MAO-B INHIBITORS USEFUL FOR TREATING OBESITY

• US 20070078172A1
• Filed: 06/15/2006
• Published: 04/05/2007
• Est. Priority Date: 06/16/2005
• Status: Abandoned Application

• Current Assignee: Jenrin Discovery Inc.
• Original Assignee: Jenrin Discovery Incorporated
• Inventors: Parthasarathi, Rajagopalan, Chorvat, Robert, McElroy, John
• Application Number:
  US11/424,274
• Publication Number:
  US 20070078172A1
• Time in Patent Office: Days
• US Class Current: 514/355
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring

Abstract

The invention provides a method of treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance) in a mammal by administering to the mammal a therapeutically effective amount of an irreversible MAO-B inhibitor.

Claims

1. A method for treating a disease, comprising:

administering to a patient in need thereof a therapeutically effective amount of a MAO-B inhibitor or a pharmaceutically acceptable salt form thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.

2. The method of claim 1, wherein the inhibitor is selected from:

L-selegiline;

desmethylselegiline;

Rasagiline;

Pargyline;

Lazabemide;

RO-16-6491, AGN 1135;

MDL 72,974;

MDL 72,145;

MDL 72,638;

LY 54761;

MD 780236;

Iproniazid;

Phenelzine;

Nialamide;

Phenylhydrazine;

1-Phenylcyclopropylamine;

Isocarboxazid;

Tranylcypromine; and

EVT 301, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the inhibitor is selected from:

L-selegiline;

Rasagiline;

Lazabemide; and

Pargyline, or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein the inhibitor is L-selegiline, or a pharmaceutically acceptable salt thereof.

5. The method of claim 3, wherein the inhibitor is Rasagiline, or a pharmaceutically acceptable salt thereof.

6. The method of claim 3, wherein the inhibitor is Lazabemide, or a pharmaceutically acceptable salt thereof

7. The method of claim 3, wherein the inhibitor is Pargyline, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein the cardiometabolic disorder is selected from hypertension, dyslipidemias, high blood pressure, and insulin resistance.

9. The method of claim 1, wherein the inhibitor is of formula I or a pharmaceutically acceptable salt thereof:

10. The method of claim 9, wherein:

X is O; and

,

R is selected from H, 3-OMe, 4-OMe, 3-Me, and 3-Cl.

11. The method of claim 1, wherein the inhibitor is of formula II or IIa or apharmaceutically acceptable salt thereof:

12. The method of claim 11, wherein:

X and Y are each O; and

,

R is selected from H, 3-OMe, 4-OMe, 3-Me, 4-Me, 3-Cl, and 4-Cl.

13. The method of claim 11, wherein:

X is S;

Y is O; and

,

R is H.

14. The method of claim 1, wherein the inhibitor is of formula III or a pharmaceutically acceptable salt thereof:

15. The method of claim 14, wherein the compound is selected from:

5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-methoxyethyl-1,3,4-oxadiazol-2(3H)-one;

5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-hydroxyethyl-1,3,4-oxadiazol-2(3H)-one;

5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-methylthioethyl-1,3,4-oxadiazol-2(3H )-one;

5-[4-(4,4,4-trifluoro-2-butenyloxy)phenyl]-3-methoxyethyl-1,3,4-oxadiazol-2(3H)-one;

5-[4-(4,4,4-trifluoro-3(R)-hydroxybutoxy)phenyl]-3-methoxyethyl-1,3,4-oxadiazol-2(3H) -one; and

,

5-[4-(tetrahydropyran-3-ylmethoxy)phenyl]-3-methoxyethyl-1,3,4-oxadiazol-2(3H)-one, or pharmaceutically acceptable salts thereof.

16. The method of claim 1, wherein the inhibitor is of formula IV or a pharmaceutically acceptable salt thereof:

17. The method of claim 16, wherein:

18. The method of claim 16, wherein the inhibitor is selected from:

3,4-Dimethyl-7-(4-isopropylphenyl)-methoxycoumarin;

3,4-Dimethyl-7-(2-naphthyl)-methoxycoumarin;

7-(4-tert-Butylphenyl)-methoxy-3,4-dimethylcoumarin;

3,4-Dimethyl-7-(2-methylphenyl)-methoxycoumarin;

3,4-Dimethyl-7-(3 -methylphenyl)-methoxycoumarin;

3,4-Dimethyl-7-(4-methylphenyl)-methoxycoumarin;

3,4-Dimethyl-7-(2,5 -dimethylphenyl)-methoxycoumarin;

7-(4-Methoxyphenyl)-methoxy-3,4-dimethylcoumarin;

7-(4-Trifluoromethylphenyl)-methoxy-3,4-dimethylcoumarin;

7-(3-Trifluoromethylphenyl)-methoxy-3,4-dimethylcoumarin;

6-Ethyl-3,4-dimethyl-7-(2-phenyl)-ethoxycoumarin;

7-(4-Isopropylphenyl)-methoxycoumarin;

4-Methyl-7-(4-isopropylphenyl)-methoxycoumarin;

3-Methyl-7-(4-isopropylphenyl)-methoxycoumarin;

3-Chloro-4-methyl-7-(4-isopropylphenyl)-methoxycoumarin;

7-(3-Phenylpropoxy)-coumarin;

3,4-Dimethyl-7-(3 -phenylpropoxy)-coumarin;

6-Chloro-3,4-dimethyl-7-(4-isopropylphenyl)-methoxycoumarin;

7-(2-Benzylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin;

7-(2-Isopropylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin;

7-(3-Cyclopentylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin;

7-[3-(1-Methoxyethyl)-isoxazol-5-yl]-methoxy-3,4-dimethylcoumarin;

7-(2-Cyclopropylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin;

6-Ethyl-7-(5-isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4-dimethylcoumarin;

6-Ethyl-3,4-dimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin;

7-(3-Cyclohexylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin;

7-(2-tert-Butylthiophen-5-yl)-methoxy-3,4-dimethylcoumarin;

3,4-Dimethyl-7-(2-cyclopropyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin;

3,4-Dimethyl-7-[3-(1-methylcyclopropyl)-isoxazol-5-yl]-methoxycoumarin;

3,4-Dimethyl-7-[3-(tetrahydrofuran-3-yl)-isoxazol-5-yl]-methoxycoumarin;

3,4-Dimethyl-7-(3-cyclopentylisoxazol-5-yl)-methoxycoumarin;

3,4-Dimethyl-7-(3-cyclohexylisoxazol-5-yl)-methoxycoumarin;

6-Chloro-3,4-dimethyl-7-(2-pyridinyl)-methoxycoumarin;

3,6-Dichloro-4-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-methoxycoumarin; and

,

3,6-Dichloro-4-methyl-7-(2-isopropylthiazol-4-yl)-methoxycoumarin,

or pharmaceutically acceptable salts thereof.

19. The method of claim 1, wherein the inhibitor is of formula V and VI or a pharmaceutically acceptable salt thereof:

20. The method of claim 19, wherein X is selected from H, 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F, 4-F, 2-Me, 3-Me, 4-Me, 2-CF₃, 3-CF₃, and 4-CF₃.

21. The methed of claim 1, wherein the inibitor is of formula VII or a pharmaceutically acceptable salt thereof:

22. The method of claim 1, wherein the inhibitor is of formula VIII, IX, or X, or a pharmaceutically acceptable salt thereof:

23. The method of claim 1, wherein the inhibitor is of formula XI or a pharmaceutically acceptable salt thereof:

24. The method of claim 23, wherein the inhibitor is selected from:

(Z)-or (E)-(p-fluorophenethyl)-3-fluoroallylamine,

(Z)-or (E)-2-(2′

-methoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(3′

-methoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(4′

-methoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(3′

-hydroxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-N-ethyl2-(3′

-methoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(3′

,4′

-dimethoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-N-ethyl2-(3′

,4′

-dimethoxy)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(4′

-chloro)phenyl-3-fluoroallylamine,

(Z)-or (E)-2-(3′

-trifluoromethyl)phenyl-3-fluoroallylamine.

(Z)-or (E)-2-(.alpha.-naphthyl)-3-fluoroallylamine,

(Z)-or (E)-2-(.beta.-naphthyl)-3-fluoroallylamine,

(E)-2-(2′

-methoxy)phenyl-3-fluoroallyl alcohol,

(E)-2-(3′

-methoxy)phenyl-3-fluoroallyl alcohol,

(E)-2-(4′

-methoxy)phenyl-3-fluoroallyl alcohol,

(E)-2-(3′

,4′

-dimethoxy)phenyl-3-fluoroallyl alcohol,

(E)-2-(2′

-methoxy)benzyl-3-fluoroallyl alcohol,

(E)-2-(3′

-methoxy)benzyl-3-fluoroallyl alcohol,

(E)-2-(4′

-methoxy)benzyl-3-fluoroallyl alcohol,

(E)-2-phenyl-3-fluoroallyl alcohol,

(E)-2-benzyl-3-fluoroallyl alcohol,

(E)-2-(3′

,4′

-dimethoxy)benzyl-3-fluoroallyl alcohol,

Z)-or (E)-2-(3′

-methoxyphenyl)-3-fluoroallylamine, and

(Z)-or (E)-2-(3′

,4′

-dimethoxyphenyl)-3-fluoroallylamine;

or pharmaceutically acceptable salts thereof.

25. The method of claim 1, wherein the inhibitor is of formula XII or a pharmaceutically acceptable salt thereof:

26. The method of claim 25, wherein the inhibitor is selected from:

N-(2-aminoethyl)-4-methoxypyridine-2-carboxamide,

N-(2-aminoethyl)thiazole-2-carboxamide,

N-(2-aminoethyl)-4-bromopyridine-2-carboxamide,

N-(2-aminoethyl)-4-chloropyridine-2-carboxamide,

N-(2-aminoethyl)-2-chlorothiazole-4-carboxamide,

N-(2-aminoethyl)-5-methylisoxazole-3-carboxamide,

N-(2-aminoethyl)-6-bromopyridine-2-carboxamide,

N-(2-aminoethyl)-6-chloropyridine-2-carboxamide,

N-(2-aminoethyl)-5-bromothiazole-4-carboxamide,

N-(2-aminoethyl)-3-aminopyridine-2-carboxamide,

N-(2-aminoethyl)pyridine-2-carboxamide,

N-(2-aminoethyl)-5-chloropyridine-2-carboxamide,

N-(2-aminoethyl)-2-chlorothiazole-4-carboxamide hydrochloride,

N-(2-aminoethyl)-3-aminopyridine-2-carboxamide dihydrochloride,

N-(2-aminoethyl)pyridine-2-carboxamide dihydrochloride, and

N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride,

or pharmaceutically acceptable salts thereof.

27. The method of claim 1, wherein the inhibitor is of formula XIII or a pharmaceutically acceptable salt thereof:

28. The method of claim 27, wherein the inhibitor is selected from:

N-(2-aminoethyl)-p-chlorobenzamide,

N-(2-aminoethyl)-p-fluorobenzamide,

N-(2-aminoethyl)-p-bromobenzamide,

N-(2-aminoethyl)-3,4-dichlorobenzamide, and

N-(2-aminoethyl)-2,4-dichlorobenzamide,

or pharmaceutically acceptable salts thereof.

29. The method of claim 1, wherein the inhibitor is of formula XIV or a pharmaceutically acceptable salt thereof:

30. The method of claim 29, wherein the inhibitor is selected from:

N-(2-propyl)-N-methylpropargylamine-HCl;

N-(2-butyl)-N-methylpropargylamine-HCl;

N-(1-butyl)-N-methylpropargylamine-HCl;

N-(2-heptyl)-N-methylpropargylamine-HCl;

N-(1-heptyl)-N-methylpropargylamine-HCl;

N-(2-pentyl)-N-methylpropargylamine-HCl;

N-(1-pentyl)-N-methylpropargylamine-oxalate;

N-(2-decyl)-N-methylpropargylamine-HCl;

N-(2-dodecyl)-N-methylpropargylamine-HCl; and

,

R(-)-N-(2-butyl)-N-methylpropargylamine-oxalate,

or pharmaceutically acceptable salts thereof.

31. The method of claim 1, wherein the inhibitor is of formula XV or a pharmaceutically acceptable salt thereof:

t,0800

wherein;

X is —

CN or —

SCN;

Y is selected from H, halogen, C_1-6 alkyl, C_1-6 alkoxy, and CF₃; and

,

n is selected from 1, 2, 3, 4, 5, and 6.

32. The method of claim 31, wherein the inhibitor is selected from:

2,4-dioxo-5-[3-(phenylmethoxy)-phenylmethylene]-4-thiazolidinebutanenitrile, and 2,4-dioxo-5-[3-(phenylmethoxy)-phenylmethylene]-4-thiazolidinepentanenitrile,

or pharmaceutically acceptable salts thereof.

33. The method of claim 1, wherein the inhibitor is of formula XVI or a pharmaceutically acceptable salt thereof:

34. The method of claim 33, wherein the inhibitor is selected from:

(RS)-3-(4-Cyclohexyl-phenyl)-5-hydroxymethyl-oxazolidin-2-one;

(RS)-3-(4-cyclohexylophenyl)-5-methoxymethyl-oxazolidin-2-one;

(R)-3-(4-cyclohexyl-phenyl)-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[4-(4-oxocyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[4-(4-hydroxy-imino-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(R)-3-[4-trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[4-(trans-4-methoxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(R)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyloxy]-propionitrile;

(RS)-trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl ester;

(RS)-3-[4-(cis-or-trans-4-hydroxymethyl-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one;

(RS)-3-[4-(cis-or trans-4-hydroxy-4-methyl-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one.

(RS)-[trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl]-acetonitrile;

(R)-[trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl]-acetonitrile;

(RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-1-(1-oxo-3-phenyl-2-(E)-propenyl)-piperidine;

(RS)-3-(trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyloxy]-ethanamine;

(R)-[trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyloxy]-acetonitrile;

(RS)-trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyloxy]-acetonitrile; and

,

(R)-3-[4-[trans-4-(3-amino-propoxy)-cyclohexyl]-phenyl]-5-methoxymethyl-oxazolidin-2-one;

or pharmaceutically acceptable salts thereof.

35. The method of claim 1, wherein the inhibitor is of formula XVII or stereoisomers or a pharmaceutically acceptable salt thereof:

36. The method of claim 35, wherein the inhibitor is selected from:

(S)-5-Methoxymethyl-3->

6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl!oxazolidin-2-one

or a pharmaceutically acceptable salt thereof.

37. The method of claim 1, wherein the inhibitor is of formula XVIII or a pharmaceutically acceptable salt thereof:

38. The method of claim 37, wherein the inhibitor is selected from:

3-(2-aminoethoxy)-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole,

3-(2-aminoethylthio)-5-fluoro-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-chloro-1,2-benzisoxazole,

3-(2-aminoethylthio)-5-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-7-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-6-methoxy-1,2-benzisoxazole,

3-(2-aminoethoxy)-7-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole,

3-(2-aminoethylthio)-5-methoxy-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-difluoromethoxy-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazole,

3-(2-aminoethylthio)-5-nitro-1,2-benzisoxazole,

3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole,

3-(2-aminoethoxy)-4-carbamoyl-1,2-benzisoxazole hydrochloride,

3-(2-aminoethylthio)-5-amino-1,2-benzisoxazole dihydrochloride,

3-(2-aminoethoxy)-1,2-naphtho[2,3-e]isoxazole hydrochloride,

3-(2-aminoethoxy)-5-methylamino-1,2-benzisoxazole dihydrochloride,

3-(2-aminoethoxy)-5-dimethylamino-1,2-benzisoxazole dihydrochloride,

3-(2-aminoethoxy)-7-carboxy-1,2-benzisoxazole hydrochloride,

3-(2-aminoethoxy)-5-hydroxy-1,2-benzisoxazole hydrochloride, and

3-(2-aminoethoxy)-5-acetoxy-1,2-benzisoxazole hydrochloride,

or pharmaceutically acceptable salts thereof.

39. The method of claim 1, wherein the inhibitor is of formula XIX or a pharmaceutically acceptable salt thereof:

40. The method of claim 39, wherein the inhibitor is selected from:

3-(2-aminoethoxy)-5-phenylisoxazole,

3-(2-aminoethoxy)-4-chloro-5-phenylisoxazole,

3-(2-aminoethoxy)-4-ethyl-5-phenylisoxazole,

3-(2-aminoethoxy)-5-phenyl-4-propylisoxazole,

3-(2-aminoethoxy)-4-isopropyl-5-phenylisoxazole,

3-(2-aminoethoxy)-4-isobutyl-5-phenylisoxazole,

3-(2-aminoethoxy)-5-(2-chlorophenyl)-4-isopropylisoxazole,

3-(2-aminoethoxy)-5-(4-chlorophenyl)isoxazole,

3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-isopropylisoxazole,

3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)-4-isopropylisoxazole,

3-(2-aminoethoxy)-5-(2-furyl)-4-isopropylisoxazole,

3-(2-aminoethoxy)-5-(2-thienyl)isoxazole,

3-(2-aminoethoxy)-4-chloro-5-(2-thienyl)isoxazole,

3-(2-aminoethoxy)-4-isopropyl-5-(2-thienyl)isoxazole, and

4-allyl-3-(2-aminoethoxy)-5-phenylisoxazole,

and pharmaceutically acceptable salts thereof.

41. The method of claim 1, wherein the inhibitor is of formula XX or a pharmaceutically acceptable salt thereof:

42. The method of claim 41, wherein the inhibitor is selected from:

2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide,

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide,

(R)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,

2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,

2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide,

2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide,

N-{2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-ethyl}-acetamide,

2-(2-amino-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione,

5-(4-fluoro-benzyloxy)-2-piperidin-4-yl-isoindole-1,3-dione,

5-(4-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione,

5-(4-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione,

5-(3-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione,

(S)-5-(4-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

(S)-5-(3-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

(S)-5-(2-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

(S)-2-(2-methoxy-1-methyl-ethyl)-5-(4-trifluoromethyl-benzyloxy)-isoindole-1,3-dione,

(S)-5-(4-bromo-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

(S)-5-(3,4-difluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

5-(3-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione,

5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione,

5-(3,5-bis-trifluoromethyl-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,

2-(2-ethylsulfanyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione,

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-thiopropionamide,

2-(2-ethylsulfanyl-ethyl)-5-(3-fluoro-benzyloxy)-isoindole-1,3-dione,

5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile, and

[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile,

or pharmaceutically acceptable salts thereof.

43. The method of claim 1, wherein the inhibitor is of formula XXI or a pharmaceutically acceptable salt thereof:

44. The method of claim 43, wherein the inhibitor is selected from:

5-(3-fluoro-benzyloxy)-pyridine-2-carboxylic acid carbamoylmethyl-amide,

5-(4-fluoro-benzyloxy)-pyridine-2-carboxylic acid carbamoylmethyl-amide,

5-(3,4-difluoro-benzyloxy)-pyridine-2-carboxylic acid carbamoylmethyl-amide,

(S)-5-(3-fluoro-benzyloxy)-pyridine-2-carboxylic acid (1-carbamoyl-ethyl)-amide,

(S)-5-(4-fluoro-benzyloxy)-pyridine-2-carboxylic acid (1-carbamoyl-ethyl)-amide,

(S)-5-(3,4-difluoro-benzyloxy)-pyridine-2-carboxylic acid (1-carbamoyl-ethyl)-amide,

6-Benzyloxy-N-carbamoylmethyl-nicotinamide,

N-Carbamoylmethyl-6-(3-fluoro-benzyloxy)-nicotinamide,

N-Carbamoylmethyl-6-(4-fluoro-benzyloxy)-nicotinamide,

(S)-6-Benzyloxy-N-(1-carbamoyl-ethyl)-nicotinamide,

(S)-N-(1-Carbamoyl-ethyl)-6-(3-fluoro-benzyloxy)-nicotinamide, and

(S)-N-(1-Carbamoyl-ethyl)-6-(4-fluoro-benzyloxy)-nicotinamide,

or pharmaceutically acceptable salts thereof.

45. The method of claim 1, wherein the inhibitor is of formula XXII or a pharmaceutically acceptable salt thereof:

46. The method of claim 45, wherein the inhibitor is selected from:

N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-malonamic acid methyl ester;

N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester;

cyclopropane-1,1-dicarboxylic acid amide [4-(3-fluoro-benzyloxy)-phenyl]-amide;

N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-malonamide;

N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(4-fluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamide;

N-(4-benzyloxy-phenyl)-malonamide;

N-[4-(4-chloro-benzyloxy)-phenyl]-malonamide;

N-[4-(3-fluoro-benzyloxy)-2-hydroxy-phenyl]-malonamide;

N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamide;

N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

cyclopropane-1,1-dicarboxylic acid amide [2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-amide;

2-Acetylamino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide;

2-Acetylamino-N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-acetamide;

N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-2-formylamino-acetamide;

N-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-2-formylamino-acetamide;

11) 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide;

14) N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamide;

N-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-malonamide;

N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester.

N-[4-(3-Fluoro-benzyloxy)-phenyl]-2-methyl-malonamic acid methyl ester;

N-[4-(3-Fluoro-benzyloxy)-phenyl]-2-methoxy-malonamic acid methyl ester;

N-[4-(3-Fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-malonamic acid methyl ester;

N-[4-(3-Fluoro-benzyloxy)-phenyl]-N-methyl-malonamic acid methyl ester;

N-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-(4-Benzyloxy-phenyl)-malonamic acid methyl ester;

N-[2-Fluoro-4-(4-trifluoromethyl-benzyloxy)-phenyl]-malonamic acid methyl ester;

N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid ethyl ester;

N-[4-(3-Fluoro-benzyloxy)-3-formyl-phenyl]-malonamic acid methyl ester;

N-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-malonamic acid methyl ester; and

N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-2,2-dimethyl-malonamic acid methyl ester.

N-[4-(3-Fluoro-phenoxymethyl)-phenyl]-malonamic acid methyl ester;

N-[4-(3-Fluoro-benzylsulfanyl)-phenyl]-malonamic acid methyl ester;

2-[4-(3-Fluoro-benzyloxy)-phenylcarbamoyl]-malonic acid dimethyl ester;

N-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(4-Fluoro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester;

N-{4-[2-(4-Chloro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester.

N-[4-(3-Fluoro-benzyloxy)-phenyl]-2,2-dimethyl-malonamide;

N-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-malonamide;

N-[2-Fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

N-[2,5-Difluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

N-[4-(3-Fluoro-benzyloxy)-phenyl]-N′

-hydroxy-malonamide;

N-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-malonamide;

N-[2-Fluoro-4-(4-trifluoromethyl-benzyloxy)-phenyl]-malonamide;

N-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-malonamide;

N-[4-(3-Fluoro-benzylsulfanyl)-phenyl]-malonamide;

N-{4-[1-(3-Fluoro-phenyl)-ethoxy]-phenyl}-malonamide;

N-[4-(3-Fluoro-phenoxymethyl)-phenyl]-malonamide;

2-Ethyl-N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamide;

N-{4-[2-(4-Fluoro-phenyl)-vinyl]-phenyl}-malonamide;

N-{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-malonamide;

N-{4-[2-(4-Fluoro-phenyl)-ethyl]-phenyl}-malonamide;

N-{4-[2-(4-Chloro-phenyl)-ethyl]-phenyl}-malonamide.

2-Cyano-N-[4-(3-fluoro-benzyloxy)-phenyl]-acetamide;

N-[4-(3-Fluoro-benzyloxy)-phenyl]-2-hydrazinocarbonyl-acetamide;

Cyclopropane-1,1-dicarboxylic acid amide [4-(3-fluoro-phenoxymethyl)-phenyl]-amide;

2-Amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1;

1) hydrochloride;

(R)-2-Amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-propionamide;

2-Amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-propionamide;

1-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenylcarbamoyl]-2S-methyl-propyl-ammonium chloride;

(R)-2-Acetylamino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-propionamide;

(R)-N-[2-Fluoro-4-(4-fluoro-benzyloxy)-phenyl]-2-formylamino-propionamide;

2-Amino-N-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-acetamide hydrochloride (1;

1);

2-Amino-N-[2-fluoro-4-(4-trifluoromethyl-benzyloxy)-phenyl]-acetamide (1;

1) hydrochloride;

2-Amino-N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-acetamide (1;

1) hydrochloride;

2-Acetylamino-N-[4-(3,5-bis-trifluoromethyl-benzyloxy)-2-fluoro-phenyl]-acetamide; and

,

2-Amino-N-[4-(3-fluoro-benzyloxy)-phenyl]-acetamide hydrochloride;

or pharmaceutically acceptable salts thereof.

47. The method of claim 1, wherein the inhibitor is of formulas XXIII, XXIV, and XXV, or a pharmaceutically acceptable salt thereof:

48. The method of claim 47, wherein the inhibitor is selected from:

2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide,

2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide

2-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-[6-(3,4-difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-(R)-[6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-(R)-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-(S)-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-(S)-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-hydroxy-propionamide,

2-(R)-[6-(2,6-difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-[6-(3-fluoro-benzyloxy)3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-[6-(4-fluoro-benzyloxy)3,4-dihydro-1H-isoquinolin-2-yl]-acetamide,

2-[6-(3-fluoro-benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide,

2-[6-(4-fluoro-benzyloxy)3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-(R)-[6-(4-fluoro-benzyloxy)-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2-(S)-[6-(4-fluoro-benzyloxy)-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-(S)-[6 (4-fluoro-benzyloxy)-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

2(R)-[6-(4-fluoro-benzyloxy)-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide

2-[1-oxo-6-(4-trifluoromethyl-benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-[6-(2-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[6-(2,6-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[6-(2-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R) [6-(2,3-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R) [6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(S)-[6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide; and

2(S)-[6-(3,4-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

6-(3-Fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one;

2-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide;

2(R)-[6-(3-Cyano-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide

2-[1-oxo-6-(4-trifluoromethyl-benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-[6-(2-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[6-(2,6-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[6-(2-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R) [6-(2,3-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R) [6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(S)-[6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(S)-[6-(3,4-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

6-(3-Fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one;

2-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide;

2(R)-[6-(3-Cyano-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide

2(R)-[6-(3,5-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

3-[6-(4-Fluoro-benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

3-[6-(3-Fluoro-benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[(3,4-Difluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-[6-(3-Chloro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

3-[6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-4-methylsulfanyl -butyramide;

2-(R)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-hydroxy-propionamide;

2-(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-4-methyl-pentanoic acid amide;

2-(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-butyramide;

2-(R)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-H-isoquinolin-2-yl]-3-phenyl-propionamide;

2-(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-butyramide;

2-(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-phenyl-propionamide;

2-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-isobutyramide;

6-(3-Fluoro-benzyloxy)-2-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-(3-Fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-(3-Fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

6-(3-Fluoro-benzyloxy)-2-(2-methoxy-ethyl)-3,4-dihydro-2H-isoquinolin-1-one;

2-(2-Ethoxy-ethyl)-6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline;

6-(4-Fluoro-benzyloxy)-2-(2-methoxy-ethyl)-1,2,3,4-tetrahydro-isoquinoline;

2-(2-Ethoxy-ethyl)-6-(4-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline;

[6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetonitrile;

3 -[6-(3-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionitrile;

6-(4-Fluoro-benzyloxy)-2-(4,4,4-trifluoro-butyl)-1,2,3,4-tetrahydro-isoquinoline;

6-(4-Fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline;

2-[6 (4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2-(R)-[6-(3-Fluoro-benzyloxy)-1-oxy-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide;

2(R)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide; and

,

2(S)-[6-(4-Fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide,

or pharmaceutically acceptable salts thereof.

49. The method of claim 1, wherein the inhibitor is of of formula XXVI and XXVII, or a pharmaceutically acceptable salt thereof:

50. The method of claim 49, wherein the inhibitor is selected from:

2-[5-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetamide,

2-[5-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionamide,

(S)-2-[6-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionamide,

(R)-2-[6-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionamide,

2-[5-(4-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetamide,

2-[1-oxo-5-(4-trifluoromethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-acetamide,

5-(3-Fluoro-benzyloxy)-2-(2-methoxy-ethyl)-2,3-dihydro-isoindol-1-one,

2-[6-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetamide,

(R)-2-[6-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionamide,

(S)-2-[1-oxo-6-(4-trifluoromethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-propionamide,

(R)-2-[1-oxo-6-(4-trifluoromethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-propionamide,

[6-(3-fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester,

[1-oxo-6-(4-trifluoromethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester,

2-(2-Methoxy-ethyl)-6-(3-fluoro-benzyloxy)-2,3-dihydro-isoindol-1-one,

2-(2-methoxy-ethyl)-6-(4-trifluoromethyl-benzyloxy)-2,3-dihydro-isoindol-1-one,

2-(2-amino-ethyl)-6-(4-trifluoromethyl-benzyloxy)-2,3-dihydro-isoindol-1-one 1;

1 hydrochloride, and

2-(2-amino-ethyl)-6-(4-trifluoromethyl-benzyloxy)-2,3-dihydro-isoindol-1-one 1;

1 hydrochloride,

or pharmaceutically acceptable salts thereof.

51. The method of claim 1, wherein the inhibitor is of formula XXVIII and XXIX, or a pharmaceutically acceptable salt thereof:

52. The method of claim 51, wherein the inhibitor is selected from:

N-methyl-3-[4-(4-methyl-benzyloxy)-phenyl]-acrylamide;

3-[4-(3-methoxy-benzyloxy)-phenyl]-N-methyl-acrylamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-2,N-dimethyl-acrylamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-N-methyl-acrylamide;

N-methyl-3-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-acrylamide;

3-[4-(3,4-difluoro-benzyloxy)-phenyl]-N-methyl-acrylamide;

3-[4-(4-fluoro-benzyloxy)-phenyl]-N-methyl-acrylamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-2,N-dimethyl-propionamide;

3-[4-(3,4-difluoro-benzyloxy)-phenyl]-propionamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-N-methyl-butyramide;

3-[4-(3-Fluoro-benzyloxy)-phenyl]-propynoic acid methylamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-acrylamide;

3-[4-(3-fluoro-benzyloxy)-phenyl]-2,N-dimethyl-propionamide; and

,

3-[4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid amide;

or pharmaceutically acceptable salts thereof.

53. The method of claim 1, wherein the inhibitor is of formula XXX or a pharmaceutically acceptable salt thereof:

54. The method of claim 53, wherein the inhibitor is selected from:

(S)-2-[5-(4-Fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide;

2-(2-Amino-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione 1;

1 hydrochloride;

4-[5-(4-Fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-butyramide;

(S)-5-(3-Methoxy-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

(S)-4-[2-(2-Methoxy-1-methyl-ethyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxymethyl]-benzonitrile;

2-(2-Ethanesulfinyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione;

(S)-2-(2-Methoxy-1-methyl-ethyl)-5-(4-trifluoromethoxy-benzyloxy)-isoindole-1,3-dione;

5-(4-Fluoro-benzyloxy)-2-thiophen-2-ylmethyl-isoindole-1,3-dione;

2-(2-Ethanesulfinyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione;

(5-(4-Fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-methoxy-propyl)-isoindole-1,3-dione;

(S)-2-[5-(3-Fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide;

2-(2-Amino-ethyl)-5-(3-fluoro-benzyloxy)-isoindole-1,3-dione 1;

1 hydrochloride;

2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide;

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide;

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide;

(R)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide;

2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide;

(2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide;

2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide;

5-(4-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione;

5-(4-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione;

5-(3-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione;

(S)-5-(4-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

(S)-5-(3-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

(S)-5-(2-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

(S)-2-(2-methoxy-1-methyl-ethyl)-5-(4-trifluoromethyl-benzyloxy)-isoindole-1,3-dione;

(S)-5-(4-bromo-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

(S)-5-(3,4-difluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

5-(3-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione;

5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione;

5-(3,5-bis-trifluoromethyl-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione;

2-(2-ethylsulfanyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione;

(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-thiopropionamide;

2-(2-ethylsulfanyl-ethyl)-5-(3-fluoro-benzyloxy)-isoindole-1,3-dione;

5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile; and

,

[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile;

or pharmaceutically acceptable salts thereof.

55. The method of claim 1, wherein the inhibitor is of formula XXXI or a pharmaceutically acceptable salt thereof:

56. The method of claim 55, wherein the inhibitor is selected from:

(S)-N-(1-carbamoyl-ethyl)-2-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

2-[4-(3-fluorobenzyloxy)-2-fluoro-benzamido]acetamide;

(S)-N-(1-carbamoyl-2-hydroxy-ethyl)-2-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

(R)-N-(1-carbamoyl-ethyl)-2-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

2-[4-(4-fluorobenzyloxy)-2-fluoro-benzamido]acetamide;

(S)-N-(1-carbamoyl-ethyl)-2-fluoro-4-(4-fluoro-benzyloxy)-benzamide;

S)-2-Fluoro-4-(3-fluoro-benzyloxy)-N-(2-methoxy-1-methyl-ethyl)-benzamide;

2-fluoro-4-(3-fluoro-benzyloxy)-N-(2-methoxy-ethyl)-benzamide;

2-fluoro-4-(3-fluoro-benzyloxy)-N-(2-hydroxy-ethyl)-benzamide;

S)-N-(1-carbamoyl-ethyl)-3-fluoro-4-(4-fluoro-benzyloxy)-benzamide;

2-[4-(4-fluorobenzyloxy)-3-fluoro-benzamido]acetamide;

(S)-N-(1-carbamoyl-2-hydroxy-ethyl)-3-fluoro-4-(4-fluoro-benzyloxy)-benzamide;

2-[4-(3-fluorobenzyloxy)-3-fluoro-benzamido]acetamide;

(S)-N-(1-carbamoyl-ethyl)-3-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

(R)-N-(1-carbamoyl-ethyl)-3-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

(S)-N-(1-carbamoyl-2-hydroxy-ethyl)-3-fluoro-4-(3-fluoro-benzyloxy)-benzamide;

2-[4-(4-trifluoromethylbenzyloxy)-3-fluoro-benzamido]acetamide;

(S)-N-(1-carbamoyl-2-hydroxy-ethyl)-3-fluoro-4-(4-trifluoromethyl-benzyloxy)-benzamide;

(S)-N-(1-carbamoyl-ethyl)-2,6-difluoro-4-(4-fluoro-benzyloxy)-benzamide;

N-carbamoylmethyl-2,6-difluoro-4-(4-fluoro-benzyloxy)-benzamide;

N-cyanomethyl-2,6-difluoro-4-(4-fluoro-benzyloxy)-benzamide;

2,6-difluoro-4-(4-fluoro-benzyloxy)-N-(2-methoxy-ethyl)-benzamide;

(S)-2,6-difluoro-4-(4-fluoro-benzyloxy)-N-(2-hydroxy-1-methyl-ethyl)-benzamide; and

,

2,6-difluoro-4-(3-fluoro-benzyloxy)-N-(2-methoxy-ethyl)-benzamide;

or pharmaceutically acceptable salts thereof.

57. The method of claim 1, wherein the inhibitor is of formula XXXII or stereoisomers or a pharmaceutically acceptable salt thereof:

58. The method of claim 57, wherein the inhibitor is selected from:

4-fluoro-N-propargyl-1-aminoindan;

5-fluoro-N-propargyl-1-aminoindan;

6-fluoro-N-propargyl-1-aminoindan;

(+)-6-fluoro-N-propargyl-1-aminoindan; and

,

or stereoisomers or pharmaceutically acceptable salts thereof.

59. The method of claim 1, wherein the inhibitor is of formula XXXIII or a pharmaceutically acceptable salt thereof:

60. The method of claim 59, wherein the inhibitor is selected from:

5-Aminomethyl-3-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-oxazolidin-2-one;

5-Aminomethyl-3-{4-[2-(3-chloro-phenyl)-vinyl]-phenyl}-oxazolidin-2-one;

5-Aminomethyl-3-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-oxazolidin-2-one;

3-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenyl}-5-methylaminomethyl-oxazolidin-2-one;

3-{4-[2-(3-Chloro-phenyl)-vinyl]-phenyl}-5-methylaminomethyl-oxazolidin-2-one;

3-[4-(3-Chloro-benzyloxy)-phenyl]-5-propylaminomethyl-oxazolidin-2-one; and

,

3-[4-(3-Chloro-benzyloxy)-phenyl]-5-ethynylaminomethyl-oxazolidin-2-one;

or pharmaceutically acceptable salts thereof.

61. The method of claim 1, wherein the inhibitor is of formula XXXIV or stereoisomers or a pharmaceutically acceptable salt thereof:

62. The method of claim 61, wherein the inhibitor is selected from:

3-[4-(3-chlorobenzyloxy)phenyl]-5-(1-dimethylaminoethyl)-oxazolidin-2-one;

3-[4-(3-methoxybenzyloxy)phenyl]-5-(1-dimethylaminoethyl)-oxazolidin-2-one;

3-[4-(3-chlorobenzyloxy)phenyl]-5-(1-methylaminoethyl)-oxazolidin-2-one;

3-[4-(3-methoxybenzyloxy)phenyl]-5-(1-methylaminoethyl)-oxazolidin-2-one;

3-[4-(3-chlorobenzyloxy)phenyl]-5-(1-aminoethyl)-oxazolidin-2-one; and

,

3-[4-(3-methoxybenzyloxy)phenyl]-5-(1-aminoethyl)-oxazolidin-2-one;

or stereoisomers or pharmaceutically acceptable salts thereof.

63. The method of claim 1, wherein the inhibitor is of formula XXXV or a pharmaceutically acceptable salt thereof:

64. The method of claim 63, wherein the inhibitor is selected from:

(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-[1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-[1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-[1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(3,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide.

(RS)-1-[4-(5-fluoro-2-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(2-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-5-oxo-1-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(4-fluoro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-chloro-benzyloxy)-3-methyl-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide

(RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(S)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide

(R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,

(RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetonitrile,

(RS)-[1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetonitrile,

(RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide

(RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(2-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(RS)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-formamide,

(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-formamide,

(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-formamide,

(RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamic acid methyl ester,

(RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-urea,

(RS)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-methanesulfonamide,

(S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-2,2-difluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-2,2,2-trifluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(RS)-N-{1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(R)-N-{1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(RS)-N-{1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-formamide,

(RS)-N-[1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetamide,

(RS)-N-{1-[4-(2-fluoro-benzyloxy-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(RS)-(E)-N-(1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidin-3-yl)-acetamide

(RS)-N-(1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidin-3-yl)-acetamide,

(RS)-N-{1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}acetamide,

(S)-N-{5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(3-methoxy-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{5-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(4-methyl-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide.

(RS)-1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidine-3-carbonitrile,

(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid amide,

(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid amide,

(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid methylamide,

(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid amide,

(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide,

(S)-N-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-acetamide,

(S)-N-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-methanesulfonamide,

(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,

(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,

(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-methanesulfonamide,

(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-methanesulfonamide,

(S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid methyl ester,

(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-formamide,

(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-formamide,

(R)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-urea,

(S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-urea,

(S)-N-{1-(S)-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,

(S)-N-{1-(S)-[4-(2,6-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide, and

(S)-N-{1-[4-(3,4-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,

or pharmaceutically acceptable salts thereof.

65. The method of claim 1, wherein the inhibitor is of formula XXXVI or a pharmaceutically acceptable salt thereof:

66. The method of claim 65, wherein the inhibitor is selected from:

2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide,

2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,

2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide,

2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide,

2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-acetamide,

2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide,

7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quinazolin-4-one,

7-(4-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quinazolin-4-one,

7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-2-methyl-3H-quinazolin-4-one,

3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one 1;

2 hydrochloride,

3-(3-amino-propyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one 1;

2 hydrochloride,

3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazolin-4-one 1;

1 hydrochloride,

2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazolin-3-yl]-ethyl-ammonium chloride,

[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetic acid ethyl ester;

fluoro-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetic acid ethyl ester;

2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionic acid ethyl ester;

[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetic acid tert-butyl ester;

2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionic acid tert-butyl ester;

[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetic acid ethyl ester;

2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionic acid ethyl ester,

3-(3-fluoro-benzyl)-7-(3-fluoro-benzyloxy)-3H-quinazolin-4-one;

3-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-propionamide;

2-[7-(3-fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acetamide;

[7-(3-fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acetonitrile;

2-cyclopropyl-7-(3-fluoro-benzyloxy)-3-(2-methoxy-ethyl)-3H-quinazolin-4-one;

[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetic acid methyl ester; and

2-[2-benzyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazolin-3-yl]-acetamide, or pharmaceutically acceptable salts thereof.

67. The method of claim 1, wherein the inhibitor is of formula XXXVII or a pharmaceutically acceptable salt thereof:

68. The method of claim 67, wherein the inhibitor is selected from:

1-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanon-e,

1-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-2-met-hoxy-ethanone,

2-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-2-oxo-acetamide,

3-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo-[d]azepin-3-yl]-3-oxo-propionamide,

7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid methyl ester,

7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carbaldehyde,

7-(3-fluoro-benzyloxy)-3-methanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]az-epine,

7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxy-lic acid amide,

7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azep-ine-3-carboxylic acid ethylamide.

2-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-acetami-de,

(RS)-2-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-propionamide,

8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one,

8-(3-fluoro-benzyloxy)-3-methyl-1,3-dihydro-benzo[d]azepin-2-one,

8-(3-fluoro-benzyloxy)-3-methoxyacetyl-1,3-dihydro-benzo[d]azepin-2-one,

3-acetyl-8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one,

8-(3-fluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one,

7-(2,3,4-trifluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one.

7-(2,3,4-trifluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one,

7-(2,6-difluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one,

7-(2,6-difluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one,

7-benzyloxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one,

7-(3-fluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one,

7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one,

3-acetyl-7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one, and

7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[c]azepin-2-one,

or pharmaceutically acceptable salts thereof.

69. The method of claim 1, wherein the inhibitor is of formula XXXVIII or pharmaceutically acceptable salts or stereoisomers thereof: