# US 11,897,845 B2 · Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,897,845 B2
- Document ID: US11897845B2
- Status: Granted
- Kind: B2
- Application number: 17/572,359
- Filed: 2022-01-10
- Published: 2022-07-14
- Granted: 2024-02-13
- Earliest claimed: 2014-12-29
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services; Vanderbilt University; The UAB Research Foundation; The Trustees of the University of Pennsylvania
- Applicants: The United States of America, AS Represented By the Secretary, Department of Health and Human Services; Vanderbilt University; The UAB Research Foundation; The Trustees of the University of Pennsylvania
- Inventors: David J. Maloney; Alex Gregory Waterson; Ganesh Rai Bantukallu; Kyle Ryan Brimacombe; Plamen Christov; Chi V. Dang; Victor Darley-Usmar; Xin Hu; Ajit Jadhav; Somnath Jana; Kwangho Kim; Jennifer L. Kouznetsova; William J. Moore; Bryan T. Mott; Leonard M. Neckers; Anton Simeonov; Gary Allen Sulikowski; Daniel Jason Urban; Shyh Ming Yang
- Web page: https://patentgrep.com/patent/US11897845B2

## CPC

- C07D 231/20: One oxygen atom attached in position 3 or 5
- A61K 31/415: 1,2-Diazoles
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5355: Non-condensed oxazines and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 495/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound or salt of formula (Ib):
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.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R10 is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, hydroxyl, hydroxyalkyl, halo, C1-C8 haloalkyl, —CN, cyanoalkyl, —NR5R6, or substituted or unsubstituted heteroarylalkyl.

### Claim 3 (depends on 2)

The compound or salt of claim 2, wherein R10 is substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted —(C1-C3 alkyl)-cyclopropyl, substituted or unsubstituted —CH═CH2, substituted or unsubstituted —C≡C-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, —OH, —CH2OH, —CF3, —CF2CF3, —Cl, —F, —I, —CN, —CH2CN, —NH2, or —CH2-tetrazolyl.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein R1 is —CO2H or —CO2(C1-C8 alkyl), wherein the C1-C8 alkyl is substituted or unsubstituted.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein R5 and R6 are the same or different and each is H or C1-C8 alkyl.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein each R3 is independently halo, C1-C8 haloalkyl, C1-C8 haloalkoxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted —(CH2)qaryl, substituted or unsubstituted —(CH2)qheteroaryl, or substituted or unsubstituted —(CH2)qheterocycloalkyl.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The compound or salt of claim 1, wherein X1 is —CR8R9—, —O—, or —NH—.

### Claim 9 (depends on 8)

The compound or salt of claim 8, wherein X1 is —CH2—.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein X2 is —S—.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein X3 is CH.

### Claim 12 (depends on 1)

The compounds of salt of claim 1, of formula (Ib-1)
wherein
Ra is hydroxyl or substituted or unsubstituted —O(C1-C8 alkyl);
Rb and Rc are hydrogen
each R2 is hydrogen;
each R3 is independently halo, C1-C8 haloalkyl, C1-C8 haloalkoxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted —(CH2)qaryl, substituted or unsubstituted —(CH2)qheteroaryl, or substituted or unsubstituted —(CH2)qheterocycloalkyl;
R10 is hydrogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted —CH═CH2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted —C≡C— cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted —C≡C— cyclobutyl, —OH, —CH2OH, —CF3, —CF2CF3, —Cl, —F, —I, —CN, —CH2CN, —NH2, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted —CH2-tetrazolyl; and
m is 1 or 2.

### Claim 13

A compound or salt of formula (Ib′):
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;
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 substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted —(C1-C3 alkyl)-cyclopropyl, substituted or unsubstituted —CH═CH2, substituted or unsubstituted —C≡C-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, —OH, —CH2OH, —CF3, —CF2CF3, —Cl, —F, —I, —CN, —CH2CN, —NH2, or —CH2-tetrazolyl;
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;
m is 0 or an integer from 1-5; and
p is 1 or 2.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 1)

A method of treating a patient with cancer cells resistant to an anti-cancer agent, comprising administering to the patient an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, whereby the compound, or the pharmaceutically acceptable salt thereof re-sensitizes the cancer cells to the anti-cancer agent.

### Claim 17 (depends on 12)

A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 12 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 12)

A method of treating fibrosis or cancer in a patient comprising administering to the patient an effective amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 12)

A method of treating a patient with cancer cells resistant to an anti-cancer agent, comprising administering to the patient an effective amount of the compound of claim 12, or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, whereby the compound, or the pharmaceutically acceptable salt thereof re-sensitizes the cancer cells to the anti-cancer agent.