Compounds and methods for modulating FXR

1. A compound of

wherein

p is 0, 1 or 2;

X 1 is C and X 2 is C;

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

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 phenyl, 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, and 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, —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 3 alkyl, and phenyl;

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

2. A compound according to claim 1 wherein

p is 0 or 1;

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

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, 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.

3. A compound according to claim 1 , wherein p is 1; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 3 is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is ethenyl, acetylene, —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, optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R 7 is COOH.

4. A compound according to claim 1 , wherein p is 1; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 3 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 optionally substituted with a group independently 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 p is 1; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl thiotrifluoromethyl, and trifluoromethoxy; R 3 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 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 p is 1; R 1 and R 2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R 3 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, 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 selected from the group consisting of:

4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoic acid,

3-[({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

3-[({4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({4-[5-Isopropyl-3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

4-[({4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methyl-benzoic acid,

3-[({4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoic acid,

or a pharmaceutically acceptable salt thereof.

8. The compound 4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoic acid.

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