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

Patent metadata

Field	Value
Publication number	US-2022017540-A1
Application number	US-202117305927-A
Country	US
Kind code	A1
Filing date	Jul 16, 2021
Priority date	Jun 14, 2017
Publication date	Jan 20, 2022
Grant date	—

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

1 - 5 . (canceled)

6 . A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of 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.

7 - 9 . (canceled)

10 . A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, 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.

11 . A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a human or animal in need thereof an effective amount of at least one compound of formula (I)

wherein
the ring Q is a diazaheterobicyclic system of the formula

wherein * denotes the

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

• A61K31/537

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/519

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

• A61K31/5386

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

• A61K31/4995 Primary

  Pyrazines or piperazines forming part of bridged ring systems · CPC title