TWI776994B - 經碸吡啶烷基醯胺取代之雜芳基化合物 - Google Patents
經碸吡啶烷基醯胺取代之雜芳基化合物 Download PDFInfo
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- TWI776994B TWI776994B TW107141159A TW107141159A TWI776994B TW I776994 B TWI776994 B TW I776994B TW 107141159 A TW107141159 A TW 107141159A TW 107141159 A TW107141159 A TW 107141159A TW I776994 B TWI776994 B TW I776994B
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- Prior art keywords
- substituted
- amino
- alkyl
- hydrogen
- carboxamide
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 5
- 125000001072 heteroaryl group Chemical class 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 193
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 212
- 229910052739 hydrogen Inorganic materials 0.000 claims description 182
- -1 CF 3 Chemical group 0.000 claims description 167
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 166
- 239000001257 hydrogen Substances 0.000 claims description 163
- 125000005842 heteroatom Chemical group 0.000 claims description 134
- 125000000623 heterocyclic group Chemical group 0.000 claims description 131
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 130
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 130
- 229910052760 oxygen Inorganic materials 0.000 claims description 129
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 72
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 49
- 229910052801 chlorine Inorganic materials 0.000 claims description 39
- 229910052731 fluorine Inorganic materials 0.000 claims description 39
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 37
- DMYLUKNFEYWGCH-UHFFFAOYSA-N pyridazine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=N1 DMYLUKNFEYWGCH-UHFFFAOYSA-N 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 32
- 125000002837 carbocyclic group Chemical group 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 19
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 239000004202 carbamide Substances 0.000 claims description 11
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 8
- FFOLNPHHJUGQBY-UHFFFAOYSA-N n-methylpyridazine-3-carboxamide Chemical compound CNC(=O)C1=CC=CN=N1 FFOLNPHHJUGQBY-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- LRXXYMMZLOCJST-YLPAKPJGSA-N 6-[[(1R,2R)-2-methylcyclopropanecarbonyl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC(=O)[C@H]1[C@@H](C1)C)C(=O)NC([2H])([2H])[2H] LRXXYMMZLOCJST-YLPAKPJGSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- VWIVBQZLVAGLMH-WQRHAFOGSA-N 4-[(3-methylsulfonylpyridin-2-yl)amino]-6-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC(=O)[C@H]1CC11CC1)C(=O)NC([2H])([2H])[2H] VWIVBQZLVAGLMH-WQRHAFOGSA-N 0.000 claims description 3
- DDNFMWRLJKLXMQ-FIBGUPNXSA-N 6-[(6-cyclopropylpyridazin-3-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C1(CC1)C1=CC=C(N=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C DDNFMWRLJKLXMQ-FIBGUPNXSA-N 0.000 claims description 3
- PPXNDDNZGSYAHS-FIBGUPNXSA-N 6-[(6-cyclopropylpyrimidin-4-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C1(CC1)C1=CC(=NC=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C PPXNDDNZGSYAHS-FIBGUPNXSA-N 0.000 claims description 3
- LRXXYMMZLOCJST-NGNDBYNWSA-N 6-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC(=O)[C@@H]1[C@H](C1)C)C(=O)NC([2H])([2H])[2H] LRXXYMMZLOCJST-NGNDBYNWSA-N 0.000 claims description 3
- GSARVCRQVTZWOS-GKOSEXJESA-N 6-[[4-chloro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(6-methyl-3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound ClC1=CC(=NC=C1C(C)(C)O)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC(=CC=C1S(=O)(=O)C)C GSARVCRQVTZWOS-GKOSEXJESA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- GYQJMBLNAWSOBK-HPRDVNIFSA-N 6-[(2,6-dimethylpyrimidin-4-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CC1=NC(=CC(=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)C GYQJMBLNAWSOBK-HPRDVNIFSA-N 0.000 claims description 2
- LWAUNILJWIAJJW-FIBGUPNXSA-N 6-[(5-fluoropyridin-2-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound FC=1C=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C LWAUNILJWIAJJW-FIBGUPNXSA-N 0.000 claims description 2
- HEMYEJNNFMUAEW-BMSJAHLVSA-N 6-[(5-methylpyrazin-2-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NC=C(N=C1)C)C(=O)NC([2H])([2H])[2H] HEMYEJNNFMUAEW-BMSJAHLVSA-N 0.000 claims description 2
- OYOWLSXLRAYJQB-FIBGUPNXSA-N 6-[(6-methoxypyridazin-3-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC=1N=NC(=CC=1)OC)C(=O)NC([2H])([2H])[2H] OYOWLSXLRAYJQB-FIBGUPNXSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 5
- JRYYVMDEUJQWRO-UHFFFAOYSA-N 2-methylnicotinamide Chemical compound CC1=NC=CC=C1C(N)=O JRYYVMDEUJQWRO-UHFFFAOYSA-N 0.000 claims 1
- FUCMZKYPKFDUEI-FIBGUPNXSA-N 4-[(3-methylsulfonylpyridin-2-yl)amino]-6-[(2-methyltriazol-4-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NN(N=C1)C)C(=O)NC([2H])([2H])[2H] FUCMZKYPKFDUEI-FIBGUPNXSA-N 0.000 claims 1
- BGMRHCRUTIGUKQ-FIBGUPNXSA-N 4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)-6-[[5-(trifluoromethoxy)pyridin-2-yl]amino]pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NC=C(C=C1)OC(F)(F)F)C(=O)NC([2H])([2H])[2H] BGMRHCRUTIGUKQ-FIBGUPNXSA-N 0.000 claims 1
- BNCXGJIASIMCFN-FIBGUPNXSA-N 4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)-6-[[5-(trifluoromethyl)pyridin-2-yl]amino]pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NC=C(C=C1)C(F)(F)F)C(=O)NC([2H])([2H])[2H] BNCXGJIASIMCFN-FIBGUPNXSA-N 0.000 claims 1
- HXAZFBYRABCUCS-BMSJAHLVSA-N 6-[(1,5-dimethylpyrazol-3-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CN1N=C(C=C1C)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C HXAZFBYRABCUCS-BMSJAHLVSA-N 0.000 claims 1
- MAIMNQSYRRZIMD-FIBGUPNXSA-N 6-[(1-methylpyrazol-3-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NN(C=C1)C)C(=O)NC([2H])([2H])[2H] MAIMNQSYRRZIMD-FIBGUPNXSA-N 0.000 claims 1
- WPSPTNUKDQEGKL-BMSJAHLVSA-N 6-[(2-cyclopropyl-6-methylpyrimidin-4-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C1(CC1)C1=NC(=CC(=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)C WPSPTNUKDQEGKL-BMSJAHLVSA-N 0.000 claims 1
- OZQGDJUNHCBDPG-BMSJAHLVSA-N 6-[(6-cyclopropyl-2-methylpyrimidin-4-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C1(CC1)C1=CC(=NC(=N1)C)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C OZQGDJUNHCBDPG-BMSJAHLVSA-N 0.000 claims 1
- BVQZYQWJZVTIMH-BMSJAHLVSA-N 6-[(6-cyclopropyl-2-methylpyrimidin-4-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridine-3-carboxamide Chemical compound C1(CC1)C1=CC(=NC(=N1)C)NC1=CC(=C(C=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C BVQZYQWJZVTIMH-BMSJAHLVSA-N 0.000 claims 1
- XGSMUYNJHINTDS-GKOSEXJESA-N 6-[(6-tert-butylpyridazin-3-yl)amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C(C)(C)(C)C1=CC=C(N=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C XGSMUYNJHINTDS-GKOSEXJESA-N 0.000 claims 1
- LLNBIPCUMNNNLO-FIBGUPNXSA-N 6-[[4-(methoxymethyl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NC=CC(=C1)COC)C(=O)NC([2H])([2H])[2H] LLNBIPCUMNNNLO-FIBGUPNXSA-N 0.000 claims 1
- LVPLAALKSOFPTF-HPRDVNIFSA-N 6-[[4-chloro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(6-methoxy-3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound ClC1=CC(=NC=C1C(C)(C)O)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC(=CC=C1S(=O)(=O)C)OC LVPLAALKSOFPTF-HPRDVNIFSA-N 0.000 claims 1
- DGTYVIQEQSLTGL-FIBGUPNXSA-N 6-[[5-(1-cyanocyclopropyl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound C(#N)C1(CC1)C=1C=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C DGTYVIQEQSLTGL-FIBGUPNXSA-N 0.000 claims 1
- HMBJIXOJMOWLMZ-HPRDVNIFSA-N 6-[[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound OC(C)(C)C=1C=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C HMBJIXOJMOWLMZ-HPRDVNIFSA-N 0.000 claims 1
- OPHGIDTYYAHCDV-GKOSEXJESA-N 6-[[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(6-methyl-3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound OC(C)(C)C=1C=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC(=CC=C1S(=O)(=O)C)C OPHGIDTYYAHCDV-GKOSEXJESA-N 0.000 claims 1
- SWRLTTOUFSQRBH-FIBGUPNXSA-N 6-[[5-(methoxymethyl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound CS(=O)(=O)C=1C(=NC=CC=1)NC1=C(N=NC(=C1)NC1=NC=C(C=C1)COC)C(=O)NC([2H])([2H])[2H] SWRLTTOUFSQRBH-FIBGUPNXSA-N 0.000 claims 1
- FHCXUFUNVNDQOI-HPRDVNIFSA-N 6-[[5-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound FC=1C(=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)C(C)(C)O FHCXUFUNVNDQOI-HPRDVNIFSA-N 0.000 claims 1
- IDQWQTSNHAHFPC-FIBGUPNXSA-N 6-[[6-(difluoromethoxy)pyridazin-3-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound FC(OC1=CC=C(N=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)F IDQWQTSNHAHFPC-FIBGUPNXSA-N 0.000 claims 1
- XRDBLQZSLOBYLL-FIBGUPNXSA-N 6-[[6-(difluoromethyl)pyridazin-3-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound FC(C1=CC=C(N=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)F XRDBLQZSLOBYLL-FIBGUPNXSA-N 0.000 claims 1
- YNYZEQLEXZYACA-HPRDVNIFSA-N 6-[[6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-4-[(3-methylsulfonylpyridin-2-yl)amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide Chemical compound FC1=C(C=CC(=N1)NC1=CC(=C(N=N1)C(=O)NC([2H])([2H])[2H])NC1=NC=CC=C1S(=O)(=O)C)C(C)(C)O YNYZEQLEXZYACA-HPRDVNIFSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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Abstract
Description
本發明係關於可用於調節IL-12、IL-23及/或IFNα之化合物,其係藉由作用於Tyk-2以引起信號轉導抑制起作用。本文提供經醯胺取代之雜環化合物、包含此等化合物之組合物及其使用方法。本發明進一步係關於含有至少一種本發明化合物之醫藥組合物,其可用於治療與哺乳動物中IL-12、IL-23及/或IFNα之調節有關之病況。
共用共同p40亞單元之異二聚體細胞介素介白素(IL)-12及IL-23係由經活化之抗原呈遞細胞產生,且在Th1及Th17細胞之分化及增殖中甚為關鍵,該等Th1及Th17細胞係在自體免疫中起關鍵作用之兩種效應T細胞譜系。IL-23係由p40亞單元以及獨特之p19亞單元構成。IL-23經由由IL-23R及IL-12Rβ1構成之異二聚體受體起作用,其對於Th17細胞之存活及擴增至關重要,該等Th17細胞產生促發炎細胞介素,例如IL-17A、IL-17F、IL-6及TNF-α (McGeachy, M.J.等人,「The link between IL-23 and Th17 cell-mediated immune pathologies」,Semin. Immunol.
, 19:372-376 (2007))。該等細胞介素在調介多種自體免疫疾病(包括類風濕性關節炎、多發性硬化、發炎性腸病及狼瘡)之病理學方面甚為關鍵。除與IL-23共有之p40亞單元以外,IL-12亦含有p35亞單元,且經由由IL-12Rβ1及IL-12Rβ2構成之異二聚體受體起作用。IL-12對於Th1細胞發育及IFNγ之分泌至關重要,該IFNγ係一種細胞介素,其藉由刺激MHC表現、將B細胞類別轉換為IgG亞類且活化巨噬細胞在免疫中起關鍵作用(Gracie, J.A.等人,「Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass」,Eur. J. Immunol.
, 26:1217-1221 (1996);Schroder, K.等人,「Interferon-gamma: an overview of signals, mechanisms and functions」,J. Leukoc. Biol.
, 75(2):163-189 (2004))。
含有p40之細胞介素在自體免疫中之重要性藉由以下發現得以證實:在多發性硬化、類風濕性關節炎、發炎性腸病、狼瘡及牛皮癬等模型中,p40、p19或IL-23R缺陷之小鼠受保護免於疾病(Kyttaris, V.C.等人,「Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice」,J. Immunol.
, 184:4605-4609 (2010);Hong, K.等人,「IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder」,J. Immunol.
, 162:7480-7491 (1999);Hue, S.等人,「Interleukin-23 drives innate and T cell-mediated intestinal inflammation」,J. Exp. Med.
, 203:2473-2483 (2006);Cua, D.J.等人,「Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain」,Nature
, 421:744-748 (2003);Murphy, C.A.等人,「Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation」,J. Exp. Med.
, 198:1951-1957 (2003))。
在人類疾病中,已在牛皮癬病灶中量測到p40及p19之高表現,且已在來自MS患者之腦中之活動性病灶中及在患有活動性克隆氏病(Crohn's disease)之患者之腸黏膜中鑑別出Th17細胞(Lee, E.等人,「Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris」,J. Exp. Med.
, 199:125-130 (2004);Tzartos, J.S.等人,「Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis」,Am. J. Pathol.
, 172:146-155 (2008))。亦顯示,與非活動性SLE患者中之彼等相比,活動性SLE患者中p19、p40及p35之mRNA含量顯著更高(Huang, X.等人,「Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients」,Mod. Rheumatol.
, 17:220-223 (2007)),且來自狼瘡患者之T細胞具有佔優之Th1表型(Tucci, M.等人,「Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis」,Clin. Exp. Immunol.
, 154:247-254 (2008))。
此外,全基因體關聯研究已鑑別出多個與慢性發炎性及自體免疫疾病相關之基因座,該等基因座編碼在IL-23及IL-12路徑中起作用之因子。該等基因包括IL23A、IL12A、IL12B、IL12RB1、IL12RB2、IL23R、JAK2、TYK2、STAT3及STAT4 (Lees, C.W.等人,「New IBD genetics: common pathways with other diseases」,Gut
, 60:1739-1753 (2011);Tao, J.H.等人,「Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases」,Mol. Biol. Rep.
, 38:4663-4672 (2011);Cho, J.H.等人,「Recent insights into the genetics of inflammatory bowel disease」,Gastroenterology
, 140:1704-1712 (2011))。
實際上,已顯示,抑制IL-12及IL-23二者之抗p40治療以及IL-23特異性抗p19療法有效治療包括牛皮癬、克隆氏病及牛皮癬性關節炎之疾病中之自體免疫性(Leonardi, C.L.等人,「PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)」,Lancet
, 371:1665-1674 (2008);Sandborn, W.J.等人,「Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease」,Gastroenterology
, 135:1130-1141 (2008);Gottlieb, A.等人,「Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial」,Lancet
, 373:633-640 (2009))。因此,預期抑制IL-12及IL-23之作用之藥劑可在人類自體免疫病症中具有治療益處。
包括IFNα成員以及IFNβ、IFNε、IFNκ及IFNω之I型干擾素(IFN)群組經由異二聚體IFNα/β受體(IFNAR)起作用。I型IFN在先天及適應性免疫系統二者中具有多重效應,包括活化細胞性及體液性免疫反應二者以及增強自體抗原之表現及釋放(Hall, J.C.等人,「Type I interferons: crucial participants in disease amplification in autoimmunity」,Nat. Rev. Rheumatol.
, 6:40-49 (2010))。
在患有全身性紅斑狼瘡(SLE)之患者中,大多數患者中已展現潛在致命之自體免疫疾病、干擾素(IFN)α (I型干擾素)之血清含量增加或外周血單核細胞中及受影響器官中I型IFN調控基因(所謂的IFNα印跡)之表現增加(Bennett, L.等人,「Interferon and granulopoiesis signatures in systemic lupus erythematosus blood」,J. Exp. Med.
, 197:711-723 (2003);Peterson, K.S.等人,「Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli」,J. Clin. Invest.
, 113:1722-1733 (2004)),且若干項研究已顯示,血清IFNα含量與疾病活動性及嚴重程度二者相關聯(Bengtsson, A.A.等人,「Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies」,Lupus
, 9:664-671 (2000))。IFNα在狼瘡病理學中之直接作用藉由以下觀察結果來證明:向患有惡性或病毒性疾病之患者投與IFNα可誘發狼瘡樣症候群。此外,狼瘡易感小鼠中IFNAR之缺失提供對自體免疫性、疾病嚴重程度及死亡率之高度保護(Santiago-Raber, M.L.等人,「Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice」,J. Exp. Med.
, 197:777-788 (2003)),且全基因體關聯研究已鑑別出與狼瘡相關之基因座,該等基因座編碼在I型干擾素路徑中起作用之因子,包括IRF5、IKBKE、TYK2及STAT4 (Deng, Y.等人,「Genetic susceptibility to systemic lupus erythematosus in the genomic era」,Nat. Rev. Rheumatol.
, 6:683-692 (2010);Sandling, J.K.等人,「A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE」,Eur. J. Hum. Genet.
, 19:479-484 (2011))。除狼瘡以外,有證據表明,I型干擾素介導之路徑之異常活化在其他自體免疫疾病(例如薛格連氏症候群(Sjögren's syndrome)及硬皮症)之病理學中係重要的(Båve, U.等人,「Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism」,Arthritis Rheum.
, 52:1185-1195 (2005);Kim, D.等人,「Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis」,Arthritis Rheum.
, 58:2163-2173 (2008))。因此,預期抑制I型干擾素反應作用之藥劑可在人類自體免疫病症中具有治療益處。
酪胺酸激酶2 (Tyk2)係非受體酪胺酸激酶之傑納斯激酶(Janus kinase,JAK)家族之成員,且已顯示在調控小鼠(Ishizaki, M.等人,「Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 AxesIn vivo
",J. Immunol
., 187:181-189 (2011);Prchal-Murphy, M.等人,「TYK2 kinase activity is required for functional type I interferon responsesin vivo
」,PLoS One
, 7:e39141 (2012))及人類(Minegishi, Y.等人,「Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity",Immunity
, 25:745-755 (2006))二者中之IL-12、IL-23及I型干擾素受體下游之信號轉導級聯中甚為關鍵。Tyk2介導受體誘導之對轉錄因子STAT家族成員之磷酸化,此係導致STAT蛋白二聚化及STAT依賴性促發炎基因轉錄之重要信號。Tyk2缺陷小鼠對結腸炎、牛皮癬及多發性硬化之實驗模型具有抗性,此展示Tyk2介導之信號傳導在自體免疫及有關病症中之重要性(Ishizaki, M.等人,「Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 AxesIn vivo
」,J. Immunol
., 187:181-189 (2011);Oyamada, A.等人,「Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis」,J. Immunol
., 183:7539-7546 (2009))。
在人類中,表現Tyk2之非活動性變體之個體受保護免於多發性硬化及可能之其他自體免疫病症(Couturier, N.等人,「Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility」,Brain
, 134:693-703 (2011))。全基因體關聯研究已顯示與自體免疫病症相關之其他Tyk2變體,該等自體免疫病症係例如克隆氏病、牛皮癬、全身性紅斑狼瘡及類風濕性關節炎,此進一步展示Tyk2在自體免疫中之重要性(Ellinghaus, D.等人,「Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci」,Am. J. Hum. Genet
., 90:636-647 (2012);Graham, D.等人,「Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families」,Rheumatology (Oxford)
, 46:927-930 (2007);Eyre, S.等人,「High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis」,Nat. Genet
., 44:1336-1340 (2012))。
鑒於可藉由涉及調節細胞介素及/或干擾素之治療而受益之病況,能夠調節細胞介素及/或干擾素(例如IL-12、IL-23及/或IFNα)之新穎化合物及使用該等化合物之方法可對眾多有需要之患者提供實質性治療益處。
本發明係關於下文之式I化合物,其可藉由抑制Tyk2介導之信號轉導用作IL-12、IL-23及/或IFNα之調節劑。
本發明亦提供用於製備本發明化合物之製程及中間體。
本發明亦提供醫藥組合物,其包含醫藥上可接受之載劑及至少一種本發明之化合物。
本發明亦提供藉由抑制Tyk-2介導之信號轉導調節IL-12、IL-23及/或IFNα之方法,其包含向需要此治療之宿主投與治療有效量之至少一種本發明之化合物。
本發明亦提供用於治療增殖性疾病、代謝性疾病、過敏性疾病、自體免疫疾病及發炎性疾病之方法,其包含向需要此治療之宿主投與治療有效量之至少一種本發明之化合物。
較佳實施例係用於治療發炎性及自體免疫疾病或病症之方法。出於本發明之目的,發炎性及自體免疫疾病或病症包括具有發炎性或自體免疫組分之任何疾病。
替代較佳實施例係用於治療代謝性疾病(包括2型糖尿病及動脈粥樣硬化)之方法。
本發明亦提供本發明之化合物之用途,其用於製造用於治療癌症之藥劑。
本發明亦提供用於療法中之本發明之化合物。
隨著本揭示內容之繼續,將以展開形式闡述本發明之該等及其他特徵。
相關申請案之交叉參考
本申請案主張2017年11月21日提出申請之美國臨時申請案第62/589165號之權益,該臨時申請案之揭示內容係以全文引用的方式併入本文中。
在本發明之第一態樣中,提供式(I)化合物
其中
Y係N或CR6
;
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係不存在、O或NH;
R4
及R5
獨立地係氫、經0至1個Rf
取代之C1-4
烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)-5員至7員雜環;
R6
係氫、鹵基、C1-4
烷基、C1-4
烷氧基、C1-4
鹵代烷基、C1-4
鹵代烷氧基、C3-6
環烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第二態樣中,提供式II化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係不存在、O或NH;
R4
及R5
獨立地係氫、經0至1個Rf
取代之C1-4
烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)-5員至7員雜環;
R6
係氫、鹵基、C1-4
烷基、C1-4
烷氧基、C1-4
鹵代烷基、C1-4
鹵代烷氧基、C3-6
環烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第三態樣中,提供式III化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係不存在、O或NH;
R4
及R5
獨立地係氫、經0至1個Rf
取代之C1-4
烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)-5員至7員雜環;
R6
係氫、鹵基、C1-4
烷基、C1-4
烷氧基、C1-4
鹵代烷基、C1-4
鹵代烷氧基、C3-6
環烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第4態樣中,提供根據式II之第一及第二態樣之化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係O;
R4
及R5
獨立地係氫、經0至1個Rf
取代之C1-4
烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)-5員至7員雜環;
R6
係氫、鹵基、C1-4
烷基、C1-4
烷氧基、C1-4
鹵代烷基、C1-4
鹵代烷氧基、C3-6
環烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第5態樣中,提供下式化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
R6
係氫、鹵基、C1-4
烷基、C1-4
烷氧基、C1-4
鹵代烷基、C1-4
鹵代烷氧基、C3-6
環烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第6態樣中,提供下式化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
R6
係氫、鹵基、C1-3
烷基、C1-3
烷氧基或C3-6
環烷基;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第7態樣中,提供下式化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、經0至2個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Ra
取代之C1-6
烷氧基、經0至2個Ra
取代之C2-6
烯基或經0至2個Ra
取代之C3-6
環烷基;
R3
係;
R6
係氫、鹵基、C1-3
烷基、C1-3
烷氧基或C3-6
環烷基;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第8態樣中,提供下式化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係吡啶、嗒嗪、嘧啶、吡嗪、吡唑、三唑、異噁唑、異噻唑或喹啉,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
R6
係氫、鹵基、C1-3
烷基、C1-3
烷氧基或C3-6
環烷基;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第9態樣中,提供式III化合物
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或C1-6
烷基、經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子之5員至14員雜環,每一基團經0至4個R2a
取代;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係O;
R4
及R5
獨立地係氫、經0至1個Rf
取代之C1-4
烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)-5員至7員雜環;
R6
係氫、鹵基、C1-4
烷基、C1-4
鹵代烷基、-OC1-4
鹵代烷基、OC1-4
烷基、CN、NO2
或OH;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地係氫、C1-6
烷基、C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在本發明之第10態樣中,提供下式化合物
其中
R1
係H、CD3
或C1-3
烷基;
R2
係-C(O)R2a
;或經0至1個R2a
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S之雜原子且經0至4個R2a
取代之5員至14員雜環;
R2a
在每次出現時獨立地係氫、OH、鹵基、OCF3
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)p
Rc
、經0至3個Ra
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至1個Ra
取代之-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至2個Ra
取代之-(CH2
)r
-5員至7員雜環;
R3
係;
X係O;
R6
係氫、鹵基、C1-3
烷基、C1-3
烷氧基或C3-6
環烷基;
R11
在每次出現時獨立地係氫、經0至3個Rf
取代之C1-4
烷基、CF3
、經0至1個Rf
取代之C3-10
環烷基、經0至3個Rd
取代之(CH2
)r-
苯基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rd
取代之-(CH2
)r
-5員至7員雜環;
Ra
及Ra1
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CHF2
、CN、NO2
、-(CH2
)r
ORb
、-(CH2
)r
SRb
、-(CH2
)r
C(O)Rb
、-(CH2
)r
C(O)ORb
、-(CH2
)r
OC(O)Rb
、-(CH2
)r
NR11
R11
、-(CH2
)r
C(O)NR11
R11
、-(CH2
)r
NRb
C(O)Rc
、-(CH2
)r
NRb
C(O)ORc
、-NRb
C(O)NR11
R11
、-S(O)p
NR11
R11
、-NRb
S(O)p
Rc
、-S(O)Rc
、-S(O)2
Rc
、經0至3個Rf
取代之C1-6
烷基、C1-6
鹵代烷基、經0至3個Ra
取代之C2-6
烯基、經0至3個Ra
取代之C2-6
炔基、-(CH2
)r
-3員至14員碳環或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環;
Rb
係氫、經0至3個Rd
取代之C1-6
烷基、C1-6
鹵代烷基、經0至2個Rd
取代之C3-6
環烷基或含有1至4個選自N、O及S(O)p
之雜原子且經0至3個Rf
取代之-(CH2
)r
-5員至7員雜環或經0至3個Rd
取代之(CH2
)r-
苯基;
Rc
係經0至3個Rf
取代之C1-6
烷基、經0至3個Rf
取代之(CH2
)r
-C3-6
環烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Rd
在每次出現時獨立地係氫、F、Cl、Br、OCF3
、CF3
、CN、NO2
、-ORe
、-(CH2
)r
C(O)Rc
、-NRe
Re
、-NRe
C(O)ORc
、C1-6
烷基或經0至3個Rf
取代之(CH2
)r
-苯基;
Re
在每次出現時獨立地選自氫、C1-6
烷基、C3-6
環烷基及經0至3個Rf
取代之(CH2
)r
-苯基;
Rf
在每次出現時獨立地係氫、鹵基、CN、NH2
、OH、C3-6
環烷基、CF3
、O(C1-6
烷基)或含有1至4個選自N、O及S(O)p
之雜原子之-(CH2
)r
-5員至7員雜環;
p為0、1或2;
r為0、1、2、3或4;
或其立體異構物或醫藥上可接受之鹽。
在另一態樣中,提供選自第一態樣範圍內之例示實例之化合物或其醫藥上可接受之鹽或立體異構物。
在另一態樣中,提供選自任一上述態樣範圍內之化合物之任一子組列表之化合物。
在另一態樣中,提供選自以下之化合物(IUPAC命名慣例):
6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(5-氟吡啶-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(6-甲氧基嗒嗪-3-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1-甲基-1H-吡唑-3-基)胺基]嗒嗪-3-甲醯胺;
6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(6-環丙基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(1,5-二甲基-1H-吡唑-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[5-(三氟甲基)吡啶-2-基]胺基}吡啶-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[6-(三氟甲基)嗒嗪-3-基]胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(2-甲氧基嘧啶-4-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[5-氟-4-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[5-(2-胺基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[1-(2,2,2-三氟乙基)-1H-吡唑-3-基]胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[6-(²H₃)甲氧基嗒嗪-3-基]胺基}-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(5-氰基吡啶-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
N-{2-[6-({5-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(²H₃)甲基胺甲醯基]嗒嗪-3-基}胺基)吡啶-3-基]丙-2-基}胺基甲酸甲基酯;
6-{[5-(1-氰基環丙基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[5-(嗎啉-4-基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;
6-[(5-環丙基吡嗪-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(6-甲基嗒嗪-3-基)胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[5-(三氟甲基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(5-甲基吡嗪-2-基)胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[4-(甲氧基甲基)吡啶-2-基]胺基}-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(2,6-二甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[6-(2,6-二氟苯基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
6-[(1S,2R)-2-氟環丙烷醯胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(1S,2S)-2-氟環丙烷醯胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{螺[2.2]戊烷-1-醯胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;
6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(2-甲基-2H-1,2,3-三唑-4-基)胺基]嗒嗪-3-甲醯胺;
6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
6-{[5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[5-(三氟甲氧基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1S)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1R)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;
6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲氧基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(2-環丙基-6-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[6-氟-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[5-(甲氧基甲基)吡啶-2-基]胺基}-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-({5-[(²H₃)甲氧基甲基]吡啶-2-基}胺基)-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[6-(二氟甲氧基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[6-(丙-2-基)嗒嗪-3-基]胺基}嗒嗪-3-甲醯胺;
6-[(6-第三丁基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-{[6-(二氟甲基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1S,2S)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;或
6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
或其立體異構物或醫藥上可接受之鹽。
在另一態樣中,提供選自以下之化合物(IUPAC命名慣例):
6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-[(6-環丙基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基吡啶-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{螺[2.2]戊烷-1-醯胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1S,2S)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;
6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-{[5-(三氟甲氧基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1S)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;
4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(²H₃)甲基-6-[(1R)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;或
6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(²H₃)甲基嗒嗪-3-甲醯胺
或其立體異構物或醫藥上可接受之鹽。
在另一實施例中,提供醫藥組合物,其包含一或多種式I化合物及醫藥上可接受之載劑或稀釋劑。
本發明亦係關於可用於治療與IL-12、IL-23及/或IFNα之調節相關之疾病之醫藥組合物,其係藉由作用於Tyk-2以引起信號轉導抑制來起作用,該等醫藥組合物包含式I化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑或稀釋劑。
本發明進一步係關於治療與IL-12、IL-23及/或IFNα之調節相關之疾病之方法,其包含向需要此治療之患者投與治療有效量之式I化合物。
本發明亦提供用於製備本發明化合物之製程及中間體。
本發明亦提供用於治療增殖性疾病、代謝性疾病、過敏性疾病、自體免疫疾病及發炎性疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之宿主投與治療有效量之至少一種本發明之化合物。
本發明亦提供治療發炎性疾病或自體免疫疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物。
本發明亦提供治療疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物,其中該疾病係類風濕性關節炎、多發性硬化、全身性紅斑狼瘡(SLE)、狼瘡性腎炎、皮膚狼瘡、發炎性腸病、牛皮癬、克隆氏病、牛皮癬性關節炎、薛格連氏症候群、全身性硬皮症、潰瘍性結腸炎、格雷氏病(Graves' disease)、盤狀紅斑性狼瘡、成年發作性史迪爾氏症(adult onset Stills)、全身發作性幼年型特發性關節炎、痛風、痛風性關節炎、1型糖尿病、胰島素依賴性糖尿病、敗血症、敗血性休克、志賀桿菌病(Shigellosis)、胰臟炎(急性或慢性)、腎小球性腎炎、自體免疫胃炎、糖尿病、自體免疫溶血性貧血、自體免疫嗜中性球減少症、血小板減少症、異位性皮膚炎、重症肌無力、胰臟炎(急性或慢性)、關節黏連性脊椎炎、尋常天疱瘡、古巴士德氏病(Goodpasture's disease)、抗磷脂質症候群、特發性血小板減少症、ANCA相關之血管炎、天疱瘡、川崎氏病(Kawasaki disease)、慢性發炎性去髓鞘型多發性神經病變(CIDP)、皮肌炎、多發性肌炎、眼色素層炎、格林-巴利症候群(Guillain-Barre syndrome)、自體免疫肺部發炎、自體免疫甲狀腺炎、自體免疫發炎性眼病及慢性去髓鞘型多發性神經病變。
本發明亦提供治療發炎性疾病或自體免疫疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物,其中該疾病係選自全身性紅斑狼瘡(SLE)、狼瘡性腎炎、皮膚狼瘡、克隆氏病、潰瘍性結腸炎、1型糖尿病、牛皮癬、類風濕性關節炎、全身發作性幼年型特發性關節炎、關節黏連性脊椎炎及多發性硬化。
本發明亦提供用於治療類風濕性關節炎之方法(或本發明之化合物用於製造用於治療類風濕性關節炎之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物。
另外,本發明亦提供治療病況之方法(或本發明之化合物用於製造用於治療該等病況之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物,其中該病況係選自急性骨髓性白血病、慢性骨髓性白血病、轉移性黑色素瘤、卡波西氏肉瘤(Kaposi's sarcoma)、多發性骨髓瘤、實體腫瘤、眼部新生血管及嬰兒血管瘤、B細胞淋巴瘤、全身性紅斑狼瘡(SLE)、類風濕性關節炎、牛皮癬性關節炎、多發性血管炎、特發性血小板減少紫斑症(ITP)、重症肌無力、過敏性鼻炎、多發性硬化(MS)、移植排斥、I型糖尿病、膜性腎炎、發炎性腸病、自體免疫溶血性貧血、自體免疫甲狀腺炎、冷凝集素及溫凝集素病(cold and warm agglutinin disease)、伊文氏症候群(Evans syndrome)、溶血性尿毒癥候群/血栓性血小板減少紫斑症(HUS/TTP)、類肉瘤病、薛格連氏症候群、周邊神經病變、尋常天疱瘡及氣喘。
本發明亦提供治療IL-12、IL-23及/或IFNα介導之疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物。
本發明亦提供治療IL-12、IL-23及/或IFNα介導之疾病之方法(或本發明之化合物用於製造用於治療該等疾病之藥劑之用途),其包含向需要此治療之患者投與治療有效量之式I化合物,其中該IL-12、IL-23及/或IFNα介導之疾病係受IL-12、IL-23及/或IFNα調節之疾病。
本發明亦提供治療疾病之方法,其包含向需要此治療之患者投與治療有效量之式I化合物與其他治療劑之組合。
本發明亦提供用於療法中之本發明之化合物。
在另一實施例中,式I化合物係選自例示化合物或例示化合物之組合或本文中之其他實施例。
在另一實施例中,為在下文所闡述分析中之至少一者中IC50
< 1000 nM之化合物。
本發明可在不背離其精神或基本屬性下以其他特定形式體現。本發明涵蓋本文所述本發明之較佳態樣及/或實施例之所有組合。應理解,本發明之任一及所有實施例可結合任何其他實施例來闡述其他更佳之實施例。亦應理解,較佳實施例之每一個別要素係自身獨立之較佳實施例。此外,實施例之任一要素意欲與任一實施例之任一及所有其他要素組合以闡述另一實施例。
本發明之詳細敘述
下文係本說明書及隨附申請專利範圍中所使用之術語之定義。除非另有指示,否則本文針對基團或術語所提供之初始定義適用於整個本說明書及申請專利範圍之該基團或術語(個別地或作為另一基團之一部分)。
本發明之化合物可具有一或多個不對稱中心。除非另有指示,否則本發明化合物之所有手性(鏡像異構及非鏡像異構)及外消旋形式均包括在本發明中。該等化合物中亦可存在烯烴之許多幾何異構物、C=N雙鍵及諸如此類,且所有此等穩定異構物均涵蓋在本發明中。闡述本發明化合物之順式及反式幾何異構物,且可分離為異構物之混合物或單獨之異構形式。本發明化合物可以光學活性或外消旋形式分離。業內已熟知如何製備光學活性形式,例如藉由拆分外消旋形式或藉由自光學活性起始材料合成來製備。除非明確指示具體立體化學或異構物形式,否則意欲涵蓋結構之所有手性(鏡像異構及非鏡像異構)及外消旋形式以及所有幾何異構形式。
當任一變量(例如R3
)在化合物之任一成分或結構式中出現一次以上時,其在每次出現時之定義均獨立於其在其他每個情況下出現時之定義。因此,舉例而言,若基團顯示經0至2個R3
取代,則該基團可視情況經最多兩個R3
基取代,且R3
在每次出現時係獨立於R3
之定義來選擇。同樣,取代基及/或變量之組合僅在此等組合可產生穩定化合物時才容許存在。
當至取代基之鍵顯示為與連結環中兩個原子之鍵交叉時,則此取代基可鍵結至該環上之任一原子。在列示取代基但未指示此取代基經由哪個原子鍵結至具有給定結構式之化合物的其餘部分上時,則此取代基可經由此取代基中之任一原子來鍵結。取代基及/或變量之組合僅在此等組合可產生穩定化合物時才容許存在。
在本發明化合物上存在氮原子(例如胺)之情形下,可藉由使用氧化劑(例如MCPBA及/或過氧化氫)進行處理而將該等氮原子轉化成N-氧化物以提供本發明之其他化合物。因此,所有所顯示及主張之氮原子均視為涵蓋所顯示氮及其N-氧化物(N®O)衍生物二者。
不在兩個字母或符號之間之破折號「-」用於指示取代基之連接點。舉例而言,-CONH2
係經由碳原子進行連接。
提及式I化合物之特定部分之術語「視情況經取代」(例如視情況經取代之雜芳基)係指具有0、1、2或更多個取代基之部分。舉例而言,「視情況經取代之烷基」涵蓋如下文所定義之「烷基」及「經取代之烷基」二者。熟習此項技術者應理解,對於任一含有一或多個取代基之基團而言,此等基團並不意欲引入任一在空間上不實際、在合成上不可行及/或固有地不穩定之取代或取代模式。
如本文所使用,術語「至少一種化學實體」可與術語「化合物」互換使用。
如本文所使用,術語「烷基」或「伸烷基」意欲包括具有指定碳原子數之具支鏈及直鏈飽和脂肪族烴基團。舉例而言,「C1 -10
烷基」(或伸烷基)意欲包括C1
、C2
、C3
、C4
、C5
、C6
、C7
、C8
、C9
及C10
烷基。另外,舉例而言,「C1
-C6
烷基」表示具有1至6個碳原子之烷基。烷基可未經取代或經取代以使得其一或多個氫經另一化學基團替代。實例烷基包括(但不限於)甲基(Me)、乙基(Et)、丙基(例如,正丙基及異丙基)、丁基(例如,正丁基、異丁基、第三丁基)、戊基(例如,正戊基、異戊基、新戊基)及諸如此類。
「烯基」或「伸烯基」意欲包括具有直鏈或具支鏈構形且具有一或多個可在沿鏈之任一穩定點存在之碳-碳雙鍵之烴鏈。舉例而言,「C2 -6
烯基」(或伸烯基)意欲包括C2
、C3
、C4
、C5
及C6
烯基。烯基之實例包括(但不限於)乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基及諸如此類。
「炔基」或「伸炔基」意欲包括具有直鏈或具支鏈構形且具有一或多個可在沿鏈之任一穩定點存在之碳-碳三鍵之烴鏈。舉例而言,「C2-6
炔基」(或伸炔基)意欲包括C2
、C3
、C4
、C5
及C6
炔基;例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及諸如此類。
當術語「烷基」與另一基團一起使用時(例如在「芳基烷基」中),此連詞更具體地定義經取代烷基所含有之至少一個取代基。舉例而言,「芳基烷基」係指如上文所定義之至少一個取代基係芳基(例如苄基)之經取代烷基。因此,術語芳基(C0-4
)烷基包括具有至少一個芳基取代基之經取代之低碳數烷基且亦包括直接鍵結至另一基團之芳基(即,芳基(C0
)烷基)。術語「雜芳基烷基」係指如上文所定義之至少一個取代基係雜芳基之經取代烷基。
在提及經取代之烯基、炔基、伸烷基、伸烯基或伸炔基時,該等基團經一至三個如上文針對經取代烷基所定義之取代基所取代。
術語「烷氧基」係指經如本文所定義之烷基或經取代烷基取代之氧原子。舉例而言,術語「烷氧基」包括基團-O-C1-6
烷基,例如甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、戊氧基、2-戊基氧基、異戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基及諸如此類。「低碳數烷氧基」係指具有一至四個碳之烷氧基。
應理解,由熟習此項技術者來選擇所有基團(例如包括烷氧基、硫烷基及胺基烷基)以提供穩定化合物。
如本文所使用之術語「經取代」意指,指定原子或基團上之任一或多個氫經所選指示基團替代,條件係不超過指定原子之正常化合價。當取代基係側氧基或酮基(即,=O)時,則原子上之2個氫經替代。酮基取代基不存在於芳香族部分上。除非另有規定,否則取代基將被命名於核心結構中。舉例而言,應理解,在將(環烷基)烷基列示為可能取代基時,此取代基至核心結構之連接點位於烷基部分中。如本文所使用之環雙鍵係在兩個毗鄰環原子之間形成之雙鍵(例如,C=C、C=N或N=N)。
取代基及/或變量之組合僅在此等組合產生穩定化合物或有用合成中間體時才容許存在。穩定化合物或穩定結構意欲暗示足夠穩健以經受自反應混合物至有用純度之分離且隨後調配成有效治療劑之化合物。較佳地,本發明所列舉之化合物不含N-鹵基、S(O)2
H或S(O)H基團。
術語「環烷基」係指環狀烷基,包括單環、二環或多環系統。C3-7
環烷基意欲包括C3
、C4
、C5
、C6
及C7
環烷基。實例環烷基包括(但不限於)環丙基、環丁基、環戊基、環己基、降莰基及諸如此類。如本文所使用,「碳環」或「碳環殘基」欲意指任何穩定之3員、4員、5員、6員或7員單環或二環,或7員、8員、9員、10員、11員、12員或13員二環或三環,其中之任一者可為飽和的、部分不飽和的、不飽和的或芳香族的。此等碳環之實例包括(但不限於)環丙基、環丁基、環丁烯基、環戊基、環戊烯基、環己基、環庚烯基、環庚基、環庚烯基、金剛烷基、環辛基、環辛烯基、環辛二烯基、[3.3.0]二環辛烷、[4.3.0]二環壬烷、[4.4.0]二環癸烷、[2.2.2]二環辛烷、茀基、苯基、萘基、二氫茚基、金剛烷基、蒽基及四氫萘基(四氫萘)。如上文所示,橋接環亦包括於碳環之定義中(例如,[2.2.2]二環辛烷)。除非另有指定,否則較佳碳環係環丙基、環丁基、環戊基、環己基及苯基。在使用術語「碳環」時,其意欲包括「芳基」。在一或多個碳原子連接兩個非毗鄰碳原子時,產生橋接環。較佳橋係一或兩個碳原子。應注意,橋總是將單環轉化成二環。在橋接環時,針對該環列舉之取代基亦可存在於橋上。
術語「芳基」係指在環部分中具有6至12個碳原子之單環或二環芳香族烴基團(例如苯基及萘基),其中之每一者可經取代。
因此,在式I化合物中,術語「環烷基」包括環丙基、環丁基、環戊基、環己基、環庚基、二環辛基等,以及以下環系統:
及諸如此類,其視情況可在環之任一可用原子處經取代。較佳環烷基包括環丙基、環戊基、環己基及。
術語「鹵基」或「鹵素」係指氯、溴、氟及碘。
術語「鹵代烷基」意指具有一或多個鹵基取代基之經取代烷基。舉例而言,「鹵代烷基」包括單氟甲基、二氟甲基及三氟甲基。
術語「鹵代烷氧基」意指具有一或多個鹵基取代基之烷氧基。舉例而言,「鹵代烷氧基」包括OCF3
。
術語「雜環(heterocycle)」、「雜環烷基」、「雜環(heterocyclo)」、「雜環(heterocyclic)」或「雜環基」可互換使用且係指經取代及未經取代之3員至7員單環基團、7員至11員二環基團及10員至15員三環基團,其中至少一個環具有至少一個雜原子(O、S或N),該含雜原子環較佳地具有1、2或3個選自O、S及N之雜原子。此一基團中含有雜原子之每一環可含有一或兩個氧或硫原子及/或一至四個氮原子,條件係每一環中之雜原子之總數量為4或以下,且另一條件係該環含有至少一個碳原子。氮及硫原子可視情況經氧化且氮原子可視情況經四級銨化。構成二環及三環基團之稠合環可僅含有碳原子且可為飽和的、部分地飽和的或完全不飽和的。雜環基團可連接在任一可用氮或碳原子處。如本文所使用,術語「雜環(heterocycle)」、「雜環烷基」、「雜環(heterocyclo)」、「雜環(heterocyclic)」及「雜環基」包括如下文所定義之「雜芳基」。
除下文所闡述之雜芳基以外,例示性單環雜環基包括氮雜環丁基、吡咯啶基、氧雜環丁基、咪唑啉基、噁唑啶基、異噁唑啉基、噻唑啶基、異噻唑啶基、四氫呋喃基、六氫吡啶基、六氫吡嗪基、2-側氧基六氫吡嗪基、2-側氧基六氫吡啶基、2-側氧基吡咯啶基、2-側氧基氮呯基、氮呯基、1-吡啶酮基(1-pyridonyl)、4-六氫吡啶酮基、四氫吡喃基、嗎啉基、硫嗎啉基、硫嗎啉基亞碸、硫嗎啉基碸、1,3-二氧雜環戊烷及四氫-1,1-二側氧基噻吩基及諸如此類。例示性二環雜環基團包含奎寧環基。其他單環雜環基包括及。
術語「雜芳基」係指在至少一個環中具有至少一個雜原子(O、S或N)之經取代及未經取代之芳香族5員或6員單環基團、9員或10員二環基團及11員至14員三環基團,該含雜原子環較佳地具有1、2或3個選自O、S及N之雜原子。雜芳基中含有雜原子之每一環可含有一或兩個氧或硫原子及/或一至四個氮原子,條件係每一環中之雜原子之總數量為4或以下且每一環具有至少一個碳原子。構成二環及三環基團之稠合環可僅含有碳原子且可為飽和的、部分飽和的或不飽和的。氮及硫原子可視情況經氧化且氮原子可視情況經四級銨化。二環或三環雜芳基必須包含至少一個完全芳香族環,但一或多個其他稠合環可為芳香族或非芳香族。雜芳基可連接在任一環之任一可用氮或碳原子處。只要化合價容許,若該另一環係環烷基或雜環,則其另外視情況經=O (側氧基)取代。
例示性單環雜芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、異噁唑基、噻唑基、噻二唑基、異噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、嗒嗪基、三嗪基及諸如此類。
例示性二環雜芳基包括吲哚基、苯并噻唑基、苯并二氧雜環戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氫異喹啉基、異喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色原酮基、香豆素基、苯并吡喃基、㖕啉基、喹喏啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氫異吲哚基、四氫喹啉基及諸如此類。
例示性三環雜芳基包括咔唑基、苯并吲哚基(benzidolyl)、菲咯啉基(phenanthrollinyl)、吖啶基、菲啶基、𠮿基及諸如此類。
除非另有指示,否則在提及具體命名之芳基(例如苯基)、環烷基(例如環己基)、雜環(例如吡咯啶基、六氫吡啶基及嗎啉基)或雜芳基(例如四唑基、咪唑基、吡唑基、三唑基、噻唑基及呋喃基)時,若適當,則所提及者意欲包括具有0至3個、較佳地0至2個選自上文針對芳基、環烷基、雜環及/或雜芳基所列舉之彼等之取代基之環。
術語「碳環基」或「碳環」係指其中所有環之所有原子均為碳之飽和或不飽和單環或二環。因此,該術語包括環烷基及芳基環。單環碳環具有3至6個環原子、仍更通常5或6個環原子。二環碳環具有7至12個例如排列為二環[4,5]、[5,5]、[5,6]或[6,6]系統之環原子或9個或10個排列為二環[5,6]或[6,6]系統之環原子。單環碳環及二環碳環之實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、1-環己-1-烯基、1-環己-2-烯基、1-環己-3-烯基、苯基及萘基。碳環可經取代,在該情形下,取代基係選自上文針對環烷基及芳基所列舉之彼等。
術語「雜原子」應包括氧、硫及氮。
在術語「不飽和」在本文中用於指環或基團時,該環或基團可為完全不飽和或部分不飽和的。
在整個本說明書中,基團及其取代基可由熟習此項技術者進行選擇以提供可用作醫藥上可接受之化合物之穩定部分及化合物及/或可用於製備醫藥上可接受之化合物之中間體化合物。
式I化合物可以游離形式(無離子化)存在或可形成亦在本發明範圍內之鹽。除非另有指示,否則提及本發明化合物應理解為包括提及其游離形式及鹽。術語「鹽」表示利用無機及/或有機酸及鹼形成之酸性及/或鹼性鹽。另外,術語「鹽」可包括兩性離子(內鹽),例如在式I化合物含有鹼性部分(例如胺或吡啶或咪唑環)及酸性部分(例如羧酸)二者時。醫藥上可接受(即無毒、生理上可接受)之鹽較佳,例如其中陽離子並不顯著促成鹽之毒性或生物活性之可接受之金屬及胺鹽。然而,其他鹽亦可用於(例如)可用於製備期間之分離或純化步驟中,且由此涵蓋於本發明範圍內。舉例而言,可藉由使式I化合物與一定量(例如一當量)酸或鹼在諸如可沈澱鹽之介質等介質中或在水性介質中反應、之後凍乾來形成式I化合物之鹽。
例示性酸加成鹽包括乙酸鹽(例如,利用乙酸或諸如三氟乙酸等三鹵代乙酸所形成之彼等)、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二葡萄糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、富馬酸鹽、葡庚酸鹽、葡庚酸鹽、半硫酸鹽、庚酸鹽、已酸鹽、鹽酸鹽(利用鹽酸形成)、氫溴酸鹽(利用溴化氫形成)、氫碘酸鹽、2-羥基乙磺酸鹽、乳酸鹽、馬來酸鹽(利用馬來酸形成)、甲烷磺酸鹽(利用甲烷磺酸形成)、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、草酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、柳酸鹽、琥珀酸鹽、硫酸鹽(例如利用硫酸所形成之彼等)、磺酸鹽(例如本文所提及之彼等)、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽(toluenesulfonate、tosylate)、十一烷酸鹽及諸如此類。
例示性鹼性鹽包括銨鹽;鹼金屬鹽,例如鈉鹽、鋰鹽及鉀鹽;鹼土金屬鹽,例如鈣鹽及鎂鹽;鋇鹽、鋅鹽及鋁鹽;與有機鹼(例如,有機胺)之鹽,例如三烷基胺(例如三乙胺)、普魯卡因(procaine)、二苄基胺、N-苄基-β-苯乙胺、1-麻黃胺(1-ephenamine)、N,N'-
二苄基乙二胺、去氫松香胺、N-乙基六氫吡啶、苄胺、二環己基胺或類似之醫藥上可接受之胺;及與胺基酸(精胺酸、離胺酸及諸如此類)之鹽。可使用諸如以下等試劑使鹼性含氮基團四級銨化:低碳數烷基鹵化物(例如,甲基、乙基及丁基之氯化物、溴化物及碘化物)、硫酸二烷基酯(例如,硫酸二甲酯、硫酸二乙酯、硫酸二丁酯及硫酸二戊酯)、長鏈鹵化物(例如,癸基、月桂基、肉豆蔻基及硬脂基之氯化物、溴化物及碘化物)、芳烷基鹵化物(例如,苄基及苯乙基之溴化物)及其他。較佳鹽包括單鹽酸鹽、硫酸氫鹽、甲磺酸鹽、磷酸鹽或硝酸鹽。
本文所採用之片語「醫藥上可接受」係指在合理藥學判斷範圍內適於與人類及動物組織接觸使用且無過度毒性、刺激性、過敏反應或其他問題或併發症且與合理益處/風險比率相稱之彼等化合物、材料、組合物及/或劑型。
如本文所使用,「醫藥上可接受之鹽」係指所揭示化合物之衍生物,其中藉由製備其酸式或鹼式鹽來修飾母體化合物。醫藥上可接受之鹽之實例包含(但不限於)鹼性基團(例如胺)之礦物或有機酸鹽;及酸性基團(例如羧酸)之鹼性或有機鹽。醫藥上可接受之鹽包括自(例如)無毒無機酸或有機酸形成之母體化合物之習用無毒鹽或四級銨鹽。舉例而言,此等習用無毒鹽包括源自無機酸之彼等,該等無機酸係(例如)鹽酸、氫溴酸、硫酸、胺基磺酸、磷酸及硝酸;及自有機酸製備之鹽,該等有機酸係(例如)乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、巴莫酸、馬來酸、羥基馬來酸、苯乙酸、麩胺酸、苯甲酸、柳酸、磺胺酸、2-乙醯氧基苯甲酸、富馬酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸及羥乙磺酸及諸如此類。
本發明之醫藥上可接受之鹽可藉由習用化學方法自含有鹼性或酸性部分之母體化合物來合成。通常,可藉由在水或有機溶劑或二者之混合物中使該等化合物之游離酸或鹼形式與化學計量量之適宜鹼或酸進行反應來製備此等鹽;通常,如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈等非水性介質較佳。適宜鹽之列表可參見Remington's Pharmaceutical Sciences
,第18版,Mack Publishing Company,Easton, PA (1990),其揭示內容係以引用的方式併入本文中。
本發明涵蓋本發明化合物之所有立體異構物,其係呈混合物形式或呈純淨形式或呈實質上純淨之形式。立體異構物可包括因具有一或多個手性原子而係光學異構物之化合物以及因受限於圍繞一或多個鍵旋轉而係光學異構物之化合物(阻轉異構物)。本發明化合物之定義囊括所有可能之立體異構物及其混合物。其極尤其囊括外消旋形式及具有指定活性之分離光學異構物。可藉由物理方法(例如分段結晶、非鏡像異構物衍生物之分離或結晶或藉由手性管柱層析之分離)來拆分外消旋形式。可利用習用方法(例如使用光學活性酸形成鹽,之後結晶)自外消旋物來獲得個別光學異構物。
本發明意欲包括在本發明化合物中出現之原子之所有同位素。同位素包括具有相同原子序數但具有不同質量數之彼等原子。概括舉例而言但不加以限制,氫之同位素包括氘及氚。碳之同位素包括13
C及14
C。經同位素標記之本發明化合物通常可藉由熟習此項技術者已知之習用技術來製備,或藉由與本文所述之彼等類似之方法使用適當經同位素標記之試劑代替原本採用之未經標記之試劑來製備。
亦涵蓋本發明化合物之前藥及溶劑合物。術語「前藥」表示在向個體投與後藉由代謝或化學過程發生化學轉化以產生式I化合物及/或其鹽及/或溶劑合物之化合物。將在活體內轉化以提供生物活性劑(即,式I化合物)之任一化合物係在本發明之範圍及精神內之前藥。舉例而言,含有羧基之化合物可形成生理學可水解之酯,該等酯本身藉由在體內水解以產生式I化合物來用作前藥。此等前藥較佳經口投與,此乃因在多種情況下,水解主要在消化酶之影響下進行。倘若酯本身具有活性,或在血液中進行水解之彼等情況下,可使用非經腸投與。式I化合物之生理學可水解之酯之實例包括C1-6
烷基苄基、4-甲氧基苄基、二氫茚基、鄰苯二甲醯基、甲氧基甲基、C1-6
烷醯基氧基-C1-6
烷基(例如乙醯氧基甲基、新戊醯基氧基甲基或丙醯基氧基甲基)、C1-6
烷氧基羰基氧基-C1-6
烷基(例如甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基、甘胺醯基氧基甲基、苯基甘胺醯基氧基甲基、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)-甲基)之酯及用於(例如)青黴素(penicillin)及頭孢菌素(cephalosporin)技術中之其他熟知生理學可水解酯。此等酯可藉由業內已知之習用技術來製備。
前藥之各種形式為業內所熟知。此等前藥衍生物之實例可參見如下:
a) Bundgaard, H.編輯,Design of Prodrugs
, Elsevier (1985)及Widder, K.等人編輯,Methods in Enzymology
, 112:309-396, Academic Press (1985);
b) Bundgaard, H.,第5章,「Design and Application of Prodrugs」,Krosgaard-Larsen, P.等人編輯,A Textbook of Drug Design and Development
,第113-191頁,Harwood Academic Publishers (1991);及
c) Bundgaard, H.,Adv.Drug Deliv.Rev.
, 8:1-38 (1992),
其各自係以引用的方式併入本文中。
式I化合物及其鹽可以其互變異構形式存在,其中氫原子轉置至分子之其他部分上且由此分子原子之間之化學鍵發生重排。應理解,可存在之所有互變異構形式均包括在本發明內。另外,本發明化合物可具有反式及順式異構物。
進一步應理解,式I化合物之溶劑合物(例如水合物)亦在本發明之範圍內。溶劑化方法為業內所眾所周知。
效用
本發明之化合物調節IL-23刺激及IFNα刺激之細胞功能,包括基因轉錄。可受本發明之化合物調節之其他類型之細胞功能包括(但不限於) IL-12刺激之反應。
因此,式I化合物可藉由作用於Tyk2以介導信號轉導來用於治療與IL-23或IFNα功能之調節且具體而言對IL-23、IL-12及/或IFNα功能之選擇性抑制相關之病況。此等病況包括IL-23、IL-12或IFNα相關之疾病,其中該等細胞介素介導發病機制。
如本文所使用,術語「治療(treating或treatment)」涵蓋治療哺乳動物、具體而言人類之疾病狀態,且包括:(a) 預防或延遲哺乳動物之該疾病狀態之發生,尤其當此哺乳動物易感染該疾病狀態但尚未確診為患有該疾病狀態時;(b) 抑制疾病狀態,即阻止其發展;及/或(c )達成症狀或疾病狀態之全部或部分降低及/或緩解、改善、減輕或治癒該疾病或病症及/或其症狀。
鑒於其作為IL-23、IL-12及IFNα刺激之細胞反應之調節劑活性,式I化合物可用於治療IL-23、IL-12或IFNα相關之疾病,該等疾病包括(但不限於)發炎性疾病,例如克隆氏病、潰瘍性結腸炎、氣喘、移植物抗宿主病、同種異體移植物排斥、慢性阻塞性肺病;自體免疫疾病,例如格雷氏病、類風濕性關節炎、全身性紅斑狼瘡、皮膚狼瘡、狼瘡性腎炎、盤狀紅斑性狼瘡、牛皮癬;自發炎性疾病,包括CAPS、TRAPS、FMF、成年發作性史迪爾氏症、全身發作性幼年型特發性關節炎、痛風、痛風性關節炎;代謝性疾病,包括2型糖尿病、動脈粥樣硬化、心肌梗塞;毀壞性骨病症,例如骨質吸收疾病、骨關節炎、骨質疏鬆症、多發性骨髓瘤相關骨病症;增殖性病症,例如急性骨髓性白血病、慢性骨髓性白血病;血管生成性病症,例如血管生成性病症,包括實體腫瘤、眼部新生血管及嬰兒血管瘤;傳染病,例如敗血症、敗血性休克及志賀桿菌病;神經退化性疾病,例如阿茲海默氏病(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、由創傷性損傷引起之大腦局部缺血或神經退化性疾病;腫瘤性及病毒性疾病,分別例如轉移性黑色素瘤、卡波西氏肉瘤、多發性骨髓瘤及HIV感染及CMV視網膜炎、AIDS。
更具體而言,可利用本發明化合物治療之特定病況或疾病包括(但不限於)胰臟炎(急性或慢性)、氣喘、過敏症、成人呼吸窘迫症候群、慢性阻塞性肺病、腎小球性腎炎、類風濕性關節炎、全身性紅斑狼瘡、皮膚狼瘡、狼瘡性腎炎、盤狀紅斑性狼瘡、硬皮病、慢性甲狀腺炎、格雷氏病、自體免疫性胃炎、糖尿病、自體免疫性溶血性貧血、自體免疫性嗜中性球減少症、血小板減少症、特應性皮炎、慢性活動性肝炎、重症肌無力、多發性硬化、發炎性腸病、潰瘍性結腸炎、克隆氏病、牛皮癬、移植物抗宿主病、由內毒素誘導之發炎反應、結核病、動脈粥樣硬化、肌肉變性、惡病質、牛皮癬性關節炎、雷德氏症候群(Reiter's syndrome)、痛風、創傷性關節炎、風疹性關節炎、急性滑膜炎、胰臟β-細胞疾病;以大量嗜中性球浸潤為特徵之疾病;類風濕性脊柱炎、痛風性關節炎及其他關節炎性病況、腦性瘧疾、慢性肺發炎性疾病、矽肺病、肺類肉瘤病、骨質吸收疾病、同種異體移植物排斥、因感染所致之發熱及肌痛、繼發於感染之惡病質、瘢痕瘤形成、瘢痕組織形成、潰瘍性結腸炎、熱病(pyresis)、流行性感冒、骨質疏鬆症、骨關節炎、急性骨髓性白血病、慢性骨髓性白血病、轉移性黑色素瘤、卡波西氏肉瘤、多發性骨髓瘤、敗血症、敗血性休克及志賀桿菌病;阿茲海默氏病、帕金森氏病、由創傷性損傷引起之大腦局部缺血或神經退化性疾病;血管生成性病症,包括實體腫瘤、眼部新生血管及嬰兒血管瘤;病毒性疾病,包括急性肝炎感染(包括A型肝炎、B型肝炎及C型肝炎)、HIV感染及CMV視網膜炎、AIDS、ARC或惡性腫瘤及疱疹;中風、心肌缺血、中風心臟病發作性局部缺血(ischemia in stroke heart attacks)、器官缺氧(organ hyposia)[或應為缺氧(hypoxia)]、血管增生、心臟及腎再灌注損傷、血栓症、心肥大、凝血酶誘導之血小板凝集、內毒血症及/或毒性休克症候群、與前列腺素內過氧化酶合酶-2相關之病況及尋常型天疱瘡。較佳治療方法係其中病況選自克隆氏病、潰瘍性結腸炎、同種異體移植物排斥、類風濕性關節炎、牛皮癬、關節黏連性脊椎炎、牛皮癬性關節炎及尋常型天疱瘡之彼等。或者,較佳治療方法係其中病況選自缺血再灌注損傷(包括由中風引起之大腦缺血再灌注損傷及由心肌梗塞引起之心臟缺血再灌注損傷)之彼等。另一較佳治療方法係病況為多發性骨髓瘤者。
當本文中使用術語「IL-23、IL-12及/或IFNα相關之病況」或「IL-23、IL-12及/或IFNα相關之疾病或病症」時,其各自意欲如同詳盡地重複一般涵蓋所有上文所鑑別之病況以及任一其他受IL-23、IL-12及/或IFNα影響之病況。
因此,本發明提供治療此等病況之方法,其包含向有需要之個體投與治療有效量之至少一種式I化合物或其鹽。「治療有效量」意欲包括在單獨投與或組合投與時有效抑制IL-23、IL-12及/或IFNα功能及/或治療疾病之本發明化合物之量。
治療IL-23、IL-12及/或IFNα相關病況之方法可包含單獨或與彼此及/或可用於治療此等病況之其他適宜治療劑組合投與式I化合物。因此,「治療有效量」亦意欲包括有效抑制IL-23、IL-12及/或IFNα功能及/或治療與IL-23、IL-12及/或IFNα相關之疾病的所主張化合物之組合之量。
此等其他治療劑之實例包括皮質類固醇、咯利普蘭(rolipram)、卡弗他丁(calphostin)、細胞介素抑制性抗發炎藥物(CSAID)、介白素-10、糖皮質激素、柳酸鹽、一氧化氮及其他免疫抑制劑;核轉位抑制劑,例如去氧精胍菌素(DSG);非類固醇抗發炎藥物(NSAID),例如布洛芬(ibuprofen)、塞來昔布(celecoxib)及羅非昔布(rofecoxib);類固醇,例如普賴松(prednisone)或地塞米松(dexamethasone);抗病毒劑,例如阿巴卡韋(abacavir);抗增殖劑,例如胺甲喋呤(methotrexate)、來氟米特(leflunomide)、FK506 (他克莫司(tacrolimus)、PROGRAF®);抗瘧疾藥,例如羥氯喹;細胞毒性藥物,例如安思平(azathiprine)及環磷醯胺;TNF-α抑制劑,例如替尼達普(tenidap)、抗TNF抗體或可溶性TNF受體及雷帕黴素(rapamycin) (西羅莫司(sirolimus)或RAPAMUNE®)或其衍生物。
在與本發明之化合物組合採用時,上述其他治療劑可以(例如)Physicians' Desk Reference
(PDR)中所指示或另外由熟習此項技術者所確定之彼等量使用。在本發明之方法中,此等其他治療劑可在本發明化合物之投與之前、與本發明化合物同時或在本發明化合物投與之後投與。本發明亦提供能夠治療IL-23、IL-12或IFNα相關病況之醫藥組合物,其係藉由抑制Tyk2介導之信號轉導起作用,該等病況包括如上文所闡述之IL-23、IL-12及/或IFNα介導之疾病。
本發明之醫藥組合物可含有其他治療劑且可藉由(例如)採用習用固體或液體媒劑或稀釋劑以及適於期望投與方式之一類醫藥添加劑(例如,賦形劑、黏合劑、防腐劑、穩定劑、矯味劑等)根據技術(例如醫藥調配物領域中熟知之彼等)來調配。
因此,本發明進一步包括包含一或多種式I化合物及醫藥上可接受之載劑之組合物。
「醫藥上可接受之載劑」係指通常為業內所接受之用於向動物、尤其哺乳動物遞送生物活性劑之介質。醫藥上可接受之載劑係根據熟習此項技術者所熟知之多種因素來調配。該等因素包括(但不限於)所調配活性劑之類型及性質;含有活性劑之組合物欲投與之個體;組合物之預期投與途徑;及所靶向之治療適應症。醫藥上可接受之載劑包括水性及非水性液體介質二者,以及多種固體及半固體劑型。此等載劑除活性劑以外亦可包括多種不同成分及添加劑,此等其他成分出於熟習此項技術者熟知之多種原因(例如,穩定活性劑、黏合劑等)而包括於調配物中。對適宜醫藥上可接受之載劑及其選擇中所涉及之因素之闡述可參見多種容易獲得之來源,例如,Remington's Pharmaceutical Sciences
, 第17版(1985),其係以全文引用的方式併入本文中。
可藉由適於欲治療病況之任一方式投與式I化合物,此可端視位點特異性治療之需要或欲遞送藥物之量而定。局部投與對於皮膚相關性疾病通常較佳,且全身性治療對於癌性或癌前病況較佳,但涵蓋其他遞送模式。舉例而言,該等化合物可以以下方式來遞送:經口,例如以錠劑、膠囊、顆粒、粉末或液體調配物(包括糖漿)之形式;局部,例如以溶液、懸浮液、凝膠或軟膏劑之形式;舌下;經頰;非經腸,例如藉由皮下、靜脈內、肌內或胸骨內注射或輸注技術(例如,作為無菌可注射水性或非水性溶液或懸浮液);經鼻,例如藉由吸入噴霧劑;局部,例如以乳霜或軟膏劑形式;經直腸,例如以栓劑形式;或脂質體方式。可投與含有無毒的醫藥上可接受之媒劑或稀釋劑之劑量單位調配物。該等化合物可以適於立即釋放或延長釋放之形式投與。立即釋放或延長釋放可利用適宜醫藥組合物或尤其在延長釋放之情形下利用諸如皮下植入物或滲透幫浦等裝置來達成。
用於局部投與之例示性組合物包括局部載劑,例如PLASTIBASE® (利用聚乙烯膠凝之礦物油)。
用於經口投與之例示性組合物包括懸浮液,其可含有(例如)微晶纖維素用於獲得容積,海藻酸或海藻酸鈉作為懸浮劑,甲基纖維素作為黏度增強劑,及甜味劑或矯味劑(例如業內已知之彼等);及立即釋放錠劑,其可含有(例如)微晶纖維素、磷酸二鈣、澱粉、硬脂酸鎂及/或乳糖及/或其他賦形劑、黏合劑、增量劑、崩解劑、稀釋劑及潤滑劑(例如業內已知之彼等)。本發明化合物亦可藉由舌下及/或經頰投與以(例如)模製、壓製或冷凍乾燥之錠劑經口遞送。例示性組合物可包括快速溶解型稀釋劑(例如甘露醇、乳糖、蔗糖及/或環糊精)。此等調配物中亦可包括高分子量賦形劑,例如纖維素(AVICEL®)或聚乙二醇(PEG);輔助黏膜黏著之賦形劑,例如羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、羧甲基纖維素鈉(SCMC)及/或馬來酸酐共聚物(例如,GANTREZ®);及控制釋放之藥劑,例如聚丙烯酸共聚物(例如,CARBOPOL 934®)。為便於製作及使用,亦可添加潤滑劑、助流劑、矯味劑、著色劑及穩定劑。
用於鼻用氣溶膠或吸入投與之例示性組合物包括可含有(例如)以下物質之溶液:苯甲醇或其他適宜防腐劑、增強吸收及/或生物利用度之吸收促進劑及/或其他增溶劑或分散劑(例如彼等業內已知者)。
用於非經腸投與之例示性組合物包括可注射溶液或懸浮液,其可含有(例如)適宜無毒的非經腸可接受之稀釋劑或溶劑,例如甘露醇、1,3-丁二醇、水、林格氏溶液(Ringer's solution)、等滲氯化鈉溶液或其他適宜分散劑或潤濕劑及懸浮劑,包括合成之單酸甘油酯或二酸甘油酯及脂肪酸(包括油酸)。
用於直腸投與之例示性組合物包括栓劑,其可含有(例如)適宜之非刺激性賦形劑,例如可可脂、合成性甘油酯或聚乙二醇,該等在常溫下為固體但在直腸腔中液化及/或溶解以釋放藥物。
熟習此項技術者可確定本發明化合物之治療有效量,且對於哺乳動物,其包括之劑量實例為每天約0.05 mg/kg體重至1000 mg/kg體重、1 mg/kg體重至1000 mg/kg體重、1 mg/kg體重至50 mg/kg體重、5 mg/kg體重至250 mg/kg體重、250 mg/kg體重至1000 mg/kg體重之活性化合物,該活性化合物可呈單一劑量或個別分開劑量形式投與,例如每天1至4次。應理解,對於任一特定個體,具體劑量及劑量頻率可變化且將端視於多種因素而定,包括所採用具體化合物之活性;該化合物之代謝穩定性及作用時間長度;個體之物種、年齡、體重、整體健康狀況、性別及飲食;投與模式及時間;排泄速率;藥物組合;及特定病況之嚴重程度。接受治療之較佳個體包括動物,最佳為哺乳動物物種,例如人類,及家畜,例如狗、貓、馬及諸如此類。因此,在本文中使用術語「患者」時,此術語意欲包括所有個體,最佳為受IL-23、IL-12及/或IFNα介導之功能之調節影響的哺乳動物物種。
製備方法
可藉由熟習有機化學技術者可獲得之許多方法來合成本發明之化合物。下文闡述製備本發明之化合物之一般合成方案。該等方案係說明性的且並不意欲限制熟習此項技術者可用於製備本文所揭示化合物之可能技術。熟習此項技術者將明瞭製備本發明之化合物之不同方法。另外,可以交替順序實施合成中之各個步驟以得到一或多種期望化合物。藉由一般方案中所闡述之方法製備之本發明化合物之實例係在下文所陳述之製備及實例部分中給出。
實例
式(I)化合物之製備及用於製備式(I)化合物之中間體可使用以下實例中所顯示之程序及相關程序來製備。該等實例中所使用之方法及條件以及該等實例中所製備之實際化合物並非意欲具有限制性,但意欲展示可如何製備式(I)化合物。該等實例中所使用之起始材料及試劑在並非藉由本文所闡述程序製備時通常係自市面購得或報導於化學文獻中,或可藉由使用化學文獻中所闡述之程序來製備。
在所給實例中,片語「乾燥並濃縮」通常係指在有機溶劑中之溶液經硫酸鈉或硫酸鎂乾燥,之後過濾並自濾液去除溶劑(通常在減壓下且在適於所製備材料穩定性之溫度下)。使用Isco中壓層析設備(Teledyne Corporation)利用預填充矽膠柱用所指示溶劑或溶劑混合物溶析來實施管柱層析。使用ChemDraw Ultra 9.0.5版(CambridgeSoft)確定化學名稱。使用以下縮寫:縮寫
製備
下文所陳述之製備係針對不自商業來源獲得且用於本發明之式I化合物之製備的試劑之合成。除非另有指定,否則表格及方案中之所有手性化合物均係外消旋的。
利用Shimadzu 8A液相層析儀使用YMC S5 ODS管柱(20 × 100、20 × 250或30 × 250毫米(「mm」))來實施反相製備型高效液相層析(「HPLC」)。在0.1%三氟乙酸(「TFA」)存在下利用甲醇(「MeOH」)/水混合物來實施梯度溶析。
實例之表徵中所採用之分析型HPLC方法
使用以下方法在Shimadzu LC10AS液相層析儀上來實施分析型HPLC:
方法A (除非另有指示,否則在所有情形中均使用):
0%至100%溶劑B之線性梯度經4分鐘(「min」),其中在100% B下保持1分鐘(「min」)
在220奈米(「nm」)下紫外(「UV」)可視化
管柱:YMC S5 ODS Ballistic 4.6 × 50 mm
流速:4毫升(「mL」)/min
溶劑A:0.2%磷酸、90%水、10%甲醇
溶劑B:0.2%磷酸、90%甲醇、10%水
方法B:
管柱:PHENOMENEX® Luna C18(2), 4.6 × 50 mm × 5 µm
移動相:(A) 10:90甲醇:水;(B) 90:10甲醇:水
緩衝液:0.1% TFA
梯度範圍:0%至100% B
梯度時間:4 min
流速:4 mL/min
分析時間:5 min
檢測:
檢測器1:220 nm下之UV
檢測器2:MS(ESI+
)
檢測器3:ELSD
方法C:
管柱:Waters SunFire C18, 4.6 × 50 mm × 5 µm
移動相:(A) 10:90甲醇:水;(B) 90:10甲醇:水
緩衝液:0.1% TFA
梯度範圍:0%至100% B
梯度時間:4 min
流速:4 mL/min
分析時間:5 min
檢測:
檢測器1:220 nm下之UV
檢測器2:MS(ESI+
)
檢測器3:ELSD
方法D:
管柱:Acquity BEH C18, 2.1 × 50 mm × 1.7 μm
移動相:(A)水;(B)乙腈
緩衝液:0.05% TFA
梯度範圍:2%至98% B (1 min);98% B (0.5 min);98%至2% B (0.6 min)
運行時間:1.7 min
流速:0.8 mL/min
分析時間:1.7 min
檢測:
檢測器1:254 nm下之UV
檢測器2:MS(ESI+
)
方法E:
管柱:Waters XBridge C18, 2.1 × 50 mm × 1.7 µm
移動相:(A) 5: 95乙腈:水 (B) 95 : 5甲醇:水
緩衝液:0.1% TFA
梯度:0%至100% B
梯度時間:3 min
運行時間:3.75 min
流速:1 mL/min
分析時間:3.75 min
檢測:
檢測器1:254 nm下之UV
檢測器2:MS(ESI+
)
步驟1
將3-側氧基戊二酸二甲基酯(3.77 g, 21.65 mmol)溶解於乙腈(70 mL)中,且添加三乙胺(3.02 mL, 21.65 mmol)。在冷卻至0℃之後,經約5分鐘將4-乙醯胺基苯磺醯疊氮化物(5.2 g, 21.65 mmol)逐份緩慢添加至反應。在添加幾乎完成後,形成沉重黃色沈澱物。將混合物在室溫下攪拌約1 h,且然後過濾以去除沈澱固體。用少量額外之ACN沖洗濾餅,直至黃色自固體完全洗掉為止,得到白色固體及渾濁黃色濾液。將含有產物之濾液在真空中濃縮,產生黃色固體,將其於1:1己烷/Et2
O混合物(約150 mL)中製漿,且再次過濾懸浮液。用額外之少量1:1己烷/Et2
O沖洗固體且將所得黃色混濁濾液濃縮,得到4.59 g含有少量固體之黃色油狀物,其為含有2-二重氮基-3-側氧基戊二酸二甲基酯之粗產物混合物。此材料直接用於下一步驟中。
步驟2
在室溫下向粗產物2-二重氮基-3-側氧基戊二酸二甲基酯(20.92 g, 104 mmol)於二乙醚(250 mL)中之混合物添加Ph3
P (27.3 g, 104 mmol),且將所得混合物在室溫下攪拌1天。將異質反應混合物濃縮以去除醚,且將所得固體溶於AcOH (240 mL)及水(24 mL)中並回流4 h。將反應冷卻並在真空中濃縮以得到淺黃色半固體,使其與2份甲苯(2 × 50 mL)一起共蒸發以去除殘餘AcOH。然後將所得固體於75 mL飽和碳酸鈉水溶液及75 mL水中製漿,且用DCM (4 × 200 mL)萃取混合物以去除雜質。過濾水層以得到澄清黃色溶液,使其於冰浴中冷卻且藉由逐滴添加6 N aq HCl小心地使其變為酸性。一旦達到期望pH (約1至2),則形成沉重乳油色沈澱物。將混合物在0℃下攪拌約5 min,然後藉由真空過濾收集固體並用少量冰冷水沖洗。使固體在漏斗中部分風乾,然後將仍潮濕之固體轉移至圓底燒瓶中且使其在真空下乾燥整個週末,得到4,6-二羥基嗒嗪-3-甲酸甲基酯(11.76 g, 69.1 mmol,66.5%產率)。
步驟3
將4,6-二羥基嗒嗪-3-甲酸甲基酯(11.7 g, 68.8 mmol)於POCl3
(110 mL, 1180 mmol)中之漿液加熱至回流持續3 h,在此期間混合物變為幾乎均質之深棕色溶液。使反應混合物冷卻至室溫,使其靜置過夜並在真空中濃縮。將所得深棕色殘餘物溶解於DCM (約300 mL)中,且在渦漩燒瓶下緩慢地傾倒至約500 mL之碎冰上。添加完成後,緩慢添加水(約200 mL)直至混合物變得可攪拌為止,且攪拌混合物同時經約3 h升溫至室溫。將所得各相分離且用額外之DCM (3 × 100 mL)萃取水性部分。用鹽水洗滌合併之萃取物,經無水硫酸鈉乾燥,傾析並在真空下濃縮,得到白色固體,其為純淨產物4,6-二氯嗒嗪-3-甲酸甲基酯(9.16 g, 44.2 mmol,64.3%產率)。材料不經任何進一步純化即原樣使用。
MS (M+1)m/z
: 206.9 (MH+
)。LC滯留時間0.80 min [A]。
步驟4
在0℃下在攪拌下向4,6-二氯嗒嗪-3-甲酸甲基酯(5.5 g, 26.6 mmol)於THF (60 mL)中之溶液添加1 M氫氧化鋰溶液(39.9 mL, 39.9 mmol)。將所得混合物在0℃下連續攪拌40 min。去除THF且用1.5 N HCl使水層酸化,得到白色固體。將混合物過濾且將固體濾餅用水洗滌並在真空下乾燥過夜,得到4,6-二氯嗒嗪-3-甲酸(5 g, 25.9 mmol,98%產率)。
MS (M+1)m/z
: 193 (MH+
)。LC滯留時間0.19 min [D]。
步驟5
在0℃下向4,6-二氯嗒嗪-3-甲酸(0.734 g, 3.80 mmol)及3-(甲硫基)吡啶-2-胺(0.68 g, 4.85 mmol)之THF (20 mL)溶液緩慢添加LIHMDS (9.51 mL, 9.51 mmol)。將反應在0℃下攪拌15 min,且然後升溫至室溫持續2 h。用水(約5 mL)使反應淬滅並用HCl (1 N, 15 mL)酸化。將所得沈澱物過濾,用水洗滌並在真空下乾燥過夜,得到呈橙色固體之6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲酸(0.712 g, 2.40 mmol,63.1%產率)。
MS (M+1)m/z
: 297.0 (MH+
)。LC滯留時間0.86 min [A]。
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.15 (s, 1H), 8.34 (dd, J=4.9, 1.7 Hz, 1H), 7.95 (dd, J=7.7, 1.7 Hz, 1H), 7.18 (dd, J=7.7, 4.8 Hz, 1H), 2.53 (s, 3H)。
步驟6
在室溫下將1-丙烷膦酸酐(0.409 mL, 0.700 mmol)添加至6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲酸(0.1385 g, 0.467 mmol)及TEA (0.130 mL, 0.933 mmol)之DMF (1.9 mL)溶液。2 min後,形成懸浮液。將反應在室溫下攪拌1小時,之後添加甲胺(0.439 g, 4.67 mmol)。將反應在室溫下攪拌2小時,用水稀釋且將懸浮液過濾並用水洗滌。使固體在真空下乾燥過夜,得到產物6-氯-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.112 g, 0.362 mmol,78%產率,中間體1)。
MS (M+1)m/z
: 311.1 (MH+
)。LC滯留時間0.92 min [E]。
NMR (400 MHz, DMSO-d6) δ 12.35 - 12.30 (m, 1H), 9.49 (br d, J=4.4 Hz, 1H), 9.14 (s, 1H), 8.30 (dd, J=4.8, 1.4 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.16 (dd, J=7.7, 4.9 Hz, 1H), 2.88 (d, J=4.9 Hz, 3H), 2.55 (s, 3H)。
步驟1
將2-二重氮基-3-側氧基戊二酸二乙基酯(180g, 789 mmol)溶解於二乙醚(1800 mL)中,添加三苯基膦(207 g, 789 mmol),並繼續攪拌過夜。在減壓下去除二乙醚,且將濃稠之橙色物質溶解於乙酸(180 mL)及水(1800 mL)中。將澄清溶液加熱至110℃,在該溫度下維持3小時。起始材料耗盡。在減壓下去除乙酸。將所獲得之濃稠物質在約0℃下保持在冷室中1天以供結晶。添加DCM且將漿液攪拌並過濾。用DCM洗滌濾餅,且收集到作為期望產物之4,6-二羥基嗒嗪-3-甲酸乙基酯(80 g, 434 mmol,55.1%產率)。
MS (M+1)m/z
: 185.1 (MH+
)。LC滯留時間0.51 min [A]。1
H NMR (400 MHz,氯仿-d) δ 6.45 - 6.22 (m, 1H), 4.65 - 4.40 (m, 2H), 1.60 - 1.40 (m, 3H)。
步驟2
於5000 ml圓底燒瓶中,將4,6-二羥基嗒嗪-3-甲酸乙基酯(200 g, 1086 mmol)溶解於THF (2000 mL)、甲醇(1000 mL)及水(800 mL)中。在室溫下緩慢添加LiOH (137 g, 3258 mmol),且在室溫下攪拌3至4小時。起始材料消失。將溶劑在減壓下在50℃下去除,得到黃色固體。在0℃下利用HCl水溶液(400 ml)使固體酸化(1:1比率),且在室溫下攪拌30至40分鐘。過濾固體並用水洗滌。然後使其在真空下乾燥1至2小時。使此固體吸收至300 ml甲醇:DCM (2 : 8)中,且在室溫下攪拌20至25分鐘。將混合物過濾,且用甲醇洗滌固體並在真空下乾燥1小時。獲得呈黃色固體之期望產物4,6-二羥基嗒嗪-3-甲酸(153 g, 951 mmol,88%產率)。
MS (M+1)m/z
: 156.9 (MH+
)。LC滯留時間0.31 min [A]。1
H NMR (400 MHz,氧化氘) δ 6.00 - 5.34 (m, 1H), 4.75 (s, 7H)
步驟3
在110℃下將4,6-二羥基嗒嗪-3-甲酸HCl (15 g, 78 mmol)及N,N-二乙基苯胺(12.39 ml, 78 mmol)於POCl3
(200 ml)中之懸浮液在乾燥管下攪拌1 h。1 h後反應完成。將POCl3
在真空下去除且與DCE一起共蒸發3×。將粗製中間體酸性氯化物溶解於200 mL THF中。添加呈固體形式之D3-甲胺HCl鹽(2.75 g, 38.9 mmol)。使反應冷卻至0℃。添加DIPEA 2 × (13.61 ml, 78 mmol)。將冰浴移除且在室溫下攪拌反應。45 min後,反應完成。在真空下去除THF。將粗產物懸浮於DCM中,然後蒸發至矽藻土上。利用於己烷中之0%至100% EtOAc經由330 g矽膠管柱溶析此固體材料。反應產生4,6-二氯-N-[D3]-甲基嗒嗪-3-甲醯胺(6.1 g, 29.2 mmol,74.9%產率)。
MS (M+1)m/z
: 209.1 (MH+
)。LC滯留時間0.64 min [B]。13
C NMR (101 MHz,氯仿-d) δ 161.7, 158.43 - 156.22 (m, 1C), 149.8, 139.8, 130.7, 26.5
步驟4
在室溫下經5 min向4,6-二氯-N-三氘代甲基嗒嗪-3-甲醯胺及3-(甲硫基)吡啶-2-胺(0.205 g, 1.464 mmol)於THF (10 mL)中之溶液添加於THF中之雙(三甲基矽基)胺基鋰(3.59 mL, 3.59 mmol)。將所得混合物在室溫下攪拌1 h。用水(5 mL)使反應淬滅。利用1 N HCl溶液將混合物調整至pH 9至10,且進一步用水(80 mL)稀釋。藉由抽吸過濾收集呈淺色固體之沈澱產物6-氯-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.297 g, 0.950 mmol,66.2%產率,中間體2),且在真空下在50℃下乾燥。
MS (M+1)m/z
: 313.1 (MH+
)。LC滯留時間0.90 min [A]。
步驟1
在氮下在0℃下向4,6-二氯菸鹼酸(24.00 g, 125 mmol)於二氯甲烷(250 mL)中之異質白色溶液添加N,N-二甲基甲醯胺(1 mL, 12.91 mmol)。然後經12 min添加草醯氯(14 mL, 162 mmol)。15 min後,將冰水浴移除且將反應攪拌至室溫。1 h後,將N,N-二甲基甲醯胺(1 mL, 12.91 mmol)添加至仍為異質之白色溶液。總計2.5 h後,反應顯示>95%轉化為期望產物。再過30 min後,將反應在真空中濃縮。添加DCM (100 mL),且將溶液在真空中濃縮。添加另一份DCM (100 mL),且將溶液在真空中濃縮以得到粗產物,其用於下一步驟中。用乙醇使樣品淬滅。所檢測到之物質係
MS (M+1)m/z
: 220.08 (MH+
)。LC滯留時間0.95 min [B]。
步驟2
在氮下在0℃下向4,6-二氯菸鹼醯氯(26.3 g, 125 mmol)及甲-d3-胺HCl鹽(11.46 g, 163 mmol)於DCM (250 mL)中之溶液注射DIPEA (65.5 mL, 375 mmol)。20 min後,將冰水浴移除,並將反應攪拌至室溫。將反應攪拌過夜且完成。用0.5 N HCl水溶液(50 mL)洗滌反應混合物。分離各層,且用DCM (2 × 150 mL)萃取水層。將有機層合併,經Na2
SO4
乾燥,過濾並在真空中濃縮。利用矽膠層析(1.5 kg二氧化矽Gold管柱)用己烷及乙酸乙酯溶析來純化含有產物之反應混合物。以60%乙酸乙酯收集產物。獲得22.83 g淺黃色固體,使其與EtOAc (40 mL)一起研磨並用EtOAc (20 mL)沖洗,得到呈白色固體之4,6-二氯-N-(甲基-d3)菸鹼醯胺(21.93 g, 105 mmol,84%產率)。
MS (M+1)m/z
: 208.1 (MH+
)。LC滯留時間0.58 min [B]。1
H NMR (400 MHz,氯仿-d) δ 8.71 - 8.63 (m, 1H), 7.47 - 7.40 (m, 1H), 6.35 - 6.08 (m, 1H)。
步驟1
在150℃下將中間體2 (0.1028 g, 0.329 mmol,6-氯-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺)、5-氟吡啶-2-胺(0.0845 g, 0.754 mmol)、Xantphos (0.0345 g, 0.060 mmol)、碳酸銫(0.2481 g, 0.761 mmol)及Pd2
dba3
(0.0483 g, 0.053 mmol)於二噁烷(5 mL)及N-甲基-2-吡咯啶酮(1 mL)中之溶液微波處理1 h。將完成之反應混合物用乙酸乙酯(10 mL)稀釋並經由矽藻土過濾。將濾液在真空中濃縮。向殘餘物添加DMSO (1 mL)及水(20 mL),之後添加飽和NaHCO3
。收集沈澱物,過濾並用水洗滌,得到呈橙色固體之粗產物。藉由急速層析使用ISCO 4g管柱利用0%至5% MeOH/DCM (4 cv, 0%;40 cv, 0%至5%)溶析來純化粗產物。收集適當流份(2%至3%溶析)並在真空中濃縮,得到呈淺黃色固體之產物6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.035 g, 0.078 mmol,23.85%產率)。
MS (M+1)m/z
: 389.2 (MH+
)。LC滯留時間0.94 min [B]。
步驟2
向反應物6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.035 g, 0.090 mmol)於乙酸(0.3 mL)中之均質黃色溶液添加鎢酸鈉二水合物(0.0311 g, 0.094 mmol)以得到漿液。添加30%過氧化氫(0.2 mL, 1.958 mmol),此產生均質性。1.5小時後,向反應添加水(2 mL),其用乙酸乙酯(3 × 15 mL)萃取。將有機層合併且用飽和亞硫酸氫鈉水溶液(5 mL)及水(5 mL)相繼洗滌,經Na2
SO4
乾燥,過濾並將濾液在真空中濃縮。用DMSO (0.5 mL)及MeOH (1.5 mL)稀釋殘餘物且經受自動製備型HPLC。收集適當流份;添加NaHCO3
(固體),且將流份在真空中不濃縮至乾燥。用DCM (3×)萃取反應混合物,將有機層合併,經Na2
SO4
乾燥,過濾並在真空中濃縮,得到產物6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.00435 g, 10.35 µmol,11.48%產率)。
MS (M+1)m/z
: 421.1 (MH+
)。LC滯留時間0.61 min [B]。1
H NMR (400 MHz, DMSO-d6
) δ 12.26 - 11.92 (m, 1H), 10.54 - 10.32 (m, 1H), 9.67 - 9.32 (m, 1H), 9.26 - 9.05 (m, 1H), 8.87 - 8.58 (m, 1H), 8.42 - 8.19 (m, 2H), 7.88 - 7.64 (m, 2H), 7.47 - 7.15 (m, 1H)。
以下實例係以與實例1之製備類似之方式來製備。
表1
步驟1
將6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(20 mg, 0.064 mmol,中間體2)、N-((6-胺基吡啶-3-基)甲基)乙醯胺(15.84 mg, 0.096 mmol)、Pd2
(dba)3
(5.86 mg, 6.39 µmol)、Xantphos (7.40 mg, 0.013 mmol)及Cs2
CO3
(41.7 mg, 0.128 mmol)於二噁烷(1.0 mL)中之混合物用氮吹掃5 min。將反應置於預加熱之130℃加熱塊中2 h,得到中間體硫化物(M+H=442)。將溶劑濃縮且將材料再溶解於AcOH (2 mL)中。向溶液添加鎢酸鈉二水合物(6.33 mg, 0.019 mmol)及過氧化氫(98 µl, 3.20 mmol),並將混合物在室溫下攪拌1 h。添加硫代硫酸鈉(505 mg, 3.20 mmol),並將反應混合物攪拌10 min。將溶劑去除,得到6-((5-(乙醯胺基甲基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(3 mg, 5.7 µmol,8.92%產率,90%純度)。
MS (M+1)m/z
: 421.1 (MH+
)。LC滯留時間0.61 min [B]。1
H NMR (500 MHz, DMSO-d6
) δ 12.14 - 12.02 (m, 1H), 10.36 - 10.25 (m, 1H), 9.57 - 9.43 (m, 1H), 9.18 - 9.05 (m, 1H), 8.69 - 8.59 (m, 1H), 8.40 - 8.33 (m, 1H), 8.32 - 8.25 (m, 1H), 8.22 - 8.14 (m, 1H), 7.67 - 7.59 (m, 2H), 7.38 - 7.28 (m, 1H), 4.21 (br s, 3H), 3.41 - 3.33 (m, 2H), 1.89 - 1.83 (m, 3H)。
以下實例係以與實例69之產物製備類似之方式來製備。
表2
步驟1
在室溫下將雙(三甲基矽基)胺基鋰(0.581 mL, 0.581 mmol,1 M於THF中)快速添加至3-(甲基磺醯基)吡啶-2-胺(0.05 g, 0.290 mmol)及4,6-二氯-N-三氘代甲基嗒嗪-3-甲醯胺(0.073 g, 0.348 mmol)於THF (5 mL)中之溶液。在完成添加之後,將反應混合物在室溫下攪拌30分鐘。用1 N HCl及MeOH使反應混合物淬滅並在真空下濃縮。使用ISCO並利用0%至10% MeOH/DCM溶析在矽膠上層析產物。將含有產物之流份合併並在真空下濃縮,提供6-氯-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(40 mg, 0.116 mmol,40%產率)。
MS (M+1)m/z
: 345.08 (MH+
)。LC滯留時間0.71 min [A]。
步驟2
於密封容器中將6-氯-N-三氘代甲基-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.025 g, 0.073 mmol)、環丙烷甲醯胺(6.79 mg, 0.080 mmol)、參(二亞苄基丙酮)二鈀(0) (0.664 mg, 0.725 µmol)、4,5-雙(二苯基膦基)-9,9-二甲基𠮿(0.420 mg, 0.725 µmol)及碳酸銫(0.071 g, 0.218 mmol)於1,4-二噁烷(2 mL)中之攪拌混合物在130℃下加熱1小時。用乙酸乙酯(5 mL)稀釋反應混合物,過濾並將濾液濃縮。將殘餘物溶解於1 mL DMF中並利用製備型HPLC進行純化。收集期望流份並濃縮,得到6-(環丙烷甲醯胺基)-N-三氘代甲基-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(4 mg, 10.17 µmol,10.4%產率)。
MS (M+1)m/z
: 394.08 (MH+
)。LC滯留時間0.64 min [A]。1
H NMR (500 MHz, DMSO-d6
) δ 9.61 - 9.36 (m, 1H), 9.31 - 9.08 (m, 1H), 8.80 - 8.53 (m, 1H), 8.37 - 8.07 (m, 1H), 7.52 - 7.20 (m, 1H), 2.19 - 2.04 (m, 1H), 0.94 - 0.73 (m, 4H)。
以下實例係以與實例159之產物類似之方式來製備。
表3
步驟1
將6-氯-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(100 mg, 0.320 mmol,中間體2)、乙醯胺(41.5 mg, 0.703 mmol)、參(二亞苄基丙酮)二鈀(0) (43.9 mg, 0.048 mmol)、Xantphos (27.7 mg, 0.048 mmol)及碳酸銫(229 mg, 0.703 mmol)於1,4-二噁烷(6 mL)中之混合物在微波條件下在150℃下加熱1 h。用乙酸乙酯(8 mL)稀釋該混合物並經由矽藻土過濾。將濾液在真空下濃縮。向殘餘物添加DMSO (5 mL),之後添加水(55 mL)及飽和NaHCO3
溶液(3 mL)。藉由過濾收集不溶材料,且藉由ISCO (24 g矽膠,固體裝載,0%至5% MeOH/二氯甲烷)進一步純化,提供呈白色固體之期望產物6-乙醯胺基-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(21 mg, 0.063 mmol,19.58%產率)。
MS (M+1)m/z
: 336.1 (MH+
)。LC滯留時間0.67 min [B]。
步驟2
向6-乙醯胺基-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(21 mg, 0.063 mmol)於乙酸(1.5 ml)中之溶液添加鎢酸鈉二水合物(21.69 mg, 0.066 mmol),之後添加30%過氧化氫(0.192 mL, 1.878 mmol)。將溶液在室溫下攪拌過夜。起始材料硫化物耗盡,但亞碸係佔優產物。添加額外之鎢酸鈉二水合物(21.69 mg, 0.066 mmol)及30%過氧化氫(0.192 mL, 1.878 mmol)。將混合物在50℃下加熱1 h。使產物過氧化以產生N-氧化物。用水(15 mL)稀釋該混合物,利用固體Na2
CO3
鹼化並用DCM (3 × 30 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥。藉由製備型HPLC分離出呈白色固體之產物2-((6-乙醯胺基-3-(三氘代甲基胺甲醯基)嗒嗪-4-基)胺基)-3-(甲基磺醯基)吡啶1-氧化物(12 mg, 0.031 mmol,50.0%產率)。
MS (M+1)m/z
: 384.08 (MH+
)。LC滯留時間0.59 min [A]。
步驟3
向2-((6-乙醯胺基-3-(三氘代甲基胺甲醯基)嗒嗪-4-基)胺基)-3-(甲基磺醯基)吡啶1-氧化物(12 mg, 0.031 mmol)於THF (3 mL)及乙醇(1 mL)中之溶液添加10% Pd/C (24.98 mg, 0.023 mmol),之後添加環己烯(0.101 mL, 1.002 mmol)。於封閉小瓶中將混合物在80℃下加熱16 h。藉由過濾去除固相。將濾液在真空下濃縮,且使殘餘物經受ISCO (12 g矽膠,固體裝載,0%至5% MeOH/二氯甲烷)以提供呈白色固體之期望產物6-乙醯胺基-N-三氘代甲基-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(2.7 mg, 7.13 µmol,22.78%產率)。
MS (M+1)m/z
: 368.08 (MH+
)。LC滯留時間0.57 min [A]。1
H NMR (400 MHz, DMSO-d6
) δ 12.15 - 12.06 (m, 1H), 11.19 - 11.02 (m, 1H), 9.59 - 9.44 (m, 1H), 9.26 - 9.12 (m, 1H), 8.66 - 8.56 (m, 1H), 8.34 - 8.23 (m, 1H), 7.38 - 7.26 (m, 1H), 3.39 - 3.35 (s, 3H), 2.19 - 2.15 (s, 3H)。
以下實例係以與實例163之產物類似之方式來製備。
表4
步驟1
於封閉小瓶中將6-氯-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(100 mg, 0.320 mmol,中間體2)、1-甲基-1H-吡唑-3-胺(68.3 mg, 0.703 mmol)及4-甲苯磺酸一水合物(91 mg, 0.480 mmol)於THF (7 mL)中之混合物在100℃下加熱36 h。將混合物在真空下濃縮至乾燥。用DMSO (1.2 mL)及MeOH (4.8 mL)稀釋殘餘物,分成3份,且藉由製備型HPLC進行純化。將期望流份合併,在真空下濃縮,利用1.5 N K2
HPO4
溶液鹼化至pH 10,且用DCM (3 × 35 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥,過濾並在真空下濃縮,得到呈白色固體之期望產物N-三氘代甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(49 mg, 0.131 mmol,41.0%產率)。
步驟2
在室溫下向N-三氘代甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(49 mg, 0.131 mmol)於乙酸(3 mL)中之溶液一次添加全量鎢酸鈉二水合物(54.1 mg, 0.164 mmol),之後添加30%過氧化氫(0.227 mL, 3.94 mmol)。將溶液在室溫下攪拌1 h。用水(25 mL)稀釋混合物,利用固體Na2
CO3
鹼化,且用DCM (3 × 45 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥,過濾並在真空下濃縮。將殘餘物溶解於DMSO (1 mL)及MeOH (3 mL)中,將其分成兩份,並藉由製備型HPLC進行純化。將期望流份合併,在真空下濃縮,利用1 N K2
HPO4
溶液鹼化至pH 10至11,且用DCM (3 × 40 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥,過濾並在真空下濃縮,得到呈白色固體之期望產物N-三氘代甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(28 mg, 0.068 mmol,52.1%產率)。
MS (M+1)m/z
: 406.1 (MH+
)。LC滯留時間0.56 min [A]。
以下實例係以與實例166之產物類似之方式來製備。
表5
步驟1
將6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(50 mg, 0.160 mmol,中間體2)、5-(2-胺基丙-2-基)吡啶-2-胺(31.4 mg, 0.208 mmol)、Xantphos (13.87 mg, 0.024 mmol)、Pd2
(dba)3
(10.98 mg, 0.012 mmol)及Cs2
CO3
(78 mg, 0.240 mmol)於二噁烷(1.5 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。冷卻後,經由過濾收集固體且原樣用於下一反應中。
MS (M+1)m/z
: 428.35 (MH+
)。LC滯留時間0.90 min [C]。
步驟2
將6-((5-(2-胺基丙-2-基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(13 mg, 0.030 mmol)與1 mL DCM混合,添加丙-2-酮(1.766 mg, 0.030 mmol),之後添加氰基硼氫化鈉(3.82 mg, 0.061 mmol)及TEA (8.48 µl, 0.061 mmol)。將混合物在室溫下攪拌過夜。用DCM (20 mL)稀釋該混合物,用飽和NaHCO3
(10 mL)及鹽水(10 mL)洗滌,乾燥並在真空下濃縮。將所得殘餘物與AcOH (1 mL)、鎢酸鈉二水合物(3.01 mg, 9.12 µmol)且然後過氧化氫(0.155 mL, 1.520 mmol)混合。將混合物在室溫下攪拌1 h。向該混合物添加硫代硫酸鈉(961 mg, 1.520 mmol),且然後攪拌10 min。過濾該混合物並利用製備型HPLC進行純化以提供期望產物6-((5-(2-(異丙基胺基)丙-2-基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(3.8 mg, 7.5 µmol,24.66%產率)。
MS (M+1)m/z
: 502 (MH+
)。LC滯留時間1.3 min [QC-ACN-AA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 9.59 - 9.44 (m, 1H), 9.23 - 9.06 (m, 1H), 8.73 - 8.60 (m, 1H), 8.40 - 8.33 (m, 1H), 8.31 - 8.24 (m, 1H), 7.92 - 7.84 (m, 1H), 7.65 - 7.56 (m, 1H), 7.37 - 7.29 (m, 1H), 1.48 - 1.33 (m, 6H), 0.93 - 0.76 (m, 6H)。
以下實例係以與實例169之產物類似之方式來製備。
表6
步驟1
於密封小瓶中將6-((5-(2-羥基丙-2-基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0627 g, 0.136 mmol,實例13)及DMAP (0.0183 g, 0.150 mmol)於0.054 M乙酸酐/THF (6.30 ml, 0.340 mmol)中之異質溶液加熱至80℃。將反應攪拌2天。使反應冷卻至室溫。添加乙酸酐(0.020 mL, 0.212 mmol, 1.56 eq.),且繼續加熱。將反應再攪拌一天且起始材料耗盡。使反應冷卻至室溫並添加DMAP及EtOH。再繼續加熱一天且使反應冷卻至室溫。用EtOAc (50 mL)稀釋反應且用水(20 mL)洗滌。將有機層用鹽水洗滌,經Na2
SO4
乾燥並過濾。將矽膠(約0.4 g)添加至濾液並在真空中濃縮。藉由急速層析使用ISCO 24g管柱利用0%至5% MeOH/乙酸乙酯溶析來純化粗產物。收集適當流份並在真空中濃縮以得到含有期望產物之殘餘物。使此殘餘物與MeOH一起研磨並在真空下乾燥過夜,得到呈白色固體之乙酸2-(6-((6-((甲基-d3)胺甲醯基)-5-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-基)胺基)吡啶-3-基)丙-2-基酯(0.01025 g, 0.019 mmol,14.23%產率)。
MS (M+1)m/z
: 503.2 (MH+
)。LC滯留時間0.67 min [B]。1
H NMR (400 MHz, DMSO-d6
) δ 12.18 - 12.04 (m, 1H), 10.40 - 10.29 (m, 1H), 9.58 - 9.45 (m, 1H), 9.23 - 9.08 (m, 1H), 8.75 - 8.64 (m, 1H), 8.38 - 8.19 (m, 2H), 7.79 - 7.71 (m, 1H), 7.70 - 7.62 (m, 1H), 7.38 - 7.30 (m, 1H), 3.42 - 3.35 (m, 3H), 2.07 - 1.95 (m, 3H), 1.82 - 1.65 (m, 6H)。
步驟1
在室溫下向6-((5-甲醯基吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(130 mg, 0.326 mmol)於DCM (11 mL)中之懸浮液逐滴添加(二乙胺基)三氟化硫(DAST) (0.28 mL, 2.119 mmol)。將混合物在45℃下加熱16 h。在冷卻至室溫之後,用水(20 mL)小心地使反應淬滅。利用固體Na2
CO3
將所得混合物鹼化至pH 9至10並用DCM (3 × 40 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥。藉由ISCO (40 g矽膠,固體裝載,0%至5%甲醇/二氯甲烷)分離出呈白色固體之期望產物6-((5-(二氟甲基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(47 mg, 0.112 mmol,34.3%產率)。
MS (M+1)m/z
: 421.08 (MH+
)。LC滯留時間0.74 min [B]。
步驟2
在室溫下向6-((5-(二氟甲基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(47 mg, 0.112 mmol)於乙酸(4 mL)中之溶液一次添加全量鎢酸鈉二水合物(46.1 mg, 0.140 mmol),之後添加30%過氧化氫(0.343 ml, 3.35 mmol)。將溶液在室溫下攪拌1 h。用水(30 mL)稀釋混合物,利用固體Na2
CO3
鹼化,且用DCM (3 × 45 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥。藉由ISCO (24 g矽膠,固體裝載,0%至5% MeOH/DCM)分離出呈白色固體之期望產物6-((5-(二氟甲基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(20 mg, 0.044 mmol,39.1%產率)。
MS (M+1)m/z
: 453.08 (MH+
)。LC滯留時間0.63 min [A]。1
H NMR (400 MHz, DMSO-d6
) δ 12.19 - 12.09 (m, 1H), 10.72 - 10.61 (m, 1H), 9.66 - 9.54 (m, 1H), 9.26 - 9.16 (m, 1H), 8.79 - 8.64 (m, 1H), 8.56 - 8.45 (m, 1H), 8.35 - 8.24 (m, 1H), 8.01 - 7.89 (m, 1H), 7.85 - 7.73 (m, 1H), 7.40 - 7.29 (m, 1H), 7.25 - 6.81 (m, 1H), 3.34 - 3.30 (m, 3H)。
步驟1
將6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(30 mg, 0.096 mmol,中間體2)、6-甲基吡嗪-2-胺(31.4 mg, 0.288 mmol)、Xantphos (8.32 mg, 0.014 mmol)、Pd2
(dba)3
(6.59 mg, 7.19 µmol)及Cs2
CO3
(125 mg, 0.384 mmol)於二噁烷(1.5 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。將混合物與MeOH/DCM (1:1, 5 mL)混合,過濾並將濾液濃縮,且殘餘物用於下一步驟中。將上述殘餘物與MeOH (1 mL)、丙酮(1 mL)及水(0.5 mL)混合。添加過硫酸氫鉀複合鹽(177 mg, 0.288 mmol),且將混合物在室溫下攪拌18 h。將反應混合物濃縮至乾燥,然後溶解於DMSO中並利用製備型HPLC進行純化。反應提供N-(甲基-d3)-6-((6-甲基吡嗪-2-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(3.4 mg, 7.74 µmol,8%產率)。
MS (M+1)m/z
: 418.1 (MH+
)。LC滯留時間0.95 min [QC-ACN-TFA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 12.27 - 12.00 (m, 1H), 10.74 - 10.47 (m, 1H), 9.68 - 9.55 (m, 1H), 9.27 - 9.10 (m, 1H), 8.77 - 8.61 (m, 2H), 8.38 - 8.21 (m, 1H), 8.13 - 8.00 (m, 1H), 7.42 - 7.31 (m, 1H), 3.37 (s, 3H), 2.47 - 2.41 (m, 3H)。
步驟1
使6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.5304 g, 1.696 mmol,中間體2)及(2,4-二甲氧基苯基)甲胺(2.1068 g, 12.60 mmol)在145℃下熔融。蒸氣在88℃時出現。1.5小時後,添加EtOAc (150 mL)及1 M K2
HPO4
水溶液(40 mL)。分離各層之後,用1 M aq. K2
HPO4
(40 mL)及鹽水(40 mL)相繼洗滌有機層,經乾燥Na2
SO4
並過濾。將矽膠添加至濾液並在真空中濃縮。藉由急速層析使用ISCO 120 g管柱利用0%至5% MeOH/DCM (0%, cv2;0%至5%, cv12)溶析來純化粗產物。收集適當流份(1.6%至2.2%)並在真空中濃縮,得到呈黃色固體之6-((2,4-二甲氧基苄基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.7215 g, 1.627 mmol,96%產率)。
MS (M+1)m/z
: 444.2 (MH+
)。LC滯留時間0.79 min [A]。
步驟2
在氮下在0℃下向6-((2,4-二甲氧基苄基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.7215 g, 1.627 mmol)於二氯甲烷(20 mL)中之均質黃色溶液逐滴添加三氟乙酸(20 mL, 260 mmol)。10 min後,將冰水浴移除且將反應在室溫下攪拌過夜。將混合物在真空中濃縮並用DCM (100 mL)及1.5 M K2
HPO4
水溶液(25 mL)稀釋。分離各層之後,用DCM (4 × 100 mL)萃取水層。將有機層合併,經Na2
SO4
乾燥,過濾並在真空中濃縮(0.68 g)。添加THF並過濾異質溶液,且將濾液在真空中濃縮。藉由急速層析使用ISCO 120 g管柱利用0%至75% MeOH/CH2
Cl2
溶析來純化粗產物。收集適當流份並在真空中濃縮,得到呈黃色固體之6-胺基-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.2534 g, 0.864 mmol,53.1%產率)。
MS (M+1)m/z
: 294.0 (MH+
)。LC滯留時間0.60 min [A]。
步驟3
向6-胺基-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.042 g, 0.143 mmol)於二氯甲烷(2.0 mL)中之異質溶液添加吡啶(0.05 ml, 0.618 mmol)。然後添加2,2-二氯環丙烷甲醯氯於DCM中之溶液(0.17 M, 1.0 ml, 0.17 mmol),從而產生均質性。1 h後,向反應添加額外之於DCM中之2,2-二氯環丙烷甲醯氯(0.17 M, 1.0 ml, 0.17 mmol)。繼續攪拌若干小時,且然後添加額外之於DCM中之2,2-二氯環丙烷甲醯氯(0.17 M, 1.0 ml, 0.17 mmol)並繼續攪拌過夜。添加額外之於DCM中之2,2-二氯環丙烷甲醯氯(0.47 M, 0.61 mL, 0.29 mmol)且在轉化之後測定為約50%。將反應容器加熱至50℃未提供進一步轉化。使反應冷卻至室溫,用DCM (40 mL)稀釋且用水(5 mL)洗滌。將有機層相繼用水(5 mL)及鹽水(5 mL)進一步洗滌,經Na2
SO4
乾燥並過濾。將矽膠添加至濾液並在真空中濃縮。藉由急速層析使用ISCO 12 g管柱利用0%至10% MeOH/CH2
Cl2
溶析來純化粗產物。收集適當流份並在真空中濃縮以得到不純期望產物(約50%純,52.8 mg),其原樣用於後續反應中。
步驟4
向6-(2,2-二氯環丙烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0528 g, 0.123 mmol)於乙酸(1.5 mL)中之均質黃色溶液添加鎢酸鈉二水合物(0.0561 g, 0.170 mmol),之後添加30%過氧化氫(0.4 mL, 3.92 mmol)。1.5 h後,添加水(25 mL),且將反應浸入冰水浴中。添加Na2
CO3
(固體)直至藉由石蕊試紙pH為鹼性為止。將此用DCM (4 × 50 mL)萃取。將有機層合併,且然後相繼用1 N HCl水溶液(30 mL)、飽和NaHCO3
水溶液(30 mL)及鹽水(30 mL)洗滌,經Na2
SO4
乾燥,過濾並在真空中濃縮。藉由急速層析使用ISCO 12 g管柱利用0%至5% MeOH/DCM (0%, cv2;0%至10% , cv20)溶析來純化粗產物。收集適當流份,在真空中濃縮並在乾燥烘箱中在50℃下乾燥,得到6-(2,2-二氯環丙烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.00691 g, 0.015 mmol,12.2%產率)。
MS (M+1)m/z
: 462.1 (MH+
)。LC滯留時間0.79 min [B]。1
H NMR (400 MHz, DMSO-d6
) δ 12.24 - 12.08 (m, 1H), 11.91 - 11.77 (m, 1H), 9.59 - 9.46 (m, 1H), 9.35 - 9.20 (m, 1H), 8.75 - 8.52 (m, 1H), 8.37 - 8.19 (m, 1H), 7.40 - 7.26 (m, 1H), 3.39 - 3.34 (m, 3H), 3.22 - 3.13 (m, 1H), 2.16 - 1.99 (m, 2H)。
步驟1及2
遵循上文所顯示之程序以製備實例174。
步驟3
將6-胺基-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(97 mg, 0.331 mmol)、(±)-反式-2-(三氟甲基)環丙烷-1-甲酸(76 mg, 0.496 mmol)、BOP (205 mg, 0.463 mmol)及N,N-二異丙基乙胺(0.202 mL, 1.157 mmol)於DMF (2 mL)中之混合物在60℃下加熱2 h。檢測到期望產物,但仍保留大部分起始材料。將混合物在60℃下繼續加熱過夜,但並未注意到有變化。用乙酸乙酯(50 mL)稀釋反應混合物,用水(3 × 15 mL)及鹽水(15 mL)洗滌,且經無水MgSO4
乾燥。分離出呈米色固體之產物(±)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-((1R,2R)-2-(三氟甲基)環丙烷-1-甲醯胺基)嗒嗪-3-甲醯胺(23.6 mg, 0.055 mmol,16.62%產率)。MS (M+1)m/z
: 430.2 (MH+
)。LC滯留時間0.90 min [A]。部分地回收到呈米色固體之起始材料6-胺基-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(60 mg, 0.205 mmol,61.9%產率)。
步驟4
在室溫下向(±)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-((1R,2R)-2-(三氟甲基)環丙烷-1-甲醯胺基)嗒嗪-3-甲醯胺(23.6 mg, 0.055 mmol)於乙酸(4 mL)中之溶液一次添加全量鎢酸鈉二水合物(22.66 mg, 0.069 mmol),之後逐滴添加30%過氧化氫(0.168 mL, 1.649 mmol)。將溶液在室溫下攪拌1 h。用水(20 mL)稀釋混合物,利用固體Na2
CO3
鹼化,且用DCM (4 × 30 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥。藉由ISCO (24 g矽膠,固體裝載,0%至5% MeOH/二氯甲烷)分離出呈白色固體之標題化合物N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-((1R,2R)-2-(三氟甲基)環丙烷-1-甲醯胺基)嗒嗪-3-甲醯胺(10 mg, 0.022 mmol,39.4%產率)。
MS (M+1)m/z
: 462.1 (MH+
)。LC滯留時間0.79 min [A]。
使如上獲得之外消旋物樣品(10 mg)經歷手性分離以得到N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-((1S,2S)-2-(三氟甲基)環丙烷-1-甲醯胺基)嗒嗪-3-甲醯胺(4.52 mg, 9.31 µmol,86%產率),1
H NMR (400 MHz, DMSO-d6
) δ 12.19 - 12.09 (m, 1H), 11.73 - 11.63 (m, 1H), 9.53 - 9.47 (m, 1H), 9.32 - 9.20 (m, 1H), 8.65 - 8.54 (m, 1H), 8.38 - 8.24 (m, 1H), 7.41 - 7.29 (m, 1H), 3.38 - 3.35 (m, 3H), 2.71 - 2.61 (m, 1H), 2.41 - 2.28 (m, 1H), 1.41 - 1.30 (m, 2H),及呈白色固體之N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-((1R,2R)-2-(三氟甲基)環丙烷-1-甲醯胺基)嗒嗪-3-甲醯胺(4.36 mg, 8.98 µmol,83%產率),1
H NMR (400 MHz, DMSO-d6
) δ 12.20 - 12.08 (m, 1H), 11.73 - 11.58 (m, 1H), 9.57 - 9.44 (m, 1H), 9.33 - 9.18 (m, 1H), 8.69 - 8.50 (m, 1H), 8.37 - 8.21 (m, 1H), 7.41 - 7.25 (m, 1H), 3.40 - 3.34 (m, 3H), 2.72 - 2.62 (m, 1H), 2.42 - 2.30 (m, 1H), 1.40 - 1.29 (m, 2H)。
該兩種鏡像異構物之絕對立體化學係隨機指配的。
步驟1
將6-氯-N-三氘代甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(150 mg, 0.480 mmol)、3,3-二氟環丁烷甲醯胺(87 mg, 0.647 mmol)、參(二亞苄基丙酮)二鈀(0) (65.9 mg, 0.072 mmol)、Xantphos (41.6 mg, 0.072 mmol)及碳酸銫(281 mg, 0.863 mmol)於1,4-二噁烷(10 mL)中之混合物在微波下在145℃下加熱1 h。用乙酸乙酯(20 mL)稀釋反應混合物且經由矽藻土過濾。用乙酸乙酯(20 mL)進一步稀釋濾液且經由矽藻土過濾。將濾液在真空下濃縮至乾燥。向殘餘物添加水(50 mL),之後添加飽和NaHCO3
溶液(5 mL)。藉由抽吸過濾收集不溶材料並藉由ISCO (40 g矽膠,固體裝載,0%至4% MeOH/DCM)進一步純化,得到呈米色固體之期望產物6-(3,3-二氟環丁烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(57 mg, 0.139 mmol,28.9%產率)。
MS (M+1)m/z
: 412.2 (MH+
)。LC滯留時間0.89 min [A]。
步驟2
在室溫下向6-(3,3-二氟環丁烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(57 mg, 0.139 mmol)於乙酸(20 mL)中之懸浮液一次添加全量鎢酸鈉二水合物(57.1 mg, 0.173 mmol),之後添加30%過氧化氫(0.425 mL, 4.16 mmol)。將溶液在室溫下攪拌1 h。起始材料全部轉化為亞碸,但不係期望碸。添加額外之鎢酸鈉二水合物(57.1 mg, 0.173 mmol)及30%過氧化氫(0.213 mL, 2.08 mmol)。將異質混合物在室溫下再攪拌1小時。用水(40 mL)稀釋該混合物,利用固體Na2
CO3
鹼化且用DCM (4 × 50 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥,過濾並在真空中濃縮。藉由ISCO (24 g矽膠,固體裝載,0%至5% MeOH/DCM)分離出呈白色固體之產物6-(3,3-二氟環丁烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲基亞磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(15 mg, 0.035 mmol,25.3%產率)。
MS (M+1)m/z
: 428.2 (MH+
)。LC滯留時間0.7 min [A]。
步驟3
在室溫下向6-(3,3-二氟環丁烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲基亞磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(15 mg, 0.035 mmol)於乙酸(3 ml)中之懸浮液一次添加全量鎢酸鈉二水合物(14.47 mg, 0.044 mmol),之後添加30%過氧化氫(0.108 mL, 1.053 mmol)。將溶液在室溫下攪拌1.5 h。用水(20 mL)稀釋混合物,利用固體Na2
CO3
鹼化且用DCM (3 × 40 mL)萃取。使合併之萃取物經無水Na2
SO4
乾燥並在真空下濃縮至乾燥。將殘餘物溶解於DMSO (1.2 mL)中並藉由製備型HPLC進行純化。獲得期望產物6-(3,3-二氟環丁烷-1-甲醯胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(5.8 mg, 0.013 mmol,36.2%產率)。
MS (M+1)m/z
: 444.0 (MH+
)。LC滯留時間1.39 min [QC-ACN-TFA-XB]。
步驟1
在室溫下向4,6-二氯-N-三氘代甲基嗒嗪-3-甲醯胺(114 mg, 0.544 mmol)及6-氟-3-(甲硫基)吡啶-2-胺(86 mg, 0.544 mmol)於THF (5 mL)中之溶液經5 min添加於THF中之雙(三甲基矽基)胺基鋰(1.359 mL, 1.359 mmol)。將所得混合物在室溫下攪拌1 h。用水(5 mL)使反應淬滅,利用1 N HCl溶液將混合物調整至pH 9至10,且進一步用水(10 mL)稀釋。藉由抽吸過濾收集呈淺色固體之沈澱產物6-氯-4-((6-氟-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(145 mg, 0.438 mmol,81%產率),並在真空下乾燥。
MS (M+1)m/z
: 331.25 (MH+
)。LC滯留時間1.19 min [C]。1
H NMR (400 MHz, DMSO-d6
) δ 12.65 - 12.53 (m, 1H), 9.62 - 9.42 (m, 1H), 9.04 - 8.85 (m, 1H), 8.22 - 8.06 (m, 1H), 7.00 - 6.83 (m, 1H)。
步驟2
將6-氯-4-((6-氟-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(30 mg, 0.091 mmol)、2,6-二甲基嘧啶-4-胺(16.75 mg, 0.136 mmol)、Xantphos (7.87 mg, 0.014 mmol)、Pd2
(dba)3
(6.23 mg, 6.80 µmol)及Cs2
CO3
(59.1 mg, 0.181 mmol)於二噁烷(1.5 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。將混合物與MeOH/DCM (1:1, 5 ml)混合,過濾並將濾液濃縮。所得殘餘物用於下一步驟中。將殘餘物與AcOH (1 mL)混合且添加鎢酸鈉二水合物(8.97 mg, 0.027 mmol)。添加過氧化氫(278 µL, 2.72 mmol),且將混合物在室溫下攪拌1 h。向此混合物添加硫代硫酸鈉(430 mg, 2.72 mmol)並將反應攪拌10 min。將混合物過濾並利用製備型HPLC進行純化以提供產物6-((2,6-二甲基嘧啶-4-基)胺基)-4-((6-氟-3-(甲基磺醯基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(6.8 mg, 0.014 mmol,15.85%產率)。
MS (M+1)m/z
: 449.9 (MH+
)。LC滯留時間1.11 min [QC-ACN-TFA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 10.83 - 10.68 (m, 1H), 9.48 - 9.34 (m, 1H), 9.32 - 9.15 (m, 1H), 8.52 - 8.35 (m, 1H), 7.42 - 7.24 (m, 1H), 7.02 (br s, 1H), 3.39 (br s, 3H), 2.57 - 2.53 (m, 6H)。
以下實例係以與實例178之產物類似之方式來製備。
表7
步驟1
在室溫下向4,6-二氯-N-三氘代甲基嗒嗪-3-甲醯胺(144 mg, 0.687 mmol)及6-甲基-3-(甲硫基)吡啶-2-胺(106 mg, 0.687 mmol)於THF (5 mL)中之溶液經5 min添加於THF中之雙(三甲基矽基)胺基鋰(1.718 mL, 1.718 mmol)。將所得混合物在室溫下攪拌1 h。用水(5 mL)使反應淬滅,利用1 N HCl溶液將混合物調整至pH 9至10,且進一步用水(10 mL)稀釋。藉由抽吸過濾收集呈淺色固體之沈澱產物6-氯-N-(甲基-d3)-4-((6-甲基-3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(160 mg, 0.490 mmol,71.2%產率),並在真空下乾燥。
MS (M+1)m/z
: 327.3 (MH+
)。LC滯留時間1.27 min [C]。1
H NMR (400 MHz, DMSO-d6
) δ 12.41 - 12.25 (m, 1H), 9.49 - 9.36 (m, 1H), 9.29 - 9.14 (m, 1H), 7.91 - 7.77 (m, 1H), 7.10 - 6.96 (m, 1H), 2.49 - 2.48 (m, 6H)。
步驟2
將6-氯-N-(甲基-d3)-4-((6-甲基-3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(30 mg, 0.092 mmol)、6-甲氧基嗒嗪-3-胺(17.23 mg, 0.138 mmol)、Xantphos (7.97 mg, 0.014 mmol)、Pd2
(dba)3
(6.30 mg, 6.88 µmol)及Cs2
CO3
(59.8 mg, 0.184 mmol)於二噁烷(1.5 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。將混合物與MeOH/DCM (1:1, 5 ml)混合,過濾並將濾液濃縮且殘餘物用於下一步驟中。將所得殘餘物與AcOH (1 mL)及鎢酸鈉二水合物(9.08 mg, 0.028 mmol)混合。添加過氧化氫(281 µl, 2.75 mmol),且將混合物在室溫下攪拌1 h。向此混合物添加硫代硫酸鈉(435 mg, 2.75 mmol)並將混合物攪拌10 min。將混合物過濾並利用製備型HPLC進行純化,得到產物6-((6-甲氧基嗒嗪-3-基)胺基)-N-(甲基-d3)-4-((6-甲基-3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(4.2 mg, 9.10 µmol,9.92%產率)。
MS (M+1)m/z
: 447.8 (MH+
)。LC滯留時間1.01 min [QC-ACN-TFA-XB]。
以下實例係以與實例183之產物類似之方式來製備。
表8
步驟1
在室溫下向4,6-二氯-N-(甲基-d3)嗒嗪-3-甲醯胺(491 mg, 2.350 mmol)及6-甲氧基-3-(甲硫基)吡啶-2-胺(400 mg, 2.35 mmol)於THF (5 mL)中之溶液經5 min添加於THF中之雙(三甲基矽基)胺基鋰(5.87 mL, 5.87 mmol)。將所得混合物在室溫下攪拌過夜。用1 N HCl (1.5 mL)使反應淬滅且添加水(20 mL)。用DCM (3 × 20 mL)萃取混合物,且使合併之有機層經Na2
SO4
乾燥並在真空下濃縮以提供產物6-氯-4-((6-甲氧基-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(600 mg, 1.75 mmol,74.5%產率)。材料原樣用於下一步驟中。
MS (M+1)m/z
: 343.3 (MH+
)。LC滯留時間1.19 min [C]。
步驟2
將6-氯-4-((6-甲氧基-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(35 mg, 0.102 mmol)、丙醯胺(11.19 mg, 0.153 mmol)、Xantphos (8.86 mg, 0.015 mmol)、Pd2
(dba)3
(7.01 mg, 7.66 µmol)及Cs2
CO3
(66.5 mg, 0.204 mmol)於二噁烷(0.7 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。將混合物與MeOH/DCM (1:1, 5 mL)混合,過濾並將濾液濃縮,且殘餘物用於下一步驟中。將殘餘物與AcOH (1 mL)混合,且添加鎢酸鈉二水合物(10.10 mg, 0.031 mmol)。添加過氧化氫(313 µl, 3.06 mmol),且將混合物在室溫下攪拌1 h。向該混合物添加硫代硫酸鈉(484 mg, 3.06 mmol)並將其攪拌10 min。將混合物過濾並藉由製備型HPLC進行純化以提供4-((6-甲氧基-3-(甲基磺醯基)吡啶-2-基)胺基)-N-(甲基-d3)-6-丙醯胺基嗒嗪-3-甲醯胺(13.0 mg, 0.031 mmol,30.95%產率)。
MS (M+1)m/z
: 412.4 (M+H+
)。LC滯留時間1.26 min [QC-ACN-TFA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 12.13 - 11.98 (m, 1H), 11.23 - 11.02 (m, 1H), 9.44 - 9.29 (m, 1H), 9.24 - 9.12 (m, 1H), 8.19 - 8.07 (m, 1H), 6.79 - 6.57 (m, 1H), 4.03 - 3.90 (m, 3H), 3.48 - 3.39 (m, 3H), 2.49 - 2.44 (q, 2H), 1.08 (s, 3H)。
以下實例係以與實例199之產物類似之方式來製備。
表9
步驟1
在室溫下向4,6-二氯-N-三氘代甲基嗒嗪-3-甲醯胺(209 mg, 0.999 mmol)及6-環丙基-3-(甲硫基)吡啶-2-胺(180 mg, 0.999 mmol)於THF (10 mL)中之溶液經5 min添加於THF中之雙(三甲基矽基)胺基鋰(2.496 mL, 2.496 mmol)。將所得混合物在室溫下攪拌1 h。用水(5 mL)使反應淬滅且利用1 N HCl溶液將混合物調整至pH 9至10,且進一步用水(10 mL)稀釋。藉由抽吸過濾收集沈澱產物並在真空下乾燥,得到呈淺色固體之6-氯-4-((6-環丙基-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(260 mg, 0.737 mmol,73.8%產率)。MS (M+1)m/z
: 353.4 (MH+)。LC滯留時間1.40 min [C]。1
H NMR (499 MHz, DMSO-d6
) δ 12.35 - 12.22 (m, 1H), 9.44 - 9.31 (m, 1H), 9.16 - 9.00 (m, 1H), 7.90 - 7.73 (m, 1H), 7.17 - 6.98 (m, 1H), 2.47 - 2.44 (m, 3H), 2.21 - 2.11 (m, 1H), 1.09 - 1.03 (m, 2H), 1.00 - 0.94 (m, 2H)。
步驟2
將6-氯-4-((6-環丙基-3-(甲硫基)吡啶-2-基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(100 mg, 0.283 mmol)、2-(6-胺基-4-氯吡啶-3-基)丙-2-醇(63.5 mg, 0.340 mmol)、Xantphos (24.60 mg, 0.043 mmol)、Pd2
(dba)3
(19.46 mg, 0.021 mmol)及Cs2
CO3
(185 mg, 0.567 mmol)於二噁烷(0.7 mL)中之混合物用氮吹掃2 min,然後在130℃下攪拌3 h。將所得混合物與MeOH/DCM (1:1, 5 mL)混合,過濾並將濾液濃縮,且殘餘物用於下一步驟中。將所得殘餘物與AcOH (1 mL)、鎢酸鈉二水合物(28.0 mg, 0.085 mmol)及過氧化氫(289 µl, 2.83 mmol)混合。在室溫下1小時後,添加硫代硫酸鈉(672 mg, 4.25 mmol)並將混合物攪拌10 min。將混合物過濾並藉由製備型HPLC進行純化以提供產物4-((6-環丙基-3-(甲基磺醯基)吡啶-2-基)胺基)-6-((4-(2-羥基丙-2-基)苯基)胺基)-N-(甲基-d3)嗒嗪-3-甲醯胺(8.3 mg, 0.015 mmol,5.42%產率)。
MS (M+1)m/z
: 535.4 (M+H+
)。LC滯留時間1.65 min [QC-ACN-AA-XB]。
以下實例係以與實例207之產物類似之方式來製備。
表10
步驟1
於1打蘭(dram)小瓶中,使參(二亞苄基丙酮)二鈀(0) (7.40 mg, 8.09 µmol)、1,1'-雙(二環己基膦基)二茂鐵(9.36 mg, 0.016 mmol)、6-氯-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.1002 g, 0.323 mmol)、6-甲氧基嗒嗪-3-胺(0.081 g, 0.647 mmol)及磷酸鉀(0.404 ml, 0.809 mmol)於1,4-二噁烷(2.5 mL)中之懸浮液經歷真空/N2循環三次。將反應混合物在80℃下加熱3小時,然後用水稀釋並過濾。用水洗滌固體並在真空下乾燥過夜,得到粗製6-((6-甲氧基嗒嗪-3-基)胺基)-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.119 g, 0.299 mmol,92%產率)。利用製備型HPLC純化14 mg粗製品,得到純淨產物6-((6-甲氧基嗒嗪-3-基)胺基)-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(8.5 mg, 0.021 mmol,6.40%產率)。
MS (M+1)m/z
: 399.3 (MH+
)。LC滯留時間1.487 min [QC-ACN-AA-XB]。
1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.37 (s, 1H), 9.30 (s, 1H), 9.20 (br d, J=4.6 Hz, 1H), 8.21 (d, J=3.7 Hz, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.83 (d, J=6.7 Hz, 1H), 7.23 (d, J=9.5 Hz, 1H), 7.09 (dd, J=7.6, 4.9 Hz, 1H), 3.99 (s, 3H), 2.86 (d, J=4.6 Hz, 3H), 2.53 (s, 3H)。
步驟2
在室溫下向6-((6-甲氧基嗒嗪-3-基)胺基)-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.1 g, 0.251 mmol)於乙酸(15 mL)中之溶液一次添加全量鎢酸鈉二水合物(0.159 g, 0.482 mmol),之後添加30%過氧化氫(0.769 mL, 7.53 mmol)。將溶液在室溫下攪拌1小時。向該反應添加0.8 mL 30% H2
O2
,將其在室溫下攪拌6小時。將反應混合物用冰水稀釋且利用Na2
CO3
粉末鹼化。將水層用DCM萃取三次,且使合併之有機層乾燥(Na2
SO4
),過濾並濃縮。將所得固體溶解於14 mL AcOH中,之後添加鎢酸鈉二水合物(0.124g)及0.8 mL 30% 過氧化氫。將反應在室溫下攪拌2小時。藉由製備型HPLC純化反應混合物以提供產物6-((6-甲氧基嗒嗪-3-基)胺基)-N-甲基-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(8.6 mg, 0.020 mmol,7.96%產率)。1
H NMR (500 MHz, DMSO-d6
) δ 12.09 - 11.97 (m, 1H), 9.24 - 9.16 (m, 1H), 9.13 - 9.02 (m, 1H), 8.65 - 8.53 (m, 1H), 8.34 - 8.23 (m, 1H), 7.94 (s, 1H), 7.31 (br s, 1H), 7.27 - 7.17 (m, 1H), 4.05 - 3.92 (m, 3H), 3.41 - 3.30 (m, 3H), 2.89 - 2.81 (m, 3H)。
此反應亦提供副產物6-((6-甲氧基嗒嗪-3-基)胺基)-N-甲基-4-((3-(甲基亞磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(6.6 mg, 0.016 mmol,6.35%產率)。
MS (M+1)m/z
: 415.2 (MH+
)。LC滯留時間0.89 min [QC-ACN-TFA-XB]。
步驟1
將對甲苯磺酸(0.091 g, 0.479 mmol)、6-氯-N-甲基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.099 g, 0.320 mmol)及1-甲基-1H-吡唑-3-胺(0.184 g, 1.895 mmol)於THF (2 mL)中之懸浮液在100℃下加熱8小時。用乙酸乙酯稀釋反應,用1 N NaOH及水洗滌。分離乙酸乙酯層,乾燥(Na2
SO4
),過濾並濃縮,得到粗產物N-甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.1268 g, 0.342 mmol,107%產率)。藉由製備型HPLC純化一部分(23 mg)粗產物以提供N-甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(12.4 mg, 0.031 mmol,9.85%產率)。
MS (M+1)m/z
: 371.2 (MH+
)。LC滯留時間1.377 min [QC-ACN-AA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 12.05 - 11.86 (m, 1H), 9.89 - 9.72 (m, 1H), 9.21 - 9.00 (m, 2H), 8.32 - 8.12 (m, 1H), 7.93 - 7.69 (m, 1H), 7.63 - 7.47 (m, 1H), 7.17 - 6.97 (m, 1H), 6.33 - 6.17 (m, 1H), 3.82 - 3.75 (m, 3H), 2.89 - 2.79 (m, 3H)。
步驟2
在室溫下向N-甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.1158 g, 0.313 mmol)於乙酸(15 mL)中之溶液一次添加全量鎢酸鈉二水合物(0.129 g, 0.391 mmol),之後添加30%過氧化氫(0.958 mL, 9.38 mmol)。將溶液在室溫下攪拌1小時。將反應混合物用冰水稀釋且利用Na2
CO3
粉末鹼化。將水層用DCM萃取三次。用硫代硫酸鈉(5%)洗滌有機層,乾燥(Na2
SO4
),過濾並濃縮。藉由製備型HPLC純化粗製殘餘物,得到N-甲基-6-((1-甲基-1H-吡唑-3-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(56 mg, 0.138 mmol,44.1%產率)。
MS (M+1)m/z
: 402.9 (MH+
)。LC滯留時間0.817 min [QC-ACN-TFA-XB]。
1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 9.94 (s, 1H), 9.12 (br d, J=4.6 Hz, 1H), 9.06 (s, 1H), 8.65 (dd, J=4.8, 1.8 Hz, 1H), 8.28 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 6.28 (d, J=2.1 Hz, 1H), 3.79 (s, 3H), 3.38 (s, 3H), 2.85 (d, J=4.8 Hz, 3H)。
步驟1
在室溫下將1-丙烷膦酸酐(0.698 mL, 1.196 mmol)添加至6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲酸(0.2365 g, 0.797 mmol)及TEA (0.222 ml, 1.594 mmol)之DMF (2.5 mL)溶液。將反應在室溫下攪拌1小時,之後添加乙胺鹽酸鹽(0.3383 g, 4.15 mmol)及TEA (0.2 mL)。將反應在室溫下攪拌16小時,用水稀釋並將懸浮液過濾且用水洗滌。使固體在真空下乾燥過夜。利用矽膠急速層析(ISCO, 12 g管柱)且利用乙酸乙酯之己烷溶液(0%至50%)進行溶析來純化粗產物,得到期望產物6-氯-N-乙基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(102 mg, 0.315 mmol,39.6%產率)。
MS (M+1)m/z
: 324.0 (MH+
)。LC滯留時間0.97 min [A]。1
H NMR (400 MHz,氯仿-d) δ 12.59 - 12.44 (m, 1H), 9.33 - 9.27 (m, 1H), 8.57 - 8.51 (m, 1H), 8.45 - 8.31 (m, 2H), 7.39 - 7.31 (m, 1H), 3.67 - 3.49 (m, 2H), 3.06 - 2.79 (m, 3H), 1.39 - 1.27 (m, 3H)。
步驟2
於1打蘭(dram)小瓶中,使參(二亞苄基丙酮)二鈀(0) (2.262 mg, 2.471 µmol)、1,1'-雙(二環己基膦基)二茂鐵(2.86 mg, 4.94 µmol)、6-氯-N-乙基-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0320 g, 0.099 mmol)、2-(6-胺基吡啶-3-基)丙-2-醇(0.0182 g, 0.120 mmol)及磷酸三鉀(0.124 mL, 0.247 mmol)於1,4-二噁烷(0.5 mL)中之懸浮液經歷真空/N2
循環三次。將反應混合物在80℃下加熱3小時。用乙酸乙酯稀釋反應且用水洗滌三次。將乙酸乙酯層分離,乾燥(Na2
SO4
),過濾並濃縮。獲得粗產物N-乙基-6-((5-(2-羥基丙-2-基)吡啶-2-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(41.3 mg, 0.094 mmol,95%產率)。粗產物原樣用於下一步驟中。
MS (M+1)m/z
: 438.4 (MH+
)。LC滯留時間0.89 min [E]。
步驟3
在室溫下向N-乙基-6-((5-(2-羥基丙-2-基)吡啶-2-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0412 g, 0.094 mmol)於乙酸(3 mL)中之溶液,一次添加全量鎢酸鈉二水合物(0.039 g, 0.117 mmol),之後添加30%過氧化氫(0.287 mL, 2.81 mmol)。將溶液在室溫下攪拌1小時。添加0.3 mL 30% H2
O2
並將反應再攪拌1小時。依此再重複3次。將反應混合物用冰水稀釋且利用Na2
CO3
粉末鹼化。將水層用DCM萃取三次。將DCM層用硫代硫酸鈉(5%)洗滌一次,乾燥(Na2
SO4
),過濾並濃縮。利用製備型HPLC純化粗製物以提供期望產物N-乙基-6-((5-(2-羥基丙-2-基)吡啶-2-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(12.3 mg, 0.026 mmol,27.8%產率)。
MS (M+1)m/z
: 472.1 (MH+
)。LC滯留時間1.299 min [QC-ACN-AA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 12.16 - 11.97 (m, 1H), 10.33 - 10.17 (m, 1H), 9.53 - 9.37 (m, 1H), 9.30 - 9.08 (m, 1H), 8.72 - 8.60 (m, 1H), 8.43 - 8.33 (m, 1H), 8.32 - 8.22 (m, 1H), 7.85 - 7.75 (m, 1H), 7.70 - 7.60 (m, 1H), 7.37 - 7.29 (m, 1H), 2.56 - 2.54 (m, 5H), 1.51 - 1.43 (m, 6H), 1.21 - 1.13 (m, 3H)。
以下實例係以與實例211之產物類似之方式來製備。
表11
步驟1
在室溫下將1-丙烷膦酸酐(0.416 mL, 0.712 mmol)添加至6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲酸(0.1408 g, 0.475 mmol)及TEA (0.132 mL, 0.949 mmol)之DMF (2 mL)溶液。用二乙醚稀釋反應並過濾。收集呈膠狀棕色固體之固體。將材料(濾液)之剩餘部分合併,濃縮並用NH4
OH處理過夜。將膠狀棕色固體懸浮於1 mL DMSO中且添加NH4
OH (2 mL)。將懸浮液劇烈攪拌。1小時後,混合物顯示完全轉化為一級醯胺。將所有以上材料合併,用乙酸乙酯稀釋並用水洗滌三次。將乙酸乙酯層分離,乾燥(Na2
SO4
),過濾並濃縮。粗產物6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(97.4 mg, 0.329 mmol,69.4%產率)原樣用於下一步驟中。
MS (M+1)m/z
: 296.1 (MH+
)。LC滯留時間0.86 min [E]。
步驟2
於1打蘭小瓶中使參(二亞苄基丙酮)二鈀(0) (7.54 mg, 8.23 µmol)、1,1'-雙(二環己基膦基)二茂鐵(9.53 mg, 0.016 mmol)、6-氯-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0974 g, 0.329 mmol)、6-甲氧基嗒嗪-3-胺(0.082 g, 0.659 mmol)及磷酸三鉀(0.412 ml, 0.823 mmol)於1,4-二噁烷(2.5 mL)中之懸浮液經歷真空/N2
循環三次。將反應混合物在80℃下加熱3小時。在加熱期間,反應混合物變為澄清溶液。用乙酸乙酯稀釋該反應混合物並用水洗滌三次。將乙酸乙酯層分離,乾燥(Na2
SO4
),過濾並濃縮以得到粗產物。
MS (M+1)m/z
: 385.2 (MH+
)。LC滯留時間0.76 min [E]。
1H NMR (400 MHz,氯仿-d) δ 12.09 (s, 1H), 9.15 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 8.30 (dd, J=4.9, 1.7 Hz, 1H), 8.09 (br d, J=2.9 Hz, 1H), 7.90 (s, 1H), 7.78 (dd, J=7.6, 1.7 Hz, 1H), 7.06 (d, J=9.4 Hz, 1H), 6.98 (dd, J=7.6, 4.9 Hz, 1H), 5.55 (br d, J=3.2 Hz, 1H), 4.13 (s, 3H), 2.52 (s, 3H)。
步驟3
在室溫下向6-((6-甲氧基嗒嗪-3-基)胺基)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.0329 g, 0.086 mmol)於乙酸(3 mL)中之溶液一次添加全量鎢酸鈉二水合物(0.035 g, 0.107 mmol),之後添加30%過氧化氫(0.262 mL, 2.57 mmol)。將溶液在室溫下攪拌20 min且觀察到懸浮液。將反應在室溫下攪拌3小時。用水(50 mL)稀釋反應且利用Na2
CO3
粉末鹼化。用DCM將水層萃取三次。將DCM層合併,乾燥(Na2
SO4
),過濾並濃縮以得到粗產物。利用製備型HPLC純化粗產物以提供期望產物6-((6-甲氧基嗒嗪-3-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(2.6 mg, 6.24 µmol,7.30%產率)。
MS (M+1)m/z
: 417.3 (MH+
)。LC滯留時間0.907 min [QC-ACN-TFA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 12.23 - 12.14 (m, 1H), 10.54 - 10.39 (m, 1H), 9.33 - 9.17 (m, 1H), 8.65 - 8.61 (m, 1H), 8.59 - 8.53 (m, 1H), 8.31 - 8.26 (m, 1H), 8.07 - 8.01 (m, 1H), 7.88 - 7.83 (m, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 4.02 - 3.95 (m, 3H)。
以下實例係以與實例213之產物類似之方式來製備。
表12
步驟1
在室溫下向4,6-二氯-N-(甲基-d3)菸鹼醯胺(30 mg, 0.144 mmol)及3-(甲硫基)吡啶-2-胺(22.24 mg, 0.159 mmol)於THF (5 mL)中之溶液經5 min添加於THF中之雙(三甲基矽基)胺基鋰(0.360 mL, 0.360 mmol)。將所得混合物在室溫下攪拌過夜。用1 N HCl (1.5 mL)使反應淬滅且添加水(20 mL)。用DCM (3 × 20 mL)萃取混合物,將其合併,乾燥(Na2
SO4
)並在真空下濃縮,且原樣用於下一步驟中。
MS (M+1)m/z
: 312.2 (MH+
)。LC滯留時間1.06 min [C]。
步驟2
於密封小瓶中將6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)菸鹼醯胺(0.13 g, 0.412 mmol)、5-氟吡啶-2-胺(0.104 g, 0.928 mmol)、Xantphos (0.046 g, 0.080 mmol)、碳酸銫(0.352 g, 1.081 mmol)及Pd2
dba3
(0.072 g, 0.079 mmol)於二噁烷(10 ml)及N-甲基-2-吡咯啶酮(2.00 mL)中之溶液微波處理至150℃持續1 h。一旦反應完成,則將反應混合物用乙酸乙酯(10 mL)稀釋並經由矽藻土過濾。將濾液在真空中濃縮。向殘餘物添加DMSO (3 mL)及水(45 mL),之後添加飽和NaHCO3 (4 mL)。收集沈澱物,過濾並用水洗滌,得到呈橙色固體之粗產物。藉由急速層析使用ISCO 40 g管柱(固體裝載)利用0%至10% MeOH/DCM (0%, 1 cv;0%至5%, 20 cv;5-10%, 8 cv)進行溶析來純化粗產物(易溶於THF)。收集適當流份(5.0%至7.5%溶析)並在真空中濃縮,得到呈淺黃色固體之6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)菸鹼醯胺(0.0367 g, 0.095 mmol,22.97%產率)。
MS (M+1)m/z
: 388.1 (MH+
)。LC滯留時間0.70 min [F]。
步驟3
向6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)菸鹼醯胺(0.0367 g, 0.095 mmol)添加乙酸(3 mL)以得到異質溶液。將溶液略微加熱且變得均質。在冷卻至室溫之後,添加鎢酸鈉二水合物(0.0411 g, 0.125 mmol),之後添加50%過氧化氫(0.2 mL, 3.47 mmol)。在1 min內,溶液變得異質。在0.5 h後,起始材料耗盡。將反應混合物再攪拌1 h以達成完全氧化。將水(25 mL)添加至反應,之後添加碳酸鈉直至藉由石蕊試紙顯示pH為鹼性為止。用DCM (4 × 50 mL)萃取混合物。將有機層合併,經Na2
SO4
乾燥並過濾。將矽膠添加至濾液並在真空中濃縮。藉由急速層析(固體裝載)使用ISCO 24 g管柱利用0%至5% MeOH/DCM (0%, 1 cv;0%至5%, 15 cv;5%, 5 cv)進行溶析來純化粗產物。收集適當流份(4.5%至5.0%)並在真空中濃縮以得到期望產物。添加MeOH並用MeOH洗滌研磨材料,且在乾燥烘箱中在55℃下乾燥,得到6-((5-氟吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)菸鹼醯胺(0.012 g, 0.029 mmol,30.3%產率)。
MS (M+1)m/z
: 420.1 (MH+
)。LC滯留時間0.59 min [B]。1
H NMR (400 MHz, DMSO-d6
) δ 11.56 - 11.47 (m, 1H), 10.02 - 9.85 (m, 1H), 8.89 - 8.78 (m, 1H), 8.70 - 8.59 (m, 1H), 8.57 - 8.50 (m, 2H), 8.26 - 8.20 (m, 2H), 7.83 - 7.74 (m, 1H), 7.71 - 7.58 (m, 1H), 7.28 - 7.20 (m, 1H), 3.39 - 3.34 (m, 3H)。
以下實例係以與實例215之產物類似之方式來製備。
表13
步驟1
遵循來自製備3 (實例1步驟1)之程序。
步驟2
將6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)菸鹼醯胺(25 mg, 0.080 mmol)、5-苯基吡啶-2-胺(17.74 mg, 0.104 mmol)、Pd2
(dba)3
(7.34 mg, 8.02 µmol)、Xantphos (9.28 mg, 0.016 mmol)、Cs2
CO3
(34.0 mg, 0.104 mmol)於二噁烷(1.0 mL)中之混合物用氮吹掃5 min,且將反應置於預加熱之130℃加熱塊中2 h,得到N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-((5-苯基吡啶-2-基)胺基)菸鹼醯胺(M+H=446)。用AcOH (2 mL)稀釋溶液且通過過濾器。向該溶液添加鎢酸鈉二水合物(7.93 mg, 0.024 mmol)、30%過氧化氫(164 µl, 1.604 mmol)且在室溫下攪拌1 h。在0℃下向混合物添加硫代硫酸鈉(254 mg, 1.604 mmol),且將反應混合物在室溫下攪拌10 min。將固體過濾出且將溶劑在真空中去除以得到不純之期望產物。將反應混合物用DMSO稀釋,過濾並利用製備型HPLC進行純化以提供N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-((5-苯基吡啶-2-基)胺基)菸鹼醯胺(3.5 mg, 7.33 µmol,9.14%產率)。
MS (M+1)m/z
: 478.2 (MH+
)。LC滯留時間1.72 min [QC-ACN-AA-XB]。1
H NMR (500 MHz, DMSO-d6
) δ 10.09 - 9.93 (m, 1H), 9.04 - 8.92 (m, 1H), 8.73 - 8.63 (m, 1H), 8.61 - 8.50 (m, 3H), 8.28 - 8.18 (m, 1H), 8.07 - 7.96 (m, 1H), 7.85 - 7.73 (m, 1H), 7.73 - 7.65 (m, 2H), 7.53 - 7.43 (m, 2H), 7.41 - 7.32 (m, 1H), 7.29 - 7.18 (m, 1H)。
以下實例係以與實例234之產物類似之方式來製備。
表14
步驟1
將4-甲氧基苄胺(4.95 ml, 37.9 mmol)、6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(2.370 g, 7.58 mmol)及氟化鉀(1.321 g, 22.74 mmol)合併於DMSO (20 ml)中,且加熱至120℃持續6小時。然後使反應冷卻至室溫,用EtOAc稀釋,並用鹼性緩衝水溶液(1.5 M K3
PO4
)、水、飽和氯化銨水溶液及鹽水洗滌。將水層用EtOAc反萃取一次且將有機層合併。隨後使有機層經硫酸鈉乾燥,過濾、濃縮。經由自動化急速層析利用於DCM中之甲醇(0%至10%)進行溶析來純化產物6-((4-甲氧基苄基)胺基-N
-(甲基-d3
)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺。(2.78 g,89%產率)。MS (M+1)m/z
: 414.3 (MH+
)。LC滯留時間0.75 min [D]。1
H NMR (400 MHz,氯仿-d) δ 12.11 - 12.04 (m, 1H), 8.44 - 8.40 (m, 1H), 8.28 - 8.22 (m, 1H), 8.19 - 8.12 (m, 1H), 7.73 - 7.66 (m, 1H), 7.39 - 7.33 (m, 2H), 6.95 - 6.86 (m, 3H), 5.31 - 5.25 (m, 1H), 4.62 - 4.57 (m, 2H), 3.82 (s, 3H), 2.53 - 2.48 (m, 3H)。
步驟2
在室溫下將鎢酸鈉二水合物(0.831 g, 2.52 mmol)添加至過氧化氫(30%水溶液,5.14 mL, 50.4 mmol)及6-((4-甲氧基苄基)胺基)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(1.041 g, 2.52 mmol)之AcOH (20 mL)懸浮液。在室溫下攪拌1小時後,用水稀釋反應,利用Na2
CO3
粉末鹼化並用乙酸乙酯萃取三次。將乙酸乙酯層合併,用1.5 M K2
HPO4
溶液洗滌兩次且用Na2
S2
O3
(5%溶液)洗滌一次。將有機層乾燥(Na2
SO4
),過濾並濃縮。藉由自動化急速層析,利用於DCM中之甲醇(0%至10%)進行溶析來純化產物6-((4-甲氧基苄基)胺基-N
-(甲基-d3
)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.66 g, 59%)。MS (M+1)m/z
: 446.1 (MH+
)。LC滯留時間0.66 min [D]。
步驟3
將TFA (4 ml, 51.9 mmol)、6-((4-甲氧基苄基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(0.4881 g, 1.096 mmol)之混合物在60℃下加熱2小時。經由真空去除溶劑。向粗製物添加乙酸乙酯,且用1.5 M K2
HPO4
及水洗滌有機層。將乙酸乙酯層乾燥(Na2
SO4
)並過濾。用DCM洗滌濾餅以最小化產物損失。將溶劑在真空中去除,且經由自動化層析利用乙酸乙酯之己烷溶液(0%至100%,保持在100%)且然後切換為於DCM中之甲醇(0%至10%)進行溶析來純化產物,以提供呈淺黃色固體之產物6-胺基-N
-(甲基-d3
)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺。(0.14 g,40%產率)。MS (M+1)m/z
: 326.3 (MH+
)。LC滯留時間0.50 min [D]。1
H NMR (400 MHz,氯仿-d) δ 12.74 - 12.63 (m, 1H), 8.73 - 8.65 (m, 1H), 8.64 - 8.58 (m, 1H), 8.45 - 8.37 (m, 1H), 7.89 - 7.78 (m, 1H), 3.37 - 3.28 (m, 3H)。
步驟4
經由真空/N2
填充循環三次使3-(第三丁基)-6-氯嗒嗪(10.49 mg, 0.061 mmol)、Pd2
(dba)3
(1.407 mg, 1.537 µmol)、6-胺基-N
-(甲基-d3
)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(10 mg, 0.031 mmol)、Xantphos (1.778 mg, 3.07 µmol)及碳酸銫(10.01 mg, 0.031 mmol)於二噁烷(0.3 mL)中之混合物脫氣,且然後在110℃下加熱16小時。用甲醇稀釋反應,過濾並使用反相製備型HPLC進行純化,得到產物6-((6-(第三丁基)嗒嗪基-3-基)胺基)-N
-(甲基-d3
)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(3.8 mg,26%產率)。MS (M+1)m/z
: 460.3 (MH+
)。LC滯留時間1.17 min [E]。1
H NMR (500 MHz, DMSO-d6
) δ 12.03 (s, 1H), 10.43 (br s, 1H), 9.22 (s, 1H), 9.04 (br s, 1H), 8.61 (br d,J
=4.5 Hz, 1H), 8.29 (d,J
=7.8 Hz, 1H), 8.05 (d,J
=9.3 Hz, 1H), 7.74 (d,J
=9.3 Hz, 1H), 7.34 (dd,J
=7.7, 4.8 Hz, 1H), 1.38 (s, 9H)(3H埋在DMSO峰下)。
實例 246 6-((6-( 二氟甲氧基 ) 嗒嗪 -3- 基 ) 胺基 )-N-( 甲基 -d3)-4-((3-( 甲基磺醯基 ) 吡啶 -2- 基 ) 胺基 ) 嗒嗪 -3- 甲醯胺
遵循實例245之製備,使用3-氯-6-(二氟甲氧基)嗒嗪作為起始材料,得到標題化合物(4.5 mg,36%產率)。MS (M+1)m/z
: 470.0 (MH+
)。LC滯留時間1.21 min [E]。
實例 247 6-((6- 異丙基嗒嗪 -3- 基 ) 胺基 )-N-( 甲基 -d3)-4-((3-( 甲基磺醯基 ) 吡啶 -2- 基 ) 胺基 ) 嗒嗪 -3- 甲醯胺
遵循實例245之製備,使用3-氯-6-異丙基嗒嗪作為起始材料,得到標題化合物(16.7 mg,54%產率)。MS (M+1)m/z
: 446.3 (MH+
)。LC滯留時間1.05 min [E]。
步驟1:6-氯嗒嗪-3-甲醛
在0℃下將DIBAL-H (5.89 ml, 5.89 mmol)添加至6-氯嗒嗪-3-甲酸甲基酯(0.5083 g, 2.95 mmol)之THF (29.5 ml)溶液。將反應在0℃下攪拌30 min。在0℃下藉由添加水(5 mL)及1 N HCl (5.89 mL)使反應淬滅。使反應混合物升溫至室溫,且添加NaHCO3
(飽和水溶液)。將粗產物用DCM萃取三次。使合併之有機層乾燥(Na2
SO4
),過濾並濃縮。使用自動化急速層析利用乙酸乙酯之己烷溶液(0%至80%)來純化粗產物,得到標題產物(0.22 g, 52%)。HPLC滯留時間:0.82 min [B]。1
H NMR (400 MHz,氯仿-d) δ 10.34 (s, 1H), 8.03 (d,J
=8.8 Hz, 1H), 7.77 - 7.71 (m, 1H)。
步驟2:3-氯-6-(二氟甲基)嗒嗪
在0℃下將DAST (0.147 mL, 1.115 mmol)添加至6-氯嗒嗪-3-甲醛(0.106 g, 0.744 mmol)之DCM (5 mL)溶液。將反應攪拌16小時,同時使其升溫至室溫。使反應再次冷卻至0℃並水水淬滅。用DCM稀釋反應且用NaHCO3
(飽和水溶液)洗滌。將DCM層分離,乾燥(Na2
SO4
),過濾並濃縮以得到粗產物(0.12 g, 36%),其原樣使用。MS (M+1)m/z
: 165.1 (MH+
)。LC滯留時間0.62 min [D]。1
H NMR (400 MHz,氯仿-d) δ 7.87 - 7.79 (m, 1H), 7.77 - 7.68 (m, 1H), 7.10 - 6.78 (t, J=54.34Hz, 1H)。19
F NMR (376 MHz,氯仿-d) δ -114.89 (s, 2F)。
步驟3
遵循實例245之製備,使用3-氯-(6-二氟甲基)嗒嗪作為起始材料,得到標題化合物6-((6-(二氟甲基)嗒嗪-3-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(5.7 mg,12%產率)。MS (M+1)m/z
: 454.2 (MH+
)。LC滯留時間0.66 min [D]。1
H NMR (400 MHz,氯仿-d) δ 12.50 (s, 1H), 9.24 (s, 1H), 8.62 (dd,J
=4.8, 1.8 Hz, 1H), 8.51 (d,J
=9.3 Hz, 1H), 8.38 (dd,J
=7.8, 1.9 Hz, 2H), 8.24 (br s, 1H), 7.82 (d,J
=9.3 Hz, 1H), 7.21 (dd,J
=7.8, 4.8 Hz, 1H),6.88 (t,J
=56.0 Hz, 1H), 3.33 (s, 3H);19
F NMR (376 MHz,氯仿-d) δ -113.93 (s, 2F)。
實例 249 6-((5-(1,3- 二氧雜環戊烷 -2- 基 ) 吡啶 -2- 基 ) 胺基 )-N-( 甲基 -d3)-4-((3-( 甲基磺醯基 ) 吡啶 -2- 基 ) 胺基 ) 嗒嗪 -3- 甲醯胺
步驟1:2-氯-5-(1,3-二氧雜環戊烷-2-基)吡啶
將對甲苯磺酸一水合物(0.0766 g, 0.403 mmol)、乙烷-1,2-二醇(0.2445 g, 3.94 mmol)及6-氯菸鹼醛(0.3174 g, 2.242 mmol)於甲苯(3 mL)中之混合物在120℃下加熱2小時。用乙酸乙酯稀釋反應且用1 N NaOH洗滌,且然後用水洗滌。將乙酸乙酯層分離,乾燥(Na2
SO4
)並過濾。藉由自動化急速層析,利用乙酸乙酯之己烷溶液(0%至30%)進行溶析來純化產物(0.26 g, 62%)。MS (M+1)m/z
: 185.9 (MH+
)。LC滯留時間0.70 min [D]。1
H NMR (400 MHz,氯仿-d) δ 8.50 (d,J
=2.3 Hz, 1H), 7.77 (dd,J
=8.2, 2.4 Hz, 1H), 7.37 (d,J
=8.3 Hz, 1H), 5.86 (s, 1H), 4.15 - 4.06 (m, 4H)。
步驟2
遵循實例245之製備,使用2-氯-5-(1,3-二氧雜環戊烷-2-基)-吡啶作為起始材料,得到標題化合物6-((5-(1,3-二氧雜環戊烷-2-基)吡啶-2-基)胺基)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(4.7 mg,31%產率)。MS (M+1)m/z
: 475.2 (MH+
)。LC滯留時間1.15 min [E]。
實例
250
N-(
甲基
-d3)-6-((5-(2-
甲基
-1,3-
二氧雜環戊烷
-2-
基
)
吡啶
-2-
基
)
胺基
)-4-((3-(
甲基磺醯基
)
吡啶
-2-
基
)
胺基
)
嗒嗪
-3-
甲醯胺
步驟1:2-氯-5-(2-甲基-1,3-二氧雜環戊烷-2-基)吡啶
遵循實例249步驟1之製備,使用1-(6-氯吡啶-3-基)乙-1-酮作為起始材料,得到標題產物2-氯-5-(2-甲基-1,3-二氧雜環戊烷-2-基)吡啶(0.125 g, 45%)。MS (M+1)m/z
: 200.0 (MH+
)。LC滯留時間0.79 min [D]。1
H NMR (400 MHz,氯仿-d) δ 8.53 - 8.50 (m, 1H), 7.75 (dd,J
=8.2, 2.5 Hz, 1H), 7.31 (dd,J
=8.2, 0.7 Hz, 1H), 4.10 - 4.07 (m, 2H), 3.80 - 3.78 (m, 2H), 1.66 (s, 3H)。
步驟2
遵循實例245之製備,使用2-氯-5-(2-甲基-1,3-二氧雜環戊烷-2-基)-吡啶作為起始材料,得到標題化合物N-(甲基-d3)-6-((5-(2-甲基-1,3-二氧雜環戊烷-2-基)吡啶-2-基)胺基)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(4.4 mg,27%產率)。MS (M+1)m/z
: 489.2 (MH+
)。LC滯留時間1.29 min [E]。1
H NMR (500 MHz, DMSO-d6
) δ 12.10 - 12.01 (m, 1H), 10.39 - 10.27 (m, 1H), 9.52 - 9.44 (m, 1H), 9.16 - 9.07 (m, 1H), 8.72 - 8.62 (m, 1H), 8.36 - 8.23 (m, 2H), 7.77 - 7.71 (m, 1H), 7.70 - 7.63 (m, 1H), 7.37 - 7.28 (m, 1H), 4.03 - 3.96 (m, 2H), 3.80 - 3.72 (m, 1H), 3.64 - 3.54 (m, 2H), 1.65 - 1.56 (m, 3H) (3H埋在DMSO峰下)。
使用真空/N2填充循環三次使1,1'-雙(二環己基膦基)二茂鐵(6.27 mg, 10.84 µmol)、Pd2
(dba)3
(4.14 mg, 4.52 µmol)、6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(56.5 mg, 0.181 mmol)、嗒嗪-3-胺(25.8 mg, 0.271 mmol)及磷酸鉀(2 M於水中,0.226 mL, 0.452 mmol)於二噁烷(2 mL)中之混合物脫氣,且然後加熱至110℃持續1.5小時。用乙酸乙酯稀釋反應並用水洗滌三次。將乙酸乙酯層分離,乾燥(Na2
SO4
),過濾並濃縮。利用於DCM中之甲醇(0%至10%)進行溶析之急速層析得到期望產物。(39.3 mg,59%產率)。MS (M+1)m/z
: 372.1 (MH+
)。LC滯留時間0.69 min [D]。
步驟2
在室溫下將鎢酸鈉二水合物(0.035 g, 0.106 mmol)添加至過氧化氫(30%水溶液,0.325 mL, 3.18 mmol)及N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-(嗒嗪-3-基胺基)嗒嗪-3-甲醯胺(0.0394 g, 0.106 mmol)於AcOH (1 mL)中之懸浮液。在室溫下攪拌6小時之後,用水稀釋反應,利用Na2
CO3
粉末鹼化且用DCM萃取三次。將DCM層合併,用Na2
S2
O3
(5%溶液)洗滌,乾燥(Na2
SO4
),過濾並濃縮。使用反相製備型HPLC純化粗製物以提供標題化合物(11 mg,24%產率)。MS (M+1)m/z
: 404.2 (MH+
)。LC滯留時間0.80 min [D]。1
H NMR (500 MHz, DMSO-d6
) δ 12.02 (s, 1H), 10.55 - 10.44 (m, 1H), 9.31 (s, 1H), 9.01 (br s, 1H), 8.84 (d,J
=4.2 Hz, 1H), 8.62 (br d,J
=4.6 Hz, 1H), 8.29 (d,J
=6.6 Hz, 1H), 8.06 (d,J
=9.0 Hz, 1H), 7.62 (dd,J
=9.0, 4.6 Hz, 1H), 7.33 (dd,J
=7.7, 4.8 Hz, 1H)(3H埋在DMSO峰下)。
中間體 4 及 5 之手性醯胺合成: (S)- 螺 [2.2] 戊烷 -1- 甲醯胺及 (R)- 螺 [2.2] 戊烷 -1- 甲醯胺
a). (E)-二氮烯-1,2-二甲酸二-第三丁基酯/PPh3
/THF;b) 手性SFC分離
c). LiOH/THF/H2
O/MeOH;d). 草醯氯(過夜);NH3
/MeOH
步驟1:螺[2.2]戊烷-1-甲酸萘-2-基甲基酯
在0℃下將(E)-二氮烯-1,2-二甲酸二-第三丁基酯(0.407 g, 1.766 mmol)添加至螺[2.2]戊烷-1-甲酸(0.1650 g, 1.472 mmol, Chembridge-BB)、萘-2-基甲醇(0.279 g, 1.766 mmol)及三苯基膦(0.463 g, 1.766 mmol)之THF (5 mL)溶液。添加完成後,使反應升溫至室溫並攪拌14小時。用DCM稀釋反應且添加矽膠。將揮發性有機溶劑在真空中蒸發,且將所得矽膠裝載至前置管柱上。藉由自動化急速層析,利用乙酸乙酯之己烷溶液(0%至5%)進行溶析來純化產物(274 mg,74%產率)。1
H NMR (400 MHz,氯仿-d) δ 7.90 - 7.83 (m, 4H), 7.55 - 7.46 (m, 3H), 5.37 - 5.24 (m, 2H), 2.12 - 2.05 (m, 1H), 1.61 - 1.58 (m, 1H), 1.46 - 1.39 (m, 1H), 1.06 - 0.96 (m, 2H), 0.95 - 0.90 (m, 2H)。HPLC滯留時間(方法A):t R
= 3.69 min。
步驟2 (pk1)及(pk2)
藉由上文所闡述之手性SFC分離0.403 g之步驟1化合物。所分離之該兩種異構物在溶析中稱為「pk1」及「pk2」。獲得pk1標題化合物0.1917 g (47%產率)及pk2標題化合物0.1728 g (43%產率)。立體化學指配係基於與相應羧酸之文獻值之比較(參見下文)。
(S)-螺[2.2]戊烷-1-甲酸萘-2-基甲基酯,pk1:1
H NMR (400 MHz,氯仿-d) δ 7.90 - 7.82 (m, 4H), 7.55 - 7.46 (m, 3H), 5.31 (q,J
=12.5 Hz, 2H), 2.07 (dd,J
=7.5, 4.2 Hz, 1H), 1.59 (t,J
=4.0 Hz, 1H), 1.43 (dd,J
=7.6, 3.8 Hz, 1H), 1.07 - 0.88 (m, 4H)。SFC滯留時間:t R
= 2.21 min。旋光度(OR):72.90 (20℃)。
(R)-螺[2.2]戊烷-1-甲酸萘-2-基甲基酯,pk2:1
H NMR (400 MHz,氯仿-d) δ 7.89 - 7.83 (m, 4H), 7.54 - 7.46 (m, 3H), 5.31 (q,J
=12.4 Hz, 2H), 2.07 (dd,J
=7.5, 4.2 Hz, 1H), 1.58 (t,J
=4.0 Hz, 1H), 1.43 (dd,J
=7.6, 3.8 Hz, 1H), 1.07 - 0.87 (m, 4H)。SFC滯留時間:t R
= 3.17 min。OR:-76.09 (20℃)。
步驟3S:(S)-螺[2.2]戊烷-1-甲酸
將氫氧化鋰(0.066 g, 2.78 mmol)及(S)-螺[2.2]戊烷-1-甲酸萘-2-基甲基酯(0.1751 g, 0.694 mmol)於THF (2 mL)、水(0.5 mL)及MeOH (0.5 mL)中之混合物在室溫下攪拌16小時。將揮發性有機物在真空下去除且向殘餘物添加水。將水溶液用DCM洗滌四次(棄掉),且然後利用1 N HCl (3.5 mL)酸化。用DCM自水層萃取三次粗產物。使合併之DCM層乾燥(Na2
SO4
),過濾並濃縮以得到期望標題化合物(62.7 mg,81%產率)。1
H NMR (400 MHz,氯仿-d) δ 1.99 (dd,J
=7.5, 4.2 Hz, 1H), 1.58 (t,J
=4.0 Hz, 1H), 1.48 (dd,J
=7.6, 3.8 Hz, 1H), 1.05 - 0.91 (m, 4H)。OR:188.25 (20℃)。
步驟3R:(R)-螺[2.2]戊烷-1-甲酸
標題產物係以與步驟3S相同之方式自pk2製備以得到標題化合物(R)-螺[2.2]戊烷-1-甲酸。(60.0 mg,83%產率)。1
H NMR (400 MHz,氯仿-d) δ 1.99 (dd,J
=7.6, 4.1 Hz, 1H), 1.58 (t,J
=4.0 Hz, 1H), 1.47 (dd,J
=7.6, 3.8 Hz, 1H), 1.04 - 0.90 (m, 4H)。OR: -187.72 (20℃)。文獻OR [α]D 25
= -113.3°至-172.7°,此取決於光學純度(K. B. Wiberg, C. Osterle,J. Org. Chem
,64
, 7763-7767 (1999)。
步驟4S:(S)-螺[2.2]戊烷-1-甲醯胺
在室溫下將草醯氯(0.054 mL, 0.612 mmol))添加至(S)-螺[2.2]戊烷-1-甲酸(0.0572 g, 0.510 mmol)之DCM (3 mL)溶液。將反應攪拌16小時,然後將揮發性有機物在真空下去除。向粗製酸性氯化物添加DCM (1.5 mL),且然後在0℃下將氨(7 M於MeOH中,2.5 mL, 17.50 mmol)溶液添加至中間體。將反應攪拌過夜,同時使其升溫至室溫。將溶劑在真空下去除,得到呈褐色固體之標題化合物(39.8 mg,70%產率)。1
H NMR (400 MHz,氯仿-d) δ 5.51 - 5.16 (m, 2H), 1.91 - 1.84 (m, 1H), 1.50 - 1.44 (m, 1H), 1.43 - 1.38 (m, 1H), 0.96 (s, 4H)。
步驟4R:(R)-螺[2.2]戊烷-1-甲醯胺
標題產物係以與步驟4S相同之方式自(R)-螺[2.2]戊烷-1-甲酸作為起始材料來製備以得到標題化合物(53.5 mg,98%產率)。1
H NMR (400 MHz,氯仿-d) δ 5.51 - 5.22 (m, 2H), 1.91 - 1.85 (m, 1H), 1.48 - 1.43 (m, 1H), 1.43 - 1.37 (m, 1H), 0.96 (s, 4H)。
實例252
步驟1
使用真空/N2填充循環三次使碳酸銫(149 mg, 0.457 mmol)、Xantphos (14.43 mg, 0.025 mmol)、Pd2
(dba)3
(11.42 mg, 0.012 mmol)、6-氯-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)嗒嗪-3-甲醯胺(65 mg, 0.208 mmol)及(R)-螺[2.2]戊烷-1-甲醯胺(50.8 mg, 0.457 mmol)於二噁烷(3 mL)中之混合物脫氣。將反應在110℃下加熱16小時。用水及DCM稀釋該反應。將DCM層分離並再用水洗滌兩次,且然後乾燥(Na2
SO4
),過濾並濃縮。經由自動化急速層析,利用於DCM中之甲醇(0%至10%)溶析進行純化得到標題化合物(R)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-(螺[2.2]戊烷-1-甲醯胺基)嗒嗪-3-甲醯胺(54 mg,67%產率)。1
H NMR (400 MHz,氯仿-d) δ 12.15 (br s, 1H), 9.88 (s, 1H), 8.68 (br s, 1H), 8.36 (br d,J
=3.5 Hz, 1H), 8.25 (br s, 1H), 7.72 (br d,J
=7.4 Hz, 1H), 6.97 (br dd,J
=7.0, 5.1 Hz, 1H),2.51 (s, 3H), 2.21 - 2.09 (m, 1H), 1.58 - 1.10 (m, 6H), 1.08 - 0.93 (m, 5H)。
LCMS (ESI)m/e
388.1 [(M+H)+
, calc’d C18
H18
D3
N6
O2
S1
, 388.1];LC/MS滯留時間(方法D):t R
= 0.80 min。
步驟2
在室溫下向過氧化氫(30%水溶液,0.258 mL, 2.52 mmol)及(R)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-(螺[2.2]戊烷-1-甲醯胺基)嗒嗪-3-甲醯胺(0.0489 g, 0.126 mmol)於AcOH (1 mL)中之懸浮液添加鎢酸鈉二水合物(0.042 g, 0.126 mmol)。在室溫下攪拌1小時後,用水稀釋反應,利用Na2
CO3
粉末鹼化且用DCM萃取三次。將DCM層合併,用Na2
S2
O3
(5%溶液)洗滌,乾燥(Na2
SO4
),過濾並濃縮。使用反相製備型HPLC來純化粗產物,得到呈無色固體之標題化合物(R)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-(螺[2.2]戊烷-1-甲醯胺基)嗒嗪-3-甲醯胺(16.2 mg, 31%)。1
H NMR (500 MHz, DMSO-d6
) δ 12.07 (s, 1H), 11.22 (s, 1H), 9.49 (s, 1H), 9.16 (s, 1H), 8.63 (dd,J
=4.6, 1.5 Hz, 1H), 8.29 (dd,J
=7.8, 1.4 Hz, 1H), 7.34 (dd,J
=7.8, 4.7 Hz, 1H),2.48 - 2.43 (m, 1H), 1.46 - 1.41 (m, 1H), 1.42 - 1.36 (m, 1H), 0.95 - 0.82 (m, 3H), 0.80 - 0.73 (m, 1H)。(3H甲基碸埋在DMSO峰下)。LCMS (ESI)m/e
420.0 [(M+H)+
, calc’d C18
H18
D3
N6
O4
S, 420.1];LC/MS滯留時間(方法E):t R
= 1.38 min;OR:-205.39 (20℃)。
實例253
步驟1
遵循實例252 (步驟1)之製備,使用(S)-螺[2.2]戊烷-1-甲醯胺,獲得標題化合物(S)-N-(甲基-d3)-4-((3-(甲硫基)吡啶-2-基)胺基)-6-(螺[2.2]戊烷-1-甲醯胺基)嗒嗪-3-甲醯胺(55 mg,72%產率)。LCMS (ESI)m/e
388.1 [(M+H)+
, calc’d C18
H18
D3
N6
O2
S1
, 388.1];LC/MS滯留時間(方法D):t R
= 0.80 min。
步驟2
遵循實例252之製備,獲得呈無色固體之標題化合物(S)-N-(甲基-d3)-4-((3-(甲基磺醯基)吡啶-2-基)胺基)-6-(螺[2.2]戊烷-1-甲醯胺基)嗒嗪-3-甲醯胺(13.3 mg, 23%產率)。1
H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 11.07 (s, 1H), 9.53 (s, 1H), 9.09 7 (s, 1H), 8.67 - 8.55 (m, 1H), 8.36 - 8.23 (m, 1H), 7.40 - 7.25 (m, 1H), 2.47 - 2.43 (m, 1H), 1.50 - 1.42 (m, 1H), 1.40 - 1.34 (m, 1H), 1.00 - 0.83 (m, 3H), 0.83 - 0.73 (m, 1H)。(3H甲基碸埋在DMSO峰下)。LCMS (ESI)m/e
420.1 [(M+H)+
, calc’d C18
H18
D3
N6
O4
S, 420.1];LC/MS滯留時間(方法E):t R
= 1.39 min。OR:160.12 (20℃)。
以下實例係以與實例177步驟2之產物類似之方式來製備。
表15
生物學分析
使用以下分析來顯示本發明之化合物之活性。
人類全血中IFNα誘導之STAT磷酸化
在與化合物一起培育1小時之後,將人類全血(利用EDTA或ACD-A作為抗凝血劑來抽血)用1000 U/mL重組人類IFNα A/D (R&D Systems 11200-2)刺激15 min。藉由添加固定/溶解緩衝液(BD 558049)來停止刺激。細胞經CD3 FITC抗體(BD 555916)染色,洗滌,且在冰上使用Perm III緩衝液(BD 558050)進行可滲透化處理。然後使細胞經Alexa-Fluor 647 pSTAT5 (pY694)抗體(BD 612599)染色30 min,之後在FACS Canto II上進行分析。在對CD3陽性群體進行門控之後,藉由中位螢光強度定量pSTAT5表現之量。
Claims (26)
- 一種具有下式I之化合物或其立體異構物或醫藥上可接受之鹽:
- 如請求項1之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有式II:
- 如請求項1之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有式III:
- 如請求項2之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有下式:
- 如請求項4之化合物或其立體異構物或醫藥上可接受之鹽,其中該化 合物具有下式:
- 如請求項5之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有下式:
- 如請求項6之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有下式:
- 如請求項3之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有下式:
- 如請求項8之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物具有下式:
- 一種化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物為:6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(5-氟吡啶-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(6-甲氧基嗒嗪-3-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1-甲基-1H-吡唑-3-基)胺基]嗒嗪-3-甲醯胺;6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N- (2H3)甲基嗒嗪-3-甲醯胺;6-[(6-環丙基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(1,5-二甲基-1H-吡唑-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[5-(三氟甲基)吡啶-2-基]胺基}吡啶-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[6-(三氟甲基)嗒嗪-3-基]胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(2-甲氧基嘧啶-4-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[5-氟-4-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[5-(2-胺基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[1-(2,2,2-三氟乙基)-1H-吡唑-3-基]胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[6-(2H3)甲氧基嗒嗪-3-基]胺基}-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(5-氰基吡啶-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;N-{2-[6-({5-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-[(2H3)甲基胺甲醯基]嗒嗪-3-基}胺基)吡啶-3-基]丙-2-基}胺基甲酸甲基酯; 6-{[5-(1-氰基環丙基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[5-(嗎啉-4-基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;6-[(5-環丙基吡嗪-2-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(6-甲基嗒嗪-3-基)胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[5-(三氟甲基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(5-甲基吡嗪-2-基)胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[4-(甲氧基甲基)吡啶-2-基]胺基}-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(2,6-二甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[6-(2,6-二氟苯基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;6-[(1S,2R)-2-氟環丙烷醯胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(1S,2S)-2-氟環丙烷醯胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N- (2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{螺[2.2]戊烷-1-醯胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(2-甲基-2H-1,2,3-三唑-4-基)胺基]嗒嗪-3-甲醯胺;6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;6-{[5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[5-(三氟甲氧基)吡啶-2-基]胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1S)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1R)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺; 6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲氧基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(2-環丙基-6-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[6-氟-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-{[5-(甲氧基甲基)吡啶-2-基]胺基}-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-6-({5-[(2H3)甲氧基甲基]吡啶-2-基}胺基)-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[6-(二氟甲氧基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[6-(丙-2-基)嗒嗪-3-基]胺基}嗒嗪-3-甲醯胺;6-[(6-第三丁基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-{[6-(二氟甲基)嗒嗪-3-基]胺基}-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1S,2S)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;或6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3) 甲基嗒嗪-3-甲醯胺。
- 如請求項10之化合物或其立體異構物或醫藥上可接受之鹽,其中該化合物為:6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(6-環丙基-2-甲基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(6-環丙基嘧啶-4-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-[(6-環丙基嗒嗪-3-基)胺基]-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;6-環丙烷醯胺基-4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基吡啶-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1R,2R)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{螺[2.2]戊烷-1-醯胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1S,2S)-2-甲基環丙烷醯胺基]嗒嗪-3-甲醯胺;6-環丙烷醯胺基-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-{[5-(三氟甲氧基) 吡啶-2-基]胺基}嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1S)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;4-[(3-甲烷磺醯基吡啶-2-基)胺基]-N-(2H3)甲基-6-[(1R)-螺[2.2]戊烷-1-醯胺基]嗒嗪-3-甲醯胺;或6-{[4-氯-5-(2-羥基丙-2-基)吡啶-2-基]胺基}-4-[(3-甲烷磺醯基-6-甲基吡啶-2-基)胺基]-N-(2H3)甲基嗒嗪-3-甲醯胺。
- 一種醫藥組合物,其包含如請求項1至13中任一項之化合物或其立體異構物或醫藥上可接受之鹽及醫藥上可接受之載劑或稀釋劑。
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US20130178478A1 (en) * | 2012-01-10 | 2013-07-11 | Hoffman-La Roche Inc. | Pyridazine amide compounds |
WO2014074661A1 (en) * | 2012-11-08 | 2014-05-15 | Bristol-Myers Squibb Company | AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHα RESPONSES |
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