Farnesoid X receptor agonists

1. A method for the treatment of cholestatic liver disease of liver fibrosis in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to Formula I:

wherein:

a is 1, 2, 3, 4 or 5;

each R 1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF 3 , —OR 6 , —S(O) f R 6 , —NR 6 R 7 , —R 5 OR 6 , —R 5 S(O) f R 6 , —R 5 NR 6 R 7 and cyano;

b is 0, 1, 2 or 3;

R 2 is selected from the group consisting of alkyl, alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, —R 5 OR 6 , —R 5 NR 6 R 7 and cyano;

Y is —O—, —S— or —N(R 8 )—;

R 3 is an acid, amide, ester or acid-equivalent group;

R 4 is H, halo, alkyl or haloalkyl;

each R 5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;

each R 6 and R 7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C 3-6 cycloalkyl and C 3-6 cycloalkenyl; and

f is 0, 1 or 2;

each R 8 is the same or different and is independently H or alkyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein a is 1 or 2.

3. The method according to claim 1 wherein each R 1 is the same or different and is independently selected from the group consisting of halo or —OR 6 .

4. The method according to claim 1 wherein each R 1 is the same or different and is independently halo.

5. The method according to claim 1 where b is 0 or 2.

6. The method according to claim 1 where b is 0.

7. The method according to claim 1 where R 2 is selected from the group consisting of alkyl or C 3-6 cycloalkyl.

8. The method according to claim 1 where Y is —O—.

9. The method according to claim 1 where R 3 is an acid.

10. The method according to claim 1 where R 4 is H.

11. The method according to claim 1 , where the method comprises a compound of Formula I that is selected from the group consisting of:

6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid sodium salt;

6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-[2-Chloro-4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-[4-({[3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)-2-naphthoic acid;

Methyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate;

7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylic acid;

7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylic acid;

7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;

6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxamide;

6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarbonitrile;

5-{6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenyl}-1H-tetrazole; and

6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.

12. The method according to claim 1 , where the method comprises a compound of Formula I that is 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 , where the method comprises a compound of Formula I that is 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.

14. A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt thereof.

15. A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl) aminomethane salt.