AVERMECTIN DERIVATIVES AS FXR MODULATORS

1 . A compound of Formula I,

stereoisomers thereof, and/or salts thereof, wherein

R 1 is a substituted or unsubstituted cyclohexyl or C 3 -C 4 alkyl group;

R 2 is

NNHR 4 , or NOR 4 ;

R 3 is H or

R 4 is H or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aralkyl or heteroaralkyl group;

R 6 is OH, NH 2 , NR 7 R 8 , NR 7 C(O)R 9 ;

R 7 and R 8 are independently H or a substituted or unsubstituted alkyl or alkenyl group;

R 9 is H, OR 10 , or a substituted or unsubstituted alkyl, alkenyl, or aralkyl group;

R 10 is an unsubstituted alkyl or aralkyl group; and

each independently indicates a single or double bond;

provided that when R 2 is

then R 3 is not

2 . The compound of claim 1 wherein

R 2 is

or NOR 4 ;

R 4 is H or an unsubstituted alkyl or cycloalkyl group;

R 6 is OH, NH 2 , NR 7 R 8 , NR 7 C(O)R 9 ; and

R 7 and R 8 are independently H or a substituted or unsubstituted alkyl group.

3 . The compound of claim 1 or claim 2 wherein R 1 is a cyclohexyl group, isopropyl group or an isobutyl.

4 . The compound of any one of claims 1 - 3 wherein R 2 is

5 . The compound of any one of claims 1 - 3 wherein R 2 is NOR 4 .

6 . The compound of any one of claims 1 - 5 wherein R 4 is H, methyl, ethyl or propyl.

7 . The compound of any one of claims 1 - 6 wherein R 3 is H.

8 . The compound of any one of claims 1 - 6 wherein R 3 is

9 . The compound of claim 8 wherein R 6 is OH, NH 2 , or NHC(O)R 9 .

10 . The compound of claim 9 wherein R 9 is H, O-t-butyl, O-fluorenylmethyl, methyl, ethyl, trifluoromethyl, isopropyl, hydroxyethyl, butyl, or methoxymethyl.

11 . The compound of any one of claims 1 - 10 wherein a double bond is present between C-22 and C-23.

12 . The compound of any one of claims 1 - 10 wherein a single bond is present between C-22 and C-23.

13 . A composition comprising one or more compounds of any one of claims 1 - 12 .

14 . The composition of claim 13 comprising a pharmaceutically acceptable carrier.

15 . A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 - 14 for treating an FXR-mediated disorder or condition.

16 . The pharmaceutical composition of claim 15 wherein the disorder or condition is selected from the group consisting of liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, atherosclerosis, and renal disease.

17 . The pharmaceutical composition of claim 15 wherein the disorder or condition is a liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis.

18 . A method of treatment comprising administering an effective amount of a compound of any one of claims 1 - 12 , or administering a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 - 12 , to a subject suffering from an FXR-mediated disorder or condition.

19 . The method of claim 18 , wherein the disorder or condition is selected from the group consisting of liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, atherosclerosis, and renal disease.

20 . The method of claim 18 , wherein the disorder or condition is a liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis.

21 . A method comprising modulating FXR by contacting FXR with an effective amount of a compound of any one of claims 1 - 12 .