Isoxazole analogs as fxr agonists and methods of use thereof

A compound represented by Formula (I),

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, cyano, optionally substituted —C1-C6 alkyl, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, optionally substituted —C3-C6 cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;
• R2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C3-C12 cycloalkyl or optionally substituted 3- to 12-membered heterocycloalkyl;
• R3a and R3b are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C1-C6 alkoxy and optionally substituted —C3-C6 cycloalkyl;
• alternatively, R3a and R3b are taken together with the carbon atom to which they are attached to form optionally substituted —C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, or optionally substituted —C3-C6 cycloalkenyl;
• {circle around (A)} is
• L1, L2, L3 are each independently C or N;
• e, f, m, and n are each independently 0, 1, 2, 3, or 4;
• A1 is O, NR3c, S, S(O) or S(O)2;
• A2 is absent, O, NR3c, S, S(O) or S(O)2;
• A1 is attached to —CR3aR3b—, and A2 is attached to {circle around (B)};
• Each X1, X2, X3 and X4 is independently selected from the group consisting of:
• O, C(O), S, S(O), S(O)2, NR3c, and CR3dR3e;
• wherein R3d and R3e are each independently selected from hydrogen, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, and optionally substituted —O—C1-C6 alkyl;
• alternatively, R3d and R3e are taken together with the carbon atom to which they are attached to form a optionally substituted —C3-C6 cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;
• R3c is hydrogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, formyl, or acetyl;
• Y1 is absent when L1 is N, and hydrogen, hydroxyl, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, or optionally substituted —O—C1-C6 alkyl when L1 is C;
• Y3 is absent when L3 is N, and hydrogen, hydroxyl, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, or optionally substituted —O—C1-C6 alkyl when L3 is C;
• Y4 is absent when L4 is N, and hydrogen, hydroxyl, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, or optionally substituted —O—C1-C6 alkyl when L4 is C;
• Y2 is hydrogen, hydroxyl, halogen, optionally substituted —C1-C6 alkyl, optionally substituted —C3-C6 cycloalkyl, or optionally substituted —O—C1-C6 alkyl;
• provided that {circle around (A)} is not
• wherein n1, n2, n3, and n4 are 0, 1, 2 or 3;
• R3q is selected from hydrogen, halogen, optionally substituted —C1-C3 alkyl, optionally substituted —C3-C6 cycloalkyl, optionally substituted —O—C1-C3 alkyl, alternatively two R3q groups are linked together to form a —C3-C6 cycloalkyl, aryl, heteroaryl or 3- to 6-membered heterocycloalkyl;
• {circle around (B)} is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 3-12 membered heterocycloalkyl;
• Z is selected from the group consisting of:
• 1) Absent;
• 2) Optionally substituted —C1-C6 alkyl;
• 3) Optionally substituted —C2-C6 alkenyl;
• 4) Optionally substituted —C2-C6 alkynyl;
• 5) Optionally substituted —C3-C8 cycloalkyl;
• 6) Optionally substituted 3- to 8-membered heterocycloalkyl;
• 7) Optionally substituted —C3-C8 cycloalkenyl;
• 8) Optionally substituted aryl;
• and
• 9) Optionally substituted heteroaryl;
• R4 is hydroxy, protected hydroxy, —O-(hydroxy prodrug group), tetrazolyl, cyano, —CO2R5, —O—Y—CO2R5, —NR4b—Y—CO2R5, —CONR4aR4b,
• wherein,
• Y is absent or optionally substituted —C1-C6 alkyl;
• R4a and R4b are independently selected from the group consisting of:
• 1) Hydrogen;
• 2) Optionally substituted —C1-C8 alkyl;
• 3) Optionally substituted —C2-C8 alkenyl;
• 4) Optionally substituted —C2-C8 alkynyl;
• and
• 5) Optionally substituted —C3-C8 cycloalkyl;
• R4c is hydrogen or optionally substituted —C1-C6 alkyl;
• R5 is selected from the group consisting of:
• 1) Hydrogen;
• 2)
• 3) Optionally substituted —C1-C8 alkyl;
• 4) Optionally substituted —C2-C8 alkenyl;
• 5) Optionally substituted —C2-C8 alkynyl;
• and
• 6) Optionally substituted —C3-C8 cycloalkyl;
• R7 is selected from the group consisting of:
• 1) Optionally substituted —C1-C8 alkyl;
• 2) Optionally substituted —C2-C8 alkenyl;
• 3) Optionally substituted —C2-C8 alkynyl;
• 4) Optionally substituted —C3-C8 cycloalkyl;
• 5) Optionally substituted —C3-C8 cycloalkenyl;
• 6) Optionally substituted 3- to 8-membered heterocycloalkyl;
• 7) Optionally substituted 3- to 8-membered heterocycloalkenyl;
• 8) Optionally substituted aryl;
• 9) Optionally substituted —C1-C8 arylalkyl;
• 10) Optionally substituted heteroaryl;
• 11) Optionally substituted —C1-C8 heteroarylalkyl;
• and
• 12) NR9R10;
• wherein R9 and R10 are each independently selected from hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C2-C8 alkenyl, optionally substituted —C2-C8 alkynyl, optionally substituted —C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl;
• alternatively, R9 and R10 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.