ALDH-2 inhibitors in the treatment of addiction

1. A compound of the formula:

wherein:

R 1 is phenyl optionally substituted with CO 2 CH 2 CH 3 , CN, CONH 2 , CO 2 H, haloalkyl, —O-haloalkyl, CO 2 CH 2 CH 2 -heterocyclyl, where heterocyclyl is morpholinyl, piperazinyl, and CO 2 -alkyl where alkyl is optionally substituted with N(CH3)2 or Si(CH3)3;

R 2 is —NHSO 2 —CH 3 , OH, NO 2 , NH 2 , CH 2 OH, NHCONHCH 3 , OCH 2 CONH 2 , OCOCH 3 , B(OH) 2 , CONH 2 , CN, CH 3 , CNHNHOH, SO 2 NH 2 , CNOCH 3 NH 2 , or NHCOCH 3 R 3 is hydrogen;

X Y and Z are chosen from —CR 7 —, in which R 7 is hydrogen, lower alkyl, lower alkoxy, or halo;

V is oxygen, sulfur, or —NH—; and

W is -Q 1 -T-Q 2 -, wherein

Q 1 is a covalent bond or C 1-6 linear or branched alkylene optionally substituted with hydroxy, lower alkoxy, amino, cyano, or ═O;

Q 2 is C 1-6 linear or branched alkylene optionally substituted with hydroxy, lower alkoxy, amino, cyano, or ═O; and

T is a covalent bond, —O—, or —NH—, or

T and Q 1 may together form a covalent bond; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein,

R 2 is —NHSO 2 —CH 3 , OH, NO 2 , NH 2 , CH 2 OH, NHCONHCH 3 , OCH 2 CONH 2 , OCOCH 3 , B(OH) 2 , CONH 2 , CN, CH 3 , CNHNHOH, SO 2 NH 2 , CNOCH 3 NH 2 , or NHCOCH 3 .

3. The compound of claim 2 , wherein V is —O—.

4. The compound of claim 3 , wherein Q 1 and Q 2 are branched alkylene.

5. The compound of claim 3 , wherein Q 1 and Q 2 together form a covalent bond and Q 2 is methylene so that W is methylene.

6. The compound of claim 5 , wherein R 2 is hydroxy or —NHSO 2 CH 3 .

7. The compound of claim 5 , where-in R 1 is phenyl optionally substituted with one to three members selected from lower alkyl, B(OH) 2 , C(O)NH 2 , CO 2 CH 2 CH 3 , CN, halogen, heteroaryl, OCF 3 , and phenyl optionally substituted with 1 to 3 members selected from CF 3 , halogen, OH, —OCH 3 , CN, heteroaryl, C(O)OH, or lower alkyl.

8. A compound selected from the group consisting of

methyl 3-((3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoic acid;

methyl-3-((3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate;

methyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate;

allyl 3-((3-(4-methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate;

3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoic acid;

methyl 3-((3-(4-(2-amino-2-oxoethoxy)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate;

methyl 3-((3-(4-acetoxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate;

3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzenecarbonitrile;

3-[3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzamide;

3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzenecarbonitrile;

methylethyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate;

3-{4-[(methasulfonyl)amino]phenyl}-7-{[3-(trifluoromethyl)phenyl]methoxy}chromen-4-one;

3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzamide;

3-(4-aminophenyl)-7-{[3-(trifluoromethyl)phenyl]methoxy}chromen-4-one;

3-(4-aminophenyl)-7-{[3-(trifluoromethoxy)phenyl]methoxy}chromen-4-one;

3-{4-[(methylsulfonyl)amino]phenyl}-7-{[3-(trifluoromethoxy)phenyl]methoxy}chromen-4-one;

methylethyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate;

methyl 3({3-[4-(hydroxymethyl)phenyl]-4-oxochromen-7-yloxy}methyl)benzoate;

methyl 3-({3-[4-(dihydroxyboramethyl)phenyl]-4-oxochromen-7-yloxy}methyl)benzoate;

3,3-dimethyl-3-silabutyl 3-{[3(4-carbamoylphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;

3,3-dimethyl-3-silabutyl 3-[(3-{3-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate;

3,3-dimethyl-3-silabutyl 3-{[3-(3-cyanphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;

methyl 3-{[3-(4-{[4-methylphenyl)sulfonyl]amino}phenyl)-4-oxochromen-7-yloxy]methyl}benzoate;

methyl 3-({3-[4-(amino(hydroxyimino)methyl)phenyl]-4-oxochromen-7-yloxy}methyl)benzoate;

3-{[3-(4-carbamoylphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid, methanol, methanol;

3-({3-[4-(methylsulfonyl)phenyl]-4-oxochromen-7-yloxy}methyl)benzoic acid;

4-((3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)phenylboronic acid;

3-((3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)phenylboronic acid;

N-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}phenyl)carboxamide;

(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}phenyl)-N-{[3-(trifluoromethyl)phenyl]methyl}carboxamide; and

methylethyl 3-{[3-(4-carbamoylphenyl)-4-oxochromen-7-yloxy]methyl}benzoate.

9. A compound selected from the group consisting of:

7-[2-(4-fluorophenyl)-2-oxoethoxy]-3-(4-methoxyphenyl)chromen-4-one;

7-[2-(4-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;

3-(4-hydroxyphenyl)-7-{[3-(trifluoromethyl)phenyl]ethoxy}chromen-4-one;

7-[2-(3-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;

3-(4-hydroxyphenyl)-7-{2-oxo-2-[4-(trifluoromethyl)phenyl]ethoxy}chromen-4-one;

3-(4-hydroxyphenyl)-7-{2-oxo-2-[2-(trifluoromethyl)phenyl]ethoxy}chromen-4-one; and

7-((2-S)-2-hydroxy-3-phenylpropoxy)-3-(4-hydroxyphenyl)chromen-4-one.

10. A compound selected from the group consisting of:

2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-n-[3-(trifluoromethyl)phenyl]acetamide;

7-(3-{[(3,5-difluorophenyl)methyl]amino}-2-hydroxypropoxy)-3-(4-methoxyphenyl)chromen-4-one;

7-[(2S)-2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]-3-(4-methoxyphenyl)chromen-4-one;

2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N[2-(trifluoromethyl)phenyl]acetamide;

N-[(1S)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]acetamide;

N-(3-fluorophenyl)-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]acetamide;

7-[(2S)-2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]-3-(4-hydroxyphenyl)chromen-4-one;

3-(4-hydroxyphenyl)-7-[2-({[3-(trifluoromethyl)phenyl]methyl}amino)ethoxy]chromen-4-one;

7-((2S)-3-{[(3,5-difluorophenyl)methyl]amino}-2-hydroxypropoxy)-3-(4-hydroxyphenyl)chromen-4-one;

N-[(1R)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]acetamide;

7-(2-{[(4-fluorophenyl)ethyl]amino}ethoxy)-3-(4-hydroxyphenyl)chromen-4-one; and

7-[2-(4-chlorophenoxy)ethoxy]-3-(4-hydroxyphenyl)chromen-4-one.

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.