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CN-121986100-A - Substituted heterocyclic carboxamides and their use

CN121986100ACN 121986100 ACN121986100 ACN 121986100ACN-121986100-A

Abstract

The present application relates to novel substituted heterocyclic carboxamides, processes for their preparation, their use alone or in combination for the treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders, including diabetic microangiopathy, and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

Inventors

  • M. delbeck
  • C. Schmeick
  • D.Lang
  • H. Ximer
  • M. HAHN
  • T. MUELLER
  • L. Dietz
  • F. Wonder
  • Meibomian D.
  • P. Boughgreber
  • N. LINDNER
  • E.M. Becker-Pelster

Assignees

  • 拜耳公司

Dates

Publication Date
20260505
Application Date
20240927
Priority Date
20230928

Claims (16)

  1. 1. Compounds of the general formula (I), and salts, solvates and solvates of said salts (I) Wherein the method comprises the steps of X is S, N or O; Y is N, S or O, and the total number of the components is equal to or less than zero, Wherein, when X is S, Z is N; wherein, when X is O, Z is N; Y is CR 4 , O or NR 4 , Wherein, when X is N and Z is N, Y is O; Wherein when X is S, Y is CR 4 or NR 4 ; R 1 is a 5-to 10-membered heteroaryl, phenyl, (C 4 -C 10 ) -heterocycloalkyl or (C 3 -C 10 ) -cycloalkyl, Wherein the 5-to 10-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, halo; wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen, Wherein (C 1 -C 4 ) -alkoxy may be up to trisubstituted by halogen, Wherein phenyl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 3 -C 5 ) -cycloalkyl, (C 1 -C 4 ) -alkoxy, cyano, hydroxy, halogen; wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen, Wherein (C 3 -C 10 ) -cycloalkyl and (C 4 -C 10 ) -heterocycloalkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 3 -C 5 ) -cycloalkyl, (C 1 -C 4 ) -alkoxy, cyano, hydroxy, halogen; wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen, Wherein (C 3 -C 10 ) -cycloalkyl and (C 4 -C 10 ) -heterocycloalkyl may be fused with 5-to 10-membered heteroaryl, Wherein the 5-to 10-membered heteroaryl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, and halogen; R 2 is hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 5 ) -cycloalkyl; wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen, Wherein (C 1 -C 4 ) -alkyl may be substituted by cyano or (C 1 -C 4 ) -alkoxy, Wherein (C 3 -C 5 ) -cycloalkyl can be up to trisubstituted by halogen, Or (b) Together with the carbon atom to which R 2 is bonded, form a (C 3 -C 4 ) -cycloalkyl ring, Or (b) R 1 and R 2 together form a (C 5 -C 8 ) -cycloalkyl or (C 5 -C 10 ) -heterocycloalkyl ring, Wherein (C 5 -C 8 ) -cycloalkyl may be fused with a 5-to 10-membered heteroaryl, Wherein the 5-to 10-membered heteroaryl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, and halogen; Wherein (C 3 -C 10 ) -heterocycloalkyl may be fused with a 5-to 10-membered heteroaryl, Wherein the 5-to 10-membered heteroaryl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, and halogen; r 3 is hydrogen, (C 1 -C 4 ) -alkyl, Wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen, R 4 in CR 4 is hydrogen, (C 1 -C 4 ) -alkyl, (C 3 -C 4 ) -cycloalkyl, phenyl, halogen; Wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen, Absent or hydrogen, (C 1 -C 4 ) -alkyl, (C 3 -C 4 ) -cycloalkyl, phenyl in NR 4 ; Wherein (C 1 -C 4 ) -alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen, R 5 is hydrogen, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, halogen, R 6 is a radical of the formula a), b), c), d), e), f) or g) Wherein represents the linkage to an adjacent piperidine ring, Wherein R 7 is hydrogen, (C 1 -C 4 ) -alkyl, (C 3 -C 4 ) -cycloalkyl, (C 1 -C 4 ) -alkoxy, (C 3 -C 4 ) -cycloalkoxy, phenyl, Wherein (C 1 -C 4 ) -alkyl can be substituted by (C 3 -C 4 ) -cycloalkyl, (C 1 -C 4 ) -alkoxy, (C 3 -C 4 ) -cycloalkoxy and is up to trisubstituted by halogen, Wherein (C 1 -C 4 ) -alkoxy may be substituted by (C 3 -C 4 ) -cycloalkyl and up to three times by halogen, Wherein (C 3 -C 4 ) -cycloalkyl can be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and is up to disubstituted by halogen, Wherein (C 1 -C 4 ) -alkoxy may be substituted by (C 3 -C 4 ) -cycloalkyl and up to three times by halogen, Wherein (C 3 -C 4 ) -cycloalkyl may be mono-or disubstituted by halogen, Wherein (C 3 -C 4 ) -cycloalkoxy may be up to disubstituted by halogen, Wherein R 8 is hydrogen or fluorine, Wherein R 9 is hydrogen, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, halogen; Wherein (C 1 -C 4 ) -alkyl may be substituted by (C 1 -C 4 ) -alkoxy, N represents 0 or 1, and the number of the n is, M represents 0, 1 or 2, P represents 0,1 or 2, and Q represents 0, 1 or 2.
  2. 2. A compound of formula (I) according to claim 1, and salts, solvates and solvates of said salts, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the formula h), i), j), k), r) or p), Wherein represents a connection to a carbonyl group and represents a connection to a nitrogen atom of an adjacent amine group, an R 1 is pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, tetrahydropyranyl or cyclohexyl, Wherein the pyridyl group may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 2 ) -alkyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, Wherein pyrazolyl can be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 2 ) -alkyl, fluoro, chloro, trifluoromethyl, Wherein the thiazolyl group may be substituted with chlorine, Wherein the thienyl group may be substituted with fluorine, Wherein phenyl may be substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 2 ) -alkyl, (C 3 -C 4 ) -cycloalkyl, methoxy, cyano, hydroxy, fluoro, chloro, trifluoromethyl, Wherein the cyclohexyl and tetrahydropyranyl groups may be fused to the pyridinyl group, R 2 is hydrogen or methyl, Wherein the methyl group may be substituted with cyano or methoxy, R 3 is hydrogen, (C 1 -C 2 ) -alkyl; R 4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromo, chloro, phenyl; wherein the phenyl group may be substituted with a chlorine, R 5 is hydrogen or fluorine; r 6 is a group of the formula a), b "), c) or h), Wherein represents the linkage to an adjacent piperidine ring, Wherein R 7 or R' 7 are independently 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, Wherein (C 1 -C 4 ) -alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and up to two times by fluorine, Wherein methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl, Wherein the cyclopropyl group may be substituted by a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, Wherein the cyclopropyl group may be up to disubstituted with fluorine, Wherein the n-butoxy group may be up to disubstituted with fluorine, Wherein (C 1 -C 2 ) -alkoxy is substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and Wherein cyclopropyl and cyclobutyl can be up to disubstituted by fluorine, Wherein (C 3 -C 4 ) -cycloalkoxy may be up to disubstituted by fluorine, N represents 0 or 1, and M represents 1 or 2.
  3. 3. A compound of formula (I) according to claim 1, and salts, solvates and solvates of said salts, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the formula h), i), j), k), r) or p), Wherein represents a connection to a carbonyl group and represents a connection to a nitrogen atom of an adjacent amine group, an R 1 is pyridinyl, 2-ethylpyridinyl, 4, 6-dimethylpyridinyl, 3, 5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethylpyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 5-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 5-chlorophenyl, 2-cyclopropyl-1-thiophene; R 2 is hydrogen or methyl; r 3 is hydrogen, methyl; R 4 is hydrogen, ethyl or trifluoromethyl; R 5 is hydrogen, methyl or fluoro; R 6 is a radical of the formula a), c') or h) Wherein represents the linkage to an adjacent piperidine ring, Wherein R 7 and R' 7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutylmethoxymethyl, 2-trifluoroethoxy, 2-trifluoroethoxymethyl 2, 2-difluorocyclopropylmethoxy, cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy, fluorine; n represents 1, and M represents 1.
  4. 4. A compound of formula (I) according to claim 1, and salts, solvates and solvates of said salts, wherein X, Y and Z are 1, 3-thiazolyl, 1, 3-oxazolyl, 1,2, 4-oxadiazolyl; R 1 is pyridinyl, 2-ethylpyridinyl, 4, 6-dimethylpyridinyl, 3, 5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethylpyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 5-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 5-chlorophenyl, 2-cyclopropyl-1-thiophene; R 2 is hydrogen or methyl; r 3 is hydrogen, methyl; R 4 is hydrogen or methyl, ethyl, trifluoromethyl; R 5 is hydrogen, methyl or fluoro; R 6 is a radical of the formula a), or c') or h) Wherein represents the linkage to an adjacent piperidine ring, Wherein R 7 and R' 7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutylmethoxymethyl, 2-trifluoroethoxy, 2-trifluoroethoxymethyl 2, 2-difluorocyclopropylmethoxy, cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy, fluorine; n represents 1, and M represents 1.
  5. 5. A compound of formula (I) according to claim 1, and salts, solvates and solvates of said salts, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the formula h'), R 1 is pyridinyl, 2-ethylpyridinyl, 4, 6-dimethylpyridinyl, 3, 5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethylpyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2, 5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropyl, 2-chlorophenyl, 5-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 5-chlorophenyl, 2-cyclopropyl-1-thiophene; R 2 is hydrogen or methyl; R 3 is hydrogen or methyl; r 5 is hydrogen or fluorine; R 6 is a radical of the formula a) or c') Wherein represents the linkage to an adjacent piperidine ring, Wherein R 7 and R' 7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3-difluorocyclobutylmethoxymethyl, 2-trifluoroethoxy, 2-trifluoroethoxymethyl 2, 2-difluorocyclopropylmethoxy, cyclobutoxy, 3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethyl cyclopropylmethoxy, fluorine; n represents 1, and M represents 1.
  6. 6. A process for preparing a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of said salt thereof, wherein [A] Reacting a compound of formula (II) with a compound of formula (III) in the presence of a base to produce a compound of formula (I-A) (II) Wherein the method comprises the steps of X, Y, Z, R 5 、R 6 , and m have the definitions given above, Hal is a leaving group, preferably chloro, bromo, iodo or methanesulfonyl, (III) Wherein the method comprises the steps of R 1 、R 2 and R 3 and n have the definitions given above, (I-A), Or (b) [B] Reacting a compound of formula (IV) with a compound of formula (V) in the presence of a reducing agent and optionally an acid, preferably an alkali metal borohydride and acetic acid, to produce a compound of formula (I-B) (IV) Wherein the method comprises the steps of X, Y, Z, R 1 、R 2 、R 3 、R 4 and R 5 , and n and m have the definitions given above, (V) Wherein the method comprises the steps of R 6 has the definition given above, (I-B), Or (b) [C] reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a condensing agent or an activator, preferably a phosphorus compound, to produce a compound of formula (I-C) (VI) Wherein the method comprises the steps of X, Y, Z, R 1 、R 2 and R 3 and n have the definitions given above, (VII) Wherein the method comprises the steps of R 5 and R 6 and m have the meanings given above, (I-C), And, the compounds of the formula (I-A), (I-B), (I-C) thus obtained are optionally separated into their enantiomers and/or diastereomers and/or are optionally converted into their solvates, salts and/or solvates of said salts with suitable (I) solvents and/or (ii) acids.
  7. 7. A compound as defined in any one of claims 1 to 5 for use in the treatment and/or prophylaxis of a disease.
  8. 8. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prophylaxis of dyspnea, dysphagia, peripheral and cardiovascular disorders and peripheral and central nervous system disorders.
  9. 9. The compound as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prophylaxis of dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders, including diabetic microangiopathy, and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.
  10. 10. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prophylaxis of dyspnea and dysphagia, including sleep-induced dyspnea, such as inter alia obstructive sleep apnea (adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome), central sleep apnea, tidal breathing, primary sleep apnea of an infant, obviously life threatening events, central sleep apnea due to use of drugs or other substances, obesity hypopnea syndrome, central respiratory drive disorder, sudden infant death, primary alveolar hypopnea syndrome, post-operative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in mountains, acute and chronic pulmonary diseases with hypoxia and hypercapnia, sleep related non-obstructive alveolar hypopnea and congenital alveolar hypopnea syndrome.
  11. 11. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prophylaxis of peripheral and cardiovascular conditions including diabetic microangiopathy, limb diabetic ulcers, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart conditions, peripheral and cardiovascular conditions, thromboembolic disorders and ischemia, peripheral circulatory disorders, reynolds' phenomenon, systemic scleroderma, CREST syndrome, microcirculation disorders and intermittent claudication.
  12. 12. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prophylaxis of peripheral and central nervous system disorders including dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity disorder, tourette's syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders resulting from changes in sex hormones, multiple sclerosis, alzheimer's disease, parkinson's disease and huntington's disease.
  13. 13. A medicament containing a compound as defined in any one of claims 1 to 5 in association with one or more inert, non-toxic, pharmaceutically suitable excipients.
  14. 14. A medicament comprising a compound as defined in any one of claims 1 to 5 in combination with one or more other active compounds selected from the group consisting of respiratory stimulators, psychotropic compounds, serotonin reuptake inhibitors, noradrenergic antidepressants, serotonergic antidepressants and tricyclic antidepressants, P2X3 antagonists, sGC stimulators, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulators, immunosuppressants and cytotoxic drugs.
  15. 15. A medicament according to claim 13 or 14 for the treatment and/or prophylaxis of dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders, including diabetic microangiopathy, and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.
  16. 16. Methods of treating and/or preventing dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders including diabetic microangiopathy, and peripheral and central nervous system disorders including neurodegenerative and neuroinflammatory disorders, in humans and animals by administering an effective amount of at least one compound as defined in any one of claims 1 to 5 or a medicament as defined in any one of claims 13 to 15.

Description

Substituted heterocyclic carboxamides and their use The present application relates to novel substituted heterocyclic carboxamides, processes for their preparation, their use alone or in combination for the treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders, including diabetic microangiopathy, and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders. The alpha 2 -adrenergic receptor (alpha 2 -AR) belongs to the family of G protein-coupled receptors. They bind to the pertussis toxin-sensitive inhibitory G proteins G 1 and G 0 and reduce adenylate cyclase activity. They are involved in the mediation of a variety of physiological effects in different tissues when stimulated by endogenous catecholamines (epinephrine, norepinephrine) released by synapses or reaching the site of action via the blood. Alpha 2 -AR plays an important physiological role, mainly in the cardiovascular and central nervous systems. Biochemical, physiological and pharmacological studies have shown that in addition to the various α 1 -AR subtypes, there are three α 2 -AR subtypes (α 2A,α2B and α 2C) in many cardiovascular-related target cells and tissues and neuronal target cells and tissues, which makes them attractive target proteins for therapeutic intervention. However, the interpretation of the exact physiological task of the receptor subtype has so far been difficult due to the lack of highly selective ligands and/or antagonists of the corresponding alpha 2 -AR [ Gyires et al , α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The α2-Adrenergic Receptors: Adrenergic Receptors in the 21st Century/Receptors, 2005, 241-265]. Obstructive Sleep Apnea (OSA) is a sleep-related respiratory disorder characterized by recurrent episodes of upper airway obstruction. The interaction between the two opposing forces ensures the patency of the upper airway during inspiration. The distention of the upper airway muscles counteracts the negative pressure in the lumen, causing the lumen to contract. Active contraction of the diaphragm and other ancillary respiratory muscles creates negative pressure in the respiratory tract, thus constituting the driving force for breathing. The stability of the upper airway is essentially dependent on the coordinated and contractile characteristics of the upper airway dilated muscle. The upper airway collapse in OSA is thought to occur early in sleep because the multiple dilated muscles of the upper airway have reduced activity, which results in the physiologically sensitive airway no longer remaining open. However, the dilated muscles of some upper airways, including the genioglossus muscle (which is the most important extensor in the upper airways and is innervated by hypoglossal nerves), may increase activity during sleep in response to respiratory stimuli, potentially counteracting some changes in early sleep. OSA patients have been observed to have an interval of no apnea during which the activity of the genioglossus muscle is increased by only 25-40% compared to sleep with recurrent obstructive apnea [ Jordan AS, white DP, loyl et al , Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32(3): 361-8]. norepinephrine is one of the most potent neuromodulators of sublingual motor neuron activity [Horner R.L. Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196]. it is believed that reduced norepinephrine stimulation results in sleep-induced reduced excitability of the sublingual motor neurons, resulting in reduced activity of the dilated muscle of the upper airway, particularly reduced activity of the genioglossus muscle. Studies have shown that increasing the concentration of norepinephrine in the brain by administration of the selective norepinephrine reuptake inhibitor reboxetine (reboxetine) can improve the severity of sleep apnea in patients with obstructive sleep apnea (Altree TJ, aishah A, loffer KA et al , The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial. J Clin Sleep Med. 2023 Jan 1;19(1):85-96). Obstructive sleep apnea patients have high mortality and high morbidity due to cardiovascular disorders such as hypertension, myocardial infarction, and stroke [ Vrints et al Acta Clin belg, 68, 169-78 (2013) ]. The α 2C -adrenergic receptor modulates norepinephrine released by central noradrenergic neurons. They are autoreceptors invol