Farnesoid X Receptor Agonists
AssigneeGlaxoSmithKline LLC
InventorsRichard Caldwell, David Norman Deaton, Robert Blount McFadyen, Frank Navas, III, Paul Kenneth Spearing
Life of this patent
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Abstract
The present invention provides novel substituted isoxazole compounds, pharmaceutical compositions, therapeutic uses and processes for preparing the same.
Claims18
A method for the treatment of a condition mediated by FXR in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to Formula I:
- wherein:
- a is 1, 2, 3, 4 or 5;
- each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF3, —OR6, —S(O)fR6, —NR6R7, —R5OR6, —R5S(O)fR6, —R5NR6R7 and cyano;
- b is 0, 1, 2 or 3;
- R2 is selected from the group consisting of alkyl, alkenyl, C3-6cycloalkyl, C3-6cycloalkenyl, —R5OR6, —R5NR6R7 and cyano;
- Y is —O—, —S— or —N(R8)—;
- R3 is an acid, amide, ester or acid-equivalent group;
- R4 is H, halo, alkyl or haloalkyl;
- each R5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;
- each R6 and R7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C3-6cycloalkyl and C3-6cycloalkenyl;
- and
- f is 0, 1 or 2;
- each R8 is the same or different and is independently H or alkyl;
- or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound according to Formula I:
- wherein:
- a is 1, 2, 3, 4 or 5;
- each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF3, —OR6, —S(O)fR6, —NR6R7, —R5OR6, —R5S(O)fR6, —R5NR6R7 and cyano;
- b is 0, 1, 2 or 3;
- R2 is selected from the group consisting of alkyl, alkenyl, C3-6cycloalkyl, C3-6cycloalkenyl, —R5OR6, —R5NR6R7 and cyano;
- Y is —O—, —S— or —N(R8)—;
- R3 is an acid, amide, ester or acid-equivalent group;
- R4 is H, halo, alkyl or haloalkyl;
- each R5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;
- each R6 and R7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C3-6cycloalkyl and C3-6cycloalkenyl;
- and
- f is 0, 1 or 2;
- each R8 is the same or different and is independently H or alkyl;
- or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of organ fibrosis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound according to Formula I:
- wherein:
- a is 1, 2, 3, 4 or 5;
- each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF3, —OR6, —S(O)fR6, —NR6R7, —R5OR6, —R5S(O)fR6, —R5NR6R7 and cyano;
- b is 0, 1, 2 or 3;
- R2 is selected from the group consisting of alkyl, alkenyl, C3-6cycloalkyl, C3-6cycloalkenyl, —R5OR6, —R5NR6R7 and cyano;
- Y is —O—, —S— or —N(R8)—;
- R3 is an acid, amide, ester or acid-equivalent group;
- R4 is H, halo, alkyl or haloalkyl;
- each R5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;
- each R6 and R7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C3-6cycloalkyl and C3-6cycloalkenyl;
- and
- f is 0, 1 or 2;
- each R8 is the same or different and is independently H or alkyl;
- or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of liver fibrosis in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to Formula I:
- wherein:
- a is 1, 2, 3, 4 or 5;
- each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF3, —OR6, —S(O)fR6, —NR6R7, —R5OR6, —R5S(O)fR6, —R5NR6R7 and cyano;
- b is 0, 1, 2 or 3;
- R2 is selected from the group consisting of alkyl, alkenyl, C3-6cycloalkyl, C3-6cycloalkenyl, —R5OR6, —R5NR6R7 and cyano;
- Y is —O—, —S— or —N(R8)—;
- R3 is an acid, amide, ester or acid-equivalent group;
- R4 is H, halo, alkyl or haloalkyl;
- each R5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;
- each R6 and R7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C3-6cycloalkyl and C3-6cycloalkenyl;
- and
- f is 0, 1 or 2;
- each R8 is the same or different and is independently H or alkyl;
- or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
Dependencies are inferred from the claim text.