PAI-1 inhibitors and uses thereof
Disclosed herein are compounds, pharmaceutical compositions comprising the compounds, methods of inhibiting PAI-1 using the compounds, and methods of treating IBDs using the compounds.
1 . A compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy;
R 3 is H, halo, or C 1 -C 4 alkyl;
wherein R 2 and R 3 are optionally taken together with the carbon atoms to which they are attached to form a 5-or 6-membered ring optionally substituted with 1 or 2 substituents independently selected from C 1 -C 4 alkyl, halo, and oxo;
X 6 is CR 6 or N;
R 6 is H, halo, or C 1 -C 4 alkyl; and
R 8 is a group of formula:
wherein R x is —(CH 2 ) n —Y or a monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from O and N, wherein the monocyclic heterocyclyl is unsubstituted or substituted with 1 C 1 -C 4 alkyl group, wherein n is 1 or 2, and Y is selected from —COOR g and —NR h R i , wherein R g , R h , and R i are each independently selected from H and C 1 -C 4 alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy; and
R 3 is H, halo, or C 1 -C 4 alkyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 6 is CR 6 and R 6 is H.
4 . The compound of claim 1 , wherein the compound is selected from:
4-chloro-2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-chloro-benzoic acid,
2-[[3-(1-tetrahydropyran-4-ylpyrazol-3-yl)benzoyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]benzoic acid,
2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-methyl-benzoic acid,
4-methyl-2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]-4-methyl-benzoic acid,
2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-4-(trifluoromethyl)benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-(trifluoromethyl)benzoic acid,
2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]-4-(trifluoromethyl)benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]-4-(trifluoromethyl)benzoic acid,
4-isopropyl-2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-isopropyl-benzoic acid,
4-isopropyl-2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]-4-isopropyl-benzoic acid,
4-tert-butyl-2-[[3-(1-tetrahydropyran-4-ylpyrazol-3-yl)benzoyl]amino]benzoic acid,
4-tert-butyl-2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]benzoic acid,
4-tert-butyl-2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]benzoic acid,
4-tert-butyl-2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]benzoic acid,
4-methoxy-2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-methoxy-benzoic acid,
4-methoxy-2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]-4-methoxy-benzoic acid,
2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-4-(trifluoromethoxy)benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4-(trifluoromethoxy)benzoic acid,
2-[[4-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyridine-2-carbonyl]amino]-4-(trifluoromethoxy)benzoic acid,
2-[[4-[1-(2-carboxyethyl)pyrazol-4-yl]pyridine-2-carbonyl]amino]-4-(trifluoromethoxy)benzoic acid,
4,5-dichloro-2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]benzoic acid,
2-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-4,5-dichloro-benzoic acid,
3-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]naphthalene-2-carboxylic acid,
3-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]naphthalene-2-carboxylic acid,
6-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-2,3-dihydro-1,4-benzodioxine-7-carboxylic acid,
[6-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-2,3-dihydro-1,4-benzodioxine-7-carbonyl]oxysodium,
6-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-2,3-dihydro-1,4-benzodioxine-7-carboxylic acid,
6-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-1,3-benzodioxole-5-carboxylic acid,
5-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]-1H-indazole-6-carboxylic acid,
1-methyl-5-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]indazole-6-carboxylic acid,
5-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-1H-indazole-6-carboxylic acid,
5-[[3-[1-(2-carboxyethyl)pyrazol-4-yl]benzoyl]amino]-1-methyl-indazole-6-carboxylic acid,
2-[[3-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]benzoyl]amino]benzoic acid,
2-[[3-[1-(4-piperidyl)pyrazol-4-yl]benzoyl]amino]benzoic acid,
2-[[3-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]benzoyl]amino]benzoic acid,
sodium 4,5-dichloro-2-(4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinamido)benzoate, and
sodium 7-(4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)picolinamido)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate,
and pharmaceutically acceptable salts thereof.
5 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6 . A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7 . A compound:
4-chloro-2-[[3-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzoyl]amino]benzoic acid,
or a pharmaceutically acceptable salt thereof.
8 . A pharmaceutical composition comprising the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.