Compounds and methods for modulating FXR
View Patent ↗Compounds of formula (I): formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and diseases related to dyslipidemia.
1. A compound of formula
wherein:
q is 1 or 2;
R 1 is chloro, fluoro, or trifluoromethoxy;
R 2 is hydrogen chloro, fluoro, or trifluoromethoxy;
R 3b is trifluoromethyl, cyclopropyl or isopropyl;
X is C or N, provided that when X is C, q is 1;
Ar 1 is selected from the group consisting of benzoisothiazolyl, benzothienyl, indazolyl, indolyl, naphthyl, phenyl and pyridinyl, each optionally substituted methyl or phenyl; or a pharmaceutically acceptable salt or enantiomer thereof.
2. A compound according to claim 1 wherein R 1 is chloro or trifluoromethoxy and R 2 is hydrogen or chloro; or a pharmaceutically acceptable salt or enantiomer thereof.
3. A compound according to claim 1 wherein R 1 and R 2 are both Chloro or wherein R 1 is trifluoromethoxy and R 2 is hydrogen; or a pharmaceutically acceptable salt or enantiomer thereof.
4. A compound according to claim 1 wherein R 3b is cyclopropyl or isopropyl; or a pharmaceutically acceptable salt or enantiomer thereof.
5. A compound according to claim 1 wherein R 3b is cyclopropyl; or a pharmaceutically acceptable salt or enantiomer thereof.
6. A compound according to claim 1 wherein Ar 1 is 6-benzoisothiazolyl, 5-benzothienyl, 6-benzothienyl, 6-indazolyl, 5-indolyl, 6-indolyl, 4-phenyl or 2-pyridinyl, each optionally substituted with methyl or phenyl; or a pharmaceutically acceptable salt or enantiomer thereof.
7. A compound according to claim 1 wherein Ar 1 is 6-benzoisothiazolyl, 5-benzothienyl, 6-benzothienyl, 6-indazolyl, 5-indolyl, 6-indolyl, or 4-phenyl, each optionally substituted with methyl; or a pharmaceutically acceptable salt or enantiomer thereof.
8. A compound according to claim 1 wherein Ar 1 group is 5-benzothienyl, 6-benzothienyl, 5-indolyl, 6-indolyl or 4-phenyl, each optionally substituted with methyl; or a pharmaceutically acceptable salt or enantiomer thereof.
9. A compound according to claim 1 wherein q is 1 and X is N; or a pharmaceutically acceptable salt or enantiomer thereof.
10. A compound according to claim 1 wherein q is 1 and X is C; or a pharmaceutically acceptable salt or enantiomer thereof.
11. A compound according to claim 1 wherein q is 2 and X is N; or a pharmaceutically acceptable salt or enantiomer thereof.
12. A compound according to claim 1 wherein R 1 is chloro or trifluoromethoxy; R 2 is hydrogen or chloro; R 3b is cyclopropyl; X is C or N and Ar 1 group is 4-phenyl, 2-pyridinyl, 6-indolyl or 6-benzothienyl each optionally substituted with methyl.
13. A compound according to claim 1 selected from the group consisting of:
5-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid,
5-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid,
5-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid,
4-{-4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-naphthalene-1-carboxylic acid,
4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-3-methyl-benzoic acid,
4-{4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-benzoic acid,
4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-benzoic acid,
4-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-2-methyl-benzoic acid,
4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-2-methyl-benzoic acid,
4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-2-methyl-benzoic acid,
4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-benzoic acid,
6-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid,
6-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-benzo[b]thiophene-3-carboxylic acid,
6-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid,
6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid,
6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-benzo[b]thiophene-3-carboxylic acid,
4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid,
4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-3-methyl-benzoic acid,
4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-benzoic acid,
6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-1-methyl-1H-indole-3-carboxylic acid,
6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-benzo[b]thiophene-3-carboxylic acid,
Trans-4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-benzoic acid,
Trans-4-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-benzoic acid,
Trans-6-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-1-methyl-1H-indole-3-carboxylic acid, and
Cis-6-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-1-methyl-1H-indole-3-carboxylic acid;
or a pharmaceutically acceptable salt or enantiomer thereof.
14. The compound 4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-benzoic acid
or a pharmaceutically acceptable salt or enantiomer thereof.
15. The compound trans-4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-benzoic acid
or a pharmaceutically acceptable salt or enantiomer thereof.
16. The compound 6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid
or a pharmaceutically acceptable salt or enantiomer thereof.
17. A method for treating dyslipidemia and related diseases comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.
18. A pharmaceutical composition comprising a compound according to claim 1 and a carrier, diluent, or excipient.