# US 7,612,099 B2 · Vinylogous acid derivatives

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

- Number: US 7,612,099 B2
- Document ID: US7612099B2
- Status: Granted
- Kind: B2
- Application number: 11/605,016
- Filed: 2006-11-28
- Published: 2007-06-07
- Granted: 2009-11-03
- Earliest claimed: 2005-12-01
- Assignees: Hoffmann-La Roche Inc.
- Inventors: David Banner; Hans Hilpert; Bernd Kuhn; Harald Mauser
- Web page: https://patentgrep.com/patent/US7612099B2

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention is concerned with vinylogous acids derivatives of formula (I) wherein A and R1 to R6 are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit chymase and can be used as medicaments.

## Claims

### Claim 1

A Compound of formula (I)
wherein
A is selected from the group consisting of —CH2—, —O— and —NR′—, wherein R′ is selected from the group consisting of hydrogen and C1-6 alkyl, or wherein R′ and R4 form C2-5 alkylene;
R1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, C1-6 alkyl, heteroalkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxy, C1-6 alkoxy, —NR′R″, —(C0-6 alkylene)-NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen, C1-6 alkyl, heteroalkyl, formyl, C1-6 alkylcarbonyl, optionally substituted C3-7 cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclylcarbonyl, C1-6 alkylsulfonyl, optionally substituted C3-7 cycloalkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl and optionally substituted heterocyclylsulfonyl, and —(C0-6 alkylene)-OR′, wherein R′ is selected from the group consisting of hydrogen, C1-6 alkyl, heteroalkyl, formyl and C1-6 alkylcarbonyl;
R2, R2′ and R2″ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, mono- or di-C1-6 alkyl substituted amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, heteroalkyl, hydroxy and C1-6 alkoxy;
R3 is selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, mono- or di-C1-6 alkyl substituted amino, C1-6 alky, C2-6 alkenyl, C2-6 alkynyl, heteroalkyl, hydroxy, C1-6 alkoxy, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C3-7 cycloalkyl-C1-6 alkyl, optionally substituted aryl-C1-6 alkyl, optionally substituted heteroaryl-C1-6 alkyl and optionally substituted heterocyclyl-C1-6 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, mono- or di-C1-6 alkyl substituted amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, heteroalkyl, hydroxy, C1-6 alkoxy, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C3-7 cycloalkyl-C1-6 alkyl, optionally substituted aryl-C1-6 alkyl, optionally substituted heteroaryl-C1-6 alkyl and optionally substituted heterocyclyl-C1-6 alkyl;
R5 is selected from the group consisting of hydrogen and C1-6 alkyl; or
R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted C3-7 cycloalkyl ring or an optionally substituted heterocyclyl ring;
R6 is selected from the group consisting of hydrogen and C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R3 is selected from the group consisting of C1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl C1-6 alkyl and optionally substituted heteroaryl C1-6 alkyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R3 is selected from the group consisting of C1-6 alkyl, phenyl C1-6 alkyl, phenyl optionally substituted by one to three fluorine atoms, and heteroaryl optionally substituted by one to three fluorine atoms, wherein heteroaryl is a monocyclic aromatic radical of 5 or 6 ring atoms, containing one or two ring nitrogen atoms or one ring sulfur atom.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R3 is phenyl.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R1 is selected from the group consisting of C1-6 alkyl, —(C0-6 alkylene)-NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen, C1-6 alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylsulfonyl and optionally substituted heteroarylsulfonyl, and —(C0-6 alkylene)-OR′, wherein R′ is selected from the group consisting of hydrogen and C1-6 alkylcarbonyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R1 is selected from the group consisting of C1-6 alkyl, —(C2-6 alkylene)-NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen, acetyl, arylcarbonyl, wherein aryl is optionally substituted by one or two trifluoromethyl groups and arylsulfonyl, and —(C2-6 alkylene)-OR′, wherein R′ is selected from the group consisting of hydrogen and acetyl.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R1 is selected from the group consisting of 2-aminoethyl, 2-acetylaminoethyl, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl and 2-hydroxyethyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R2, R2′ and R2″ are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl and C1-6 alkoxy.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein two of R2, R2′ and R2″ are hydrogen, and the other is selected from the group consisting of hydrogen, halogen, C1-6 alkyl and C1-6 alkoxy.

### Claim 10 (depends on 1)

A compound according to claim 1, wherein two of R2, R2′ and R2″ are hydrogen, and the other is selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl or methoxy.

### Claim 11 (depends on 1)

A compound according to claim 1, wherein two of R2, R2′ and R2″ are hydrogen, and the other is at 5 or 6 position of the indole ring and selected from the group consisting of hydrogen, chloro, fluoro, methyl and ethyl.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R6 is hydrogen.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein
R4 is selected from the group consisting of hydrogen, C1-6 alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted C3-7 cycloalkyl C1-6 alkyl and optionally substituted aryl C1-6 alkyl and
R5 is selected from the group consisting of hydrogen and C1-6 alkyl; or
R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted C3-7 cycloalkyl ring.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein A is —CH2—.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein A is —CH2—, R4 is phenyl and R5 is hydrogen.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein A is —NR′—, wherein R′ is selected from the group consisting of hydrogen and C1-6 alkyl.

### Claim 17 (depends on 1)

A compound according to claim 1, wherein A is —NR′—, wherein R′ is selected from the group consisting of hydrogen and methyl, R4 is isopropyl and R5 is hydrogen.

### Claim 18 (depends on 1)

A compound according to claim 1, wherein A is —O—.

### Claim 19 (depends on 1)

A compound according to claim 1, wherein A is —O—, R4 is selected from the group consisting of hydrogen, phenyl, C1-6 alkyl, optionally substituted C3-7 cycloalkyl C1-6 alkyl and optionally substituted aryl C1-6 alkyl, and R5 is selected from the group consisting of hydrogen and C1-6 alkyl; or
R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted C3-7 cycloalkyl ring.

### Claim 20 (depends on 1)

A compound according to claim 1, wherein A is —O—, R4 is selected from the group consisting of phenyl, benzyl, isobutyl, 2-cyclohexylethyl and phenethyl and R5 is selected from the group consisting of hydrogen and methyl.

### Claim 21 (depends on 1)

A compound according to claim 1 selected from the group consisting of
3-[(5-Fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one,
3-[(5-Fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-isopropyl-1-methyl-1,5-dihydro-pyrrol-2-one,
4-Hydroxy-5-isopropyl-3-[(3-methyl-1H-indol-2-yl)-phenyl-methyl]-1,5-dihydro-pyrrol-2-one,
3-[(5-Fluoro-3-isopropyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one,
N-(2-{2-[(5-Benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-6-fluoro-1H-indol-3-yl}-ethyl)-acetamide,
5-Benzyl-3-{[6-fluoro-3-(2-hydroxy-ethyl)-1H-indol-2-yl]-phenyl-methyl}-4-hydroxy-5H-furan-2-one,
3-{[3-(2-Amino-ethyl)-6-fluoro-1H-indol-2-yl]-phenyl-methyl}-5-benzyl-4-hydroxy-5H-furan-2-one; salt with acetic acid,
5-Benzyl-3-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenyl-methyl]-4-hydroxy-5H-furan-2-one,
(2-{6-Fluoro-2-[(4-hydroxy-5-methyl-2-oxo-5-phenyl-2,5-dihydro-furan-3-yl)-phenyl-methyl]-indol-3-yl}-ethyl)-acetamide,
(2-{2-[(4-Hydroxy-5-isobutyl-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-indol-3-yl}-ethyl)-acetamide,
N-[2-(2-{[5-(2-Cyclohexyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl]-phenyl-methyl}-6-fluoro-1H-indol-3-yl)-ethyl]-acetamide,
N-(2-{6-Fluoro-2-[(4-hydroxy-2-oxo-5-phenethyl-2,5-dihydro-furan-3-yl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide,
N-(2-{2-[(2-Hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide,
N-(2-{6-Fluoro-2-[(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide,
N-(2-{5-Ethyl-2-[(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide,
N-(2-{2-[(2-Hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-5-methyl-1H-indol-3-yl}-ethyl)-acetamide,
2-{[3-(2-Amino-ethyl)-6-ethyl-1H-indol-2-yl]-phenyl-methyl}-3-hydroxy-4-phenyl-cyclopent-2-enone, and,
N-(2-{6-Chloro-2-[(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-acetamide,
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A process for the manufacture of a compound of Formula (I) as defined in claim 1, comprising the step of coupling of a compound of Formula (III)
a compound of Formula (IV)
and a compound of Formula (V)
wherein A, R1, R2, R2′, R2″, R3, R4, R5 and R6 are as defined in claim 1.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.