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

Patent metadata

Field	Value
Publication number	US-12180227-B2
Application number	US-202117305927-A
Country	US
Kind code	B2
Filing date	Jul 16, 2021
Priority date	Jun 14, 2017
Publication date	Dec 31, 2024
Grant date	Dec 31, 2024

Abstract

The present invention relates to novel diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives, such as compounds of the general formula (I):

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 method for treatment of obstructive sleep apnoeas, comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I)

wherein
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. A method for treatment of obstructive sleep apnoeas, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition comprising 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,
in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

3. The method 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 a

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

• A61P11/00 Primary

  Drugs for disorders of the respiratory 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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/5386

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

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title