Kappa opioid receptor compounds

1. A method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety and addiction, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is a group of the general formula (II):

or

X 1 is a heteroaryl ring, selected from the list comprising 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-2-yl, 1,2,4-thiadiazol-4-yl, 1,2,3-triazolyl-2-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3-pyrimidin-2-yl, 1,2-pyrazin-3-yl and 1,2,4-triazin-3-yl;

R5, R6 and R7 are independently selected from the list consisting of H, C 1 -C 6 alkyl, C 3 -C 7 -cycloalkyl, aryl and heteroaryl; or

R5 and R6, taken together with the N—C═N group to which they are attached, form a 5-10 membered cyclic or bicyclic ring, optionally substituted with up to two additional heteroatoms selected from the group consisting of N, O and S; or

R6 and R7 taken together with the nitrogen atom to which they are attached form a 5-10 membered cyclic or bicyclic ring, optionally substituted with up to two additional heteroatoms selected from the group consisting of N, O and S, and comprising the rings azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine and thiomorpholine;

X 2 is H, Cl or F;

R1 and R2 are independently hydrogen or methyl;

R3 is hydrogen; and

n is zero, one or two.

2. The method of claim 1 , wherein R1 and R2 are both hydrogen.

3. The method of claim 1 , wherein R3 is hydrogen.

4. The method of claim 1 , wherein X 2 is 4-fluoro.

5. The method of claim 1 , wherein n is one.

6. The method of claim 1 , wherein X 1 is a heteroaryl ring selected from the list comprising 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-2-yl, 1,2,4-thiadiazol-4-yl, 1,2,3-triazolyl-2-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3-pyrimidin-2-yl, 1,2-pyrazin-3-yl and 1,2,4-triazin-3-yl.

7. The method of claim 1 , wherein X 1 is a group of the general formula (II):

8. The method of claim 1 , wherein R5 and R6, taken together with the N—C═N group to which they are attached form a 4-7 membered cyclic or bicyclic ring, optionally substituted with up to two additional heteroatoms selected from the group consisting of N, O and S.

9. The method of claim 1 , wherein R6 and R7, taken together with the nitrogen atom to which they are attached form a 4-7 membered cyclic or bicyclic ring, optionally substituted with up to two additional heteroatoms selected from the group consisting of N, O and S, and comprising the rings azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine, thiomorpholine, oxazole and thiazole.

10. The method of claim 1 , wherein R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, n is one, X 2 is 4-fluoro.

11. The method of claim 1 , wherein the compound is:

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole.

12. The method of claim 1 , wherein the compound is selected from the group consisting of:

2-(1-[3-aminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-(1-[3-(methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-oxazole;

4-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,3-thiazole;

3-(1-[3-dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2-isothiazole;

4-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-2-methyl-1H-imidazole;

5-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-2,4-dimethyl-1H-imidazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-1,3,4-triazole;

2-(1-[3-(dimethylamino)ethyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-(1-[3-(dimethylamino)butyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-4-methyl-1H-imidazole;

5-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-tetrazole;

1-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-5-methyl-2H-tetrazole;

3-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2,4-thiadiazole;

3-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1,2,4-oxadiazole;

1-methyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

4-methyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2(S)-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2(R)-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-benzimidazole;

4,5-dimethyl-2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl])-1H-imidazole;

2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)methanimine;

2-(1-[3-dimethylaminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl})-1,3-pyrimidine;

3-(1-[3-dimethylaminopropyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl})-1,2,4-triazine;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1H-4,5-dihydro-imidazole;

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-4,5,6,7-tetrahydro-1H-1,3-diazepine; and

2-(1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl)-1,4,5,6-tetrahydro-pyrimidine.