Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10351532-B2
Application number	US-201515540893-A
Country	US
Kind code	B2
Filing date	Dec 29, 2015
Priority date	Dec 29, 2014
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

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 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, —C(O)R 4 , —CH 2 OH, —C(O)NHCN, —C(O)NHSO 2 H, —C(S)R 4 , —CO 2 R 4 , —C(O)NR 5 R 6 , —(C 1 -C 8 hydrocarbyl), —C(O)NHOH, —C(O)OCR 5 R 6 OC(O)OR 4 , —P(O)(OH) 2 , —B(OR 13 )(OR 14 ), —SO 2 (OH), —C(O)NHS(O) 2 Me, —SO 2 NR 5 R 6 —(C 0 -C 4 hydrocarbyl)(mono- or bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), and —C(O)O—(C 0 -C 4 hydrocarbyl)(mono- or bicyclic heterocycle having 1 to 4 heteroatoms independently chosen from N, O, and S), each of which R 1 except halo, —P(O)(OH) 2 , and —SO 2 (OH), is substituted or unsubstituted;
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 (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;
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 , —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
two R 3 moieties and the phenyl group to which they are attached form a naphthyl group or its heterocyclic analog that is optionally substituted;
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, 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, halo, —CN, —NO 2 , —CO 2 R 4 , —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—, —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 prodrug or pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein
R 1 is independently chosen from hydroxyl, halo, —CO 2 H, —SO 2 NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl optionally substituted with halo, C 1 -C 2 haloalkoxy, and —CO 2 (C 1 -C 6 alkyl),
R 2 is chosen from F and —SO 2 NH 2 , where one of R 2 is —SO 2 NH 2 ;
R 3 is independently chosen from
(a) halogen, hydroxyl, SF 5 ;
(b) C 1 -C 6 hydrocarbyl where any alkylene (CH 2 ) group in the hydrocarbyl chain is optionally replaced with NH, O, or S;
(c) —C 0 -C 2 hydrocarbyl (phenyl), —C 0 -C 2 hydrocarbyl (phenyl), —C 0 -C 2 hydrocarbyl (thiophenyl), —C 0 -C 2 hydrocarbyl (oxazolyl), —C 0 -C 2 hydrocarbyl(thiazolyl), —C 0 -C 2 hydrocarbyl (tetrahydrofuranyl), —C 0 -C 2 hydrocarbyl(C 3 -C 6 cycloalkyl), —C 0 -C 2 hydrocarbyl(C 3 -C 6 cycloalkyl), —C 0 -C 2 hydrocarbyl(C 3 -C 6 cycloalkanyl), —C 0 -C 2 hydrocarbyl(C 3 -C 6 cycloalkenyl), —C 0 -C 2 hydrocarbyl (tetrahydropyrenyl), —C 0 -C 2 hydrocarbyl (imidazolyl), —C 0 -C 2 hydrocarbyl(thiophenyl), where any alkylene (CH 2 ) group in the C 0 -C 2 hydrocarbyl chain is optionally replaced with NH, O, or S;
where each of (b) is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, amino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
where each of (c) is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, amino, C 1 -C 4 alkyl, C 1 -C 6 cycloalkyl, mono- or di-C 1 -C 4 alkylamino, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

3. The compound or salt of claim 2 , wherein one of 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 and n is 1.

4. The compound or salt of claim 2 , wherein each R 3 is independently halo, C 1 -C 8 haloalkyl, C 3 -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, and m is 1 or 2.

5. The compound or salt of claim 4 , wherein X 1 is —CH 2 — and X 2 is —S.

6. The compound or salt of claim 1 , wherein only one of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is N.

7. The compound or salt of cla

Assignees

• 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D403/04

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

• C07D417/04

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