# US 8,785,442 B2 · Compound as antagonist of lysophosphatidic acid receptor, composition, and use thereof

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- Number: US 8,785,442 B2
- Document ID: US8785442B2
- Status: Granted
- Kind: B2
- Application number: 13/982,456
- Filed: 2011-01-30
- Published: 2014-01-30
- Granted: 2014-07-22
- Earliest claimed: 2011-01-30
- Assignees: Curegenix, Inc.
- Applicants: Songzhu An; Chufang Li; Guisheng Zhou; Chen Huang
- Inventors: Songzhu An; Chufang Li; Guisheng Zhou; Chen Huang
- Web page: https://patentgrep.com/patent/US8785442B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 261/14: Nitrogen atoms
- C07D 261/16: Benzene-sulfonamido isoxazoles
- C07D 295/26: Sulfur atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a compound as antagonist of LPA receptor, and a pharmaceutical composition comprising the same. The present invention also relates to the use of the compound and the composition, and a method of using the compound to treat, prevent or diagnose diseases, disorders or conditions associated with one or more of the LPA receptors.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein,
when R4 is H, R1 is C(═O)R5 or SO2R5; or
R4 and NHR1, together with the two C atoms of the phenyl ring to which R4 and NHR1 are respectively attached, form a fused saturated, partially saturated or unsaturated 5-7 membered heterocycle which optionally contains 1-2 heteroatoms selected from N, O or S in addition to the N atom shown;
each R2 and R3 is independently selected from H, F, Cl, Br, CN, OH, or C1-C4alkyl;
R5 is C1-C6 alkyl, C1-C6 aryl, C1-C6 alkoxyl, C3-6 cycloalkyl, 5 or 6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S; 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, wherein C1-C6 alkyl, C1-C6 aryl, C1-C6 alkoxyl, C3-6 cycloalkyl, 5 or 6 membered heteroaryl and 5-6 membered heterocyclyl are optionally substituted with F, Cl, Br, I, —CN, —C(═O)—OH, —C(═O)—O—C1-6 alkyl, —S(═O)2—C1-6 alkyl;
each m and n is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound according to claim 1 having Formula (II)

### Claim 3 (depends on 1)

The compound according to claim 1, wherein an atom in any substituent group is H, 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 35S, 18F, 36I and/or 123I.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the compound is selected from:
1-(2-chlorophenyl)ethyl(5-(1H-indol-5-yl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(1H-indazol-5-yl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-acetamidophenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-propionamidophenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-isobutyramidophenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(cyclopropanecarboxamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(methyl(4-methylisoxazol-3-yl)phenyl)carbamate)carbamate;
methyl 3-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)amino)-3-oxopropanoate;
methyl 1-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)carbamoyl)cyclopropanecarboxylate;
1-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)carbamoyl)cyclopropanecarboxylic acid;
4-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)amino)-4-oxobutanoic acid;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(2-(methylsulfonyl)acetamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(2-cyanoacetamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(2-ethoxyacetamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-benzamidophenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(thiazole-2-carboxamido)phenyl)isoxazol-4-yl)carbamate;
4-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)carbamoyl)benzoic acid;
(R)-1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(ethylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(1-methylethylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(cyclopropanesulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(cyclohexanesulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(2,2,2-trifluoroethylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(morpholine-4-sulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(4-(1-ethylpiperidine-4-sulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
methyl 3-(N-(4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)sulfamoyl)propanoate;
3-(N-(4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)sulfamoyl)propanoic acid;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(phenylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(4-(pyridine-3-sulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(3-fluoro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(2-fluoro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(3,5-difluoro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(3-chloro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(5-(2-chloro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
1-(2-chlorophenyl)ethyl(3-methyl-5-(3-methyl-4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(3-chlorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(3-fluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(3,4-difluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(3,4-dichlorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(4-chlorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2-chloro-4-fluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(2,4-dichlorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
1-(4-chloro-2-fluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
(R)-1-(2-chloro-4-fluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
(R)-1-(2-chloro-4-fluorophenyl)ethyl(3-methyl-5-(4-(methylsulfonamido)phenyl)isoxazol-4-yl)carbamate;
(R)-1-(2-chlorophenyl)ethyl(5-(2-fluoro-4-(methylsulfonamido)phenyl)-3-methylisoxazol-4-yl)carbamate;
(R)-3-(N-(4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)sulfamoyl)propanoic acid;
(R)-3-(N-(4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)-3-fluorophenyl)sulfamoyl)propanoic acid;
(R)-4-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)phenyl)amino)-4-oxobutanoic acid; or
(R)-4-((4-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)-3-fluorophenyl)amino)-4-oxobutanoic acid.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable inactive ingredient.

### Claim 6 (depends on 5)

The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop.

### Claim 7 (depends on 6)

The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a tablet or gelatin capsule comprising the present compound together with a) diluents, selected from lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, selected from silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; c) binders, selected from magnesium aluminum silicate, starch paste, gelatin, tragamayth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; d) disintegrants, selected from starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.

### Claim 8 (depends on 6)

The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is aqueous isotonic solution or suspension.

### Claim 9 (depends on 6)

The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a suppository and may be prepared from a fatty emulsion or a suspension.