Bile acid analogs as FXR/TGR5 agonists and methods of use thereof

A method for ameliorating an FXR-mediated disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula I:

• or a pharmaceutically acceptable salt, solvate or ester thereof,
• wherein:
• R1 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Substituted or unsubstituted —C1-C8 alkyl;
• 3) Substituted or unsubstituted —C2-C8 alkenyl;
• 4) Substituted or unsubstituted —C2-C8 alkynyl;
• 5) Substituted or unsubstituted —C3-C8 cycloalkyl;
• 6) Substituted or unsubstituted aryl;
• 7) Substituted or unsubstituted arylalkyl;
• 8) Substituted or unsubstituted heterocycloalkyl;
• 9) Substituted or unsubstituted heteroaryl;
• and
• 10) Substituted or unsubstituted heteroarylalkyl;
• Ra, Rb, and Rc are each independently selected from R1;
• or Ra and Rb, or Ra and Rc, or Rb and Rc are taken together with the two nitrogen atoms to which they are attached and the intervening carbon atom to form a heterocyclic, heteroaryl or heterocycloalkenyl ring;
• R2 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) Substituted or unsubstituted —C1-C8 alkyl;
• 4) Substituted or unsubstituted —C2-C8 alkenyl;
• 5) Substituted or unsubstituted —C2-C8 alkynyl;
• 6) Substituted or unsubstituted arylalkyl;
• and
• 7) Substituted or unsubstituted aryl;
• m is 0, 1, 2 or 3;
• R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —PPO3H2 or —OPO32−;
• R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2, or R3 and R4 are taken together with the carbons to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
• R5 and R6 are each independently hydrogen or hydroxyl protecting group;
• and
• R7 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) Substituted or unsubstituted —C1-C8 alkyl;
• 4) Substituted or unsubstituted —C2-C8 alkenyl;
• 5) Substituted or unsubstituted —C2-C8 alkynyl;
• and
• 6) Substituted or unsubstituted —C2-C8 cycloalkyl.