Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12365653-B2
Application number	US-202418433099-A
Country	US
Kind code	B2
Filing date	Feb 5, 2024
Priority date	Dec 29, 2014
Publication date	Jul 22, 2025
Grant date	Jul 22, 2025

Abstract

Provided is a compound of formula (I)

in which Ar 1 , R 1 , U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

First claim

The invention claimed is:

1. The compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia-1)

wherein
R 2 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, or halo;
R 3 is halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or substituted or unsubstituted phenyl;
R 10 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted —CH 2 -cyclopropyl, —CH 2 CH 2 -cyclopropyl, substituted or unsubstituted —CH═CH 2 , substituted or unsubstituted —C≡C-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, —I, —CF 3 , —NH 2 , or —CN;
n is an integer from 0 to 3; and
m is 0 or an integer from 1-5.

2. The compound or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, of claim 1 , wherein m is 0 and 1 or 2.

3. The compound or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, of claim 1 , wherein R 2 is halogen and n is 1.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —CH 2 -cyclopropyl.

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is

6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is

7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is

8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is

9. A pharmaceutical composition comprising a compound or pharmaceutically acceptable thereof of claim 1 , and a pharmaceutically acceptable excipient.

10. A method of inhibiting lactate dehydrogenase A (LDHA) activity in a cell comprising contacting the cell with a compound of claim 1 , whereby activity of LDHA in the cell is inhibited.

11. A method of treating fibrosis or cancer in a patient, comprising administering to the patient an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein method is a method for treating idiopathic pulmonary fibrosis in a patient.

Assignees

• Us Health
• Univ Vanderbilt
• Uab Res Found
• Univ Pennsylvania
• The Us Secretary Department Of Health And Human Servic

Inventors

• Maloney David J
• Waterson Alex Gregory
• Bantukallu Ganesh Rai
• Brimacombe Kyle Ryan
• Christov Plamen
• Dang Chi V
• Darley-Usmar Victor
• Hu Xin
• Jadhav Ajit
• Jana Somnath
• Kim Kwangho
• Kouznetsova Jennifer L
• Moore William J
• Mott Bryan T
• Neckers Leonard M
• Simeonov Anton
• Sulikowski Gary Allen
• Urban Daniel Jason
• Yang Shyh Ming

Classifications

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title