EP3386993A1 - Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same - Google Patents

Abstract

The invention relates to novel (2-phenylimidazo[1,2-a]pyridin-3-yl)methyl-substituted perhydropyrrolo[3,4-c]pyrrole derivatives, to methods for producing same, to the use thereof alone or in combination for the treatment and/or prevention of diseases, and to the use thereof for producing drugs for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of breathing disorders including sleep-related breathing disorders such as obstructive and central sleep apnea and snoring.

Description

 Substituted Perhvdropvrrolo | 3.4-c | pvrrol derivatives and their use

The present application relates to novel, (2-phenylimidazo [l, 2-a] pyridin-3-yl) methyl-substituted perhydropyrrolo [3,4-c] pyrrole derivatives, processes for their preparation, their use alone or in Combinations for the treatment and / or prevention of diseases, and their use for the manufacture of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of respiratory disorders, including sleep-disordered breathing disorders such as obstructive and central sleep apnea and snoring.

Potassium channels are nearly ubiquitous membrane proteins involved in a variety of different physiological processes. This includes the regulation of the membrane potential and electrical excitability of neurons and muscle cells. Kaiium channels are subdivided into three larger groups, which differ in the number of transmembrane domains (2, 4 or 6). The group of potassium channels, in which two pore-forming domains are flanked by four transmembrane domains, are called K2P channels. Functionally, the K2P channels mediate largely K ⁺ background currents, independent of time and voltage, and contribute significantly to the maintenance of the resting membrane potential. The family of K2P channels comprises 15 members subdivided into six subfamilies based on sequence, structure, and function similarities: TWIK, TREK, TASK, TALK, THiK, and TRESK.

Of particular interest are TASK-1 (KCNK3 or K2P3.1) and TASK. -3 (KCNK9 or K2P9.1) of the TASK (TWIK-related acid-sensitive IC c / tararae /) subfamily. These channels are functionally characterized by the flow of so-called "leak" or "background" currents as they maintain the voltage-independent kinetics, thereby responding to a variety of physiological and pathological influences with an increase or decrease in activity. Characteristic for TASK channels is the sensitive reaction to a change in the extracellular pH: The channels are inhibited at acidic pH and activated at alkaline pH.

TASK-1 is expressed predominantly in the central nervous system and in the cardiovascular system. Relevant expression of TASK-1 was found in the brain, spinaigangia, motor neurons of the

Hypoglossal nerve and trigeminal nerve, in the heart, carotid body, pulmonary artery, aorta, lung, pancreas, placenta, uterus, kidney, adrenal gland, small intestine and stomach as well as on T-lymphocytes. TASK-3 is mainly expressed in the central nervous system. Relevant expression of TASK-3 was found in the brain, in motor neurons of the hypoglossal and trigeminal nerves, and in neuro-epithelial lines of the carotid body and lungs as well as on T-lymphocytes. Lower expression is found in the heart, stomach, testes and adrenals.

TASK-1 and TASK-3 channels play a role in the regulation of respiration. Both channels are expressed in respiratory neurons of the respiratory center in the brainstem, among others in neurons that generate the respiratory rhythm (ventral respiratory group with the pre-Bötzinger complex), and in the noradrenergic locus caeruleus as well as in serotonergic neurons of the raphe nucleus , Due to the pH dependence, the TASK channels here take on the function of a sensor that translates extracellular pH changes into corresponding cellular signals [Bayliss et al., Pflugers Ar eh. 467. 917-929 (2015)]. Also in the carotid body, a peri- pheral chemoreceptor that measures pH, O2 and ( ^' ) of the blood and sends signals to the respiratory center in the brain stem to regulate respiration, TASK-1 and TASK-3 TASK-1 knockout mice have been shown to have a decreased ventilatory response (increase in respiratory rate and tidal volume) to hypoxia and normoxic hypercapnia [Trapp et al., J. Neurosci., 28, 8844-8850 (2008). In addition, TASK-1 and TASK-3 channels were detected in motor neurons of the hypoglossal nerve, the XIIth Himnerv, which plays an important role in the maintenance of the upper respiratory tract [Berg et al., J. Neurosci. 6693-6702 (2004)].

Intranasal administration of a potassium channel blocker blocking the TASK-1 channel in the nanomolar range in an S chapafon model 1 on the anesthetized pig resulted in an inhibition of the collapse- ability of the pharyngeal airway muscles and in a sensitization of the negative pressure reflex upper respiratory tract. Intra-nasal administration of the kaiium channel blocker is thought to depolarize mechanoreceptors in the upper respiratory tract, and activation of the negative pressure reflex leads to increased upper airway muscle activity, stabilizing the upper respiratory tract and preventing collapse. Over such upper airway stabilization, TASK channel blockade may be of major importance for obstructive sleep apnea and snoring [Wirth et al., Sleep 36: 699-708 (2013); Kiper et al., Pflugers Arch. 467, 1081-1090 (2015)].

Obstructive sleep apnea (OSA) is a sleep-disordered breathing disorder characterized by repeated episodes of upper airway obstruction. During inhalation, the patency of the upper respiratory tract is ensured by the interaction of two opposing forces. The adjunctive effects of the upper airway muscles counteract the negative intraluminal pressure that narrows the lumen. The active contraction of the diaphragm and the other auxiliary respiratory muscles creates a negative pressure in the airways and thus represents the driving force for breathing. The stability of the upper respiratory tract is determined by the Coordination and contraction property of the dilating muscles of the upper respiratory tract determined.

The genioglossus muscle plays a crucial role in the pathogenesis of obstructive sleep apnea. The activity of the genioglossus muscle increases with decreasing pressure in the pharynx in the sense of a dilating compensatory mechanism. Innervated by the hypoglossal nerve, it pulls the tongue forward and down, thus expanding the pharyngeal airway [Verse et ah, Somnologie 3, 14-20 (1999)]. The tension of the dilating muscles of the upper respiratory tract is modulated among other things by mechanoreceptors / expansion receptors in the nasopharyngeal space [Bouillette et al., J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]. Local anesthesia of the upper airway may cause an additional reduction in the activity of the genioglossus muscle in patients with severe sleep apnea during sleep [Berry et al., Am. J. Respir. Grit. Care Med. 156, 127-132 (1997)]. Patients with obstructive sleep apnea have high mortality and morbidity in the wake of cardiovascular diseases such as cardiovascular disease. Hypertension, heart attack and stroke [Vrints et ah, Acta Clin. Belg. 68, 169-178 (2013)].

In the case of central sleep apnea episodic inhibitions of the respiratory drive occur as a result of a disturbed brain function or a disturbed respiratory regulation. Central respiratory disorders lead to mechanical respiratory arrest, i. no respiratory activity takes place during these episodes, all respiratory muscles, including the diaphragm, temporarily stand still. In central sleep apnea, there is no upper airway obstruction.

Primary snoring also does not cause upper airway obstruction. However, the narrowing of the upper respiratory tract increases the flow rate of the inhaled and exhaled air. This, in conjunction with the relaxed muscles, causes the soft tissues of the mouth and throat to flutter in the airstream. This slight vibration then generates the typical low noise sounds.

Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by recurring partial upper airway obstruction during sleep. This leads to an increase of the airway resistance and thus to an increase in the work of breathing with considerable intrathoracic pressure fluctuations. The negative intra-thoracic pressure development during inspiration can reach values that occur as a result of complete airway obstruction in obstructive sleep apnea. The pathophysiological effects on the heart, circulation and sleep quality correspond to those in obstructive sleep apnea. The pathogenesis, as in obstructive sleep apnea, is a disturbed reflex mechanism of the pharyngeal dilating muscles during sleep during inspiration to accept. Obstructive snoring is often the precursor to obstructive sleep apnea [Hollandt et al, ENT 48, 628-634 (2000)].

TASK channels also appear to play a role in the cell death of neurons. In the animal model of myelin oligodendrocyte glycoprotein (MOG) -induced autoimmune encephalomyelitis, an animal model of multiple sclerosis, TASK-1 knock-out mice showed reduced neuronal degeneration. Inhibition of TASK channels appears to be neuroprotective via prevention of neuronal apoptosis, and may therefore be of interest for the treatment of neurodegenerative diseases [Bittner et al, Brain 1, 2, 2501-2516 (2009)].

Furthermore, it has been described that T lymphocytes express TASK-1 and TASK-3 channels and that inhibition of these channels results in decreased cytokine production and proliferation following stimulation of T lymphocytes. Selective inhibition of TASK channels on T lymphocytes improved disease progression in an animal model of multiple sclerosis. The blockade of TASK channels may therefore also be of importance for the treatment of autoimmune diseases [Meuth et al, J. Biol. Chem. 283, 14559-14579 (2008)]. TASK-1 and TASK-3 are also expressed in the heart [Rinne et al, .1. Mol Cell Cardio l 8 1. 71 -80 (2015)]. Since TASK-1 is particularly strongly expressed in the conduction system and in the atrium, this channel could play a role in the induction of conduction disorders or supraventricular arrhythmias. At the heart, TASK-1 appears to contribute to a background current, which in turn contributes to the maintenance of resting potential, action potential duration, and repolarization [Kim et al, Am. J. Physiol 277, H1669-1678 (1999)]. It has been shown on human heart muscle cells that the blockade of the TASK-1 ionic current leads to an extension of the action potential [Limberg et al., Cell. Physiol. Biochem. 28, 61 3-624 (201 1)]. Furthermore, an extended QT time was detected in TASK-1 knockout mice [Decher et al, Cell. Physiol. Biochem. 28, 77-86 (201 1)]. The inhibition of TASK channels could thus be of importance for the treatment of cardiac arrhythmias, especially atrial fibrillation.

TASK channels also appear to play a role in the regulation of vascular tone in certain vessels. Relevant expression of TASK-1 was found in the smooth muscle of pulmonary and mesenteric arteries. In studies on smooth muscle cells from human pulmonary arteries TASK-1 has been shown to play a role in the regulation of pulmonary vascular tone. TASK-1 may be involved in hypoxic and acidosis-induced pulmonary vasoconstriction [Tang et al., Am. J. Respir. Cell. Mol. Biol. 41, 476-483 (2009)]. In glomerulosa cells of the adrenal cortex, TASK-1 plays a role in potassium conductance [Czirjak et al, Mol. Endocrinol. 14, 863-874 (2000)].

TASK channels may also be important in apoptosis and tumorigenesis. In breast cancer, colon cancer and lung cancer biopsies as well as metastatic prostate cancer and melanoma cells, TASK-3 has been found to be highly overexpressed [Mu et al, Cancer Cell 3, 297-302 (2003); Kim et al, APMIS U2, 588-594 (2004); Pocsai et al., Cell. Mol. Life. 63, 2364-2376 (2006)]. A point mutation on the TASK-3 channel, which shuts off the channel function, simultaneously abolishes the tumor-forming effect (proliferation, tumor growth, apoptosis resistance) [Mu et al., Cancer Cell 3, 297-302 (2003)]. Overexpression of TASK-3 and TASK-1 in a murine fibroblast cell line (C8 cells) inhibits intracellular apoptosis pathways [Liu et al., Brain Res. 1031. 164-173 (2005)]. The blockade of TASK channels may therefore also be important for the treatment of various cancers.

The object of the present invention is therefore to provide novel substances which act as potent and selective blockers of TASK-1 and TASK-3 channels and, as such, in particular for the treatment and / or prevention of respiratory disorders, including sleep-related respiratory disorders as obstructive and central sleep apnea and snoring, as well as other diseases.

US 2002/0022624-A1 describes various azaindole derivatives, including imidazo [1,2-a] pyridines, as substance P antagonists for the treatment of CNS diseases. WO 2004/035578-A1 discloses 3- (aminomethyl) imidazo [1,2-a] pyridine derivatives as inhibitors of NO synthase, which can be used to treat a variety of diseases. WO 2009/143156 A2 claims 2-phenylimidazo [1,2-a] pyridine derivatives which are likewise suitable as modulators of GABA _A receptors for the treatment of CNS disorders. WO 2011/113606-A1 and WO 2012/143796-A2 disclose bicyclic imidazole derivatives which are suitable for the treatment of bacterial infections or inflammatory diseases. EP 2 671 582 A1 discloses bicyclic imidazole derivatives and their therapeutic applications as inhibitors of T-type calcium channels. WO 2012/130322 A1 describes 2,6-diaryl-3- (piperazinomethyl) imidazo [1,2-a] pyridine derivatives which, owing to their HIF-1-inhibiting activity, in particular for the treatment of inflammatory and hyperproliferative Diseases are suitable. In WO 2014/187922-A1 various 2-phenyl-3- (piperazinomethyl) imidazo [1,2-a] pyridine derivatives are disclosed as inhibitors of glucose transporters (GLUT), which are used for the treatment of inflammatory, proliferative, metabolic , neurological and / or autoimmune diseases can be used. In WO 2015/144605-A1, aeylated bicyclic amine compounds are inhibitors of autotaxine and lysophosphatidic acid production, which are suitable for the treatment of various diseases.

The present invention relates to compounds of the general formula (I)

in which

R ^{1 is} halogen, cyano or (C i -Ct) alkyl and

R- is (C4-C6) -cycloalkyl, wherein a ring CH ₂ group can be replaced by -O-. or

R - represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

stands,

* marked the link to the adjacent carbonyl group and

Is hydrogen, fluorine, chlorine, bromine, cyano, (Ci-C3) alkyl or (Ci-C3) alkoxy, wherein (Ci-C ₃ ) -Aikyi and (Ci-C ₃ ) -Aikoxy up to three times with fluorine can be substituted

Hydrogen, fluorine, chlorine, bromine or methyl, R ^{5 is} hydrogen, fluorine, chlorine, bromine or methyl and

R ^{6 is} hydrogen or (C 1 -C 3) -alkoxy which may be substituted up to three times by fluorine,

is a group -OR ⁷ or -NR ⁸ R ⁹ , in which

R and R ^{8 are} each (Ci-C ₄ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl, phenyl, benzyl, 1-phenylethyl or

2-phenylethyl, wherein (Ci-C ₄ ) alkyl may be substituted up to three times with fluorine and wherein phenyl and the phenyl groups in benzyl, 1-phenylethyl and 2-phenylethyl up to two times, same or different, with a Rest selected from the series fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and ethoxy may be substituted, and

R ^{9 is} hydrogen or methyl, or

R ⁸ and R ⁹ are linked together and, together with the nitrogen atom to which they are bonded, a tetrahydro quinoline ring of the formula (c) or tetrahydroisoquinoline ring of the formula (d)

 form (c) (d),

where ** denotes the linkage to the carbonyl group, and their salts, solvates and solvates of the salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas (IA), (IB) and (IC) and their salts, solvates and solvates encompassed by formula (I) the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of Salts acts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, benzoic and embonic acids.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that co-ordinates with water. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atrop isomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds according to the invention. Under an isotopic variant of a compound of the invention In this case, a compound is understood in which at least one atom is exchanged within the inventive compound for another atom of the same atomic number, but with a different atomic mass than the usual or predominantly occurring in nature atomic mass. Examples of isotopes which can be incorporated in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium) , ¹³ C ^{,! 4} C, ¹⁵ N, ¹⁷ O, ^ls O, 2 P, ³³ P, ³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of drug in the body; Due to the comparatively easy production and detectability, compounds labeled with Ή or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging body half-life or reducing the required dose of the active ingredient; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" here denotes compounds which may themselves be biologically active or inactive, but are reacted during their residence time in the body by, for example, metabolic or hydrolytic routes to them in accordance with the invention.

In the context of the present invention, the substituents and radicals, unless specified otherwise, have the following meaning:

In the context of the invention (yCi) -alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

(CVC -) -Alkvl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 3 carbon atoms. Examples include: methyl, ethyl, propyl and isopropyl. (CVC ^'alkoxy represents for the purposes of the invention a straight-chain or branched alkoxy radical having 1 to 3 Kohienstoffatomen Examples are:.. Methoxy, ethoxy, w-propoxy and isopropoxy l Ci-C h) -Cvcloalkyl is in the context of Inventive of a monocyclic, saturated cycloalkyl group having 4 to 6 carbon atoms. Examples include cyclobutyl, cyclopentyl and cyclohexyl. In the context of the invention, ogen includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine or bromine. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} chlorine, bromine or isopropyl and

R - represents cyclobutyl, cyclopentyl or cyclohexyl or

R - represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent carbonyl group and

R ^{3 is} fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,

R "means hydrogen or fluorine,

IV is hydrogen, fluorine, chlorine or methyl and

R "is methoxy, difluoromethoxy, trifluoromethoxy or isopropoxy,

is a group -OR or -NR ⁸ R ⁹ , in which

R is isopropyl, isobutyl, ferric butyl, cyclopentyl, phenyl or benzyl, where phenyl and the phenyl group in benzyl up to two times, identically or differently, with a radical selected from the group fluorine, chlorine, methyl, trifluoromethyl , Methoxy and ethoxy may be substituted,

R ⁸ Phenyi, benzyl or 1 -Phenyi ethyl, wherein phenyl and the Phenyi groups in benzyl and I -Phenyiethyl up to two times, same or different, selected from the group fluorine, chlorine, methyl, trifluoromethyl, methoxy and Ethoxy can be substituted, and

R ^{9 is} hydrogen or methyl, or

R ⁸ and R ⁹ are linked together and, together with the nitrogen atom to which they are attached, a tetrahydro quinoline ring of the formula (c)

 (c) form,

 in which ** marks the linkage to the carbonyl group, and their salts, derivatives and solvates of the salts.

A particular embodiment of the present invention relates to compounds of the formula

(I), in softer

R ^{1 is} chlorine or bromine, and their salts, solvates and solvates of the salts.

Another particular embodiment of the present invention relates to compounds of the formula (I) in which

R ^{2 is} cyclobutyl or cyclopentyl, and their salts, solvates and solvates of the salts.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R - represents a phenyl group of the formula (a)

where * denotes the linkage to the adjacent Carbonyi group,

R ^{3 is} fluorine, chlorine, methyl, trifluoromethyl or methoxy and

R ^{4 is} hydrogen or fluorine, and their salts, solvates and solvates of the salts. A further particular embodiment of the present invention relates to compounds of the formula (I) in which

R- for a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent Carbonyi group, R ^{5 is} hydrogen and

R ⁶ (C 1 -C 3) -alkoxy, which may be substituted up to three times by fluorine, and their salts, solvates and solvates of the salts.

Another particular embodiment of the present invention relates to compounds of formula (I) in which

R ² for a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent carbonyl group,

R ^{5 is} hydrogen, fluorine or methyl and

R 'is methoxy, and their salts, solvates and solvates of the salts.

Another particular embodiment of the present invention relates to compounds of

Formula (I), in softer

R- is a group -OR in which

R is phenyl or benzyl, where phenyl and the phenyl group in benzyl may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy, and their salts , Solvates and solvates of salts. Another particular embodiment of the present invention relates to compounds of

Formula (I) in which

R- is a group -NR ^S R ⁹ wherein

R ^{8 is} phenyl or 1-phenylethyl, where phenyl and the phenyl group in 1-phenylethyl may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy, and

R 'is hydrogen, or

R ⁸ and R ⁹ are linked together and, together with the nitrogen atom to which they are attached, form a tetrahydroquinoline ring of the formula (c)

 (c) in which ** marks the linkage to the carbonyl group, and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} chlorine, bromine or isopropyl and R- is cyclobutyl or cyclopentyl or

R - represents a phenyl group of the formula (a) or a pyridyl group of the formula (b) where * denotes the linkage to the adjacent carbonyl group and

R ^{3 is} fluorine, chlorine, methyl, trifluoromethyl or methoxy,

R ^{4 is} hydrogen or fluorine,

R ^{5 is} hydrogen, fluorine or methyl and

R 'means methoxy,

is a group -OR ⁷ or -NR ⁸ R ⁹ , in which

R is isopropyl, cyclopentyl, phenyl or benzyl, where phenyl and the phenyl group in benzyl may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,

R ⁸ represents phenyl or 1-phenylethyl, wherein the phenyl and the phenyl group in 1-phenylethyl may be substituted up to two times by identical or different radicals selected from the series comprising fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy, and

R ^{9 is} hydrogen, or

R ⁸ and R ⁹ are linked together and, together with the nitrogen atom to which they are attached, form a tetrahydroquinino ring of the formula (c)

 (c) form,

 where ** denotes the linkage to the carbonyl group, and their salts, derivatives and solvates of the salts.

Especially preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} chlorine or isopropyl and

R- for a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent carbonyl group,

Hydrogen, fluorine or methyl means and

R "denotes methoxy, as well as their salts, derivatives and derivatives of the salts The definitions of radicals given in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations independently of the particular combinations of radicals indicated ,

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges. The invention further provides a process for preparing the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)

in which R ^{1 has} the meaning given above. in the presence of a suitable reducing agent, either [A] with a compound of the formula (III) in which R ^{2 has} the meaning given above, to give a compound of formula (I) or

[B] with a protected perhydropyrrolo [3,4-c] pyrrole of the formula (IV)

PGN CO I NH

 (IV) in which PG is a suitable amino-protecting group such as tert. Butoxycarbo- nyl, benzyloxycarbonyl or (9if-fluoren-9-ylmethoxy) carbonyl, first to a compound of formula (V)

(V) in which PG and R ^{1 have} the meanings given above, then the protective group PG is split off and the resulting compound of the formula (VI)

in which R ^{1 has} the abovementioned meaning, then depending on the specific meaning of the radical R

[Bl] with a carboxylic acid of the formula (VII) in which R ^{2A is} (C 4 -C 9) -cycloalkyl in which a Ri ng- i: -G nippe may be exchanged for -O-, or for a phenyl group of the formula (a) or a pyridyl group of the formula (b) as described above, with activation of the carboxylic acid function in (VII) or with the corresponding acid chloride of the formula (VIII) o

_R 2A Λ _,

Cl (VIII), in which R ^{2A has} the abovementioned meaning, to give a compound of the formula (IA)

in which R ¹ and R ^{2A have} the meanings given above,

 implements

or

 [B-2] with a chloroformate or carbamoyl chloride of the formula (IX)

R ^2B ^ CI (IX),

 in which

is the group -OR ⁷ or -NR ⁸ R ^9A , wherein

R and R ^{8 have} the meanings given above

 and

R ^{9A has} the abovementioned meaning of R ', but is not hydrogen, to give a compound of the formula (IB)

in which R ¹ and R ^{2 have} the meanings given above, translates or

[B-3] with an isocyanate of the formula (X)

R ™ = C = O (X) in which R ^{8 has} the abovementioned meaning, to give a compound of the formula (IC)

^R (IC) in which R ¹ and R ^{8 have} the abovementioned meanings, and the compounds of the formulas (I), (IA), (IB) or (IC) thus obtained are optionally reacted with the appropriate (z) solvents and / or or (ii) converting acids into their solvates, salts and / or solvates of the salts.

As a reducing agent for the process steps [A] (II) + (III)> (I) and [B] (II) + (IV) -> (V)

[Reductive aminations] are suitable for such purposes conventional alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; Preferably, sodium triacetoxyborohydride is used. The addition of an acid, such as in particular acetic acid, and / or a dehydrating agent, such as molecular sieve or trimethyl or trimethyl orthoformate, may be advantageous in these reactions.

Particularly suitable solvents for these reactions are alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl-ethyl-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N, N-dimethylformamide (DMF) or mixtures of such solvents; is preferred Tetrahydrofuran used. The reactions generally take place in a temperature range from 0 ° C to + 50 ° C.

As the protective group PG in compound (IV), a common amino-protecting group such as tert. Butoxy carbonyl (Boc), benzyloxycarbonyl (Z) or (9 // - fluoren-9-ylmethoxy) carbonyl (Fmoc) can be used; tert is preferred. Butoxy carbonyl (Boc) used. The cleavage of the protective group in process step [B] (V) -> (VI) is carried out by known methods. So the tert. -Butoxy carbonyl -GroUP e usually by treatment with a strong acid, such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid, in an inert solvent such as diethyl ether, 1, 4-dioxane, dichloromethane or acetic acid cleaved. In the case of benzyloxycarbonyl as protective group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst, for example palladium on activated carbon. The (9H-fluoren-9-ylmethoxy) carbonyl group is generally cleaved with the aid of a secondary amine base such as diethylamine or piperidine [see, eg TW Greene and PGM Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999; PJ. Kocienski, Protecting Groups, 3 ^rd edition, Thieme, 2005].

Certain compounds of the formula (V), for example those in which PG is tert. -Butoxycarbonyl or benzyloxycarbonyl, also have a significant inhibitory activity against TASK-1 and TASK-3 and are insofar also included in the scope of the present invention, ie the compounds of formula (I). The process step [Bl] (VI) + (VII)> (IA) [amide formation] is carried out by known methodology with the aid of a condensation or activating agent. Carbodiimides such as NN'-diethyl, Λ ^' , for example, are suitable as such agents. Λ ^' ' -Dipropyl, NN -diisopropyl, N, N-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole ( CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-oxazolium Ethoxy-1-ethoxy-carbonyl-1,2-dihydroquinoline, α-chloroeneamines such as 1-chloro-N, N, 2-trimethylprop-1 -ene-1-amine, 1, 3, 5-triazine derivatives, such as 4 - (4,6-dimethoxy-1,3,5-triazm-2-yl) -4-methylmonominium chloride, phosphorus compounds such as n-propanephosphonic anhydride (PPA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), (2-oxo-3-oxazoiidinyl) -phosphoryichloride, benzotriazole-1-ynyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazole-1-ynyloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as 0- (benzotriazol-1-yl) -NNN'N'-tetramet hyluronium tetrafiuoroborate (TBTU), 0- (li7-6-chlorobenzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 0- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl- uronium hexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) or 2- (2-oxo-1 - (2H) -pyridyl ) -l, 1, 3,3-tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with other auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as the base of an alkali metal carbonate, eg Sodium or potassium carbonate, or a tertiary amine base, such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine or 4-N, N-dimethylaminopyridine (DMAP). As condensation or activating agent is preferably used 0- (7-Azabenzotriazol-l -yl) -NNN ', N'-tetramethyluronium hexafluorophosphate (HATU) in combination with A ^ N-diisopropylethylamine as the base. The alternative process via the carboxylic acid chloride (VIII) [(VI) + (VIII)> (IA)] is generally carried out in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine (NMM), N- Methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine, 4-N, N-dimethylaminopyridine (DMAP), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo [5.4. 0] undec-7-ene (DBU); Preferably triethylamine or NN-diisopropylethylamine is used.

Suitable inert solvents for these amide-forming reactions are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, Toluene, xylo !, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethylsulf oxide (DMSO), N, N-dimethylformamide (DMF), N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP); also mixtures of such solvents can be used. Preferably, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, N, N-dimethylformamide or mixtures thereof are used. The reactions are usually carried out in a temperature range from -20 ° C to + 60 ° C, preferably at 0 ° C to + 40 ° C.

The process [B-2] (VI) + (IX) -> (IB) [formation of urethanes or substituted ureas] is carried out under similar reaction conditions with respect to solvent, base addition and temperature as previously described for the amide formation [Bl] (VI) + (VIII) ~~> (IA). The reaction [B-3] (VI) + (X)> (IC) is also carried out in one of the aforementioned inert solvents or solvent mixtures at a temperature in the range of 0 ° C to + 60 ° C; the addition of a base may optionally be omitted in this reaction. The amine compound (VI) can be used in the process steps [Bl] (VI) + (VII) or (VIII) -> (IA), [B-2] (VI) + (IX)> (IB) and [ B-3] (VI) + (X) -> (IC) are also used in the form of a salt, for example as hydrochloride or trifluoroacetate. In such a case, the reaction takes place in the presence of a correspondingly increased amount of the auxiliary base used in each case.

The processes described above may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar); In general, one works at normal pressure.

The compounds of the formula (II) in turn can be prepared by the process known from the literature by reacting 2-aminopyridine (XI) under the influence of a base with an acetophenone derivative of the formula (XII) in which R ^{1 has} the meaning given above and

X is a suitable leaving group, for example chlorine, bromine or iodine, to give a 2-phenylimidazo [1,2-a] pyridine of the formula (XIII) in which R ^{1 has} the abovementioned meaning, condensed and then formylated with a mixture of N, N-dimethylformamide and phosphorus oxychloride to (II).

The condensation reaction (XI) + (XII) - »(XIII) is usually carried out in an alcoholic

Solvents, such as methanol, ethanol, -P -propanol, isopropanol or -B -butanol, in an ether, such as diethyl ether, diisopropyl ether, methyl-feri.-butyl ether, T etrahydro furan, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, or in a dipoiar-aprotic solvent, such as NN-dimethylformamide (DMF), N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP), carried out at a temperature in the range of + 20 ° C to + 120 ° C; Ethanol is preferably used as solvent.

Suitable bases for this reaction are in particular alkali metal bicarbonates or carbonates, such as sodium or potassium bicarbonate or lithium, sodium, potassium or cesium carbonate, or else aluminum oxide; Sodium bicarbonate is preferably used. If appropriate, the reaction can also take place-with a corresponding increase in the reaction temperature-without addition of a base.

The regioselective formylation (XIII) - »(II) is carried out under the usual conditions of a Vilsmaier-Haack reaction by treating (XIII) with a preformed mixture of N, N-dimethylformamide and phosphorus oxychloride, which is used in large excess and at the same time serves as a solvent. The reaction is generally carried out in a temperature range from 0 ° C to + 100 ° C.

The compounds of formulas (III), (IV), (VII), (VIII), (IX), (X), (XI) and (XII) are either commercially available or described as such in the literature, or they may , starting from other commercially available compounds, can be prepared in a simple manner by methods known from the literature and known to the person skilled in the art. Numerous detailed regulations and further references are also contained in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates.

The preparation of the compounds of the invention can be exemplified by the following reaction schemes:

[R ^2A = (C4-C ") - cycloalkyl, wherein a ring-C H -C iruppc may be replaced by -O-, or a phenyl group of formula (a) or a pyridyl group of formula (b) (as described above as part of the scope of R)]. ScaJ

[R ^2A : see Scheme 1; R ^2B = -OR ⁷ or -NR ⁸ R ⁹ (as described above as part of the scope of R ² , but here R ⁹ is not hydrogen)]. The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

The compounds according to the invention are potent and selective blockers of TASK-1 and TASK-3 channels and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular those caused by activation of TASK-1 and or TASK-3 or by activated TASK-1 and / or TASK-3, as well as diseases secondary to TASK-1 and / or TASK-3 induced damage.

For the purposes of the present invention, disorders include disorders from the group of respiratory disorders and sleep-related respiratory disorders, such as obstructive sleep apnea (in adults and children), primary snoring, upper airway resistance syndrome, heavy snoring, hypopnea syndrome, central sleep apnea, mixed sleep apnea, Cheyne-Stoke respiration, primary sleep apnea in childhood, preterm apnea, central sleep apnea due to medication or use of other substances, obesity hypothermia ventilation syndrome, disturbed central respiratory drive, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders in high altitude adaptation, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and the congenital central alveolar hypoventilation syndrome.

The compounds of the invention may be further used for the treatment and / or prevention of neurodegenerative diseases such as dementia, dementia with Lewy bodies, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, silver grain disease , frontotemporal dementia and parkinsonism of chromosome 17, multisystem atrophy, spinocerebellar ataxia, Kennedy spinobulbar muscle atrophy, Friedreich's ataxia, dentatorubro- pallidoluysic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob Disease, infantile neuroaxonal dystrophy, neurodegeneration with iron deposition in the brain, frontotemporal ileal degeneration with ubiquitin-proteasome system, and familial encephalopathy with Neu-Γββφίηη-βηβαΜύβββη.

The compounds according to the invention can moreover be used for the treatment and / or prevention of neuroinflammatory and neuroimmunological disorders of the central nervous system (CNS), such as multiple sclerosis (encephalomyelitis disseminata), transverse myelitis, neuromyelitis optica, acute disseminated encephalomyelitis, optic neuritis , Meningitis, encephalitis, demyelinating diseases and inflammatory vascular changes in the central nervous system.

The compounds of the invention are also useful in the treatment and or prevention of cancers, such as skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

The compounds according to the invention are also suitable for the treatment and / or prevention of cardiac arrhythmias and arrhythmias, such as, for example, arrhythmia and ventricular disorders, conduction disorders such as grade I-III atrio-ventricular blockades, supraventricular tachyarrhythmias. Atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncope, and AV knotcn-reemry tachycardia. Other cardiovascular diseases for the treatment and / or prevention of which the compounds according to the invention can be used are, for example, cardiac insufficiency, coronary heart disease, stable and unstable angina pectoris, hypertension, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension ( PH), renal hypertension, peripheral and cardiac vascular diseases, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, thromboembolic disorders and ischaemia such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular disease, coronary and peripheral arterial spasm, edema formation such as b For example, pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, Rep Fusions, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and macrovascular damage (vasculitis), as well as for the prevention of restenosis example after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass surgery.

For the purposes of the present invention, the term cardiac failure encompasses both acute and chronic manifestations of cardiac insufficiency as well as specific or related forms of disease thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac insufficiency in valvular heart failure, mitral stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary artery stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure , alcoholic cardiomyopathy, cardiac storage disorders as well as diastolic and systolic heart failure.

The compounds of the present invention may further be used for the treatment and / or prevention of asthmatic disorders of varying severity with intermittent or persistent history (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma) of various types Forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchial ectasia, pneumonia, farmer's lung and related diseases, cough and colds (chronic inflammatory cough, iatrogenic Cough), nasal mucosal inflammations (including medicinal rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and polyps.

In addition, the compounds according to the invention are suitable for the treatment and / or prevention of kidney diseases, in particular kidney insufficiency and kidney failure. For the purposes of the present invention, the terms renal insufficiency and renal failure include both acute and chronic causes of it as well as these underlying or related kidney diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases , nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection and immune complex-induced renal diseases, toxicology-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, Hypertensive nephrosclerosis and nephrotic syndrome, which has been diagnosed to be abnormally abnormal, for example, due to an abnormally reduced creatinine and / or water loss Blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such. Glutamyl synthase, altered urinary or urine output, increased microalbuminuria, macro albuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism ,

Moreover, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes (LUTS) , neurogenic overactive bladder (OAB), incontinence such as mixed, urgency. Stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain as well as erectile dysfunction and female sexual dysfunction. The compounds of the invention are further useful in the treatment and / or prevention of inflammatory and autoimmune diseases, such as rheumatoid diseases, inflammatory ocular diseases, chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS). acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema (eg, pulmonary emphysema induced by cigarette smoke), Cystic fibrosis (CF), sepsis (SI RS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis, oophoritis , Salpingitis and vulvovaginitis, as well as for the treatment and / or prevention of fibro diseases of the internal organs, such as the lung, heart, kidney, bone marrow and especially the liver, dermatological fibroses and F brotische diseases of the eye suitable. For the purposes of the present invention, the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders. Scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis). The compounds according to the invention can also be used for promoting wound healing, for combatting postoperative scarring, for example after glaucoma operations, and for cosmetic purposes in the case of aging or keratinizing skin.

In addition, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dysiipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, fatty addiction (Obesity), obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), anemias such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, anemia due to acute blood loss, displacement anaemias and aplastic anemias, gastrointestinal disorders and abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea. Celiac disease, hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis), diseases of the central nervous system (stroke, epilepsy, depressions), immune diseases, child thyroid disorders (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis , Keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, Sweet syndrome, Weber-Christian syndrome, scarring, wart formation, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, Uveitis, choroiditis, ophthalmitis), viral diseases (by influenza, adeno- and coronaviruses, such as HPV, HC MV, HIV, SARS), skeletal, joint and skeletal muscle diseases. Inflammatory arterial changes (various forms of arteritis such as endarteritis, mesteritis, periarteritis, panarteritis, rheumatoid arthritis, deformity of the arteritis, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, as well as the Horton syndrome, Churg-Strauss syndrome and the Takayasu's arteritis), the Muckle-Well syndrome, the Kikuchi. inflexibility, polychondritis, scleroderma, and other diseases with an inflammatory or immunological component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, organ transplantation rejection reactions, and wound healing and angiogenesis especially in chronic wounds. Because of their characteristic profiles, the compounds according to the invention are preferably suitable for the treatment and / or prevention of respiratory disorders, in particular sleep-related respiratory disorders such as obstructive and central sleep apnea and primary and obstructive snoring, for the treatment and / or prevention of cardiac arrhythmias and arrhythmias and for treatment and / or prevention of neurodegenerative, neuroinflammatory and neuro-immunological diseases.

The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete. Another object of the present invention is thus the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. A further subject of the present invention are therefore medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned diseases. As suitable combination active ingredients are exemplified and preferably mentioned:

Respiratory stimulants, such as by way of example and preferably theophylline, doxapram, nicethamide or caffeine;

· Psychostimulating compounds, such as by way of example and preferably modafmil or armodafilm;

 • Amphetamines and amphetamines - The i va t e. as exemplified and preferably amphetamine, metamphetamine or methylphenidate;

 Serotonin reuptake inhibitors such as, by way of example and by way of illustration, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone;

Serotonin precursors, such as by way of example and preferably L -tryptophan; Selective serotonin norepinephrine reuptake inhibitors, such as by way of example and preferably venlafaxine or duloxetine;

 »Noradrenergic and specific serotonergic antidepressants, such as by way of example and preferably mirtazapine;

Selective norepinephrine reuptake inhibitors, such as by way of example and preferably reboxetine;

Tricyclic antidepressants, such as by way of example and preferably amitriptyline, protriptyline,

Doxepin, trimipramine, imipramine. Clomipramine or desipramine;

 Alpha2-adrenergic agonists, such as, by way of example and by way of illustration, clonidine;

 GABA agonists, such as by way of example and preferably baclofen;

Alpha sympathomimetics such as, by way of example and by way of illustration, xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetryzolin or tramazoline;

 Giucocorticoids, such as by way of example and preferably fluticasone, budesonide, beclomethasone, mometasone, tixocortol or triamcinolone;

 • cannabinoid receptor agonists;

Carbonic anhydrase inhibitors, such as by way of example and preferably acetazolamide, methazolamide or diclofenamide;

 Opioid and benzodiazepine receptor antagonists, such as by way of example and preferably flumazole, naloxone or naltrexone;

 Cholinesterase inhibitors, such as by way of example and preferably neostigmine, pyridotestine, physostigmine, donepezii, galantamine or rivastigmine;

• Λ ^' -methyl-D-aspartate and glutamate antagonists, such as by way of example and preferably amantadine, memantine or sabeluzol;

 Nicotine receptor agonists;

 Leukotriene receptor antagonists, such as, by way of example and by way of preference, montelukast or tripelukast;

 Dopamine receptor antagonists, such as by way of example and preferably dromperidone, metoclopramide or benzamide, butyrophenone or phenothiazine derivatives;

Appetite suppressants, such as by way of example and preferably sibutramine, topiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists; Proton pump inhibitors, such as by way of example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;

 • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafü, Avanafil, Mirodenafil or Lodenafil;

NO and heme-independent activators of the soluble guany latcy clas e (sGC), in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO

02/070510 compounds described;

NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), in particular riociguat, vericiguat and those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 201 1/147809 WO 2012/004258, WO 2012/028647 and WO 2012/059549;

 Prostacyclin analogs and IP receptor agonists such as, by way of example, and preferably iloprost, heraprost. Treprostinil, epoprostenol or selexipag;

 Endothelin receptor antagonists such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan;

Compounds that inhibit human neutrophil elastase (HNE), such as by way of example and preferably Sivelestat or DX-890 (Reltran);

 Compounds which inhibit the degradation and remodeling of the extracellular matrix, by way of example and preferably inhibitors of the matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (here in particular of MMP-1, MMP-3, MMP) 8, MMP-9, MMP-10, MMP-1 1 and MMP-13) as well as the metallo-elastase

(MMP-12);

Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT ₂ B receptor such as PRX-08066;

 • Antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-ß, CTG F. I L-1. I L -4, IL-5, IL-6, IL-8, IL-1 3 and integrins;

The Rho kinase inhibiting compounds, as exemplified and preferably Fasudil, Y-27632, SLx-21 19, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

the signal transduction cascade inhibiting compounds, by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine Thr eoninkinas e inhibitors, such as exemplified and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, Sunitinib, cediranib, axitinib, telatinib, imatinib, Ii ri v anib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;

anti-obstructive agents, e.g. for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma are used, by way of example and preferably from the group of inhaled or systemically applied beta-adrenergic receptor agonists (beta-mimetics) and the inhaled anti-mam carcinogenic substances; anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids and dimethyl fumarate, fingolimod, glatiramer acetate, β-interferons, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tripelukast, Azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, interferon-γ, pirfenidone or etanercept;

antifibrotic agents such as, by way of example and by way of illustration, lysophosphatidic acid receptor 1 (LPA-I) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists or pirfenidone;

antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances; antihypertensive agents, by way of example and with preference from the group of calcium antagonists, angiotensin all antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelialin antagonists, renin inhibitors, aipha receptor blockers, beta-receptor blockers, Mineralocorticoid receptor antagonists and diuretics; and or

lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha -. PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, (i acidic reabsorption inhibitors and lipoprotein (a) antagonists. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, by way of example and by way of preference, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.

By antithrombotic agents are preferably understood compounds from the group of platelet aggregation onshemmer, anticoagulants and the profibrinolytic substances. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, ivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-1 76b. PMD-3112, YM-I50, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin ΑΠ antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with an alpha-1 receptor blocker. as exemplified and preferably prazosin administered.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetaioi, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucidinol. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin all antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril. Delapril, fosinopril, Q inopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a minerocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth - azon, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene administered.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the AC AT inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors, and the lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, compounds of the invention in combination with a thyroid receptor agonist such as, for example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), ( ^"GS 23425 or Axitirome (CGS 26214) administered In a preferred embodiment of the invention, the compounds according to the invention are used in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, Lovas tatin, Simvasatin, Pravasatin, Fluvastatin, Atorvas tatin, Rosuvastatin or Pitavas tatin administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an AC AT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably impiitapid. BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a PPAR-gamma agonist, as exemplified and preferably

Pioglitazone or rosiglitazone. In a preferred embodiment of the invention, the compounds of the invention are used in combination with a PPAR delta agonist, as exemplified and preferably

GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, such as, for example and preferably, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the present invention are used in combination with a bile acid reabsorption inhibitor, such as, by way of example and preferably, AS BT (= IBAT) inhibitors, e.g. AZD-7806, S-8921, AK-105, BARI! 74 1. SC-435 or SC -635. administered.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

Particularly preferred are combinations of the compounds according to the invention with one or more further active compounds selected from the group consisting of respiratory stimulants, psycho-stimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonin and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.

If required, the substances according to the invention can also be used in conjunction with the use of one or more medical-technical devices or aids, as long as this does not lead to undesired and unacceptable side effects. Medical devices and auxiliaries which are suitable for such a combination application are exemplary and preferably:

• Devices for positive airway ventilation, such as CPAP (contra- ion positive airway pressure) devices, BiPAP (bilevel positive airway pressure) devices, and preferably

IPPV (intermittent positive pressure ventilation) device &te;

 • Neuro stimulator of the hypoglossal nerve;

 Intraoral aids, such as by way of example and preferably protrusion clips;

 • nasal one-way valves;

· Nasal stents.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above. The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, otic, or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), rapidly disintegrating in the oral cavity Tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebuizers, metered dose aerosols), nasal drops, solutions or sprays, throat sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shakes - Mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, scattering powders, implants or stents.

Preferred are oral, intravenous, intranasal and pharyngeal administration.

According to one embodiment, the application is intranasal. According to one embodiment, the intranasal application is carried out with the aid of nasal drops or a nasal spray. According to one embodiment, the intranasal administration is carried out with the aid of a nasal spray. The compounds of the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. For oral administration, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg of body weight. According to one embodiment, the dosage for intranasal administration is about 0.1 g to 500 μg per day. According to another embodiment, the dosage for intranasal administration is about 1 μg to 250 μg per day. According to a further embodiment, the dosage for intranasal administration is about 1 g to 120 g per day. According to a further embodiment, the dose of about 0.1 μg to 500 μg per day, or of about 1 μg to 250 μg per day, or of about 1 μg to 120 μg per day, once a day before sleep is administered intranasally. According to one embodiment, the dose is applied from about 0.1 μg to 500 μg per day, or from about 1 μg to 250 μg per day, or from about 1 μg to 120 μg per day, once a day, half each in each nostril. According to one embodiment, the dose is from about 0.1 μg to 500 μg per day. or from about 1 μg to 250 μg per day, or from about 1 μg to 120 μg per day, once daily before sleeping, each half applied to each nostril.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

A. Examples

Abbreviations and acronyms: abs. absolutely

 Ac acetyl

aq. aqueous, aqueous solution

 Boc tert-butoxycarbonyl

br. wide (at NMR signal)

 Example. Example

 Bu Butyl

c concentration

about circa, about cat. catalytic

 CI chemical ionization (in MS)

d doublet (by NMR)

d day (s)

 DCi direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DMF IV, N-dimethylformamide

 DM SO dimethylsulfoxide

dq doublet by quartet (by NMR)

dt doublet of triplet (by NMR)

d. Th. Of theory (in chemical yield)

 EI electron impact ionization (in MS)

eq. Equivalent (s)

 ESI electrospray ionization (in MS)

 Et ethyl

h hour (s)

 H ATU 0- (7 -azabenzotriazole-1-yl) -N, N, N ', iV'-tetramethyluronium hexafluorophosphate

 HOBt 1-Hydroxy-lH-benzotriazole hydrate

 HPLC high pressure, high performance liquid chromatography iPr isopropyl

conc. concentrated (at solution)

 LC liquid chromatography

 LC-MS Fiüssigchromatographie-coupled mass spectrometry

Literature (position)

m multiplet (by NMR)

 Me methyl

min minute (s)

 MS mass spectrometry

 NMR nuclear resonance spectrometry

 Ph phenyl

 Pr Propyl

q quartet (by NMR)

quant. quantitative (at chemical yield)

 RP reverse phase (reversed phase, for HPLC)

RT room temperature Retention time (by HPLC, LC-MS)

s singlet (by NMR)

t triplet (by NMR)

tBu tert-butyl

 TFA trifluoroacetic acid

 THF T etrahy dro furan

 UV ultraviolet spectrometry e

v / v volume to volume ratio (of a solution)

together

LC-MS and H PL methods:

Method 1 (LC-MS):

 Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 1 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; Gradient: 0.0 min 90% A -► 1.2 min 5% A ► 2.0 min 5% A; Temperature: 50 ° C; Flow: 0.40 ml / min; UV detection: 208-400 nm.

Method 2 (LC-MS):

Instrument MS: Thermo Scientific FT-MS; UHPLC device: Thermo Scientific UltiMate 3000; Column: Waters HSS T3 C18 1.8 μιη, 75 mm x 2.1 mm; Eluent A: 1: 1 water + 0.01% formic acid, eluent B: 1: 1 acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B ^~~ * 2.5 min 95% B 3.5 min 95% B; Temperature: 50 ° C; Flow: 0.90 ml / min; UV detection: 210-300 nm.

Method 3 (LC-MS):

 Instrument MS: Waters Micromass QM; Instrument H LC: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.5 μιη, 50 mm x 3.0 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A> 0.2 min 98% A ► 3.0 min 5% A

-> 4.5 min 5% A; Temperature: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.

Method 4 (LC-M S):

 Instrument MS: Waters Micromass Quattro Micro; Instrument H LC: Waters UPLC Acquity; Pillar: Waters BE I! C18 1.7 μm, 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A> 0.1 min 95% A ► 2.0 min 15% A ► 2.5 min 15% A - »2.51 min 10% A ► 3.0 min 10% A; Temperature: 40 ° C; Flow: 0.5 ml / min;

UV detection: 210 nm. Method 5 (LC-S):

 Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l

Acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A ► 0.3 min 90% A 1.7 min 5% A ► 3.0 min 5% A; Flow: 1.20 ml / min; Temperature: 50 ° C; UV detection: 205-305 nm.

Method 6 (LC-MS):

 Instrument MS: Waters SQD; Instrument HPLC: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 μιη; Eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; Gradient: 0.0 min 98% A - 0.9 min 25% A- 1.0 min 5% A-► 1.4 min 5% A * 1.41 min 98% A -► 1.5 min 98% A; Oven: 40 ° C; Flow: 0.60 ml / min; UV detection:

DAD, 210 nm.

Method 7 (preparative HPLC):

 Instrument: Abimed Gilson 305; Column: Reprosii C18 10 μm, 250 mm × 30 mm; Eluent A: water, eluent B: acetonitrile; Gradient: 0-3 min 10% B, 3-27 min 10% B - 95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B> 10% B, 35.5-36.5 min 10% B; Flow: 50 ml / min; Room temperature; UV detection: 210 nm.

More information:

 The following descriptions of the coupling patterns of H-NMR signals are based on the visual appearance of the signals concerned and do not necessarily correspond to a rigorous, physically correct interpretation. In general, the indication of the chemical shift refers to the center of the relevant signal; In the case of broad multiplets, an interval is usually specified.

Melting points and melting ranges, where indicated, are not corrected. In cases where reaction products were obtained by stirring, stirring or recrystallization, it was often possible to further product quantities from the respective mother liquor through

Isolate chromatography. The description of this chromatography is omitted below, however, because a large part of the total yield could only be isolated in this step. For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below, and which were not commercially available or obtained from sources which are not generally available, a reference to the published literature is described in which their preparation is described.

Starting compounds and intermediates:

Example 1A

2- (4-chlorophenyl) imidazo [1,2-a] pyridine A solution of 20 g (85.65 mmol) of 2-bromo-1- (4-chlorophenyl) ethanone and 8.87 g (94.22 mmol) of pyridin-2-amine in 200 ml of ethanol was treated with 10.95 g (130 mmol) of sodium bicarbonate and 5 hours stirred at 80 ° C. Subsequently, the batch was first cooled to room temperature and then to 0 ° C (ice bath). The resulting precipitate was filtered off and washed several times with an ethanol / water mixture (2: 1). The solid was then dried in vacuo overnight at 40 ° C. There were obtained 19.8 g of the target product, which were used without further purification in subsequent reactions.

'H-NMR (400 MHz, DMSO-ά, δ / ppm): 6.87-6.94 (m, 1H), 7.23-7.29 (m, 1H), 7.50 (d, 2H), 7.58 (d, 1H), 7.99 (d, 2H), 8.43 (s, 1H), 8.53 (d, 1H).

LC-MS (Method 1): R, = 0.58 min; mz = 229/231 (M + H) ⁺ . Analogously to Example 1A, the following compounds were prepared from the respective starting materials indicated: Example Name / Structure / Educts Analytical data

 2A 2- (4-bromophenyl) imidazo [1,2-a] pyridine 'H-NMR (400 MHz, DMSO-δ, δ / ppm): 6.88-6.94 (m, 1H), 7.23-2.29 (m, 1H ), 7.58 (d, 1H), 7.63 (d, 211). 7.92 (d, 2 H). 8.44 (s, 1H),

8.53 (d, 1H).

 from 2-bromo-1- (4-bromophenyl) ethanone and

 Pyridine-2-amine LC-MS (Method 1):

R _t = 0.63 min; m / z = 273/275

(M + H) ⁺ .

3A 2- 2- (4-fluorophenyl) imidazo [1,2-a] pyridine ¹ H-NMR (400 MHz, DMSO - δ / ppm): 6.90 (t, 1H), 7.20-7.32 (m, 3H ), 7.57 (d, 1H), 8.00 (dd, 2H), 8.38 (s, 1H), 8.52 (d, 1H).

 from 2-Bromo-1 - (4-fluorophenyl) ethanone and LC-MS (Method 1):

Pyridine-2-amine R _t = 0.49 min; m / z = 213 (M + H) ⁺ .

4A 2- (4-Isopropylphenyl) imidazo [1,2-a] pyridine 'H-NMR (400 MHz, DM S () - </, δ / ppm): 1.23 (d, 61 1). 2.85-2.96 (m, 1H), 6.88 (t, 1H), 7.19-7.26 (m, 1H), 7.31 (d, 2H), 7.56 (d, 1H), 7.88 (d, 2H), 8.34 (s, 1H), from 2-bromo-1- (4-isopropylphenyl) ethanone and

 8.51 (d, 1H).

 Pyridin-2-amine

 LC-MS (Method 1):

Rt = 0.68 min; m / z = 237 (M + H) ⁺ .

5A 2- (4-methylphenyl!) Imidazo [1,2-a] pyridine 'H-NMR (400 MHz, DMSO-A, δ / ppm): 2.33 (s, 3H), 6.88 (t, 1H), 7.18-7.29 (m, 3H), 7.55 (d, 1H), 7.85 (d, 2H), 8.34 (s, 1H), 8.50 (d, 1H).

 from 2-bromo-1- (4-methylphenyl) ethanone and

 Pyridine-2-amine LC-MS (Method 1):

R _t = 0.49 min; m / z = 209 (M + H) ⁺ . Example Name / Structure / Educts Analytical data

 6A 4- (imidazo [1,2-a] pyridin-2-yl) benzonitrile 'H-NMR (400 MHz, DMSO-δ, δ / ppm): 6.94 (t, 1H), 7.30 (dd, 1H), 7.61 (d, 1H), 7.90 (d, 2H), 8.15 (d, 2H). 8.56 (d, 1H), 8.59 (s,

1H).

 from 4- (bromoacetyl) benzonitrile and pyridine-2-amine LC-MS (Method 1):

R, = 0.51 min; m / z = 220 (M + H) ⁺ .

Example 7A

2- (4-tert-butylphenyl) imidazo [1,2-a] pyridine A mixture of 1 g (5.67 mmol) of 1- (4-tert-butylphenyl) ethanone, 1.23 g (13.05 mmol) of pyridine-2-amine and 1728 g (6.81 mmol) of iodine was 2 hours at a temperature of 120 ° C. touched. Subsequently, 15 ml of water and 8.51 ml of 1 N sodium hydroxide solution were added and the mixture was stirred at 100 ° C. for a further hour. After cooling to room temperature, about 100 ml of water and about 100 ml of ethyl acetate were added. After separation of the phases, the organic phase was washed twice with water, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The residue obtained was applied to silica gel and purified by column chromatography on silica gel (Biotage 100 g KP-sil, flow: 100 ml / min, eluent gradient: 1.3 min cyclohexane ethyl acetate 92: 8 + within 13 min

Cyclohexane / ethyl acetate 34:66 -> 2.6 min cyclohexane ethyl acetate 34:66). This gave 970 mg (3.87 mmol, 68% of theory) of the target compound.

¹ H-NMR (400 MHz, DMSO-A, δ / ppm): 1.32 (s, 9H), 6.88 (t, 1H), 7.19-7.26 (m, 1H), 7.46 (d, 2H), 7.57 (i.e. , 1H), 7.88 (d, 2H), 8.34 (s, 1H), 8.51 (d, 1H).

LC-MS (Method 1): R _t = 0.72 min; mz = 251 (M + H) ⁺ .

Example 8A 2- (4-Chlorophenyl) imidazo [1,2-a] pyridine-3-carbaldehyde

300 ml of DMF was cooled to 0 ° C. Subsequently, 44 ml (470.08 mmol) of phosphorus oxychloride were slowly added dropwise. The reaction solution was then slowly warmed to room temperature and stirred for one hour at this temperature. Then, 4 g (188.03 mmol) of 2- (4-chlorohexyl) imidazo [1,2-a] pyridine was added portionwise. The reaction solution heated to 35 ° C. After completion of the addition, the reaction mixture was heated to 80 ° C and stirred for 2 hours at this temperature. After cooling to room temperature, the solution was slowly added to 3 liters of ice-water. The resulting solid was filtered off with suction, washed several times with water and dried overnight at 40 ° C. in a high-vacuum drying oven. There were obtained 39.6 g (154.27 mmol, 82% of theory) of the target product.

'H-NMR (400 MHz, DMSO-A, δ / ppm): 7.37 (t, 1H), 7.63 (d, 2H), 7.78 (t, 1H), 7.90-7.99 (m, 3H), 9.58 (i.e. , 1H), 10.02 (s, 1H).

LC-MS (Method 1): R _t = 0.97 min; mz = 257/259 (M + Fff.

Analogously to Example 8A, the following compounds were prepared from the reactant indicated in each case:

Example name / structure / educt Analytical data

 9A 2- (4-Bromophenyl) imidazo [1,2-a] pyridine-3 'H-NMR (400 MHz, DMSO-A, carbaldehyde δ / ppm): 7.35 (t, 1H), 7.72-7.80 (m .

 3 I i). 7.85-7.95 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H).

 LC-MS (Method 2):

R _t = 1.76 min; m / z = 301/303

(M + H) ⁺ .

from 2- (4-bromophenyl) imidazo [1,2-a] pyridine Example name / structure / educt Analytical data

 10A 2- (4-fluorophenyl) imidazo [1,2-a] pyridine-3'H-NMR (400 MHz, DMSO-A, carbaldehyde δ / ppm): 7.32-7.45 (m, 31 l). 7.77 (t,

 1H), 7.92 (d, 1H), 7.99 (dd, 2H), 9.58 (d, 1H), 10.01 (s, 1H).

 LC-MS (Method 1):

o R _t = 0.79 min; m / z = 241 (M + H) ⁺ . from 2- (4-fluorophenyl) imidazo [1,2-a] pyridine

 I 1 A 2- (4-Isopropylphenyl) imidazo [1,2-a] pyridine-3 'H-NMR (400 MHz, DMSO-A, carbaldehyde δ / ppm): 1.27 (d, 6H), 2.93-3.05

(m, 1H), 7.33 (t, 1H), 7.44 (d, 2H), 7.74 (t, 1H), 7.85 (d, 2H), 7.91 (d, 1H), 9.58 (d, 1H), 10.03 ( s, 1H). LC-MS (Method 1):

R _t = 1.03 min; m / z = 265 (M + H) ⁺ . from 2- (4-isopropylphenyl) imidazo [1,2-a] pyridine

 12A 2- (4-methylphenyl) imidazo [1,2-a] pyridine-3'-H NMR (400 MHz, DM S (> - </ ,.

 carbaldehyde δ / ppm): 2.41 (s, 3H), 7.34-7.43

 (m, 3H). 7.77-7.86 (m, 3H), 7.94 (d, 1H), 9.60 (d, 1H), 10.02 (s,

1H).

 LC-MS (Method 1):

Rt = 0.89 min; m / z = 237 (M + H) ⁺ . from 2- (4-methylphenyl) imidazo [1,2-a] pyridine

 13A 4- (3-Formylimidazo [1,2-a] pyridin-2-yl) - 'H NMR (400 MHz, DMSO-Ä, benzonitrile δ / ppm): 7.38 (t, 1H), 7.79 (t, 1H),

 7.96 (d, 1H), 8.03 (d, 2H), 8.14 (d, 2 I I), 9.59 (d, 1H), 10.05 (s, 1H).

LC-MS (Method 1):

Rt = 0.77 min; m / z = 248 (M + H) ⁺ . from 4- (imidazo [1,2-a] pyridin-2-yl) benzonitrile Example name / structure / educt Analytical data

 14A 2- (tert-butylphenyi) imidazo [1,2-a] pyridine-3-Ή-NMR (400 MHz, DMSO-,, carbaldehyde δ / ppm): 1.35 (s, 9H), 7.35 (t, 1H),

 7.59 (d, 2H). 7.73-7.80 (m, 1H), 7.87 (d, 2H), 7.89-7.97 (m, 1H),

9.59 (d, 1H), 10.04 (s, 1H).

 o LC-MS (Method 2):

R _t = 2.13 min; m / z = 279 (M + H) ⁺ . from 2- (4-tert-butylphenyl) imidazo [1,2-a] pyridine

Example ISA

2- (4-chlorophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrole-2 (1-ff) -ylmethyl) imidazo [1,2-a] pyridine dihydrochloride

3.1 g (6.84 mmol) tert. Butyl-5- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} hexahydro-pyrrolo [3,4-c] pyrrole-2 (117) -carboxylate was synthesized in Dissolved 100 ml of dioxane and added with stirring with 17.11 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 5 hours. The solid obtained was then filtered off with suction, washed several times with diethyl ether and dried under high vacuum. There were obtained 3.17 g of the target product, which were used without further purification in subsequent reactions.

LC-MS (Method 1): = 0.35 min; m / z = 353/355 (M + H) ⁺ .

Analogously to Example 15A, the following compounds were prepared from the reactant indicated in each case: Example name / structure / educt Analytical data

 16A 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] LC-MS (Method 1):

pyrrol-2 (1H) -ylmethyl) imidazo [1,2-a] pyridine R _t = 0.41 min; m / z = 397/399

Dihydrochloride (M + H) ⁺ .

from tert. Butyl-5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate

 17A 3 - (hexahydropyrrolo [3,4-c] pyrrole-2 (1 H) -y-LC-MS (Method 4):

methyl) -2- (4-isopropylphenyl) imidazo [1,2-a] - R _t = 1 .43 min; m / z = 361 (M + H) ⁺ .

 pyridine dihydrochloride

from tert. Butyl-5- {[2- (4-isopropylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate

- (4-bromophenyl) -3 - {hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -ylmethyl) imidazo [1,2-a] pyridine

16.1 g (34.24 mmol) of 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -ylmethyl) -imidazo [1,2-a] pyridine dihydrochloride were dissolved in 200 ml Dissolved THF, mixed with 24 ml (171 mmol) of triethylamine and stirred for 2 hours at room temperature. Thereafter, the reaction solution with water and ethyl acetate was added and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo on a rotary evaporator to dryness. There were obtained 9.72 g (24.46 mmol, 71% of theory) of the target product, which were used without further purification in subsequent reactions. LC-MS (Method 1): R _t = 0.46 min; m / z = 397/399 (M + Ff.

Ausfüfarungsbeispieie: Example 1 tert. Butyl-5 - {[2- (4-chlorophenyl) imidazo [1,2-a] pyridine-3-ylmethyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1-i /) carboxylate

1.81 g (7.07 mmol) of 2- (4-chlorophenyl) imidazo [1,2-a] pyridine-3-carbaldehyde were dissolved in 30 ml of THF under argon at room temperature and tert with 3 g (14.13 mmol) of tert. Butyl hexahydropyrrolo [3, 4-c] pyrrole-2 (l) carboxylate and 0.81 ml (14.13 mmol) of acetic acid. subse- ßend were added in portions 4.49 g (21.20 mmol) of sodium triacetoxyborohydride. The reaction solution was then further stirred overnight at room temperature. After the reaction was slowly and carefully added dropwise water (gas evolution) and then treated with ethyl acetate. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo on a rotary evaporator to dryness. The residue obtained was applied to silica gel and purified by column chromatography on silica gel (Biotage, eluent: cyclohexane / ethyl acetate 1: 1). 3.2 g (6.58 mmol, 93% of theory) of the title compound were obtained. Of these, 100 mg were further purified by preparative HPLC (method 7) (yield: 81 mg).

'H-NMR (400 MHz, DMSO-ife, δ / ppm): 1 .35 (s, 9H), 2.43 (d, 211). 2.47-2.59 (m, 211. partially obscured by DMSO-Signai), 2.71 (brs s, 211). 3.02 (d, 2H). 3.42 (dd, 2 H). 4.06 (s, 2H). 6.94 (t, 1H), 7.30 (t, 1H), 7.51 (d, 2H), 7.59 (d, 1H), 7.92 (d, 2 (1), 8.57 (d, 1H).

LC-MS (Method 1): R, = 0.76 min; m / z = 453/455 (M + H) ⁺ .

Analogously to Example 1, the following compounds were prepared from the educts indicated in each case:

Example Name / Structure / Educts Analytical data

 3 tert. Butyl-5- {[2- (4-isopropylphenyl) imidazo-1 H-NMR (400 MHz, DMSO-A, [1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo δ / ppm): 1.24 (d, 6H), 1 .36 (s, 9H),

 [3,4-c] pyrrole-2 (1H) -carboxylate 2.43 (d, 2H), 2.47-2.60 (m, 211.

 partially obscured by DMSO signal), 2.72 (br s, 2H), 2.87-2.98 (m, 1H), 3.03 (d, 2 l i). 3.42 (dd, 2H), 4.06 (s, 211). 6.91 (t, 1H), 7.27 (t, 1H), 7.35 (d, 2H), 7.58 (d, 1H), 7.79 (d, 2H), 8.55 (d, 1H).

LC-MS (Method 2):

R _t = 1.56 min; m / z = 461 (M + H) ⁺ . from 2- (4-isopropylphenyl) imidazo [1,2-a] pyridine-3-carbaldehyde and tert. Butyl hexahydro-pyrrolo [3,4-c] pyrrole-2 (li7) carboxylate

Example 4

[5 - {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1 /) -yl] (6-methoxypyridine 2-yi) methanone

Synthesis Brain /

65 mg (0.42 mmol) of 6-methoxypyridine-2-carboxylic acid were dissolved in 2 ml of DMF, with 174 mg (0.46 mmol) of 2- (7-aza-1: i-benzotriazol-1-yl) -1,3 , 3-tetramethyltronium hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Subsequently, 150 mg (0.35 mmol) of 2- (4-chlorophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrol-2 (liί) -yimethyl) imidazo [1,2-a] pyridine dihydrochloride were used 0.18 ml (1.06 mmol) of N, N-diisopropylethylamine was added and the mixture was further stirred at room temperature overnight. After that, the reaction mixture became separated directly via preparative HPLC (Method 7) into its components. There were 106 mg

(0.22 mmol, 62% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.70 min; m / z = 488/490 (M + H) ⁺ .

'H-NMR (400 MHz, DMSO-A): δ [ppm] = 2.41-2.52 (m, 2H partially masked by DMSO signal), 2.55-2.64 (in, 2H), 2.79 (br. S, 2H ). 3.44-3.60 (m, 211). 3.66-3.84 (m, 2H), 3.76 (s, 3H), 4.00-4.13 (m, 2H), 6.84-6.92 (m, 2H), 7.24 (d, 1H), 7.28 (t, 1H), 7.49 ( d, 2H), 7.58 (d, 1H), 7.78 (t, 1H), 7.89 (d, 2H), 8.57 (d, 1H).

Example 5

[5 - {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] (cyclopentyl) methanone

Synthesis method 2

 41 mg (0.36 mmol) of cyclopentanecarboxylic acid were dissolved in 1.5 ml of DMF, with 172 mg (0.45 mmol) of 2- (7-azalH-benzotriazol-1-yl) -1,3,3-tetramethyluronium-H exafluoropho Sphat (HATU) and stirred for 30 min at room temperature. Then, 120 mg (0.30 mmol) of 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrole-2 (1/7) -ylmethyl) imidazo [1,2-a] pyridine and 0.11 ml

(0.60 mmol) of N, N-diisopropyl ethylamine and the mixture was further stirred overnight at room temperature. Thereafter, the reaction mixture was separated directly into its components by preparative HPLC (Method 7). 87 mg (0.18 mmol, 58% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.71 min; m / z = 493/495 (M + H) ⁺ .

'H-NMR (400 MHz, DMSO-A): δ [ppm] = 2.41-2.52 (m, 2H, partially obscured by DMSO signal), 2.55-2.64 (m, 2H), 2.79 (br. S, 2H ), 3.44-3.60 (m, 2H), 3.66-3.84 (m, 2H), 3.76 (s, 311). 4.00-4.13 (m, 2H), 6.84-6.92 (m, 2H), 7.24 (d, 1H), 7.28 (t, 1H), 7.49 (d, 2H), 7.58 (d, 1H), 7.78 (t, 1H), 7.89 (d, 2H), 8.57 (d, 1H). In accordance with the synthesis methods 1 and 2 described above, the following compounds were also prepared from the reactants indicated:

Example Name / Structure / Educts Analytical data

 8 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine-MR (400 MHz, DMSO-A): δ

3 -yl] ethyl} hexahydropyrrolo [3,4-c] pyrrole [ppm] = 1.04-1.34 (m, 5H), 1.48-

2 (1H) -yl] (cyclohexyl) methanone 1.73 (m, 5H), 2.24-2.35 (m, 1H),

 2.42-2.58 (m, 4H, partially obscured by DMSO signal), 2.63-

2.75 (m, 1H), 2.75-2.86 (m, 1H), 3.1 3-3.21 (m, 1H), 3.21-3.27 (m, 1H), 3.40-3.49 (m, 1H), 3.58-3.67 (m, 1H), 4.06 (s, 2H), 6.91 (t, 1H), 7.29 (t, 1H), 7.59 (d, 1H), 7.64 (d, o

 2H), 7.84 (d, 2H), 8.55 (d, 1H). from 2- (4-bromophenyl) -3- (hexahydropyrrolo LC-MS (Method 1):

[3,4-c] pyrrol-2 (1H) -ylmethyl) imidazo [1,2-a] -1 = 0.78 min; m / z = 507/509 pyridine dihydro chloride and cyclohexane (M + H) ⁺ .

 carboxylic acid (according to synthesis method 1)

 9 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine] H-NMR (400 MHz, DMSO-A): δ

3-ylmethylhexahydropyrrolo [3,4-c] pyrroli- [ppm] = 1.61-1.74 (m, 1H), 1.76-

2 (1H) -yl] (cyclobutyl) -methanone 1.90 (m, 1H), 1.92-2.1 5 (m, 4H),

 2.36-2.43 (m, 1H), 2.44-2.60 (m,

3 H, partially obscured by

DMSO signal), 2.63-2.82 (m, 2H), 3.04-3.17 (m, 2H), 3.23 (dd, 1H), 3.38-3.48 (m, 2H), 4.04 (q, 2H), 6.91 (t, 1H), 7.29 (t, 1H), 7.59 (d, 1H), 7.64 (d, 2H), 7.83 (d,

O

 2H), 8.54 (d, 1H).

 from 2- (4-bromophenyl) -3- (hexahydropyrrolo LC-MS (Method 1):

[3,4-c] pyrrole-2 (1H) -ylmethyl) imidazo [1,2-a] R _t = 0.70 min; m / z = 479/481 pyridine dihydrochloride and cyclobutane (M + H) ⁺ .

carboxylic acid (according to synthesis method 1) Example Name / Structure / Educts Analytical data

 10 [[5- [2- (4-Bromophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

3-ylmethyl jhexahydropyrrolo [3,4-e] pyrri- [ppm] = 2.30-2.40 (m, 1H), 2.40-

2 (1 //) - yl] (3-methoxyphenyl) methanone 2.64 (m, 3H, partially occluded by DMSO signal), 2.69-2.83

(m, 2H). 3.07-3.17 (m, 1H), 3.40-3.60 (m, 2H), 3.63-3.74 (m, 1H),

3.71 (s, 3H). 3.99-4.12 (m, 21 1), 6.83-7.00 (m, 4H). 7.24-7.34 (m,

2H), 7.59 (d, 1H), 7.65 (d, 2H). 7.85 (d, 2H 1. 8.58 (d, 1H).

 0

 LC-MS (Method 1):

 from 2- (4-bromophenyl) -3- (hexahydropyrrolo)

R _t = 0.75 min; m / z = 53 1 -533

[3,4-c] pyrrole-2 (li) -ylmethyl) imidazo [1,2-a] -

(M + H) ⁺ .

 pyridine dihydrochloride and 3-methoxybenzoic acid (according to synthesis method 1)

 11 [[5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine-Ή-NMR (400 MHz, DMSO-A): δ

3-ylmethyl Jhexahydropyrrio [3,4-c] pyrrole [ppm] = 2.25-2.34 (m, 1H), 2.45

2 (l / f) -yl] (2-methoxyphenyl) methanone (t, 1H), 2.48-2.57 (m, 1H, obscured by DMSO signal), 2.60 (t,

1H), 2.64-2.73 (m, 1H), 2.73-2.83

(m, 1H), 2.83-2.92 (m, 1H), 3.23-

3.39 (m, 2H, partially obscured by H O signal). 3.59-3.75 (m,

1H), 3.69 (s, 3H), 4.07 (s, 2H),

6.88-6.99 (m, 2H), 7.00-7.08 (m,

0

 2H), 7.27-7.38 (m, 2H), 7.60 (d, from 2- (4-bromophenyl) -3- (hexahydropyrrolo-1H), 7.65 (d, 2H), 7.84 (d, 2H),

[3,4-c] pyrrole-2 (177) -ylmethyl) imidazo [1,2-a] - 8.58 (d, 1H).

 pyridine and 2-methoxybenzoic acid (according to LC-MS (Method 1):

 Synthesis method 2) Rt = 0.70 min; m / z = 531/533

(M + H) ⁺ . Example Name / Structure / Educts Analytical data

 12 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

3 -yl] ethyl} hexahydropyrrolo [3,4-c] pyrrole [ppm] = 2.28-2.36 (m, 1H), 2.46

2 (l /) - yl] (5-fluoro-2-methoxy-p-zenyl) -methanone (t, 1H), 2.48-2.56 (m, 1 h. Concealed by DMSO signal), 2.59 (t,

1H), 2.65-2.74 (m, 1H), 2.74-2.84

(m, 1H), 2.85-2.94 (m, 1H), 3.26-

3.39 (m, 2H, partially obscured by H ₂ 0 signal), 3.60-3.73 (m,

1H), 3.68 (s, 3H), 4.01 -4.13 (m,

2H), 6.87-6.99 (m, 2H). 7.01 -7.08

 (m, 1H), 7.14-7.22 (m, 1H), 7.31 from 2- (4-bromophenyl) -3- (hexahydropyrrolo- (t, 1H), 7.60 (d, 1H), 7.65 (d, 2H).

 [3,4-c] pyrrol-2 (1H) -ylmethyl) imidazo [1,2-a] - 7.84 (d, 2H), 8.58 (d, 1H).

 pyridine and 5-fluoro-2-methoxybenzoic acid LC-MS (Method 1):

 (according to synthesis method 2) Rt = 0.73 min; m / z = 549 55 1

(M + H) ⁺ .

 13 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

3 -ylmethyl} hexahydropyrrolo [3,4-c] pyrrole - [ppm] = 2.07 (s, 3H), 2.24-2.3 1

2 (1HT) -yl] (2-methylphenyl) methanone (m, 1H), 2.44 (t, 1H), 2.48-2.57

 (m, 1 h. obscured by DMSO)

Signal), 2.60 (t, 1H), 2.65-2.74 (m,

1H), 2.74-2.86 (m, 2H), 3.22-3.29 (m, 1H), 3.42 (dd, 1H), 3.60-3.69 (in, 1H), 4.01 -4.13 (m, 2H), 6.95

(t, 1H), 7.02 (d, 1H), 7.11-7.35 (m,

4H), 7.60 (d, 1H), 7.65 (d, 2H), 0 7.83 (d, 2H), 8.56 (d, 1H).

 LC-MS (Method 1):

 from 2- (4-bromophenyl) -3- (hexahydropyrrolo)

R _t = 0.73 min; m / z = 515/517 [3,4-c] pyrrol-2 (1H) -ylmethyl) imidazo [1,2-a] - (M + H) ⁺ .

 pyridine and 2-methylbenzoic acid (according to

Synthesis method 2) Example Name / Structure / Educts Analytical data

 16 [5- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

3 -ylmethyl} hexahydropyrrolo [3,4-c] pyrrole [ppm] = 1.06-1.34 (m, 511). 1.47-

2 (1H) -yl] (cyclohexyl) methanone 1.71 (m, 5H), 2.24-2.35 (m, 1H),

 2.43-2.58 (m, 4H partially obscured by DMSO signal), 2.64-

2.75 (m, 1H), 2.75-2.86 (m, 1H), 3.17 (dd, 1H), 3.24 (dd, 1H), 3.45 (dd, 1H), 3.63 (dd, 1H), 4.06 (s, 2H) , 6.91 (td, 1H), 7.29 (t, 1H), 7.51 (d, 2H). 7.59 (d, 1H), 7.90 (d,

O

 2H), 8.55 (d, 1H).

 from 2 - (4 -CI 1 (i rp ho Ii v 1) -3 - (hexahydropyrrolo LC-MS (Method 1):

[3,4-c] pyrrole-2 (1/7) -ylmethyl) imidazo [1,2-a] R, = 0.74 min; m / z = 463-465 pyridine dihydro chloride and cyclohexane (M + H) ⁺ .

 carboxylic acid (according to synthesis method 1)

 17 [[5- [[2- (4-Chlorophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

3 -ylmethyl JhexahydropyiToio [3,4-c] pyrrole [ppm] = 2.3 1 -2.4! (m, 1H), 2.41 -

2 (1H) -yl] (3-methoxyphenyl) methanone 2.53 (m, 1H partially occluded by DMSO signal). 2.53-2.64

(m, 2H. partially obscured by

DMSO signal), 2.69-2.84 (m,

2H), 3.05-3.17 (in, 1H), 3.41-3.60 (m, 2H), 3.63-3.74 (m, 1H), 3.71

(s, 3H). 3.97-4. 1 2 (m, 2H), 6.84-7.00 (m, 4H). 7.24-7.34 (m, 2H). O

 7.52 (d, 2H), 7.59 (d, 1H), 7.91 (d, from 2- (4-chlorophenyl) -3- (hexahydropyrrolo-2H), 8.58 (d, 1H).

 [3,4-c] pyrrol-2 (II7) -ylmethyl) imidazo [l, 2-a] -

LC-MS (Method 1):

 pyridine dihydrochloride and 3-methoxy

R _t = 0.71 min; m / z = 487/489 benzoic acid (according to synthesis method 1)

(M + H) ⁺ . Example Name / Structure / Educts Analytical data

 22 [5- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridine 'H NMR (400 MHz, DMSO-A): δ

 3 -ylmethyl} hexahydropyrrolo [3,4-c] pyrrole [ppm] = 2.31-2.65 (m, 4H, partial

2 (1H) -yl] [3- (trifluoromethoxy) phenyl] methanone concealed by DMSO signal), 2.70-2.85 (m, 2H), 3.03-3.16 (m, 1H), 3.41-3.50 (m, 1H) , 3.50-3.61 (m, 1H), 3.65-3.76 (m, 1H), 4.06 (q, 2H), 6.94 (td, 1H), 7.25-7.33 (m, 2H), 7.36-7.45 (m, 2H) , 7.47-7.56 (m, 3H), 7.59 (d, 1H), 7.90 (d, 2H), 8.58 (d, 1H).

0

 LC-MS (Method 1):

 from 2- (4-chlorophenyl) -3- (hexahydropyrrolo)

R _t = 0.81 min; m / z = 541/543 [3,4-c] pyrrole-2 (li7) -yimethyl) imidazo [1,2-a] -

(M + H) ⁺ .

 pyridine dihydrochloride and 3- (trifluoromethoxy) benzoic acid (by synthesis method 1)

 23 [5 - {[2- (4-ίΐοφίΐ6η) <'1) πΓ 3ζο [1, 2-a] pyridine' H NMR (400 MHz, DMSO-A): δ

 3 -ylmethyl} hexahydropyrrolo [3,4-c] pyrrole [ppm] = 2.35-2.68 (m, 411. part 2 (1 //) - ylJ [3- (trifluoromethyl) phenyl] methanone concealed by DMSO signal) , 2.70-2.86 (m, 2H), 3.03-3.16 (m, 1H), 3.45-3.54 (m, 1H), 3.54-3.63 (m, 1H), 3.67-3.78 (m, 1H), 4.06 (q, 2H), 6.94 (t, 1H), 7.30 (d, 1H), 7.36-7.45 (m, 2H), 7.51 (d, 2H), 7.56-7.70 (m, 4H), 7.79 (d, 1H), 7.90 (d, 2H), 8.58 (d,

O

 1H).

 from 2- (4-chlorophenyl) - - (hexahydropyrrolo LC-MS (Method 1):

[3,4-c] pyrrole-2 (1 //) ylmethyl) imidazo [1,2-a] R _t = 0.79 min; m / z = 525/527 pyridine dihydrochloride and 3- (trifluoromethyl) - (M + H) ⁺ .

benzoic acid (according to synthesis method 1) Example Name / Structure / Educts Analytical data

 24 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine-H-NMR (400 MHz, DMSO-A): δ3-yl] ethyl} hexahydropyrrolo [3,4-c ] pyrrole [ppm] = 2.42-2.64 (m, 4H, part 2 (1H) -yl] (6-methoxypyridin-2-yl) methanone concealed by DMSO signal), 2.73-2.84 (m, 2H), 3.44 3.60 (m, 2H), 3.65-3.74 (in, 1H), 3.74-3.83 (m, 1H), 3.76 (s, 3H), 4.00-4.12 (m, 2H), 6.84-6.92 (m,

H ₃ C _^ .Q

 2H), 7.21-7.31 (m, 2H), 7.55-7.66 (m, 3H), 7.78 (t, 1H), 7.83 (d, 2H), 8.57 (d, 1H).

 O

LC-MS (Method 2):

 from 2- (4-bromophenyl) -3- (hexahydropyrrolo)

R _t = 1.31 min; m / z = 532/534

[3,4-c] pyrrole-2 (1H) -ylmethyl) imidazo [1,2-a] - (M + H) ⁺ .

 pyridine and 6-methoxypyridine-2-carboxylic acid

 (according to synthesis method 2)

 25 [5- {[2- (4-Isopropylphenyl) imidazo [1,2-a] pyridine-Ή-NM R (400 MHz, DMSO-A): δ

 3 -ylmethyl} hexahydropyrrolo [3,4-c] pyiTol- [ppm] = 1 .24 (d, 6H), 2.42-2.65 2 (1 //) - yl] (6-methoxypyridin-2-yl) methanone ( m, 4H, partially obscured by

DMSO signal), 2.74-2.85 (m, 2H), 2.87-2.98 (m, 1H), 3.48 (dd, 1H), 3.57 (dd, 1H), 3.67-3.75 (m, 1H), 3.75-3.85 ( m, 1H), 3.77 (s, h ^3c - o 3H), 4.02-4.13 (m, 2 H). 6.85 (td,

 1H), 6.89 (d, 1H), 7.20-7.34 (m,

0 4M). 7.56 (d, 1H), 7.73-7.81 (m,

 3H), 8.55 (d, 1H).

from 3- (hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -ylmethyl) -2- (4-isopropylphenyl) imidazo [1,2-a] LC-MS (Method 2): pyridine Dihydrochloride and 6-methoxypyridine Rt = 1.38 min; m / z = 496 (M + H) ⁺ .

2-carboxylic acid (according to synthesis method 1) Example Name / Structure / Educts Analytical data

 26 (2-fluorophenyl) [5 - {[2- (4-isopropylphenyl) - 1 H-NMR (400 MHz, DMSO-A): δ-imidazo [1,2-a] pyridin-3-yl] methyl} hexahydro - [ppm] = 1 .25 (d, 6H), 2.34-2.41 pyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanone (m, 1H), 2.42-2.63 (m, 3H). partially occluded by DMSO signal), 2.69-2.87 (m, 2H), 2.88-3.03 (m, 2H), 3.36-3.45 (m, 2H), 3.65-3.75 (m, 1H), 4.01 -4.14 (m, 2H), 6.93 (t, 1H), 7.17-7.37 (m, 6H). 7.41 -7.51 (m, 1H), 7.58 (d, 1H). 7.78 (d, 2H), 8.56 (d, 1H).

LC-MS (Method 2):

from 3- (hexahydropyrrolo [3,4-c] pyrrolid-2 (1H) -yl- R _t = 1.40 min; m / z = 483 (M + H) ⁺ . methyl) -2- (4-isopropylphenyl) imidazo [l, 2-a] - pyridine dihydrochloride and 2-fluorobenzoic acid

 (according to synthesis method 1)

27 [5- {[2- (4-Isopropyl-phenyl) -imidazo [1,2-a] pyridine-1 H-NMR (400 MHz, DMSO-ii _tf ): δ3-ylmethylhexa-hexropyrrolo [3,4-c] pyrrole - [ppm] = 1 .25 (d, 6H), 2.31-2.42 2 (1H) -yl] (3-methoxyphenyl) methanone (m, 1H), 2.42-2.56 (m, 1 I I. partially obscured by DMSO signal), 2.56-2.64 (m, 2H), 2.69-2.83 (in, 2H), 2.89-2.98 (m, 1H), 3.08-3.18 (m, 1H), 3.41 -3.50 (in, 1H), 3.5 1 -3.61 (m, 1H), 3.63-3.75 (m, 1H), 3.71 (s, 311). 3.98-4. 1 3 o (m, 2H), 6.86-7.01 (in, 411). 7.23- 7.36 (m, 411). 7.58 (d, 1H), 7.78 from 3- (hexahydropyrrolo [3,4-c] pyrrole-2 (1 //) - yl- (d, 2H), 8.56 (d, 1H).

methyl) -2- (4-isopropylphenyl) imidazo [1,2-a] pyridine dihydrochloride and 3-methoxy LC-MS (Method 2): benzoic acid (by Synthetic method 1) R _t = 1.40 min; m / z = 495 (M + H) ⁺ . Example Name / Structure / Educts Analytical data

 28 Cyclopentyl [5- {[2- (4-isopropylphenyl) imidazo 'H-NMR (400 MHz, DMSO-A): δ [1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo [ppm] = 1.24 (d, 6H), 1.40-1.76

[3,4-c] pyrrol-2 (1H) -yl] methanone (m, 8H), 2.43-2.61 (m, 411. partially obscured by DMSO signal), 2.65-2.86 (m, 3H), 2.88- 2.99 (m, 1H), 3.17-3.30 (m, 211), 3.46 (dd, 1H), 3.62 (dd, 1H), 4.06 (s, 2H), 6.88 (t, 1H), 7.27 (t, 1H) . 7.32 (d, 2H), 7.57 (d, 1H), 7.79 (d,

 2H), 8.53 (d, 1H).

 O

 LC-MS (Method 2):

from 3- (hexahydropyrrolo [3,4-c] pyrrole-2 (1 //) - yl-R, = 1.36 min; m / z = 457 (M + H) ⁺ . methyl) -2- (4-isopropylphenyl ) imidazo [1,2-a] -pyridine dihydrochloride and cyclopentane carboxylic acid (according to synthesis method 1)

Example 29

5 - {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} -N-methyl-N-phenyl-hexahydropyrrolo

[3, 4-c] pyrrole-2 (1H) -carboxamide

16.9 mg (0.10 mmol) of methyl (phenyl) carbamoyl chloride were placed in a well of a 96-well multititer plate and cooled to 0 ° C. Separately, 39.7 mg (0.10 mmol) of 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -ylmethyl) imidazo [1,2-a] pyridine in 0.8 ml Dissolved 1,2-di-chloroethane, with 0.052 ml (0.3 mmol) of NN-diisopropylethylamine and cooled to 0 ° C. The two solutions were combined on the multi-well plate and shaken first at 0 ° C for 1 h. The mixture was then allowed to warm to RT and kept at RT overnight. telt. Thereafter, the solvent was completely removed by centrifugal dryer. The residue was dissolved in 0.6 ml of DMF, filtered and the filtrate was separated into its components by preparative LC-MS by one of the following methods:

Instrument MS: Waters, Instrument HPLC: Waters; Column: Waters X-Bridge C18, 19 mm x 50 mm, 5 μτη; Eluent A: water + 0.05% ammonia, eluent B: acetonitrile, with eluent gradient; Flow: 40 ml / min; UV detection: DAD. 210-400 nm

respectively.

 Instrument MS: Waters, Instrument HPLC: Waters; Column: Phenomenex Lima 5μ C18 (2) 100A, AXIA Tech., 50mm x 21.2mm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid, with eluent gradient; Flow: 40 ml / min; UV detection: DAD, 210-400 nm.

This gave 18.9 mg (36% of theory, purity 100%) of the title compound.

LC-MS (method 6. ESIpos): R = 0.84 min; m / z = 530 (M + H) ⁺ .

In a manner similar to Example 29, in a parallel synthetic manner, the following compounds were prepared starting from 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrol-2 (1) -ylmethyl) imidazo [1,2] a] - pyridine and the corresponding carbamoyl chloride or chloroformate prepared:

Example: lUPAC name / structure LC-MS (method 6)

 (Yield, purity)

30 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine R _t = 0.88 min; mz = 556 (M + H) ⁺

 3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] (3,4-dihydroquinolin-1 (2H) -yl) -methanone

O

(52% of theory: purity 97%) Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

31 [5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine R _t = 0.87 min; m / z = 556 (M + H) ⁺

 3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrole

2 (1H) -yl] (3,4-dihydroisochmolin-2 (li 7) -yl) -methanone

O

(18% of theory, purity 96%)

32 isobutyl 5- {[2- (4-bromophenyl) imidazo [1,2-a] - Rt = 0.88 min; m / z = 497 (M + H) ⁺ pyridine-3-ylmethyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate

0

(ll% of theory, purity 96%)

Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

33 Benzyl 5- {[2- (4-bromophenyl) imidazo [1,2-a] - R _t = 0.90 min; m / z = 531 (M + H) ⁺ pyridin-3-ylmethyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate

0

(39% of theory, purity 100%)

34 cyclopentyl 5 - {[2- (4-bromophenyl) imidazo-R _t = 0.88 min; m / z = 509 (M + H) ⁺

[1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1 /) -carboxylate

0

(46% of theory, purity 97%)

Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

37 2-fluoroethyl 5- {[2- (4-bromophenyl) imidazo-R _t = 0.78 min; m / z = 487 (M + H) ⁺ [1,2-a] pyridin-3-yl] methyl} hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate

(10% of theory, purity 98%)

Example 38

5 - {[2- (4-BΓomphenyl) imidazo [l, 2-a] pyridin-3-yl] methyl} - N- (2,4-liflohexyl) -hexahydro-pyrrolo [3,4-c] pyrrole 2 (lH) -carboxamide

15.5 mg (0.10 mmol) of 2,4-difluoro-1-isocyanatobenzene were introduced into a well of a 96-well multititer plate and mixed with a solution of 39.7 mg (0.10 mmol) of 2- (4-bromophenyl) -3- (hexafluoride). hydropyrrolo [3,4-c] pyrrole -2 (1H) -ylmethyl) imidazo [1,2-a] pyridine in 0.8 ml of 1,2-dichloroethane. Some molecular sieve (4A) was added and the plate was then shaken and shaken overnight at room temperature. Subsequently, the solvent was completely removed by centrifugal dryer. The residue was dissolved in 0.6 ml of DMF, filtered and the filtrate was separated into its components by preparative LC-MS by one of the following methods: Instrument MS: Waters, Instrument HPLC: Waters; Column: Waters X-Bridge C18, 19 mm x 50 mm, 5 μιη; Eluent A: water + 0.05% ammonia, eluent B: acetonitrile, with eluent gradient; Flow: 40 ml / min; UV detection: DAD, 210-400 nm

respectively.

Instrument MS: Waters, Instrument HPLC: Waters; Column: Phenomenex Lima 5μ C18 (2) 100A, AXIA Tech., 50mm x 21.2mm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05%) formic acid, with eluent gradient; Flow: 40 ml / min; UV detection: DAD, 210-400 nm.

This gave 7.0 mg (12% of theory, purity 97%) of the title compound.

LC-MS (Method 6, E Sipos): R, = 0.80 min; m / z = 552 (M + H) ⁺ . In analogous, analogous manner to Example 38, the following compounds were prepared from 2- (4-bromophenyl) -3- (hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -ylmethyl) imidazo [l, 2]. a] - pyridine and the corresponding isocyanate:

Example IUPAC name / structure LC-MS (method 6)

 (Yield, purity)

39 5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridine R _t = 0.81 min; m / z = 566 (M + H) ⁺ 3-yl] methyl} -N- (2,6-difluorobenzyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

O

(17% of theory, purity 98%) Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

40 5- {[2- (4-Bromophenyl) imidazo [1,2-aipyridine-R _t = 0.81 min; m / z = 544 (M + H) ⁺ 3-yl] methyl} -N- (2,6-dimethylphenyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

(9% of theory, purity 92%)

41 5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridine R _t = 0.80 min; m / z = 534 (M + H) ⁺

3-yl] methyl} ^-Λ Γ - (2-fluoφhenyl) -hexahydΓO- pyrrolo [3,4-c] pyrrol-2 (lH) -carboxamide

(22% of theory, purity 99%) Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

42 5- {[2- (4-bromophenyl) imidazo [1,2-ajpyridine-R _t = 0.87 min; m / z = 558 (M + H) ⁺ 3-yl] methyl} - N - (2-ethoxyphenyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

(29% of theory, purity 95%)

43 5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridine Rt = 0.94 min; m / z = 618 (M + H) ⁺

 3 -ylmethyl} - V- [4-chloro-3 - (trifluoromethyl) -phenyl] -hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

(14% of theory, purity 96%) Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

44 5- {[2- (4-bromophenyl) imidazo [1,2-aipyridine-R _t = 0.97 min; m / z = 618 (M + H) ⁺

 3-yl] methyl} - N - [2-chloro-5- (trifluoromethyl) -phenyl] -hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

(26% of theory, purity 99%)

45 5- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridine Rt = 0.82 min; m / z = 522 (M + H) ⁺ 3-yl] methyl} -N-cyclohexyl-hexahydropyrrolo- [3,4-c] pyrrole-2 (1H) -carboxamide

H

(29% of theory, purity 100%) Example IIJPAC Name / Structure LC-MS (Method 6)

 (Yield, purity)

46 rac-5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridine R _t = 0.84 min; m / z = 544 (M + H) ⁺

 3-yl] methyl} -N- (1-phenylethyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxamide

(33% of theory, purity 100%)

47 5- {[2- (4-bromophenyl) imidazo [1,2-a] pyridine Rt = 0.81 min; m / z = 534 (M + H) ⁺

3-yl] methyl} -Λ ^L (4-fluoro-phenyl) -he-ahydro-pyrrolo [3,4-c] pyrrole-2 (li) -carboxamide

(7% of theory, purity 97%)

Following the synthesis method 1 described above, the following compounds were also prepared from the reactants indicated: B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo assays as known to those skilled in the art. The following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.

B-l. In vitro electrophysiological analysis of the human TASK-1 and TASK-3 channels via two-electrode voltage-clamp technique in Xenopus / aev s-Oozvten

Xenopus / aev / s oocytes were selected as exemplified elsewhere [Decher et al., FEBS Lett. 492, 84-89 (2001)]. Subsequently, the oocytes were injected with 0.5-5 ng cRNA solution encoding TASK-1 or TASK-3. For the electrophysiological analysis of the channel proteins expressed in the oocytes, the two-electrode voltage-clamp technique was used [Stühmer, Methods Enzymol. 207. 319-339 (1992)]. The measurements were carried out as described [Decher et al, FEBS Lett. 492, 84-89 (2001)] at room temperature (21-22 ° C) with a turbo TEC-1 (CD amplifier (NPI), recorded at 2 kHz and filtered at 0.4 kHz.) The substance application was carried out by a gravitationally driven The oocyte is located in a measuring chamber and is exposed to the solution flow of 10 ml / min.The level of the measuring chamber is checked and regulated by aspirating the solution with a peristaltic pump.

The following Table 1A shows the half-maximal inhibition of the human TASK-1 and TASK-3 channels (IC 50 value) determined in this test by representative examples of the invention:

Table 1A

From the data in Table 1A, it can be seen that blockade is achieved at both TASK-1 and TASK-3. The results in Table 1A thus prove the mechanism of action of the compounds according to the invention as T ASK-1/3 inhibitors. E is a further (2-phenylimidazo [1,2-a] pyridin-3-yl) methyl-substituted perhydropyrrolo [3,4-c] pyrrole derivative, which can be considered as the structurally closest prior art [see WO 2014/187922-A1 as inhibitors of glucose transporters (GLUT) described compounds], was also examined in this test for the inhibition of human TASK-1 and TASK-3 anäie for comparison purposes. The result obtained for this compound is shown in Table 1B below:

Table 1B

 Thus, according to this test, the comparative compound of the prior art listed in Table 1B has an inhibitory activity with respect to TASK-1 channels which is approximately 1 to 3 orders of magnitude lower, and no appreciable inhibition of TASK-3 channels.

B-2. Inhibition of recombinant TASK-1 and TASK-3 in vitro

The studies on the inhibition of recombinant TASK-1 and TASK-3 channels were performed on stably transfected CHO cells. The compounds according to the invention were tested by applying 40 mM potassium chloride in the presence of a voltage-sensitive dye according to the method described in detail in the following references [Whiteaker et al., Validation of FLIPR membrane potential dye for high-throughput screening of potassium channel modulators, J Biomol. Screen. 6 (5), 305-312 (2001); Molecular Devices FLIPR Application Note: Measuring membrane potential using the FLIPR ^® membrane potential assay kit on fluoro metric Imaging Plate Reader (FLIPR ^®) system, http://www.moleculardevices.com/reagents- supplies / assay kits / Ion channels / FLIPR membrane-potential-assay kits]. The activity of the test substances was determined as their ability to express one in the recombinant cells by 40 mM potency. to inhibit chloride induced depolarization. The concentration that can block half of this depolarization is termed IC50.

The following Table 2A shows the IC ₅₀ values obtained from this assay for the exemplary embodiments of the invention (in part as mean values from several independent individual determinations):

Table 2A

Example TASK-1 TASK-3 Example TASK-1 TASK-3 No. IC50 | nM | IC50 | · m | No. IC50 | nM | IC50 | nM |

1 2410 6100 23 728 100

2 1730 5400 24 330 800

3 2500 7400 25 230 410

4 947 2300 26 220 310

5 1 130 1600 27 170 170

6 683 1300 28 300 190

7 787 4300 29 920 2100

8 1360 810 30 480 1200

9 749 660 32 1100 1200

10 206 485 33 460 4400

11 1210 2500 34 500 3300

12 1200 960 35 700 1700

13 712 1300 36 180 450

14 1060 3400 37 600 1800

15 1000 2900 38 1500 1900

16 1940 1100 41 580 2900

17 721 1900 42 740 3700

18 1680 4900 43 1700 2000

19 1250 1500 44 700 2000

20 1020 2500 45 2300 5800

21 1250 230 46 460 2200

22 1460 320 47 1000 240 Step Example! TASK-1 TASK-3 Example TASK-1 TASK-3 No. ICso | nM | ICso | nM | No. ICso | nM | ICso | nM |

48 78 79 50 1100 1 10

49 94 4.6 51 1400 80

From the data in Table 2A, it can be seen that blockade is achieved at both TASK-1 and TASK-3. The results in Table 2A thus prove the mechanism of action of the compounds according to the invention as T ASK-1/3 inhibitors.

Another (2-phenylimidazo [1,2-a] pyridin-3-yl) methyl-substituted perhydropyrrolo [3,4-c] pyrrole derivative which can be considered structurally closest prior art [see WO 2014/187922-A1 as inhibitors of glucose transporters (GLUT) described compounds], was for recombinant purposes also in this test for inhibition

TASK-1 and TASK-3 channels investigated. The result obtained for this compound is listed in Table 2B below: TABLE 2B

 The comparison compound from the prior art listed in Table 2B thus has a markedly weaker than non-specific inhibitory activity with respect to TASK-1 in this test.

B-3. Animal model of obstructive sleep apnea in pigs The use of negative pressure can be used in anesthetized, spontaneously breathing pigs

Collapse and thus a closure of the upper respiratory tract are triggered [Wirth et ah, Sleep 36. 699-708 (2013)]. For the model German country pigs are used. The pigs are anesthetized and tracheotomized. In each of the rostral and caudal parts of the trachea a cannula is inserted. The rostral cannula is connected by means of a T-piece on the one hand to a device which generates negative pressures and on the other hand to the caudal cannula. The caudal cannula is connected to the rostral cannula by means of a T-piece, as well as a tube which permits spontaneous respiration, bypassing the upper respiratory tract. By appropriately closing and opening the hoses, it is possible for the pig to change from a normal nasal breathing to a breathing via the caudal cannula, while the upper respiratory tracts are isolated and connected to the negative pressure generating device. Muscle activity of the genioglossus muscle is registered by electromyogram (EMG).

At certain times, the upper airway collapse is tested by breathing the pig over the caudal cannula and applying negative pressures of -50, -100 and -150 cm of water (cmH ₂ 0) to the upper respiratory tract. This causes the upper airways to collapse, as indicated by the interruption of airflow and a drop in pressure in the tubing system. This test is carried out before administration of the test substance and at certain intervals after administration of the test substance. A suitably effective test substance can prevent this collapse of the respiratory tract in the inspiratory phase.

After switching from nasal breathing to respiration through the caudal cannula, no E MG activity of the genioglossus muscle is measurable in the anesthetized pig. As a further test, the negative pressure is determined, in which the EMG activity starts again. This threshold value is shifted to more positive values when a test substance is effective. The examination is also carried out before administration of the test substance and at certain times after administration of the test substance. The administration of the test substance may be intranasal, intravenous, subcutaneous, intraperitoneal or intragastral.

C.

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

 The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Oral applizierhare suspension:

Composition:

1000 mg of the inventive compound, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

Hers:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Oral applicator solution:

Composition:

 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

 The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the erfmdungsgemäßen connection. i.v. solution: The compound of the invention is dissolved at a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and bottled in sterile and pyrogen-free injection containers.

Nasal Applicable Solution: The compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., purified water, phosphate buffer, citrate buffer). The solution may contain further additives for isotonization, for preservation, for the adjustment of the pH, for the improvement of the solubility and / or for the stabilization.

Claims

claims

1. Compound of formula (I)

in which

R ^{> is} halogen, cyano or (GC ₄ ) -alkyl and

R ^{2 is} (C 4 -C 6) -cycloalkyl, in which a ring-CH; -G nippe may be replaced by -O-. or R ^{2 is} a phenyl group of the formula (a) or a pyridyl group of the formula (b)

stands,

* marked the link to the adjacent carbonyl group and

Hydrogen, fluorine, chlorine, bromine, cyano, (Ci-C ₃ ) alkyl or (GC ₃ ) - alkoxy, wherein (Ci-C3) alkyl and (Ci-C3) alkoxy be substituted up to three times with fluorine can,

Is hydrogen, fluorine, chlorine, bromine or methyl, hydrogen, fluorine, chlorine, bromine or methyl and

R 'is hydrogen or (C 1 -C 3) -alkoxy which may be substituted up to three times by fluorine,

is a group -OR or -NR ⁸ R ⁹ , in which

R ^' and R ^{8 are in} each case (C 1 -C ₄ ) -alkyl, (C ₄ -C 6) -cycloalkyl, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl, where (C 1 -C ₄ ) -alkyl is up to three times may be substituted by fluorine and wherein phenyl and the phenyl groups in benzyl, 1-phenyl ethyl and 2-phenylethyl up to two times, same or different, selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and ethoxy may be substituted, and

R ^{9 is} hydrogen or methyl, or

R ⁸ and R 'are linked together and together with the nitrogen atom to which they are attached form a tetrahydroquinoline ring of the formula (c) or tetrahydroisoquinoline ring of the formula (d)

 form (c) (d),

 where ** denotes the linkage to the carbonyl group, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim I, in which R ^{1 is} chlorine, bromine or isopropyl and

R is cyclobutyl, cyclopentyl or cyclohexyl or R is a phenyl group of the formula (a) or a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent carbonyl group and

R "is fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,

R ^{4 is} hydrogen or fluorine,

R ^{5 is} hydrogen, fluorine, chlorine or methyl and

R 'is methoxy, difluoromethoxy, trifluoromethoxy or isopropoxy,

is a group -OR or -NR ⁸ R ⁹ , in which

R is isopropyl, isobutyl, tert-butyl, cyclopentyl, phenyl or benzyl, where phenyl and the phenyl group in benzyl up to two times, identically or differently, with a radical selected from the group fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy may be substituted,

R ^{8 is} phenyl, benzyl or 1-phenylethyl, where phenyl and the phenyl groups in benzyl and 1-phenyl ethyl up to two times, identically or differently, with a radical selected from among Fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy may be substituted, and

R ^{9 is} hydrogen or methyl, or

R ⁸ and R 'are linked to one another and together with the nitrogen atom to which they are attached form a tetrahydroquinoline ring of the formula (c)

 (c) form,

 where ** denotes the linkage to the carbonyl group, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1 or 2, in which

R ^{1 is} chlorine, bromine or isopropyl and

R ^{2 is} cyclobutyl or cyclopentyl or

R ^{2 represents} a phenyl group of the formula (a) or a pyridyl group of the formula (b)

stands,

* denotes the linkage to the adjacent carbonyl group and is fluoro, chloro, methyl, trifluoromethyl or methoxy, R ^{4 is} hydrogen or fluorine,

R ^{3 is} hydrogen, fluorine or methyl and

R 'means methoxy,

is a group -OR or -NR ⁸ R ⁹ , in which

R is isopropyl, cyclopentyl, phenyl or benzyl, where phenyl and the phenyl group in benzyl may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,

R ^{8 is} phenyl or 1-phenylethyl, where phenyl and the phenyl group in 1-phenylethyl may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy, and

R 'is hydrogen, or

R ⁸ and R ⁹ are linked together and, together with the nitrogen atom to which they are attached, form a tetrahydroquinoline ring of the formula (c)

(c) where * * denotes the linkage to the carbonyl group, their salts, solvates and derivatives of the salts. A compound of the formula (I) as claimed in claim 1, 2 or 3, in

R ^{1 is} chlorine or isopropyl and

R - for a pyridyl group of the formula (b)

where * denotes the linkage to the adjacent carbonyl group,

R is hydrogen, fluorine or methyl and

R "means methoxy, and their salts, solvates and solvates of the salts.

5. Process for the preparation of a compound of the formula (I) as defined in claims 1 to 4, characterized in that a compound of the formula (II)

in which R ^{1 has} the meaning given in claims 1 to 4, in the presence of a suitable reducing agent either

[A] with a compound of the formula (III)

> ^N CX (in), in which R ^{2 has} the meaning given in claims 1 to 4, to give a compound of formula (I) or

[B] with a protected perhydropyrrolo [3,4-c] pyrrole of the formula (IV) in which PG is a suitable amino-protecting group such as, for example, tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluorene-9-ylmethoxy) carbonyl, first to give a compound of the formula (V)

in which PG and R ^{1 have} the meanings given above, then the protective group PG is split off and the resulting compound of the formula (VI)

in which soft R ^{1 has} the abovementioned meaning, then depending on the specific meaning of the radical R ²

[Bl] with a carboxylic acid of the formula (VII) R ^2A OH (VII), in which

R ^{A is} (C4-C9) -cycloalkyl, in which a ring-CH ₂ group may be substituted by -O-, or by a phenyl group of the formula (a) or a

Pyridyl group of the formula (b) as described in claims 1 to 4, with activation of the carboxylic acid function in (VII) or with the corresponding acid chloride of the formula (VIII)

O

R 1 Cl (VIII), in which R ^{A has} the meaning indicated above, to give a compound of the formula (IA)

in which R ¹ and R ^{2A have} the meanings given above, or

[B-2] with a chloroformate or carbamoyl chloride of the formula (IX)

O

R ^2B ^ CI (IX), in which R ^{2B is} the group -OR ⁷ or -NR ⁸ R ^9A wherein

R and R ^{8 have} the meanings given in claims 1 to 3 and

R ^{9A has} the meaning of R ⁹ given in claims 1 to 3, but is not hydrogen, to give a compound of formula (IB)

in which R ¹ and R ^{2B have} the meanings given above, or

[B-3] with an isocyanate of the formula (X)

R ™ N = C = O (X), in which R ^{8 has} the meaning given in claims 1 to 3, to give a compound of formula (IC) in which R ¹ and R ^{8 have} the meanings given above, and the compounds of the formulas (I), (IA), (IB) or (IC) thus obtained, if appropriate with the corresponding (z) solvents and / or () acids into their solvates, salts and / or solvates of the salts.

6. A compound as defined in any one of claims 1 to 4 for the treatment and / or prevention of diseases.

A compound as defined in any one of claims 1 to 4 for use in a method of treating and / or preventing respiratory disorders, respiratory distress disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinfiratory disorders and neuroimmunological diseases.

Use of a compound as defined in any of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinfiratory disorders and neuroimmunological diseases.

9. A medicament containing a compound as defined in any one of claims 1 to 4, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

10. A medicament comprising a compound as defined in any one of claims 1 to 4, in combination with one or more further active ingredients selected from the group consisting of respiratory stimulants, p sy cho stimulatory compounds, erosinone inhibitors of uptake, noradrenergic , serotonergic and tricyclic antidepressants, sGC- Stimulators, mineralocorticoid receptor antagonists, anti-inflammatory

Agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.

A medicament according to claim 9 or 10 for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmia, arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological disorders.

A method for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunologic diseases in humans and animals by administering an effective amount of at least one compound as in any of Claims 1 to 4, or a medicament as defined in any one of claims 9 to 11.