FXR agonists

1. A compound of formula

p is 0 or 1 or 2;

X 1 is C or N and X 2 is C or N; provided that both X 1 and X 2 are not N;

R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, —SC 1 -C 6 alkyl, and —S—C 1 -C 3 haloalkyl;

each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and halo;

R 4a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 alkylcycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;

R 4b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 alkylcycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;

R 5 and R 5a are independently selected from the group consisting of hydrogen, and C 1 -C 3 alkyl;

R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NO 2 , C 3 -C 8 cycloalkyl, and C 4 -C 8 alkylcycloalkyl;

L 1 is selected from the group consisting of a bond, C 1 -C 6 alkyl, CR a ═CR b , ethynyl, C 1 -C 5 alkylene, C 1 -C 5 alkyl-S—, C 1 -C 5 alkyl-O—, N(R c )—C 1 -C 5 alkyl, and —C 1 -C 5 alkyl-N(R c )—, wherein R a and R b are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and R c is independently selected from the group consisting of H, C 1 -C 5 alkyl, C 1 -C 3 alkylphenyl and C 4 -C 8 alkylcycloalkyl;

Ar 1 is selected from the group consisting of indolyl, thienyl, benzothienyl, naphthyl, phenyl, pyridinyl, pyrazolyl, oxazolyl, benzoisoxazolyl, benzofuranyl, pyrrolyl, thiazolyl, benzoisothiazolyl, indazolyl, and furanyl, each optionally substituted with one or two groups independently selected from the group consisting of hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, —OC 1 -C 2 alkylphenyl, N(R C )SO 2 C 1 -C 6 alkyl, —C(O)R 10 , and NHC(O)R 10 ;

R 7 is selected from the group consisting of COOH, C 1 -C 5 alkylCOOH, —O—C 1 -C 5 alkylCOOH, C 2 -C 4 alkenylCOOH, C 3 -C 8 cycloalkylCOOH, and CONR 11 R 11 ;

each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and phenyl;

each R 11 is independently hydrogen, or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.

2. A compound of according to claim 1 wherein

p is 0 or 1 or 2;

X 1 is C or N and X 2 is C or N; provided that both X 1 and X 2 are not N;

R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 thiohaloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and halo;

R 3 is absent or independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and halo;

R 4a is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and C 4 -C 5 alkylcycloalkyl;

R 4b is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and C 4 -C 5 alkylcycloalkyl;

R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl;

R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halo, and —NO 2 ;

L 1 is selected from the group consisting of a bond, CR a ═CR b , ethynyl, C 1 -C 3 alkyl-S—, C 1 -C 3 alkyl-O—, N(R c )—C 1 -C 3 alkyl, and —C 1 -C 3 alkyl-N(R c )—, wherein R a and R b are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and R c is independently selected from the group consisting of H, C 1 -C 5 alkyl, C 1 -C 3 alkylphenyl, and C 4 -C 8 alkylcycloalkyl;

Ar 1 is selected from the group consisting of indolyl, benzothienyl, benzoisothiazolyl, indazolyl, naphthyl, phenyl, pyridinyl, pyrazolyl, pyrrolyl, thienyl, thiazolyl, and furanyl, each optionally substituted with one or two groups independently selected from the group consisting of hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halo, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, —OC 1 -C 2 alkylphenyl, —NHC(O)R 10 ;

R 7 is selected from the group consisting of —COOH, —C 1 -C 3 alkylCOOH, —O—C 1 -C 3 alkylCOOH, and, —CONR 11 R 11 ;

each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, and phenyl;

each R 11 is independently hydrogen, or C 1 -C 5 alkyl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein

p is 0 or 1;

X 1 and X 2 are both C, or X 1 is N and X 2 is C;

R 1 and R 2 are independently selected from the group consisting of hydrogen, fluoro, chloro, CF 3 , SCF 3 , OCF 3 ,

R 3 is fluoro, chloro C 1 -C 3 alkyl, CF 3 , SCF 3 , or OCF 3 ;

R 4a is hydrogen, methyl, ethyl or isopropyl or cyclopropyl;

R 4b is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, or C 3 -C 4 cycloalkyl;

R 5 and R 5a are each independently selected from H or C 1 -C 3 alkyl;

Ar 1 group is phenyl, indolyl, pyridinyl, pyrrolyl, thienyl, naphthyl, thiazolyl, furanyl, pyrazolyl, indazolyl, benzoisothiazolyl, and benzothienyl each optionally substituted with one to two groups independently selected from C 1 -C 5 alkyl, C 1 -C 3 alkoxy, C 1 -C 2 haloalkoxy, and C 1 -C 3 haloalkyl;

R 6 is hydrogen, methyl, ethyl or chloro;

L 1 is a bond, ethenyl, —CH(CH 3 )—S—, C(CH 3 ) 2 —S—, —CH 2 O—, —CH 2 CH 2 O—, —CH(CH 3 )—O—, —CH(CH 3 )CH 2 —O—, —CH(CH 2 CH 3 )—O—, —CH 2 NH—, —CH 2 CH 2 NH—, —N(R c )CH 2 —, N(R c )CH 2 CH 2 —, or N(R c )CH 2 CH 2 CH 2 —; wherein R c is hydrogen, C 1 -C 2 alkyl, benzyl or —CH 2 CH 2 —O—CH 2 —;

R 7 is COOH, —CH 2 COOH, —CH(CH 3 )COOH, -cyclopropylCOOH, —C(CH 3 ) 2 COOH, CONH 2 , C(O)NHCH 3 , or C(O)NHCH 2 CH 3 ;

R 10 is hydrogen or C 1 -C 2 alkyl; and

R 11 is hydrogen or C 1 -C 2 alkyl.

4. A compound according to claim 1 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is ethenyl, ethynyl, —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, chloro or bromo; Ar 1 is phenyl, indolyl, indazolyl, benzothienyl, or benzoisothiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

5. A compound according to claim 1 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

6. A compound according to claim 1 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

7. A compound according to claim 1 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is a bond, —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

8. A compound according to claim 2 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

9. A compound according to claim 2 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is a bond; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

10. A compound according to claim 2 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is a bond; R 5 and R 4a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

11. A compound according to claim 2 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is ethenyl; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

12. A compound according to claim 1 , wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 3 is hydrogen; R 4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is ethenyl, —N(CH 3 )CH 2 —, or —N(CH 3 )CH 2 CH 2 —; R 5 and R 5a are both hydrogen; R 6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

13. A compound selected from the group consisting of:

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methyl-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-isopropoxy-benzoic acid,

2-Butoxy-4-[({4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

2-Benzyloxy-4-[({4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-naphthalene-1-carboxylic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-pentyl-benzoic acid,

3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-5-methyl-benzoic acid,

2-Butyrylamino-4-[({4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-trifluoromethyl-benzoic acid,

3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-5-trifluoromethyl-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-3-hydroxy-benzoic acid,

5-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-fluoro-benzoic acid,

3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-4-fluoro-benzoic acid,

3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-4-methoxy-benzoic acid,

2-Butoxy-5-[({4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

3-Butoxy-5-[({4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

3-[({4-[4-Cyclopropyl-2-(2,6-dichloro-phenyl)-2H-pyrazol-3-ylmethoxy]-phenyl}methyl-amino)-methyl]-benzoic acid,

4-[({-4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

3-[({-4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-benzoic acid,

3-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-benzoic acid,

5-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methoxy-benzoic acid,

4-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-pentyl-benzoic acid,

4-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoic acid,

6-{4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H-indole-3-carboxylic acid,

6-{4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylic acid,

5-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-thiophene-2-carboxylic acid,

5-{4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-thiophene-2-carboxylic acid,

2-{4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-4-methyl-thiazole-5-carboxylic acid,

6-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-nicotinic acid,

4-[({4-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methyl-benzoic acid,

3-[({-4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethyl-amino)-methyl]-benzoic acid, and a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. The compound 2-[2-({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-ethyl]-5-methyl-benzoic acid.

15. The compound 3-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-5-methyl-benzoic acid.

16. The compound-[({4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethyl-amino)-methyl]-benzoic acid.

17. A method of treating dyslipidemia comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.

18. A method of treating atherosclerosis comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.

19. A pharmaceutical composition comprising a compound according to claim 1 and a carrier, diluent, or excipient.