Bicyclically substituted uracils and the use thereof

Patent metadata

Field	Value
Publication number	US-9481672-B2
Application number	US-201314399945-A
Country	US
Kind code	B2
Filing date	May 3, 2013
Priority date	May 9, 2012
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

The present application relates to novel bicyclically substituted uracil derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of 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 is hydrogen or (C 1 -C 4 )-alkyl,
R 2 is a group of the formula

where
* is the attachment site to the uracil nitrogen atom,
A is —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen,
in which
## is the attachment site to the phenyl ring,

m is a number 0, 1 or 2,
R 4 is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy,
R 5A is hydrogen or deuterium,
R 5B is hydrogen, deuterium or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or fluorine,
R 7 is hydrogen or fluorine,
R 8 is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl or nitro,
R 9 is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, nitro or (C 1 -C 4 )-alkylthio,

R 3 is a group of the formula

where
# is the attachment site to the uracil nitrogen atom,
the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl may be substituted by 1 to 4 substituents independently selected from the group of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkylsulphonyl,
in which (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl may in turn be substituted by 1 to 3 substituents independently selected from the group of halogen, cyano, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy and 4- to 7-membered heterocyclyl,
 and
in which two (C 1 -C6)-alkyl radicals bonded to a carbon atom of 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, together with the carbon atom to which they are bonded, may form a 3- to 6-membered carbocycle,

R 24 is halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
n is a number 0, 1, 2 or 3,

and the salts, solvates and solvates of the salts thereof.

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

where
* is the attachment site to the uracil nitrogen atom,
A is —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen,
in which
## is the attachment site to the phenyl ring,

R 4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R 4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
with the proviso that at least one of the R 4A and R 4B radicals is not hydrogen,
R 5A is hydrogen,
R 5B is hydrogen,
R 6 is hydrogen,
R 7 is hydrogen,
R 8 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R 9 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,

R 3 is a group of the formula

where
# is the attachment site to the uracil nitrogen atom,
E is CR 11 or N,
in which
R 11 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl or aminocarbonyl,

E 2 is CR 12 or N,
in which
R 12 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,

E 3 is NR 14 or S,
in which
R 14 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,

G 1 is C═O or SO 2 ,
G 2 is CR 16A R 16B , NR 17 , O or S,
in which
R 16A is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxyl,
R 16B is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 16A and R 16B together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle,
R 17 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

G 3 is CR 18A R 18B , NR 19 , O or S,
in which
R 18A is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxyl,
R 18B is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 18A and R 18B together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle,
R 19 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

G 4 is CH 2 , C═O or SO 2 ,
K 1 is CH 2 or O,
K 2 is CH 2 or O,
with the proviso that only one of the K 1 and K 2 groups is O,
D 1 , D 2 , D 3 and D 4 are each independently CR 23 or N,
in which
R 23 is hydrogen, halogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,

with the proviso that not more than 2 of the D 1 , D 2 , D 3 and D 4 groups are N,
R 24 is fluorine or methyl,
n is a number 0 or 1,
R 10 is (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

R 13 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
R 15 is hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

R 20 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylcarbonyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

R 21 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylsulphonyl,
R 22A is hydrogen or (C 1 -C 4 )-alkyl,
R 22B is hydrogen or (C 1 -C 4 )-alkyl,
or
R 22A and R 22B together with the carbon atom to which they are bonded form a carbonyl group,

and the salts, solvates and solvates of the salts thereof.

3. The compound of claim 1 in which
R 1 is hydrogen,
R 2 is a group of the formula

where
* is the attachment site to the uracil nitrogen atom,
A is —CH 2 —,
R 4A is chlorine or trifluoromethyl,
R 4B is hydrogen,

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
• Börngen Kirsten

Classifications

• A61P9/04

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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