Substituted uracils and use thereof

Patent metadata

Field	Value
Publication number	US-9751843-B2
Application number	US-201415034499-A
Country	US
Kind code	B2
Filing date	Nov 5, 2014
Priority date	Nov 8, 2013
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

Substituted uracil derivatives of the compound of Formula (I), processes for their preparation, their use alone or in combinations for treatment and/or prophylaxis of diseases, and their use for preparing medicaments for treatment and/or prophylaxis of diseases.

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,

R 2 represents a group of the formula

where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen, in which ## represents the point of attachment to the phenyl ring,
m represents a number 0, 1 or 2,
R 8 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy,
R 9A represents hydrogen or deuterium,
R 9B represents hydrogen, deuterium or (C 1 -C 4 )-alkyl,
R 10 represents hydrogen, halogen, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 )-alkylthio,
R 11 represents hydrogen, halogen, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, nitro or (C 1 -C 4 )-alkylthio,
R 12 represents hydrogen or halogen,
R 13 represents hydrogen or halogen,

R 3 represents hydrogen,
R 4 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,

R 5 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, (C 1 -C 4 )-alkylsulfonyl or —N(R 14 R 15 ),
where (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy, 4- to 7-membered heterocyclyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl and di-(C 1 -C 4 )-alkylaminocarbonyl,
in which 4- to 7-membered heterocyclyl may be substituted by 1 or 2 halogen or oxo substituents,
where (C 1 -C 4 )-alkoxy may be substituted by a substituent independently of one another selected from the group consisting of hydroxy, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl and di-(C 1 -C 4 )-alkylaminocarbonyl,
where
R 14 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl or (C 1 -C 4 )-alkylaminocarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
and
in which (C 1 -C 4 )-alkylaminocarbonyl may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,

R 15 represents hydrogen or (C 1 -C 4 )-alkyl,

or
R 5 represents 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl,
where 4- to 7-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R 16 R 17 ),
in which R 6 represents hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkylcarbonyl,
in which R 17 represents hydrogen or (C 1 -C 4 )-alkyl,

where 5- to 6-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R 16 R 17 ),
in which R 16 represents hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkylcarbonyl,
in which R 17 represents hydrogen or (C 1 -C 4 )-alkyl,

R 6 represents hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R 7 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy, a salt or a solvate thereof, or a solvate of the salt.

2. The compound of claim 1 in which
R 1 represents hydrogen, methyl or ethyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 —, —CH 2 —CH 2 — or oxygen,
R 8a represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R 8b represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,

R 9A represents hydrogen,
R 9B represents hydrogen, methyl or ethyl,
R 10 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R 11 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R 12 represents hydrogen,
R 13 represents hydrogen,

R 3 represents hydrogen,
R 4 represents hydrogen, fluorine, chlorine or methoxy,
R 5 represents (C 1 -C 4 )-alkoxy, 5- or 6-membered heterocyclyl or 5-membered heteroaryl,
where 5- to 6-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, methyl, ethyl, hydroxy, oxo and (C 1 -C 4 )-alkoxycarbonyl,
in which methyl and ethyl may be substituted by —N(R 16 R 17 ),
in which R 16 represents (C 1 -C 4 )-alkylcarbonyl,
in which R 17 represents hydrogen,

where 5-membered heteroaryl may be substituted by fluorine, chlorine, trifluoromethyl, methyl, hydroxy, amino or (C 1 -C 4 )-alkoxycarbonyl,
in which methyl may be substituted by hydroxy,

R 6 represents hydrogen, fluorine, chlorine or methyl,
R 7 represents hydrogen, fluorine, chlorine or methyl, a salt or a solvate thereof, or a solvate of the salt.

3. The compound of claim 1 in which
R 1 represents hydrogen, methyl or ethyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
R 8a represents hydrogen, chlorine, trifluoromethyl or methyl,
R 8b represents hydrogen,

R 9A represents hydrogen,
R 9B represents hydrogen, methyl or ethyl,
R 10 represents hydrogen, chlorine, trifluoromethyl or methyl,
R 11 represents fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,

R 12 represents hydrogen,
R 13 represents hydrogen,

R 3 represents hydrogen,
R 4 represents hydrogen, fluorine, chlorine or methoxy,
R 5 represents 5- or 6-membered heterocyclyl or 5-membered heteroaryl,
where 5- to 6-membered heterocyclyl may be substituted by 1 or 2 methyl, ethyl or oxo substituents,

where 5-membered heteroaryl may be substituted by methyl or amino, in which methyl may be substituted by hydroxy,
R 6 represents hydrogen, fluorine, chlorine or methyl,
R 7 represents hydrogen, fluorine or methyl, a salt or a solvate thereof, or a solvate of the salt.

4. The compound of claim 1 in which
R 1 represents hydrogen, methyl or ethyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
R 8a represents chlorine or trifluoromethyl,
R 8b represents hydrogen,

R 9A represents hydrogen,
R 9B represents hydrogen,
R 10 represents chlorine, trifluor

Assignees

• Bayer Pharma AG

Inventors

• Fürstner Chantal
• Ackerstaff Jens
• Straub Alexander
• Meier Heinrich
• Tinel Hanna
• Zimmermann Katja
• Tersteegen Adrian
• Zubov Dmitry
• Kast Raimund
• Schamberger Jens
• Schäfer Martina

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title