Diazabicyclic substituted imidazopyrimidines and their use for the treatment of breathing disorders

Patent metadata

Field	Value
Publication number	US-11098063-B2
Application number	US-201816622233-A
Country	US
Kind code	B2
Filing date	Jun 7, 2018
Priority date	Jun 14, 2017
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention relates to novel diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives, to methods for producing the same, to the use thereof either alone or in combinations for the treatment and/or prevention of diseases, as well as to their use for preparing medicaments for the treatment and/or prevention of diseases, especially for treatment and/or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnoea and snoring.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group;

A is CH or N;
R 1 is halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
wherein (C 1 -C 4 )-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine;

R 2 is hydrogen or methyl;
and
R 3 is (C 4 -C 6 )-cycloalkyl wherein a ring CH 2 group is optionally replaced by —O—;
or
R 3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and
R 4 is hydrogen, fluorine, chlorine, bromine or methyl;
R 5 is hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy,
wherein (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy are optionally up to trisubstituted by fluorine;
R 6 is hydrogen, fluorine, chlorine, bromine or methyl;
R 7 is hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino or (C 1 -C 3 )-alkylsulfanyl,
wherein (C 1 -C 3 )-alkoxy may be up to trisubstituted by fluorine;

R 8 is hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy,
R 9A and R 9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl, cyclopropyl or (C 1 -C 3 )-alkoxy,
wherein (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy are optionally up to trisubstituted by fluorine;

and
Y is O or S;

or
R 3 is an —OR 10 or —NR 11 R 12 group wherein
R 10 is (C 1 -C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl or [(C 3 -C 6 )-cycloalkyl]methyl;
R 11 is hydrogen or (C 1 -C 3 )-alkyl;
and
R 12 is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl,
wherein (C 1 -C 6 )-alkyl is optionally up to trisubstituted by fluorine;
and
wherein phenyl and the phenyl group in benzyl are optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl;

or
R 11 and R 12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring,

or a salt, a solvate, or a solvate of the salt thereof.

2. The compound of formula (I) according to claim 1 , wherein
the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group;

A is CH;
R 1 is fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl;
R 2 is hydrogen;
and
R 3 is cyclobutyl, cyclopentyl or cyclohexyl;
or
R 3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and
R 4 is hydrogen, fluorine or chlorine;
R 5 is fluorine, chlorine, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy or trifluoromethoxy;
R 6 is hydrogen, fluorine, chlorine, bromine or methyl;
R 7 is (C 1 -C 3 )-alkoxy, cyclobutyloxy or (C 1 -C 3 )-alkylsulfanyl,
wherein (C 1 -C 3 )-alkoxy is optionally up to trisubstituted by fluorine;

R 9A and R 9B are identical or different and are independently hydrogen, chlorine, bromine, (C 1 -C 3 )-alkyl or cyclopropyl,
wherein (C 1 -C 3 )-alkyl may be up to trisubstituted by fluorine;

and
Y is O or S,

or a salt, a solvate, or a solvate of the salt thereof.

3. The compound of formula (I) according to claim 1 , wherein
the ring Q is a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group;

A is CH;
R 1 is chlorine, bromine, isopropyl or cyclopropyl;
R 2 is hydrogen;
and
R 3 is cyclopentyl or cyclohexyl;
or
R 3 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f)

wherein *** marks the bond to the adjacent carbonyl group; and
R 4 is hydrogen, fluorine or chlorine;
R 5 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy;
R 6 is hydrogen, fluorine, chlorine, bromine or methyl;
R 7 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl;
R 9A and R 9B are identical or different and are independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl;
and
Y is O or S,

or a salt, a solvate, or a solvate of the salt thereof.

4. A process for preparing a compound of formula (I) according to claim 1 , wherein the radical R 2 is hydrogen, comprising reacting a compound of formula (II)

wherein A and R 1 are as defined in claim 1 ,
in the presence of a suitable reducing agent either
[A] with a compound of formula (III)

wherein R 3 and the ring Q are as defined in claim 1 ,
to give a compound of formula (I-A)

wherein A, R 1 , R 3 and the ring Q are as defined above;

or
[B] with a protected diazaheterobicyclic system of the formula (IV)

wherein the ring Q is as defined in claim 1 ,
and
PG is a suitable amino protecting group,
at first to give a compound of formula (V)

wherein A, PG, R 1 and the ring Q are as defined above,
then cleaving the protecting group PG to give a compound of formula (VI) and reacting the resulting compound of formula (VI)

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Delbeck Martina
• Hahn Michael
• Müller Thomas
• Lustig Klemens
• Collins Karl
• Lindner Niels
• Nicolai Janine
• Beck-Broichsitter Moritz
• Albus Udo
• Gehring Doris
• Rosenstein Björn

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61K31/537

  spiro-condensed or forming part of bridged ring systems · CPC title