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

1. A compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:

A and X each independently represent hydrogen or C 1-6 alkyl;

R 1 represents NR 2 R 3 ;

R 2 and R 3 independently represent H, C 1-6 alkyl, (CH 2 ) n C 5-10 heterocyclyl and (CH 2 ) n C 6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a ; or

R 2 and R 3 together with the nitrogen atom to which they are attached form a 5-10 membered ring that is optionally substituted with 1 to 3 groups independently selected from halo, OH, C 2-6 alkenyl, (CH 2 ) n C 5-10 heterocyclyl and (CH 2 ) n C 6-10 aryl;

Y represents phenyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpiperidinyl, quinolyl, indolyl, indazolyl, or pyridyl, any of which is optionally substituted with 1 to 3 groups of R a ;

each R a independently represents C 1-6 alkyl, halogen, hydroxyl, (CH 2 ) n CF 3 , OCHF 2 , OCF 3 , C 3-6 cycloalkyl, O(CH 2 ) n C 3-6 cycloalkyl, NR 2 C(O)R 2 , C(O)N(R 2 ) 2 , C(R 2 ) 2 OR 2 , C(O)R 2 , NO 2 , CN, N(R 2 ) 2 , (CH 2 ) n C(O)OR 2 , SO 2 R 2 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, NH(CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, O(CH 2 ) n C 6-10 aryl, or O(CH 2 )C 5-10 heterocyclyl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of R b ;

each R b independently represents C 1-6 alkyl, halogen, CHF 2 , N(R 2 ) 2 , CH 2 OH, OR 2 , (CH 2 ) n CF 3 , or CN; and

n represents 0 to 5.

2. The compound of claim 1 , wherein A and X each represent hydrogen.

3. The compound of claim 1 , wherein at least one of said 1 to 3 groups of R a is selected from (CH 2 ) n C 5-10 heterocyclyl and (CH 2 ) n C 6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R b .

4. The compound of claim 1 , wherein each of R 2 and R 3 independently represents H or C 1-6 alkyl.

5. The compound of claim 1 , wherein NR 2 R 3 represents NHCH 3 or NH 2 .

6. The compound of claim 1 , wherein Y represents phenyl optionally substituted with 1 to 3 groups of R a .

7. The compound of claim 6 , wherein each R a independently represents C 1-6 alkyl, halogen, hydroxyl, CF 3 , OCHF 2 , OCF 3 , C 3-6 cycloalkyl, O(CH 2 ) n C 3-6 cycloalkyl, CN, N(R 2 ) 2 , (CH 2 ) n C(O)OR 2 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, NH(CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, O(CH 2 ) n C 6-10 aryl, or O(CH 2 ) n C 5-10 heterocyclyl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of R b .

8. A compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:

A and X each independently represent hydrogen or C 1-6 alkyl;

Y represents benzimidazolyl, benzthiazolyl, benzoxazolyl, benzpiperidinyl, quinolyl, indolyl, tetrahydroquinolinyl, indazolyl, or pyridyl, any of which is optionally substituted with 1 to 3 groups of R a ;

R 1 represents hydrogen or C 1-10 alkyl;

each of R 2 and R 3 independently represents H, OH, C 1-6 alkyl and N(CH 3 ) 2 ;

each R a independently represents C 1-6 alkyl, halogen, hydroxyl, CF 3 , OCHF 2 , OCF 3 , C 3-6 cycloalkyl, O(CH 2 ) n C 3-6 cycloalkyl, NR 2 C(O)R 2 NR 2 C(O)R 2 , C(O)N(R 2 ) 2 , C(R 2 ) 2 OR 2 , C(O)R 2 , NO 2 , CN, N(R 2 ) 2 , SO 2 R 2 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, NH(CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, O(CH 2 ) n C 6-10 aryl, or O(CH 2 ) n C 5-10 heterocyclyl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of R b ;

each R b independently represents C 1-6 alkyl, halogen, CHF 2 , N(R 2 ) 2 , S(O) 2 NR 2 R 3 , (CH 2 ) n C 6-10 aryl, (CH 2 ) n heterocyclyl, C(O)(CH 2 ) n heterocyclyl, NH(CH 2 ) n heterocyclyl, C(O)NHC 3-6 cycloalkyl, CH 2 OH, CF 3 , —O—, OR 2 , C 3-6 cycloalkyl, or CN; and

n represents 0 to 5.

9. The compound of claim 8 , wherein A, X, and R 1 each represent hydrogen.

10. The compound of claim 9 , wherein Y represents benzimidazolyl.

11. The compound of claim 10 , wherein each R a independently represents C 1-6 alkyl, halogen, hydroxyl, CF 3 , OCHF 2 , OCF 3 , C 3-6 cycloalkyl, O(CH 2 ) n C 3-6 cycloalkyl, CN, N(R 2 ) 2 , (CH 2 ) n C(O)OR 2 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, NH(CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, O(CH 2 ) n C 6-10 aryl, or O(CH 2 ) n C 5-10 heterocyclyl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with 1 to 3 groups of R b .

12. The compound of claim 8 , wherein at least one of said 1 to 3 groups of R a is selected from (CH 2 ) n C 5-10 heterocyclyl and (CH 2 ) n C 6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R b .

13. The compound of claim 8 , wherein the aryl of (CH 2 ) n C 6-10 aryl is phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.

14. The compound of claim 8 , wherein the aryl of (CH 2 ) n C 6-10 aryl is phenyl, said phenyl optionally substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halogen, CHF 2 , CF 3 , O C 1-6 alkyl, C 3-6 cycloalkyl, and CN.

15. A compound represented by structural formula I:

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:

A and X each independently represent hydrogen or C 1-6 alkyl;

R 1 represents C 1-10 alkyl, said alkyl optionally substituted with 1 to 3 groups independently selected from C 3-6 cycloalkyl, halo, OH, CF 3 , OR 2 , NR 2 R 3 , cyano, C 6-10 aryl, and C 5-10 heterocyclyl, wherein said aryl and heterocyclyl optionally substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halogen, hydroxyl, CF 3 , OCF 3 , OCHF2, CN, OR 2 , and NR 2 R 3 ;

R 2 and R 3 are independently selected from H, OH, and C 1-6 alkyl;

Y is phenyl substituted with 1 to 3 groups of R a ;

each R a is independently selected from C 1-6 alkyl, halogen, (CH 2 ) n CF 3 , OR 2 , (CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 6-10 aryl, O(CH 2 ) n C 6-10 aryl, and O(CH 2 ) n C 5-10 heterocyclyl, said alkyl, heterocyclyl and aryl are optionally substituted with 1 to 3 groups of R b ; provided that at least one of said R a on Y is aryl or heterocyclyl optionally substituted with 1 to 3 groups of R b ;

each R b is independently selected from C 1-6 alkyl, halogen, CHF 2 , N(R 2 ) 2 , CH 2 OH, OR 2 , (CH 2 ) n CF 3 , and CN; and

n represents 0 to 5.

16. The compound of claim 15 , wherein at least one of said 1 to 3 groups of R a on Y is selected from C 6-10 aryl and C 5-10 heterocyclyl.

17. The compound of claim 16 , wherein said C 6-10 aryl and C 5-10 heterocyclyl for R a is selected from naphthyridine, indolyl, benzodioxaolyl, pyridyl, furopyridinyl, isoindolyl, pyridooxazinyl, pyrrolopyridinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phenyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridine, 1,2,3,4-tetrahydroisoquinoline, 1,3-benzodioxole, 1-benzothiophene, 1H-indazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 2,1,3-benzoxadiazole, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, furo[2,3-c]pyridine, furo[3,2-b]pyridine, imidazo[1,2-a]pyridine, quinazoline, and thieno[3,2-c]pyridin-4(5H)-one, any of which is optionally substituted with 1 to 3 groups of R b .

18. The compound of claim 17 , wherein said 1 to 3 groups of R b is independently selected from halogen and C 1-6 alkyl.

19. The compound of claim 15 , wherein R 1 represents C 1-10 alkyl, said alkyl optionally substituted with 1 to 3 groups independently selected from OH, and CF 3 , C 6-10 aryl, and C 5-10 heterocyclyl.

20. The compound of claim 19 , wherein said R 1 represents C 1-10 alkyl optionally substituted with 1 to 2 groups independently selected from OH and phenyl.

21. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .

22. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 8 .

23. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 15 .

24. The composition according to any one of claims 21 , 22 and 23 further comprising one or more therapeutically active compounds selected from the group consisting of opiate agonists or antagonists, calcium channel antagonists, 5HT, 5-HT 1A complete or partial receptor agonists or antagonists, sodium channel antagonists, N-methyl-D-aspartate (NMDA) receptor agonists or antagonists, COX-2 selective inhibitors, neurokinin receptor 1 (NK1) antagonists, non-steroidal anti-inflammatory drugs (NSAID), selective serotonin reuptake inhibitors (SSRI) and/or selective serotonin and norepinephrine reuptake inhibitors (SSNRI), tricyclic antidepressant drugs, norepinephrine modulators, lithium, valproate, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), alpha-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, corticotropin releasing factor (CRF) antagonists, neurontin (gabapentin) and pregabalin.

25. A method of augmenting the effect of an anti-psychotic in treatment of schizophrenia, or treating a neurological or psychiatric disorder or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder or disease is selected from schizophrenia, major depressive disorder, obsessive-compulsive disorder, bipolar disorder, anxiety disorder, DA deficiency related disease, ADD, ADHD, substance dependency, weight gain or food craving associated with quitting smoking or use of an antipsychotic, dementia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, cognitive disorder, and cognitive deficit associated with any of said disorders or diseases.

26. A method of augmenting the effect of an anti-psychotic in treatment of schizophrenia, or treating a neurological or psychiatric disorder or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder or disease is selected from schizophrenia, major depressive disorder, obsessive-compulsive disorder, bipolar disorder, anxiety disorder, DA deficiency related disease, ADD, ADHD, substance dependency, weight gain or food craving associated with quitting smoking or use of an antipsychotic, dementia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, cognitive disorder, and cognitive deficit associated with any of said disorders or diseases.

27. A method of augmenting the effect of an anti-psychotic in treatment of schizophrenia, or treating a neurological or psychiatric disorder or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder or disease is selected from schizophrenia, major depressive disorder, obsessive-compulsive disorder, bipolar disorder, anxiety disorder, DA deficiency related disease, ADD, ADHD, substance dependency, weight gain or food craving associated with quitting smoking or use of an antipsychotic, dementia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, cognitive disorder, and cognitive deficit associated with any of said disorders or diseases.

28. The method of any one of claims 25 , 26 and 27 , wherein the compound is administered separately or in conjunction with an anti-depressant.

29. The method of claim 25 , wherein the compound is 1-(biphenyl-3-yl)-5-hydroxy-2-(methylamino)pyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

30. The method of claim 26 , wherein the compound is 1-(2-biphenyl-4-yl-1H-benzimidazol-5-yl)-3-hydroxypyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

31. The method of claim 26 , wherein the compound is 3-hydroxy-6′-phenyl-4H-1,2′-bipyridin-4-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

32. The method of claim 26 , wherein the compound is 1-[1-(2-chlorobenzyl)-1H-benzimidazol-4-yl]-3-hydroxypyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

33. The method of claim 25 , wherein the compound is 2-amino-1-(biphenyl-3-yl)-5-hydroxypyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

34. The compound of claim 8 , which is 1-(2-biphenyl-4-yl-1H-benzimidazol-5-yl)-3-hydroxypyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

35. The compound of claim 8 , which is 1-(2-biphenyl-4-yl-1H-benzimidazol-5-yl)-3-hydroxypyridin-4(1H)-one.

36. The compound of claim 8 , which is 3-hydroxy-6′-phenyl-4H-1,2′-bipyridin-4-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

37. The compound of claim 8 , which is 3-hydroxy-6′-phenyl-4H-1,2′-bipyridin-4-one.

38. The compound of claim 8 , which is 1-[8-(2-chlorobenzyl)-1H-benzimidazol-4-yl]-3-hydroxypyridin-4(1H)-one or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

39. The compound of claim 8 , which is 1-[1-(2-chlorobenzyl)-1H-benzimidazol-4-yl]-3-hydroxypyridin-4(1H)-one.

40. The compound of claim 1 , which is 2-amino-1-(biphenyl-3-yl)-5-hydroxypyridin-4(1H)-one.

41. The compound of claim 1 , which is 1-(biphenyl-3-yl)-5-hydroxy-2-(methylamino)pyridin-4(1H)-one.