US 12,233,051 B2
Treating primary or idiopathic hyperoxaluria with small molecule inhibitors of lactate dehydrogenase
Matthew Hall, Damestown, MD (US); Daniel J. Urban, Poolesville, MD (US); John Knight, Birmingham, AL (US); Ross Holmes, Birmingham, AL (US); Kyle David Wood, Birmingham, AL (US); Alex Waterson, Birmingham, AL (US); Victor M. Darley-Usmar, Birmingham, AL (US); and Leonard M. Neckers, Bethesda, MD (US)
Assigned to VANDERBILT UNIVERSITY, Nashville, TN (US); THE UAB RESEARCH FOUNDATION, Nashville, TN (US); and THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, Bethesda, MD (US)
Filed by VANDERBILT UNIVERSITY, Nashville, TN (US); The UAB Research Foundation, Birmingham, AL (US); and The United States of America, as Represented by the Secretary, Department of Health and Human Services, Bethesda, MD (US)
Filed on Jul. 14, 2023, as Appl. No. 18/352,721.
Application 18/352,721 is a continuation of application No. 17/322,260, filed on May 17, 2021, granted, now 11,752,138.
Claims priority of provisional application 63/026,296, filed on May 18, 2020.
Prior Publication US 2023/0372308 A1, Nov. 23, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/427 (2006.01); A61K 31/4439 (2006.01); A61K 31/506 (2006.01)
CPC A61K 31/427 (2013.01) [A61K 31/4439 (2013.01); A61K 31/506 (2013.01)] 19 Claims
 
1. A method of treating a disease or disorder associated with elevated oxalate levels in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein the compound of Formula I is
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methyl-2′,3′,4′,5′-tetrahydro-[1, l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-(trifluoromethyl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-2′-methyl-2′,3′,4′,5′-tetrahydro-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methoxy-2′,3′,4′,5′-tetrahydro-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1H-inden-2-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′,4′,6-trifluoro-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(spiro[2.5] oct-5-en-6-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(3-(3-(but-1-yn-1-yl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(3-(3-((5-(tert-butyl) thiophen-2-yl) ethynyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((2-methylthiazol-5-yl)ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-3-(4-fluoro-3-((5-methylthiophen-2-yl) ethynyl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((5-methylthiazol-2-yl)ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(1-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-((5-cyclopropylthiophen-2-yl ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-((5-chlorothiophen-2-yl)ethynyl)phenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic,
(E)-2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(2-(5-methylthiophen-2-yl)vinyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((3-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-((5-(difluoromethyl) thiophen-2-yl)ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methyloxazol-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(4-(3-fluoro-4-sulfamoylbenzyl)-5-((1-methylcyclopropyl) methyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-(trifluoromethyl)thiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-((3,5-dimethylthiophen-2-yl)ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-isopropylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylpropan-2-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylfuran-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(2-(5-methylthiophen-2-yl)cyclopropyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-5-(spiro[2.2] pentan-1-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((cis)-3-(5-methylthiophen-2-yl)cyclobutyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(3-(5-methylthiophen-2-yl)cyclobutyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-([1, 1′-bi (cyclopropan)]-2-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3′,4′,6-trifluoro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′,6-difluoro-4′-methyl-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4-chloro-6-fluoro-[1, 1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-acetyl-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-3′-methyl-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-isopropyl-[1, 1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5,6,7,8-tetrahydronaphthalen-2-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-chloro-3′,6-difluoro-[1,l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-(pyrrolidine-1-carbonyl) phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(tert-butylcarbamoyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-(4,5-dihydrofuran-2-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methoxy-3′-methyl-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-3′,5′-dimethyl-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-benzamido-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-3′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(2-oxopyrrolidin-1-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-(2,3-dihydro-1H-inden-5-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3′,5′,6-trifluoro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′,5′-dichloro-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(6-isopropyl-2,6-diazaspiro[3.3] heptan-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1H-imidazol-2-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(1H-benzo[d] imidazol-2-yl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(2-methyl-1H-imidazol-5-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((5-methylthiophen-2-yl) ethynyl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxamide,
2-(3-(4′-chloro-3′-fluoro-[1,r-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-methoxy-3 ‘-methyl-[1,1’-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-chloro-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-fluoro-4′-methyl-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-isopropyl-[11,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-chloro-4′-methoxy-[1,l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 ‘-isopropyl-[1,1’-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(5,6,7,8-tetrahydronaphthalen-2-yl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-chloro-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid,
2-(3-(4′-cyano-[1, l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4′-(dimethylamino)-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-ethyl-4′-methoxy-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-cyclopropyl-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-cyclobutyl-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-chloro-6-fluoro-3′-methyl-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-ethyl-6-fluoro-4′-methoxy-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-(2,2,2-trifluoroethyl)-[1, 1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(tert-butylcarbamoyl) phenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(1H-benzo[d] imidazol-2-yl) phenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4′-(dimethylamino)-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-chloro-6-fluoro-4′-methoxy-[1,l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-(tert-butyl)-6-fluoro-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-(tert-butyl)-6-fluoro-[1,l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-(dimethylamino)-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4′, 6-difluoro-3′-methyl-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′,6-difluoro-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-(4,5-dihydrofuran-2-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-methyl-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-3′-isopropyl-[1, l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3′-cyano-6-fluoro-[1,l′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-cyano-6-fluoro-[1,1′-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(2-oxopyrrolidin-1-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(5-methylpyridin-2-yl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(6-methylpyridin-3-yl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-(perfluoroethyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-isopropyl-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-isobutyl-[1, l′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-(5-methylthiophen-2-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-(5-methylthiophen-2-yl)-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[5-(4-isopropylphenyl) pyridin-3-yl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[6-(4-isopropylphenyl)pyridin-2-yl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-{3-[3-(4-cyclopropyl-3-fluorophenyl)-4-fluorophenyl]-5-(cyclopropyhnethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl] pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-3-[4-fluoro-3-(4-isopropyl-3-methylphenyl)phenyl]-4-[(3-fluoro-4-sulfamoylphenyl)methyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[3-(2-methylpyrimidin-5-yl) phenyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[3-(5-isopropyl-1,3-thiazol-2-yl)phenyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[3-(5-isopropylpyrimidin-2-yl)phenyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[3-(5-methylpyrimidin-2-yl)phenyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylicacid,
2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl) methyl]-3-[3-(5-isopropylpyridin-2-yl)phenyl] pyrazol-1-yl]-1,3-thiazole-4-carboxylicacid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-(2,3-dihydro-1H-inden-5-yl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(1H-benzo[d] imidazol-2-yl) phenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(4′-cyclopropyl-[1,r-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-ethyl-6-fluoro-4′-methoxy-[1,l′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-(perfluoroethyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-(perfluoroethyl)-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-isobutyl-[1,l′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-isobutyl-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid),
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4′-hydroxy-3 ‘-methyl-[1,1’-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-fluoro-4′-hydroxy-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3′-fluoro-4′-isopropyl-[1,1′-biphenyl]-3-yl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(6-((5-methylthiophen-2-yl) ethynyl) pyridin-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylfuran-2-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(5-((5-methylthiophen-2-yl) ethynyl) thiophen-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiazol-2-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((2-methylthiazol-5-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((2-methylthiazol-4-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-((5-methylthiophen-2-yl) ethynyl) thiophen-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-3-(3-((2,5-dimethylthiophen-3-yl) ethynyl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-3-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-3-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(3-((2,5-dimethylthiophen-3-yl) ethynyl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(2-(5-methylthiophen-2-yl)-2-oxoethyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((2-methylthiazol-4-yl) ethynyl) phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(2-cyclopropylethyl)-3-(3-((5-cyclopropylthiophen-2-yl) ethynyl) phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-((5-cyclobutylthiophen-2-yl) ethynyl) phenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-((5-cyclobutylthiophen-2-yl) ethynyl) phenyl)-5-(2-cyclopropylethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)oxazole-4-carboxylic acid,
2-(5-(3-cyclopropylpropyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-((5-methylthiophen-2-yl)ethynyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((5-methylthiophen-2-yl)ethynyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methyl-[1,l′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(5-(cyclopropylmethyl)-4-(2-fluoro-4-sulfamoylbenzyl)-3-(4′-methyl-[1,l′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
2-(3-(3-(cyclopentylethynyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,
or a pharmaceutically acceptable salt of any of the foregoing.