# US 8,541,587 B2 · Lysophosphatidic acid receptor antagonists

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- Number: US 8,541,587 B2
- Document ID: US8541587B2
- Status: Granted
- Kind: B2
- Application number: 13/439,495
- Filed: 2012-04-04
- Published: 2012-10-11
- Granted: 2013-09-24
- Earliest claimed: 2011-04-05
- Assignees: Amira Pharmaceuticals, Inc.
- Applicants: Thomas Jon Seiders; Jeffrey Roger Roppe; Timothy Andrew Parr
- Inventors: Thomas Jon Seiders; Jeffrey Roger Roppe; Timothy Andrew Parr
- Web page: https://patentgrep.com/patent/US8541587B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.

## Claims

### Claim 1

A compound having the structure of Formula (I), or N-oxide, or a pharmaceutically acceptable salt thereof:
wherein,
R1 is
and R3 is H or C1-C4alkyl;
or R1 is H or C1-C4alkyl and R3 is
R2 is —OH, —OC1-C4alkyl, or —NHSO2R7;
R7 is C1-C4alkyl or a substituted or unsubstituted phenyl;
R4 is absent or —OH;
R5 is absent or —OH;
each R6 is independently C1-C4alkyl, C1-C4deuteroalkyl, C1-C4monofluoroalkyl, C1-C4difluoroalkyl, or C3-C6cycloalkyl;
ring A is a substituted or unsubstituted monocyclic six-membered C3-C5heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 RA, each RA is independently halogen, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, or C1-C4alkoxy;
m is 1 or 2;
n is 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The compound of claim 1, N-oxide, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula (II):

### Claim 3 (depends on 2)

The compound of claim 2, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
R2 is —OH, —OCH3, —OCH2CH3, —NHSO2CH3 or —NHSO2CH2CH3;
R3 is —CH3 or —CH2CH3;
R4 is absent;
R5 is absent;
n is 1.

### Claim 4 (depends on 1)

The compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula (III):

### Claim 5 (depends on 4)

The compound of claim 4, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
R1 is —CH3 or —CH2CH3;
R2 is —OH, —OCH3, —OCH2CH3, —NHSO2CH3 or —NHSO2CH2CH3;
R4 is absent;
R5 is absent;
n is 1.

### Claim 6 (depends on 1)

The compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
ring A is

### Claim 7 (depends on 1)

The compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
R2 is —OH;
R4 is absent;
R5 is absent;
ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with RA;
m is 1;
n is 1.

### Claim 8 (depends on 1)

The compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula (IV), or a pharmaceutically acceptable salt thereof:
wherein,
X1 is CH, CRA or N;
X2 is CH, CRA or N; provided that at least one of X1 and X2 is N;
R2 is —OH, —OC1-C4alkyl, or —NHSO2R7;
R6 is C1-C4alkyl;
R7 is C1-C4alkyl.

### Claim 9 (depends on 8)

The compound of claim 8, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
X1 is N, and X2 is CH; or
X1 is CH; and X2 is N.

### Claim 10 (depends on 8)

The compound of claim 8, N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
R2 is —OH;
R6 is —CH3;
X1 is N, and X2 is CH; or
X1 is CH, and X2 is N.

### Claim 11 (depends on 1)

The compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure of Formula (V), or a pharmaceutically acceptable salt thereof:
wherein,
X1 is CH, CRA or N;
X2 is CH, CRA or N; provided that at least one of X1 and X2 is N;
R2 is —OH, —OC1-C4alkyl, or —NHSO2R7;
R6 is C1-C4alkyl;
R7 is C1-C4alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, or N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
X1 is N, and X2 is CH; or
X1 is CH; and X2 is N.

### Claim 13 (depends on 11)

The compound of claim 11, N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
R2 is —OH;
R6 is —CH3;
X1 is N, and X2 is CH; or
X1 is CH, and X2 is N.

### Claim 14 (depends on 10)

The compound of claim 10, N-oxide, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is a sodium salt.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A method of treating lung fibrosis, renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, and scleroderma, comprising administering a therapeutically effective amount of a compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

### Claim 17 (depends on 1)

A method of treating fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of claim 1, or N-oxide, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.

### Claim 18 (depends on 16)

The method of claim 16 further comprising administering to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agents, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and β-2 agonists.