ES2334990T3 - Piridinonas sustituidas como moduladores de p38 map quinasa. - Google Patents
Piridinonas sustituidas como moduladores de p38 map quinasa. Download PDFInfo
- Publication number
- ES2334990T3 ES2334990T3 ES03713478T ES03713478T ES2334990T3 ES 2334990 T3 ES2334990 T3 ES 2334990T3 ES 03713478 T ES03713478 T ES 03713478T ES 03713478 T ES03713478 T ES 03713478T ES 2334990 T3 ES2334990 T3 ES 2334990T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- methyl
- oxy
- bromo
- difluorobenzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 150000001875 compounds Chemical class 0.000 claims abstract description 240
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 223
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 131
- 150000002367 halogens Chemical class 0.000 claims abstract description 131
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 91
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 44
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 31
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 28
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 23
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 17
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 17
- 125000002071 phenylalkoxy group Chemical group 0.000 claims abstract description 13
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 11
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 9
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims abstract description 8
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract 8
- 238000002360 preparation method Methods 0.000 claims description 146
- -1 indolon-2-yl Chemical group 0.000 claims description 110
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 51
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 14
- 125000006542 morpholinylalkyl group Chemical group 0.000 claims description 12
- 230000001404 mediated effect Effects 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- USRKMHMDWVNWLX-UHFFFAOYSA-N 1-benzyl-3-bromo-4-[(3-chlorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC=CC=2)C(C)=CC=1OCC1=CC=CC(Cl)=C1 USRKMHMDWVNWLX-UHFFFAOYSA-N 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- KNCDMZFDFYDADF-UHFFFAOYSA-N 1-benzyl-4-[(3-chlorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound C=1C(=O)N(CC=2C=CC=CC=2)C(C)=CC=1OCC1=CC=CC(Cl)=C1 KNCDMZFDFYDADF-UHFFFAOYSA-N 0.000 claims description 7
- CBOJIVFOPAIKRA-UHFFFAOYSA-N 1-benzyl-6-methyl-4-phenylmethoxypyridin-2-one Chemical compound C=1C(=O)N(CC=2C=CC=CC=2)C(C)=CC=1OCC1=CC=CC=C1 CBOJIVFOPAIKRA-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- BGSKLTFWWOSTJG-UHFFFAOYSA-N 1-benzyl-3-bromo-6-methyl-4-phenylmethoxypyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC=CC=2)C(C)=CC=1OCC1=CC=CC=C1 BGSKLTFWWOSTJG-UHFFFAOYSA-N 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- PYTYOIVBADCUDS-UHFFFAOYSA-N 3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(C=2C(=CC=CC=2Cl)Cl)C(C)=CC=1OCC1=CC=C(F)C=C1F PYTYOIVBADCUDS-UHFFFAOYSA-N 0.000 claims description 5
- LJRWEWAERUZBPM-UHFFFAOYSA-N 3-bromo-1-(2,6-dichlorophenyl)-6-methyl-4-phenylmethoxypyridin-2-one Chemical compound BrC=1C(=O)N(C=2C(=CC=CC=2Cl)Cl)C(C)=CC=1OCC1=CC=CC=C1 LJRWEWAERUZBPM-UHFFFAOYSA-N 0.000 claims description 5
- KBFGSUTZQQUJCZ-UHFFFAOYSA-N 3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound CC1=CC=CC(C)=C1N1C(=O)C(Br)=C(OCC=2C=CC(F)=CC=2)C=C1C KBFGSUTZQQUJCZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000005190 thiohydroxy group Chemical group 0.000 claims description 5
- PFMILNLGQLSMLX-UHFFFAOYSA-N 3-acetyl-1-(2-chlorophenyl)-6-methyl-4-phenylmethoxypyridin-2-one Chemical compound C1=C(C)N(C=2C(=CC=CC=2)Cl)C(=O)C(C(=O)C)=C1OCC1=CC=CC=C1 PFMILNLGQLSMLX-UHFFFAOYSA-N 0.000 claims description 4
- IJHZHMDMJCJCDV-UHFFFAOYSA-N 3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(C=2C(=CC=CC=2Cl)Cl)C(C)=CC=1OCC1=CC=C(F)C=C1 IJHZHMDMJCJCDV-UHFFFAOYSA-N 0.000 claims description 4
- CFCCLYABTGQRRK-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-1-[(4-hydroxyphenyl)methyl]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC(O)=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F CFCCLYABTGQRRK-UHFFFAOYSA-N 0.000 claims description 4
- HVUPCGDITCGWTG-UHFFFAOYSA-N 4-[[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]methyl]-n-(2-hydroxyethyl)benzamide Chemical compound BrC=1C(=O)N(CC=2C=CC(=CC=2)C(=O)NCCO)C(C)=CC=1OCC1=CC=C(F)C=C1F HVUPCGDITCGWTG-UHFFFAOYSA-N 0.000 claims description 4
- KCAJXIDMCNPGHZ-UHFFFAOYSA-N PH 797804 Chemical compound CNC(=O)C1=CC=C(C)C(N2C(C(Br)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 KCAJXIDMCNPGHZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 4
- XIAJFWOACHIGML-UHFFFAOYSA-N 1-[[2-(aminomethyl)phenyl]methyl]-3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C(=CC=CC=2)CN)C(C)=CC=1OCC1=CC=C(F)C=C1F XIAJFWOACHIGML-UHFFFAOYSA-N 0.000 claims description 3
- NWWGASAIFNYQIF-UHFFFAOYSA-N 1-[[4-(aminomethyl)phenyl]methyl]-3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC(CN)=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F NWWGASAIFNYQIF-UHFFFAOYSA-N 0.000 claims description 3
- ZQLPVBNKJHIHFZ-UHFFFAOYSA-N 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-n-(2-hydroxyethyl)-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NCCO)C=C1N1C(=O)C(Br)=C(OCC=2C(=CC(F)=CC=2)F)C=C1C ZQLPVBNKJHIHFZ-UHFFFAOYSA-N 0.000 claims description 3
- KZKMIYIQLWQAOL-UHFFFAOYSA-N 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(N2C(C(Br)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 KZKMIYIQLWQAOL-UHFFFAOYSA-N 0.000 claims description 3
- SFIVNQRKHWCDQO-UHFFFAOYSA-N 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]benzamide Chemical compound BrC=1C(=O)N(C=2C=C(C=CC=2)C(N)=O)C(C)=CC=1OCC1=CC=C(F)C=C1F SFIVNQRKHWCDQO-UHFFFAOYSA-N 0.000 claims description 3
- LHBZOPRJAVNQFH-UHFFFAOYSA-N 3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2-one Chemical compound O=C1C(C(=O)C)=C(O)C=C(C)N1C1=CC=CC=C1Cl LHBZOPRJAVNQFH-UHFFFAOYSA-N 0.000 claims description 3
- WWKDYZXSYNVDLC-UHFFFAOYSA-N 3-bromo-1-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorophenyl)methoxy]pyridin-2-one Chemical compound CC1=CC=CC(C)=C1N1C(=O)C(Br)=C(OCC=2C(=CC(F)=CC=2F)F)C=C1C WWKDYZXSYNVDLC-UHFFFAOYSA-N 0.000 claims description 3
- CPOYXKVGUFVISK-UHFFFAOYSA-N 3-bromo-1-[[3-(bromomethyl)phenyl]methyl]-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=C(CBr)C=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F CPOYXKVGUFVISK-UHFFFAOYSA-N 0.000 claims description 3
- CDXILCRPUHVRAP-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-1-[5-(2-hydroxypropan-2-yl)-2-methylphenyl]-6-methylpyridin-2-one Chemical compound CC1=CC=C(C(C)(C)O)C=C1N1C(=O)C(Br)=C(OCC=2C(=CC(F)=CC=2)F)C=C1C CDXILCRPUHVRAP-UHFFFAOYSA-N 0.000 claims description 3
- DIDKAZVJVLTZIN-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2-one Chemical compound CC1=CC=C(CO)C=C1N1C(=O)C(Br)=C(OCC=2C(=CC(F)=CC=2)F)C=C1C DIDKAZVJVLTZIN-UHFFFAOYSA-N 0.000 claims description 3
- RFNPFHVTUALNRU-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-1-[[4-(hydroxymethyl)phenyl]methyl]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC(CO)=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F RFNPFHVTUALNRU-UHFFFAOYSA-N 0.000 claims description 3
- ASWPKEVNQRQXHL-UHFFFAOYSA-N 3-chloro-4-[(2,4-difluorophenyl)methoxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2-one Chemical compound CC1=CC=C(CO)C=C1N1C(=O)C(Cl)=C(OCC=2C(=CC(F)=CC=2)F)C=C1C ASWPKEVNQRQXHL-UHFFFAOYSA-N 0.000 claims description 3
- PHGFIDCHPGXZAU-UHFFFAOYSA-N 4-[[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]methyl]benzamide Chemical compound BrC=1C(=O)N(CC=2C=CC(=CC=2)C(N)=O)C(C)=CC=1OCC1=CC=C(F)C=C1F PHGFIDCHPGXZAU-UHFFFAOYSA-N 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
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- 108091000080 Phosphotransferase Proteins 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 102000020233 phosphotransferase Human genes 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- KTPQPAGLITZOAF-UHFFFAOYSA-N 1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(C=2C=C(CN)C=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F KTPQPAGLITZOAF-UHFFFAOYSA-N 0.000 claims description 2
- LUVJHJDVISUMCN-UHFFFAOYSA-N 1-benzyl-3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methylpyridin-2-one Chemical compound BrC=1C(=O)N(CC=2C=CC=CC=2)C(C)=CC=1OCC1=CC=C(F)C=C1F LUVJHJDVISUMCN-UHFFFAOYSA-N 0.000 claims description 2
- PJPBTNREUVPPLY-UHFFFAOYSA-N 3-[3-chloro-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-4-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(F)C(N2C(C(Cl)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 PJPBTNREUVPPLY-UHFFFAOYSA-N 0.000 claims description 2
- UVYXMJXLBYAVTQ-UHFFFAOYSA-N 3-[3-chloro-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-n,4-dimethylbenzamide Chemical compound CNC(=O)C1=CC=C(C)C(N2C(C(Cl)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 UVYXMJXLBYAVTQ-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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