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US 2011/0034507 A1Published application
Farnesoid x receptor agonists
AssigneeSmithKline Beecham Corporation
InventorsAdwoa Akwabi-Ameyaw, David Norman Deaton, Robert Blount McFadyen, Frank Navas, III
Life of this patent
Estimating the term…
Abstract
The present invention relates to farnesoid X receptors (FXR, NR1H4). FXR is a member of the nuclear receptor class of ligand-activate transcription factors. More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same. Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease, liver fibrosis, and metabolic syndrome.
Claims27
A compound of formula (I):
- wherein:
- Ring A is phenyl or a 5-6 membered heteroaryl comprising 1, 2 or 3 heteroatoms selected from N, O and S, wherein said phenyl or heteroaryl is substituted with R1 and further optionally substituted with one or two substituents independently selected from C1-6alkyl, halo and haloalkyl;
- R1 is selected from —CO2H, —C(O)NH2, —CO2alkyl, —CH2CH2CO2H, —CH2CH2CO2alkyl, —NHC(O)CH3, —N(C(O)CH3)2, —N(SO2CF3)2, —OCF3 and an acid equivalent group
- Z1 is —CH2—, —CO—, —NH—, —S—, —SO— or —SO2—;
- a is 0 or 1;
- Ring B is selected from
- Z2 is —O—, —S—, —CH2— 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)c—, 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;
- and
- Ring D is selected from C3-6cycloalkyl and a moiety of formula D-i, D-ii, D-iii, D-iv or D-v
- wherein n is 0, 1, 2 or 3;
- each R9 is the same or different and is independently selected from halo, alkyl, alkenyl, —O-alkyl, haloalkyl, hydroxyl substituted alkyl, and —OCF3;
- R9 is —O—, —NH— or —S—;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A compound selected from the group consisting of
- 3-{[5-({[3-{[(2,6-Dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 3-[(5-{[(5-(1-Methylethyl)-3-{[(2,4,6-trifluorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}-1H-indol-1-yl)methyl]benzoic acid;
- 3-[(5-{[(5-(1-Methylethyl)-3-{[(2,4,6-trichlorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}-1H-indol-1-yl)methyl]benzoic acid;
- 3-{[5-({[3-{[(2,6-Dichlorophenyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 3-{[5-({[3-{[(2,6-Dibromophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 3-({5-[({5-(1-Methylethyl)-3-[(1,3-thiazol-2-ylthio)methyl]-4-isoxazolyl}methyl)oxy]-1H-indol-1-yl}methyl)benzoic acid;
- 3-[(5-{[(5-(1-Methylethyl)-3-{2-[(trifluoromethyl)oxy]phenyl}-4-isoxazolyl)methyl]oxy}-1H-indol-1-yl)methyl]benzoic acid;
- 3-{[6-({[3-(3,5-Dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 4-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-benzothien-2-yl]benzoic acid;
- 3-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazoly]methyl}oxy)-1H-indol-1-yl]carbonyl}benzoic acid;
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1,3-benzothiazol-2-yl]benzoic acid;
- 5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-{[3-(1H-tetrazol-5-yl)phenyl]methyl}-1H-indole;
- 4-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 3-{[5-({[3-{[(2,6-Dichloro-4-fluorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 3-{[5-({[3-{[(2,6-Dichlorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- 4-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-benzothien-2-yl]benzoic acid;
- 5-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-3-pyridinecarboxylic acid;
- 6-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-2-pyridinecarboxylic acid;
- 5-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-2-pyridinecarboxylic acid;
- 4-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-2-pyridinecarboxylic acid;
- 2-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-4-pyridinecarboxylic acid;
- 4-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]benzoic acid;
- 1-{3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}methanamine;
- 3-{4-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}propanoic acid;
- 6-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-3-pyridinecarboxylic acid;
- 5-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-2-thiophenecarboxylic acid;
- N-{3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}-1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide;
- N-Acetyl-N-{3-[6-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}acetamide;
- N-{3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}-1,1,1-trifluoromethanesulfonamide;
- N-{3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}acetamide;
- 3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-{[(6-{3-[(trifluoromethyl)oxy]phenyl}-2-naphthalenyl)oxy]methyl}isoxazole;
- N-{4-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}acetamide;
- N-{4-[6-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]phenyl}-1,1,1-trifluoromethanesulfonamide;
- 3-[7-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]benzoic acid;
- 2-Chloro-5-[6-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]benzoic acid;
- 5-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]-2-fluorobenzoic acid;
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-benzothien-2-yl]benzoic acid;
- 3-[2-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}amino)-1,3-benzothiazol-6-yl]benzoic acid;
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-naphthalenyl]benzoic acid;
- 3-(2-{2-[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]ethyl}-1,3-benzoxazol-5-yl)benzoic acid;
- 3-{[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-naphthalenyl]amino}benzoic acid;
- 3-[(2-{2-[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]ethyl}-1,3-benzoxazol-7-yl)amino]benzoic acid;
- 3-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-benzimidazol-1-yl]methyl}benzoic acid;
- 3-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]sulfonyl}benzoic acid;
- 3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]benzoic acid;
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-oxo-3,4-dihydro-2(1H)-isoquinolinyl]benzoic acid;
- 5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-{[4-(1H-tetrazol-5-yl)phenyl]methyl}-1H-indole;
- 2-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}-1,3-oxazole-4-carboxylic acid;
- 5-[([5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl]oxy)-1H-indol-1-yl]methyl}-2-methylbenzoic acid;
- 6-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}-2-pyridinecarboxylic acid;
- 3-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-3-yl]methyl}benzoic acid;
- 2-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}-1,3-thiazole-4-carboxylic acid;
- 3-{[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-3-yl]methyl}benzoic acid;
- (3R)-1-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]carbonyl}-3-pyrrolidinecarboxylic acid;
- 3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-benzothien-2-yl]benzoic acid;
- (3S)-1-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]carbonyl}-3-pyrrolidinecarboxylic acid;
- 3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-2-yl]benzoic acid;
- 3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2,3-dihydro-1H-inden-2-yl]benzoic acid;
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-inden-2-yl]benzoic acid;
- 3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-inden-2-yl]benzoic acid;
- 3-{[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid;
- and
- 3-[6-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-oxo-3,4-dihydro-2(1H)-isoquinolinyl]benzoic acid;
- and pharmaceutically acceptable salts thereof.
61 more elements
3-[5-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1-benzothien-2-yl]benzoic acid or a pharmaceutically acceptable salt thereof.
3-{[5-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-1H-indol-1-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof.
-24. (canceled)
(canceled)
-31. (canceled)
Dependencies are inferred from the claim text.