ALDH-2 inhibitors in the treatment of addiction

1. A compound of Formula I:

wherein:

R 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted phenyl;

R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted phenyl;

R 3 is hydrogen, cyano, optionally substituted amino, alkyl, alkoxy, or halo; and

X, Y and Z are chosen from —CR 4 —, in which R 4 is hydrogen, alkyl, lower alkoxy, or halo;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is optionally substituted alkyl and R 2 is optionally substituted alkyl or optionally substituted cycloalkyl.

3. The compound of claim 2 , wherein R 1 is alkyl of 1-6 carbon atoms optionally substituted by halo, hydroxyl, cyano, optionally substituted alkoxy of 1-6 carbon atoms, optionally substituted acyl, optionally substituted amino, optionally substituted carboxylalkyl, optionally substituted carboxylcycloalkyl, or optionally substituted alkoxycarbonylamino.

4. The compound of claim 3 , wherein X, Y and Z are —CR 4 — and R 3 is hydrogen, selected from the group consisting of:

N-(4-(7-(3-methoxyprop-1-ynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-(3-hydroxy-3-methylbut-1-ynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide; and

N-(4-(7-(3-methoxyprop-1-ynyl)-4-oxo-4H-chromen-3-yl)phenyl)cyclopropane-sulfonamide.

5. The compound of claim 1 , wherein R 1 is optionally substituted cycloalkyl and R 2 is optionally substituted alkyl or optionally substituted cycloalkyl.

6. The compound of claim 5 , wherein R 1 is cycloalkyl optionally substituted by halo, hydroxyl, cyano, alkoxy, optionally substituted acyl, optionally substituted amino, optionally substituted carboxylalkyl, optionally substituted carboxylcycloalkyl, or optionally substituted alkoxycarbonylamino.

7. A compound of claim 6 , wherein X, Y and Z are —CR 4 — and R 3 is hydrogen.

8. A compound of claim 1 , selected from the group consisting of:

N-(4-(7-(cyclopropylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-(((1S,2R)-2-hydroxycyclopentyl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-hydroxycyclopentyl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-aminocyclohexyl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide; and

N-(4-(7-((1-hydroxycyclohexyl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.

9. A compound of claim 1 , wherein R 1 is optionally substituted heteroaryl and R 2 is optionally substituted alkyl or optionally substituted cycloalkyl.

10. A compound of claim 9 , wherein R 1 is heteroaryl optionally substituted by, halo, hydroxyl, cyano, alkoxy, optionally substituted acyl, optionally substituted amino, optionally substituted carboxylalkyl, optionally substituted carboxylcycloalkyl, or optionally substituted alkoxycarbonylamino.

11. A compound of claim 10 , wherein X, Y and Z are —CR 4 — and R 3 is hydrogen.

12. A compound of claim 11 , selected from the group consisting of:

N-(4-(4-oxo-7-(pyrimidin-5-ylethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(4-oxo-7-(pyridin-2-ylethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(4-oxo-7-(pyridin-3-ylethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-methyl-1H-imidazol-5-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.

N-(4-(7-((1,2-dimethyl-1H-imidazol-5-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-methyl-1H-imidazol-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide; and

N-(4-(7-((1-methyl-1H-imidazol-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.

13. The compound of claim 1 , wherein R 1 is optionally substituted phenyl, R 2 is optionally substituted alkyl or optionally substituted cycloalkyl, and R 3 is hydrogen.

14. A compound of claim 13 , wherein R 1 is phenyl and R 2 is methyl, namely N-(4-(4-oxo-7-(phenylethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.

15. A compound of claim 13 , wherein R 1 is optionally substituted heterocyclyl and R 2 is optionally substituted alkyl or optionally substituted cycloalkyl.

16. A compound of claim 15 , wherein X, Y and Z are —CR 4 — and R 3 is hydrogen.

17. A compound of claim 13 , wherein R 1 is optionally substituted piperidine or optionally substituted tetrahydropyran.

18. A compound of claim 17 selected from the group consisting of:

tert-butyl 4-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)piperidine-1-carboxylate;

N-(4-(4-oxo-7-(piperidin-4-ylethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(cyclopropanecarbonyl)piperidin-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide; and

N-(4-(4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.

19. A compound of claim 17 , wherein R 1 is azetidine.

20. A compound of claim 19 , wherein R 2 is methyl, namely N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.

21. A compound of claim 17 , wherein R 1 is N-substituted azetidine, wherein the N-substitution is chosen from optionally substituted alkyl of 1-6 carbon atoms, optionally substituted acyl, optionally substituted amino, optionally substituted carboxylalkyl, optionally substituted carboxylcycloalkyl, and optionally substituted alkoxycarbonylamino.

22. A compound selected from the group consisting of:

tert-butyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carboxylate;

N-(4-(7-(1-(cyclopropanecarbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

cyclopentyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carboxylate;

N-(4-(7-((1-isobutylazetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(3-methoxypropanoyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(3,3-difluorocyclobutanecarbonyl)-azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(3-(dimethylamino)propanoyl)-azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(2-hydroxyacetyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(3-hydroxy-3-methylcyclobutane-carbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(2-hydroxy-2-methylpropanoyl)-azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(3-methyloxetane-3-carbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(2-hydroxypropanoyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(1-methylpiperidine-4-carbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(2,2-difluorocyclopropane-carbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(cyclobutanecarbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

N-(4-(7-((1-(1-methylcyclopropanecarbonyl)-azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide;

tert-butyl 1-(3-((3-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carbonyl)-cyclobutylcarbamate;

N-(4-(4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide;

tert-butyl 1-(3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carbonyl)cyclopropylcarbamate; and

tert-butyl (1-(3-((3-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carbonyl)cyclopropyl)-methylcarbamate.

23. The compound of formula:

also known as N-(4-(7-((1-(cyclopropanecarbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

24. The compound of formula:

also known as N-(4-(7-((1-(cyclopropanecarbonyl)piperidin-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

25. The compound of formula:

also known as tert-butyl (1-(3-((3-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carbonyl)cyclopropyl)-methylcarbamate, or a pharmaceutically acceptable salt thereof.

26. The compound of formula

also known as N-(4-(7-((1-isopropyl-1H-imidazol-5-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 and one or more pharmaceutically acceptable carriers.

28. A method of treating chemical dependency on a dopamine-producing agent selected from the group consisting of cocaine, opiates, amphetamines, nicotine, food and alcohol, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 26 to a patient in need thereof.

29. The method of claim 28 , wherein the dopamine-producing agent is cocaine.

30. The method of claim 28 , wherein the dopamine-producing agent is nicotine.