# US 9,434,690 B2 · Substituted oxopyridine derivatives and use thereof in the treatment of cardiovascular disorders

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- Number: US 9,434,690 B2
- Document ID: US9434690B2
- Status: Granted
- Kind: B2
- Application number: 14/780,925
- Filed: 2014-03-27
- Published: 2016-02-25
- Granted: 2016-09-06
- Earliest claimed: 2013-03-28
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Susanne Röhrig; Alexander Hillisch; Julia Straβburger; Stefan Heitmeier; Martina Victoria Schmidt; Karl-Heinz Schlemmer; Adrian Tersteegen; Anja Buchmüller; Christoph Gerdes; Martina Schäfer; Tom Kinzel; Henrik Teller; Hartmut Schirok; Jürgen Klar; Eloisa Jimenez Nunez
- Web page: https://patentgrep.com/patent/US9434690B2

## CPC

- C07D 405/06: 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 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 213/64: attached in position 2 or 6
- C07D 213/69: Two or more oxygen atoms
- C07D 213/84: Nitriles
- C07D 213/85: in position 3
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

## Claims

### Claim 1

A compound of the formula
in which
R1 represents a group of the formula
where * is the point of attachment to the oxopyridine ring,
R6 represents bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
R7 represents bromine, chlorine, fluorine, cyano, nitro, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,
R8 represents hydrogen, chlorine or fluorine,
R2 represents hydrogen, bromine, chlorine, fluorine, cyano, C1-C3-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C1-C3-alkoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or cyclopropyl,
R3 represents hydrogen, C1-C5-alkyl, C1-C4-alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentadeuteroethyl, 3,3,3-trifluoro-2-hydroxyprop-1-yl, 3,3,3-trifluoro-2-methoxyprop-1-yl, 3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or cyclobutyloxy,
where alkyl may be substituted by a substituent selected from the group consisting of fluorine, cyano, hydroxy, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, 4- to 6-membered oxoheterocyclyl, 4- to 6-membered thioheterocyclyl, 1,4-dioxanyl, phenyl and pyridyl,
where cycloalkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy,
and
where oxoheterocyclyl and thioheterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluoro, methyl, ethyl, difluoromethyl and trifluoromethyl,
R4 represents hydrogen,
R5 represents a group of the formula
where # is the point of attachment to the nitrogen atom,
R9 represents hydroxycarbonyl or 5-membered heterocyclyl,
where heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy, thioxo, sulphanyl, methyl, difluoromethyl, trifluoromethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
where methyl may be substituted by a methoxy substituent,
R10 represents hydrogen, chlorine, fluorine or methyl,
R11 and R12 together with the carbon atoms to which they are attached form a 5-membered heterocycle,
where the heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, hydroxy, hydroxycarbonyl, methyl, difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
R13 represents hydrogen, chlorine, fluorine, methyl or methoxy,
or a salt thereof, solvate thereof or solvate of a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
R1 represents a group of the formula
where * is the point of attachment to the oxopyridine ring,
R6 represents chlorine,
R7 represents bromine, chlorine, cyano, nitro, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, ethynyl or cyclopropyl,
R8 represents hydrogen,
R2 represents hydrogen, chlorine, fluorine, cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy or 2,2,2-trifluoroethoxy,
R3 represents hydrogen, C1-C5-alkyl, ethoxy, 1,1,2,2,2-pentadeuteroethyl or prop-2-yn-1-yl,
where C1-alkyl may be substituted by a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-dioxanyl, phenyl and pyridyl,
where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, ethyl, methoxy and trifluoromethyl,
and
where tetrahydrofuranyl, tetrahydro-2H-pyranyl and tetrahydro-2H-thiopyranyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, methyl and ethyl,
and
where C2-C4-alkyl may be substituted by a substituent selected from the group consisting of fluorine, hydroxy, trifluoromethyl, methoxy and trifluoromethoxy,
R4 represents hydrogen,
R5 represents a group of the formula
where # is the point of attachment to the nitrogen atom,
R9 represents hydroxycarbonyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or dihydrooxazolyl,
where oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl and dihydrooxazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy, thioxo, sulphanyl, methyl, trifluoromethyl and 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,
where methyl may be substituted by a methoxy substituent,
R10 represents hydrogen, chlorine, fluorine or methyl,
or
R5 represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl or 1H-indazol-5-yl,
where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl and 1H-indazol-5-yl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, hydroxycarbonyl, methyl and trifluoromethyl,
and
where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl and 1H-indazol-5-yl may be substituted by a substituent selected from the group consisting of fluorine and methoxy,
or a salt thereof, solvate thereof or solvate of a salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein
R1 represents a group of the formula
where * is the point of attachment to the oxopyridine ring,
R6 represents chlorine,
R7 represents cyano or difluoromethoxy,
R8 represents hydrogen,
R2 represents chlorine, cyano, methoxy, ethoxy or difluoromethoxy,
R3 represents methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,
where methyl may be substituted by a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl,
where cyclopropyl, cyclobutyl and cyclohexyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, methoxy and trifluoromethyl,
and
where ethyl, n-propyl and n-butyl may be substituted by a substituent selected from the group consisting of fluorine, methoxy and trifluoromethoxy,
R4 represents hydrogen,
R5 represents a group of the formula
where # is the point of attachment to the nitrogen atom,
R9 represents hydroxycarbonyl, oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl,
where oxadiazolyl and pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy and trifluoromethyl,
and
where triazolyl may be substituted by a substituent selected from the group consisting of trifluoromethyl and 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,
R10 represents hydrogen or fluorine,
or
R5 represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, 2,3-dihydro-1H-benzimidazol-5-yl or 1H-indazol-5-yl,
where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo and methyl,
and
where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl may be substituted by a fluorine substituent,
and
where the 5-membered heterocycle in 1H-benzimidazol-6-yl may be substituted by a hydroxycarbonyl substituent,
and
where the 5-membered heterocycle in 2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an oxo substituent,
and
where the 5-membered heterocycle in 1H-indazol-5-yl may be substituted by a chlorine substituent,
or a salt thereof, solvate thereof or solvate of a salt thereof.

### Claim 4 (depends on 1)

A process for preparing a compound of formula (I) or a salt thereof, solvate thereof or solvate of a salt thereof according to claim 1, comprising
[A] reacting a compound of the formula
in which
R1, R2, R3, R4 and R10 have the meaning given in claim 1, and
R14 represents tert-butyl,
with an acid to give a compound of the formula
in which
R1, R2, R3, R4 and R10 have the meaning given in claim 1, and
R9 represents hydroxycarbonyl,
or
[B] reacting a compound of the formula
in which
R1, R2, R3, R4 and R10 have the meaning given in claim 1, and
R14 represents methyl or ethyl,
with a base to give a compound of the formula
in which
R1, R2, R3, R4 and R10 have the meaning given in claim 1, and
R9 represents hydroxycarbonyl,
or
[C] reacting a compound of the formula
in which
R1, R2 and R3 have the meaning given in claim 1,
with a compound of the formula
in which
R4 and R5 have the meaning given in claim 1,
in the presence of a dehydrating agent to give a compound of the formula (I),
or
[D] reacting a compound of the formula
in which
R2, R3, R4 and R5 have the meaning given in claim 1, and
X1 represents chlorine, bromine or iodine,
with a compound of the formula
R1-Q (VI),
in which
R1 has the meaning given in claim 1, and
Q represents —B(OH)2, a boronic ester, or radical —BF3−K+,
under Suzuki coupling conditions to give a compound of the formula (I).

### Claim 5 (depends on 4)

The process of claim 4, wherein the boronic ester is boronic acid pinacol ester.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and an inert, nontoxic, pharmaceutically suitable excipient.

### Claim 7 (depends on 1)

A method for the treatment of a thrombotic or thromboembolic disorder comprising administering a therapeutically effective amount of at least one compound of claim 1 to a human or animal in need thereof.

### Claim 8 (depends on 1)

A method for the treatment of an ophthalmic disorder comprising administering a therapeutically effective amount of at least one compound of claim 1 to a human or animal in need thereof.