Farnesoid X Receptor Agonists
AssigneeSmithKline Beecham Corporation
InventorsDavid Norman Deaton, Frank Navas, III, Paul Kenneth Spearing
Life of this patent
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Abstract
The present invention provides novel isoxazole compounds, pharmaceutical compositions, therapeutic uses and processes for preparing the same.
Claims30
A compound of formula (I):
- wherein:
- Ring A is selected from
- wherein
- R1 is selected from —CO2H, —C(O)NH2, —CO2alkyl, and an acid equivalent group;
- R2 is H or —OH;
- Y1 is selected from —CH2—, —NH—, —O— and —S—;
- Y2 is selected from —CH— and —NH—;
- or
- Ring A is a substituted naphthalene when a=1;
- Z1 is —NH— or —S—;
- a is 0 or 1;
- each R4 is selected from halo, alkyl and fluoroalkyl;
- b is 0, 1 or 2, except that when b is 2 and Y3 is C, R4 is not bound at position 2 or
- 6 of Ring B;
- Y3 is —N— or —CH—;
- Z2 is —O—, —S— or —N(R5)—, wherein R5 is H or alkyl;
- R6 is selected from alkyl, 2,2,2-trifluoroethyl, C3-6cycloalkyl, alkenyl, C3-6cycloalkenyl and fluoro-substituted C3-6cycloalkyl;
- R7 is —C1-3alkylene-,
- Z3 is —O—, —S(O)S, or —NH—, where c is 0, 1 or 2;
- d and e are both 0 or d is 1 and e is 0 or 1;
- Ring D is selected from C3-6cycloalkyl and a moiety selected from formula D-i, D-ii and D-iii:
- wherein
- n is 0, 1, 2 or 3;
- each R8 is the same or different and is independently selected from halo, alkyl, alkenyl, —O-alkyl, haloalkyl, —O-haloalkyl, hydroxyl substituted alkyl, and —OCF3;
- and pharmaceutically acceptable salts thereof.
A compound selected from
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indole-2-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,3-dihydro-1H-indene-1-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indole-3-carboxylic acid;
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-benzofuran-2-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indole-2-carboxylic acid;
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,3-dihydro-1H-indene-2-carboxylic acid;
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-1-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indazole-3-carboxylic acid;
- 3-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-benzothiophene-5-carboxylic acid;
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-benzothiophene-3-carboxylic acid;
- 5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-benzothiophene-2-carboxylic acid;
- 6-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-pyridinyl]-1H-indole-3-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-oxo-4H-chromene-2-carboxylic acid;
- 7-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-oxo-2H-chromene-4-carboxylic acid;
- 7-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-oxo-4H-chromene-2-carboxylic acid;
- 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid;
- 8-{[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]amino}-2-naphthalenecarboxylic acid;
- 4-{[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]thio}-1-benzothiophene-2-carboxylic acid;
- Ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1,2-benzisoxazole-3-carboxylate;
- 2-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-benzimidazole-4-carboxylic acid;
- and pharmaceutically acceptable salts thereof.
6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
5-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
-26. (canceled)
(canceled)
A method for the treatment of cholestatic liver disease in a mammal 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]-1H-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
-46. (canceled)
Dependencies are inferred from the claim text.