CA2476012C - Substituted pyridinones as modulators of p38 map kinase - Google Patents
Substituted pyridinones as modulators of p38 map kinase Download PDFInfo
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- CA2476012C CA2476012C CA2476012A CA2476012A CA2476012C CA 2476012 C CA2476012 C CA 2476012C CA 2476012 A CA2476012 A CA 2476012A CA 2476012 A CA2476012 A CA 2476012A CA 2476012 C CA2476012 C CA 2476012C
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- CA
- Canada
- Prior art keywords
- alkyl
- oxy
- difluorobenzyl
- nr6r7
- methyl
- Prior art date
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- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title claims abstract description 29
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title claims abstract description 29
- 150000005299 pyridinones Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 286
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 745
- 229910052736 halogen Inorganic materials 0.000 claims description 560
- 150000002367 halogens Chemical class 0.000 claims description 560
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 430
- 125000000217 alkyl group Chemical group 0.000 claims description 403
- -1 indolon-2-yl Chemical group 0.000 claims description 202
- 125000003545 alkoxy group Chemical group 0.000 claims description 192
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 181
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 174
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 174
- 125000002252 acyl group Chemical group 0.000 claims description 169
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 163
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 156
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 129
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 115
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 105
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 104
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 100
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 100
- 125000001188 haloalkyl group Chemical group 0.000 claims description 94
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 92
- 125000004193 piperazinyl group Chemical group 0.000 claims description 91
- 125000002757 morpholinyl group Chemical group 0.000 claims description 89
- 229910052757 nitrogen Inorganic materials 0.000 claims description 82
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 82
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 81
- 125000004076 pyridyl group Chemical group 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 73
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 71
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 66
- 125000003386 piperidinyl group Chemical group 0.000 claims description 66
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 57
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 56
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 54
- 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 description 50
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- 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 45
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 44
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 43
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 30
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 125000001544 thienyl group Chemical group 0.000 claims description 25
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 24
- 125000001041 indolyl group Chemical group 0.000 claims description 23
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 208000035475 disorder Diseases 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 17
- 230000001404 mediated effect Effects 0.000 claims description 16
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 15
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 15
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 13
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 11
- 206010003246 arthritis Diseases 0.000 claims description 9
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 9
- 208000006673 asthma Diseases 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000002685 pulmonary effect Effects 0.000 claims description 8
- 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 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 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 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
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 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 4
- 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 4
- 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 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
- LZQSJJLHDYOERR-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2-one Chemical compound CC1=CC=CC(C)=C1N1C(=O)C(Br)=C(OCC=2C(=CC(F)=CC=2)F)C=C1C LZQSJJLHDYOERR-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
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- 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
- 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 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
- 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
- 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
- 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 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
- 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 2
- WYGTZMORWGQIPR-UHFFFAOYSA-N 3-[[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]methyl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(CN2C(C(Br)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 WYGTZMORWGQIPR-UHFFFAOYSA-N 0.000 claims description 2
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- UNWSFAOYRXPZNL-UHFFFAOYSA-N 3-chloro-4-[(2,4-difluorophenyl)methoxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2-one Chemical compound ClC=1C(=O)N(C=2C(=CC(F)=CC=2F)F)C(C)=CC=1OCC1=CC=C(F)C=C1F UNWSFAOYRXPZNL-UHFFFAOYSA-N 0.000 claims description 2
- FSTHIQRUHPGZGE-UHFFFAOYSA-N 4-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-3,5-dichlorobenzenesulfonamide Chemical compound BrC=1C(=O)N(C=2C(=CC(=CC=2Cl)S(N)(=O)=O)Cl)C(C)=CC=1OCC1=CC=C(F)C=C1F FSTHIQRUHPGZGE-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims description 2
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Classifications
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