US 11,897,845 B2
Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
David J. Maloney, Point of Rocks, MD (US); Alex Gregory Waterson, Nashville, TN (US); Ganesh Rai Bantukallu, Arlington, VA (US); Kyle Ryan Brimacombe, Bethesda, MD (US); Plamen Christov, Nashville, TN (US); Chi V. Dang, Penn Valley, PA (US); Victor Darley-Usmar, Birmingham, AL (US); Xin Hu, Frederick, MD (US); Ajit Jadhav, Chantilly, VA (US); Somnath Jana, Nashville, TN (US); Kwangho Kim, Nashville, TN (US); Jennifer L. Kouznetsova, Silver Spring, MD (US); William J. Moore, Hagerstown, MD (US); Bryan T. Mott, College Park, MD (US); Leonard M. Neckers, Bethesda, MD (US); Anton Simeonov, Bethesda, MD (US); Gary Allen Sulikowski, Nashville, TN (US); Daniel Jason Urban, Rockville, MD (US); and Shyh Ming Yang, Doylestown, PA (US)
Assigned to THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, Bethesda, MD (US); VANDERBILT UNIVERSITY, Nashville, TN (US); THE UAB RESEARCH FOUNDATION, Birmingham, AL (US); and THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA (US)
Filed by THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, Bethesda, MD (US); VANDERBILT UNIVERSITY, Nashville, TN (US); The UAB Research Foundation, Birmingham, AL (US); and The Trustees of the University of Pennsylvania, Philadelphia, PA (US)
Filed on Jan. 10, 2022, as Appl. No. 17/572,359.
Application 17/572,359 is a continuation of application No. 17/160,868, filed on Jan. 28, 2021, granted, now 11,247,971.
Application 17/160,868 is a continuation of application No. 16/455,848, filed on Jun. 28, 2019, granted, now 10,961,200.
Application 16/455,848 is a continuation of application No. 15/540,893, granted, now 10,351,532, previously published as PCT/US2015/067895, filed on Dec. 29, 2015.
Claims priority of provisional application 62/097,226, filed on Dec. 29, 2014.
Prior Publication US 2022/0220078 A1, Jul. 14, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 231/20 (2006.01); C07D 231/38 (2006.01); C07D 401/04 (2006.01); C07D 403/04 (2006.01); C07D 403/06 (2006.01); C07D 409/04 (2006.01); C07D 413/04 (2006.01); C07D 417/04 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 495/04 (2006.01); C07D 495/14 (2006.01); A61K 31/415 (2006.01); A61K 31/4155 (2006.01); A61K 31/422 (2006.01); A61K 31/427 (2006.01); A61K 31/437 (2006.01); A61K 31/4439 (2006.01); A61K 31/454 (2006.01); A61K 31/496 (2006.01); A61K 31/501 (2006.01); A61K 31/506 (2006.01); A61K 31/519 (2006.01); A61K 31/5355 (2006.01); A61K 45/06 (2006.01); A61K 31/4178 (2006.01)
CPC C07D 231/20 (2013.01) [A61K 31/415 (2013.01); A61K 31/4155 (2013.01); A61K 31/4178 (2013.01); A61K 31/422 (2013.01); A61K 31/427 (2013.01); A61K 31/437 (2013.01); A61K 31/4439 (2013.01); A61K 31/454 (2013.01); A61K 31/496 (2013.01); A61K 31/501 (2013.01); A61K 31/506 (2013.01); A61K 31/519 (2013.01); A61K 31/5355 (2013.01); A61K 45/06 (2013.01); C07D 231/38 (2013.01); C07D 401/04 (2013.01); C07D 403/04 (2013.01); C07D 403/06 (2013.01); C07D 409/04 (2013.01); C07D 413/04 (2013.01); C07D 417/04 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 495/04 (2013.01); C07D 495/14 (2013.01)] 19 Claims
 
1. A compound or salt of formula (Ib):

OG Complex Work Unit Chemistry
wherein
R1 is independently chosen from halo, —CO2R4, —C(O)NR5R6, —(C1-C8hydrocarbyl), —C(O)NHOH, —C(O)OCR5R6OC(O)OR4, —(C0-C4hydrocarbyl)((mono- or bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —C(O)O—(C0-C4hydrocarbyl)(mono- or bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —P(O)(OH)2, —B(OR13)(OR14), —SO2(OH), —C(O)NHS(O)2Me and —SO2NR5R6, each of which R1 except halo is substituted or unsubstituted;
R2 is independently chosen from hydroxyl, halo, —CN, —NO2, C1-C8hydrocarbyl, —O(C1-C8hydrocarbyl), —(C0-C4hydrocarbyl)C3-C8cycloalkyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —(C0-C4hydrocarbyl)C3-C8cycloalkenyl, —O(C0-C4hydrocarbyl)C3-C8cycloalkenyl, —O(C0-C4hydrocarbyl)C6-C12aryl, —(C0-C4hydrocarbyl)C6-C12aryl, —O(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —C(O)R4, —CO2R4, —C(O)NR5R6, —NR5C(O)R4, —(CH2)qNR5(SO2)R4, —(CH2)qNR5C(O)R4, —(CH2)qNR7C(O)NR5R6, —(CH2)qNR5R6, —(CH2)qSO2NR5R6, —(CH2)qSO2R4, —(CH2)qaryl, —(CH2)qheteroaryl, or —(CH2)qheterocycloalkyl, each of which C1-C8hydrocarbyl, —O(C1-C8hydrocarbyl), —(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C6-C12aryl, —(C0-C4hydrocarbyl)C6-C12aryl, —O(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S) is substituted or unsubstituted;
R3 is independently chosen from hydroxyl, halo, —CN, —NO2, —SF5, C1-C8hydrocarbyl, —O(C1-C8hydrocarbyl), —(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C6-C12aryl, —(C0-C4hydrocarbyl)C6-C12aryl, —O(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —C(O)R4, —CO2R4, —C(O)NR5R6, —NR5C(O)R4, —(CH2)qNR5(SO2)R4, —(CH2)qNR5C(O)R4, —(CH2)qNR7C(O)NR5R6, —(CH2)qNR5R6, —(CH2)qSO2NR5R6, —(CH2)qSO2R4, each of which C1-C8hydrocarbyl, —O(C1-C8hydrocarbyl), —(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C6-C12aryl, —(C0-C4hydrocarbyl)C6-C12aryl, —O(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S) is substituted or unsubstituted; or
each R4, R5, R6, R7, R8, and R9 is the same or different and each is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, each of which C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted or unsubstituted;
R10 is hydrogen, halo, —CN, —NO2, —CO2R4, —C(O)NR5R6, —NR5(SO2)R4, —NR5C(O)R4, —NR7C(O)NR5R6, —NR5R6, —SO2NR5R6, —SO2R4, C1-C8hydrocarbyl, —O(C1-C8hydrocarbyl), —(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkyl, —(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C3-C8 cycloalkenyl, —O(C0-C4hydrocarbyl)C6-C12aryl, —(C0-C4hydrocarbyl)C6-C12aryl, —O(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C0-C4hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), each of which R10 except hydrogen, halo, —CN, and —NO2 is substituted or unsubstituted;
each R13 and R14 is the same or different and each is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C12 aryl, wherein R13 and R14 are optionally connected to each other to form a ring;
X1 is a bond, —CR8R9—, —NR5—, —CR8NR5—, —NR5CR8—, —NR5C(O)—, —O—, —CO—, —SO—, —SO2—, or —S—;
X2 is —NR5—, —O—, or —SO2—, or —S—;
X3 is CH or N;
n is an integer from 1-5;
m is an integer from 1-5;
o is 0 or an integer from 1-5; and
p is 1 or 2.