# US 10,766,863 B2 · Monocarboxylate transport modulators and uses thereof

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- Number: US 10,766,863 B2
- Document ID: US10766863B2
- Status: Granted
- Kind: B2
- Application number: 15/527,137
- Filed: 2015-11-17
- Published: 2018-10-11
- Granted: 2020-09-08
- Earliest claimed: 2014-11-17
- Assignees: Nirogyone Therapeutics, Inc.
- Applicants: Nirogyone Therapeutics, Inc.
- Inventors: Vincent Sandanayaka; Qiong Wu
- Web page: https://patentgrep.com/patent/US10766863B2

## CPC

- C07D 215/56: with oxygen atoms in position 4
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention generally relates to the field of monocarboxylate transport modulators, e.g., monocarboxylate transport inhibitors, and more particularly to new substituted-quinolone compounds, the synthesis and use of these compounds and their pharmaceutical compositions, e.g., in treating, modulating, forestalling and/or reducing physiological conditions associated with monocarboxylate transport activity such as in treating cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth and fibrosis including cardiomyopathy, obesity, diabetes, cardiovascular diseases, tissue and organ transplant rejection, and malaria.

## Claims

### Claim 1

A compound having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
1) n is 0; W is a bond; X is CH2; and
B is selected from:
or
2) n is 1; W is a bond; X is —NCH3; and
B is selected from:
R1 is selected from the group consisting of halogen, —CHF2, —CF3, —NO2, —CN, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, —C(O)N(OR″)R″ and
R4 is selected from the group consisting of
(a) —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, or —N(OR″)R″; and
(b) a group selected from
(1)
(2) a 3-8 membered saturated or partially unsaturated cycloalkyl ring,
(3) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
(4) phenyl, and
(5) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
R″ is hydrogen or an optionally substituted group selected from:
(a) C1-6 alkyl or C3-6 cycloalkyl;
(b) a 3-8 membered saturated or partially unsaturated cycloalkyl ring formed from two R″;
(c) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring formed from two R″ having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
(d) phenyl; and
(e) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
or
3) n is 0; W is C(O);
X is —NR5— or —CH2—, wherein R5 is hydrogen or C1-C3 alkyl;
B is selected from the group consisting of phenyl; phenyl substituted with halogen, C1-C3 alkoxy, and trifluoromethyl; cyclohexyl; thiazolyl; oxazolyl; di(C1-C3 alkyl)pyrazolyl; thiophenyl; tetrahydropyranyl; pyridinyl; and N-(C1-C3 alkyl)piperidinyl;
R1 is halogen, trifluoromethyl, cyano, or
wherein
represents azetidinyl, pyrrolidinyl, piperidinyl or azepinyl; and
R4 is selected from the group consisting of:

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R4 is selected from:

### Claim 3 (depends on 2)

A compound according to claim 2, wherein R1 is —F or

### Claim 4 (depends on 1)

A compound according to claim 1, wherein n is 1; W is a bond; X is —NCH3; B is selected from:

### Claim 5 (depends on 4)

A compound according to claim 4, wherein, R4 is selected from:

### Claim 6 (depends on 5)

A compound according to claim 5, wherein R1 is —F or

### Claim 7 (depends on 1)

A compound according to claim 1, wherein the compound has the formula
wherein:
X is —N(C1-C3 alkyl)— or —CH2—;
R1 is halogen, trifluoromethyl, cyano, or
and
B is slected from:

### Claim 8 (depends on 7)

A compound according to claim 7 wherein the compound has the formula
wherein
R1 F; and
B is selected from:

### Claim 9 (depends on 1)

A compound according to claim 1, selected from the group consisting of:

### Claim 10 (depends on 1)

A method for inhibiting monocarboxylate transport comprising contacting a monocarboxylate transporter with an effective amount of a compound according to claim 1.

### Claim 11 (depends on 1)

A method for treating a disorder associated with monocarboxylate transport comprising administering a therapeutically effective amount of a compound according to claim 1.

### Claim 12 (depends on 11)

A method according to claim 11, wherein the disorder is chosen from cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth, metabolic disorders, diabetes, obesity, malaria, and tissue and organ rejection.