US 11,752,138 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, Nashville, TN (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, Birmingham, AL (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 May 17, 2021, as Appl. No. 17/322,260.
Claims priority of provisional application 63/026,296, filed on May 18, 2020.
Prior Publication US 2021/0369683 A1, Dec. 2, 2021
Int. Cl. A61K 31/427 (2006.01); A61K 31/506 (2006.01); A61K 31/4439 (2006.01)
CPC A61K 31/427 (2013.01) [A61K 31/4439 (2013.01); A61K 31/506 (2013.01)] 22 Claims
 
1. A method of treating a disease or disorder associated with elevated oxalate levels in a patient comprising, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the patient:

OG Complex Work Unit Chemistry
wherein
the A ring,

OG Complex Work Unit Chemistry
 is phenyl or pyridyl;
X is hydrogen or a halogen;
Y is hydrogen or C1-C2alkyl;
Z is —CO2H, —CONH2, —CONH(CN), —CONHSO2CH3, —CONH(OH), —COCF3, CH(OH)CF3,
—CH2OH, or —B(OH)2;
n is 0, 1, 2, or 3;
R is independently chosen at each occurrence from halogen, hydroxyl, C1-C4alkyl, and C1-C4 alkoxy;
R3 is a —C(O)CH3, a substituted or unsubstituted phenyl group, a substituted or unsubstituted indanyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted cyclohexenyl group, a substituted or unsubstituted indenyl group, substituted or unsubstituted 2,6-diazaspiro[3.3]heptanyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted dihydrofuranyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted spiro[2.5]oct-5-enyl, a substituted or unsubstituted benzimidazolyl group, or
R3 is -L-Q, wherein L is an C2-C4alkynyl group, an ethylenylene group, a cyclopropylene group, or a cyclobutylene group, and wherein Q is hydrogen, a C1-C5alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted five-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S; or
R3 is —NR5C(O)R4 or —C(O)NR5R6, wherein R4 is hydrogen, C1-C5alkyl, or substituted or unsubstituted phenyl, and R5 and R6 are each independently hydrogen or C1-C5alkyl, wherein R5 and R6 optionally form a ring, and wherein R4 and R5 optionally form a ring; and R10 is hydrogen or (cyclopropyl)C0-C4alkyl, which cyclopropyl is optionally substituted with methyl or cyclopropyl or fused to a cyclopropyl group in spiro orientation, or R10 is (cyclopropyl)C1-C4alkyl in which the C1-C4alkyl is substituted with cyclopropyl.