Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11247971-B2
Application number	US-202117160868-A
Country	US
Kind code	B2
Filing date	Jan 28, 2021
Priority date	Dec 29, 2014
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

Provided is a compound of formula (I),in which Ar1, R1, 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 of formula (Ia):

wherein
Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently CH or N;
R 1 is independently chosen from halo, —CO 2 R 4 , —CONH 2 , —C(O)NHOH, —P(O)(OH) 2 , —B(OR 13 )(OR 14 ), —SO 2 (OH), —SO 2 NR 5 R 6 , —(C 1 -C 8 alkylene)OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, d-C 2 haloalkyl, C 1 -C 2 haloalkoxy, heteroaryl, and —C(O)O— heteroaryl, each of which R 1 except hydrogen, halo, —P(O)(OH) 2 , —CONH 2 , and —SO 2 (OH), is substituted or unsubstituted;
R 2 is independently chosen from hydroxyl, halo, —CN, —NO 2 C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, —O—C 3 -C 6 cycloalkyl, C 6 -C 12 aryl, —O—C 6 -C 12 aryloxy, —(CH 2 ) q aryl, —(CH 2 ) q heteroaryl, —(CH 2 ) q heterocycloalkyl, —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 (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 , and —(CH 2 ) q SO 2 R 4 , each of which R 2 except hydrogen, hydroxyl, halo, —CN, —NO 2 , SF 5 , is substituted or unsubstituted;
R 3 is independently chosen from hydroxyl, halo, —CN, —NO 2 , SF 5 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 alkenynyl, C 1 -C 8 alkoxy, —(CH 2 ) q C 3 -C 8 cycloalkyl, —O(CH 2 ) q C 3 -C 8 cycloalkyl, —(CH 2 ) q C 3 -C 8 cycloalkenyl, —(C 2 -C 4 alkynyl)(C 3 -C 6 cycloalkenyl), —(CH 2 ) q C 6 -C 12 aryl, —O(CH 2 ) q C 6 -C 12 aryl, —(CH 2 ) q heteroaryl, —O(CH 2 ) q heteroaryl, —(C 2 -C 4 alkenyl)heteroaryl, —(C 2 -C 4 alkynyl)heteroaryl, —(CH 2 ) q heterocycloalkenyl, —O(CH 2 ) q (heterocyloalkenyl, —(C 2 -C 4 alkenyl)heterocycloalkenyl, —(C 2 -C 4 alkynyl)heterocycloalkenyl, —(CH 2 ) q heterocycloalkyl, —O(CH 2 ) q heterocycloalkyl, —(C 2 -C 4 alkenyl)heterocycloalkyl, and —(C 2 -C 4 alkynyl)heterocycloalkyl, each of which R except hydrogen, hydroxyl, halo, —CN, —NO 2 , and SF 5 is substituted or unsubstituted;
each R 4 , R 5 , and R 6 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, heteroaryl, or heterocycloalkyl, each of which R 4 , R 5 , and R 6 except H is substituted or unsubstituted;
each 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, C 6 -C 12 aryl, C 1 -C 12 heteroaryl, or C 1 -C 12 heterocycloalkyl, each of which C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 12 aryl, C 1 -C 12 heteroaryl, or C 1 -C 12 heterocycloalkyl is substituted or unsubstituted;
R 10 is hydrogen, —CN, hydroxyl, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, —(C 0 -C 2 alkyl)NR 5 R 6 , —(C 0 -C 2 alkyl)C 3 -Cecycloalkyl, —C≡C(C 3 -C 6 cycloalkyl) —(C 0 -C 2 alkyl)C 6 -C 12 aryl, —(C 0 -C 2 alkyl)heterocycloalkyl, or —(C 0 -C 2 alkyl)heteroaryl, each of which R 10 except hydrogen, hydroxyl, and halo is substituted or unsubstituted;

or pharmaceutically acceptable salt thereof; and
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—, —SO 2 —, or —S—;
m, n, and q are the same or different and each is 0, 1, 2, 3, 4, or 5; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:
R 1 is independently chosen from halo, hydroxyl, —CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CO 2 R 4 , —CH 2 OH, —CHCF 3 OH, —C(CF 3 ) 2 OH, —C(O)NHOH, —P(O)(OH) 2 , —B(OR 13 )(OR 14 ), —SO 2 (OH), —SO 2 NR 5 R 6 , —C(O)O-2,3-dihydro-1H-indenyl, —C(O)O-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, 1,3,4-oxadiazol-2(3H)-one, isoxazol-3(2H)-one, and tetrazolyl, each of which R 1 except hydrogen, halo is substituted or unsubstituted;
R 2 is independently chosen from halo, C 1 -C 4 alkyl C 1 -C 4 alkoxy and —(CH 2 ) q SO 2 NR 5 R 6 , where one of R 2 is —(CH 2 ) q SO 2 NR 5 R 6 ;
R 3 is independently chosen from hydroxyl, halo, —CN, —NO 2 , SF 5 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 alkenynyl, C 1 -C 8 alkoxy, —(CH 2 ) q C 3 -C 8 cycloalkyl, —O(CH 2 ) q C 3 -C 6 cycloalkyl, —(CH 2 ) q C 3 -C 6 cycloalkenyl, —(C 2 -C 4 alkynyl)(C 3 -C 6 cycloalkenyl), —(CH 2 ) q C 6 -C 12 phenyl, —O(CH 2 ) q C 6 -C 12 phenyl, —(CH 2 ) q heteroaryl, —O(CH 2 ) q heteroaryl, —(C 2 -C 4 alkenyl)heteroaryl, and —(C 2 -C 4 alkynyl)heteroaryl, where the heteroaryl group is a oxazolyl, thienyl, thiazolyl, furanyl, pyrazolyl, or imidazolyl group; —(CH 2 ) q heterocycloalkenyl, —O(CH 2 ) (heterocyloalkenyl, —(C 2 -C 4 alkenyl)heterocycloalkenyl, —(C 2 -C 4 alkynyl)heterocycloalkenyl, where the heterocycloalkenyl is dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, or dihydropyridinyl, —(CH 2 ) heterocycloalkyl, —O(CH 2 ) q heterocycloalkyl, —(C 2 -C 4 alkenyl)heterocycloalkyl, —(C 2 -C 4 alkynyl)heterocycloalkyl, where the heterocycloalkyl is tetrahydropyranyl, tetrahydrofuranyl, piperazinyl, piperidinyl, or pyrrolidinyl, each of which R except hydrogen, hydroxyl, halo, —CN, —NO 2 , and SF 5 is substituted or unsubstituted;
each R 4 , R 5 , and R 6 is the same or different and each is H or C 1 -C 8 alkyl, wherein C 1 -C 8 alkyl is substituted or unsubstituted;
R 10 is hydrogen, —OH, halo, —CH 2 OH, —CN, —CH 2 CN, —NH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, —(C 0 -C 3 alkyl)-cyclopropyl, —(C 0 -C 3 alkyl)-cyclobutyl, —C≡C-cyclopropyl, —C≡C-cyclobutyl phenyl, benzyl, or —CH 2 -tetrazolyl, each of which cyclopropyl, —(C 1 -C 3 alkyl)-cyclopropyl, —CH═CH 2 , —C≡C-cyclopropyl, phenyl, or benzyl is substituted or unsubstituted; and
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.

3. The compound of claim 1 , wherein n is 1.

4. The compound of claim 1 , wherein m is 1 or 2.

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

6. The compound of claim 1 , wherein X is —S—.

7. The compound of claim 1 , wherein the compound is a compound of formula (Ia-1)

wherein:
R a is —R 4 , —OR 4 , or —NR 5 R 6 , each of which is substituted or unsubstituted;
R b and R c are the same or different and each is H or substituted or unsubstituted C 1 -C 8 alkyl;
R 2 is independently chosen from hydroxyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, C 3 -C 6 cycloalkyloxy, aryloxy, halo, C 1 -C 8 haloalkoxy, C 1 -C 8 haloalkyl, haloaryl, haloaryloxy, —CN, —NO 2 , —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 (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, and —(CH 2 ) 2 heterocycloalkyl, each of which R except hydroxyl and halo is substituted or unsubstituted;
one of R 3 is selected from C 2 -C 6 alkynyl, —(C 0 -C 2 alkyl)C 3 -C 6 cycloalkyl, —(C 4 -C 4 alkenyl)C 3 -C 6 cycloalkyl, —(C 2 -C 4 alkynyl)C 3 -C 6 cycloalkyl, —(C 0 -C 2 alkoxy)C 3 -C 6 cycloalkyl, dihydropyranyl, —(C 0 -C 4 alkoxy)phenyl, —(C 0 -C 4 alkyl)phenyl, —(C 2 -C 4 alkenyl)phenyl, —(C 2 -C 4 alkynyl)phenyl, —(C 0 -C 4 alkoxy)heteroaryl, —(C 0 -C 4 alkyl)heteroar

Assignees

• Us Health
• Univ Vanderbilt
• Uab Res Found
• Univ Pennsylvania

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

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D401/04

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

• C07D413/04

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

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D403/04

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