Heterocyclic amide derivatives as RXR agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes

1. A compound of Formula I

wherein

R 1 is H or C 1-3 alkyl;

W is

V is —O—, wherein

R 2 and R 3 can be the same or different, each being independently selected from H and optionally substituted C 1-3 alkyl;

R 4 is independently

 wherein

Z is selected from

X is selected from a bond, optionally substituted —O—C 1-5 alkyl, and optionally substituted C 1-6 alkylene;

R a is optionally substituted C 1-3 alkoxy; and

n is 0, 1, 2, or 3;

or alternatively R 4 is H or optionally substituted C 1-3 alkyl;

with the proviso that when R 4 is

 then R 5 cannot be

 provided further that when R 4 is H or optionally substituted C 1-3 alkyl, then R 5 cannot be H or optionally substituted C 1-3 alkyl;

and

R 5 is independently

 wherein

Z is selected from

X is selected from a bond, optionally substituted —O—C 1-5 alkyl-, and optionally substituted C 1-6 alkylene;

R a is optionally substituted C 1-3 alkoxy; and

n is 0, 1, 2, or 3;

or alternatively R 5 is H or optionally substituted C 1-3 alkyl;

with the proviso that when R 5 is

 then R 4 cannot be

 provided further that when R 5 is H or optionally substituted C 1-3 alkyl, then R 4 cannot be H or optionally substituted C 1-3 alkyl;

or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R 1 is H or C 1-3 alkyl.

3. The compound of claim 1 wherein R 2 and R 3 are independently selected from H and C 1-3 alkyl.

4. The compound of claim 1 wherein Z is

5. The compound of claim 1 wherein

R 4 or R 5 is

 wherein Z is

6. The compound of claim 1 wherein

R 4 or R 5 is

 wherein X is a bond.

7. The compound of claim 1 wherein

R 4 or R 5 is

 wherein X is optionally substituted C 1-5 alkylene.

8. The compound of claim 7 wherein the C 1-5 alkylene is saturated.

9. The compound of claim 8 wherein the C 1-5 alkylene is

10. The compound of claim 9 wherein 1, 2, or 3 of the hydrogen atoms in the C 1-5 alkylene is further substituted with halo.

11. The compound of claim 1 wherein

R 4 or R 5 is

 wherein X is optionally substituted C 1-6 alkylene.

12. The compound of claim 11 wherein the C 1-6 alkylene is saturated.

13. The compound of claim 12 wherein the C 1-6 alkylene is

14. The compound of claim 13 wherein 1, 2, or 3 of the hydrogen atoms in the C 1-6 alkylene is further substituted with halo.

15. The compound of claim 7 wherein the alkylene is unsaturated.

16. The compound of claim 15 wherein the alkylene contains a double or triple bond.

17. The compound of claim 11 wherein the alkylene is unsaturated.

18. The compound of claim 17 wherein the alkylene contains a double or triple bond.

19. The compound of claim 1 wherein R a is H.

20. The compound of claim 1 wherein R a is —OCF 3 , —OCH 3 , —OCH 2 CF 3 , or —CH═CH—C(O)OH.

21. The compound of claim 1 , wherein

R 1 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 ;

R 2 and R 3 are independently selected from H, —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 ;

R 4 is

 wherein

Z is

X is selected from

 and —CH═C(CH 3 )—; and

R a is —OCF 3 or —OCH 2 CF 3 ; and

n is 1;

or alternatively R 4 is —CH 3 ;

with the proviso that when R 4 is

 then R 5 cannot be

 provided further that when R 4 is —CH 3 , then R 5 cannot be —CH 3 ,

and

R 5 is

 wherein

Z is

X is selected from

 and —CH═C(CH 3 )—; and

R a is —OCF 3 or —OCH 2 CF 3 ; and

n is 1;

or alternatively R 5 is —CH 3 ;

with the proviso that when R 5 is

 then R 4 cannot be

 provided further that when R 5 is CH 3 , then R 4 cannot be —CH 3 .

22. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

23. A method for treating a retinoid x receptor (RXR) mediated condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1 , wherein the RXR condition is selected from Type 2 diabetes mellitus, hynercholesterolemia, insulin resistance, dyslipidemia, artherosclerosis, hypertension, schemia, irritable bowel disorder and cataracts.

24. The method of claim 23 wherein the RXR condition is selected from Type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, and associated symptoms or complications thereof.

25. A method for inhibiting the onset of a RXR mediated condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound according to claim 1 , wherein the RXR condition is selected from Type 2 diabetes mellitus, hynercholesterolemia, insulin resistance, dyslipidemia, artherosclerosis, hypertension, ischemia, irritable bowel disorder and cataracts.

26. The method of claim 25 wherein the RXR condition is selected from type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, and associated symptoms or complications thereof.

27. A process for making a pharmaceutical composition comprising admixing any of the compounds according to claim 1 and a pharmaceutically acceptable carrier.

28. The method of claim 23 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 5 mg/kg/day.