Glutamine fructose-y-phosphate amidotransferase (GFAT) inhibitors

1. A compound of formula (I):

R 1 is —COOH, -lower alkyl-COOH, -lower alcohol, —CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 NHSO 2 R 7 , —C(═O)R 8 , —CNHCH 2 CH 2 —R 8 , —C(═NH)—R 8 , —(CH 2 ) n NHC(═O)R 9 , —(CH 2 ) m C(═O)N(R 11 )(R 12 ), —C(═NH)—R 13 , or —(CH 2 ) n —R 14 ;

R 2 is

 wherein

X is —CH or —N;

R 3 , R 4 , R 5 , and R 6 are each selected from the group consisting of —H, -lower alkyl, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 2 CH 3 )CH 2 CH 3 , -halo, —O-lower alkene, -lower alkoxy, —O-lower alcohol, and —O(CH 2 ) n -cycloalkyl; or

where R 5 and R 6 are substituents on adjacent ring carbon atoms, optionally R 5 and R 6 together with the C atoms to which they are attached form a 5 or 6 membered saturated carbocyclic ring;

R 7 is —CF 3 , -lower alkyl, —CH 2 Cl, —CH 2 CF 3 , or —R 8 ;

R 8 is a 5 or 6 membered saturated substituted or unsubstituted heterocyclic ring containing one hetero atom which is selected from N, O, and S wherein the substituted ring is the heterocyclic ring substituted with —OH or -phenyl;

R 9 is -lower alkyl, -lower alkoxy, or —(CH 2 ) n R 10 ;

R 10 is a 5 or 6 membered saturated or unsaturated heterocyclic ring containing one or two hetero atoms which are selected from N and O;

R 11 is —H or —CH 3 ;

R 12 is —H, -lower alkyl, —C≡N, —OH, -lower alkoxy, or —CH 2 COOCH 2 CH 3 ;

R 13 is -lower alkoxy, —NH 2 or —N-lower alkyl;

R 14 is a saturated or unsaturated 5 membered substituted or unsubstituted heterocyclic ring containing from 1 to 4 hetero atoms wherein the hetero atoms are selected from N, O and S, wherein the substituted ring is the heterocyclic ring which is substituted at one or two ring carbons with ═O, or substituted at a ring N with -lower alcohol or -lower alkyl;

m is 0, 1 or 2;

n is 0 or 1;

or a pharmaceutically acceptable salt or ester thereof.

2. The compound according to claim 1 , wherein R 1 is —COOH, lower alkyl-COOH, (CH 2 ) n NHC(═O)R 9 , —CH 2 NHSO 2 R 7 , or —(CH 2 ) n —R 14 .

3. The compound according to claim 2 , wherein R 1 is —COOH, -lower alkyl-COOH wherein -lower alkyl-COOH is —CH 2 COOH, or —(CH 2 ) n —R 14 .

4. The compound according to claim 3 , wherein R 1 is —COOH or —(CH 2 ) n —R 14 and R 14 is an unsubstituted heterocyclic ring.

5. The compound according to claim 4 , wherein R 1 is tetrazole.

6. The compound according to claim 2 , wherein R 1 is —(CH 2 ) n NHC(═O)R 9 or —CH 2 NHSO 2 R 7 .

7. The compound according to claim 6 , wherein R 9 is lower alkyl.

8. The compound according to claim 6 , wherein R 7 is —CF 3 .

9. The compound according to claim 1 , wherein R 2 is

10. The compound according to claim 1 , wherein X is is —CH.

11. The compound according to claim 1 , wherein X is —N.

12. The compound according to claim 1 , wherein

R 1 is —(CH 2 ) n R 14 wherein R 14 is an unsubstituted ring, —COOH, —CH 2 COOH, -lower alcohol, —CH 2 OCH 3 , or —CH 2 NH 2 ;

R 2 is

 wherein

X is —CH or —N;

R 3 , R 4 , R 5 , and R 6 are each selected from the group consisting of:

—H, -lower alkoxy,

—N(CH 3 )CH 3 ,

-lower alkyl, and —O-lower alkene; or

where R 5 and R 6 are substituents on adjacent ring carbon atoms, optionally R 5 and R 6 together with the C atoms to which they are attached form a 5 or 6 membered saturated carbocyclic ring.

13. The compound according to claim 1 , wherein -lower alkyl is methyl, -lower alcohol is -methanol, -lower alkoxy is -methoxy, and -lower alkyl —COOH is —CH 2 —COOH.

14. The compound according to claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are each selected from the group consisting of:

—H, -lower alkyl which contains from 1 to 4 carbon atoms, —N(CH 3 ) 2 , -lower alkoxy which contains from 1 to 4 carbon atoms, -halo, and —O-lower alkene which contains from 1 to 4 carbon atoms; or

where R 5 and R 6 are substituents on adjacent ring carbon atoms, optionally R 5 and R 6 together with the C atoms to which they are attached form a 6 membered saturated carbocyclic ring.

15. The compound according to claim 1 , selected from the group consisting of:

(Naphthalen-2-yl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone, and

(Naphthalen-1-yl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone,

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , selected from the group consisting of:

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-quinolin-3-yl-methanone, and

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-quinolin-8-yl-methanone,

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , selected from the group consisting of:

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(4-methoxy-naphthalen-1-yl)-methanone,

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(4-dimethylamino-naphthalen-1-yl)-methanone.

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(4-methyl-naphthalen-1-yl)-methanone,

(2-Allyloxy-naphthalen-1-yl)-[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-methanone,

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(7-methyl-naphthalen-2-yl)-methanone,

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(1,2,3,4-tetrahydro-phenanthren-9-yl)-methanone, and

[6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(2-methoxy-naphthalen-1-yl)-methanone;

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , selected from the group consisting of:

1-(4-Dimethylamino-naphthalene-1-carbonyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid, and

1-(4-methoxy-naphthalene-1-carbonyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid, and

6,7-Dimethoxy-1-(1,2,3,4-tetrahydro-phenanthrene-9-carbonyl)-isoquinoline-4-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 , 6,7-Dimethoxy-1-(naphthalene-1-carbonyl)-isoquinoline-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.

21. A method for the treatment of type II diabetes in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 , in an amount of from about 10 mg to about 1,000 mg per day.