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

A method for ameliorating a 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 IA or Formula IB, or a pharmaceutically acceptable salt, ester, solvate or combination thereof:

• wherein:
• R1 is selected from:
• R1′ is selected from:
• Ra is hydrogen, substituted or unsubstituted C3-C8-cycloalkyl or substituted or unsubstituted C1-C8 alkyl;
• Rb is selected from the group consisting of:
• 1) Hydrogen
• 2) Halogen;
• 3) Hydroxyl;
• 4) Substituted or unsubstituted —C1-C8 alkyl;
• 5) Substituted or unsubstituted —C2-C8 alkenyl;
• 6) Substituted or unsubstituted —C2-C8 alkynyl;
• 7) Substituted or unsubstituted —C3-C8 cycloalkyl;
• 8) Substituted or unsubstituted aryl;
• 9) Substituted or unsubstituted alkylaryl;
• 10) Substituted or unsubstituted heterocycloalkyl;
• 11) Substituted or unsubstituted heteroaryl;
• 12) Substituted or unsubstituted alkylheteroaryl;
• and
• 13) —NR10R11;
• wherein R10 and R11 are each independently selected from hydrogen, substituted or unsubstituted —C1-C8 alkyl, substituted or unsubstituted —C2-C8 alkenyl, Substituted or unsubstituted —C2-C8 alkynyl, substituted or unsubstituted —C3-C8 cycloalkyl, or R10 and R11, taken together with the nitrogen atom to which they are attached, form a hetercyclic ring.
• R2 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 alkylaryl;
• and
• 6) Substituted or unsubstituted aryl
• m is 0, 1, 2 or 3;
• R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2 or —OPO32−;
• R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H,—OAc, —OPO3H2, —OPO32−, —SR2 or —NHR12, wherein R12 is hydrogen;
• substituted or unsubstituted —C1-C8 alkyl;
• substituted or unsubstituted —C2-C8 alkenyl;
• substituted or unsubstituted —C2-C8 alkynyl;
• substituted or unsubstituted alkylaryl;
• or substituted or unsubstituted aryl;
• Alternatively, R3 and R4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring such as, but not limited to, cyclopropyl or epoxide;
• R5 and R6 are independently selected from hydrogen or a hydroxyl protecting group;
• 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 —C3-C8 cycloalkyl;
• and
• R8 and R9 are independently selected from hydrogen;
• substituted or unsubstituted
• —C1-C8 alkyl;
• substituted or unsubstituted —C2-C8 alkenyl;
• substituted or unsubstituted
• —C2-C8 alkynyl;
• substituted or unsubstituted alkylaryl;
• or substituted or unsubstituted aryl.