PYRIMIDINE CARBOXAMIDES USEFUL AS INHIBITORS OF PDE4 ISOZYMES

摘要

1. A compound of Formula (1. 0. 0): or a pharmaceutical acceptable salt thereof; where R<1> is -H, -F or -Cl, R<2> is -H, -F, -Cl or -CH3, R is -H or -CH3, Z is phenyl, cyclopentyl, cyclohexyl, furanyl, thienyl, thiazolyl, oxazolyl, indolin-2-onyl, pyridyl or pyrazinyl; E is -H, -F, -OCH3, -OH, -CH(OH)CH3, -CH(OH) (CH3)2, -OC(=O)R<12>, -NHS(=O)2CH3, -S(=O)2NH2, -NH2OR-N(CH3)2, Z is pyridyl or phenyl, where R<4> is taken twice and is -F or -Cl, or else R<4> is a single substituent consisting of -F, -Cl, -CN, -NO2, -NH2, -N(CH3)2, -CF3, -SCH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)OCH3, -COMH2, -NHS(=O)2CH3, or Z is phenyl where two R<4> are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form indolyl, quinolinyl, 1,3-benzodioxolyl, benzoxazolyl, 1,3-benzodithiolyl, benzothiazolyl, benzimidazolyl or 1,4-benzodioxanyl, R<7> and R<8> are each a member independently selected from the group consisting of-H, -F, -Cl, -OR<12>; (C1-C4)alkyl; hydroxy-(C1-C4)alkyl, CF3,, -OC(=O)R<12>, NR<12>R<13>, hydroxy-(C1-C4)alkylamino, phenyl, benzyl or heterocyclyl radical, selected from the group consisting of pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyridinyl, tetrazolyl, indolyl and benzimidazolyl, wherein each of said phenyl, benzyl or heterocyclyl radicals is independently substituted with 0-2 substituents R<10>, R<10> is a radical selected from the group consisting of -F, -Cl, -CF3, -CN, -OR<12>; (C1-C2)alkyl; hydroxy-(C1-C2)alkyl, -O-C(=O)R<13>, -O-C(=O)NR<12>R<13>, -NR<12>R<13>, -NR<12>C(=O)R<13>, -NR<12>C(=O)OR<13>, -NR<12>S(=O)2R<13>; and -S(=O)2NR<12>R<13> and R<12> and R<13> are each a member independently selected from the group consisting of -H; -(C1-C4)alkyl; phenyl; or benzyl; wherein said alkyl, phenyl, or benzyl is substituted by 0 to 3 substituents selected from the group consisting of F and Cl. 2. A compound of claim 1, where R<1> is -H, Z is phenyl, furanyl, or thienyl, E is -OCH3, -OH, -CH(OH)CH3, or -C(OH)(CH3)2, Z is phenyl or pyridyl where R<4> is taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl, and R<7>and R<8> each independently selected from the group consisting of -H, -CH3, -OCH3, -CF3 or -NH2. 3. A compound according to Claim 1, selected from the group consisting of: 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (6.0.1); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-(1-hydroxy-1-methyl-ethyl)-benzylamide of Formula (6.0.2); 2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.3); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(methoxy)benzyl]-carboxamide Formula (6.0.4); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(thiophene-2-yl)methyl]-carboxamide of Formula (6.0.5); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (thiophen-2-ylmethyl)-amide of Formula (6.0.6); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(furan-2-yl)methyl]-carboxamide of Formula (6.0.7); 2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.8); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(4-methoxy)benzyl]-carboxamide of Formula (6.0.9); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(thiophene-2-yl)methyl]-carboxamide of Formula (6.0.10); 2-N-[1-Methyl-1-(thiophene-2-yl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-y]-carboxamide of Formula (6.0.11); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (1-thiophen-2-yl-ethyl)amide of Formula (6.0.12); 1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[(3-methyl)thiophene-2-yl)methyl]-carboxamide of Formula (6.0.13); 2-N-[(4-Methoxy)phenyl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide of Formula (6.0.14); 2-N[(4-Chloro-thiophene-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.15); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (4-chloro-thiophen-2ylmethyl)-amide of Formula (6.0.16); 2-N-[(5-Chloro-furan-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.17); 1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[thiazol-2-yl)methyl]-carboxamide of Formula (6.0.18); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)benzyl]-carboxamide of Formula (6.0.19); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid4-(1-hydroxy-ethyl)-benzylamide of Formula (6.0.20); 2-N-(2,3-Difluoro-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.21); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-hydroxy-benzyl)-carboxamide of Formula (6.0.22); 2-N-(2-Chloro-benzyl)-1-{6-[3-(N,N-dimethylamino)-phenoxy]-pyrimidin-5-yl}-carboxamide of Formula (6.0.23); 2-N-(2-Chloro-benzyl)-1-[6-(4-cyano-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.24); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-chloro-benzylamide of Formula (6.0.25); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-methylsulfoamino-benzyl)-carboxamide of Formula (6.0.26); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(1-methyl-1-(5-chloro-2-thiopheneyl)methyl]-carboxamide of Formula (6.0.27); 4-(Benzo[1,3]dioxol-5-yloxy]-pyrimidine-5-carboxylic acid[1-(5-chloro-thiophen-2-yl)-ethyl]-amide of Formula (6.0.28); 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-nitro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.29); 1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide of Formula (6.0.30); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide of Formula (6.0.31); 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-trifluoromethyl-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.32); 1-[6-(3-Chloro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide of Formula (6.0.33); 2-N-(2-Fluoro-benzyl)-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide of Formula (6.0.34); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-imino-benzyl)-carboxamide of Formula (6.0.35); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-amino-benzylamide of Formula (6.0.36); 2-N-[5-(1-Hydroxyethyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide of Formula (6.0.37); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [5-(1-hydroxy-ethyl)thiophen-2-ylmethyl]-amide of Formula (6.0.38); 2-N-[5-(1-Hydroxy-iso-propyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide of Formula (6.0.39); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid[5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-amide of Formula (6.0.40); 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylthio-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.41); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylcohexyl]methyl}-carboxamide of Formula (6.0.42); 1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(5-methyl-pyrazin-2-yl)methyl]-carboxamide of Formula (6.0.43); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (5-methyl-pyrazin-2ylmethyl)-amide of Formula (6.0.44); 2-N-(4-N,N-Dimethyl-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.45); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-dimethylaminbenzylamide of Formula (6.0.46); 2-N-[(4-Aminosulfonyl)-benzyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.47); 4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide of Formula (6.0.48); 2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylcarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.49); 1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylcohexyl]methyl}-carboxamide of Formula (6.0.50); 2-N-[4-(9-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methoxycarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.51); and 2-N-(2-Chloro-benzyl)-1-[6-(3-methylcarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide of Formula (6.0.52). 4. A pharmaceutical composition for use in treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme whereby it regulates the activation and degranulation of eosinophils, comprising a therapeutical effective amount of a compound of Formula (1.0.0) as defined in Claim 1, together with a pharmaceutically acceptable carrier therefor. 5. Use of a therapeutically effective amount of a compound of Formula (1. 0. 0) as defined in Claim 1, for manufacturing a medicament for treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme whereby it regulates the activation and degranulation of eosinophils. 6. Use according to Claim 5 wherein said disease, disorder, or condition comprises one or more members selected from the group consisting of: -asthma of whatever type, etiology, or pathogenesis; or asthma that is a member selected from the group consisting of atopic asthma; non-atopic asthma; allergic asthma; atopic, bronchial, IgE-mediated asthma; bronchial asthma; essential asthma; true asthma; intrinsic asthma caused by pathophysiologic disturbances; extrinsic asthma caused by environmental factors; essential asthma of unknown or in apparent cause; non-atopic asthma; bronchitic asthma; emphysematous asthma; exercise-induced asthma; occupational asthma; infective asthma caused by bacterial, fungal, protozoal, or viral infection; non-allergic asthma; incipient asthma; wheezy infant syndrome; -chronic or acute bronchoconstriction; chronic bronchitis; small airways obstruction; and emphysema; -obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis; or an obstructive or inflammatory airways disease that is a member selected from the group consisting of asthma; pneumoconiosis; chroniceosinophilic pneumonia; chronic obstructive pulmonary disease (COPD); COPD that includes chr