# US 12,180,227 B2 · Diazabicyclic substituted imidazopyrimidines and their use for the treatment of breathing disorders

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- Number: US 12,180,227 B2
- Document ID: US12180227B2
- Status: Granted
- Kind: B2
- Application number: 17/305,927
- Filed: 2021-07-16
- Published: 2022-01-20
- Granted: 2024-12-31
- Earliest claimed: 2017-06-14
- Assignees: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft
- Inventors: Martina Delbeck; Michael Hahn; Thomas Müller; Klemens Lustig; Karl Collins; Niels Lindner; Janine Nicolai; Moritz Beck-Broichsitter; Udo Albus; Doris Gehring; Björn Rosenstein
- Web page: https://patentgrep.com/patent/US12180227B2

## CPC

- C07D 519/00: 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
- A61K 31/4995: Pyrazines or piperazines forming part of bridged ring systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/537: spiro-condensed or forming part of bridged ring systems
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/00: Drugs for disorders of the nervous system
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 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 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.

### Claim 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 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.

### Claim 3 (depends on 1)

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 CHR2 group and ** the bond to the carbonyl group;
A is CH;
R1 is chlorine, bromine, isopropyl or cyclopropyl;
R2 is hydrogen;
and
R3 is cyclopentyl or cyclohexyl;
or
R3 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
R4 is hydrogen, fluorine or chlorine;
R5 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy;
R6 is hydrogen, fluorine, chlorine, bromine or methyl;
R7 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl;
R9A and R9B 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.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is tert-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate of the formula

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone of the formula

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is ((3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone of the formula

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl) [6-(methylamino) pyridin-2-yl] methanone of the formula

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-methoxyphenyl)methanone of the formula

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(cyclopentyl)methanone of the formula