Compositions and methods for modulating farnesoid X receptors
The present invention relates to compounds of Formula I, a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).
1. A compound according to formula (I),
or a pharmaceutical acceptable salt thereof, wherein,
R 0 is Ring A or C 1-6 alkyl;
Ring A is aryl; 5-10 membered heteroaryl comprising 1-3 N, O or S heteroatoms; 4-6 membered heterocycle comprising 1-2 N, O or S heteroatoms; or C 3-7 cycloalkyl; and said Ring A is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
Ring B is aryl; 5-10 membered heteroaryl comprising 1-3 N, O or S heteroatoms; 4-6 membered heterocycle comprising 1-2 N, O or S heteroatoms; or C 3-7 cycloalkyl; and said Ring B is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
X is —(CR 4 R 5 )— or —C(O)—;
Y is —O—, —(CR 4 R 5 )—, *—O(CR 4 R 5 )— or —NR—, wherein “*” indicates the point of attachment of Y to the ring containing the Z ring atoms;
Z 1 , Z 2 , Z 3 , and Z 4 are each independently —CR 3 — or —N—;
L 1 is * 1 —(CR 4 R 5 ) 1-2 - or * 1 —(CR 4 R 5 )—C(O)—NR—, wherein “* 1 ” indicates the point of attachment of L 1 to N;
L 2 is * 2 —(CR 4 R 5 ) 1-2 —, * 2 —(CR 4 R 5 )—C(O)—, * 2 —(CR 4 R 5 )—C(O)—NR—, * 2 —(CR 4 R 5 ) 2 —O—, * 2 —(CR 4 R 5 ) 2 —NR—, * 2 —(CR 4 R 5 ) 2 —SO 2 —, * 2 —(CR 4 R 5 ) 2 —NR—C(O)—, or * 2 —(CR 4 R 5 )—C(O)—NR—(CR 4 R 5 )—;
wherein “* 2 ” indicates the point of attachment of L 2 to N;
L 3 is —(CR 4 R 5 )— or —C(O)—;
each R 2 is independently halo, hydroxyl, C 1-6 alkyl, or halo-substituted C 1-6 alkyl;
each R 3 is independently hydrogen, halo, or C 1-6 alkyl; and
R, R 4 and R 5 are independently hydrogen or C 1-6 alkyl.
2. The compound of claim 1 , wherein,
R 0 is Ring A or C 1-6 alkyl;
Ring A is aryl; 5-10 membered heteroaryl comprising 1-3 N, O or S heteroatoms; or C 3-7 cycloalkyl; and said Ring A is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
Ring B is aryl; 5-10 membered heteroaryl comprising 1-3 N, O or S heteroatoms; or C 3-7 cycloalkyl; and said Ring B is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
X is —(CR 4 R 5 )—;
Y is —O—, —(CR 4 R 5 )—, or *—O(CR 4 R 5 )—, wherein “*” indicates the point of attachment of Y to the ring containing the Z ring atoms;
Z 1 , Z 2 , Z 3 , and Z 4 are each independently —CR 3 — or —N—;
L 1 is * 1 —(CR 4 R 5 ) 1-2 — wherein “* 1 ” indicates the point of attachment of L 1 to N;
L 2 is * 2 —(CR 4 R 5 ) 1-2 —, * 2 —(CR 4 R 5 )—C(O)—NR—, * 2 —(CR 4 R 5 ) 2 —O—, * 2 —(CR 4 R 5 ) 2 —NR— or * 2 —(CR 4 R 5 )—C(O)—NR—(CR 4 R 5 )—; wherein “* 2 ” indicates the point of attachment of L 2 to N;
L 3 is —C(O)—;
each R 2 is independently halo, C 1-6 alkyl, or halo-substituted C 1-6 alkyl;
each R 3 is independently hydrogen, halo, or C 1-6 alkyl;
R, R 4 and R 5 are independently hydrogen or C 1-6 alkyl.
3. The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof; wherein,
R 0 is Ring A or C 1-6 alkyl; wherein Ring A is phenyl, pyridyl or cyclopropyl, each of which is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
Ring B is selected from phenyl, pyridyl, 1H-indolyl, and C 3-7 cycloalkyl, each of which is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
X is —(CR 4 R 5 )—;
Y is —O—, —(CR 4 R 5 )— or *—O(CR 4 R 5 )—, wherein “*” indicates the point of attachment of Y to the ring containing the Z ring atoms;
Z 1 , Z 2 , Z 3 , and Z 4 are each independently —CR 3 — or —N—;
L 1 is * 1 —(CR 4 R 5 ) 1-2 — wherein “* 1 ” indicates the point of attachment of L 1 to N;
L 2 is * 2 —(CR 4 R 5 ) 1-2 —, * 2 —(CR 4 R 5 )—C(O)—NR—, * 2 —(CR 4 R 5 ) 2 —O—, * 2 —(CR 4 R 5 ) 2 —NR— or * 2 —(CR 4 R 5 )—C(O)—NR—(CR 4 R 5 )—; where “* 2 ” indicates the point of attachment of L 2 to N;
each R 2 is independently halo, C 1-6 alkyl, or halo-substituted C 1-6 alkyl;
each R 3 is independently hydrogen, halo, or C 1-6 alkyl; and
R, R 4 and R 5 are independently hydrogen or C 1-6 alkyl.
4. The compound of claim 1 , wherein R 0 is selected from * 3 —CH 2 C(CH 3 ) 2 —, * 3 —CH 2 CH(CH 3 )—, and * 3 -cyclopropane-1,1,-diyl, wherein “* 3 ” indicates the point of attachment of R 0 to L 2 .
5. The compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof; wherein
Ring A is phenyl or pyridyl, each of which is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
Ring B is selected from phenyl, pyridyl, 1H-indolyl, and cyclopentyl, each of which is unsubstituted or substituted by 1-2 substituents independently represented by R 2 ;
L 1 is —(CR 4 R 5 )—;
L 2 is selected from —(CH 2 )—, * 2 —CH 2 C(O)NH—, * 2 —CH(CH 3 )C(O)NH—, * 2 —CH 2 C(O)NHCH 2 —, * 2 —(CH 2 ) 2 O—, and * 2 —(CH 2 ) 2 NH—; wherein “* 2 ” indicates the point of attachment of L 2 to N;
X is CH 2 ;
Y is selected from —O—, —CH 2 —, —C(CH 3 ) 2 — and *—O—CH 2 —, wherein “*” indicates the point of attachment of Y to the ring containing the Z ring atoms;
Z 1 is CR 3 or N;
Z 2 is CR 3 ;
Z 3 is CR 3 ;
Z 4 is CR 3 or N;
each R 2 is independently selected from halo, methyl, and trifluoromethyl;
each R 3 is independently hydrogen, halo, or C 1-6 alkyl; and
each of R 4 and R 5 is independently hydrogen or methyl.
6. The compound of claim 1 , wherein Y is —O—.
7. The compound of claim 1 , wherein L 1 is —CH 2 —.
8. The compound of claim 1 , wherein L 2 is selected from —(CH 2 )—, * 2 —CH 2 C(O)NH—, * 2 —(CH 2 ) 2 O—, and * 2 —(CH 2 ) 2 NH—; wherein “* 2 ” indicates the point of attachment of L 2 to N.
9. The compound of claim 1 , wherein L 2 is —CH 2 —.
10. The compound of claim 1 , wherein each R 2 is independently fluoro or methyl.
11. The compound of claim 1 , wherein each R 3 is independently selected from hydrogen, fluoro, chloro, and methyl.
12. The compound of claim 1 , wherein
Z 1 is selected from CH, CF, CCH 3 , and N;
Z 2 is selected from CH, CF, CCl, and CCH 3 ;
Z 3 is selected from CH, CF, CCl, and CCH 3 ; and
Z 4 is CH or N.
13. The compound of claim 1 , wherein said compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof; wherein
each phenyl ring is optionally further substituted by 1-2 substituents independently represented by R 2 , wherein R 2 is fluoro or methyl;
L 2 is selected from —CH 2 —, * 2 —CH 2 CH 2 NH—, * 2 —CH 2 CH 2 O—, and * 2 —CH 2 C(O)NH—, wherein “* 2 ” indicates the point of attachment of L 2 to N;
Z 2 is selected from CH, CF, CCl, and CCH 3 ; and
Z 3 is selected from CH, CF, CCl, and CCH 3 .
14. The compound of claim 1 selected from:
4-fluoro-3-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
4-fluoro-3-(2-(1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(N-(2-fluorobenzyl)-1,8-dimethyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(N-(2-fluorobenzyl)-1,6-dimethyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(7-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(7-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(6,8-difluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1,7-dimethyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1,6-dimethyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-6-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(7,8-difluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(7,8-difluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(N-benzyl-7,8-difluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
4-fluoro-3-(2-(8-fluoro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(N-(2-fluorobenzyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(N-(2-fluorobenzyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-3-carboxamido)acetamido)benzoic acid;
(S)-4-fluoro-3-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)propanamido)benzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-7-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(N-(3-fluorobenzyl)-1,5,5-trimethyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(N-benzyl-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(N-benzyl-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(9-chloro-N-(2-fluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[2,3]oxepino[4,5-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-N-(cyclopentylmethyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(8-chloro-N-(cyclopentylmethyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-5-fluorobenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-4-methylbenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-2-methylpropanoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-2,2-dimethylpropanoic acid;
1-((2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)methyl)cyclopropanecarboxylic acid;
4-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
4-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-methylbenzoic acid;
4-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-3,5-dimethylbenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-4-fluorobenzoic acid;
4-(2-(8-chloro-N-(cyclopentylmethyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3,5-dimethylbenzoic acid;
4-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-3,5-difluorobenzoic acid;
4-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-3-(trifluoromethyl)benzoic acid;
4-(2-(N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3,5-difluorobenzoic acid;
3,5-difluoro-4-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
4-(2-(N-benzyl-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3,5-difluorobenzoic acid;
4-(2-(N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
4-(2-(N-benzyl-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
4-(2-(N-benzyl-7,8-difluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
3-fluoro-4-(2-(8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
4-(2-(7,8-difluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
4-(2-(8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
3-fluoro-4-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
4-(2-(7,8-difluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethoxy)-3-fluorobenzoic acid;
3-((2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-((2-(8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
3-((2-(8-chloro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
4-fluoro-3-((2-(8-fluoro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
3-((2-(7,8-difluoro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
4-fluoro-3-((2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
4-fluoro-3-((2-(N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
3-((2-(N-benzyl-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
3-((2-(N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
3-((2-(7,8-difluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
3-((2-(N-benzyl-7,8-difluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-3-fluorobenzoic acid;
4-((8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3,5-difluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((N-benzyl-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-3-fluorobenzoic acid;
4-((8-chloro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(2,3-difluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3-fluoro-5-methylbenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((N-(3,5-difluorobenzyl)-8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-3-fluorobenzoic acid;
3-fluoro-4-((8-fluoro-1-methyl-N-(3-methylbenzyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((N-((1H-indol-5-yl)methyl)-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
5-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)picolinic acid;
4-((8-chloro-N-((5-fluoropyridin-3-yl)methyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-((5-chloropyridin-3-yl)methyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-2-fluorobenzoic acid;
4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-2-fluorobenzoic acid;
N-benzyl-N-(4-carbamoylbenzyl)-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide;
4-((8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-3-fluorobenzoic acid;
3-fluoro-4-((8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-3-fluorobenzoic acid
4-((8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-2-fluorobenzoic acid;
6-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)nicotinic acid;
5-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)-6-methylpicolinic acid;
4-fluoro-3-((2-(8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid; and
3-((2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 selected from:
4-fluoro-3-(2-(8-fluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
4-fluoro-3-(2-(8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(7-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)acetamido)benzoic acid;
3-(2-(7,8-difluoro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)acetamido)-4-fluorobenzoic acid;
3-(2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethoxy)benzoic acid;
3-((2-(8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
3-((2-(8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4, 3-c]pyrazole-3-carboxamido)ethyl)amino)-4-fluorobenzoic acid;
4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(2-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid;
4-((8-chloro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid; and
4-fluoro-3-((2-(8-fluoro-N-(3-fluorobenzyl)-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)ethyl)amino)benzoic acid;
or a pharmaceutically acceptable salt thereof.
16. An compound of Formula (V)
wherein each phenyl ring is optionally further substituted by 1-2 substituents independently represented by R 2 , wherein R 2 is fluoro or methyl;
L 2 is selected from —CH 2 —, * 2 —CH 2 CH 2 NH—, * 2 —CH 2 CH 2 O—, and * 2 —CH 2 C(O)NH—, wherein “* 2 ” indicates the point of attachment of L 2 to N;
Z 2 is selected from CH, CF, CCl, and CCH 3 ;
Z 3 is selected from CH, CF, CCl, and CCH 3 ; and
R 6 is C 1-6 alkyl.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A combination comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.
19. A method for treating a condition mediated by farnesoid X receptors (FXR) in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and optionally in combination with a second therapeutic agent.
20. The method of claim 19 , wherein said condition mediated by FXR is a liver disease or a gastrointestinal disease.
21. The method of claim 20 , wherein said condition mediated by FXR is a liver disease selected from intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis of pregnancy, parenteral nutrition-associated cholestasis, progressive familial cholestasis (PFIC), Alagille syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, ductopenic liver transplant rejection, liver transplant associated graft versus host disease, cystic fibrosis liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, and parenteral nutrition-associated liver disease.
22. The method of claim 20 , wherein said condition mediated by FXR is a gastrointestinal disease selected from primary bile acid diarrhea, secondary bile acid diarrhea, bile reflux gastritis, and inflammatory bowel disease.
23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is
27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is