Inhibitors of adrenoreceptor adrac2

Patent metadata

Field	Value
Publication number	US-2023115270-A1
Application number	US-202017774459-A
Country	US
Kind code	A1
Filing date	Nov 5, 2020
Priority date	Nov 6, 2019
Publication date	Apr 13, 2023
Grant date	—

Abstract

The present application relates to novel substituted heterocyclic carboxamides, 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 producing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of breathing difficulties including sleep-induced breathing difficulties such as central and obstructive sleep apnoea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiac vascular disorders including diabetic microangiopathies and disorders of the peripheral and central nervous system including neurodegenerative and neuroinflammatory disorders.

First claim

1 . A compound of formula (I)

in which
X represents S, N or O;
Y represents N, S or O,
where, if X represents S, then Y represents N;
where, if X represents O, then Y represents N;
Z represents CR 4 , O or NR 4 ,
where, if X represents N and Y represents N, then Z represents O;
where, if X represents S, then Z represents CR 4 or NR 4
R 1 represents 5- or 6-membered heteroaryl, phenyl,
where 5- to 6-membered heteroaryl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;
where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen,
where (C 1 -C 4 )-alkoxy may be up to trisubstituted by halogen,

where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 4 )-alkyl, (C 3 -C 5 )-cycloalkyl, (C 1 -C 4 )-alkoxy, cyano, hydroxy, halogen;

where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen,
R 2 represents hydrogen, (C 1 -C 4 )-alkyl;
where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen,
or

together with the carbon atom to which R 2 is attached forms a (C 3 -C 4 )-cycloalkyl ring,
R 3 represents hydrogen, (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen,
R 4 in CR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl, halogen;
where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen,

in NR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl;
where (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen,

R 5 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen,
R 6 represents a group of formula a), b), c), d), e), f) or g)

where *** marks the attachment to the adjacent piperidine ring,
where R 7 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, phenyl,
where (C 1 -C 4 )-alkyl may be substituted by (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkoxy and up to trisubstituted by halogen,
where (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and up to trisubstituted by halogen,
 where (C 3 -C 4 )-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen,

where (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and up to trisubstituted by halogen,
where (C 3 -C 4 )-cycloalkyl may be mono- or disubstituted by halogen,

where (C 3 -C 4 )-cycloalkoxy may be up to disubstituted by halogen,

where R 8 represents hydrogen or fluorine,
where R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;
where (C 1 -C 4 )-alkyl may be substituted by (C 1 -C 4 )-alkoxy,

n represents 0 or 1,
m represents 0, 1 or 2,
P represents 0, 1 or 2 and
q represents 0, 1 or 2,
or a salt, a solvate, or a solvate of a salt thereof.

2 . The compound of claim 1 , wherein
X represents S or N; Y represents N, S or O,
where, if X represents S, then Y represents N;
Z represents CR 4 , N or O,
where, if X represents N and Y represents N, then Z represents O;
where, if X represents S, then Z represents N or CR 4
R 1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, phenyl,
where pyridinyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,
where pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,
where thiazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of fluorine, chlorine,
where thienyl may be substituted by 1 to 2 substituents independently of one another selected from the group of fluorine, chlorine,
where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;
R 2 represents hydrogen, (C 1 -C 2 )-alkyl,
or
together with the carbon atom to which R 2 is attached forms a cyclopropyl ring,
R 3 represents hydrogen, (C 1 -C 2 )-alkyl; R 4 represents hydrogen, (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl;
where phenyl may be substituted by halogen,
R 5 represents hydrogen, (C 1 -C 2 )-alkyl, methoxy, fluorine; R 6 represents a group of the formula a), b), c) or e),

where *** marks the attachment to the adjacent piperidine ring,
where R 7 or R′ 7 independently of one another represent hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,
where (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine,
 where methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,
 where cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,
 where cyclobutyl may be up to disubstituted by fluorine,
where n-butoxy may be up to disubstituted by fluorine,
where (C 1 -C 2 )-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and
 where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,
where (C 3 -C 4 )-cycloalkoxy may be up to disubstituted by fluorine,

where R 8 or R′ 8 independently of one another represent hydrogen or fluorine,
where R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 2 )-alkoxy,

methoxyethyl, fluorine, chlorine;
n represents 0 or 1 and
m represents 1 or 2,
q represents 0 or 2,
or a salt, a solvate, or a solvate of a salt thereof.

3 . The compound of claim 1 , wherein
X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k) or (r),

where * marks the attachment to the carbonyl group and ** marks the attachment to the nitrogen atom of the adjacent piperidine ring and

R 1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, phenyl,
where pyridinyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,
where pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,

where thiazolyl may be substituted by chlorine,
where thienyl may be substituted by fluorine,
where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

R 2 represents hydrogen, methyl,
or
together with the carbon atom to which R 2 is

Assignees

• Bayer Ag

Inventors

• Delbeck Martina
• Hahn Michael
• Müller Thomas
• Dietz Lisa
• Platzk Magdalena
• Meibom Daniel
• Buchgraber Philipp
• Lindner Niels
• Becker-Pelster Eva Maria
• Schmeck Carsten

Classifications

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title