化合物选自式(Ia11)化合物、式(Ia15)化合物、式(Ia18)化合物或式(Ib1)化合物:
其中(当存在时),
R1a选自氟、氯、羟基、甲基、二氟甲基、氨基、甲氧基或1H-吡唑基或1H-咪唑-1-基,
其中,1H-吡唑基任选地被1个或2个取代基取代,每个取代基选自R3a;
R3a选自硝基或甲基或氨基;和,
R4a是甲基或乙基;
R5a是氢或甲基;
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia1)化合物或其形式)的用途,其中,取代基R1a、R1b和X(当存在时)如下表所示,具有用逗号分隔的多个取代基;并且,“--”表示不存在一个或多个R1a、R1b和X取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia2)化合物或其形式)的用途,其中,取代基R1a、R1b和R4a(当存在时)如下表所示,具有用逗号分隔的多个取代基;并且,“--”表示不存在一个或多个R1a、R1b和R4a取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia3)化合物或其形式)的用途,其中,取代基R1a、R1b和X(当存在时)如下表所示,具有用逗号分隔的多个取代基;并且,“--”表示不存在一个或多个R1a、R1b和X取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia4)化合物或其形式)的用途,其中,取代基X、R1a、R1b和R4a(当存在时)如下表所示,具有用逗号分隔的多个取代基;并且,“--”表示不存在一个或多个X、R1a、R1b和R4a取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia5)化合物或其形式)的用途,其中,取代基R1a和R1b(当存在时)如下表所示,具有用逗号分隔的多个取代基;并且,“--”表示不存在一个或多个R1a和R1b取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia6)化合物或其形式)的用途,其中,取代基R1a(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a取代基:
化合物 | R<sub>1a</sub> |
239 | -- |
246 | 2,3-(CH<sub>3</sub>)<sub>2</sub> |
247 | 2-CH<sub>3</sub> |
248 | 3-CH<sub>3</sub> |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia7)化合物或其形式)的用途,其中,取代基R1a(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a取代基:
化合物 | R<sub>1a</sub> |
258 | -- |
260 | 2-CH<sub>3</sub> |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia8)化合物或其形式)的用途,其中取代基R1a和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a和B取代基:
化合物 | R<sub>1a</sub> | B |
209 | -- | 6-((3aR,6aS)-5-CH<sub>3</sub>-六氢吡咯并[3,4-c]吡咯-2(1H)-基) |
269 | 2-CN | 哌嗪-1-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia9)化合物或其形式)的用途,其中,取代基R1a和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a和B取代基:
化合物 | R<sub>1a</sub> | B |
214 | -- | 6-((3aR,6aS)-5-CH<sub>3</sub>-六氢吡咯并[3,4-c]吡咯-2(1H)-基) |
270 | -- | 哌嗪-1-基 |
291 | 3-CH<sub>3</sub> | 哌嗪-1-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia10)化合物或其形式)的用途,其中,取代基R1a和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a和B取代基:
化合物 | R<sub>1a</sub> | B |
268 | 2-CN | 哌嗪-1-基 |
271 | -- | 1,2,3,6-四氢吡啶-4-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia11)化合物或其形式)的用途,其中,取代基A、X和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个A、X和R4a取代基:
本发明的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia11)化合物或其形式),其中,取代基A、X和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个A、X和R4a取代基:
化合物 | A | X |
420 | 2-OCH<sub>3</sub>-4-(4-NO<sub>2</sub>-1H-吡唑-1-基)苯基 | N(CH<sub>3</sub>) |
428 | 2,5-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
430 | 2,3-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
431 | 2,5-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | O |
434 | 2-OCH<sub>3</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
435 | 4-(1H-吡唑-4-基)苯基 | O |
437 | 2-F-4-(1H-吡唑-4-基)苯基 | O |
438 | 4-(1-CH<sub>3</sub>-1H-吡唑-4-基)噻吩-2-基 | O |
440 | 2-F-4-OH-苯基 | N(CH<sub>3</sub>) |
442 | 2-CH<sub>3</sub>-2H-吲唑-5-基 | N(CH<sub>3</sub>) |
443 | 2-CH<sub>3</sub>-2H-吲唑-5-基 | O |
444 | 4-Cl-2-OCH<sub>3</sub>-苯基 | O |
445 | 2-CH<sub>3</sub>-吡唑并[1,5-a]吡啶-3-基 | N(CH<sub>3</sub>) |
446 | 咪唑并[1,2-a]吡啶-6-基 | O |
447 | 2-OCH<sub>3</sub>-4-(1H-吡唑-1-基)苯基 | O |
448 | 5-(1H-吡唑-4-基)噻吩-2-基 | O |
449 | 5-(1-CH<sub>3</sub>-1H-吡唑-4-基)噻吩-2-基 | O |
450 | 4-(1H-吡唑-4-基)噻吩-2-基 | O |
451 | 2-OH-4-[3,5-(CH<sub>3</sub>)<sub>2</sub>-1H-吡唑-4-基]苯基 | O |
452 | 2-F-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
453 | 2-OCH<sub>3</sub>-4-OH-苯基 | O |
454 | 2-OCH<sub>3</sub>-4-(4-NO<sub>2</sub>-1H-吡唑-1-基)苯基 | O |
455 | 2,4-(OH)<sub>2</sub>-苯基 | O |
456 | 2-Cl-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
457 | 5-氨基-2-(1H-吡唑-4-基)嘧啶-4-基 | O |
458 | 2,6-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | O |
464 | 2-(CHF<sub>2</sub>)-4-(1H-吡唑-4-基)苯基 | O |
465 | 2-(CHF<sub>2</sub>)-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia11)化合物或其形式)的用途,其中,取代基A、X和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个A、X和R4a取代基:
化合物 | A | X |
420 | 2-OCH<sub>3</sub>-4-(4-NO<sub>2</sub>-1H-吡唑-1-基)苯基 | N(CH<sub>3</sub>) |
428 | 2,5-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
430 | 2,3-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
431 | 2,5-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | O |
434 | 2-OCH<sub>3</sub>-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
435 | 4-(1H-吡唑-4-基)苯基 | O |
437 | 2-F-4-(1H-吡唑-4-基)苯基 | O |
438 | 4-(1-CH<sub>3</sub>-1H-吡唑-4-基)噻吩-2-基 | O |
440 | 2-F-4-OH-苯基 | N(CH<sub>3</sub>) |
442 | 2-CH<sub>3</sub>-2H-吲唑-5-基 | N(CH<sub>3</sub>) |
443 | 2-CH<sub>3</sub>-2H-吲唑-5-基 | O |
444 | 4-Cl-2-OCH<sub>3</sub>-苯基 | O |
445 | 2-CH<sub>3</sub>-吡唑并[1,5-a]吡啶-3-基 | N(CH<sub>3</sub>) |
446 | 咪唑并[1,2-a]吡啶-6-基 | O |
447 | 2-OCH<sub>3</sub>-4-(1H-吡唑-1-基)苯基 | O |
448 | 5-(1H-吡唑-4-基)噻吩-2-基 | O |
449 | 5-(1-CH<sub>3</sub>-1H-吡唑-4-基)噻吩-2-基 | O |
450 | 4-(1H-吡唑-4-基)噻吩-2-基 | O |
451 | 2-OH-4-[3,5-(CH<sub>3</sub>)<sub>2</sub>-1H-吡唑-4-基]苯基 | O |
452 | 2-F-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
453 | 2-OCH<sub>3</sub>-4-OH-苯基 | O |
454 | 2-OCH<sub>3</sub>-4-(4-NO<sub>2</sub>-1H-吡唑-1-基)苯基 | O |
455 | 2,4-(OH)<sub>2</sub>-苯基 | O |
456 | 2-Cl-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
457 | 5-氨基-2-(1H-吡唑-4-基)嘧啶-4-基 | O |
458 | 2,6-F<sub>2</sub>-4-(1H-吡唑-4-基)苯基 | O |
464 | 2-(CHF<sub>2</sub>)-4-(1H-吡唑-4-基)苯基 | O |
465 | 2-(CHF<sub>2</sub>)-4-(1H-吡唑-4-基)苯基 | N(CH<sub>3</sub>) |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia12)化合物或其形式)的用途,其中,取代基X、R1a和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和B取代基:
化合物 | R<sub>1a</sub> | X | B |
66 | H | NH | 氮杂环丁-3-基 |
82 | OH | -- | 哌嗪-1-基 |
85 | H | -- | 1,2,3,6-四氢吡啶-4-基 |
86 | OH | -- | 1,2,3,6-四氢吡啶-4-基 |
87 | OH | -- | 2,2,6,6-四甲基-(1,2,3,6-四氢吡啶-4-基) |
88 | OH | -- | 1-CH<sub>3</sub>-(1,2,3,6-四氢吡啶-4-基) |
89 | OH | -- | 哌啶-4-基 |
99 | H | CH<sub>2</sub> | 哌啶-4-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia13)化合物或其形式)的用途,其中,取代基X、R1a和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和R4a取代基:
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia14)化合物或其形式)的用途,其中,取代基X和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个X和B取代基:
化合物 | X | B |
55 | O | 哌啶-4-基 |
56 | O | (2S,4R,6R)-2,6-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
57 | O | 2,6-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
58 | O | 吡咯烷-3-基 |
59 | O | 2-CH<sub>3</sub>-哌啶-4-基 |
60 | OCH<sub>2</sub> | 1H-吡咯烷-3-基 |
61 | O | 3-F-哌啶-4-基 |
65 | -- | 哌嗪-1-基 |
67 | NH | 氮杂环丁-3-基 |
68 | -- | 3,5-(CH<sub>3</sub>)<sub>2</sub>-哌嗪-1-基 |
69 | -- | 7-CH<sub>3</sub>-2,7-二氮杂螺[4.4]壬-2-基 |
70 | -- | [1,4]二氮杂庚-1-基 |
71 | -- | 4-CH<sub>2</sub>CH<sub>2</sub>OH-哌嗪-1-基 |
72 | -- | 2,7-二氮杂螺[3.5]壬-7-基 |
73 | -- | 2,7-二氮杂螺[3.5]壬-7-基 |
74 | -- | 3-CH<sub>2</sub>OH-哌嗪-1-基 |
75 | -- | 1,7-二氮杂螺[4.4]壬-7-基 |
76 | -- | 4-NH<sub>2</sub>-4-CH<sub>3</sub>-哌啶-1-基 |
77 | -- | 3-N(CH<sub>3</sub>)<sub>2</sub>-哌啶-1-基 |
79 | -- | 3,3-(CH<sub>3</sub>)<sub>2</sub>-哌嗪-1-基 |
80 | -- | 7-CH<sub>2</sub>CH<sub>2</sub>OH-2,7-二氮杂螺[4.4]壬-2-基 |
83 | -- | 1,2,3,6-四氢吡啶-4-基 |
84 | -- | 哌啶-4-基 |
102 | O | (6S)-6-[(S)-CH(OH)CH3]-2,2-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
133 | O | 2,2-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia15)化合物或其形式)的用途,其中,取代基X、R1a和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和R4a取代基:
本发明的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia15)化合物或其形式),其中,取代基X、R1a和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和R4a取代基:
化合物 | X | R<sub>1a</sub> | R<sub>4a</sub> |
413 | NH | 1H-吡唑-4-基 | -- |
414 | O | 1-CH<sub>3</sub>-1H-吡唑-4-基 | -- |
416 | N(CH<sub>3</sub>) | 5-CH<sub>3</sub>-1H-吡唑-4-基 | -- |
417 | O | 1H-咪唑-1-基 | -- |
418 | O | 5-CH<sub>3</sub>-1H-吡唑-4-基 | -- |
419 | N(CH<sub>3</sub>) | 4-NO<sub>2</sub>-1H-吡唑-1-基 | -- |
421 | O | 5-NH<sub>2</sub>-1H-吡唑-1-基 | -- |
423 | O | 4-NO<sub>2</sub>-1H-吡唑-1-基 | -- |
460 | N(CH<sub>3</sub>) | 1H-吡唑-4-基 | -- |
461 | O | 1H-吡唑-4-基 | -- |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia15)化合物或其形式)的用途,其中,取代基X、R1a和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和R4a取代基:
化合物 | X | R<sub>1a</sub> |
413 | NH | 1H-吡唑-4-基 |
414 | O | 1-CH<sub>3</sub>-1H-吡唑-4-基 |
416 | N(CH<sub>3</sub>) | 5-CH<sub>3</sub>-1H-吡唑-4-基 |
417 | O | 1H-咪唑-1-基 |
418 | O | 5-CH<sub>3</sub>-1H-吡唑-4-基 |
419 | N(CH<sub>3</sub>) | 4-NO<sub>2</sub>-1H-吡唑-1-基 |
421 | O | 5-NH<sub>2</sub>-1H-吡唑-1-基 |
423 | O | 4-NO<sub>2</sub>-1H-吡唑-1-基 |
460 | N(CH<sub>3</sub>) | 1H-吡唑-4-基 |
461 | O | 1H-吡唑-4-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia16)化合物或其形式)的用途,其中,取代基R1a和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a和R4a取代基:
化合物 | R<sub>1a</sub> | R<sub>4a</sub> |
81 | 1H-吡唑-1-基 | -- |
199 | 1H-吡唑-4-基 | (CH<sub>2</sub>)<sub>2</sub>OH |
200 | 1H-吡唑-4-基 | -- |
201 | 1H-吡唑-4-基 | CH<sub>3</sub> |
202 | 4-(1-CH<sub>3</sub>-吡啶-2(1H)-酮) | CH<sub>3</sub> |
203 | 4-(1-CH<sub>3</sub>-吡啶-2(1H)-酮) | CH<sub>3</sub> |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia17)化合物或其形式)的用途,其中,取代基R1a(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a取代基:
化合物 | R<sub>1a</sub> |
204 | 1H-吡唑-4-基 |
205 | 4-(1-CH<sub>3</sub>-吡啶-2(1H)-酮) |
本发明的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia18)化合物或其形式),其中,取代基X和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个X和B取代基:
化合物 | X | B |
411 | N(CH<sub>3</sub>) | (1R,5S)-8-氮杂二环[3.2.1]辛-3-基 |
412 | NH | (1R,5S)-8-氮杂二环[3.2.1]辛-3-基 |
415 | O | (1R,5S)-8-氮杂二环[3.2.1]辛-3-基 |
422 | -- | 1-CH<sub>3</sub>-(1,2,3,6-四氢吡啶-4-基) |
424 | -- | 1,2,3,6-四氢吡啶-4-基 |
425 | -- | 1-CH<sub>3</sub>CH<sub>2</sub>-(1,2,3,6-四氢吡啶-4-基) |
425 | N(CH<sub>3</sub>) | 哌啶-4-基 |
427 | NH | 哌啶-4-基 |
429 | -- | 8-氮杂二环[3.2.1]辛-2-烯-3-基 |
432 | O | 哌啶-4-基 |
433 | NH | (1R,5S)-8-氮杂二环[3.2.1]辛-3-基 |
436 | O | 2,6-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
439 | -- | 2,7-二氮杂螺[3.5]壬-2-基 |
441 | O | 2,6-(CH<sub>3</sub>)<sub>2</sub>-哌啶-4-基 |
459 | -- | 2,6-二氮杂螺[3.5]辛-2-基 |
本发明的方法的另一实施方式包括式(Ia)化合物或其形式(选自式(Ia18)化合物或其形式)的用途,其中,取代基X、R1a和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个X、R1a和B取代基:
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib1)化合物或其形式)的用途,其中,取代基A如下表所示:
化合物 | A |
302 | 6-(萘-2-酚) |
320 | 6-(萘-2,7-二酚) |
331 | 7-OCH<sub>3</sub>-喹啉-6-基 |
332 | 7-OH-喹啉-6-基 |
337 | 2-CN-7-OCH<sub>3</sub>-喹啉-6-基 |
355 | 3-F-5-(1H-吡唑-4-基)-吡啶-2-基 |
364 | 2-(6-OCH<sub>3</sub>-3,4-二氢异喹啉-1(2H)-酮) |
392 | 6-OH-1-氧代-2,3-二氢-1H-茚-5-基 |
401 | 3-(4-OCH<sub>3</sub>-1-CH<sub>3</sub>-喹啉-1(2H)-酮) |
402 | 3-(4-OH-1-CH<sub>3</sub>-喹啉-1(2H)-酮) |
403 | 3-(喹啉-2(1H)-酮) |
404 | 3-(1-OCH<sub>3</sub>-喹啉-2(1H)-酮) |
408 | 5-CN-苯并[b]噻吩-2-基 |
409 | 5-Cl-苯并[b]噻吩-2-基 |
本发明的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib1)化合物或其形式),其中,取代基A如下表所示:
化合物 | A |
462 | 3-(1H-吡唑-4-基)苯氧基 |
463 | 4-(1H-吡唑-4-基)苯氧基 |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib1)化合物或其形式)的用途,其中,取代基A如下表所示:
化合物 | A |
462 | 3-(1H-吡唑-4-基)苯氧基 |
463 | 4-(1H-吡唑-4-基)苯氧基 |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib2)化合物或其形式)的用途,其中,取代基A如下表所示:
化合物 | A |
321 | 6-萘-2,7-二酚 |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib3)化合物或其形式)的用途,其中,取代基R1a、R1b和B(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a、R1b和B取代基:
本发明的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib4)化合物或其形式)的用途,其中,取代基R1a、R1b、R1c、R1d(每个代表R1的范围)和X(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a、R1b、R1c、R1d和X取代基:
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib5)化合物或其形式)的用途,其中,取代基R1a、R1b、R1c、R1d(每个代表R1的范围)和R4a(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a、R1b、R1c、R1d和R4a取代基:
化合物 | R<sub>1a</sub> | R<sub>1b</sub> | R<sub>1c</sub> | R<sub>1d</sub> | R<sub>4a</sub> |
353 | 1H-吡唑-4-基 | F | F | H | -- |
362 | 1H-吡唑-4-基 | OCH<sub>3</sub> | H | F | CH<sub>3</sub> |
370 | 1H-咪唑-1-基 | Cl | H | H | CH<sub>3</sub> |
379 | 1-CH<sub>3</sub>-1H-吡唑-4-基 | Cl | H | H | CH<sub>3</sub> |
380 | 1H-吡唑-4-基 | Cl | H | H | CH<sub>3</sub> |
384 | 1H-吡唑-4-基 | F | H | H | CH<sub>3</sub> |
396 | 1H-吡唑-4-基 | F | H | OH | -- |
405 | 1H-吡唑-4-基 | Cl | H | H | -- |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib6)化合物或其形式)的用途,其中,取代基R1a、R1b、R1c和R1d(每个代表R1的范围)(当存在时)如下表所示;并且,“--”表示不存在一个或多个R1a、R1b、R1c和R1d取代基:
化合物 | R<sub>1a</sub> | R<sub>1b</sub> | R<sub>1c</sub> | R<sub>1d</sub> |
386 | 1-CH<sub>3</sub>-1H-吡唑-4-基 | OCH<sub>3</sub> | H | H |
395 | 1-CH<sub>3</sub>-1H-吡唑-4-基 | OH | H | H |
399 | 1H-吡唑-4-基 | H | F | F |
400 | 1H-吡唑-4-基 | OH | H | F |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib7)化合物或其形式)的用途,其中,取代基R1b(当存在时)如下表所示:
化合物 | R<sub>1b</sub> |
304 | OCH<sub>3</sub> |
322 | OH |
本发明的方法的另一实施方式包括式(Ib)化合物或其形式(选自式(Ib8)化合物或其形式)的用途,其中,取代基R1b(当存在时)如下表所示:
化合物 | R<sub>1b</sub> |
303 | OCH<sub>3</sub> |
323 | OH |
式(I)化合物或其形式的用途的实施方式包括使用式(I)化合物或其形式用于治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的选自由以下组成的组的式(I)化合物或其形式:
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
在另一方面,式(I)化合物或其形式包括选自由以下组成的组的化合物:
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
式(I)化合物或其形式的用途的另一实施方式包括使用式(I)化合物或其形式用于治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的选自由以下组成的组的式(I)化合物或其形式(其中,化合物编号(#1)表示分离了盐形式):
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
在一个方面,式(I)化合物或其形式包括选自由以下组成的组的化合物:
4111 2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
4121 2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4131 5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
414 5-(1-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
4151 2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
416 5-(5-甲基-1H-吡唑-4-基)-2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
417 5-(1H-咪唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
418 5-(5-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
4191 2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚
420 6-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
421 5-(4-氨基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
4221 2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
423 5-(4-硝基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
4241 5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚
4251 2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4261 2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
4271 2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4281 6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
4291 2-[6-(8-氮杂二环[3.2.1]辛-2-烯-3-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4301 6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
4311 3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
432 2-[6-(哌啶-4-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4331 2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
4341 6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
435 3-[4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4361 2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
4371 3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
438 3-[4-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4391 2-[6-(2,7-二氮杂螺[3.5]壬-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
440 3-氟代-4-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
441 2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-1-基)苯酚
442 N-甲基-6-(2-甲基-2H-吲唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
443 2-甲基-5-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}-2H-吲唑
444 3-(4-氯代-2-甲氧基苯基)-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
445 N-甲基-6-(2-甲基吡唑并[1,5-a]吡啶-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
446 6-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}咪唑并[1,2-a]吡啶
447 3-[2-甲氧基-4-(1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4481 3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
449 3-[5-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4501 3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
451 5-(3,5-二甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
452 6-[2-氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
453 3-甲氧基-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
454 3-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
455 4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯-1,3-二酚
4561 6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
457 2-(1H-吡唑-4-基)-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}嘧啶-5-胺
4581 3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
459 2-[6-(2,6-二氮杂螺[3.4]辛-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
4601 3-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-6-(1H-吡唑-4-基)吡啶-2-醇
461 6-(1H-吡唑-4-基)-3-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}吡啶-2-醇
4621 N,2,2,6,6-五甲基-N-{5-[3-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺
4631 N,2,2,6,6-五甲基-N-{5-[4-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺
4641 3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪,和
4651 6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
其中,化合物的形式选自由以下组成的组:其前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
式(I)化合物盐或其形式的用途的另一实施方式包括使用式(I)化合物盐或其形式用于治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的选自由以下组成的组的式(I)化合物盐或其形式:
其中,化合物盐的形式选自由以下组成的组:其前药形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
在一个方面,式(I)化合物盐或其形式包括选自由以下组成的组的化合物:
411 2-{6-[8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚盐酸盐
412 2-[6-(8-氮杂二环[3.2.1]辛-3-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
413 5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚盐酸盐
415 2-[6-(8-氮杂二环[3.2.1]辛-3-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
419 2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚二盐酸盐
422 2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
424 5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚三盐酸盐
425 2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
426 2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚四盐酸盐
427 2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
428 6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺四盐酸盐
429 2-[6-(8-氮杂二环[3.2.1]辛-2-烯-3-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
430 6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
431 3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
433 2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚盐酸盐
434 6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
436 2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚三盐酸盐
437 3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
439 2-[6-(2,7-二氮杂螺[3.5]壬-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
448 3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
450 3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
456 6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺三盐酸盐
458 3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
460 3-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-6-(1H-吡唑-4-基)吡啶-2-醇盐酸盐
462 N,2,2,6,6-五甲基-N-{5-[3-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺盐酸盐
463 N,2,2,6,6-五甲基-N-{5-[4-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺盐酸盐
464 3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐,和
465 6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
其中,化合物盐的形式选自由以下组成的组:其前药形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
本发明的另一实施方式包括使用式(I)化合物或其形式用于治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的式(I)化合物或其形式。
本发明的另一实施方式包括使用式(I)化合物或其形式用于治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的式(I)化合物盐或其形式。
本发明的另一实施方式包括式(I)化合物或其形式用于治疗或改善有此需要的对象中的HD的用途,该用途包括给对象施用有效量的式(I)化合物或其形式。
本发明的另一实施方式包括式(I)化合物盐或其形式用于治疗或改善有此需要的对象中的HD的用途,该用途包括给对象施用有效量的式(I)化合物盐或其形式。
化学定义
如本文所用,术语“C1-4烷基”通常是指具有直链或支链构型的一个至四个碳原子的饱和烃基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。在一些实施方式中,C1-4烷基包括C1-3烷基、C1-2烷基等。在可获得的化合价允许的情况下,C1-4烷基可以任选地被取代。
如本文所用,术语“C2-6烯基”通常是指具有直链或支链构型的两个至五个碳原子且其中具有一个或多个碳-碳双键的部分不饱和烃基,包括但不限于乙烯基、烯丙基、丙烯基等。在一些实施方式中,C2-6烯基包括C2-4烯基、C2-3烯基等。在可获得的化合价允许的情况下,C2-6烯基可以任选地被取代。
如本文所用,术语“C1-4烷氧基”通常是指具有式-O-C1-4烷基的直链或支链构型的一个至四个碳原子的饱和烃基,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。在一些实施方式中,C1-4烷氧基包括C1-3烷氧基、C1-2烷氧基等。在可获得的化合价允许的情况下,C1-4烷氧基可以任选地被取代。
如本文所用,术语“C3-14环烷基”通常是指饱和的单环、二环或多环烃基,包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、1H-茚满基、茚基、四氢萘基等。在一些实施方式中,C3-14环烷基包括C3-10环烷基、C3-8环烷基、C3-7环烷基、C5-8环烷基、C9-10环烷基等。在可获得的化合价允许的情况下,C3-14环烷基可以任选地被取代。
如本文所用,术语“C3-14环烯基”通常是指其中具有一个或多个化学稳定的碳-碳双键的部分不饱和的单环、二环或多环烃基,包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基等。在一些实施方式中,C3-14环烯基包括C3-7环烯基、C3-8环烯基、C5-8环烯基、C3-10环烯基等。在可获得的化合价允许的情况下,C3-14环烯基可以任选地被取代。
如本文所用,术语“芳基”通常是指单环、二环或多环芳香族碳原子环结构基团,包括但不限于苯基、萘基、蒽基、芴基、薁基、菲基等。在可获得的化合价允许的情况下,芳基可以任选地被取代。
如本文所用,术语“杂芳基”通常是指单环、二环或多环芳香族碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被一个或多个杂原子(例如O、S或N原子)替代,包括但不限于呋喃基、噻吩基(也称为苯硫基)、吡咯基、吡唑基、咪唑基、异噁唑基、异噻唑基、噁唑基、噻唑基、***基、噁二唑基、噻二唑基、四唑基、吡喃基、噻喃基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、吲唑基、吲嗪基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噻唑基、苯并噁唑基、9H-嘌呤基、喹喔啉基、异吲哚基、喹啉基、异喹啉基、喹唑啉基、吖啶基、酞嗪基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、咪唑并[5,l-a]异喹啉基、1,4-二氢茚并[1,2-c]-1H-吡唑基、2,3-二氢-1H-茚-1-酮、2,3-二氢-1H-茚基、3,4-二氢喹啉-2(1H)-酮、5,6-二氢咪唑并[5,1-a]异喹啉基、8H-茚并[1,2-d]噻唑基、苯并[c][1,2,5]噁二唑基、苯并[d]噁唑-2(3H)-酮、喹啉-2(1H)-酮、喹唑啉-4(1H)-酮、喹唑啉-2,4(1H,3H)-二酮、苯并-[d]噁唑基、吡唑并[1,5-a]吡啶基等。在可获得的化合价允许的情况下,杂芳基在碳原子环成员或氮原子环成员上可以任选地被取代。
如本文所用,术语“杂环基”通常是指饱和或部分不饱和的单环、二环或多环碳原子环结构基团,其中,在结构稳定性允许的情况下,一个或多个碳原子环成员被杂原子(例如O、S或N原子)替代,包括但不限于环氧乙基、氧杂环丁基、氮杂环丁基、二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、吡咯啉基、吡咯烷基、二氢吡唑基、吡唑啉基、吡唑烷基、二氢咪唑基、咪唑啉基、咪唑烷基、异噁唑啉基、异噁唑烷基、异噻唑啉基、异噻唑烷基、噁唑啉基、噁唑烷基、噻唑啉基、噻唑烷基、***啉基、***烷基、噁二唑啉基、噁二唑烷基、噻二唑啉基、噻二唑烷基、四唑啉基、四唑烷基、二氢-2H-吡喃基、二氢吡啶基、四氢吡啶基、1,2,3,6-四氢吡啶基、六氢吡啶基、二氢嘧啶基、四氢嘧啶基、1,4,5,6-四氢嘧啶基、二氢吡嗪基、四氢吡嗪基、二氢哒嗪基、四氢哒嗪基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、二氢三嗪基、四氢三嗪基、六氢三嗪基、1,4-二氮杂环庚基、二氢吲哚基、吲哚啉基、四氢吲哚基、二氢吲唑基、四氢吲唑基、二氢异吲哚基、二氢苯并呋喃基、四氢苯并呋喃基、二氢苯并噻吩基、四氢苯并噻吩基、二氢苯并咪唑基、四氢苯并咪唑基、二氢苯并噁唑基、2,3-二氢苯并[d]噁唑基、四氢苯并噁唑基、二氢苯并噁嗪基、3,4-二氢-2H-苯并[b][1,4]噁嗪基、四氢苯并噁嗪基、苯并[1,3]二氧杂环戊烯基、苯并[1,4]二噁烷基、二氢嘌呤基、四氢嘌呤基、二氢喹啉基、四氢喹啉基、1,2,3,4-四氢喹啉基、二氢异喹啉基、3,4-二氢异喹啉-(1H)-基、四氢异喹啉基、1,2,3,4-四氢异喹啉基、二氢喹唑啉基、四氢喹唑啉基、二氢喹喔啉基、四氢喹喔啉基、1,2,3,4-四氢喹喔啉基、1,3-二氧戊环基、2,5-二氢-1H-吡咯基、4,5-二氢-1H-咪唑基、四氢-2H-吡喃基、六氢吡咯并[3,4-b][1,4]噁嗪-(2H)-基、(4aR,7aS)-六氢吡咯并[3,4-b][1,4]噁嗪-(4aH)-基、3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪基、(顺式)-八氢环戊二烯并[c]吡咯基、六氢吡咯并[3,4-b]吡咯-(1H)-基、(3aR,6aR)-六氢吡咯并[3,4-b]吡咯-(1H)-基、(3aR,6aS)-六氢吡咯并[3,4-c]吡咯-(1H)-基、5H-吡咯并[3,4]-b]吡啶-(7H)-基、5,7-二氢-6H-吡咯并[3,4-b]吡啶基、四氢-1H-吡咯并[3,4-b]吡啶-(2H,7H,7aH)-基、六氢-1H-吡咯并[3,4-b]吡啶-(2H)-基、(4aR,7aR)-六氢-1H-吡咯并[3,4-b]吡啶-(2H)-基、八氢-6H-吡咯并[3,4-b]吡啶基、2,3,4,9-四氢-1H-咔唑基、1,2,3,4-四氢吡嗪并[1,2-a]吲哚基、2,3-二氢-1H-吡咯并[1,2-a]吲哚基、(3aR,6aR)-六氢环戊二烯并[c]吡咯-(1H)-基、(3aR,4R,6aS)-六氢环戊二烯并[c]吡咯-(1H)-基、(3aR,4S,6aS)-六氢环戊二烯并[c]吡咯-(1H)-基、(3aR,5r,6aS)-六氢环戊二烯并[c]吡咯-(1H)-基、1,3-二氢-2H-异吲哚基、八氢-2H-异吲哚基、(3aS)-1,3,3a,4,5,6-六氢-2H-异吲哚基、(3aR,4R,7aS)-1H-异吲哚-(3H,3aH,4H,5H,6H,7H,7aH)-基、(3aR,7aS)-八氢-2H-异吲哚基、(3aR,4R,7aS)-八氢-2H-异吲哚基、(3aR,4S,7aS)-八氢-2H-异吲哚基、2,5-二氮杂二环[2.2.1]庚基、2-氮杂二环[2.2.1]庚烯基、3-氮杂二环[3.1.0]己基、3,6-二氮杂二环[3.1.0]己基、(1R,5S)-3-氮杂二环[3.1.0]己基、(1S,5R)-3-氮杂二环[3.2.0]庚基、5-氮杂螺[2.4]庚基、2,6-二氮杂螺[3.3]庚基、2,5-二氮杂螺[3.4]辛基、2,6-二氮杂螺[3.4]辛基、2,7-二氮杂螺[3.5]壬基、2,7-二氮杂螺[4.4]壬基、2-氮杂螺[4.5]癸基、2,8-二氮杂螺[4.5]癸基、3,6-二氮杂二环[3.2.1]辛基、1,4-二氢茚并[1,2-c]吡唑基、二氢吡喃基、二氢吡啶基、二氢喹啉基、8H-茚并[1,2-d]噻唑基、四氢咪唑并[1,2-a]吡啶基、吡啶-2(1H)-酮、(1R,5S)-8-氮杂二环[3.2.1]辛基、8-氮杂二环[3.2.1]辛-2-烯基等。在可获得的化合价允许的情况下,杂环基在碳原子环成员或氮原子环成员上可以任选地被取代。
如本文所用,术语“C2-4烯基-氨基-羰基”是指下式的基团:-C(=O)-NH-C2-4烯基。
如本文所用,术语“C1-4烷氧基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-O-C1-4烷基。
如本文所用,术语“C1-4烷氧基-羰基”是指下式的基团:-C(=O)-O-C1-4烷基。
如本文所用,术语“C1-4烷氧基-羰基-氨基”是指下式的基团:-NH-C(=O)-O-C1-4烷基。
如本文所用,术语“C1-4烷氧基-羰基-氨基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-NH-C(=O)-O-C1-4烷基。
如本文所用,术语“C1-4烷基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-C1-4烷基。
如本文所用,术语“C1-4烷基-氨基”是指下式的基团:-NH-C1-4烷基。
如本文所用,术语“(C1-4烷基)2-氨基”是指下式的基团:-N(C1-4烷基)2。
如本文所用,术语“C1-4烷基-氨基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-NH-C1-4烷基。
如本文所用,术语“(C1-4烷基)2-氨基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-N(C1-4烷基)2。
如本文所用,术语“C1-4烷基-氨基-C1-4烷基”是指下式的基团:-C1-4烷基-NH-C1-4烷基。
如本文所用,术语“(C1-4烷基)2-氨基-C1-4烷基”是指下式的基团:-C1-4烷基-N(C1-4烷基)2。
如本文所用,术语“C1-4烷基-氨基-羰基”是指下式的基团:-C(=O)-NH-C1-4烷基。
如本文所用,术语“(C1-4烷基)2-氨基-羰基”是指下式的基团:-C(=O)-N(C1-4烷基)2。
如本文所用,术语“C1-4烷基-氨基-羰基-C1-4烷基”是指下式的基团:-C1-4烷基-C(=O)-NH-C1-4烷基。
如本文所用,术语“(C1-4烷基)2-氨基-羰基-C1-4烷基”是指下式的基团:-C1-4烷基-C(=O)-N(C1-4烷基)2。
如本文所用,术语“C1-4烷基-羰基”是指下式的基团:-C(=O)-C1-4烷基。
如本文所用,术语“C1-4烷基-羰基-氨基”是指下式的基团:-NH-C(=O)-C1-4烷基。
如本文所用,术语“C1-4烷基-羰基-氨基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-NH-C(=O)-C1-4烷基。
如本文所用,术语“C1-4烷基-羰基-氨基-C1-4烷基”是指下式的基团:-C1-4烷基-NH-C(=O)-C1-4烷基。
如本文所用,术语“氨基”是指下式的基团:-NH2。
如本文所用,术语“氨基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-NH2。
如本文所用,术语“氨基-C1-4烷基”是指下式的基团:-C1-4烷基-NH2。
如本文所用,术语“氨基-羰基”是指下式的基团:-C(=O)-NH2。
如本文所用,术语“氰基”是指下式的基团:-CN。
如本文所用,术语“C3-7环烷基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-C3-7环烷基。
如本文所用,术语“卤代-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-卤代,其中,在可获得的化合价允许的情况下,C1-4烷基可以被一个或多个卤素原子部分或完全取代。在一些实施方式中,卤代-C1-4烷氧基包括卤代-C1-6烷氧基、卤代-C1-4烷氧基等。
如本文所用,术语“卤代-C1-4烷基”是指下式的基团:-C1-4烷基-卤代,其中,在可获得的化合价允许的情况下,C1-4烷基可以被一个或多个卤素原子部分或完全取代。在一些实施方式中,卤代-C1-4烷基包括卤代-C1-6烷基、卤代-C1-4烷基等。
如本文所用,术语“杂芳基-C1-4烷基”是指下式的基团:-C1-4烷基-杂芳基。
如本文所用,术语“杂芳基-C1-4烷基-氨基”是指下式的基团:-NH-C1-4烷基-杂芳基。
如本文所用,术语“杂芳基-C1-4烷基-氨基-羰基”是指下式的基团:-C(=O)-NH-C1-4烷基-杂芳基。
如本文所用,术语“杂芳基-C1-4烷基-氨基-羰基-C1-4烷基”是指下式的基团:-C1-4烷基-C(=O)-NH-C1-4烷基-杂芳基。
如本文所用,术语“杂芳基-C1-4烷基-羰基-氨基”是指下式的基团:-NH-C(=O)-C1-4烷基-杂芳基。
如本文所用,术语“杂芳基-C1-4烷基-羰基-氨基-C1-4烷基”是指下式的基团:-C1-4烷基-NH-C(=O)-C1-4烷基-杂芳基。
如本文所用,术语“杂环基-C1-4烷氧基”是指下式的基团:-C1-4烷氧基-杂环基。
如本文所用,术语“杂环基-C1-4烷基”是指下式的基团:-C1-4烷基-杂环基。
如本文所用,术语“羟基”是指下式的基团:-OH。
如本文所用,术语“羟基-C1-4烷氧基”是指下式的基团:-O-C1-4烷基-OH,其中,在可获得的化合价允许的情况下,C1-4烷基可以被一个或多个羟基基团部分或完全取代。
如本文所用,术语“羟基-C1-4烷基”是指下式的基团:-C1-4烷基-OH,其中,在可获得的化合价允许的情况下,C1-4烷基可以被一个或多个羟基基团部分或完全取代。
如本文所用,术语“羟基-C1-4烷基-氨基”是指下式的基团:-NH-C1-4烷基-OH,其中,在可获得的化合价允许的情况下,C1-4烷基可以被一个或多个羟基基团部分或完全取代。
如本文所用,术语“羟基-亚氨基”是指式C(=NOH)的=NOH基团。
如本文所用,术语“氧代”是指下式的基团:C=O。
如本文所用,术语“苯基-C1-4烷氧基”是指下式的基团:-C1-4烷氧基-苯基。
如本文所用,术语“取代基”是指在指定原子位置上取代的核心分子的原子上的位置变体,其在指定原子上替代一个或多个氢,条件是不超过指定原子的正常价态,并且该取代产生稳定的化合物。只有当取代基和/或变体的组合产生稳定的化合物时,这种组合才是允许的。本领域技术人员应该注意,如本文所述或显示的具有似乎不满足的化合价的任何碳以及杂原子假定为具有足够数量的氢原子以满足所述或所示的化合价。在某些情况下,在取代基团中,在本文中可以描述、显示或列出作为连接点的一个或多个具有双键的取代基(例如“氧代”或“=O”),其中,该结构可以仅显示作为与式(I)的核心结构的连接点的单键。本领域技术人员将理解,虽然仅显示单键,但对于那些取代基也意指双键。
如本文所用,参考本文提供的化学术语的定义,术语“等”意指本领域技术人员可以预期的化学结构的变体,包括但不限于异构体(包括链的、支化的或位置结构的异构体)、环系的水合(包括单环、二环或多环环结构的饱和或部分不饱和)和在可获得的化合价允许的情况下、产生稳定的化合物的所有其他变体。
为了本说明书的目的,当式(I)化合物或其形式的一个或多个取代基变体包括并入式(I)化合物中的官能团时,在所公开的化合物内任何位置出现的每个官能团可以是独立地选择的,并且是独立地和/或任选地被取代的(在适当时)。
如本文所用,术语“独立地选择”或“各自地选择”是指取代基列表中可以在式(I)的结构上出现多于一次的官能变体,每次出现的取代模式独立于任何其他出现的模式。此外,本文所述化合物的任何式或结构上使用通用取代基变体应理解为包括用包括在特定属中的种取代基替代通用取代基,例如,芳基可以用苯基或萘基等替代,并且所得化合物包括在本文所述化合物的范围内。
如本文所用,当在短语(例如,“...C3-14环烷基、C3-14环烷基-C1-4烷基、芳基、芳基-C1-4烷基、杂芳基、杂芳基-C1-4烷基、杂环基和杂环基-C1-4烷基)之前使用时,术语“…的每个实例”或“在每个实例中(当存在时)”意指C3-14环烷基、芳基、杂芳基和杂环基环系(当各自单独存在或作为取代基存在时)。
如本文所用,术语“任选地被取代”是指用指定的取代基变体、基团(group)、基团(radical)或部分任选的取代。
化合物形式
如本文所用,术语“形式”是指具有选自由以下组成的组的形式的式(I)化合物:其游离酸形式、游离碱形式、前药形式、盐形式、水合物形式、溶剂化物形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式、多晶型形式和互变异构体形式。
在本文所述的某些实施方式中,式(I)化合物的形式是其游离酸、游离碱或盐。
在本文所述的某些实施方式中,式(I)化合物的形式是其盐。
在本文所述的某些实施方式中,式(I)化合物的形式是其同位素体。
在本文所述的某些实施方式中,式(I)化合物的形式是其立体异构体、外消旋体、对映体或非对映体。
在本文所述的某些实施方式中,式(I)化合物的形式是其互变异构体。
在本文所述的某些实施方式中,式(I)化合物的形式是药学上可接受的形式。
在本文所述的某些实施方式中,式(I)化合物或其形式是分离的以供使用。
如本文所用,术语“分离的”是指根据本文所述的分离或纯化方法或本领域技术人员熟知的方法(例如,色谱法、重结晶等),从合成工艺(例如,从反应混合物)或天然来源或其组合中分离和/或纯化后的式(I)化合物或其形式的物理状态,其纯度足以通过本文所述的或本领域技术人员熟知的标准分析技术来表征。
如本文所用,术语“保护的”是指式(I)化合物或其形式中的官能团是经修饰的形式,以在化合物进行反应时防止在保护位点处的不希望的副反应。合适的保护基团是本领域技术人员以及参考标准教科书(例如,T.W.Greene等人,Protective Groups in organicSynthesis(1991),Wiley,纽约)所公认的。这些官能团包括羟基、酚基、氨基和羧酸。羟基或酚基的合适保护基团包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如,叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基、取代的苄基、甲基、甲氧基甲醇等。氨基、脒基和胍基的合适保护基团包括叔丁氧基羰基、苄氧基羰基等。羧酸的合适保护基团包括烷基酯、芳基酯或芳烷基酯。在某些情况下,保护基团也可以是聚合物树脂,例如Wang树脂或2-氯三苯甲基氯树脂。可以根据本领域技术人员熟知的以及如本文所述的标准技术添加或去除保护基团。本领域技术人员还将理解,尽管本文所述化合物的这种保护的衍生物可能自身不具有药理学活性,但它们可以施用给对象,然后在体内代谢以形成具有药理学活性的本文所述化合物。因此,这些衍生物可以描述为“前药”。本文所述化合物的所有前药都包括在本文所述用途的范围内。
如本文所用,术语“前药”是指在体内转化以产生式(I)的活性化合物或其形式的本发明(instant)化合物的形式(例如,药物前体)。转化可以通过各种机制(例如,通过代谢和/或非代谢化学过程)发生,例如通过血液、肝脏和/或其他器官和组织中的水解和/或代谢。以下提供了前药用途的讨论:T.Higuchi和W.Stella,“Pro-drugs as Novel DeliverySystems”,美国化学协会研讨会系列卷14,以及Bioreversible Carriers in DrugDesign,编者Edward B.Roche,美国药学会和培格曼出版社,1987年。
在一个示例中,当式(I)化合物或其形式含有羧酸官能团时,前药可以包含通过用官能团(例如烷基等)替代酸基团的氢原子而形成的酯。在另一示例中,当式(I)化合物或其形式含有羟基官能团时,可以通过用另一种官能团(例如烷基、烷基羰基或膦酸酯等)替代羟基的氢原子来制备前药形式。在另一示例中,当式(I)化合物或其形式含有胺官能团时,可以通过用官能团(例如烷基或取代的羰基)替代一个或多个胺的氢原子来制备前药形式。式(I)化合物或其形式的药学上可接受的前药包括被下列基团中的一种或多种取代的那些化合物:羧酸酯、磺酸酯、氨基酸酯、膦酸酯和单磷酸酯、二磷酸酯或三磷酸酯或烷基取代基(在适当时)。如本文所述,本领域技术人员应该理解,这些取代基中的一种或多种可以用于提供作为前药的式(I)化合物或其形式。
本文所述的一种或多种化合物可以以非溶剂化形式以及以与药学上可接受的溶剂(例如水、乙醇等)的溶剂化形式存在,并且本文的描述旨在包括溶剂化形式和非溶剂化形式。
如本文所用,术语“溶剂化物”是指本文所述化合物与一种或多种溶剂分子的物理缔合。该物理缔合涉及不同程度的离子键结合和共价键结合,包括氢键结合。在某些情况下,溶剂化物能够分离,例如当一种或多种溶剂分子掺入结晶固体的晶格中时。如本文所用,“溶剂化物”包括溶液相和可分离的溶剂化物。合适的溶剂化物的非限制性实例包括乙醇化物、甲醇化物等。
如本文所用,术语“水合物”是指其中溶剂分子是水的溶剂化物。
式(I)化合物可以形成盐,其旨在包括在本说明书的范围内。除非另有说明,否则本文提及的式(I)化合物或其形式应理解为包括提及其盐形式。本文所用的术语“盐”表示与无机酸和/或有机酸形成的酸式盐,以及与无机碱和/或有机碱形成的碱式盐。此外,当式(I)化合物或其形式含有碱性部分(例如但不限于胺部分)和酸性部分(例如但不限于羧酸)时,两性离子(“内盐”)可以形成并且包括在本文所用的术语“盐”中。
如本文所用,尽管其他盐也是有用的,术语“药学上可接受的盐”是指本文所述化合物的那些盐,其用于哺乳动物是安全和有效的(即,无毒、生理学上可接受的)并且具有生物活性。式(I)化合物的盐可以例如通过使式(I)化合物或其形式与一定量的酸或碱(例如等量)在介质(例如盐在其中沉淀的介质)中反应而形成,或在含水介质中反应、然后冻干而形成。
药学上可接受的盐包括存在于本文所述化合物中的一种或多种酸性基团或碱性基团的盐。酸加成盐的实施方式包括但不限于乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、氯化物、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、龙胆酸盐、葡糖酸盐、葡萄糖醛酸盐(glucaronate)、谷氨酸盐、碘化物、异烟酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、硝酸盐、草酸盐、双羟萘酸盐、泛酸盐、磷酸盐、丙酸盐、糖酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(也称为甲苯磺酸盐(tosylate))、三氟乙酸盐等。酸加成盐的某些实施方式包括氯化物、二氯化物、三氯化物、溴化物、乙酸盐、甲酸盐或三氟乙酸盐。
另外,以下讨论了通常认为适合于由碱性药物化合物形成药学上有用的盐的酸:例如,P.Stahl等人,Camille G.(编者)Handbook of Pharmaceutical Salts.Properties,Selection and Use.(2002)苏黎世:Wiley-VCH;S.Berge等人,Journal ofPharmaceutical Sciences(1977)66(1)1-19;P.Gould,International J.ofPharmaceutics(1986)33,201-217;Anderson等人,The Practice of MedicinalChemistry(1996),学术出版社,纽约;以及The Orange Book(美国食品药品监督管理局网站,华盛顿特区)。这些公开内容通过引入并入本文。
合适的碱式盐包括但不限于铝盐、铵盐、钙盐、锂盐、镁盐、钾盐、钠盐和锌盐。
所有这些酸式盐和碱式盐都旨在包括在如本文所述的药学上可接受的盐的范围内。此外,出于本说明书的目的,认为所有这些酸式盐和碱式盐等同于相应化合物的游离形式。
式(I)化合物及其形式还可以以互变异构形式存在。所有这些互变异构形式是预期的并且旨在包括在如本文所述式(I)化合物或其形式的范围内。
式(I)化合物或其形式可以含有不对称中心或手性中心,因此以不同的立体异构形式存在。本说明书旨在包括式(I)化合物的所有立体异构形式及其混合物,包括外消旋混合物。
本文所述化合物可以包括一个或多个手性中心,因此可以以外消旋混合物(R/S)或以基本上纯的对映体和非对映体存在。化合物也可以作为基本上纯的(R)或(S)对映体存在(当存在一个手性中心时)。在一个实施方式中,本文所述化合物是(S)异构体并且可以作为对映体纯的组合物(基本上仅包含(S)异构体)存在。在另一实施方式中,本文所述化合物是(R)异构体并且可以作为对映体纯的组合物(基本上仅包含(R)异构体)存在。如本领域技术人员将认识到的,当存在多于一个手性中心时,本文所述化合物还可以作为如IUPAC命名法所定义的(R,R)异构体、(R,S)异构体、(S,R)异构体或(S,S)异构体存在。
如本文所用,术语“基本上纯的”是指基本上由大于或等于90%的量的单一异构体、大于或等于92%的量的单一异构体、大于或等于95%的量的单一异构体、大于或等于98%的量的单一异构体、大于或等于99%的量的单一异构体、或等于100%的量的单一异构体组成的化合物。
在本说明书的一个方面,式(I)化合物或其形式是基本上纯的(S)对映体形式,其以大于或等于90%的量、大于或等于92%的量、大于或等于95%的量、大于或等于98%的量、大于或等于99%的量、或等于100%的量存在。
在本说明书的一个方面,式(I)化合物或其形式是基本上纯的(R)对映体形式,其以大于或等于90%的量、大于或等于92%的量、大于或等于95%的量、大于或等于98%的量、大于或等于99%的量、或等于100%的量存在。
如本文所用,“外消旋体”是非“对映体纯的”异构体形式的任何混合物,包括例如但不限于比例为约50/50、约60/40、约70/30、或约80/20的混合物。
此外,本说明书包括所有几何异构体和位置异构体。例如,如果式(I)化合物或其形式包含双键或稠合环,则顺式形式和反式形式以及混合物都包括在本说明书的范围内。非对映体混合物可以通过本领域技术人员熟知的方法(例如通过色谱法和/或分级结晶)基于它们的物理化学差异而分离成它们各自的非对映体。可以通过使用手性HPLC柱或本领域技术人员已知的其他色谱方法分离对映体。通过与适当的光学活性化合物(例如手性助剂,如手性醇或Mosher酸性氯化物)反应将对映体混合物转化为非对映体混合物、分离非对映体和转化(例如,水解)每个非对映体为相应的纯对映体,也可以分离对映体。此外,式(I)化合物中的一些可以是阻转异构体(例如,取代的联芳基)并且被认为是本发明的一部分。
本发明化合物(包括化合物的盐、溶剂化物、酯和前药以及前药的盐、溶剂化物和酯的那些)的所有立体异构体(例如,几何异构体、光学异构体等),例如由于各种取代基上的不对称碳原子而存在的那些,包括对映体形式(甚至在没有非对称碳的情况下可以存在)、旋转异构体形式、阻转异构体形式和非对映体形式,也包括在本发明的范围内,如同位置异构体(例如,4-吡啶基和3-吡啶基)一样。本文所述化合物的每个立体异构体可以例如基本上不含其他异构体,或可以存在于如上所述的外消旋体混合物中。
术语“盐”、“溶剂化物”、“酯”、“前药”等的使用旨在同样适用于本发明化合物的对映体、立体异构体、旋转异构体、互变异构体、位置异构体、外消旋体或同位素体的盐、溶剂化物、酯和前药。
术语“同位素体”是指同位素富集的本文所述化合物,其与本文所述的那些化合物相同,但是事实上一个或多个原子被原子质量或质量数不同于通常在自然界发现的原子质量或质量数的原子替代。可以包含到本文所述化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F、35C和36Cl,其各自也在本发明的范围内。
本文所述的某些同位素富集的化合物(例如,用3H和14C标记的那些)可用于化合物和/或底物组织分布测定。因为氚化(即,3H)同位素和碳-14(即,14C)同位素的易于制备和可检测性,它们是特别优选的。此外,用较重的同位素(例如氘(即2H))取代可以提供某些治疗优势,这是由于更高的代谢稳定性(例如,体内半衰期延长或剂量需求减少),因此在某些情况下会是优选的。
式(I)化合物的多晶型和无定形形式以及式(I)化合物的盐、溶剂化物、水合物、酯和前药进一步旨在包括在本发明中。
化合物用途
本发明涉及使用式(I)化合物或其形式在治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的化合物或其形式。
本发明还涉及式(I)化合物或其形式在治疗或改善有此需要的对象中的HD的用途。
本发明还涉及对HD具有活性的式(I)化合物或其形式的用途。
本发明还涉及式(I)化合物或其形式在组合疗法中以提供附加活性或协同活性的用途,从而能够开发用于治疗或改善HD的组合产品。
除单一治疗用途外,本发明化合物可用于与现有标准药剂的联合治疗,与一种或多种已知药剂具有附加活性或协同活性。
包含本文所述化合物和一种或多种已知药物的组合的组合疗法可以用于治疗HD,无论HD是否对已知药物有反应。
本发明的实施方式包括式(I)化合物或其形式在联合疗法中用于治疗或改善有此需要的对象中的HD的用途,该用途包括施用有效量的式(I)化合物或其形式和有效量的一种或多种药剂。
本发明的实施方式包括式(I)化合物或其形式在联合疗法中用于治疗或改善有此需要的对象中的HD的用途,该用途包括施用有效量的式(I)化合物或其形式和有效量的一种或多种药剂。
在本文提供的用途或方法的实施方式中,与一种或多种另外的药剂组合使用的式(I)化合物或其形式可以施用于对象或在施用于对象或患者之前、同时或之后、与对象或患者的细胞接触,或使细胞与另外的药剂接触。式(I)化合物或其形式和另外的药剂可以以单一组合物或不同组合物施用于对象或与细胞接触。在具体实施方式中,式(I)化合物或其形式与基因疗法组合使用以抑制HTT表达(使用例如病毒递送载体)或施用另一种小分子HTT抑制剂。在另一具体实施方式中,式(I)化合物或其形式与使用分化的非突变HTT干细胞的细胞替代组合使用。在另一具体实施方式中,式(I)化合物或其形式与使用分化的HTT干细胞的细胞替代组合使用。
在一个实施方式中,本文提供了式(I)化合物或其形式与支持性标准护理疗法(包括姑息护理)组合的用途。
本发明的实施方式包括式(I)化合物或其形式在制备试剂盒(包含式(I)化合物或其形式、和用于施用有效量的式(I)化合物或其形式和有效量的一种或多种在用于治疗或改善有此需要的对象中的HD的组合疗法中药剂的说明书)中的用途。
因此,本发明涉及式(I)化合物或其形式用于治疗或改善HD的用途。根据本发明的用途,确定了可用于选择性治疗或改善HD的化合物,并提供了这些化合物用于治疗或改善HD的用途。
本发明的用途的一个实施方式涉及式(I)化合物或其形式治疗或改善有此需要的对象中的HD的用途,该用途包括给对象施用有效量的式(I)化合物或其形式。
本发明的用途的一个实施方式涉及使用式(I)化合物或其形式治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的化合物。。
本发明的用途的实施方式涉及使用式(I)化合物或其形式治疗或改善有此需要的对象中的HD的方法,该方法包括给对象施用有效量的化合物。
本发明的用途的实施方式涉及式(I)化合物或其形式在制备用于治疗或改善有此需要的对象中的HD的药物中的用途,该用途包括给对象施用有效量的药物。
本发明的用途的实施方式涉及式(I)化合物或其形式在制备试剂盒(包含式(I)化合物或其形式、和用于施用治疗或改善有此需要的对象中的HD的化合物的说明书)中的用途。
在一个方面,对于这些实施方式中的每一个,对象是未经治疗的。在另一方面,对于这些实施方式中的每一个,对象是经治疗的。
如本文所用,术语“治疗”是指:(i)预防可能易患疾病、病症和/或症状但尚未被诊断为患有疾病、病症和/或症状的对象发生疾病、病症或症状;(ii)抑制疾病、病症和/或症状,即,阻止其发展;和/或(iii)缓解疾病、病症和/或症状,即,使得疾病、病症和/或症状消退。
如本文所用,术语“对象”是指动物或具有感觉和自主运动能力并且需要氧气和有机食物的任何活的生物体。非限制性实例包括人、灵长类动物、马、猪、牛、鼠科、家鼠、犬和猫科物种的成员。在一些实施方式中,对象是哺乳动物或温血脊椎动物。在其他实施方式中,对象是人。如本文所用,术语“患者”可以与“对象”和“人”互换使用。
如本文所用,术语“有效量”或“治疗有效量”是指式(I)化合物或形式、组合物或其药物有效抑制上述疾病并因此在有此需要的对象中产生期望的治疗、改善、抑制或预防作用的量。
施用以实现有效目标血浆浓度的剂量,还可以基于对象或患者的重量来施用。基于重量施用的剂量可以在以下范围内:约0.001mg/kg/天至约3500mg/kg/天、或约0.001mg/kg/天至约3000mg/kg/天、或约0.001mg/天至约2500mg/kg/天、或约0.001mg/kg/天至约2000mg/kg/天、或约0.001mg/kg/天至约1500mg/kg/天、或约0.001mg/kg/天至约1000mg/kg/天、或约0.001mg/kg/天至约500mg/kg/天、或约0.001mg/kg/天至约250mg/kg/天、或约0.001mg/kg/天至约100mg/kg/天、或约0.001mg/kg/天至约75mg/kg/天、或约0.001mg/kg/天至约50mg/kg/天、或约0.001mg/kg/天至约40mg/kg/天、或约0.001mg/kg/天至约30mg/kg/天、或约0.001mg/kg/天至约20mg/kg/天、或约0.001mg/kg/天至约10mg/kg/天、或约0.01mg/kg/天至约2000mg/kg/天、或约0.01mg/kg/天至约1500mg/kg/天、或约0.01mg/kg/天至约1000mg/kg/天、或约0.01mg/kg/天至约600mg/kg/天、或约0.01mg/kg/天至约500mg/kg/天、或约0.01mg/kg/天至约300mg/kg/天、或约0.015mg/kg/天至约200mg/kg/天、或约0.02mg/kg/天至约100mg/kg/天、或约0.025mg/kg/天至约100mg/kg/天、或约0.03mg/kg/天至约100mg/kg/天,其中,所述量根据对象重量每天口服施用一次(约24小时一次)、两次(约12小时一次)或三次(约8小时一次)。
在某些实施方式中,对于重量在约40kg至约200kg范围内的患者或对象以单次、分次或连续剂量(对于高于或低于该范围的患者或对象、尤其是40kg以下的儿童,可以调整剂量),有效量将在以下范围内:约0.001mg/kg/天至约500mg/kg/天、或约0.01mg/kg/天至约500mg/kg/天、或约0.1mg/kg/天至约500mg/kg/天、或约1.0mg/kg/天至约500mg/kg/天。典型的成年对象预期具有在约70kg的范围内的中位重量。
在基于对象或患者的重量调整日剂量的另一实施方式中,本文所述化合物可以配制为以约0.02mg/kg/天、约0.025mg/kg/天、约0.03mg/kg/天、约0.05mg/kg/天、约0.06mg/kg/天、约0.075mg/kg/天、约0.08mg/kg/天、约0.09mg/kg/天、约0.10mg/kg/天、约0.20mg/kg/天、约0.25mg/kg/天、约0.30mg/kg/天、约0.50mg/kg/天、约0.60mg/kg/天、约0.75mg/kg/天、约0.80mg/kg/天、约0.90mg/kg/天、约1.0mg/kg/天、约1.10mg/kg/天、约1.20mg/kg/天、约1.25mg/kg/天、约1.50mg/kg/天、约1.75mg/kg/天、约2.0mg/kg/天、约3.0mg/kg/天、约5.0mg/kg/天、约10mg/kg/天、约20mg/kg/天、约30mg/kg/天、约40mg/kg/天、约50mg/kg/天、约100mg/kg/天、约150mg/kg/天、约200mg/kg/天、约250mg/kg/天、约300mg/kg/天、约400mg/kg/天或约500mg/kg/天递送。基于对象或患者的重量调整的日剂量可以作为单次、分次或连续剂量施用。在化合物剂量每天给予超过一次的实施方式中,剂量可以每天施用两次、三次或更多次。
在本发明的范围内,用于制造药物、用于制备药物试剂盒或用于治疗或改善有此需要的对象中的HD的方法中的式(I)化合物或其形式的“有效量”旨在包括以下范围内的量:约0.001mg/kg/天至约3500mg/kg/天、或约0.001mg/kg/天至约3000mg/天、或约0.001mg/kg/天至约2500mg/kg/天、或约0.001mg/kg/天至约2000mg/kg/天、或约0.001mg/kg/天至约1500mg/kg/天、或约0.001mg/kg/天至约1000mg/kg/天、或约0.001mg/kg/天至约500mg/kg/天、或约0.001mg/kg/天至约250mg/kg/天、或约0.001mg/kg/天至约100mg/kg/天、或约0.001mg/kg/天至约75mg/kg/天、或约0.001mg/kg/天至约50mg/kg/天、或约0.001mg/kg/天至约40mg/kg/天、或约0.001mg/kg/天至约30mg/kg/天、或约0.001mg/kg/天至约20mg/kg/天、或约0.001mg/kg/天至约10mg/kg/天、或约0.01mg/kg/天至约2000mg/kg/天、或约0.01mg/kg/天至约1500mg/kg/天、或约0.01mg/kg/天至约1000mg/kg/天、或约0.01mg/kg/天至约600mg/kg/天、或约0.01mg/kg/天至约500mg/kg/天、或约0.01mg/kg/天至约300mg/kg/天、或约0.015mg/kg/天至约200mg/kg/天、或约0.02mg/kg/天至约100mg/kg/天、或约0.025mg/kg/天至约100mg/kg/天、或约0.03mg/kg/天至约100mg/kg/天,其中,所述量根据对象重量每天施用一次(约24小时一次;即“q.d.”)、两次(约12小时一次;即“b.i.d.”或“q.l2h”)、三次(约8小时一次;即“t.i.d.”或“q.8h”)或四次(约6小时一次;即“q.d.s.”、“q.i.d.”或“q.6h”)。
该量可以进一步包括以下范围内的量:每天施用约0.001mg至约3500mg的量;每天施用0.001mg至约3000mg;每天施用0.001mg至约2500mg;每天施用0.001mg至约2000mg;每天施用0.001mg至约1500mg;每天施用0.001mg至约1000mg;每天施用0.001mg至约500mg;每天施用0.001mg至约250mg;每天施用1.0mg至约3500mg;每天施用1.0mg至约1500mg;每天施用1.0mg至约1000mg;每日施用10.0mg至约600mg;每天施用0.5mg至约2000mg;或每天施用的量在约5.0mg至约300mg的范围内。
例如,有效量可以是治疗对象(更具体地,人)中的HD所需的量。对于对象的有效量将取决于各种因素,包括对象的体重、尺寸和健康状况。对于给定患者的有效量可以通过在临床医生的技能和判断范围内的常规实验来确定。
对于任何化合物,最初可以在细胞培养测定中或在相关的动物模型(例如小鼠、黑猩猩、绒猴或绢毛猴动物模型)中预估有效量。相关动物模型也可以用于确定合适的浓度范围和施用途径。然后,这些信息可以用于确定人施用的有用剂量和途径。治疗功效和毒性可以通过细胞培养物或实验动物中的标准药学方法测定,例如ED50(在50%的群体中治疗有效的剂量)和LD50(对50%的群体致死的剂量)。治疗作用和毒性作用之间的剂量比是治疗指数,并且可以表示为比例LD50/ED50。在一些实施方式中,有效量使得实现大的治疗指数。在进一步的实施方式中,剂量在包括毒性很小或没有毒性的ED50的循环浓度范围内。取决于所用的剂型、患者的敏感性和施用途径,剂量可以在该范围内变化。
更具体地,关于式(I)化合物或其形式观察到的浓度-生物效应关系表明,目标血浆浓度范围为约0.001μg/mL至约50μg/mL、约0.01μg/mL至约20μg/mL、约0.05μg/mL至约10μg/mL、或约0.1μg/mL至约5μg/mL。对于重量为约10kg至约100kg的患者(对于在该重量范围内的患者(特别是对于40kg以下的儿童),可以调整剂量),为了达到这种血浆浓度,取决于单次、分次或连续剂量的施用途径,本文所述化合物可以以变化的剂量(例如但不限于0.1ng至10000mg)施用。
根据与对象相关的因素,准确的剂量将由执业医师确定。可以调整剂量和施用以提供足够水平的活性剂或维持所期望的效果。可以考虑的因素包括疾病状态的严重程度、对象的一般健康状况、种族、年龄、体重、性别、饮食、当天的时间和施用频率、药物组合、反应敏感性、经历其他疗法、以及对治疗的耐受性/反应。取决于特定制剂的半衰期和清除率,长效药物组合物可以每2天、每3天或每4天施用、每周施用一次或每两周施用一次。
本文所述的化合物和组合物可以通过本领域已知的任何药物递送途径施用给对象。非限制性实例包括经口、经眼、直肠、口腔、局部、经鼻、舌下、透皮、皮下、肌内、静脉内(推注和输注)、脑内和肺部施用途径。
在一个方面,本文提供了用于调节HTT(亨廷顿蛋白)的量的方法,该方法包括使人细胞与式(I)化合物或其形式接触。在具体实施方式中,本文提供了调节HTT的量的方法,该方法包括使人细胞与调节HTT表达的式(I)化合物或其形式接触。人细胞可以在体外或体内(例如在非人动物内或在人体内)与式(I)化合物或其形式接触。在具体实施方式中,人细胞来自人或在人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中,HD由Htt基因中的CAG重复引起,导致HTT表达和/或功能丧失。在另一实施方式中,人细胞来自患有HD的人。在另一实施方式中,人细胞在患有HD的人体中。在一个实施方式中,化合物是式(I)化合物的形式。
在具体实施方式中,本文提供了用于增强从Htt基因转录的突变型HTT的抑制的方法,该方法包括使人细胞与式(I)化合物或其形式接触。人细胞可以在体外或体内(例如在非人动物内或在人体内)与式(I)化合物或其形式接触。在具体实施方式中,人细胞来自人或在人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中,HD由Htt基因中的CAG重复引起,导致野生型“正常”HTT表达和/或功能丧失。在另一实施方式中,人细胞来自患有HD的人。在另一实施方式中,人细胞在患有HD的人体中。在一个实施方式中,化合物是式(I)化合物的形式。
在另一方面,本文提供了用于调节从Htt基因转录的突变型HTT的抑制的方法,该方法包括向HD的非人动物模型施用式(I)化合物或其形式。在具体实施方式中,本文提供了用于调节从Htt基因转录的突变型HTT的抑制的方法,该方法包括向HD的非人动物模型施用式(I)化合物或其形式。在具体实施方式中,化合物是式(I)化合物的形式。
在另一方面,本文提供了用于降低突变型HTT量的方法,该方法包括使人细胞与式(I)化合物或其形式接触。在具体实施方式中,本文提供了用于降低突变HTT量的方法,该方法包括使人细胞与抑制突变型HTT(亨廷顿蛋白mRNA)从Htt基因转录的式(I)化合物接触。在另一具体实施方式中,本文提供了用于降低HTT量的方法,该方法包括使人细胞与抑制从Htt基因转录的突变型HTT的表达的式(I)化合物接触。人细胞可以在体外或体内(例如在非人动物内或在人体内)与式(I)化合物或其形式接触。在具体实施方式中,人细胞来自人或在人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中。在另一具体实施方式中,人细胞来自患有HD的人或在患有HD的人体中,HD由Htt基因中的CAG重复引起,导致HTT表达和/或功能丧失。在另一实施方式中,人细胞来自患有HD的人。在另一实施方式中,人细胞在患有HD的人体中。在一个实施方式中,化合物是式(I)化合物的形式。
在某些实施方式中,用式(I)化合物或其形式(单独或与另外的药剂组合)治疗或改善HD具有治疗效果和/或有益效果。在具体实施方式中,用式(I)化合物或其形式(单独或与另外的药剂组合)治疗HD导致以下效果中的一种、两种或更多种:(i)降低或改善HD的严重程度;(ii)延迟HD的发作;(iii)抑制HD的进展;(iv)减少对象的住院治疗;(v)减少对象的住院时间;(vi)增加对象的存活率;(vii)改善对象的生活质量;(viii)减少与HD有关的症状数量;(ix)减少或改善与HD相关的症状的严重程度;(x)减少与HD有关的症状的持续时间;(xi)预防与HD相关的症状再次发生;(xii)抑制HD症状的发展或发作;和/或(xiii)抑制与HD相关的症状的进展。
化合物的代谢物
还包括在本发明的范围内的是本文所述化合物的体内代谢产物的用途。这些产物可以例如由所施用化合物的氧化、还原、水解、酰胺化、酯化等产生,主要是由于酶促过程。因此,该说明书包括通过包括使本文所述化合物与哺乳动物组织或哺乳动物接触足以产生其代谢产物的一段时间的方法所产生的化合物的用途。
这些产物通常通过以下确定:制备本文所述化合物的放射性标记的同位素体(例如,14C或3H),给哺乳动物(例如大鼠、小鼠、豚鼠、狗、猴或人)施用可检测的剂量(例如,大于约0.5mg/kg)的放射性标记的化合物,允许足够时间以进行代谢(通常约30秒至约30小时),以及从尿液、胆汁、血液或其他生物样本确定代谢转化产物。转化产物是容易分离的,因为它们由于同位素富集而是“放射性标记的”(其它通过使用能够与在代谢物中存活的表位结合的抗体而分离)。以常规方式、例如通过MS或NMR分析来测定代谢物结构。通常,代谢物的分析可以以与本领域技术人员熟知的常规药物代谢研究相同的方式进行。转化产物(只要它们在体内没有被发现)可用于本文所述化合物的治疗剂量的诊断测定,即使它们不具有它们自身的生物活性。
药物组合物
本发明的实施方式包括式(I)化合物或其形式在用于治疗或改善有此需要的对象中的HD的药物组合物中的用途,该用途包括施用与一种或多种药学上可接受的赋形剂混合的有效量的式(I)化合物或其形式。
本发明的实施方式包括式(I)化合物或其形式的药物组合物在制备试剂盒中的用途,该试剂盒包含式(I)化合物或其形式的药物组合物以及用于施用治疗或改善有此需要的对象中的HD的化合物的说明书。
如本文所用,术语“组合物”是指包含特定量的特定成分的产品,以及直接或间接由特定量的特定成分的组合产生的任何产品。
药物组合物可以配制为达到生理学上相容的pH,范围为约pH 3至约pH 11。在一些实施方式中,药物组合物配制为达到约pH 3至约pH 7的pH。在其他实施方式中,药物组合物配制为达到约pH 5至约pH 8的pH。
术语“药学上可接受的赋形剂”是指用于施用药剂(例如本文所述化合物)的赋形剂。该术语是指可以在没有过度毒性的情况下施用的任何药物赋形剂。药学上可接受的赋形剂可以部分地由所施用的具体组合物以及具体的施用模式和/或剂型来确定。药学上可接受的赋形剂的非限制性实例包括载体、溶剂、稳定剂、佐剂、稀释剂等。因此,存在多种用于本文所述本发明化合物的药物组合物的合适制剂(参见例如Remington'sPharmaceutical Sciences)。
合适的赋形剂可以是载体分子,其包括大的、代谢缓慢的大分子,例如蛋白质、多糖、聚乳酸、聚乙醇酸、聚合氨基酸、氨基酸共聚物和无活性抗体。其他示例性赋形剂包括抗氧化剂,例如抗坏血酸;螯合剂,例如EDTA;碳水化合物,例如糊精、羟烷基纤维素、羟烷基甲基纤维素(例如,羟丙基甲基纤维素,也称为HPMC)、硬脂酸;液体,例如油、水、盐水、甘油和乙醇;润湿剂或乳化剂;pH缓冲物质;等等。脂质体也包括在药学上可接受的赋形剂的定义内。
本文所述的药物组合物可以以适合于本文所述预期用途的任何形式配制。用于口服施用的合适制剂包括固体、液体溶液、乳液和混悬液,而用于肺部施用的合适的可吸入制剂包括液体和粉末。替选的制剂包括糖浆、乳膏、软膏、片剂和冻干固体,该冻干固体可以在施用前用生理学相容的溶剂恢复原状。
当旨在用于口服使用时,可以制备例如片剂、锭剂(troche)、锭剂(lozenge)、水性或油性混悬液、非水溶液、可分散的粉末或颗粒(包括微粉化颗粒或纳米颗粒)、乳液、硬胶囊或软胶囊、糖浆或酏剂。旨在用于口服使用的组合物可以根据本领域已知的任何制造药物组合物的方法制备,并且这种组合物可以含有一种或多种试剂(包括甜味剂、调味剂、着色剂和防腐剂),以提供可口的制剂。
适合与片剂结合使用的药学上可接受的赋形剂包括例如,惰性稀释液,例如纤维素、碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;崩解剂,例如交联羧甲基纤维素钠、交联聚维酮、玉米淀粉、或海藻酸;粘合剂,例如聚维酮、淀粉、明胶或***胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过已知技术(包括微囊化以延迟在胃肠道中的崩解和吸收)包衣,从而提供更长时间的持续作用。例如,可以单独使用或与蜡一起使用延时材料(例如单硬脂酸甘油酯或二硬脂酸甘油酯)。
口服使用的制剂也可以呈现为硬明胶胶囊、其中活性成分与惰性固体稀释剂(例如纤维素、乳糖、磷酸钙或高岭土)混合,或呈现为软明胶胶囊、其中活性成分与非水性介质或油性介质(例如甘油、丙二醇、聚乙二醇、花生油、液体石蜡或橄榄油)混合。
在其他实施方式中,本文所述药物组合物可以配制为包含式(I)化合物或其形式与一种或多种适合于制造混悬液的药学上可接受的赋形剂混合的混悬液。在其他实施方式中,本文所述药物组合物可以配制为适合于通过添加一种或多种赋形剂制备混悬液的可分散粉末和颗粒。
适合用于与混悬液相关的赋形剂包括混悬剂,例如,羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶、***树胶;分散剂或润湿剂,例如,天然存在的磷脂(例如卵磷脂)、环氧烷与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如,十七烷氧基乙醇)、环氧乙烷与衍生自脂肪酸的偏酯和己糖醇酐的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯);以及增稠剂,例如,卡波姆、蜂蜡、硬石蜡或鲸蜡醇。混悬液还可以含有一种或多种防腐剂,例如乙酸、对羟基苯甲酸甲酯和/或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种调味剂;和一种或多种甜味剂,例如蔗糖或糖精。
本文所述的药物组合物还可以是水包油乳液的形式。油相可以是植物油、例如橄榄油或花生油,矿物油、例如液体石蜡,或这些的混合物。合适的乳化剂包括天然存在的树胶,例如***树胶和黄蓍胶;天然存在的磷脂,如大豆卵磷脂,衍生自脂肪酸的或酯偏酯;己糖醇单油酸酯等己糖醇酐;这些偏酯与环氧乙烷的缩合产物,如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可以含有甜味剂和调味剂。糖浆和酏剂可以用甜味剂(例如甘油、山梨糖醇或蔗糖)配制。这种制剂还可以含有缓和剂、防腐剂、调味剂或着色剂。
此外,本文所述药物组合物可以是无菌可注射制剂的形式,例如无菌可注射含水乳液或含油混悬液。这种乳液或混悬液可以根据已知技术使用上面提到的那些合适的分散剂或润湿剂和混悬剂配制。无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释液或溶剂中的无菌可注射溶液或混悬液,例如在1,2-丙二醇中的溶液。无菌可注射制剂也可以制备成冻干粉末。可以使用的可接受的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,无菌固定油可以用作溶剂或混悬介质。出于此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸(例如油酸)同样可以用于制备注射剂。
本文所述化合物可以基本上不溶于水并且微溶于大多数药学上可接受的质子溶剂和植物油,但通常可溶于中链脂肪酸(例如辛酸和癸酸)或甘油三酯和中链脂肪酸的丙二醇酯中。因此,在本发明中考虑的是通过使得它们更适合于递送(例如,增加溶解度、生物活性、适口性、减少不良反应等)的化学或生物化学部分的取代或添加来修饰的化合物,例如通过酯化、糖基化、聚乙二醇化等。
在一些实施方式中,本文所述化合物配制为用于在适合于低溶解度化合物的基于脂质的组合物中口服施用。基于脂质的制剂通常可以增强这些化合物的口服生物利用度。因此,本文所述药物组合物可以包含有效量的式(I)化合物或其形式以及至少一种选自中链脂肪酸或其丙二醇酯的药学上可接受的赋形剂(例如,可食用的脂肪酸(例如辛酸脂肪酸和癸酸脂肪酸)的丙二醇酯)和药学上可接受的表面活性剂(例如,聚山梨醇酯20或聚山梨醇酯80(也分别称为20或80)或聚氧乙烯40氢化蓖麻油)。
在其他实施方式中,可以使用粒度优化技术增强低溶解度化合物的生物利用度,该粒度优化技术包括使用本领域技术人员已知的技术制备纳米颗粒或纳米悬浮液。存在于这种制剂中的化合物形式包括无定形形式、部分无定形形式、部分结晶形式或结晶形式。
在替选实施方式中,药物组合物可以进一步包含一种或多种水溶性增强剂,例如环糊精。环糊精的非限制性实例包括α-环糊精、β-环糊精和γ-环糊精的羟丙基、羟乙基、葡糖基、麦芽糖基和麦芽三糖基衍生物,和羟丙基-β-环糊精(HPBC)。在一些实施方式中,药物组合物还包含在约0.1%至约20%、约1%至约15%、或约2.5%至约10%的范围内的HPBC。所用溶解度增强剂的量可以取决于组合物中化合物的量。
化合物的制备
本文提供的化合物可以由本领域技术人员制备,例如通过2014年2月20日公开的国际申请公开号WO2014/028459 A1、2014年7月31日公开的国际申请公开号WO2014/116845A1、2014年2月5日公开的国际申请公开号WO2015/017589 A1提出的合成方法制备,其各自通过引用并入本文。
一般方案
以下反应方案举例说明了制备本文所述化合物的方法。应该理解,本领域技术人员将能够通过类似方法或通过本领域技术人员已知的方法制备这些化合物。
通常,起始组分和试剂可以从各种来源(例如商业供应商)商购获得、根据本领域技术人员已知的方法合成、或如本文描述地制备。应该理解,在以下说明书中,仅当所描述的式的取代基和/或变体的组合的结果产生稳定的化合物时,才允许该组合。
通常,本文所述式(I)化合物可以按照以下方案1的一般流程合成。
方案1
方案1的一般流程
用于上述反应方案的原料可商购获得、或可以根据本领域技术人员已知的方法或通过本文公开的方法制备。通常,本文所述化合物在上述反应方案1中如下制备:使用置换或金属介导的交叉偶联反应(例如Buchwald反应),卤代化合物Ia(其中,Hal是选自溴或氯的卤素)与化合物1b(其中,H是胺或醇X官能团中的活泼氢原子,其中,式(I)化合物的X和B如本文所述)反应,以提供中间体化合物1c。化合物1c继续进行,并且使用过渡金属介导的交叉偶联反应(例如Suzuki反应)与硼酸或硼酸酯化合物1d反应(其中,B代表硼原子,R代表酸或酯官能团或形成环系(当与硼一起时),式(I)化合物的A如本文所述),以提供式(I)化合物。
以互补的方式,式(I)化合物也可以以相反的顺序合成,其中,硼酸酯化合物1d首先与化合物1a反应,然后中间体与胺化合物1b反应。其他变化(代表用于取代化合物1a上的硼酸酯化合物1d和胺化合物1b中的一种或两种的不同组合)旨在包括在本文所述的合成方法的范围内。
具体实施例
为了帮助理解本发明,包括以下具体实施例。当然,与本发明相关的实验不应该解释为具体地限制本发明,并且认为现在已知或以后开发的变化(其在本领域技术人员的认知范围内)落入如本文所述和下文要求保护的发明的范围内。
除了在工作实施例中之外,除非另有说明,否则说明书和权利要求中使用的表示材料数量、试剂数量、反应条件、实验数据等的所有数字应该理解为由术语“约”修饰。因此,所有这些数字代表可以根据试图通过反应获得的所期望性质或作为可变实验条件的结果而变化的近似值。因此,在实验可再现性的预期范围内,在所得数据的上下文中,术语“约”是指所提供的可以根据与平均值的标准偏差而变化的数据的范围。同样,对于所提供的实验结果,可以将得到的数据上舍入或下舍入以一致地呈现数据,而不会丢失有效数字。至少,并且不是将等同原则的应用限制在权利要求的范围内的尝试,每个数值参数应该根据有效数字的数量和普通的舍入技术来解释。
虽然阐述发明的宽范围的数值范围和参数是近似值,但是工作实施例中列出的数值是尽可能精确地报告的。然而,任何数值固有地包含必然由其各自的测试测量中发现的标准偏差引起的某些误差。
用于产物纯化的柱色谱***是ISCO CombiFlashTM牌色谱***(由Teledyne Isco制造)。
合成实施例
参考以下非限制性实施例提供了本发明的更多细节,提供这些实施例以更全面地举例说明本发明,但不应该解释为限制其范围。实施例举例说明了本文所述某些化合物的制备,以及这些化合物在体外和/或体内的测试。本领域技术人员将理解,这些实施例中描述的技术代表本发明人描述的在本发明的实践中很好地起作用的技术,并且因此构成了其实践的优选模式。然而,根据本公开内容,本领域技术人员应该理解,在不脱离本发明的精神和范围的情况下,可以对所公开的具体方法进行许多改变并仍然获得相同或相似的结果。
如上所用,并且在整个说明书中,除非另有说明,否则以下缩写应该理解为具有以下含义:
实施例1(化合物411)
2-{6-[8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚盐酸盐
步骤1:将3,6-二溴哒嗪(133.7mg,0.56mmol)、(1R,5S)-3-(甲基氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(85mg,0.28mmol)和DIPEA(0.15mL,0.84mmol)在1mL ACN中混合并加热至100℃保持1小时,直至LC-MS显示原料完全消耗。将反应混合物浓缩并通过柱色谱法纯化:用CH2Cl2/MeOH(0%至30%的MeOH)梯度洗脱,柱:二氧化硅4g,得到(1S,5R)-3-[(6-溴哒嗪-3-基)-甲基-氨基]-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(55mg,收率49.25%)。
步骤2:将3-[(6-溴哒嗪-3-基)-甲基-氨基]-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(55mg,0.14mmol)、4-[3-(甲氧基甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基]-1-四氢吡喃-2-基-吡唑(68.82mg,0.17mmol)、Pd(dppf)Cl2(10.34mg,0.01mmol)、K2CO3(57.98mg,0.42mmol)在舒伦克管中混合。将反应物用N2脱气15分钟,加入二噁烷(2mL)和水(0.5mL),将反应物加热至90℃保持16小时。将反应物冷却至室温,在EtOAc和水之间分层。将有机层经Na2SO4干燥,在真空下浓缩,通过柱色谱法纯化:用CH2Cl2/EtOAc(0%至80%)梯度洗脱,柱:二氧化硅4g,得到棕褐色固体(1S,5R)-3-[[6-[2-(甲氧基甲氧基)-4-(1-四氢吡喃-2-基吡唑-4-基)苯基]哒嗪-3-基]-甲基-氨基]-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(52mg,62%)。
步骤3:向(1S,5R)-3-[[6-[2-(甲氧基甲氧基)-4-(1-四氢吡喃-2-基吡唑-4-基)苯基]哒嗪-3-基]-甲基-氨基]-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(52mg,0.086mmol)的1mL CH2Cl2和0.5mL MeOH混合物溶液中加入1,4-二噁烷(0.06mL)中的HCl(4mol/L)。将反应物搅拌过夜。过滤沉淀物,然后真空干燥,得到黄色固体2-[6-[8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基]-5-(1H-吡唑-4)基)苯酚盐酸盐(15mg,收率42.25%)。
LC-MS:377[M+H]+.1H NMR(500MHz,DMSO-d6)δ:9.37-9.51(m,IH),8.87-8.96(m,IH),8.31(d,J=9.8Hz,IH),8.12(s,2H),7.74(d,J=8.2Hz,2H),7.19-7.27(m,2H),4.80-4.92(m,IH),4.08-4.14(m,3H),3.07(s,3H),2.30(td,J=12.6,2.8Hz,2H),1.99-2.15(m,4H),1.74-1.87(m,2H)
使用以上实施例1所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例2(化合物416)
5-(5-甲基-1H-吡唑-4-基)-2-{6-[甲基(2,2,6,6-四甲基哌啶4-基)氨基]哒嗪-3-基)苯酚
步骤1:将3-甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基三氟甲磺酸盐(80mg,0.16mmol)、(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡唑-1-羧酸叔丁酯(59mg,0.19mmol)、Pd(dppf)Cl2(7mg,0.01mmol)、K2CO3(66mg,0.48mmol)在舒伦克管中混合。将反应物用N2脱气15分钟,加入二噁烷(2mL)和水(0.5mL),将反应加热至90℃保持16小时。将反应物冷却至室温,在EtOAc和水之间分层。有机层经Na2SO4干燥,在真空下浓缩,然后通过柱色谱法纯化:用CH2Cl2/MeOH(0%至30%的MeOH)梯度洗脱,柱:二氧化硅4g,得到浅棕色固体4-(3-甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-3-甲基-1H-吡唑-1-羧酸叔丁酯(46mg,54%)。
步骤2:将4-(3-甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-3-甲基-1H-吡唑-1-羧酸叔丁酯(46mg,0.09mmol)的2mL无水CH2Cl2溶液在冰水浴中冷却。加入CH2Cl2中的1.0M三溴化硼(0.45mL,0.45mmol),将反应混合物在室温下搅拌16小时。用2mL MeOH淬灭反应,搅拌30分钟,然后浓缩并通过柱色谱纯化:用CH2Cl2/MeOH(2.5%的NH4OH)(0%至30%的MeOH/NH4OH)梯度洗脱,柱:二氧化硅4g,得到黄色固体2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(3-甲基-1H-吡唑-4-基)叔丁基苯酚(20mg,55%)。
LC-MS:421[M+H]+.1H NMR(500MHz,DMSO-d6)δ:13.74(s,1H),12.63-12.71(m,1H),8.20(d,J=9.5Hz,1H),8.03-8.04(m,1H),7.86(d,J=8.0Hz,1H),7.73-7.75(m,1H),7.36(d,J=9.5Hz,1H),7.03-7.06(m,2H),4.90-5.05(m,1H),2.92(s,3H),2.43(s,3H),1.43-1.54(m,2H),1.15-1.43(m,2H),1.14(s,6H),1.09(s,6H)
使用以上实施例2所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例3(化合物419)
2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚二盐酸盐
步骤1:将3-甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基三氟甲磺酸酯(335mg,0.67mmol)、4-硝基-lH-吡唑(340mg,4.5mmol)、Pd2(dba)3(67mg,0.07mmol)、Me4tBu-XPhos(35mg,0.07mmol)、K3PO4(368mg,1.73mmol)在舒伦克管中混合。将反应物用N2脱气15分钟,加入二噁烷(8mL),将反应物加热至90℃保持16小时。将反应物冷却至室温,通过硅藻土过滤,浓缩,通过柱色谱纯化:用CH2Cl2/MeOH(0%至30%的MeOH)梯度洗脱,柱:二氧化硅12g,得到6-(2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(202mg,65%)。
LC-MS:466[M+H]+.1H NMR(500MHz,DMSO-d6)δ:9.81-9.85(m,IH),8.61(d,J=0.6Hz,IH),7.91(d,J=8.5Hz,IH),7.81(d,J=9.8Hz,IH),7.73(d,J=1.9Hz,IH),7.68(dd,J=8.2,2.2Hz,IH),7.10-7.21(m,IH),5.08-5.26(m,IH),3.96(s,3H),2.95(s,3H),1.59-1.75(m,4H),1.40(s,6H),1.33,(s,6H),(未观察到对应于OH或NH的1个H)
步骤2:将6-(2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(150mg,0.32mmol)、苯硫酚(33μL,0.32mmol)和K2CO3(44mg,0.32mmol)在微波管中混合。将反应物用N2脱气15分钟,加入无水NMP(1.5mL)。将反应物在Biotage微波中在190℃下加热20分钟,然后用10mL EtOAc稀释,并用水和盐水洗涤。将产物经Na2SO4干燥,在真空下浓缩,然后通过柱色谱法纯化:用CH2Cl2/MeOH(0%至30%的MeOH)梯度洗脱,柱:二氧化硅4g,得到棕色固体2-(6-(甲基)(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(4-硝基-1H-吡唑-1-基)苯酚(60mg,42%)。
LC-MS:452[M+H]+.1H NMR(500MHz,DMSO-d6)δ:9.77(s,1H),8.68(d,J=9.8Hz,1H),8.62(s,1H),8.27(d,J=8.8Hz,1H),7.87-7.94(m,1H),7.66(dd,J=8.5,2.6Hz,1H),7.64(d,J=2.6Hz,1H),5.03-5.22(m,1H),3.01(s,3H),1.84-1.94(m,2H),1.70-1.77(m,2H),1.53(s,6H),1.43(s,6H),(未观察到对应于OH和NH的2个氢)
使用以上实施例3所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例4(化合物424)
5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚三盐酸盐
步骤1:将3-溴代-6-(2-甲氧基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哒嗪(100mg,0.24mmol)、(1-(叔丁氧基羰基)-1,2,3,6-四氢吡啶-4-基)硼酸(66mg,0.29mmol)、PddppfCl2(8mg,0.012mmol)、K2CO3(99mg,0.72mmol)在舒伦克管中混合。将反应物用N2脱气15分钟,加入二噁烷(2mL)和水(0.5mL),将反应物加热至90℃保持16小时。将反应物冷却至室温,在EtOAc和水之间分层。将有机层经Na2SO4干燥,然后在真空下浓缩,通过柱色谱法纯化:用CH2Cl2/MeOH(0%至20%的MeOH)梯度洗脱,柱:二氧化硅4g,得到灰白色固体5-(1H-吡唑-4-基)-2-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)苯酚(102mg,82%)。
步骤2:将5-(1H-吡唑-4-基)-2-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)苯酚(102mg,0.196mmol)的2mL无水CH2Cl2溶液在冰水浴中冷却。加入1.0M溴代三溴化物的CH2Cl2溶液(0.98mL,0.98mmol),将反应混合物在室温下搅拌16小时。将反应用2mL MeOH淬灭,搅拌30分钟,然后浓缩并使用制备型HPLC纯化,得到灰白色固体5-(1H-吡唑-4-基)-2-(6-(1,2,3,6-)四氢吡啶-4-基)哒嗪-3-基)苯酚(41mg,66%)。
LC-MS:320[M+H]+.1H NMR(500MHz,DMSO-d6)δ:9.19(br S,2H),8.54(d,J=9.6Hz,1H),8.22,(d,J=9.6Hz,1H),8.18(s,1H),8.05(d,J=8.8Hz,1H),7.25-7.29(m,2H),6.92(s,1H),3.85-3.92(m,2H),3.38-3.41(m,2H),2.88-2.98(m,2H),(未观察到对应于OH或NH的1个氢)
使用以上实施例4所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例5(化合物427)
2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
步骤1:将3,6-二溴代哒嗪(500mg,2.1mmol)、4-(3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑(970mg,2.52mmol)、Pd(dppf)Cl2(77mg,0.11mmol)、K2CO3(870mg,6.3mmol)在舒伦克管中混合。将反应物用N2脱气15分钟,加入二噁烷(8mL)和水(1mL),将反应物加热至90℃保持16小时。将反应物冷却至室温,在EtOAc和水之间分层。将有机层经Na2SO4干燥,在真空下浓缩,通过柱色谱法纯化:用己烷/EtOAc(0%至40%的EtOAc)梯度洗脱,柱:二氧化硅4g,得到灰白色蓬松固体3-溴代-6-(2-甲氧基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哒嗪(690mg,79%)。
步骤2:将3-溴代-6-(2-甲氧基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哒嗪(50mg,0.12mmol)、4-氨基哌啶-1-羧酸叔丁酯(36mg,0.18mmol)、叔丁醇钾(41mg,0.36mmol)、tBuXPhos-Pd-G3(10mg,0.012mmol)在舒伦克管中混合。将反应物用Ar脱气,然后加入无水THF(2mL),将反应物加热至80℃保持12小时。将反应物冷却至室温,然后在EtOAc和水之间分层。将有机层经Na2SO4干燥,在真空下浓缩,通过柱色谱法纯化:用CH2Cl2/MeOH(0%至15%的MeOH)梯度洗脱,柱:二氧化硅4g,得到棕褐色固体4-((6-(2-甲氧基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哒嗪-3-基)氨基)哌啶-1-羧酸叔丁酯(45mg,70%)。
步骤3:将4-((6-(2-甲氧基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哒嗪-3-基)氨基)哌啶-1-羧酸酯(45mg,0.084mmol)的2mL无水CH2Cl2溶液在冰水浴中冷却。加入1.0M三溴化硼的CH2Cl2溶液(0.42mL,0.42mmol),将反应混合物在室温下搅拌16小时。用2mL MeOH淬灭反应,搅拌30分钟,然后浓缩,使用制备型HPLC纯化,得到淡黄色固体2-(6-(哌啶-4-基氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚(21mg,73%)。
LC-MS:377[M+H]+.1H NMR(500MHz,DMSO-d6)δ:8.95(s,2H),8.25(d,J=9.6Hz,1H),8.09(s,2H),7.69(d,J=8.8Hz,1H),7.49-7.41(m,1H),7.21-7.24(m,2H),4.11-4.15(m,1H),3.34-3.39(m,4H),3.01-3.08(m,2H),2.11-2.17(m,2H),1.79(q,J=9.2Hz,2H)
使用以上实施例5所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例6(化合物430)
6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
步骤1:向配备有N2入口的RBF中加入:6-溴-N-甲基-N-(2,2,6,6-四甲基-4-哌啶基)哒嗪-3-胺(90mg,0.28mmol)、4-[2,3-二氟代-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基]-1-四氢吡喃-2-基-吡唑(128.8mg,0.33mmol)、Pd(PPh3)4(31.8mg,0.03mmol)、Na2CO3(87.43mg,0.83mmol)。将反应物用N2脱气15分钟,然后加入二噁烷(8mL)和水(2mL)。将反应加热至90℃保持16小时,然后冷却至室温,并在EtOAc和水之间分层。将有机层经Na2SO4干燥,在旋转蒸发仪上浓缩,并通过柱色谱法纯化:用CH2Cl2/MeOH(0%至30%)梯度洗脱,柱:二氧化硅4g,得到灰色固体6-(2,3-二氟代-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(88mg,63%)。
步骤2:将6-[2,3-二氟代-4-(1-四氢吡喃-2-基吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基-4-哌啶基)哒嗪-3-胺(88mg,0.17mmol)溶解在MeOH(2mL)中,滴加4M HCl的二噁烷溶液(90μL,0.34mmol)。将反应混合物在室温下搅拌30分钟,直到LC-MS显示原料完全消耗。减压浓缩反应混合物,得到6-(2,3-二氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶)-4-基)哒嗪-3-胺盐酸盐。
LC-MS:427[M+H]+.1H NMR(500MHz,DMSO-d6)δ:9.21-9.33(m,IH),8.27-8.43(m,IH),8.20(s,2H),8.01(d,J=9.8Hz,IH),7.60-7.79(m,3H),5.01-5.14(m,IH),3.05(s,3H),2.10(td,J=13.2,1.6Hz,2H),1.79(dd,J=12.9,4.1Hz,2H),1.55(s,6H),1.50(s,6H)
使用以上实施例6所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
实施例7(化合物434)
6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
将6-(2-甲氧基-6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(6mg)溶于1mL 4N HCl/二噁烷中,并将得到的混合物在室温下搅拌20分钟。蒸发混合物,用***研磨,得到6-(2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-)四甲基哌啶-4-基)哒嗪-3-胺(4mg,75%)。
LC-MS:422[M+H]+.1H NMR(500MHz,甲醇-d4)δ:8.42-8.47(m,1H),8.33-8.42(m,2H),8.09-8.17(m,1H),7.99-8.08(m,1H),7.50-7.56(m,1H),5.0(m,1H),4.16(s,3H),3.20(s,3H),1.94-2.15(m,4H),1.65(s,6H),1.57(s,6H)
实施例8(化合物460)
3-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-6-(lH-吡唑-4-基)吡啶-2-醇盐酸盐
步骤1:将6-氯代-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(280mg,1.0mmol)溶于10mL二噁烷和水(4:1)的混合物中。向该溶液中加入碳酸钠(190mg,3当量)、(6-氯代-2-甲氧基吡啶-3-基)硼酸(190mg,1当量)和Pd(Ph3P)4(70mg,0.1当量)。将反应混合物在90℃下搅拌16小时,然后应用于柱并使用DCM/MeOH纯化,得到(133mg,55%)6-(6-氯代-2-甲氧基吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺。
LC-MS:390[M+H]+.1H NMR(500MHz,DMSO-d6)δ:8.25(d,J=7.88Hz,
1H),7.83(d,J=9.77Hz,1H),7.24(d,J=7.88Hz,1H),7.11(d,J=9.77Hz,1H),5.00-5.24(m,1H),3.93(s,3H),2.87-2.96(m,3H),1.40-1.57(m,4H),1.21-1.29(m,7H),1.10(br s,6H)
步骤2:将6-(6-氯代-2-甲氧基吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(90mg)溶于二噁烷和水(4:1,5mL)的混合物中。向该溶液中加入碳酸钠(100mg,3当量)、1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡唑(70mg,1.1当量)和Pd(Ph3P)4(27mg,0.1当量)。将反应混合物在90℃下搅拌16小时,然后使用DCM/MeOH通过柱色谱法纯化,得到80mg(68%)的6-(2-甲氧基-6-(1-(四氢-2H-吡喃)-2-基)-1H-吡唑-4-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺。
步骤3:将6-(2-甲氧基-6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(45mg)溶于4mL的4N HCl/二噁烷中,并将所得混合物在60℃F下加热2小时。蒸发所得混合物并用***研磨,得到3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-6-(1H-吡唑-4-基)吡啶-2-醇(24mg,61%)。
LC-MS:408[M+H]+;1H NMR(500MHz,甲醇-d4)δ:8.62-8.69(m,1H),8.55-8.61(m,1H),8.39(s,2H),7.95-8.06(m,1H),7.04-7.14(m,1H),5.02-5.24(m,1H),3.18(s,3H),2.03(s,4H),1.67(s,6H),1.57(s,6H)
使用以上实施例8所述流程,可以通过取代适当的原料试剂和反应条件制备本文所述另外化合物,得到例如选自下列化合物的化合物:
生物学实施例
以下体外生物学实施例证明了本发明的化合物用于治疗亨廷顿病的有效性。
为了更详细地描述并帮助理解本发明,提供以下非限制性生物学实施例以更全面地举例说明本发明的范围,而不应解释为具体限制其范围。认为现在已知或以后开发的本发明的这些变化(在本领域技术人员的认知范围内确定)落入本发明的范围内并且如下文中所要求保护。
实施例1
Meso Scale Discovery(MSD)测定的开发和验证以定量突变型亨廷顿蛋白和总亨廷顿蛋白(HTT)-内源性HTT检测的最佳配对分析
为了确定用于HTT减少的口服生物可利用小分子,需要高通量ELISA法以检测和测量来自HD患者和动物模型的细胞和组织中的总HTT(野生型和突变型)(tHTT)和突变型HTT(mHTT)。本文描述的方法允许来自HD患者和在HD动物模型中的细胞和组织中的tHTT和mHTT水平的相对高通量蛋白质测量。本文所述ELISA法能够筛选分子降低HTT水平的能力,并确定和优化用于治疗HD的小分子。
为了确定以灵敏、高通量形式检测HTT(野生型和突变型)的抗体组合,筛选了捕获/检测组合的多种市售抗体(表1)。
用于检测细胞中总HTT和突变型HTT的抗体比较的最佳配对分析方案
1.将细胞在细胞培养相容的96孔板中培养。
2.除去培养基,向细胞加入每孔50μl至100μl裂解缓冲液(下述组合物)以提供“细胞裂解物”。在4℃下将板置于振荡器上30分钟,然后储存在-20℃。
3.如板布局中所述,通过在PBS中稀释用于标准板的捕获抗体来制备捕获抗体稀释液,然后每孔加入30μl捕获抗体稀释液。将板密封并在4℃下温育过夜。
4.将板用200μl洗涤缓冲液洗涤3次。加入封闭缓冲液(每孔150μl),然后将板密封并在板振荡器上在室温(RT)下温育3小时至4小时。
5.倾倒封闭缓冲液,用200μl洗涤缓冲液洗涤板3次。然后加入细胞裂解物(每孔25μL)。将板密封并在4℃下温育过夜。
6.通过在测定抗体稀释液中稀释用于配对的第一检测抗体来制备第一检测抗体稀释液。将板用200μl洗涤缓冲液洗涤3次,然后每孔加入25μl第一次检测抗体稀释液。将板密封并在板振荡器上在室温下温育1小时。
7.通过在测定抗体稀释液中稀释用于配对的第二检测抗体来制备第二检测抗体稀释液。将板用200μL洗涤缓冲液洗涤3次,然后每孔加入25μl第二检测抗体稀释液。将板密封并在板振荡器上在室温下温育1小时。
8.将读取缓冲液稀释4倍。将板用200μl洗涤缓冲液洗涤3次,然后每孔加入150μL读取缓冲液。随后立即读取该板。
表1中显示了在最佳配对分析中筛选的各种市售抗体,提供了不同的捕获/检测组合。表2中显示了评估的捕获/检测抗体对。给出最大传播值(更高信噪比)的两个抗体对选为用于延伸的多聚谷氨酰胺(mHTT)和全人HTT检测。
表1
表2
最佳配对捕获/检测抗体对的特征是提供最小背景和最大信号的那些组合。这种高灵敏度的ELISA测定可以用于在筛选试剂(小分子和大分子和基因疗法)的药物发现的背景下检测HTT,并用于在临床研究中检测作为生物标志物的HTT。用于定量总HTT的这种捕获/检测抗体对选自MAB2166/MAB2174和MAB2166/#5656S。用于定量突变型HTT的这种捕获/检测抗体对选自MAB1574/#5656S、P1874/#5656S和MW1/#5656S。来自该分析的用于mHTT的抗体对(MW1/#5656S)和用于总HTT的另一抗体对(MAB2166/#5656S)进一步被优化和验证,以提供能够在患者成纤维细胞和淋巴细胞中进行HTT检测的高通量测定。
使用表2中确定的最佳配对抗体开发了实施例2中使用的内源性亨廷顿蛋白质测定,其为多细胞体系中的延伸的多聚谷氨酰胺(mHTT)和总人HTT提供高灵敏度、高通量的检测测定。用于测定的平台是基于ELISA的Meso Scale Discovery(MSD)电化学发光测定平台。
实施例2
内源性亨廷顿蛋白质测定
Meso Scale Discovery(MSD)96孔板或384孔板在4℃下用在PBS(30μL每孔)中浓度为1μg/mL的MW1(延伸的多聚谷氨酰胺)或MAB2166单克隆抗体(用于捕获)涂覆过夜。然后将板用300μl洗涤缓冲液(0.05%Tween-20的PBS溶液)洗涤三次,在室温下旋转振荡封闭(100μl封闭缓冲液;5%BSA的PBS溶液)4小时至5小时,然后用洗涤缓冲液洗涤三次。
将样品(25μL)转移至涂覆有抗体的MSD板上,并在4℃下温育过夜。去除裂解物后,将板用洗涤缓冲液洗涤三次,并将25μL#5656S(细胞信号传导;兔单克隆)第二抗体(在0.05%Tween-20的封闭缓冲液中稀释至0.25μg/mL)加入每个孔中并在室温下振荡温育1小时。在用第二抗体温育后,用洗涤缓冲液冲洗孔,之后将25μL山羊抗兔SULFO TAG第二检测抗体(MSD***的必需方面)(在0.05%Tween-20的封闭缓冲液中稀释至0.25μg/mL)加入每个孔中并在室温下振荡温育1小时。在用洗涤缓冲液冲洗三次后,向每个空的孔中加入150μL具有表面活性剂(MSD)的读取缓冲液T,并且根据提供的96孔板或384孔板制造商说明书,在SI 6000成像仪(MSD)上使该板成像。所测试化合物的所得IC50值(μM)显示在表3中。
如表3中所示,本文所述测试化合物具有以下IC50值,单个星(*)表示在>3μM和≤9μM之间的IC50值,两个星(**)表示在>1μM和≤3μM之间的IC50值,三个星(***)表示在>0.5μM和≤1μM之间的IC50值,四个星(****)表示在在>0.1μM和≤0.5μM之间IC50值,五个星(*****)表示≤0.1μM的IC50值。
表3
不考虑本文引用的文献是否明确地和单独地如通过引用并入的指出,本文提及的所有文献均出于任何和所有目的以如同每个单独的参考文献在本文中完全阐述相同的程度通过引用并入到本申请中。
现在已经充分描述了权利要求的主题,本领域技术人员将理解,可以在宽范围的等同物内执行同样的操作而不影响本文描述的主题或实施方式的范围。所附权利要求旨在被解释为包括所有这些等同物。
Claims (22)
1.一种用于治疗或改善有此需要的对象中的HD的方法,所述方法包括给所述对象施用有效量的式(Ia)化合物或其形式:
其中,
X是CH2、O、NR5、或键;
A是芳基、杂芳基、杂环基、或C9-10环烷基,其中:
芳基选自被1个、2个、3个或4个各自选自R1和羟基的取代基取代的苯基和任选地被1个、2个、3个或4个各自选自R1和羟基的取代基取代的萘基,
杂芳基是单环、二环或多环芳香族碳原子环结构基团,具有选自O、S和N的一个或多个杂原子,每个所述芳香族碳原子环结构基团任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R1,
杂环基是饱和的或部分不饱和的单环、二环或三环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R2,和
C9-10环烷基是饱和的或部分不饱和的二环环系,所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R2;
B是单环杂环基,其中,杂环基是饱和的或部分不饱和的环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R4;
R1是卤素、氰基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,其中:
杂芳基是单环、二环或多环芳香族碳原子环结构基团,具有选自O、S和N的一个或多个杂原子,
杂环基是饱和的或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个所述取代基选自R3;
R2是卤素、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基、或杂环基-C1-4烷基,其中:
杂环基是饱和的或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
杂环基的每个实例任选地被1个或2个取代基取代,每个所述取代基选自R3;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4-烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;
R4独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;和
R5是氢、C1-4烷基、或羟基-C1-4烷基;
其中,所述化合物的形式选自由以下组成的组:其盐形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
2.根据权利要求1所述的方法,
其中,
X是CH2、O、NR5、或键;
A是芳基、杂芳基、杂环基、或C9-10环烷基,
其中,芳基选自被1个、2个、3个或4个各自选自R1和羟基的取代基取代的苯基和任选地被1个、2个、3个或4个各自选自R1和羟基的取代基取代的萘基,其中:
杂芳基是单环、二环或多环芳香族碳原子环结构基团,具有独立地选自N、O或S的一个或多个杂原子,每个所述芳香族碳原子环结构基团任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R1,
杂环基是饱和的或部分不饱和的单环、二环或三环环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R2,和
C9-10环烷基是饱和的或部分不饱和的二环环系,所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R2;
B是单环杂环基,其中,杂环基是饱和的或部分不饱和的环系,具有1个、2个、或3个独立地选自N、O或S的杂原子环成员,每个所述环系任选地被1个、2个、3个、4个、或5个取代基取代,每个所述取代基选自R4;
R1是卤素、氰基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,其中:
杂芳基是单环、二环或多环芳香族碳原子环结构基团,具有独立地选自N、O和S的一个或多个杂原子,
杂环基是饱和的或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个所述取代基选自R3;
R2是卤素、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基、或杂环基-C1-4烷基;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;
R4独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;和
R5是氢、C1-4烷基、或羟基-C1-4烷基;
其中,所述化合物的形式选自由以下组成的组:其盐形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
3.根据权利要求1所述的方法,其中:
X是O、NH、N(CH3)、或键;
A是芳基、杂芳基、或杂环基,
其中,芳基选自由以下组成的组:
其中,杂芳基选自由以下组成的组:
其中,杂环基选自由以下组成的组:
B是选自由以下组成的组的单环杂环基:
在可获得的化合价允许的情况下,R1a和R1b各自是分别选自以下的一个或多个取代基:卤素、羟基、氰基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、杂环基-C1-4烷氧基、苯基、或苯基-C1-4烷氧基,其中,当A是杂芳基时,R1a和R1b不是羟基,其中:
杂芳基是单环、二环或多环芳香族碳原子环结构基团,具有独立地选自N、O和S的一个或多个杂原子,
杂环基是饱和的或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
苯基、杂芳基或杂环基的每个实例任选地被1个或2个取代基取代,每个所述取代基选自R3;
在可获得的化合价允许的情况下,R2a、R2b和R2c各自是分别选自以下的一个或多个取代基:卤素、氰基、氧代、羟基-亚氨基、C1-4烷基、卤代-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基-羰基、C2-4烯基、C3-7环烷基、或杂环基-C1-4烷基,其中:
杂环基是饱和的或部分不饱和的单环或二环环系,具有1个、2个、或3个选自N、O和S的杂原子环成员,和
杂环基的每个实例任选地被1个或2个取代基取代,每个所述取代基选自R3;
R3是卤素、羟基、硝基、氧代、羟基-亚氨基、C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、氨基-C1-4烷基、C1-4烷基-氨基-C1-4烷基、(C1-4烷基)2-氨基-C1-4烷基、氨基-羰基、C1-4烷基-氨基-羰基、(C1-4烷基)2-氨基-羰基、C1-4烷基-氨基-羰基-C1-4烷基、(C1-4烷基)2-氨基-羰基-C1-4烷基、C1-4烷基-羰基-氨基、C1-4烷基-羰基-氨基-C1-4烷基、羟基-C1-4烷基、C1-4烷基-羰基、C1-4烷氧基、卤代-C1-4烷氧基、氨基-C1-4烷氧基、羟基-C1-4烷氧基、C1-4烷基-C1-4烷氧基、C1-4烷基-氨基-C1-4烷氧基、(C1-4烷基)2-氨基-C1-4烷氧基、C1-4烷基-羰基-氨基-C1-4烷氧基、C1-4烷氧基-C1-4烷氧基、C1-4烷氧基-羰基、C1-4烷氧基-羰基-氨基、C1-4烷氧基-羰基-氨基-C1-4烷氧基、C2-4烯基、C2-4烯基-氨基-羰基、C3-7环烷基、C3-7环烷基-C1-4烷氧基、C3-7环烯基、杂芳基、杂芳基-C1-4烷基、杂芳基-C1-4烷基-氨基、杂芳基-C1-4烷基-氨基-羰基、杂芳基-C1-4烷基-羰基-氨基、杂芳基-C1-4烷基-氨基-羰基-C1-4烷基、杂芳基-C1-4烷基-羰基-氨基-C1-4烷基、杂环基、杂环基-C1-4烷基、苯基、或苯基-C1-4烷氧基;和
R4a、R4b、R4c、R4d、R4e、R4f和R4g独立地选自卤素、C1-4烷基、羟基-C1-4烷基、氨基、C1-4烷基-氨基、(C1-4烷基)2-氨基、或羟基-C1-4烷基-氨基;
其中,所述化合物的形式选自由以下组成的组:其盐形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
4.根据权利要求1所述的方法,其中,所述化合物选自由以下组成的组:
6-(萘-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[b]噻吩-2-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-(6-(2,2,6,6-四甲基哌啶-4-基-氨基)-哒嗪-3-基)苯酚
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯并[b]-噻吩-5-甲腈
6-(喹啉-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-(苯并[b]-噻吩-2-基)-6-(2,2,6,6-四甲基哌啶-4-基-氧基)哒嗪
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)苯酚
6-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)萘-2-酚
6-(苯并[b]-噻吩-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉
6-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉
N-甲基-6-(喹啉-7-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
N-甲基-6-(喹啉-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(异喹啉-7-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(异喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(咪唑并[1,2-a]吡啶-6-基-哒嗪-3-基)-甲基-(2,2,6,6-四甲基哌啶-4-基)-胺
N-甲基-6-(6-苯基吡啶-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(6-(1H-吡咯-1-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(6-(1H-吡唑-1-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
甲基-(6-喹喔啉-2-基-哒嗪-3-基)-(2,2,6,6-四甲基哌啶-4-基)-胺
甲基-(6-喹啉-3-基-哒嗪-3-基)-(2,2,6,6-四甲基哌啶-4-基)-胺
N-甲基-6-(酞嗪-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[c][1,2,5]氧杂-二唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[d]噻唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(2-甲基苯并-[d]噁唑-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
5-氯代-2-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-(6-(2,2,6,6-四甲基哌啶-4-基-氨基)哒嗪-3-基)萘-2-酚
5-氯代-2-(6-(1,2,2,6,6-五甲基哌啶-4-基氨基)哒嗪-3-基)苯酚
4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2-酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(三氟代甲基)苯酚
2-氟代-6-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
3,5-二甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4,5-二甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4,5-二氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
1-烯丙基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
6-(苯并[b]噻吩-2-基)-N-(1,2,2,6,6-五甲基哌啶-4-基)哒嗪-3-胺
N-烯丙基-3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲酰胺
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-(5-甲基-噁唑-2-基)-2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
5-(4-羟甲基)-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-咪唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(4-氨基-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-(3-氨基-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-(2-吗啉代-乙基)-1H-吡唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
5-(5-氨基-1H-吡唑-1-基)-2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-1-基)苯酚
2-((6-((2-羟基-乙基)-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)-5-吡唑-1-基)苯酚
2-(6-(哌啶-4-基氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(((2S,4R,6R)-2,6-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-((-2,6-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-(1H-吡唑-1-基)-2-(6-(吡咯烷-3-基-氧基)哒嗪-3-基)苯酚
2-(6-(((2S,4S)-2-甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
(5-(1H-吡唑-1-基)-2-(6-(吡咯烷-3-基甲氧基)哒嗪-3-基)苯酚
2-(6-((3-氟代哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,2,2,6,6-五甲基-哌啶-4-基-氧基)-哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-1H-吡唑-1-基-2-(6-(2,2,6,6-四甲基哌啶-4-基-氧基)-哒嗪-3-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚
2-(6-哌嗪-1-基-哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
3-(6-(氮杂环丁-3-基氨基)-哒嗪-3-基)萘-2-酚
2-(6-(氮杂环丁-3-基氨基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3,5-二甲基哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,4-二氮杂庚-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(4-(2-羟乙基)哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3-(羟甲基)哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(4-氨基-4-甲基哌啶-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3-(二甲基氨基)哌啶-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,2,2,6,6-五甲基哌啶-4-基氨基)-哒嗪-3-基)-5-1H-吡唑-1-基-苯酚
2-(6-(3,3-二甲基哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
3-(6-(哌嗪-1-基)哒嗪-3-基)萘-2,7-二酚
5-(1H-吡唑-1-基)-2-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)苯酚
2-(6-哌啶-4-基-哒嗪-3-基)-5-1H-吡唑-1-基-苯酚
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2-酚
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(哌啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2,7-二酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
3-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
(3-((7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-基)氧基)丙基)氨基甲酸叔丁酯
7-(3-氨基-丙氧基)-3-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)萘-2-酚
N-(3-((7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-基)氧基)丙基)乙酰胺
7-(3-羟基丙氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3-甲氧基丙氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(2-吗啉代乙氧基)-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2-酚
3-(6-(哌啶-4-基甲基)哒嗪-3-基)萘-2-酚
5-(1H-吡唑-1-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)甲基)哒嗪-3-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6-三甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
2-(6-((6S)-6-((S)-1-羟基乙基)-2,2-二甲基哌啶-4-基氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2-萘甲腈
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(哌啶基甲基)萘-2-酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(吡咯烷基甲基)萘-2-酚
1-溴代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
1-氯代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
7-甲氧基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-甲氧基-3-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3,6-二氢-2H-吡喃-4-基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(四氢-2H-吡喃-4-基)萘-2-酚
7-(二氟代甲基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-((4-羟基-2-甲基丁-2-基)氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3-羟基-3-甲基丁氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯-1,3-二酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-3-(三氟代甲氧基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)-3-(三氟代甲氧基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)-3-(三氟代甲氧基)苯酚
4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(三氟代甲氧基)苯基)-1-甲基吡啶-2(1H)-酮
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-3-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(吡啶-3-基)苯酚
5-(1-环戊基-1H-吡唑-4-基)-3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3’,5-二甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-(1,1’-二苯基)-3-酚
3-(苄氧基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
3-乙氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
3-(环丙基甲氧基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
5-氯代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-吡唑-1-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
2-(6-((2,2-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)吡啶-3-基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)苯酚
4-(1H-吲哚-2-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(环戊-1-烯-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-3-基)苯酚
4-(4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
4-(4-羟基-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(4-羟基-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)吡啶-2-醇
5-(1H-吲唑-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-氯代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
4-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-氟代-4-(1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-4-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-5-基)苯酚
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮肟
5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1,6-二醇
4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-N-((1-甲基-1H-吡唑-4-基)甲基)苯甲酰胺
4-(4-(羟基甲基)-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)甲基)哒嗪-3-基)苯酚
6-(3-(苄氧基)异喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(1-(苄氧基)异喹啉-7-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-氟代-5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
3-氟代-5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚
5-氯代-3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
5-(5-甲氧基吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3-羟基-4-(6-甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
4-(3-羟基-4-(6-甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
5-(6-甲氧基吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-3-(三氟代甲基)吡啶-2-醇
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)吡啶-2-醇
5-(6-(二甲基氨基)吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(嘧啶-5-基)苯酚
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-3-醇
1-环丙基-4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1,2,3,6-四氢吡啶-4-基)苯酚
5-(环戊-1-烯-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3,6-二氢-2H-吡喃-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,5-a]吡啶-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,2-a]吡啶-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(2-甲基吡啶-4-基)苯酚
5-(1H-咪唑-2-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,2-a]吡嗪-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(4-甲基-1H-咪唑-2-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-咪唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-咪唑-5-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(4-硝基-1H-咪唑-2-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(2-甲基-1H-咪唑-4-基)苯酚
5-(1,2-二甲基-1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
1-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1H-吡唑-4-甲酰胺
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
5-(1-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
5-(5-甲基-1H-吡唑-4-基)-2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
5-(1H-咪唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
5-(5-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚
6-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
5-(4-氨基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
5-(4-硝基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚
2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
2-[6-(哌啶-4-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[4-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-氟代-4-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-1-基)苯酚
N-甲基-6-(2-甲基-2H-吲唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-甲基-5-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}-2H-吲唑
3-(4-氯代-2-甲氧基苯基)-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
N-甲基-6-(2-甲基吡唑并[1,5-a]吡啶-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}咪唑并[1,2-a]吡啶
3-[2-甲氧基-4-(1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[5-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
5-(3,5-二甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
6-[2-氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-甲氧基-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
3-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯-1,3-二酚
6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-(1H-吡唑-4-基)-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}嘧啶-5-胺
3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪和
6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺;
其中,所述化合物的形式选自由以下组成的组:其盐形式、包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
5.根据权利要求4所述的方法,其中,所述化合物为选自由以下组成的组的化合物盐:
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(三氟代甲基)苯酚盐酸盐
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-1-基)苯酚盐酸盐
3-(6-(哌嗪-1-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(哌啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮肟盐酸盐
3-氟代-5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚盐酸盐
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮盐酸盐
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮盐酸盐
5-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮盐酸盐
3-氟代-5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚盐酸盐
5-氯代-3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚盐酸盐
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚盐酸盐
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚盐酸盐
5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚盐酸盐
2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚二盐酸盐
2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚三盐酸盐
2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚四盐酸盐
2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺四盐酸盐
6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚三盐酸盐
3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺三盐酸盐
3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐和
6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐;
其中,所述化合物盐的形式选自由以下组成的组:其包合物形式、同位素体形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
6.根据权利要求1所述的方法,其中,所述化合物的有效量在约0.001mg/kg/天至约500mg/kg/天的范围内。
7.根据权利要求1所述的方法,其中,所述化合物与一种或多种药学上可接受的赋形剂混合。
8.根据权利要求4所述的方法,其中,所述化合物的有效量在约0.001mg/kg/天至约500mg/kg/天的范围内。
9.根据权利要求4所述的方法,其中,所述化合物与一种或多种药学上可接受的赋形剂混合。
10.根据权利要求5所述的方法,其中,所述化合物的有效量在约0.001mg/kg/天至约500mg/kg/天的范围内。
11.根据权利要求5所述的方法,其中,所述化合物与一种或多种药学上可接受的赋形剂混合。
12.一种用于治疗或改善有此需要的对象中的HD的方法,所述方法包括给所述对象施用有效量的化合物或其形式,所述化合物选自由以下组成的组:
6-(萘-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[b]噻吩-2-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-(6-(2,2,6,6-四甲基哌啶-4-基-氨基)-哒嗪-3-基)苯酚
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯并[b]-噻吩-5-甲腈
6-(喹啉-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-(苯并[b]-噻吩-2-基)-6-(2,2,6,6-四甲基哌啶-4-基-氧基)哒嗪
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)苯酚
6-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)萘-2-酚
6-(苯并[b]-噻吩-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉
6-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉
N-甲基-6-(喹啉-7-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
N-甲基-6-(喹啉-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(异喹啉-7-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(异喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(咪唑并[1,2-a]吡啶-6-基-哒嗪-3-基)-甲基-(2,2,6,6-四甲基哌啶-4-基)-胺
N-甲基-6-(6-苯基吡啶-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(6-(1H-吡咯-1-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(6-(1H-吡唑-1-基)吡啶-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
甲基-(6-喹喔啉-2-基-哒嗪-3-基)-(2,2,6,6-四甲基哌啶-4-基)-胺
甲基-(6-喹啉-3-基-哒嗪-3-基)-(2,2,6,6-四甲基哌啶-4-基)-胺
N-甲基-6-(酞嗪-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[c][1,2,5]氧杂-二唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(苯并[d]噻唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(2-甲基苯并-[d]噁唑-6-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
5-氯代-2-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-(6-(2,2,6,6-四甲基哌啶-4-基-氨基)哒嗪-3-基)萘-2-酚
5-氯代-2-(6-(1,2,2,6,6-五甲基哌啶-4-基氨基)哒嗪-3-基)苯酚
4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2-酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(三氟代甲基)苯酚
2-氟代-6-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
3,5-二甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4,5-二甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4,5-二氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
1-烯丙基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
6-(苯并[b]噻吩-2-基)-N-(1,2,2,6,6-五甲基哌啶-4-基)哒嗪-3-胺
N-烯丙基-3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲酰胺
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-(5-甲基-噁唑-2-基)-2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
5-(4-羟甲基)-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-咪唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(4-氨基-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-(3-氨基-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-(2-吗啉代-乙基)-1H-吡唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
5-(5-氨基-1H-吡唑-1-基)-2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-1-基)苯酚
2-((6-((2-羟基-乙基)-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)-5-吡唑-1-基)苯酚
2-(6-(哌啶-4-基氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(((2S,4R,6R)-2,6-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-((-2,6-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-(1H-吡唑-1-基)-2-(6-(吡咯烷-3-基-氧基)哒嗪-3-基)苯酚
2-(6-(((2S,4S)-2-甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
(5-(1H-吡唑-1-基)-2-(6-(吡咯烷-3-基甲氧基)哒嗪-3-基)苯酚
2-(6-((3-氟代哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,2,2,6,6-五甲基-哌啶-4-基-氧基)-哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
5-1H-吡唑-1-基-2-(6-(2,2,6,6-四甲基哌啶-4-基-氧基)-哒嗪-3-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚
2-(6-哌嗪-1-基-哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
3-(6-(氮杂环丁-3-基氨基)-哒嗪-3-基)萘-2-酚
2-(6-(氮杂环丁-3-基氨基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3,5-二甲基哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(7-甲基-2,7-二氮杂螺[4.4]壬-2-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,4-二氮杂庚-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(4-(2-羟乙基)哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3,6-二氮杂二环[3.2.1]辛-3-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(2,7-二氮杂螺[3.5]壬-7-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3-(羟甲基)哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,7-二氮杂螺[4.4]壬-7-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(4-氨基-4-甲基哌啶-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(3-(二甲基氨基)哌啶-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(1,2,2,6,6-五甲基哌啶-4-基氨基)-哒嗪-3-基)-5-1H-吡唑-1-基-苯酚
2-(6-(3,3-二甲基哌嗪-1-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(7-(2-羟乙基)-2,7-二氮杂螺[4.4]-壬-2-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
3-(6-(哌嗪-1-基)哒嗪-3-基)萘-2,7-二酚
5-(1H-吡唑-1-基)-2-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)苯酚
2-(6-哌啶-4-基-哒嗪-3-基)-5-1H-吡唑-1-基-苯酚
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2-酚
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-(哌啶-4-基)哒嗪-3-基)萘-2,7-二酚
3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2,7-二酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
3-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
(3-((7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-基)氧基)丙基)氨基甲酸叔丁酯
7-(3-氨基-丙氧基)-3-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)萘-2-酚
N-(3-((7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-基)氧基)丙基)乙酰胺
7-(3-羟基丙氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3-甲氧基丙氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(2-吗啉代乙氧基)-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)萘-2-酚
3-(6-(哌啶-4-基甲基)哒嗪-3-基)萘-2-酚
5-(1H-吡唑-1-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)甲基)哒嗪-3-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6-三甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
2-(6-((6S)-6-((S)-1-羟基乙基)-2,2-二甲基哌啶-4-基氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2-萘甲腈
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(哌啶基甲基)萘-2-酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(吡咯烷基甲基)萘-2-酚
1-溴代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
1-氯代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2,7-二酚
7-甲氧基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-甲氧基-3-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3,6-二氢-2H-吡喃-4-基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-7-(四氢-2H-吡喃-4-基)萘-2-酚
7-(二氟代甲基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-((4-羟基-2-甲基丁-2-基)氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
7-(3-羟基-3-甲基丁氧基)-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)萘-2-酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯-1,3-二酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-3-(三氟代甲氧基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)-3-(三氟代甲氧基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)-3-(三氟代甲氧基)苯酚
4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(三氟代甲氧基)苯基)-1-甲基吡啶-2(1H)-酮
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-3-基)苯酚
3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(吡啶-3-基)苯酚
5-(1-环戊基-1H-吡唑-4-基)-3-甲氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3’,5-二甲氧基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-(1,1’-二苯基)-3-酚
3-(苄氧基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
3-乙氧基-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
3-(环丙基甲氧基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)-5-(5-甲基噁唑-2-基)苯酚
2-甲基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-1H-苯并[d]咪唑-6-醇
5-氯代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-吡唑-1-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯甲腈
2-(6-((2,2-二甲基哌啶-4-基)氧基)哒嗪-3-基)-5-(1H-吡唑-1-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)吡啶-3-基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)苯酚
4-(1H-吲哚-2-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(环戊-1-烯-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-3-基)苯酚
4-(4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
4-(4-羟基-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(4-羟基-3-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)吡啶-2-醇
5-(1H-吲唑-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-氯代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
4-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
5-氟代-4-(1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-4-基)苯酚
5-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-5-基)苯酚
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-1,4-二氢茚并[1,2-c]-1H-吡唑-7-醇
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮肟
5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1,6-二醇
2-氨基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-8H-茚并[1,2-d]噻唑-5-醇
9-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5,6-二氢咪唑并[5,1-a]异喹啉-8-醇
4-羟基-3-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-N-((1-甲基-1H-吡唑-4-基)甲基)苯甲酰胺
4-(4-(羟基甲基)-1H-吡唑-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)甲基)哒嗪-3-基)苯酚
6-(3-(苄氧基)异喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-(1-(苄氧基)异喹啉-7-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-氟代-5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
3-氟代-5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚
5-氯代-3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
5-(5-甲氧基吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3-羟基-4-(6-甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
4-(3-羟基-4-(6-甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2-醇
5-(6-甲氧基吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-3-(三氟代甲基)吡啶-2-醇
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)吡啶-2-醇
5-(6-(二甲基氨基)吡啶-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
4-(3-羟基-4-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(嘧啶-5-基)苯酚
5-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-3-醇
1-环丙基-4-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1,2,3,6-四氢吡啶-4-基)苯酚
5-(环戊-1-烯-1-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(3,6-二氢-2H-吡喃-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,5-a]吡啶-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,2-a]吡啶-7-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(2-甲基吡啶-4-基)苯酚
5-(1H-咪唑-2-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
5-(咪唑并[1,2-a]吡嗪-3-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(4-甲基-1H-咪唑-2-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-咪唑-4-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-咪唑-5-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(4-硝基-1H-咪唑-2-基)苯酚
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(2-甲基-1H-咪唑-4-基)苯酚
5-(1,2-二甲基-1H-咪唑-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚
1-(3-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1H-吡唑-4-甲酰胺
2-(6-((3aR,6aS)-5-(2-羟基乙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
2-(6-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
2-(6-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
4-(3-羟基-4-(6-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(3-羟基-4-(6-((3aR,6aR)-1-甲基六氢吡咯并[3,4-b]吡咯-5(1H)-基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮
2-(6-(2,7-二氮杂螺[4.5]癸-2-基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚
4-(4-(6-(2,7-二氮杂螺[4.5]癸-2-基)哒嗪-3-基)-3-羟基苯基)-1-甲基吡啶-2(1H)-酮
2-(6-(甲基-(2,2,6,6-四甲基哌啶-4-基)-氨基)-哒嗪-3-基)苯酚
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
6-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
6-(6-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
7-(6-(甲基(1,2,2,6,6-五甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉-6-醇
7-(6-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哒嗪-3-基)异喹啉-6-醇
1-环丙基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1,6-二醇
6-羟基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1-甲腈
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-7-醇
8-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
2-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
3-氯代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
3-溴代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-3-甲腈
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-3-(1-甲基-1H-咪唑-4-基)喹啉-7-醇
3-(1H-咪唑-1-基)-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-3,7-二醇
3-乙基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
3-异丙基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2(1H)-酮
7-羟基-1-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2(1H)-酮
4-甲氧基-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(吡咯烷-1-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-吗啉代喹啉-7-醇
4-(二甲基氨基)-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
4-乙氧基-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1-甲基-1H-吡唑-4-基)喹啉-7-醇
4-甲氧基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹喔啉-6-醇
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-3-(四氢-2H-吡喃-4-基)喹啉-7-醇
3-氯代-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
3-溴代-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
3-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
5-溴代-3-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
6-羟基-1-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-4(1H)-酮
2,3-二甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
2-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹喔啉-6-醇
3-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹喔啉-6-醇
4-甲氧基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
4-(氮杂环丁-1-基)-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
7-羟基-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹诺酮-4-甲腈
4-环丙基-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-喹啉-7-醇
4-(3,6-二氢-2H-吡喃-4-基)-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(四氢-2H-吡喃-4-基)喹啉-7-醇
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(氧杂环丁-3-基)喹啉-7-醇
4-(二甲基氨基)-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-喹啉-7-醇
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹唑啉-4(1H)-酮
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹唑啉-7-醇
7-羟基-1-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-3,4-二氢喹啉-2(1H)-酮
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹唑啉-7-醇
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1-甲腈
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2-甲腈
6-羟基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2-甲腈
6-羟基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1-甲酰胺
7-羟基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2-甲酰胺
6-羟基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2-甲酰胺
6-羟基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2-羧酸甲酯
6-羟基-7-(6-(哌嗪-1-基)哒嗪-3-基)喹啉-2-甲腈
7-羟基-6-(6-(哌嗪-1-基)哒嗪-3-基)喹啉-2-甲腈
7-(6-(哌嗪-1-基)哒嗪-3-基)异喹啉-6-醇
7-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)喹啉-6-醇
1-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-7-醇
1-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
1,3-二甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-羟基-3-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1-甲腈
1-氨基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-羟基-1,3-二甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹唑啉-2,4(1H,3H)-二酮
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯并[d]噁唑-2(3H)-酮
2-甲基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2H-吲唑-6-醇
1-甲基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-1H-吲唑-6-醇
6-羟基-2-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1(2H)-酮
2-乙基-6-羟基-7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉-1(2H)-酮
1-乙氧基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)异喹啉-1,6-二醇
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-哒嗪-3-基)-3-苯基异喹啉-6-醇
3-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
3-环丙基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
3-异丙基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-6-醇
3-丙基-7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)-哒嗪-3-基)异喹啉-6-醇
3-异丙基-7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)-哒嗪-3-基)异喹啉-6-醇
3-甲基-7-(6-(哌嗪-1-基)哒嗪-3-基)异喹啉-6-醇
6-(3-(苄氧基)异喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-氯代-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
3-异丙基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
3-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹喔啉-6-醇
4-氯代-2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇
4-氯代-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇
5-(2-甲氧基-4-(1H-吡唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
6-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)萘-2-酚
5-(2-甲氧基喹啉-3-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(3-甲氧基-萘-2-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1H-吡唑-1基)苯基)-N-(1,2,2,6,6-五甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
4-(3-甲氧基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(3-甲氧基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)吡啶-2-醇
5-(3-甲氧基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
N-甲基-5-(2-甲基-4-(1-甲基-1H-吡唑-4-基)苯基)-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
1-甲基-4-(4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-3-(三氟代甲氧基)苯基)吡啶-2(1H)-酮
5-(4-(3,5-二甲基-1H-吡唑-4-基)-2-甲氧基苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4,-噻二唑-2-基-5-(1-甲基-1H-吡唑-4-基)苯酚
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4,-噻二唑-2-基-5-(1H-吡唑-1-基)苯酚
5-(3-羟基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(3-羟基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(3-羟基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)吡啶-2-醇
3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)萘-2,7-二酚
3-(5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑-2-基)萘-2,7-二酚
3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)萘-2-酚
3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2-醇
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-4-(1H-吡唑-1-基)苯酚
5-(2-氯代-4-(1-甲基-1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
3-氯代-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
5-(2-氯代-4-(1-甲基-1H-吡唑-4-基)苯基)-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
3-甲氧基-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-甲基噁唑-2-基)苯酚
2-(2-甲氧基-4-(1H-吡唑-1-基)苯基)-5-(1,2,3,6-四氢吡啶-4-基)-1,3,4-噻二唑
2-(5-(哌嗪-1-基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-1-基)苯酚
5-(7-甲氧基喹啉-6-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
6-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-7-醇
3-甲氧基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯甲腈
3-氟代-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯甲腈
甲基-3-氟代-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯甲酸盐
5-(2-甲氧基-4-(3-(甲基氨基)-1H-吡唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
7-甲氧基-6-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2-甲腈
4-(3-甲氧基-4-(5-((2,2,6,6-四甲基哌啶-4-基)氧基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
4-(3-氯代-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)-1-甲基吡啶-2(1H)-酮
5-(2-氯代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氯代-4-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
N-甲基-5-(5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(2-氯代-4-(1-甲基-1H-吡唑-4-基)苯基)-5-((2,2,6,6-四甲基哌啶-4-基)氧基-1,3,4-噻二唑
5-(2-氯代-4-(6-甲氧基吡啶-3-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(6-氨基吡啶-3-基)-2-氟代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氟代-4-(3-甲基-1H-吡唑-5-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氟代-4-(1H-吡唑-5-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2,3-二氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2,3-二氟代-4-(1H-吡唑-5-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2,5-二氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2,5-二氟代-4-(1H-吡唑-5-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2,6-二氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(2,5-二氟代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
5-(2-氯代-5-氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(3-氟代-5-(1H-吡唑-4-基)吡啶-2-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(2-氨基嘧啶-4-基)-2-氯代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(5-(2-氨基嘧啶-4-基)-2-氯代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(2,4-二甲基噻唑-5-基)-2,5-二氟代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(2,4-二甲基噻唑-5-基)-2,3-二氟代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
4-(3-羟基-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(三氟代甲氧基)苯基)-1-甲基吡啶-2(1H)-酮
5-(2-氟代-6-甲氧基-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(2-氟代-6-甲氧基-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
5-(2,3-二氟代-6-甲氧基-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
6-甲氧基-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-3,4-二氢异喹啉-1-(2H)-酮
5-(2-氯代-4-(1H-吡唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氯代-4-(1H-1,2,3-***-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氯代-4-(2H-1,2,3-***-2-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氯代-4-(1H-1,2,4-***-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(3-氨基-1H-吡唑-1-基)-2-氯代苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(2-氯代-4-(1H-咪唑-1-基)苯基)-5-((3aR,6aS)-5-甲基六氢吡咯并[3,4c]吡咯-2(1H)-基)-1,3,4-噻二唑
5-(2-氯代-4-(1H-咪唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氟代-4-(1H-咪唑-1-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1H-吡唑-5-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(4-(2,4-二甲基噻唑-5-基)-2-甲氧基苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(吡啶-3-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-氟代-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(2-甲氧基吡啶-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(6-甲氧基吡啶-3-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-(2-氯代-4-(1-甲基-1H-吡唑-4-基)苯基)-5-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aR)-1-甲基六氢吡咯并[3,4-b]吡咯-5(1H)-基)-1,3,4-噻二唑
(R)-1-(4-(5-(2-氯代-4-(1H-吡唑-4-基)苯基)-1,3,4-噻二唑-2-基)吗啉-2-基)-N,N-二甲基甲胺
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-(2-甲基-2,7-二氮杂螺[4.5]癸-7-基)-1,3,4-噻二唑
2-(2-氟代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
2-(2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)-5-(2,6-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑
2-(2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)-5-(2,7-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-1-基)苯酚
5-(3-氯代-4-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯基)吡啶-2(1H)-酮
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(3-(甲基氨基)-1H-吡唑-1-基)苯酚
3-氟代-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚
3,4-二氟代-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚
6-羟基-5-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-2,3-二氢-1H-茚-1-酮
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚
2-(5-(2,6-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑-2-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
2-(5-(2,7-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑-2-基)-5-(1-甲基-1H-吡唑-4-基)苯酚
3-氟代-2-(5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚
3-氯代-2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚
2-(2-甲氧基-4-(1H-吡唑-1-基)苯基)-5-((2,2,6,6-四甲基哌啶-4-基)甲基)-1,3,4-噻二唑
2-(2,3-二氟代-4-(1H-吡唑-4-基)苯基)-5-(2,7-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑
2-(5-(2,7-二氮杂螺[3.5]壬-2-基)-1,3,4-噻二唑-2-基)-3-氟代-5-(1H-吡唑-4-基)苯酚
4-甲氧基-1-甲基-3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2(1H)-酮
4-羟基-1-甲基-3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2(1H)-酮
3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2(1H)-酮
1-甲基-3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)喹啉-2(1H)-酮
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-(2,7-二氮杂螺[4.5]癸-2-基)-1,3,4-噻二唑
(R)-(4-(5-(2-氯代-4-(1H-吡唑-4-基)苯基)-1,3,4-噻二唑-2-基)哌嗪-2-基)甲醇
2-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)苯并[b]噻吩-5-甲腈
5-(3-氯代苯并[b]噻吩-2-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
5-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺
2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
5-(1-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
5-(5-甲基-1H-吡唑-4-基)-2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
5-(1H-咪唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
5-(5-甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚
6-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
5-(4-氨基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
5-(4-硝基-1H-吡唑-1-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚
2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-[6-(8-氮杂二环[3.2.1]辛-2-烯-3-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
2-[6-(哌啶-4-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-[4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚
3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[4-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
2-[6-(2,7-二氮杂螺[3.5]壬-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
3-氟代-4-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-1-基)苯酚
N-甲基-6-(2-甲基-2H-吲唑-5-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-甲基-5-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}-2H-吲唑
3-(4-氯代-2-甲氧基苯基)-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
N-甲基-6-(2-甲基吡唑并[1,5-a]吡啶-3-基)-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
6-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}咪唑并[1,2-a]吡啶
3-[2-甲氧基-4-(1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[5-(1-甲基-1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
5-(3,5-二甲基-1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
6-[2-氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
3-甲氧基-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯酚
3-[2-甲氧基-4-(4-硝基-1H-吡唑-1-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}苯-1,3-二酚
6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺
2-(1H-吡唑-4-基)-4-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}嘧啶-5-胺
3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪
2-[6-(2,6-二氮杂螺[3.4]辛-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚
3-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-6-(1H-吡唑-4-基)吡啶-2-醇
6-(1H-吡唑-4-基)-3-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}吡啶-2-醇
N,2,2,6,6-五甲基-N-{5-[3-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺
N,2,2,6,6-五甲基-N-{5-[4-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺
3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪和
6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺;
其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
13.根据权利要求12所述的方法,其中,所述化合物为选自由以下组成的组的化合物盐:
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(三氟代甲基)苯酚盐酸盐
2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(1H-吡唑-1-基)苯酚盐酸盐
2-(6-哌嗪-1-基-哒嗪-3-基)-5-1H-吡唑-1-基-苯酚盐酸盐
3-(6-(哌嗪-1-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
3-(6-(哌啶-4-基)哒嗪-3-基)萘-2,7-二酚三氟代乙酸盐
6-羟基-5-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-1-酮肟盐酸盐
2-氨基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-8H-茚并[1,2-d]噻唑-5-醇盐酸盐
9-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5,6-二氢咪唑并[5,1-a]异喹啉-8-醇盐酸盐
3-氟代-5-(2-甲氧基吡啶-4-基)-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚盐酸盐
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)吡啶-2(1H)-酮盐酸盐
4-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮盐酸盐
5-(3-氟代-5-羟基-4-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯基)-1-甲基吡啶-2(1H)-酮盐酸盐
3-氟代-5-(1H-吡唑-4-基)-2-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)苯酚盐酸盐
5-氯代-3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)苯酚盐酸盐
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1H-吡唑-4-基)苯酚盐酸盐
3-氟代-2-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-5-(1-甲基-1H-吡唑-4-基)苯酚盐酸盐
3-(1H-咪唑-1-基)-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-7-醇盐酸盐
6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-3,7-二醇甲酸盐
7-羟基-1-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-2(1H)-酮盐酸盐
4-甲氧基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹啉-6-醇甲酸盐
7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)喹喔啉-6-醇盐酸盐
2-甲基-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-4-(四氢-2H-吡喃-4-基)喹啉-7-醇甲酸盐
4-(二甲基氨基)-6-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)-喹啉-7-醇甲酸盐
6-羟基-2-甲基-7-(6-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)哒嗪-3-基)异喹啉-1(2H)-酮盐酸盐
3-(5-(甲基(2,2,6,6-四甲基哌啶-4-基)氨基)-1,3,4-噻二唑-2-基)萘-2-酚氢溴酸盐
N-甲基-5-(5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-N-(2,2,6,6-四甲基哌啶-4-基)-1,3,4-噻二唑-2-胺盐酸盐
3-氟代-2-(5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑-2-基)-5-(1H-吡唑-4-基)苯酚二盐酸盐
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,3,4-噻二唑盐酸盐
2-(2-氯代-4-(1H-吡唑-4-基)苯基)-5-(2,7-二氮杂螺[4.5]癸-2-基)-1,3,4-噻二唑盐酸盐
(R)-(4-(5-(2-氯代-4-(1H-吡唑-4-基)苯基)-1,3,4-噻二唑-2-基)哌嗪-2-基)甲醇盐酸盐
2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基(甲基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚盐酸盐
2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
5-(1H-吡唑-4-基)-2-{6-[(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}苯酚盐酸盐
2-[6-((1R,5S)-8-氮杂二环[3.2.1]辛-3-基氧基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
2-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-5-(4-硝基-1H-吡唑-1-基)苯酚二盐酸盐
2-[6-(1-甲基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
5-(1H-吡唑-4-基)-2-[6-(1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]苯酚三盐酸盐
2-[6-(1-乙基-1,2,3,6-四氢吡啶-4-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚三盐酸盐
2-{6-[甲基(哌啶-4-基)氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚四盐酸盐
2-[6-(哌啶-4-基氨基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
6-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺四盐酸盐
2-[6-(8-氮杂二环[3.2.1]辛-2-烯-3-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚盐酸盐
6-[2,3-二氟代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
3-[2,5-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
2-{6-[(1R,5S)-8-氮杂二环[3.2.1]辛-3-基氨基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚盐酸盐
6-[2-甲氧基-6-(1H-吡唑-4-基)吡啶-3-基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐
2-{6-[(2,6-二甲基哌啶-4-基)氧基]哒嗪-3-基}-5-(1H-吡唑-4-基)苯酚三盐酸盐
3-[2-氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
2-[6-(2,7-二氮杂螺[3.5]壬-2-基)哒嗪-3-基]-5-(1H-吡唑-4-基)苯酚四盐酸盐
3-[5-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
3-[4-(1H-吡唑-4-基)噻吩-2-基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐
6-[2-氯代-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺三盐酸盐
3-[2,6-二氟代-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪三盐酸盐
3-{6-[甲基(2,2,6,6-四甲基哌啶-4-基)氨基]哒嗪-3-基}-6-(1H-吡唑-4-基)吡啶-2-醇盐酸盐
N,2,2,6,6-五甲基-N-{5-[3-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺盐酸盐
N,2,2,6,6-五甲基-N-{5-[4-(1H-吡唑-4-基)苯氧基]-1,3,4-噻二唑-2-基}哌啶-4-胺盐酸盐
3-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪盐酸盐和
6-[2-(二氟代甲基)-4-(1H-吡唑-4-基)苯基]-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺盐酸盐;
其中,所述化合物盐的形式选自由以下组成的组:其外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
14.根据权利要求12所述的方法,其中,所述化合物的有效量在约0.001mg/kg/天至约500mg/kg/天的范围内。
15.根据权利要求12所述的方法,其中,所述化合物与一种或多种药学上可接受的赋形剂混合。
16.根据权利要求13所述的方法,其中,所述化合物的有效量在约0.001mg/kg/天至约500mg/kg/天的范围内。
17.根据权利要求13所述的方法,其中,所述化合物与一种或多种药学上可接受的赋形剂混合。
18.根据权利要求1所述的方法,其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
19.根据权利要求2所述的方法,其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
20.根据权利要求3所述的方法,其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
21.根据权利要求4所述的方法,其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
22.根据权利要求5所述的方法,其中,所述化合物的形式选自由以下组成的组:其盐形式、外消旋体形式、对映体形式、非对映体形式、立体异构体形式和互变异构体形式。
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