Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof

A compound represented by Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

• wherein:
• Ra is hydrogen or substituted or unsubstituted —C1-C8 alkyl;
• preferably Ra is hydrogen or methyl;
• Rb is selected from from the group consisting of:
• 1) Hydrogen;
• 2) —C(O)NR10R11;
• 3) —C(O)NHSO2R1;
• and
• 4) —SO2R1;
• R1 is selected from the group consisting of:
• 1) Halogen;
• 2) Hydroxyl;
• 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 —C3-C8 cycloalkyl;
• 7) Substituted or unsubstituted aryl;
• 8) Substituted or unsubstituted arylalkyl;
• 9) Substituted or unsubstituted heterocycloalkyl;
• 10) Substituted or unsubstituted heteroaryl;
• 11) Substituted or unsubstituted heteroarylalkyl;
• and
• 12) —NR10R11;
• 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 arylalkyl;
• and
• 6) Substituted or unsubstituted aryl. preferably R2 is hydrogen;
• m is selected from 0, 1, 2 and 3, preferably m is from 0 to 2;
• R3 is hydrogen, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2 or —OPO32−;
• preferably R3 is hydrogen;
• R4 is hydrogen, halogen, CN, N3, hydroxyl, —OSO3H, —OSO3−, —OAc, —OPO3H2, —OPO32−, —SR2 or —NHR2, wherein, R2 is as defined previously;
• preferably R4 is hydrogen;
• Or R3 and R4 are taken together with the carbons they attached form —CH═CH— or cycloalkyl ring or heterocycloalkyl ring such as, but not limited to cyclopropyl, or epoxide;
• R5 and R6 are independently selected from hydrogen or hydroxyl protecting group such as, but not limited to acetyl, trimethyl silyl, or benzyl;
• preferably R5 and R6 are hydrogen;
• 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;
• preferably R7 is C1-C4-alkyl, more preferably R7 is ethyl;
• 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 are taken together with the nitrogen they attached form a heterocyclic ring.