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

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 CHR2 group and ** the bond to the carbonyl group;
• A is CH or N;
• R1 is halogen, cyano, (C1-C4)-alkyl, cyclopropyl or cyclobutyl,
• wherein (C1-C4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine;
• R2 is hydrogen or methyl;
• and
• R3 is (C4-C6)-cycloalkyl wherein a ring CH2 group is optionally replaced by —O—;
• or
• R3 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
• R4 is hydrogen, fluorine, chlorine, bromine or methyl;
• R5 is hydrogen, fluorine, chlorine, bromine, cyano, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• R6 is hydrogen, fluorine, chlorine, bromine or methyl;
• R7 is hydrogen, (C1-C3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C1-C3)-alkylamino, di-(C1-C3)-alkylamino or (C1-C3)-alkylsulfanyl,
• wherein (C1-C3)-alkoxy may be up to trisubstituted by fluorine;
• R8 is hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• R9A and R9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl, cyclopropyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• and
• Y is O or S;
• or
• R3 is an —OR10 or —NR11R12 group wherein
• R10 is (C1-C6)-alkyl, (C4-C6)-cycloalkyl or [(C3-C6)-cycloalkyl]methyl;
• R11 is hydrogen or (C1-C3)-alkyl;
• and
• R12 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or benzyl,
• wherein (C1-C6)-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
• R11 and R12 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.

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 CHR2 group and ** the bond to the carbonyl group;
• A is CH or N;
• R1 is halogen, cyano, (C1-C4)-alkyl, cyclopropyl or cyclobutyl,
• wherein (C1-C4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine;
• R2 is hydrogen or methyl;
• and
• R3 is (C4-C6)-cycloalkyl wherein a ring CH2 group is optionally replaced by —O—;
• or
• R3 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
• R4 is hydrogen, fluorine, chlorine, bromine or methyl;
• R5 is hydrogen, fluorine, chlorine, bromine, cyano, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• R6 is hydrogen, fluorine, chlorine, bromine or methyl;
• R7 is hydrogen, (C1-C3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C1-C3)-alkylamino, di-(C1-C3)-alkylamino or (C1-C3)-alkylsulfanyl,
• wherein (C1-C3)-alkoxy may be up to trisubstituted by fluorine;
• R8 is hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• R9A and R9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl, cyclopropyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• and
• Y is O or S;
• or
• R3 is an —OR10 or —NR11R12 group wherein
• R10 is (C1-C6)-alkyl, (C4-C6)-cycloalkyl or [(C3-C6)-cycloalkyl]methyl;
• R11 is hydrogen or (C1-C3)-alkyl;
• and
• R12 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or benzyl,
• wherein (C1-C6)-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
• R11 and R12 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.

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 bond to the adjacent CHR2 group and ** the bond to the carbonyl group;
• A is CH or N;
• R1 is halogen, cyano, (C1-C4)-alkyl, cyclopropyl or cyclobutyl,
• wherein (C1-C4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine;
• R2 is hydrogen or methyl;
• and
• R3 is (C4-C6)-cycloalkyl wherein a ring CH2 group is optionally replaced by —O—;
• or
• R3 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
• R4 is hydrogen, fluorine, chlorine, bromine or methyl;
• R5 is hydrogen, fluorine, chlorine, bromine, cyano, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• R6 is hydrogen, fluorine, chlorine, bromine or methyl;
• R7 is hydrogen, (C1-C3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C1-C3)-alkylamino, di-(C1-C3)-alkylamino or (C1-C3)-alkylsulfanyl,
• wherein (C1-C3)-alkoxy may be up to trisubstituted by fluorine;
• R8 is hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• R9A and R9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl, cyclopropyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• and
• Y is O or S;
• or
• R3 is an —OR10 or —NR11R12 group wherein
• R10 is (C1-C6)-alkyl, (C4-C6)-cycloalkyl or [(C3-C6)-cycloalkyl]methyl;
• R11 is hydrogen or (C1-C3)-alkyl;
• and
• R12 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or benzyl,
• wherein (C1-C6)-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
• R11 and R12 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.

A pharmaceutical combination comprising a compound of formula (I),

• wherein
• the ring Q is a diazaheterobicyclic system of the formula
• wherein * denotes the bond to the adjacent CHR2 group and ** the bond to the carbonyl group;
• A is CH or N;
• R1 is halogen, cyano, (C1-C4)-alkyl, cyclopropyl or cyclobutyl,
• wherein (C1-C4)-alkyl is optionally up to trisubstituted by fluorine, and cyclopropyl and cyclobutyl are optionally up to disubstituted by fluorine;
• R2 is hydrogen or methyl;
• and
• R3 is (C4-C6)-cycloalkyl wherein a ring CH2 group is optionally replaced by —O—;
• or
• R3 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
• R4 is hydrogen, fluorine, chlorine, bromine or methyl;
• R5 is hydrogen, fluorine, chlorine, bromine, cyano, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• R6 is hydrogen, fluorine, chlorine, bromine or methyl;
• R7 is hydrogen, (C1-C3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C1-C3)-alkylamino, di-(C1-C3)-alkylamino or (C1-C3)-alkylsulfanyl,
• wherein (C1-C3)-alkoxy may be up to trisubstituted by fluorine;
• R8 is hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl or (C1-C3)-alkoxy,
• R9A and R9B are identical or different and are independently hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl, cyclopropyl or (C1-C3)-alkoxy,
• wherein (C1-C3)-alkyl and (C1-C3)-alkoxy are optionally up to trisubstituted by fluorine;
• and
• Y is O or S;
• or
• R3 is an —OR10 or —NR11R12 group wherein
• R10 is (C1-C6)-alkyl, (C4-C6)-cycloalkyl or [(C3-C6)-cycloalkyl]methyl;
• R11 is hydrogen or (C1-C3)-alkyl;
• and
• R12 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or benzyl,
• wherein (C1-C6)-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
• R11 and R12 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 further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.