Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders

A compound which is:

• 3-hydroxy-1-methyl-5-naphthalen-2-ylpyridin-2(1H)-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-hydroxypyridin-2(1H)-one;
• 3-hydroxy-5-(isoquinolin-4-yl)pyridin-2(1H)-one;
• 3-hydroxy-5-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;
• 3-hydroxy-1-methyl-5-[4-(trifluoromethoxy)phenyl]pyridin-2(1H)-one;
• 3-hydroxy-1-methyl-5-[4-(2-methylpropyl)phenyl]pyridin-2(1H)-one;
• 3-hydroxy-5-(naphthalen-1-yl)pyridin-2(1H)-one;
• 3-(5-hydroxy-6-oxo- 1,6-dihydropyridin-3-yl)benzonitrile;
• 3-hydroxy-5-[3-(trifluoromethoxy)phenyl]pyridin-2(1H)-one;
• N-[3-(5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-methylbenzenesulfonamide;
• N-[5-(5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazol-2-yl]acetamide;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-1-ethyl-3-hydroxypyridin-2(1H)-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one;
• 3-hydroxy-1-methyl-5-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]pyridin-2(1H)-one;
• N-cyclohexyl-4-(5-hydroxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methylbenzamide;
• 5-[(2,4-dichlorophenyl)ethynyl]-3-hydroxy-1-methylpyridin-2(1H)-one;
• 5-biphenyl-3-yl-6-bromo-3-hydroxypyridin-2(1H)-one;
• 3-hydroxy-1-methyl-6-(phenylethynyl)pyridin-2(1H)-one;
• 6-biphenyl-4-yl-3-hydroxy-1-methylpyridin-2(1H)-one;
• 3-hydroxy-1-methyl-6-[4-(phenylcarbonyl)phenyl]pyridin-2(1H)-one;
• 5-[4-(2,3-dihydro-1,4-benzoxazepin-4(5H)-ylcarbonyl)phenyl]-3-hydroxy-1-methylpyridin-2(1H)-one;
• 5-[4-chloro-3-(trifluoromethyl)phenyl]-3-hydroxy-1-methylpyridin-2(1H)-one;
• 6-(3,4-dichlorophenyl)-3-hydroxy-1-methylpyridin-2(1H)-one;
• 5-(2,4-Dichloro-phenyl)-3-hydroxy-1-methyl-1H-pyridin-2-one;
• 5-[4-Chloro-3-(trifluoromethyl)phenyl]-3-hydroxy-1-(propan-2-yl)pyridin-2(1H)-one;
• 5-[4-Chloro-3-(trifluoromethyl)phenyl]-1-(difluoromethyl)-3-hydroxypyridin-2(1H)-one;
• 5-Biphenyl-3-yl-3-hydroxy-1-methylpyridin-2(1H)-one;
• 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyridin-2(1H)-one;
• 3-Hydroxy-1-methyl-5-(2-oxo-4-phenylpyrrolidin-1-yl)pyridin-2(1H)-one;
• 3-Hydroxy-1-methyl-5-(3-phenyl-1H-pyrazol-1-yl)pyridin-2(1H)-one;
• 3-Hydroxy-1-methyl-5-(4-phenyl-1H-imidazol-1-yl)pyridin-2(1H)-one;
• 3-hydroxy-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one;
• 2-(biphenyl-3-yl)-5-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile;
• 3-(biphenyl-3-yl)-5-hydroxy-6-oxo-1,6-dihydropyridine-2-carbonitrile;
• 5-Biphenyl-3-yl-4-fluoro-3-hydroxypyridin-2(1H)-one;
• 5-Biphenyl-3-yl-4-fluoro-3-hydroxy-1-methylpyridin-2(1H)-one;
• 5-(Biphenyl-3-yl)-3-hydroxy-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one;
• 6-(1-Benzyl-1H-pyrazol-4-yl)-3-hydroxy-1H-pyridin-2-one;
• 6-(4-Chlorophenyl)-3-hydroxy-1-methylpyridin-2(1H)-one;
• including tautomers or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof.

A compound of structural formula I:

• including tautomers or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:
• Y represents CN, C2-6 alkynyl, CH2C5-10 heterocyclyl, (CH2)2C5-10 heterocyclyl, (CH2)3C5-10 heterocyclyl, (CH2)4C5-10 heterocyclyl, (CH2)5 C5-10 heterocyclyl, (CH2)nC 6-10 aryl, said alkynyl, heterocyclyl and aryl substituted with 1 to 3 groups of Ra;
• X represents hydrogen, halo, CN, C1-6 alkyl, C2-6 alkynyl, (CH2)nC5-10 heterocyclyl, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
• X1 represents hydrogen, halo, CN, C1-6 alkyl, C2-6 alkynyl, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, said alkyl, heterocyclyl, and aryl optionally substituted with 1 to 3 groups of Ra;
• R1 represent halo, CN, C2-6 alkynyl, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, said alkynyl, heterocyclyl, and aryl optionally substituted with 1 to 3 groups of Ra;
• R2 represents H, OH, C1-6 alkyl, N(CH3)2, (CH2)nC3-10 cycloalkyl, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
• Ra represents C1-6 alkyl, halogen, hydroxyl, C2-4alkynyl, (CH2)nCF3, OCHF2, OCF3, C3-6 cycloalkyl, NR2C(O)R2, C(O)N(R2)2, C(R2)2OR2, C(O)R2, NO2, CN, N(R2)2, (CH2)nC(O)OR2, SO2R2, NHSO2R2, OR2, (CH2)nC5-10 heterocyclyl, C(O)(CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, or C(O)(CH2)nC6-10 aryl, said alkyl, alkynyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of Rb;
• Rb represents C1-6 alkyl, halogen, CHF2, OCHF2, —O—, N(R2)2, CH2OH, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, OR2, C3-6cycloalkyl, (CH2)nCF3, or CN;
• and
• n represents 0 to 5.

A compound of structural formula I:

• including tautomers or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:
• Y represents C2-6 alkynyl, CH2C5-10 heterocyclyl, (CH2)2C5-10 heterocyclyl, (CH2)3C5-10 heterocyclyl, (CH2)4C5-10 heterocyclyl, (CH2)5 C5-10 heterocyclyl, CH2C6-10 aryl, (CH2)2C6-10 aryl, (CH2)3C6-10 aryl, (CH2)4C6-10 aryl, (CH2)5C6-10 aryl, said alkynyl, heterocyclyl and aryl substituted with 1 to 3 groups of Ra;
• X, X1, and R1 independently represent hydrogen, halo, CN, C1-6 alkyl, C2-6 alkynyl, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, said alkyl, heterocyclyl, and aryl optionally substituted with 1 to 3 groups of Ra;
• R2 represents H, OH, C1-6 alkyl, N(CH3)2, (CH2)nC3-10 cycloalkyl, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
• Ra represents C1-6 alkyl, halogen, hydroxyl, C2-4alkynyl, (CH2)nCF3, OCHF2, OCF3, C3-6 cycloalkyl, NR2C(O)R2, C(O)N(R2)2, C(R2)2OR2, C(O)R2, NO2, CN, N(R2)2, (CH2)nC(O)OR2, SO2R2, NHSO2R2, OR2, (CH2)nC5-10 heterocyclyl, C(O)(CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, or C(O)(CH2)nC6-10 aryl, said alkyl, alkynyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of Rb;
• Rb represents C1-6 alkyl, halogen, CHF2, OCHF2, —O—, N(R2)2, CH2OH, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, OR2, C3-6cycloalkyl, (CH2)nCF3, or CN;
• and
• n represents 0 to 5.

A compound of structural formula I:

• including tautomers or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:
• Y represents C2-6 alkynyl, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, said alkynyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of Ra;
• provided that when Y is (CH2)nC5-10 heterocyclyl, Y is quinolinyl, isoquinolinyl, thiazolyl, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl or imidazolyl;
• X, X1, and R1 independently represent hydrogen, halo, CN, C1-6 alkyl, C2-6 alkynyl, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, said alkyl, heterocyclyl, and aryl optionally substituted with 1 to 3 groups of Ra;
• provided that when Y is (CH2)nC6-10 aryl, X and X1 both are hydrogen;
• R2 represents H, OH, C1-6 alkyl, N(CH3)2, (CH2)nC3-10 cycloalkyl, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
• Ra represents C1-6 alkyl, halogen, hydroxyl, C2-4alkynyl, (CH2)nCF3, OCHF2, OCF3, C3-6 cycloalkyl, NR2C(O)R2, C(O)N(R2)2, C(R2)2OR2, C(O)R2, NO2, CN, N(R2)2, (CH2)nC(O)OR2, SO2R2, NHSO2R2, OR2, (CH2)nC5-10 heterocyclyl, C(O)(CH2)nC5-10 heterocyclyl, (CH2)nC6-l0 aryl, or C(O)(CH2)nC6-10 aryl, said alkyl, alkynyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of Rb;
• Rb represents C1-6 alkyl, halogen, CHF2, OCHF2, —O—, N(R2)2, CH2OH, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, OR2, C3-6cycloalkyl, (CH2)nCF3, or CN;
• and
• n represents 0 to 5.