Substituted bridged diazepane derivatives and use thereof as TASK-1 and TASK-3 inhibitors

Patent metadata

Field	Value
Publication number	US-11208422-B2
Application number	US-201816622779-A
Country	US
Kind code	B2
Filing date	Jun 7, 2018
Priority date	Jun 14, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present application relates to novel imidazopyridinyl- or imidazopyrimidinyl-substituted, bridged 1,4-diazepane derivatives of formula (I), to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including, sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring. Formula (I) in which the ring Q represents a bridged 1,4-diazepane cycle.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein the ring Q is a bridged 1,4-diazepane cycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group;

A is CH or N,
D 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;

and
R 2 is (C 4 -C 6 )-cycloalkyl wherein a ring CH 2 group is optionally replaced by —O—; or
R 2 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), (f) or (g),

wherein *** marks the bond to the adjacent carbonyl group; and

R 3 is hydrogen, fluorine, chlorine, bromine or methyl;
R 4 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 5 is hydrogen, fluorine, chlorine, bromine or methyl,
R 6 is hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan- 3 -yloxy, tetrahydrofuran- 3 -yloxy, tetrahydro- 2 H-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 is optionally up to trisubstituted by fluorine;

R 7 is hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy;
R 8A and R 8B 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;

R 9 is hydrogen, (C 1 -C 3 )-alkyl or amino;
and

Y is O or S;
or
R 2 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
where phenyl and the phenyl group in benzyl is optionally up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy;
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 bridged 1,4-diazepane cycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group;

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

wherein *** marks the bond to the adjacent carbonyl group; and

R 3 is hydrogen, fluorine or chlorine;
R 4 is fluorine, chlorine, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy or trifluoromethoxy;
R 5 is hydrogen, fluorine, chlorine, bromine or methyl;
R 6 is (C 1 -C 3 )-alkoxy, cyclobutyloxy or (C 1 -C 3 )-alkylsulfanyl,
wherein (C 1 -C 3 )-alkoxy may be up to trisubstituted by fluorine;

R 8A and R 8B 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;
R 9 is methyl or amino;
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 bridged 1,4-diazepane cycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** the bond to the carbonyl group;

A is CH or N;
D is CH or N;
R 1 is chlorine, bromine, isopropyl or cyclopropyl; and
R 2 is cyclopentyl or cyclohexyl;
or
R 2 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (g),

wherein *** marks the bond to the adjacent carbonyl group; and

R 3 is hydrogen, fluorine or chlorine;
R 4 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy;
R 5 is hydrogen, fluorine, chlorine, bromine or methyl;
R 6 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl;
and
R 9 is methyl or amino,

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

4. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

5. A pharmaceutical combination comprising a compound according to claim 1 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.

6. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, or cardiac arrhythmias, comprising administering to a human or animal in need thereof an effective amount of a compound of formula (I) according to claim 1 .

7. The method of claim 6 , wherein the method is a method for treatment of respiratory disorders.

8. The method of claim 6 , wherein the method is a method for treatment of sleep-related respiratory disorders.

9. A method for treatment of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, or cardiac arrhythmias, in a human or animal in need thereof, comprising administering an effective amount of at least one compound according to claim 1 to the human or animal.

10. The method of claim 9 , wherein the method is a method for treatment of respiratory disorders.

11. The method of claim 9 , wherein the method is a method for treatment of sleep-related respiratory disorders.

12. A m

Assignees

• Bayer Pharma AG
• Bayer Ag

Inventors

• Delbeck Martina
• Hahn Michael
• Müller Thomas
• Lustig Klemens
• Anlahr Johanna
• Collins Karl
• Nicolai Janine
• Beck-Broichsitter Moritz
• Albus Udo
• Gehring Doris
• Rosenstein Björn
• Dang Hongkai
• Duan Dehe
• Yang Jianfei
• Chen Denghui

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• 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

• A61P11/00 Primary

  Drugs for disorders of the respiratory system · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title