Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10961200-B2
Application number	US-201916455848-A
Country	US
Kind code	B2
Filing date	Jun 28, 2019
Priority date	Dec 29, 2014
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

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. A compound or salt of formula (Ib):

wherein
R 1 is CO 2 R 4 ;
R 2 is independently chosen from hydroxyl, halo, —CN, —NO 2 , C 1 -C 8 hydrocarbyl, —O(C 1 -C 8 hydrocarbyl), —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —O(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —C(O)R 4 , —CO 2 R 4 , —C(O)NR 5 R 6 , —NR 5 C(O)R 4 , —(CH 2 ) q NR 5 R(SO 2 )R 4 , —(CH 2 ) q NR 5 C(O)R 4 , —(CH 2 ) q NR 7 C(O)NR 5 R 6 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q SO 2 NR 5 R 6 , —(CH 2 ) q SO 2 R 4 , —(CH 2 ) q aryl, —(CH 2 ) q heteroaryl, or —(CH 2 ) q heterocycloalkyl, each of which C 1 -C 8 hydrocarbyl, —O(C 1 -C 8 hydrocarbyl), —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —O(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S) is substituted or unsubstituted;
R 3 is independently chosen from hydroxyl, halo, —CN, —NO 2 , —SF 5 , C 1 -C 8 hydrocarbyl, —O(C 1 -C 8 hydrocarbyl), —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —O(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —C(O)R 4 , —CO 2 R 4 , —C(O)NR 5 R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 4 , —(CH 2 ) q NR 5 (SO 2 )R 4 , —(CH 2 ) q NR 5 C(O)R 4 , —(CH 2 ) q NR 7 C(O)NR 5 R 6 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q SO 2 NR 5 R 6 , —(CH 2 ) q SO 2 R 4 , each of which C 1 -C 8 hydrocarbyl, —O(C 1 -C 8 hydrocarbyl), —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —O(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S) is substituted or unsubstituted; or
each R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is the same or different and each is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, each of which C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted or unsubstituted;
R 10 is hydrogen, halo, —CN, —NO 2 , —C(O)NR 5 R 6 , —NR 5 (SO 2 )R 4 , —NR 5 C(O)R 4 , —NR 7 C(O)NR 5 R 6 , —NR 5 R 6 , —SO 2 NR 5 R 6 , —SO 2 R 4 , C 1 -C 8 hydrocarbyl, —O(C 1 -C 8 hydrocarbyl), —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkyl, —(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 3 -C 8 cycloalkenyl, —O(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —(C 0 -C 4 hydrocarbyl)C 6 -C 12 aryl, —O(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), —(C 0 -C 4 hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), each of which R 10 except hydrogen, halo, —CN, and —NO 2 is substituted or unsubstituted;
each R 13 and R 14 is the same or different and each is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 12 aryl, wherein R 13 and R 14 are optionally connected to each other to form a ring;
X 1 is a bond, —CR 8 R 9 —, —NR 5 —, —CR 8 NR 5 —, —NR 5 CR 8 —, —NR 5 C(O)—, —O—, —CO—, —SO—, —SO 2 —, or —S—;
X 2 is —NR 5 —, —O—, or —SO 2 —, or —S—;
X 3 is CH or N;
m and q are the same or different and each is 0 or an integer from 1-5;
n is an integer from 1-5; and
p is 1 or 2.

2. The compound or salt of claim 1 , wherein R 10 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, hydroxyl, hydroxyalkyl, halo, C 1 -C 8 haloalkyl, —CN, cyanoalkyl, —NR 5 R 6 , or substituted or unsubstituted heteroarylalkyl.

3. The compound or salt of claim 2 , wherein R 10 is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted —(C 1 -C 3 alkyl)-cyclopropyl, substituted or unsubstituted —CH═CH 2 , substituted or unsubstituted —C≡C-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, —OH, —CH 2 OH, —CF 3 , —CF 2 CF 3 , —F, —I, —CN, —CH 2 CN, —NH 2 , or —CH 2 -tetrazolyl.

4. The compound or salt of claim 1 , wherein R 1 is —CO 2 H or —CO 2 (C 1 -C 8 alkyl), wherein the C 1 -C 8 alkyl is substituted or unsubstituted.

5. The compound or salt of claim 1 , wherein R 5 and R 6 are the same or different and each is H or C 1 -C 8 alkyl.

6. The compound or salt of claim 1 , wherein each R 3 is independently halo, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted —(CH 2 ) q aryl, substituted or unsubstituted —(CH 2 ) q heteroaryl, or substituted or unsubstituted —(CH 2 ) q heterocycloalkyl.

7. The compound or salt of claim 1 , wherein m is 0, 1, or 2.

8. The compound or salt of claim 1 , wherein X 1 is —CR 8 R 9 —, —O—, or —NH—.

9. The compound or salt of claim 8 , wherein X 1 is —CH 2 —.

10. The compound or salt of claim 1 , wherein X 2 is —S—.

11. The compound or salt of claim 1 , wherein X 3 is CH.

12. The compound or salt of claim 1 , wherein the compound is

13. The compound or salt of claim 1 , wherein the compound is

14. A compound or salt of claim 1 , wherein
R 1 is —CO 2 H or —CO 2 (C 1 -C 8 alkyl), wherein the C 1 -C 8 alkyl is substituted or unsubstituted;
R 2 is —SO 2 NR 5 R 6 and R 5 and R 6 are the same or different and each is H or C 1 -C 8 alkyl;
R 3 is halo, —C(O)R 4 , C 2 -C 8 alkynyl, halo

Assignees

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

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

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• C07D403/04

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

• C07D231/20 Primary

  One oxygen atom attached in position 3 or 5 · CPC title

• C07D401/04

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

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title