Diazabicyl-substituted imidazopyrimidines and their use in treating respiratory tract diseases

Description

[0001] The present application relates to novel, diazabicyclic substituted imidazo[1,2-a]pyrimidine derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnea and snoring.

[0002] Potassium channels are virtually ubiquitous membrane proteins that are involved in a wide variety of physiological processes. This includes the regulation of membrane potential and the electrical excitability of neurons and muscle cells. Potassium channels are divided into three major 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 is called K2P channels. Functionally, K2P channels mediate background K+ / < currents in a largely time- and voltage-independent manner and play a crucial role in maintaining the resting membrane potential. The K2P channel family comprises 15 members, divided into six subfamilies based on similarities in sequence, structure, and function: TWIK, TREK, TASK, TALK, THIK, and TRESK.

[0003] Of particular interest are TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 or K2P9.1) of the TASK (TWIK-related acid-sensitive K +< channel ) subfamily. These channels are functionally characterized by the fact that so-called "leakage" or "background" currents flow through them while maintaining voltage-independent kinetics, responding to a variety of physiological and pathological influences with an increase or decrease in activity. TASK channels are characterized by their sensitive response to changes in extracellular pH: the channels are inhibited at acidic pH and activated at alkaline pH.

[0004] TASK-1 is predominantly expressed in the central nervous system and the cardiovascular system. Relevant expression of TASK-1 has been observed in the brain, spinal ganglia, motor neurons of the Nervus hypoglossus and Nervus trigeminus , in heart, Glomus caroticum , 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 has been found in the brain, motor neurons of the Nervus hypoglossus and Nervus trigeminus and in neuroepithelial cells of the Glomus caroticum and lungs, as well as on T lymphocytes. Lower expression is found in the heart, stomach, testicular tissue, and adrenal gland.

[0005] TASK-1 and TASK-3 channels play a role in the regulation of respiration. Both channels are expressed in the respiratory neurons of the respiratory center in the brainstem, including 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 nuclei. Due to their pH dependence, the TASK channels act as a sensor that translates extracellular pH changes into corresponding cellular signals [Bayliss et al., Pflügers Arch. 467, 917-929 (2015)]. Glomus caroticum TASK-1 and TASK-3 are expressed in the TASK-1 receptor, a peripheral chemoreceptor that measures pH, O 2 , and CO 2 levels in the blood and transmits signals to the respiratory center in the brainstem to regulate respiration. TASK-1 knock-out mice have been shown to exhibit a reduced ventilatory response (increase in respiratory rate and tidal volume) to hypoxia and normoxic hypercapnia [Trapp et al., J. Neurosci. 28, 8844-8850 (2008)]. Furthermore, TASK-1 and TASK-3 channels have been identified in motor neurons of the Nervus hypoglossus , the XII cranial nerve, which plays an important role in maintaining the patency of the upper airways [Berg et al., J. Neurosci. 24, 6693-6702 (2004)].

[0006] In a sleep apnea model in an anesthetized pig, intranasal administration of a potassium channel blocker that blocks the TASK-1 channel in the nanomolar range inhibited the collapsibility of the pharyngeal airway muscles and sensitized the negative pressure reflex of the upper airway. It is hypothesized that intranasal administration of the potassium channel blocker depolarizes mechanoreceptors in the upper airway and, via activation of the negative pressure reflex, leads to increased activity of the upper airway muscles, thereby stabilizing the upper airway and preventing collapse. Through such stabilization of the upper airway, TASK channel blockade may be of great importance for obstructive sleep apnea and snoring [Wirth et al., Sleep 36, 699-708 (2013); Kiper et al., Pflügers Arch. 467, 1081-1090 (2015)].

[0007] Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by repeated episodes of upper airway obstruction. During inspiration, the patency of the upper airway is maintained by the interplay of two opposing forces. The dilating effects of the upper airway muscles counteract the negative intraluminal pressure that constricts the lumen. The active contraction of the diaphragm and other accessory respiratory muscles creates negative airway pressure, thus providing the driving force for breathing. The stability of the upper airway is largely determined by the coordination and contractile properties of the dilating muscles of the upper airway.

[0008] The Musculus genioglossus plays a crucial role in the pathogenesis of obstructive sleep apnea. The activity of the Musculus genioglossus increases with decreasing pressure in the pharynx in the sense of a dilating compensatory mechanism. Innervated by the Nervus hypoglossus It pulls the tongue forward and downward, thus expanding the pharyngeal airway [Verse et al., Somnologie 3, 14-20 (1999)]. The tension of the dilating muscles of the upper airway is modulated, among other things, by mechanoreceptors / stretch receptors in the nasopharynx [Bouillette et al., J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]. Local anesthesia of the upper airway can result in an additional reduction in the activity of the Musculus genioglossus [Berry et al., Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]. Patients with obstructive sleep apnea have a high mortality and morbidity due to cardiovascular diseases such as hypertension, myocardial infarction, and stroke [Vrints et al., Acta Clin. Belg. 68, 169-178 (2013)].

[0009] In central sleep apnea, episodic inhibition of the respiratory drive occurs as a result of impaired brain function or impaired respiratory regulation. Centrally caused respiratory disorders lead to mechanical apnea, meaning that during these episodes, no breathing activity occurs; all respiratory muscles, including the diaphragm, temporarily stop working. In central sleep apnea, there is no obstruction of the upper airway.

[0010] Primary snoring also doesn't involve an obstruction of the upper airway. However, the narrowing of the upper airway increases the velocity of inhaled and exhaled air. This, combined with the relaxed muscles, causes the soft tissues of the mouth and throat to flutter in the airstream. This slight vibration then produces the typical snoring noise.

[0011] Obstructive snoring ( upper airway resistance syndrome , heavy snoring Hypopnea syndrome (hypopnea syndrome) is caused by recurrent partial obstruction of the upper airways during sleep. This leads to an increase in airway resistance and thus to an increase in the work of breathing with significant intrathoracic pressure fluctuations. The negative intrathoracic pressure development during inspiration can reach levels similar to those resulting from complete airway obstruction in obstructive sleep apnea. The pathophysiological effects on the heart, circulation, and sleep quality are similar to those in obstructive sleep apnea. As with obstructive sleep apnea, the pathogenesis is assumed to be a disturbed reflex mechanism of the pharyngeal dilating muscles during inspiration. Obstructive snoring is often a precursor to obstructive sleep apnea [Hollandt et al., HNO 48, 628-634 (2000)].

[0012] TASK channels also appear to play a role in neuronal cell death. In the animal model of myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis, an animal model for multiple sclerosis, TASK-1 knockout mice showed reduced neuronal degeneration. Inhibition of TASK channels appears to exert a neuroprotective effect by preventing neuronal apoptosis and may therefore be of interest for the treatment of neurodegenerative diseases [Bittner et al., Brain 132, 2501-2516 (2009)].

[0013] Furthermore, it has been described that T lymphocytes express TASK-1 and TASK-3 channels, and that inhibition of these channels leads to reduced cytokine production and proliferation after stimulation of T lymphocytes. Selective inhibition of TASK channels on T lymphocytes improved disease progression in an animal model of multiple sclerosis. Blockade of TASK channels may therefore also be important for the treatment of autoimmune diseases [Meuth et al., J. Biol. Chem. 283, 14559-14579 (2008)].

[0014] TASK-1 and TASK-3 are also expressed in the heart [Rinné et al., J. Mol. Cell. Cardiol. 81, 71-80 (2015)]. Since TASK-1 is particularly highly expressed in the conduction system and in the atrium, this channel may play a role in the initiation of conduction disturbances or supraventricular arrhythmias. In the heart, TASK-1 appears to contribute to a background current, which in turn contributes to the maintenance of the resting potential, action potential duration, and repolarization [Kim et al., Am. J. Physiol. 277, H1669-1678 (1999)]. It has been shown in human cardiac myocytes that blockade of the TASK-1 ion current leads to a prolongation of the action potential [Limberg et al., Cell. Physiol. Biochem. 28, 613-624 (2011)]. Furthermore, a prolonged QT interval was demonstrated in TASK-1 knock-out mice [Decher et al., Cell. Physiol. Biochem. 28, 77-86 (2011)].The inhibition of TASK channels could therefore be important for the treatment of cardiac arrhythmias, especially atrial fibrillation.

[0015] TASK channels also appear to play a role in the regulation of vascular tone in certain vessels. Significant expression of TASK-1 has been observed in the smooth muscle of pulmonary and mesenteric arteries. Studies on smooth muscle cells from human pulmonary arteries have shown that TASK-1 plays 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)].

[0016] In glomerulosa cells of the adrenal cortex, TASK-1 plays a role in potassium conductance [Czirjak et al., Mol. Endocrinol. 14, 863-874 (2000)].

[0017] TASK channels may also play an important role in apoptosis and tumorigenesis. TASK-3 has been found to be highly overexpressed in breast cancer, colon cancer, and lung cancer biopsies, as well as in metastatic prostate cancer and melanoma cells [Mu et al., Cancer Cell 3, 297-302 (2003); Kim et al., APMIS 112, 588-594 (2004); Pocsai et al., Cell. Mol. Life Sci. 63, 2364-2376 (2006)]. A point mutation in the TASK-3 channel, which inactivates channel function, simultaneously abolishes the tumorigenic 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)]. Blockade of TASK channels may therefore also be important for the treatment of various cancers.

[0018] The object of the present invention is therefore to provide new substances that act as potent and selective blockers of TASK-1 and TASK-3 channels and as such are particularly suitable for the treatment and / or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnea and snoring, as well as other diseases.

[0019] 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 02 / 02557-A2 and WO 2009 / 143156-A2 disclose 2-phenylimidazo[1,2-a]pyridine derivatives, which, as modulators of GABA A receptors, are also suitable for the treatment of CNS diseases. WO 2011 / 113606-A1 and WO 2012 / 143796-A2 disclose bicyclic imidazole derivatives suitable for the treatment of bacterial infections and inflammatory diseases, respectively. EP 2 671 582-A1 describes further 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, due to their HIF-1 inhibiting activity, are particularly suitable for the treatment of inflammatory and hyperproliferative diseases.WO 2014 / 187922-A1 discloses various 2-phenyl-3-(heterocyclomethyl)imidazo[1,2-a]pyridine and -imidazo[1,2-a]pyrazine derivatives that can be used as inhibitors of glucose transporters (GLUT) for the treatment of inflammatory, proliferative, metabolic, neurological, and / or autoimmune diseases. WO 2015 / 144605-A1 and WO 2017 / 050732-A1, among others, describe acylated bicyclic amine compounds that are suitable as inhibitors of autotaxin and lysophosphatidic acid production for the treatment of various diseases. WO 2016 / 084866-A1, WO 2016 / 085783-A1 and WO 2016 / 088813-A1 disclose acylated diazabicyclic compounds which, due to their antagonistic effect on orexin receptors, can be used for the treatment of neurodegenerative, neurological and psychiatric diseases, mental disorders and eating and sleeping disorders, in particular insomnia.WO 2013 / 037914 A1 describes 4,5,6,7-tetrahydro-IH-pyrazolo[4,3-c]pyridines as TASK inhibitors for the treatment of sleep-related breathing disorders.

[0020] Furthermore, the compound ethyl 4-[(2-phenylimidazo[1,2-a]pyrimidin-3-yl)methyl]piperazine-1-carboxylate [CAS Registry No. 1783141-19-4] is Chemical Abstracts Indexed as a "Chemical Library" substance without literature reference; no medical-therapeutic application has yet been described for this compound.

[0021] The present invention relates to compounds of the general formula (I) in which the ring Q represents a diaza-heterobicycle of the formula or where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, A represents CH or N, R 1< represents halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl, where (C 1 -C 4 )-alkyl may be substituted up to three times by fluorine and cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, R 2< represents hydrogen or methyl, and R 3< represents (C 4 -C 6 )-cycloalkyl, where one ring CH 2 group may be replaced by -O-, or R 3< represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) wherein *** marks the link to the adjacent carbonyl group and R 4< denotes hydrogen, fluorine, chlorine, bromine or methyl, R 5< denotes hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy, where (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may each be substituted up to three times by fluorine, R 6< denotes hydrogen, fluorine, chlorine, bromine or methyl, R 7< denotes hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino or (C 1 -C 3 )-alkylsulfanyl, where (C 1 -C 3 )-alkoxy may be substituted up to three times by fluorine, R 8< denotes hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy, R 9A< and R 9B< are identical or different and independently of one another denote hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl, cyclopropyl or (C 1 -C 3 )-alkoxy,where (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may each be substituted up to three times by fluorine, and Y represents YO or S, or , R 3< represents a group -OR 10< or -NR 11< R 12<, in which R 10< is (C 1 -C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl or [(C 3 -C 6 )-cycloalkyl]methyl, R 11< is hydrogen or (C 1 -C 3 )-alkyl and R 12< is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl, where (C 1 -C 6 )-alkyl may be substituted up to three times by fluorine and where phenyl and the phenyl group in benzyl may be substituted up to three times, identically or differently, by a radical selected from the series fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl, or R 11< and R 12< are linked to one another and together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, as well as their salts, solvates and solvates of salts.

[0022] Compounds according to the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts, the compounds encompassed by formula (I) of the formulas (IA), (IB), (IC), (ID) and (IE) mentioned below and their salts, solvates and solvates of the salts, as well as the compounds encompassed by formula (I) and mentioned below as working examples and their salts, solvates and solvates of the salts, insofar as the compounds encompassed by formula (I) and mentioned below are not already salts, solvates and solvates of the salts.

[0023] As Salze For the purposes of the present invention, physiologically acceptable salts of the compounds according to the invention are preferred. Also included are salts that 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.

[0024] Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and embonic acid.

[0025] As Solvate For the purposes of the invention, "hydrates" refer to those forms of the compounds according to the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Hydrates are preferred as solvates for the purposes of the present invention.

[0026] Depending on their structure, the compounds according to the invention can exist in different stereoisomeric forms, i.e., in the form of configurational isomers or, optionally, also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses 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; chromatographic methods are preferably used for this purpose, in particular HPLC chromatography on chiral or achiral separating phases. In the case of chiral amines as intermediates or end products, separation via diastereomeric salts using enantiomerically pure carboxylic acids can alternatively be carried out.

[0027] If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

[0028] The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass usually or predominantly occurring in nature. Examples of isotopes that can be incorporated into a compound according to 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, 14<C, 15<N, 17<O, 18<O, 32<P, 33<P, 33<S, 34<S, 35<S, 36<S, 18<F, 36<Cl, 82<Br, 123<I, 124<I, 129<I and 131<I.Certain isotopic variants of a compound according to the invention, particularly those incorporating one or more radioactive isotopes, can be useful, for example, for investigating the mechanism of action or the distribution of the active ingredient in the body. Due to their comparative ease of preparation and detection, compounds labeled with 3< H or 14< C isotopes are particularly suitable for this purpose. Furthermore, the incorporation of isotopes, such as deuterium, can lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as an extension of the half-life in the body or a reduction of the required effective dose. Such modifications of the compounds according to the invention can therefore also represent 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 instructions given in the working examples, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

[0029] In the context of the present invention, the substituents and radicals, unless otherwise specified, have the following meaning: (C 1 -C 6 )-Alkyl In the context of the invention, R represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples include: methyl, ethyl, n -Propyl, Isopropyl, n -Butyl, Isobutyl, sec .-Butyl, tert .-Butyl, n -Pentyl, 2-Pentyl, 3-Pentyl, Neopentyl, n-Hexyl, 2-hexyl and 3-hexyl. (C 1 -C 4 )-Alkyl In the context of the invention, R represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n -Propyl, Isopropyl, n -Butyl, Isobutyl, sec. -Butyl and tert .-Butyl. (C 1 -C 3 )-Alkyl In the context of the invention, R represents a straight-chain or branched alkyl radical having 1 to 3 carbon atoms. Examples include: methyl, ethyl, n -Propyl and isopropyl. (C 1 -C 3 )-Alkoxy In the context of the invention, R represents a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms. Examples include: methoxy, ethoxy, n -Propoxy and isopropoxy. Mono-(C 1 -C 3 )-alkylamino In the context of the invention, represents an amino group with a straight-chain or branched alkyl substituent having 1 to 3 carbon atoms. Examples include: methylamino, ethylamino, n -Propylamino and Isopropylamino. Di-(C 1 -C 3 )-alkylamino In the context of the invention, represents an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 3 carbon atoms. Examples include: N,N -Dimethylamino, N,N -Diethylamino, N- Ethyl- N -methylamino, N -Methyl- N - n -propylamino, N -Isopropyl- N -methylamino, N,N -Di- n -propylamino, N -Isopropyl- N-n -propylamino and N,N -Diisopropylamino. (C 1 -C 3 )-Alkylsulfanyl [also referred to as (C 1 -C 3 )-alkylthio] represents, in the context of the invention, a straight-chain or branched alkyl radical having 1 to 3 carbon atoms, which is linked to the rest of the molecule via an S atom. Examples include: methylsulfanyl, ethylsulfanyl, n -Propylsulfanyl and isopropylsulfanyl. (C 3 -C 6 )-Cycloalkyl In the context of the invention, R represents a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. (C 4 -C 6 )-Cycloalkyl In the context of the invention, represents a monocyclic, saturated cycloalkyl group having 4 to 6 carbon atoms. Examples include: cyclobutyl, cyclopentyl, and cyclohexyl. Halogen Within the scope of the invention, includes fluorine, chlorine, bromine, and iodine. Fluorine, chlorine, or bromine are preferred.

[0030] Within the scope of the present invention, the meaning of all radicals that occur multiple times is independent of one another. If radicals in the compounds according to the invention are substituted, the radicals may be mono- or polysubstituted, unless otherwise specified. Substitution with one or two identical or different substituents is preferred. Substitution with one substituent is particularly preferred.

[0031] Preferred in the context of the present invention are compounds of formula (I) in which the ring Q represents a diaza-heterobicycle of the formula where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, A represents CH, R 1< represents fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, R 2< represents hydrogen, and R 3< represents cyclobutyl, cyclopentyl or cyclohexyl or R 3< represents a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d), (e) or (f) wherein *** marks the linkage to the adjacent carbonyl group and R 4< denotes hydrogen, fluorine or chlorine, R 5< denotes fluorine, chlorine, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy or trifluoromethoxy, R 6< denotes hydrogen, fluorine, chlorine, bromine or methyl, R 7< denotes (C 1 -C 3 )-alkoxy, cyclobutyloxy or (C 1 -C 3 )-alkylsulfanyl, where (C 1 -C 3 )-alkoxy may be substituted up to three times by fluorine, R 9A< and R 9B< are identical or different and independently denote hydrogen, chlorine, bromine, (C 1 -C 3 )-alkyl or cyclopropyl, where (C 1 -C 3 )-alkyl may be substituted up to three times by fluorine, and Y denotes S, as well as their salts, solvates and solvates of salts.

[0032] A particular embodiment of the present invention relates to compounds of formula (I) in which the ring Q represents a diaza-heterobicycle of the formula where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, as well as their salts, solvates and solvates of the salts.

[0033] A further particular embodiment of the present invention relates to compounds of formula (I) in which the ring Q represents a diaza-heterobicycle of the formula where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, as well as their salts, solvates and solvates of the salts.

[0034] A further particular embodiment of the present invention relates to compounds of formula (I) in which the ring Q represents a diaza-heterobicycle of the formula where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, as well as their salts, solvates and solvates of the salts.

[0035] A further particular embodiment of the present invention relates to compounds of formula (I) in which A stands for CH, as well as their salts, solvates and solvates of salts.

[0036] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 1< represents chlorine, bromine, isopropyl or cyclopropyl, as well as their salts, solvates and solvates of salts.

[0037] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 2< stands for hydrogen, as well as their salts, solvates and solvates of salts.

[0038] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 3< represents cyclopentyl or cyclohexyl, as well as their salts, solvates and solvates of salts.

[0039] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 3< represents a phenyl group of formula (a) where *** marks the linkage to the adjacent carbonyl group, R 4< is hydrogen, fluorine or chlorine and R 5< is fluorine, chlorine, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy, as well as their salts, solvates and solvates of salts.

[0040] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 3< represents a pyridyl group of formula (b) where *** marks the linkage to the adjacent carbonyl group, R 6< is hydrogen, fluorine, chlorine, bromine or methyl and R 7< is (C 1 -C 3 )-alkoxy, cyclobutyloxy or (C 1 -C 3 )-alkylsulfanyl, where (C 1 -C 3 )-alkoxy may be substituted up to three times by fluorine, as well as their salts, solvates and solvates of salts.

[0041] A further particular embodiment of the present invention relates to compounds of formula (I) in which R 3< represents an azole group of formula (d), (e) or (f) wherein *** marks the linkage to the adjacent carbonyl group, R 9A< and R 9B< are the same or different and independently of one another represent hydrogen, chlorine, bromine, (C 1 -C 3 )-alkyl or cyclopropyl, where (C 1 -C 3 )-alkyl may be substituted up to three times by fluorine, and Y represents S, as well as their salts, solvates and solvates of salts.

[0042] Particularly preferred in the context of the present invention are compounds of formula (I) in which the ring Q represents a diaza-heterobicycle of the formula where * denotes the linkage to the adjacent CHR 2< group and ** denotes the linkage to the carbonyl group, A represents CH, R 1< represents chlorine, bromine, isopropyl or cyclopropyl, R 2< represents hydrogen, and R 3< represents cyclopentyl or cyclohexyl or R 3< represents a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d), (e) or (f) wherein *** marks the linkage to the adjacent carbonyl group and R 4< is hydrogen, fluorine or chlorine, R 5< is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy, R 6< is hydrogen, fluorine, chlorine, bromine or methyl, R 7< is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl, R 9A< and R 9B< are the same or different and independently of one another are hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl and Y is YO or S, as well as their salts, solvates and solvates of salts.

[0043] The individual radical definitions specified in the respective combinations or preferred combinations of radicals can be replaced at will by radical definitions of other combinations, regardless of the respective specified combinations of radicals. Combinations of two or more of the above-mentioned preferred ranges are particularly preferred.

[0044] The invention further relates to a process for the preparation of compounds of the formula (I) according to the invention, in which the radical R 2< is hydrogen, characterized in that a compound of the formula (II) in which A and R 1< have the meanings given above, in the presence of a suitable reducing agent either [A] with a compound of formula (III) in which R 3< and the ring Q have the meanings given above, to a compound of formula (IA) in which A, R 1< , R 3< and the ring Q have the meanings given above, or [B] with a protected diaza-heterobicycle of the formula (IV) in which the ring Q has the meaning given above and PG represents a suitable amino protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl, initially to a compound of formula (V) in which A, PG, R 1< and the ring Q have the meanings given above, then the protecting group PG is split off and the resulting compound of formula (VI) in which A, R 1< and the ring Q have the meanings given above, then depending on the specific meaning of the radical R 3< [B-1] with a carboxylic acid of the formula (VII) in which R 3A< represents (C 4 -C 6 )-cycloalkyl, in which a ring CH 2 group may be replaced by -O-, or represents a phenyl group of formula (a), a pyridyl group of formula (b) or (c) or an azole group of formula (d), (e) or (f), as described above, with activation of the carboxylic acid function in (VII) or with the corresponding acid chloride of formula (VIII) in which R 3A< has the meaning given above, to a compound of formula (IB) in which A, R 1< , R 3A< and the ring Q have the meanings given above, or [B-2] with a chloroformate or carbamoyl chloride of the formula (IX) in which R 3B< represents the group -OR 10< or -NR 11A< R 12<, in which R 10< and R 12< have the meanings given above and R 11A< has the meaning given above of R 11<, but is not hydrogen, to a compound of the formula (IC) in which A, R 1< , R 3B< and the ring Q have the meanings given above, or [B-3] with an isocyanate of the formula (X) R 12< -N=C=O (X), in which R 12< has the meaning given above, to give a compound of the formula (ID) in which A, R 1< , R 12< and the ring Q have the meanings given above, and the resulting compounds of the formulas (IA), (IB), (IC) or (ID) are optionally separated into their enantiomers and / or diastereomers and / or optionally treated with the corresponding ( i ) solvents and / or ( ii ) Acids are converted into their solvates, salts and / or solvates of the salts.

[0045] Suitable reducing agents for process steps [A] (II) + (III) -> (IA) and [B] (II) + (IV) -> (V) [reductive aminations] are conventional alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; sodium triacetoxyborohydride is preferably used. The addition of an acid, such as acetic acid, and / or a dehydrating agent, such as molecular sieve or trimethyl or triethyl orthoformate, can be advantageous in these reactions.

[0046] Solvents used for these reactions are particularly alcohols such as methanol, ethanol, n -Propanol or isopropanol, ethers such as diisopropyl ether, methyl- tert .-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 are suitable; tetrahydrofuran is preferred. The reactions generally take place in a temperature range from 0°C to +50°C.

[0047] As a protecting group PG in compound (IV) a common amino protecting group such as tert .-Butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or (9 H -Fluoren-9-ylmethoxy)carbonyl (Fmoc) can be used; preference is given to tert .-Butoxycarbonyl (Boc) is used. The cleavage of the protecting group in process step [B] (V) —> (VI) is carried out according to known methods. tert The .-butoxycarbonyl group is usually removed 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. In the case of benzyloxycarbonyl as the protecting group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst, such as palladium on activated carbon. The (9 H- The fluoren-9-ylmethoxy)carbonyl group is generally cleaved using a secondary amine base such as diethylamine or piperidine [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; PJ Kocienski, Protecting Groups, 3rd edition, Thieme, 2005].

[0048] Certain compounds of formula (V), in particular those in which PG represents tert .-Butoxycarbonyl, also exhibit significant inhibitory activity against TASK-1 and / or TASK-3 and are therefore also encompassed by the scope of the present invention, ie the compounds of formula (I).

[0049] Process step [B-1] (VI) + (VII) -> (IB) [amide formation] is carried out according to known methods using a condensing or activating agent. Suitable agents include, for example, carbodiimides such as N,N '-Diethyl-, N,N '-Dipropyl-, N,N '-Diisopropyl-, N,N'- Dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N '-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-perchlorat, Acylamino-Verbindungen wie 2-Ethoxy-1-ethoxycarbonyl-1,2-di-hydrochinolin, α-Chlorenamine wie 1-Chlor- N,N ,2-trimethylprop-1-en-1-amin, 1,3,5-Triazin-Derivate wie 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchlorid, Phosphor-Verbindungen wie n -Propanphosphonsäureanhydrid (PPA), Cyanophosphonsäurediethylester, Diphenylphosphorylazid (DPPA), Bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid, Benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium-hexafluorophosphat oder Benzotriazol-1-yloxy-tris(pyrrolidino)-phosphonium-hexafluorophosphat (PyBOP), oder Uronium-Verbindungen wie O -(Benzotriazol-1-yl)- N,N,N',N '-tetramethyluronium-tetrafluoroborat (TBTU), O -(1 H -6-Chlorbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborat (TCTU), O -(Benzotriazol-1-yl)- N,N,N',N '-tetramethyl-uronium-hexafluorophosphat (HBTU), O -(7-Azabenzotriazol-1-yl)- N ,N , N ', N '-tetramethyluronium hexafluorophosphate (HATU) or 2-(2-oxo-1-(2 H )-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as base an alkali carbonate, e.g. 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). The preferred condensation or activating agent is O -(7-Azabenzotriazol-1-yl)- N,N,N',N '-tetramethyluronium hexafluorophosphate (HATU) in combination with N,N-diisopropylethylamine as base.

[0050] The alternative process via the carboxylic acid chloride (VIII) [(VI) + (VIII) —> (IB)] 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 N,N -Diisopropylethylamine is used.

[0051] Suitable inert solvents for these amide formation 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, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N -Dimethylformamide (DMF), N,N '-Dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP); mixtures of such solvents can also be used. Preferred solvents are dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N Dimethylformamide or mixtures thereof are used. The reactions are generally carried out in a temperature range from -20°C to +60°C, preferably from 0°C to +40°C.

[0052] The process [B-2] (VI) + (IX) —> (IC) [formation of urethanes or substituted ureas] is carried out under similar reaction conditions regarding solvent, base addition and temperature as previously described for the amide formation [B-1] (VI) + (VIII) —> (IB).

[0053] The reaction [B-3] (VI) + (X) —> (ID) is also carried out in one of the previously listed inert solvents or solvent mixtures at a temperature in the range of 0°C to +60°C; the addition of a base can be omitted in this reaction if necessary.

[0054] The amine compound (VI) can also be used in the form of a salt, for example as hydrochloride or trifluoroacetate, in process steps [B-1] (VI) + (VII) or (VIII) → (IB), [B-2] (VI) + (IX) → (IC), and [B-3] (VI) + (X) → (ID). In such a case, the reaction takes place in the presence of a correspondingly increased amount of the auxiliary base used.

[0055] Compounds of the formula (I) according to the invention, in which the radical R 2< is methyl, can be obtained by reacting the above-mentioned carbaldehyde of the formula (II) in which A and R 1< have the meanings given above, first with methylmagnesium bromide to give the secondary alcohol of formula (XI) in which A and R 1< have the meanings given above, which is then converted into the corresponding bromide of formula (XII) with the aid of triphenylphosphine and carbon tetrabromide in which A and R 1< have the meanings given above, then with a protected diaza-heterobicycle of the formula (IV) in which the ring Q has the meaning given above and PG represents a suitable amino protecting group such as tert .-Butoxycarbonyl, benzyloxycarbonyl or (9 H -Fluoren-9-ylmethoxy)carbonyl, to a compound of formula (XIII) in which A, PG, R 1< and the ring Q have the meanings given above, subsequently splitting off the protecting group PG and the resulting compound of formula (XIV) in which A, R 1< and the ring Q have the meanings given above, then, depending on the specific meaning of the radical R 3<, according to one of the processes [B-1], [B-2] or [B-3] described above, into the target compound of the formula (IE) in which A, R 1< , R 3< and the ring Q have the meanings given above, and the latter is optionally separated into its enantiomers and / or diastereomers and / or optionally treated with the corresponding ( i ) solvents and / or ( ii ) acids to their solvates, salts and / or solvates of the salts.

[0056] The reaction of carbaldehyde (II) with methylmagnesium bromide to the secondary alcohol (XI) is typically carried out in an ethereal solvent such as diethyl ether, diisopropyl ether, methyl tert butyl ether, tetrahydrofuran, or a mixture thereof, in a temperature range from -20°C to +40°C. The subsequent conversion to the bromide (XII) is advantageously carried out under mild conditions using the reagent combination of triphenylphosphine and carbon tetrabromide in the presence of triethylamine as a base ("Appel reaction"). The reaction is preferably carried out in dichloromethane as an inert solvent in a temperature range from -10°C to +30°C. For the subsequent reaction with the diaza-heterobicycle (IV), the bromide (XII) is preferably not isolated beforehand, but used directly as a crude product in a one-pot process by changing the solvent. For this reaction (XII) + (IV) -> (XIII), acetonitrile is preferably used as the solvent, and the reaction generally takes place in a temperature range from +20°C to +60°C.

[0057] Finally, the process steps (XIII) —> (XIV) and (XIV) —> (IE) are carried out in an analogous manner as previously described for the processes [B] (V) —> (VI) and [B-1], [B-2] and [B-3], respectively.

[0058] The processes described above can be carried out at normal, elevated, or reduced pressure (e.g., in the range of 0.5 to 5 bar); in general, the pressure is normal.

[0059] Separation of the compounds according to the invention into the corresponding enantiomers and / or diastereomers can optionally, depending on expediency, also take place at the stage of the compounds (III), (IV), (V) or (VI) or (XI), (XIII) or (XIV), which are then further reacted in separated form according to the process steps described above. Such separation of the stereoisomers can be carried out by customary methods known to the person skilled in the art. In the context of the present invention, chromatographic processes on chiral or achiral separation phases are preferably used; in the case of chiral amines as intermediates or end products, separation via diastereomeric salts using enantiomerically pure carboxylic acids can alternatively be carried out.

[0060] The compounds of formula (II) can be prepared by a process known from the literature by reacting 2-aminopyrimidine (XV) under the influence of a base with a compound of formula (XVI) in which A and R 1< have the meanings given above and X represents a suitable leaving group such as chlorine, bromine or iodine, to an imidazo[1,2-a]pyrimidine derivative of the formula (XVII) in which A and R 1< have the meanings given above, and then condensed with a mixture of N,N -Dimethylformamide and phosphorus oxychloride to (II).

[0061] The condensation reaction (XV) + (XVI) —> (XVII) is usually carried out in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol, in an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, in a dipolar aprotic solvent such as N,N -Dimethylformamide (DMF), N,N '-Dimethylpropyleneurea (DMPU) or N-Methylpyrrolidinone (NMP), or in water at a temperature in the range of +50°C to +150°C; ethanol or water is preferably used as solvent.

[0062] Suitable bases for this reaction include, in particular, alkali metal bicarbonates or carbonates such as sodium or potassium bicarbonate or lithium, sodium, potassium, or cesium carbonate; alkali metal hydroxides such as sodium or potassium hydroxide; or even aluminum oxide; sodium bicarbonate or sodium hydroxide is preferred. If necessary, the reaction can also be carried out without the addition of a base—with a corresponding increase in the reaction temperature.

[0063] The regioselective formylation (XVII) —> (II) is carried out under the usual conditions of a Vilsmaier-Haack reaction by treating (XVII) with a preformed mixture of N,N- Dimethylformamide and phosphorus oxychloride, which is used in large excess and also serves as a solvent. The reaction is generally carried out at a temperature range of 0°C to +100°C.

[0064] The compounds of formulas (III), (IV), (VII), (VIII), (IX), (X), (XV), and (XVI) are either commercially available or described as such in the literature, or they can be readily prepared starting from other commercially available compounds using methods known from the literature and familiar to the person skilled in the art. Numerous detailed procedures and further references can also be found in the Experimental Section in the section on the preparation of starting compounds and intermediates.

[0065] The preparation of the compounds according to the invention can be illustrated by the following reaction schemes:

[0066] The compounds of the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0067] 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 induced secondarily by TASK-1 and / or TASK-3-induced damage.

[0068] In the context of the present invention, these include in particular diseases from the group of breathing disorders and sleep-related breathing disorders, such as obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring ( upper airway resistance syndrome , heavy snoring , hypopnea syndrome), central sleep apnea, mixed sleep apneas, Cheyne-Stokes respiration, primary sleep apnea in childhood, apnea of ​​prematurity, central sleep apnea due to medication or substance use, obesity hypoventilation syndrome, impaired central respiratory drive, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscular-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders during adaptation in high mountains, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome.

[0069] The compounds according to the invention can further be 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, Silberkorn disease, frontotemporal dementia and parkinsonism of chromosome 17, multiple system atrophy, spinocerebellar ataxias, spinobulbar muscular atrophy of Kennedy type, Friedreich's ataxia, dentatorubropallidoluysian 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 lobe degeneration with ubiquitin-proteasome system and familial encephalopathy with Neuroserpin inclusions.

[0070] The compounds according to the invention can furthermore be used for the treatment and / or prevention of neuroinflammatory and neuroimmunological diseases of the central nervous system (CNS), such as multiple sclerosis (disseminated encephalomyelitis), transverse myelitis, neuromyelitis optica, acute disseminated encephalomyelitis, optic neuritis, meningitis, encephalitis, demyelinating diseases and inflammatory vascular changes of the central nervous system.

[0071] The compounds according to the invention are also suitable for the treatment and / or prevention of cancers, such as skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

[0072] The compounds according to the invention are also suitable for the treatment and / or prevention of cardiac arrhythmias and arrhythmias, such as, for example, atrial and ventricular rhythm disturbances, conduction disturbances such as grade I-III atrioventricular blocks, supraventricular tachyarrhythmia, 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 nodal reentrant tachycardia.

[0073] Other cardiovascular diseases for the treatment and / or prevention of which the compounds according to the invention can be used include, for example, heart failure, coronary heart disease, stable and unstable angina pectoris, high blood pressure (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 diseases (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, as well as thromboembolic diseases and ischemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, Preeclampsia, inflammatory cardiovascular diseases, spasms of coronary arteries and peripheral arteries,Edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure-related edema, peripheral circulatory disorders, reperfusion injuries, arterial and venous thrombosis, microalbuminuria, heart muscle weakness, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as for the prevention of restenosis, for example, after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.

[0074] For the purposes of the present invention, the term heart failure includes both acute and chronic manifestations of heart failure as well as specific or related disease forms 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, heart valve defects, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxic Cardiomyopathy, cardiac storage diseases, and diastolic and systolic heart failure.

[0075] The compounds according to the invention can further be used for the treatment and / or prevention of asthmatic diseases of varying severity with an intermittent or persistent course (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug-induced or dust-induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammations of the nasal mucosa (including drug-induced rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, e.g. hay fever) and polyps.

[0076] In addition, the compounds according to the invention are suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and renal failure. For the purposes of the present invention, the terms renal insufficiency and renal failure encompass both acute and chronic manifestations thereof, as well as underlying or related kidney diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection and immune complex-induced kidney diseases, toxic substance-induced nephropathy, contrast medium-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, kidney cysts, nephrosclerosis,Hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes such as glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

[0077] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain as well as erectile dysfunction and female sexual dysfunction.

[0078] The compounds according to the invention are also suitable for the treatment and / or prevention of inflammatory diseases and autoimmune diseases, such as rheumatoid diseases, inflammatory eye diseases, chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary emphysema (e.g.Suitable for the treatment of diseases such as cigarette smoke-induced pulmonary emphysema, cystic fibrosis (CF), sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epiduralism, oophoritis, salpingitis and vulvovaginitis, as well as for the treatment and / or prevention of fibrotic diseases of the internal organs, such as the lungs, heart, kidneys, bone marrow and especially the liver, dermatological fibroses and fibrotic diseases of the eye.For the purposes of the present invention, the term "fibrotic diseases" encompasses, in particular, diseases such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis, peritoneal fibrosis, and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy, and connective tissue diseases (e.g., sarcoidosis). The compounds according to the invention can also be used to promote wound healing, to combat postoperative scarring, e.g., after glaucoma surgery, and for cosmetic purposes in aging or keratinizing skin.

[0079] In addition, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier disease, obesity, metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and late diabetic complications such as retinopathy, nephropathy and neuropathy), anemias such as hemolytic anemias, in particular hemoglobinopathies such as sickle cell anemia and thalassemia, megaloblastic anemias, iron deficiency anemias, anemias due to acute blood loss, displacement anemias and aplastic anemias, diseases of the gastrointestinal tract 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, depression), immune diseases, thyroid diseases (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphomas, skin cancer, Sweet's syndrome, Weber-Christian syndrome, scarring, warts, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, Ophthalmitis), viral diseases (caused by influenza, adenoviruses and coronaviruses, such as HPV, HCMV, HIV, SARS), diseases of the skeletal bones, joints and skeletal muscles,Inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, polyarteritis, rheumatic arteritis, deforming arteritis, temporal arteritis, cranial arteritis, gigantocellular arteritis, and granulomatous arteritis, as well as Horton syndrome, Churg-Strauss syndrome, and Takayasu arteritis), Muckle-Well syndrome, Kikuchi disease, polychondritis, scleroderma, and other diseases with an inflammatory or immunological component, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome, and paraneoplastic syndrome, in rejection reactions after organ transplantation, and for wound healing and angiogenesis, particularly in chronic wounds.

[0080] Due to their property profile, 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 the treatment and / or prevention of neurodegenerative, neuroinflammatory and neuroimmunological diseases.

[0081] The aforementioned well-characterized human diseases can also occur in other mammals with comparable etiology and can also be treated there with the compounds of the present invention.

[0082] For the purposes of the present invention, the term "treatment" or "treat" encompasses inhibiting, delaying, stopping, alleviating, attenuating, limiting, reducing, suppressing, repressing, or curing a disease, ailment, illness, injury, or health disorder, the development, course, or progression of such conditions, and / or the symptoms of such conditions. The term "therapy" is understood here as synonymous with the term "treatment."

[0083] The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of getting, experiencing, suffering or having a disease, ailment, illness, injury or health disorder, the development or progression of such conditions and / or the symptoms of such conditions.

[0084] The treatment or prevention of a disease, condition, illness, injury or health disorder may be partial or complete.

[0085] The present invention further relates to the use of the compounds according to the invention for producing a medicament for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0086] The present invention further relates to a medicament containing at least one of the compounds according to the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0087] The present invention further relates to the compounds according to the invention for use in a method for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0088] The present invention further relates to the compounds according to the invention for use in 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 according to the invention.

[0089] The compounds according to the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. The present invention therefore further relates to medicaments containing at least one of the compounds according to the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Examples of suitable combination active ingredients include, but are not limited to: Respiratory stimulants, such as, for example and preferably, theophylline, doxapram, nicethamide or caffeine; psychostimulant compounds, such as, for example and preferably, modafinil or armodafinil; amphetamines and amphetamine derivatives, such as, for example and preferably, amphetamine, methamphetamine or methylphenidate; serotonin reuptake inhibitors, such as, for example and preferably, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone; serotonin precursors, such as, for example and preferably, L-tryptophan; selective serotonin-noradrenaline reuptake inhibitors, such as, for example and preferably, venlafaxine or duloxetine; noradrenergic and specifically serotonergic antidepressants, such as, for example and preferably, mirtazapine; selective noradrenaline reuptake inhibitors, such as, for example and preferably, reboxetine; tricyclic antidepressants, such as, by way of example and preference, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine;Alpha2-adrenergic agonists, such as, for example and preferably, clonidine; GABA agonists, such as, for example and preferably, baclofen; alpha-sympathomimetics, such as, for example and preferably, xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetryzoline or tramazoline; glucocorticoids, such as, for example and preferably, fluticasone, budesonide, beclomethasone, mometasone, tixocortol or triamcinolone; cannabinoid receptor agonists; carbonic anhydrase inhibitors, such as, for example and preferably, acetazolamide, methazolamide or diclofenamide; opioid and benzodiazepine receptor antagonists, such as, for example and preferably, flumazenil, naloxone or naltrexone; Cholinesterase inhibitors, such as, by way of example and preferably, neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine; ; N-Methyl-D-aspartate and glutamate antagonists, such as, for example and preferably, amantadine, memantine or sabeluzole; nicotine receptor agonists; leukotriene receptor antagonists, such as, for example and preferably, montelukast or tripelukast; dopamine receptor antagonists, such as, for example and preferably, dromperidone, metoclopramide or benzamide, butyrophenone or phenothiazine derivatives; appetite suppressants, such as, for example and preferably, sibutramine, topiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists; proton pump inhibitors, such as, for 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, as well as inhaled NO;Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as, for example, inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil; NO- and heme-independent activators of soluble guanylate cyclase (sGC), such as in particular the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510; NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), such as in particular riociguat, vericiguat, and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647, and WO 2012 / 059549; prostacyclin analogues and IP receptor agonists, such as, by way of example and by way of preference, iloprost, beraprost, treprostinil, epoprostenol, or selexipag;Endothelin receptor antagonists, such as, for example and preferably, bosentan, darusentan, ambrisentan, or sitaxsentan; compounds that inhibit human neutrophil elastase (HNE), such as, for example and preferably, sivelestat or DX-890 (Reltran); compounds that inhibit the degradation and remodeling of the extracellular matrix, for example and preferably, inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases, and aggrecanases (especially MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11, and MMP-13) as well as metalloelastase (MMP-12); Compounds that block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT 2B receptor such as PRX-08066; antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;Rho kinase-inhibiting compounds, such as, by way of example and preferably, fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, or BA-1049; compounds influencing cardiac energy metabolism, such as, by way of example and preferably, etomoxir, dichloroacetate, ranolazine, or trimetazidine; compounds which inhibit the signal transduction cascade, by way of example and with preference from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and with preference nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;anti-obstructive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably from the group of inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics) and inhaled anti-muscarinic substances; anti-inflammatory, immunomodulating, immunosuppressive and / or cytotoxic agents, for example and preferably from the group of systemically or inhaled corticosteroids as well as 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, for example and preferably, lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists, or pirfenidone; antithrombotic agents, for example and preferably from the group of platelet aggregation inhibitors, anticoagulants, and profibrinolytic substances; blood pressure-lowering agents, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and diuretics;and / or active substances that modify lipid metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as for 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 adsorbers, bile acid reabsorption inhibitors and lipoprotein(a) antagonists. ;

[0090] 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, reproterol, salbutamol or salmeterol.

[0091] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinic substance, such as, by way of example and by way of preference, ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0092] 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 by way of preference, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.

[0093] Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

[0094] 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 preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0095] 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, bivalirudin or clexane.

[0096] 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 preferably, tirofiban or abciximab.

[0097] 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 with preference, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0098] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0099] 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.

[0100] Antihypertensive agents preferably include compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

[0101] 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.

[0102] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, such as, by way of example and preferably, prazosin.

[0103] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-receptor blocker, such as, by way of example and with preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0104] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as, by way of example and by way of preference, losartan, candesartan, valsartan, telmisartan or embusartan.

[0105] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as, by way of example and with preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0106] 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 preferably, bosentan, darusentan, ambrisentan or sitaxsentan.

[0107] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as, by way of example and by way of preference, aliskiren, SPP-600 or SPP-800.

[0108] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, by way of example and preferably, spironolactone, eplerenone or finerenone.

[0109] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as, by way of example and with preference, furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0110] Lipid metabolism-altering agents are preferably understood to mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT 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 lipoprotein(a) antagonists.

[0111] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and preferably, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

[0112] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0113] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as, by way of example and with preference, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0114] 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.

[0115] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, by way of example and by way of preference, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0116] 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, implitapide, BMS-201038, R-103757 or JTT-130.

[0117] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

[0118] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as, by way of example and preferably, GW 501516 or BAY 68-5042.

[0119] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, by way of example and preferably, ezetimibe, tiqueside or pamaqueside.

[0120] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, by way of example and preferably, orlistat.

[0121] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0122] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as, for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0123] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, such as, by way of example and preferably, Gemcabene calcium (CI-1027) or nicotinic acid.

[0124] Particularly preferred are combinations of the compounds according to the invention with one or more further active ingredients selected from the group consisting of respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents and cytotoxic agents.

[0125] If necessary, the substances according to the invention can also be used in conjunction with one or more medical devices or aids, as long as this does not lead to undesirable and unacceptable side effects. Medical devices and aids considered for such a combined application are, by way of example and preference: Devices for positive airway pressure ventilation, such as, for example and preferably, CPAP ( continuous positive airway pressure ) devices, BiPAP ( bilevel positive airway pressure ) devices and IPPV ( intermittent positive pressure ventilation ) devices; neurostimulators of the Nervus hypoglossus ; intraoral devices, such as, for example and preferably, protrusion braces; nasal one-way valves; nasal stents.

[0126] The present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to their use for the aforementioned purposes.

[0127] The compounds of the invention can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, such as orally, parenterally, pulmonarily, intrapulmonarily (by inhalation), nasally, intranasally, pharyngeally, lingually, sublingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, or as an implant or stent.

[0128] For these routes of administration, the compounds according to the invention can be administered in suitable administration forms.

[0129] For oral administration, suitable dosage forms which function according to the state of the art and release the compounds according to the invention rapidly and / or in a modified form and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are used, such as tablets (uncoated or coated tablets, for example with gastro-resistant or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0130] Parenteral administration can be performed without an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Suitable administration forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0131] Other routes of application include, for example, inhalation dosage forms (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, throat sprays, lingual, sublingual or buccally administered tablets, films / wafers or capsules, suppositories, eye drops, ointments or baths, ocular inserts, ear drops, sprays, powders, rinses or tampons, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (e.g. plasters), milk, pastes, foams, dusting powders, implants or stents.

[0132] Oral, intravenous, intranasal and pharyngeal administration are preferred.

[0133] According to one embodiment, the application is intranasal. According to one embodiment, the intranasal application is carried out using nasal drops or a nasal spray. According to one embodiment, the intranasal application is carried out using a nasal spray.

[0134] The compounds according to the invention can be converted into the stated application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others: Fillers and carriers (e.g. cellulose, microcrystalline cellulose such as Avicel ®< , lactose, mannitol, starch, calcium phosphates such as Di-Cafos ®< ); ointment bases (e.g. petrolatum, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols); suppository bases (e.g. polyethylene glycols, cocoa butter, hard fat); solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins); Surfactants, emulsifiers, dispersing or wetting agents (for example sodium dodecyl sulfate, lecithin, phospholipids, fatty alcohols such as Lanette ®< , sorbitan fatty acid esters such as Span ®< , polyoxyethylene sorbitan fatty acid esters such as Tween ®< , polyoxyethylene fatty acid glycerides such as Cremophor ®< , polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such asPluronic ®< ); buffer substances as well as acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide, ammonium carbonate, trometamol, triethanolamine); isotonic agents (e.g. glucose, sodium chloride); adsorbents (e.g. highly dispersed silicon dioxide); viscosity-increasing agents, gelling agents, thickeners or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, starch, carbomers, polyacrylic acids such as Carbopol ®< , alginates, gelatin); disintegrants (e.g. modified starch, carboxymethylcellulose sodium, sodium starch glycolate such as Explotab ®< , cross-linked polyvinylpyrrolidone, croscarmellose sodium such as AcDiSol ®< ); Flow regulators, lubricants, sliding agents and mold release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicon dioxides such asAerosil ®< ); coating agents (e.g. sugar, shellac) and film-forming agents for rapidly dissolving or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidones such as Kollidon ®< , polyvinyl alcohol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as Eudragit ®< ); capsule materials (e.g. gelatin, hydroxypropylmethylcellulose); natural polymers (e.g. albumins); synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates such as Eudragit ®< , polyvinylpyrrolidones such asKollidon ®< , polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers); plasticizers (e.g. polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate); penetration enhancers; stabilizers (e.g. antioxidants such as ascorbic acid, sodium ascorbate, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate); preservatives (e.g. parabens, sorbic acid, sodium benzoate, thiomersal, benzalkonium chloride, chlorhexidine acetate); dyes (e.g. inorganic pigments such as iron oxides, titanium dioxide); flavorings, sweeteners, taste and / or odor correctors.

[0135] In general, it has proven advantageous to administer active ingredient amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg body weight, for parenteral administration to achieve effective results. For oral administration, the dosage is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg body weight. For intrapulmonary administration, the active ingredient amount is generally approximately 0.1 to 50 mg per inhalation.

[0136] According to one embodiment, the dosage for intranasal administration is approximately 0.1 µg to 500 µg per day. According to another embodiment, the dosage for intranasal administration is approximately 1 µg to 250 µg per day. According to another embodiment, the dosage for intranasal administration is approximately 1 µg to 120 µg per day. According to another embodiment, the dose of approximately 0.1 µg to 500 µg per day, or approximately 1 µg to 250 µg per day, or approximately 1 µg to 120 µg per day, is administered intranasally once daily before bedtime. 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, administered once daily, half into 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, applied once daily before bedtime, half into each nostril.

[0137] Nevertheless, it may be necessary to deviate from the stated amounts of active ingredient, depending on body weight, route of administration, individual response to the active ingredient, type of preparation, and time or interval at which administration takes place. In some cases, it may be sufficient to use less than the aforementioned minimum amount, while in other cases the stated upper limit must be exceeded. When administering larger amounts, it may be advisable to distribute them into several individual doses throughout the day.

[0138] The following examples illustrate the invention. The invention is not limited to the examples. A. Beispiele Abkürzungen und Akronyme:

[0139] abs.absolute AcAcetyl aq.aqueous, aqueous solution Boc tert .-Butoxycarbonyl br.broad (at NMR signal) Example BuButyl cConcentration approx. circa , approximately cat.catalytic CIchemical ionization (in MS) dDoublet (in NMR) dDay(s) DCIdirect chemical ionization (in MS) ddDoublet of Doublet (in NMR) DMF N,N -Dimethylformamide DMSODimethyl sulfoxide dqDoublet of quartet (in NMR) dtDoublet of triplet (in NMR) d. Th.of theory (at chemical yield) EIElectron impact ionization (in MS) eq.Equivalent(s) ESIElectrospray ionization (in MS) EtEthyl hhour(s) HATU O -(7-Azabenzotriazol-1-yl)- N,N,N',N '-tetramethyluronium hexafluorophosphate HOBt1-Hydroxy-1 H-benzotriazole hydrate HPLCHigh pressure, high performance liquid chromatography iPrIsopropyl conc. concentrated (in solution) LCLiquid chromatography LC-MSLiquid chromatography coupled to mass spectrometry Lit.Literature (reference) mMultiplet (in NMR) MeMethyl minMinute(s) MSMass spectrometry NMRNuclear magnetic resonance spectrometry PhPhenyl PrPropyl qQuartet (in NMR) quant.quantitative (in chemical yield) RPreverse phase (reverse phase, in HPLC) RTRoom temperature R tRetention time (in HPLC, LC-MS) sSinglet (in NMR) SFCSupercritical fluid chromatography tTriplet (in NMR) tBu tert .-Butyl TFATrifluoroacetic acid THFTetrahydrofuran UVUltraviolet spectrometry v / vVolume to volume ratio (of a solution) together LC-MS- und HPLC-Methoden: Methode 1 (LC-MS):

[0140] Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µm, 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. Methode 2 (LC-MS):

[0141] MS instrument: Thermo Scientific FT-MS; UHPLC device type: Thermo Scientific UltiMate 3000; Column: Waters HSS T3 C18 1.8 µm, 75 mm x 2.1 mm; Eluent A: 1 l water + 0.01% formic acid, Eluent B: 1 l 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 nm / optimum integration path 210-300 nm. Methode 3 (LC-MS):

[0142] Instrument MS: Waters Micromass QM; Instrument HPLC: Agilent 1100 Serie; Säule: Agilent ZORBAX Extend-C18 3.5 µm, 50 mm x 3.0 mm; Eluent A: 1 1 Wasser + 0.01 mol Ammoniumcarbonat, Eluent B: 1 1 Acetonitril; Gradient: 0.0 min 98% A → 0.2 min 98% A → 3.0 min 5% A ----> 4.5 min 5% A; Temperatur: 40°C; Fluss: 1.75 ml / min; UV-Detektion: 210 nm. Methode 4 (LC-MS):

[0143] Instrument MS: Waters Micromass Quattro Micro; Instrument HPLC: Waters UPLC Acquity; Säule: Waters BEH C18 1.7 µm, 50 mm x 2.1 mm; Eluent A: 1 1 Wasser + 0.01 mol Ammoniumformiat, Eluent B: 1 l Acetonitril; 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; Temperatur: 40°C; Fluss: 0.5 ml / min; UV-Detektion: 210 nm. Methode 5 (LC-MS):

[0144] Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 µm, 50 mm x 2.1 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 → 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. Methode 6 (LC-MS):

[0145] Instrument MS: Waters Single Quad MS system; Instrument HPLC: Waters UPLC Acquity; Column: Waters BEH C18 1.7 µm, 50 mm x 2.1 mm; Eluent A: 11 water + 1.0 ml 25% ammonia, eluent B: 11 acetonitrile; Gradient: 0.0 min 92% A ----> 0.1 min 92% A → 1.8 min 5% A → 3.5 min 5% A; Temperature: 50°C; Flow: 0.45 ml / min; UV detection: 210nm (208-400nm). Methode 7 (LC-MS):

[0146] MS instrument: Waters SQD; HPLC instrument: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 µm; 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; Temperature: 40°C; Flow: 0.60 ml / min; UV detection: DAD, 210 nm. Method 8 (preparative HPLC):

[0147] Instrument: Abimed Gilson 305; Column: Reprosil C18 10 µm, 250 mm x 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. Method 9 (preparative HPLC):

[0148] Instrument: Waters Prep LC / MS system; column: XBridge C18 5 µm, 100 mm x 30 mm; eluent A: water, eluent B: acetonitrile; gradient profile: 0-2 min 10% B, 2-2.2 min to 30% B, 2.2-7 min to 70% B, 7-7.5 min to 92% B, 7.5-9 min 92% B; flow: 65 mL / min + 5 mL 2% ammonia in water; room temperature; UV detection: 200-400 nm; at-column injection (complete injection). More information:

[0149] Unless otherwise stated, percentages in the following example and test descriptions are by weight; parts are by weight. Solvent ratios, dilution ratios, and concentrations of liquid / liquid solutions are all by volume.

[0150] Purity information generally refers to the corresponding peak integrations in the LC-MS chromatogram, but may also have been determined using the 1< H NMR spectrum. If no purity is specified, it is usually >95% purity based on automatic peak integration in the LC-MS chromatogram, or the purity was not explicitly determined.

[0151] Yields in % of theory are generally purity-corrected if a purity of <100% is stated. For solvent-containing or contaminated batches, the yield may formally be ">100%"; in these cases, the yield is not solvent- or purity-corrected.

[0152] In cases where reaction products were obtained by stirring, agitating, or recrystallization, it was often possible to isolate additional amounts of product from the respective mother liquor by chromatography. However, a description of this chromatography will be omitted below unless a large portion of the total yield could only be isolated in this step.

[0153] Melting points and melting ranges, where indicated, are uncorrected.

[0154] The following descriptions of the coupling patterns of 1< H NMR signals were partly taken directly from suggestions provided by the ACD SpecManager (ACD / Labs Release 12.00, Product version 12.5) and were not necessarily rigorously examined. Some of the SpecManager suggestions were manually adapted. Manually adapted or assigned descriptions are generally based on the visual appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. The chemical shift is usually given at the center of the respective signal. For wide multiplets, an interval is given. Signals obscured by solvent or water were either tentatively assigned or are not listed.

[0155] The 1< H NMR data of synthesis intermediates and working examples can also be presented in the form of 1< H NMR peak lists. For each signal peak, the δ value in ppm is listed first, followed by the signal intensity in parentheses. The δ value / signal intensity pairs of different signal peaks are listed separated by commas; the peak list for a compound therefore has the form: δ 1 (intensity 1 ), δ 2 (intensity 2 ), ... , δ i (intensity i ), ... , δ n (intensity n ).

[0156] The intensity of sharp peaks correlates with the height of the peaks (in cm) in a printed NMR spectrum sample and, when compared to other signals, shows the true ratios of the signal intensities. For broad signals, multiple peaks or the center of the signal and their relative intensity compared to the most intense signal in the spectrum may be listed. The 1< H NMR peak lists are similar to classical 1< H NMR printouts and thus usually contain all peaks listed in a classical NMR interpretation. In addition, like classical 1< H NMR printouts, they may contain solvent signals, signals from stereoisomers of the target compound, impurity peaks, 13< C satellite peaks, and / or rotational sidebands.Peaks of stereoisomers of the target compound and / or impurity peaks usually have a lower average intensity than the peaks of the target compound (e.g., at a purity of >90%). Such stereoisomers and / or impurities may be typical for the respective manufacturing process. Their peaks can therefore help identify a reproduction of the manufacturing process based on "by-product fingerprints." An expert calculating the peaks of a target compound using known methods (MestreC, ACD simulation, or using empirically determined expected values) can isolate the peaks of the target compound as needed, applying additional intensity filters if necessary. This isolation would be similar to the relevant "peak picking" in classical 1< H NMR interpretation.

[0157] A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, August 1, 2014). In the peak picking routine described in the cited Research Disclosure, the "Minimum Height" parameter can be set between 1% and 4%. However, depending on the type of chemical structure and / or the concentration of the compound to be measured, it may also be useful to set the "Minimum Height" parameter to values ​​<1%.

[0158] For all reactants or reagents whose preparation is not explicitly described below, it is assumed that they were obtained commercially from publicly accessible sources. For all other reactants or reagents whose preparation is also not described below and which were not commercially available or were obtained from sources that are not publicly accessible, a reference to the published literature describing their preparation is provided. Starting compounds and intermediates: Example 1A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine

[0159]

[0160] A solution of 2-bromo-1-(4-chlorophenyl)ethanone (20.0 g, 85.7 mmol) and pyrimidine-2-amine (8.96 g, 94.2 mmol) in 200 mL of ethanol was treated with sodium bicarbonate (10.8 g, 128 mmol) and stirred at 80°C for 5 hours. The mixture was then cooled to 0°C (ice bath). The resulting precipitate was filtered off and washed twice with an ethanol / water mixture (1:1). The solid was then dried in vacuo overnight at 40°C. 15.9 g (69.23 mmol, 80.8% of theory) of the target product were obtained.

[0161] LC-MS (Method 2): R t = 1.25 min; m / z = 230 (M+H) +< .

[0162] 1< H-NMR (400 MHz, DMSO- d 6 , δ / ppm): 7.07 (dd, 1H), 7.53 (d, 2H), 8.03 (d, 2H), 8.41 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H). Example 2A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine

[0163]

[0164] A solution of 2-bromo-1-(4-isopropylphenyl)ethanone (1.0 g, 4.15 mmol) and pyrimidine-2-amine (0.43 g, 4.6 mmol) in 50 mL of ethanol was treated with sodium bicarbonate (0.52 g, 6.22 mmol) and stirred at 80°C for 5 hours. The mixture was then evaporated to dryness. The residue was triturated with diethyl ether, and the remaining solid was filtered off and dried in vacuo overnight at 40°C. This yielded 1.15 g of the crude target product, which was used in subsequent reactions without further purification.

[0165] LC-MS (Method 2): R t = 1.48 min; m / z = 238 (M+H) +< .

[0166] 1< H-NMR (400 MHz, DMSO- d 6 , δ / ppm): 1.24 (d, 6H), 2.87-3.00 (m, 1H), 7.04 (dd, 1H), 7.34 (d, 2H), 7.92 (d, 2H), 8.33 (s, 1H), 8.51 (dd, 1H), 8.95 (dd, 1H).

[0167] Analogously to Examples 1A and 2A, the following compound was prepared from the indicated starting materials: Example Name / Structure / Educts Analytical data 3A 2-(4-Bromophenyl)imidazo[1,2-a]pyrimidine 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 7.07 (dd, 1H), 7.67 (d, 2H), 7.97 (d, 2H), 8.42 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H). from 2-bromo-1-(4-bromophenyl)ethanone and pyrimidin-2-amine LC-MS (Method 2): R t = 1.34 min; m / z = 274 / 276 (M+H) +< . Example 4A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

[0168]

[0169] 300 ml of DMF were initially charged and cooled to 0°C. Phosphorus oxychloride (16 ml, 173 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for one hour. 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine (15.9 g, 69.2 mmol) was then added portionwise. After the addition was complete, the reaction mixture was heated to 80°C and stirred at this temperature for one hour. The reaction mixture was then cooled to 0°C (ice bath). The resulting solid was filtered off with suction, washed several times with water, and dried overnight in a high-vacuum oven at 40°C. This gave 13.75 g (53.36 mmol, 77% of theory) of the target product.

[0170] LC-MS (Method 2): R t = 1.44 min; m / z = 258 (M+H) +< .

[0171] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 7.46 (dd, 1H), 7.65 (d, 2H), 8.01 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H). Example 5A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidin-3-carbaldehyd

[0172]

[0173] 50 ml of DMF was initially charged and cooled to 0°C. Phosphorus oxychloride (2.86 ml, 30.66 mmol) was then slowly added dropwise. The solution was then slowly warmed to room temperature and stirred at this temperature for one hour. 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine (2.91 g, 12.26 mmol) was then added portionwise. After the addition was complete, the reaction mixture was heated to 80°C and stirred at this temperature for one hour. The reaction mixture was then cooled to 0°C (ice bath). The resulting solid was filtered off with suction and dried in vacuo. The resulting crude product was subsequently purified by two column chromatography steps (Biotage Isolera, Biotage SNAP-KP-NH column, eluent: cyclohexane / ethyl acetate gradient). This yielded 3 g (11.3 mmol, 92% of theory) of the target compound.

[0174] LC-MS (Method 2): R t = 1.75 min; m / z = 266 (M+H) +< .

[0175] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.27 (d, 6H), 2.92-3.07 (m, 1H), 7.39-7.52 (m, 3H), 7.90 (d, 2H), 8.89 (dd, 1H), 9.83 (dd, 1H), 10.08 (s, 1H).

[0176] Analogously to Examples 4A and 5A, the following compound was prepared from the indicated starting material: Example Name / Structure / Educt Analytical data 6A 2-(4-Bromophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 7.46 (dd, 1H), 7.79 (d, 2H), 7.94 (d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H). aus 2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin LC-MS (Method 1): R t = 0.78 min; m / z = 302 / 304 (M+H) +< . Example 7A 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

[0177]

[0178] tert.-Butyl 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonane-9-carboxylate (1.52 g, 3.23 mmol) was treated with 12 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 1.76 g of the target product were obtained.

[0179] LC-MS (Method 2): R t = 0.71 min; m / z = 370 (M+H) +< . Example 8A 7-{[2-(4-Isopropylphenyl)imidazo[l,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride

[0180]

[0181] tert.-Butyl 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylate (420 mg, 0.88 mmol) was treated with 2.2 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 430 mg of the target product were obtained.

[0182] LC-MS (Method 2): R t = 0.87 min; m / z = 378 (M+H) +< . Example 9A 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride

[0183]

[0184] tert.-Butyl 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.72 g, 6.00 mmol) was treated with 15 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 3.5 g of the target product were obtained.

[0185] LC-MS (Method 6): R t = 1.36 min; m / z = 354 (M+H) +< . Example 10A 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride

[0186]

[0187] tert.-Butyl-3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-3,8-diazabicyclo-[3.2.1]octane-8-carboxylate (493 mg, 1.03 mmol) was added with stirring to 2.57 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred overnight at room temperature. The reaction solution was then evaporated to dryness, and the resulting residue was dried under high vacuum at 40°C. 393 mg of the target product was obtained.

[0188] LC-MS (Method 2): R t = 0.93 min; m / z = 362 (M+H) +< . Example 11A 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[l,2-a]pyrimidine dihydrochloride ( Enantiomer 1 )

[0189]

[0190] tert.-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-octane-2-carboxylate (enantiomer 1; 1.29 g, 2.84 mmol) was treated with 7.1 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 1.4 g of the target product were obtained.

[0191] LC-MS (Method 2): R t = 0.79 min; m / z = 354 (M+H) +< . Example 12A 2-(4-Chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride ( Enantiomer 2 )

[0192]

[0193] tert.-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (enantiomer 2; 710 mg, 1.56 mmol) was treated with 3.9 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 740 mg of the target product were obtained.

[0194] LC-MS (Method 1): R t = 0.49 min; m / z = 354 (M+H) +< . Example 13A 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride ( Enantiomer 1 )

[0195]

[0196] tert.-Butyl-5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo-[2.2.2]octane-2-carboxylate (enantiomer 1; 774 mg, 1.88 mmol) was treated with 4.2 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 850 mg of the target product were obtained.

[0197] LC-MS (Method 1): R t = 0.54 min; m / z = 362 (M+H) +< . Example 14A 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride ( Enantiomer 2 )

[0198]

[0199] tert.-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo-[2.2.2]octane-2-carboxylate (enantiomer 2; 734 mg, 1.59 mmol) was treated with 4.0 ml of a 4 M solution of hydrogen chloride in dioxane while stirring. The mixture was stirred overnight at room temperature. The resulting solid was then filtered off with suction, washed several times with diethyl ether, and dried under high vacuum at 40°C. 761 mg of the target product were obtained.

[0200] LC-MS (Method 1): R t = 0.55 min; m / z = 362 (M+H) +< . Example 15A 1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol ( Racemate )

[0201]

[0202] 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.94 mmol) was suspended in 5 mL of THF. Methylmagnesium bromide in diethyl ether (3.0 M, 710 µL, 2.1 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 h. A further 4 mL of THF and another methylmagnesium bromide in diethyl ether (3.0 M, 237 µL, 0.7 mmol) were then added. The mixture was stirred overnight at room temperature. Aqueous ammonium chloride solution was then added, followed by water and ethyl acetate. The resulting organic phase was separated, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness in a rotary evaporator under reduced pressure. The residue was stirred in diethyl ether. The remaining solid was filtered off with suction and dried overnight in a high-vacuum oven at 40°C. 370 mg (1.35 mmol, 70% of theory) of the target product were obtained.

[0203] LC-MS (Method 2): R t = 1.22 min; m / z = 274 (M+H) +< . Example 16A 2-(4-Chlorophenyl)-3-[1-(3,8-diazabicyclo[3.2.1]oct-3-yl)ethyl]imidazo[1,2-a]pyrimidine dihydrochloride ( Racemate )

[0204]

[0205] tert. -Butyl 3-{1-[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]-octane-8-carboxylate (racemate; 39.8 mg, 0.09 mmol) was treated with 0.21 ml of a 4 M solution of hydrogen chloride in dioxane and 0.2 ml of dioxane while stirring. The mixture was stirred overnight at room temperature. The reaction solution was then evaporated to dryness, and the resulting residue was dried under high vacuum at 40°C. 41 mg of the target product was obtained.

[0206] LC-MS (Method 2): R t = 0.86 min; m / z = 256 / 258 (M+H) +< .

[0207] Analogously to Examples 7A-14A, the following compounds were prepared from the indicated starting materials: Example Name / Structure / Educt Analytical data 17A 2-(4-Bromphenyl)-3-(2,5-diazabicyclo[2.2.2]-oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Racemate ) LC-MS (Method 6): R t = 1.65 min; m / z = 398 / 400 (M+H) +< . aus tert .-Butyl-5-{ [2-(4-bromphenyl)imidazo-[1,2-a]pyrimidin-3-yl]methyl}-2,5-diaza-bicyclo[2.2.2]octan-2-carboxylat ( Racemate ) 18A 2-(4-Bromophenyl)-3-(3,8-diazabicyclo[3.2.1]-oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride LC-MS (Method 6): R t = 1.56 min; m / z = 398 / 400 (M+H) +< . aus tert .-Butyl-3-{ [2-(4-bromphenyl)imidazo-[1,2-a]pyrimidin-3-yl]methyl}-3,8-diaza-bicyclo[3.2.1]octan-8-carboxylat Example 19A 2-(4-Cyclopropylphenyl)-3-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)imidazo[l,2-a]pyrimidine dihydrochloride

[0208]

[0209] tert. Butyl 3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl}-3,8-diazabicyclo-[3.2.1]octane-8-carboxylate (720 mg, 1.57 mmol) was dissolved in 3 ml of dioxane, and 3.92 ml of a 4 M solution of hydrogen chloride in dioxane was added while stirring. The mixture was stirred overnight at room temperature. The reaction solution was then concentrated to dryness, and the resulting residue was dried under high vacuum at 40°C. 808 mg of the target product was obtained.

[0210] LC-MS (Method 1): R t = 0.48 min; m / z = 360 (M+H) +< . Examples of implementation : Example 1 tert.-Butyl-7-{[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-9-carboxylat

[0211]

[0212] Under argon at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.82 mmol) was dissolved in 25 mL of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1.59 g, 6.99 mmol) and acetic acid (670 µl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and subsequently treated with ethyl acetate. The resulting organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness in a rotary evaporator under reduced pressure. The resulting residue was crystallized from diethyl ether.The resulting crystals were filtered off with suction and dried overnight in a high-vacuum oven at 40°C. 1.52 g (3.23 mmol, 56% of theory) of the target compound were obtained.

[0213] LC-MS (Method 2): R t = 1.65 min; m / z = 470 / 472 (M+H) +< .

[0214] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.40 (s, 9H), 2.42 (br. d, 2H), 2.87 (br. d, 2H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.92 (s, 2H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.96 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H). Example 2 tert. -Butyl-7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylate

[0215]

[0216] Under argon at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (500 mg, 1.89 mmol) was dissolved in 10 mL of THF, and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (516 mg, 2.26 mmol) and acetic acid (220 µl, 3.77 mmol) were added. Sodium triacetoxyborohydride (599 mg, 2.83 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and subsequently ethyl acetate was added. The resulting organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo on a rotary evaporator.The resulting residue was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, eluent: cyclohexane / ethyl acetate gradient). 431 mg (0.9 mmol, 48% of theory) of the target compound were obtained.

[0217] LC-MS (Method 2): R t = 1.79 min; m / z = 478 (M+H) +< .

[0218] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.40 (s, 9H), 2.39 (br. d, 2H), 2.87 (br. d, 2H), 2.90 (m, 1H), 3.57 (br. d, 2H), 3.72 (br. dd, 2H), 3.84 (br. d, 2H), 3.95 (s, 2H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.27 (dd, 1H). Example 3 tert .-Butyl-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-octane-2-carboxylate ( Racemate )

[0219]

[0220] Under argon at room temperature, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (4.00 g, 15.5 mmol) was dissolved in 100 ml of THF and treated with tert.-Butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (3.95 g, 18.6 mmol) and acetic acid (1.8 ml, 31 mmol) were added. Sodium triacetoxyborohydride (4.93 g, 23.3 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Afterward, further tert.-Butyl 2,5-diaza-bicyclo[2.2.2]octane-2-carboxylate (1.6 g, 7.76 mmol) and sodium triacetoxyborohydride (1.2 g, 5.8 mmol) were added, and the reaction solution was stirred again overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and subsequently ethyl acetate was added. The resulting 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 to dryness in a rotary evaporator under reduced pressure. The resulting residue was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase: cyclohexane / ethyl acetate gradient). 3.17 g (6.7 mmol, 43% of theory) of the target compound were obtained.

[0221] LC-MS (Method 2): R t = 1.55 min; m / z = 454 / 456 (M+H) +< . Example 4 and Example 5 tert.-Butyl-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-octane-2-carboxylate ( Enantiomers 1 and 2 )

[0222]

[0223] 3.17 g (6.70 mmol) of the racemic tert .-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 3) was separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 µm, 250 mm x 30 mm; eluent: carbon dioxide / ethanol 85:15 (v / v); flow: 150 ml / min; pressure: 135 bar; UV detection: 210 nm; temperature: 38°C]: Example 4 ( Enantiomer 1 ):

[0224] Yield: 1.29 g R t = 4.15 min; chemical purity >99%; >99% ee [column: Daicel Chiralpak OJ-H, 3 µm, 100 mm x 4.6 mm; eluent: carbon dioxide / ethanol 85:15 (v / v); flow: 3 ml / min; pressure: 130 bar; temperature: 40°C; UV detection: 210 nm].

[0225] LC-MS (Methode 2): R t = 1.55 min; m / z = 454 / 456 (M+H) +< .

[0226] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.36 (d, 9H), 1.42-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.79-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.09-3.17 (m, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.93 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H). Example 5 (Enantiomer 2):

[0227] Ausbeute: 720 mg R t = 6.6 min; chemische Reinheit >99%; >99% ee [Säule: Daicel Chiralpak OJ-H, 3 µm, 100 mm x 4.6 mm; Elutionsmittel: Kohlendioxid / Ethanol 85:15 (v / v); Fluss: 3 ml / min; Druck: 130 bar; Temperatur: 40°C; UV-Detektion: 210 nm].

[0228] LC-MS (Methode 2): R t = 1.56 min; m / z = 454 / 456 (M+H) +< .

[0229] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.36 (d, 9H), 1.43-1.55 (m, 1H), 1.57-1.73 (m, 2H), 1.80-1.92 (m, 1H), 2.63-2.80 (m, 3H), 3.14 (br. dd, 1H), 3.47-3.56 (m, 1H), 3.80 (br. d, 1H), 4.18-4.29 (m, 2H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.84-7.94 (m, 2H), 8.59 (dd, 1H), 9.02 (br. d, 1H). Example 6 tert .-Butyl-3-{[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]-octan-8-carboxylat

[0230]

[0231] Unter Argon wurde bei Raumtemperatur 2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-carbaldehyd (1.50 g, 5.82 mmol) in 25 ml THF gelöst und mit tert.-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.48 g, 6.99 mmol) and acetic acid (670 µl, 12 mmol) were added. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and then ethyl acetate was added. The resulting organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness in a rotary evaporator under reduced pressure. The residue obtained was crystallized from diethyl ether. The resulting crystals were dissolved in acetonitrile, and the remaining precipitate was filtered off and dried overnight in a high-vacuum oven at 40°C. 840 mg (1.85 mmol, 32% of theory) were obtained.) of the target connection.

[0232] LC-MS (Method 2): R t = 2.06 min; m / z = 454 / 456 (M+H) +<

[0233] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.39 (s, 9H), 1.64 (br. s, 4H), 2.26 (br. d, 2H), 2.42-2.60 (m, 2H, obscured by DMSO signal), 3.96-4.05 (m, 4H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.95 (dd, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). Example 7 tert. -Butyl-5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo-[2.2.2]octane-2-carboxylate ( Racemate )

[0234]

[0235] Under argon at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (1.50 g, 5.65 mmol) was dissolved in 20 ml of THF and treated with tert.-Butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate; 1.44 g, 6.78 mmol) and acetic acid (650 µl, 11.31 mmol) were added. Sodium triacetoxyborohydride (1.8 g, 8.48 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and then ethyl acetate was added. The resulting organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness in a rotary evaporator under reduced pressure. The residue was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phase: cyclohexane / ethyl acetate gradient). 1760 mg (3.81 mmol, 67% of theory) of the target compound were obtained.

[0236] LC-MS (Method 2): R t = 1.71 min; m / z = 462 (M+H) +< . Example 8 and Example 9 tert. -Butyl-5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo-[2.2.2]octane-2-carboxylate ( Enantiomers 1 and 2 )

[0237]

[0238] 1.66 g (3.59 mmol) of the racemic tert .-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Example 7) was separated into the enantiomers by preparative SFC-HPLC on a chiral phase [column: Daicel Chiralpak OX-H (SFC), 5 µm, 250 mm x 30 mm; eluent: carbon dioxide / methanol 62:38 (v / v); flow: 80 g / min; pressure: 120 bar; UV detection: 210 nm; temperature: 38°C]: Example 8 (Enantiomer 1):

[0239] Ausbeute: 774 mg R t = 4.91 min; chemische Reinheit >99%; >99% ee [Säule: Daicel Chiralpak OX-3 (SFC), 3 µm, 100 mm x 4.6 mm; Elutionsmittel: Kohlendioxid / Ethanol 70:30 (v / v); Fluss: 3 ml / min; Druck: 130 bar; Temperatur: 40°C; UV-Detektion: 210 nm].

[0240] LC-MS (Methode 1): R t = 0.85 min; m / z = 462 (M+H) +< .

[0241] [α] D 20< = +16.21° (c = 0.270, Methanol).

[0242] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.95 (m, 1H), 2.65-2.83 (m, 3H), 2.89-3.03 (m, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H). Example 9 (Enantiomer 2):

[0243] Ausbeute: 734 mg R t = 6.88 min; chemische Reinheit >99%; >99% ee [Säule: Daicel Chiralpak OX-3 (SFC), 3 µm, 100 mm x 4.6 mm; Elutionsmittel: Kohlendioxid / Ethanol 70:30 (v / v); Fluss: 3 ml / min; Druck: 130 bar; Temperatur: 40°C; UV-Detektion: 210 nm].

[0244] LC-MS (Methode 1): R t = 0.85 min; m / z = 462 (M+H) +< .

[0245] [α] D 20< = -15.67° (c = 0.270, Methanol).

[0246] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.36 (2s, 9H), 1.44-1.56 (m, 1H), 1.66 (br. s, 2H), 1.79-1.94 (m, 1H), 2.64-2.83 (m, 3H), 2.95 (dt, 1H), 3.09-3.20 (m, 1H), 3.53 (br. d, 1H), 3.81 (br. d, 1H), 4.24 (s, 2H), 7.10 (dd, 1H), 7.37 (d, 2H), 7.78 (dd, 2H), 8.56 (dd, 1H), 8.99 (br. d, 1H). Example 10 tert. -Butyl-3-{1-[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]-octan-8-carboxylat ( Racemate )

[0247]

[0248] 1-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]ethanol (473 mg, 1.73 mmol) and triphenylphosphine (906 mg, 3.46 mmol) were initially dissolved in 10 ml of dichloromethane, and carbon tetrabromide (1.15 g, 3.46 mmol) was added portionwise while cooling (ice bath). Triethylamine (480 µl, 3.5 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated, and the residue was dissolved in 10 ml of acetonitrile. tert.-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (734 mg, 3.46 mmol) was added, and the reaction mixture was stirred overnight at 40°C. The mixture was then evaporated to dryness. 400 mg of the resulting residue was directly separated into its components by preparative HPLC (Method 8). The remaining residue was applied to silica gel and prepurified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, eluent: cyclohexane / ethyl acetate gradient). The prepurified product was then purified by preparative HPLC (Method 8). This yielded 50 mg (0.11 mmol, 6% of theory) of the title compound.

[0249] LC-MS (Method 2): Rε = 2.14 min; MS (ESIpos): m / z = 468 / 470 [M+H] +< .

[0250] Analogous to Examples 1-3 and 6-7, the following compounds were prepared from the indicated starting materials: Example Name / Structure / Educts Analytical data 11 tert .-Butyl-5-{[2-(4-bromphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-2,5-diaza-bicyclo[2.2.2]octan-2-carboxylat ( Racemate ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = -0.149 (0.44), -0.008 (3.64), 0.008 (3.55), 0.146 (0.45), 1.345 (14.48), 1.374 (16.00), 1.402 (4.45), 1.489 (0.55), 1.654 (0.95), 1.859 (0.54), 2.328 (0.58), 2.670 (1.91), 2.709 (1.58), 2.774 (0.64), 3.118 (0.57), 3.146 (0.65), 3.155 (0.60), 3.515 (0.56), 3.774 (0.61), 3.827 (0.68), 4.235 (4.16), 5.754 (5.06), 7.108 (1.24), 7.119 (1.32), 7.125 (1.31), 7.136 (1.29), 7.679 (3.52), 7.700 (4.83), 7.812 (1.99), 7.824 (1.97), 7.833 (1.62), 7.845 (1.39), 8.579 (1.48), 8.584 (1.62), 8.590 (1.53), 8.594 (1.45), 9.013 (1.24), 9.030 (1.21). aus tert .-Butyl-2,5-diazabicyclo[2.2.2]octan-2-carboxylat ( Racemat ) und 2-(4-Bromphenyl)-imidazo[1,2-a]pyrimidin-3-carbaldehyd LC-MS (Methode 2): R t = 1.68 min; m / z = 498 / 500 (M+H) +< . 12 tert .-Butyl-3-{[2-(4-bromphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.39 (s, 9H), 1.56-1.73 (m, 4H), 2.26 (br. d, 2H), 2.46-2.60 (m, 2H, verdeckt durch DMSO-Signal), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). aus tert .-Butyl-3,8-diazabicyclo[3.2.1]octan-8-carboxylat und 2-(4-Bromphenyl)imidazo-[1,2-a]pyrimidin-3-carbaldehyd LC-MS (Methode 5): R t = 1.42 min; m / z = 498 / 500 (M+H) +< . Beispiel 13 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(6-methoxypyridin-2-yl)methanone

[0251]

[0252] 6-Methoxypyridine-2-carboxylic acid (35.1 mg, 230 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N Diisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 74 mg (0.15 mmol, 70% of theory) of the title compound was obtained.

[0253] LC-MS (Methode 2): R t = 1.48 min; m / z = 505 / 507 (M+H) +< .

[0254] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.46-2.66 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.91 (br. d, 1H), 3.05 (br. d, 1H), 3.66-3.83 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.93-4.03 (m, 2H), 4.20 (br. s, 1H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.09 (dd, 1H), 7.29 (d, 1H), 7.54 (d, 2H), 7.83 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H). Beispiel 14 (3-Chlor-6-methoxypyridin-2-yl)(7-{[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanon

[0255]

[0256] 3-Chlor-6-methoxypyridin-2-carbonsäure (43.1 mg, 230 µmol) wurde in 1.5 ml DMF gelöst, mit 2-(7-Aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N Diisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 78 mg (0.15 mmol, 70% of theory) of the title compound were obtained.

[0257] LC-MS (Method 1): R t = 0.86 min; m / z = 539 / 541 (M+H) +< . Beispiel 15 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

[0258]

[0259] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (39.3 mg, 230 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N Diisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 82 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

[0260] LC-MS (Method 1): R t = 0.82 min; m / z = 523 / 525 (M+H) +< .

[0261] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.45-2.60 (m, 2H, obscured by DMSO signal), 2.90 (br. d, 1H), 3.05 (br. d, 1H), 3.58-3.70 (m, 3H), 3.72-3.84 (m, 1H), 3.80 (s, 3H), 3.89 (d, 1H), 3.98 (s, 2H), 4.45 (br. s, 1H), 6.97 (dd, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.80 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H). Example 16 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl) [6-(methylsulfanyl)pyridin-2-yl]methanone

[0262]

[0263] 6-(Methylsulfanyl)pyridine-2-carboxylic acid (38.8 mg, 230 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,NDiisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 84 mg (0.16 mmol, 77% of theory) of the title compound were obtained.

[0264] LC-MS (Method 1): R t = 0.85 min; m / z = 521 / 523 (M+H) +< .

[0265] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.46 (s, 3H), 2.56-2.65 (m, 2H), 2.91 (br. d, 1H), 3.06 (br. d, 1H), 3.65-3.81 (m, 3H), 3.86-4.03 (m, 3H), 4.15 (br. s, 1H), 4.46 (br. s, 1H), 7.09 (dd, 1H), 7.40 (dd, 2H), 7.55 (d, 2H), 7.77 (t, 1H), 7.98 (dd, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H). Example 17 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(cyclopentyl)methanone

[0266]

[0267] Cyclopentanecarboxylic acid (18 µl, 230 µmol) was dissolved in 1.5 ml DMF, with 2-(7-Aza-1H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-chlorophenyl)imidazo-[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N Diisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 72 mg (0.15 mmol, 74% of theory) of the title compound was obtained.

[0268] LC-MS (Method 1): R t = 0.81 min; m / z = 466 / 468 (M+H) +< .

[0269] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.43-1.81 (m, 8H), 2.31-2.61 (m, 2H, partially obscured by DMSO signal), 2.86-2.97 (m, 3H), 3.47-3.54 (m, 1H), 3.56-3.63 (m, 1H), 3.77 (dd, 2H), 3.94 (s, 2H), 4.04 (br. s, 1H), 4.32 (br. s, 1H), 7.08 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.27 (dd, 1H). Example 18 (3-Fluoro-6-methoxypyridin-2-yl)(7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

[0270]

[0271] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (39 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,NDiisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 83 mg (0.16 mmol, 76% of theory) of the title compound were obtained.

[0272] LC-MS (Method 1): R t = 0.84 min; m / z = 531 (M+H) +< .

[0273] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 2.46-2.58 (m, 2H, hidden by DMSO signal), 2.86-3.01 (m, 2H), 3.06 (br. d, 1H), 3.57-3.70 (m, 3H), 3.75 (br. d, 1H), 3.79 (s, 3H), 3.89 (d, 1H), 3.99 (s, 2H), 4.46 (br. s, 1H), 6.97 (dd, 1H), 7.06 (dd, 1H), 7.36 (d, 2H), 7.74-7.84 (m, 3H), 8.55 (dd, 1H), 9.26 (dd, 1H). Example 19 [6-(Difluoromethoxy)pyridin-2-yl](7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanone

[0274]

[0275] 6-(Difluoromethoxy)pyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (117 mg, 0.31 mmol) was added and stirred at room temperature for 30 min. Subsequently, 7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N Diisopropylethylamine (180 µl, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 72 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0276] LC-MS (Method 1): R t = 0.89 min; m / z = 549 (M+H) +< .

[0277] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 2.45-2.64 (m, 3H, partially obscured by DMSO signal), 2.86-2.99 (m, 2H), 3.05 (br. d, 1H), 3.65-3.79 (m, 3H), 3.89 (d, 1H), 4.00 (s, 2H), 4.09 (br. s, 1H), 4.44 (br. s, 1H), 7.06 (dd, 1H), 7.21 (d, 1H), 7.36 (d, 2H), 7.54-7.62 (m, 1H), 7.81 (d, 2H), 8.06 (t, 1H), 8.55 (dd, 1H), 9.28 (dd, 1H). Example 20 (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(6-methoxypyridin-2-yl)methanone

[0278]

[0279] 6-Methoxypyridine-2-carboxylic acid (36.4 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,NDiisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 79 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

[0280] LC-MS (Method 1): R t = 1.76 min; m / z = 489 / 491 (M+H) +< .

[0281] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.63-1.84 (m, 4H), 2.45 (br. d, 1H), 2.56-2.65 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 4.00-4.12 (m, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.57 (d, 2H), 7.82 (t, 1H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). Example 21 (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0282]

[0283] 3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N Diisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 56 mg (0.11 mmol, 49% of theory) of the title compound were obtained.

[0284] LC-MS (Method 2): R t = 1.81 min; m / z = 523 / 524 / 525 (M+H) +< .

[0285] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.62-1.82 (m, 4H), 2.34-2.46 (m, 2H), 2.47-2.59 (m, 1H, obscured by DMSO signal), 2.69-2.78 (m, 1H), 3.62 (br. s, 1H), 3.79 (s, 3H), 4.06 (s, 2H), 4.59 (br. s, 1H), 6.92 (d, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.87 (d, 1H), 7.94 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). Example 22 (3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(3-fluoro-6-methoxypyridin-2-yl)methanone

[0286]

[0287] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,NDiisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 93 mg (0.18 mmol, 85% of theory) of the title compound were obtained.

[0288] LC-MS (Method 2): R t = 1.73 min; m / z = 507 / 509 (M+H) +< .

[0289] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.62-1.83 (m, 4H), 2.44 (br. t, 2H), 2.48-2.58 (m, 1H, partially obscured by DMSO signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.01-4.12 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.57 (d, 2H), 7.77 (t, 1H), 7.95 (dd, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). Example 23 (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone ( Enantiomer 1 )

[0290]

[0291] 3-Chloro-6-methoxypyridine-2-carboxylic acid (44.5 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (enantiomer 1; 100 mg) and N,N Diisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 87 mg (0.16 mmol, 74% of theory) of the title compound were obtained.

[0292] LC-MS (Method 2): R t = 1.62 min; m / z = 523 / 524 / 525 (M+H) +< .

[0293] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.52-2.00 (m, 4H), 2.57-3.24 (m, 3.75H), 3.35-3.46 (m, 1.25H), 3.70-3.86 (m, 3.75H), 4.20-4.40 (m, 2.25H), 6.84-6.96 (m, 1H), 7.08-7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.93 (m, 3H), 8.56-8.64 (m, 1H), 8.98-9.07 (m, 1H). Example 24 (5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(3-fluoro-6-methoxypyridin-2-yl)methanone ( Enantiomer 2 )

[0294]

[0295] 3-Fluoro-6-methoxypyridine-2-carboxylic acid (40.6 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (enantiomer 2; 100 mg) and N,NDiisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 84 mg (0.17 mmol, 77% of theory) of the title compound were obtained.

[0296] LC-MS (Method 6): Rε = 1.52 min; MS (ESIpos): m / z = 507 / 509 [M+H] +< .

[0297] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.50-2.00 (m, 4H), 2.62-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38-3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.89-6.99 (m, 1H), 7.07-7.17 (m, 1H), 7.49-7.60 (m, 2H), 7.70-7.83 (m, 1H), 7.84-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.99-9.09 (m, 1H). Example 25 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(6-methoxy-3-methylpyridin-2-yl)methanone ( Enantiomer 1 )

[0298]

[0299] 6-Methoxy-3-methylpyridine-2-carboxylic acid (39.7 mg, 237 µmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (123 mg, 324 µmol) was added and stirred at room temperature for 30 min. Subsequently, 2-(4-chlorophenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (enantiomer 1; 100 mg) and N,N Diisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). This yielded 25 mg (0.05 mmol, 23% of theory) of the title compound.

[0300] LC-MS (Method 2): Rε = 1.55 min; MS (ESIpos): m / z = 503 / 505 [M+H] +< .

[0301] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.49-1.97 (m, 4H), 2.02-2.12 (m, 3H), 2.58-2.84 (m, 2.25H), 2.91-3.02 (m, 1H), 3.23 (br. s, 0.75H), 3.34-3.45 (m, 1H), 3.65-3.83 (m, 3.75H), 4.19-4.42 (m, 2.25H), 6.71-6.81 (m, 1H), 7.06-7.17 (m, 1H), 7.49-7.65 (m, 3H), 7.82-7.94 (m, 2H), 8.56-8.63 (m, 1H), 8.97-9.08 (m, 1H). Example 26 (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyriinidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone ( Enantiomer 2 )

[0302]

[0303] 3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.21 mmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and stirred at room temperature for 30 min. Subsequently, 3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (enantiomer 2; 100 mg) and N,NDiisopropylethylamine (190 µl, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 82 mg (0.15 mmol, purity 96%, 70% of theory) of the title compound were obtained.

[0304] LC-MS (Method 2): R t = 1.73 min; m / z = 531 / 533 (M+H) +< .

[0305] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.31 (m, 6H), 1.53-2.01 (m, 4H), 2.62 (br. d, 0.75H), 2.69-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.85 (m, 3.75H), 4.21-4.35 (m. 2H), 4.39 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05-7.14 (m, 1H), 7.30-7.43 (m, 2H), 7.70-7.87 (m, 2.75H), 7.90 (d, 0.25H), 8.56 (dd, 1H), 8.95-9.04 (m, 1H). Example 27 (5-Cyclopropyl-1,3-oxazol-4-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone ( Enantiomer 2 )

[0306]

[0307] 5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (32 mg, 0.21 mmol) was dissolved in 1.35 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (109 mg, 0.29 mmol) was added and stirred at room temperature for 30 min. Subsequently, 3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (enantiomer 2; 90 mg) and N,N Diisopropylethylamine (170 µl, 0.96 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 67 mg (0.14 mmol, 71% of theory) of the title compound was obtained.

[0308] LC-MS (Method 2): R t = 1.51 min; m / z = 497 (M+H) +< .

[0309] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.83-0.95 (m, 2H), 0.96-1.08 (m, 2H), 1.25 (d, 6H), 1.51-1.61 (m, 1H), 1.67-1.99 (m, 3H), 2.44-2.57 (m, 0.7H, teilweise verdeckt durch DMSO-Signal), 2.57-2.66 (m, 0.3H), 2.73-3.01 (m, 4H), 3.37 (dd, 0.7H), 3.64-3.76 (m, 1H), 4.03 (br. d, 0.3H), 4.23-4.33 (m, 2H), 4.37 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.20 (m, 1H), 8.53-8.59 (m, 1H), 8.98-9.06 (m, 1H). Example 28 (3-Fluor-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanon

[0310]

[0311] 3-Fluor-6-methoxypyridin-2-carbonsäure (39.2 mg, 0.21 mmol) wurde in 1.5 ml DMF gelöst, mit 2-(7-Aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 0.31 mmol) was added and stirred at room temperature for 30 min. Subsequently, 3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,N Diisopropylethylamine (180 µl, 1.04 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0312] LC-MS (Method 5): Rε = 1.22 min; MS (ESIpos): m / z = 515 [M+H] +< .

[0313] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 1.63-1.86 (m, 4H), 2.44 (br. t, 2H), 2.48-2.60 (m, 1H, partially obscured by DMSO signal), 2.76 (dd, 1H), 2.96 (quin, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 4.00-4.11 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.36 (d, 2H), 7.77 (t, 1H), 7.83 (d, 2H), 8.57 (dd, 1H), 9.02 (dd, 1H). Example 29 (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0314]

[0315] 3-Chloro-6-methoxypyridine-2-carboxylic acid (43 mg, 0.23 mmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) was added and stirred at room temperature for 30 min. Subsequently, 3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (98 mg) and N,NDiisopropylethylamine (180 µl, 1.04 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 8). 67 mg (0.13 mmol, 60% of theory) of the title compound was obtained.

[0316] LC-MS (Method 5): Rε = 1.27 min; MS (ESIpos): m / z = 531 / 533 [M+H] +< .

[0317] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 1.63-1.84 (m, 4H), 2.41 (br. t, 2H), 2.46-2.57 (m, 1H, obscured by DMSO signal), 2.75 (br. d, 1H), 2.96 (quin, 1H), 3.63 (br. s, 1H), 3.79 (s, 3H), 4.00-4.11 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.82 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.01 (dd, 1H).

[0318] Analogously to Examples 13-29, the following compounds were prepared from the indicated starting materials: Example Name / Structure / Educts Analytical data 30 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]-non-9-yl)(2-fluorophenyl)methanone 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.43 (br. d, 1H), 2.47-2.59 (m, 1H, partially obscured by DMSO signal), 2.87 (br. d, 1H), 3.02 (br. d, 1H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.65-3.76 (m, 2H), 3.87 (d, 1H), 3.97 (s, 2H), 4.47 (br. s, 1H), 7.08 (dd, 1H), 7.24-7.34 (m, 2H), 7.41-7.53 (m, 2H), 7.55 (d, 2H), 7.95 (d, 2H), 8.58 (dd, 1H), 9.27 (dd, 1H). aus 7-{[2-(4-Chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Method 2): R t = 1.53 min; m / z = 492 / 494 (M+H) +< . 31 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]-non-9-yl)(3-methoxyphenyl)methanone 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.46-2.55 (m, 1H, verdeckt durch DMSO-Signal), 2.59 (br. d, 1H), 2.86 (br. d, 1H), 2.99 (br. d, 1H), 3.54-3.75 (m, 4H), 3.77 (s, 3H), 3.85 (d, 1H), 3.98 (s, 2H), 4.39 (br. s, 1H), 6.91-7.12 (m, 4H), 7.36 (t, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.57 (dd, 1H), 9.29 (dd, 1H). aus 7-{[2-(4-Chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 3-Methoxybenzoesäure LC-MS (Methode 2): R t = 1.53 min; m / z = 504 / 506 (M+H) +< . 32 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2-fluorphenyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.60-1.79 (m, 4H), 2.25 (br. d, 1H), 2.42 (br. d, 1H), 2.47-2.60 (m, 1H, teilweise verdeckt durch DMSO-Signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24-7.32 (m, 2H), 7.40-7.53 (m, 2H), 7.57 (d, 2H), 7.95 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Methode 2): R t = 1.73 min; m / z = 476 / 478 (M+H) +< . 33 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-[6-(methylsulfanyl)pyridin-2-yl]methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.64-1.83 (m, 4H), 2.40-2.63 (m, 3H, teilweise verdeckt durch DMSO-Signal), 2.43 (s, 3H), 2.74 (br. d, 1H), 3.99-4.11 (m, 2H), 4.63 (br. s, 2H), 7.15 (dd, 1H), 7.42 (dd, 2H), 7.57 (d, 2H), 7.75 (t, 1H), 7.97 (d, 2H), 8.55-8.62 (m, 1H), 9.06 (d, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 6-(Methylsulfanyl)pyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.86 min; m / z = 505 / 507 (M+H) +< . 34 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(cyclopentyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.44-1.66 (m, 7H), 1.66-1.80 (m, 5H), 2.26 (br. d, 2H), 2.47-2.66 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.80-2.92 (m, 1H), 3.94-4.06 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und Cyclopentancarbonsäure LC-MS (Methode 2): R t = 1.83 min; m / z = 450 / 452 (M+H) +< . 35 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-[6-(methylamino)pyridin-2-yl]methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.63-1.81 (m, 4H), 2.42 (br. d, 1H), 2.47-2.62 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.64-2.75 (m, 1H), 2.67 (d, 3H), 3.97-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.82 (d, 1H), 7.14 (dd, 1H), 7.44 (t, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 6-(Methylamino)pyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.51 min; m / z = 532 / 534 (M-H+HCOOH) -< . 36 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(3-methoxyphenyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.64-1.80 (m, 4H), 2.30-2.47 (m, 2H), 2.57-2.74 (m, 2H), 3.78 (s, 3H), 3.92 (br. s, 1H), 4.05 (s, 2H), 4.54 (br. s, 1H), 6.92-7.08 (m, 3H), 7.30 (br. t, 1H), 7.35 (t, 1H), 7.61 (d, 2H), 7.93 (d, 2H), 8.71 (br. d, 1H), 9.15 (br. d, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 3-Methoxybenzoesäure LC-MS (Methode 2): R t = 1.73 min; m / z = 488 / 490 (M+H) +< . 37 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(cyclopentyl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.38-1.79 (m, 11H), 1.82-1.96 (m, 1H), 2.63-2.86 (m, 4H), 3.19 (dd, 0.5H), 3.37 (dd, 0.5H), 3.54 (br. d, 0.5H), 3.75 (br. d, 0.5H), 3.93 (br. d, 0.5H), 4.18-4.31 (m, 2.5H), 7.12 (dd, 1H), 7.56 (d, 2H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.03 (dt, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und Cyclopentancarbonsäure LC-MS (Methode 2): R t = 1.42 min; m / z = 450 / 452 (M+H) +< . 38 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(3-methoxyphenyl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.44-1.99 (m, 4H), 2.61-2.72 (m, 1H), 2.76-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.69-3.82 (m, 3.75H), 4.21-4.34 (m, 2.25H), 6.80-6.88 (m, 1.5H), 6.94-7.06 (m, 1.5H), 7.08-7.17 (m, 1H), 7.26-7.39 (m, 1H), 7.50-7.61 (m, 2H), 7.86-7.96 (m, 2H), 8.55-8.63 (m, 1H), 9.00-9.09 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 3-Methoxybenzoesäure LC-MS (Methode 2): R t = 1.46 min; m / z = 488 / 490 (M+H) +< . 39 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo [2.2.2] oct-2-yl)-(2-fluorphenyl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.47-1.82 (m, 3H), 1.84-1.98 (m, 1H), 2.46-2.57 (m, 0.75H, verdeckt durch DMSO-Signal), 2.60-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.42 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.33 (m, 2H), 4.37 (br. s, 0.25H), 7.09-7.17 (m, 1H), 7.20-7.40 (m, 3H), 7.41-7.61 (m, 3H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 2-Fluorbenzoesäure LC-MS (Methode 2): R t = 1.49 min; m / z = 476 / 478 (M+H) +< . 40 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(6-methoxypyridin-2-yl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.46-1.99 (m, 4H), 2.63-2.73 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.48 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08-7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.49-7.60 (m, 2H), 7.74-7.94 (m, 3H), 8.55-8.62 (m, 1H), 9.00-9.08 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.41 min; m / z = 489 / 491 (M+H) +< . 41 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(3-fluor-6-methoxypyridin-2-yl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.49-2.01 (m, 4H), 2.62-2.87 (m, 2.25H), 2.92 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.38-3.50 (m, 1.5H), 3.56 (br. d, 0.25H), 3.69-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.87-6.99 (m, 1H), 7.08-7.17 (m, 1H), 7.49-7.59 (m, 2H), 7.70-7.82 (m, 1H), 7.83-7.95 (m, 2H), 8.56-8.63 (m, 1H), 8.98-9.08 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.51 min; m / z = 507 / 509 (M+H) +< . 42 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(2-fluorphenyl)methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.48-1.83 (m, 3H), 1.83-1.98 (m, 1H), 2.46-2.57 (m, 0.75H, verdeckt durch DMSO-Signal), 2.60-2.88 (m, 2.25H), 2.92 (br. s, 0.75H), 3.02 (br. d, 0.25H), 3.43 (br. d, 1H), 3.77 (br. d, 0.75H), 4.20-4.34 (m, 2H), 4.38 (br. s, 0.25H), 7.08-7.17 (m, 1H), 7.19-7.40 (m, 3H), 7.41-7.60 (m, 3H), 7.83-7.95 (m, 2H), 8.55-8.63 (m, 1H), 8.97-9.08 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 2-Fluorbenzoesäure LC-MS (Methode 2): R t = 1.50 min; m / z = 476 / 478 (M+H) +< . 43 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(3-methoxyphenyl)methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.44-1.99 (m, 4H), 2.61-2.72 (m, 1H), 2.74-2.84 (m, 1H), 2.90 (br. s, 1H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.63 (br. d, 0.25H), 3.67-3.82 (m, 3.75H), 4.18-4.35 (m, 2.25H), 6.76-6.87 (m, 1.5H), 6.92-7.05 (m, 1.5H), 7.08-7.17 (m, 1H), 7.25-7.39 (m, 1H), 7.49-7.61 (m, 2H), 7.84-7.96 (m, 2H), 8.52-8.63 (m, 1H), 8.98-9.09 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 3-Methoxybenzoesäure LC-MS (Methode 2): R t = 1.46 min; m / z = 488 / 490 (M+H) +< . 44 (5-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(6-methoxypyridin-2-yl)methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.46-1.99 (m, 4H), 2.63-2.74 (m, 1H), 2.80-2.94 (m, 2H), 3.39 (dd, 0.75H), 3.49 (br. d, 0.25H), 3.69-3.83 (m, 3.75H), 3.92 (br. d, 0.25H), 3.98 (br. s, 0.75H), 4.24-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.08-7.20 (m, 1.75H), 7.29 (d, 0.25H), 7.48-7.60 (m, 2H), 7.73-7.95 (m, 3H), 8.54-8.63 (m, 1H), 9.00-9.09 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.41 min; m / z = 489 / 491 (M+H) +< . 45 (3-Chlor-6-methoxypyridin-2-yl)(5-{[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.52-2.00 (m, 4H), 2.72 (br. d, 0.75H), 2.73 (br. d, 1H), 2.80 (br. s, 0.5H), 2.94-3.01 (m, 1H), 3.20 (br. s, 0.75H), 3.35-3.47 (m, 1H), 3.70-3.86 (m, 3.75H), 4.20-4.33 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.97 (m, 1H), 7.08-7.19 (m, 1H), 7.49-7.61 (m, 2H), 7.79-7.94 (m, 3H), 8.56-8.64 (m, 1H), 8.97-9.08 (m, 1H). aus 2-(4-Chlorphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 3-Chlor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.63 min; MS (ESIpos): m / z = 523 / 524 / 525 [M+H] +< . 46 (7-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)(5-cyclopropyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.88-0.97 (m, 2H), 1.03-1.13 (m, 2H), 2.44-2.65 (m, 3H, teilweise verdeckt durch DMSO-Signal), 2.92-3.06 (m, 2H), 3.62-3.73 (m, 2H), 3.77-3.90 (m, 2H), 3.96 (s, 2H), 4.41 (br. s, 1H), 4.75 (br. s, 1H), 7.08 (dd, 1H), 7.54 (d, 2H), 7.98 (d, 2H), 8.20 (s, 1H), 8.59 (dd, 1H), 9.29 (dd, 1H). aus 7-{[2-(4-Chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 5-Cyclopropyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 1): R t = 0.76 min; MS (ESIpos): m / z = 505 / 507 [M+H] +< . 47 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2-cyclopropyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.89-0.98 (m, 2H), 1.00-1.09 (m, 2H), 1.57-1.87 (m, 4H), 2.08-2.18 (m, 1H), 2.30-2.42 (m, 2H), 2.58-2.70 (m, 2H), 4.02 (s, 2H), 4.53 (br. s, 1H), 5.15 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.37 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Cyclopropyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 2): R t = 1.75 min; MS (ESIpos): m / z = 489 / 491 [M+H] +< . 48 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(5-methyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.59-1.84 (m, 4H), 2.35-2.44 (m, 2H), 2.52 (s, 3H, teilweise verdeckt durch DMSO-Signal), 2.60-2.69 (m, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.12 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.56 (dd, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 5-Methyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 2): R t = 1.59 min; MS (ESIpos): m / z = 463 / 465 [M+H] +< . 49 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(5-isopropyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.21 (t, 6H), 1.63-1.82 (m, 4H), 2.39 (br. t, 2H), 2.64 (br. t, 2H), 3.62 (quin, 1H), 4.02 (s, 2H), 4.57 (br. s, 1H), 4.97 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.29 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 5-Isopropyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 2): R t = 1.86 min; MS (ESIpos): m / z = 491 / 493 [M+H] +< . 50 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2,4-dimethyl-1,3-oxazol-5-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.74 (br. s, 4H), 2.27 (s, 3H), 2.34-2.45 (m, 2H), 2.40 (s, 3H), 2.60-2.70 (m, 2H), 4.04 (s, 2H), 4.58 (br. s, 2H), 7.17 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.07 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2,4-Dimethyl-1,3-oxazol-5-carbonsäure LC-MS (Methode 2): R t = 1.53 min; MS (ESIpos): m / z = 477 / 479 [M+H] +< . 51 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(5-ethyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.17 (t, 3H), 1.61-1.83 (m, 4H), 2.39 (br. d, 2H), 2.64 (br. d, 2H), 2.95 (q, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.07 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.96 (d, 2H), 8.30 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 5-Ethyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 2): R t = 1.73 min; MS (ESIpos): m / z = 477 / 479 [M+H] +< . 52 (4-Brom-5-methyl-1,3-thiazol-2-yl)(3-{[2-(4-chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.67-1.77 (m, 2H), 1.79-1.91 (m, 2H), 2.39-2.48 (m, 2H), 2.43 (s, 3H), 2.66 (br. d, 1H), 2.72 (br. d, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 5.46 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 4-Brom-5-methyl-1,3-thiazol-2-carbonsäure LC-MS (Methode 1): R t = 1.10 min; MS (ESIpos): m / z = 557 / 559 [M+H] +< . 53 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(5-cyclopropyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.86-0.99 (m, 2H), 1.02-1.13 (m, 2H), 1.61-1.85 (m, 4H), 2.36-2.46 (m, 2H), 2.60-2.75 (m, 3H), 4.03 (s, 2H), 4.58 (br. s, 1H), 5.12 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.18 (s, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 5-Cyclopropyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 1): R t = 0.91 min; MS (ESIpos): m / z = 489 / 491 [M+H] +< . 54 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2-isopropyl-1,3-thiazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.31 (d, 6H), 1.63-1.85 (m, 4H), 2.40-2.48 (m, 2H), 2.65 (br. d, 2H), 3.23-3.33 (m, 1H, teilweise verdeckt durch H 2 O-Signal), 4.04 (s, 2H), 4.59 (br. s, 1H), 4.99 (br. s, 1H), 7.14 (dd, 1H), 7.55 (d, 2H), 7.96 (d, 2H), 8.06 (s, 1H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Isopropyl-1,3-thiazol-4-carbonsäure LC-MS (Methode 1): R t = 1.01 min; MS (ESIpos): m / z = 507 / 509 [M+H] +< . 55 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(1,3-thiazol-5-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.62-1.94 (m, 4H), 2.39-2.59 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.68 (dd, 2H), 4.06 (s, 2H), 4.37-4.65 (m, 2H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.97 (d, 2H), 8.29 (s, 1H), 8.60 (dd, 1H), 9.07 (dd, 1H), 9.23 (s, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 1,3-Thiazol-5-carbonsäure LC-MS (Methode 1): R t = 0.77 min; MS (ESIpos): m / z = 465 / 467 [M+H] +< . 56 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2,5-dimethyl-1,3-oxazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.60-1.81 (m, 4H), 2.31-2.42 (m, 2H), 2.36 (s, 3H), 2.47 (s, 3H), 2.63 (br. d, 2H), 4.02 (s, 2H), 4.54 (br. s, 1H), 5.18 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2,5-Dimethyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 5): R t = 1.16 min; MS (ESIpos): m / z = 477 / 479 [M+H] +< . 57 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-[2-methoxy-4-(trifluormethyl)-1,3-thiazol-5-yl]-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.62-1.77 (m, 4H), 2.21-2.40 (m, 2H), 2.63 (br. d, 2H), 3.92 (br. s, 1H), 4.04 (s, 2H), 4.10 (s, 3H), 4.51 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.93 (d, 2H), 8.59 (dd, 1H), 9.03 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Methoxy-4-(trifluormethyl)-1,3-thiazol-5-carbonsäure LC-MS (Methode 5): R t = 1.30 min; MS (ESIpos): m / z = 563 / 565 [M+H] +< . 58 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-[2-(trifluormethyl)-1,3-thiazol-4-yl]methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.65-1.89 (m, 4H), 2.45 (br. d, 2H), 2.67 (br. t, 2H), 4.05 (s, 2H), 4.61 (br. s, 1H), 4.74 (br. s, 1H), 7.15 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.59 (dd, 1H), 8.62 (s, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-(Trifluormethyl)-1,3-thiazol-4-carbonsäure LC-MS (Methode 5): R t = 1.31 min; MS (ESIpos): m / z = 533 / 535 [M+H] +< . 59 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(5-methyl-1,3-thiazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.63-1.79 (m, 4H), 2.34-2.45 (m, 2H), 2.46-2.61 (m, 1H, teilweise verdeckt durch DMSO-Signal), 2.55 (s, 3H), 2.68 (dd, 1H), 4.04 (s, 2H), 4.34 (br. s, 1H), 4.60 (br. s, 1H), 7.15 (dd, 1H), 7.57 (d, 2H), 7.96 (d, 2H), 8.59 (dd, 1H), 8.89 (s, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 5-Methyl-1,3-thiazol-4-carbonsäure LC-MS (Methode 5): R t = 1.11 min; MS (ESIpos): m / z = 479 / 481 [M+H] +< . 60 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-[4-(trifluormethyl)-1,3-thiazol-2-yl]methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.68-1.80 (m, 2H), 1.83-1.95 (m, 2H), 2.45 (br. d, 1H), 2.48-2.57 (m, 1H, teilweise verdeckt durch DMSO-Signal), 2.65 (br. d, 1H), 2.80 (br. d, 1H), 4.05 (s, 2H), 4.61 (br. s, 1H), 5.43 (br. s, 1H), 7.15 (dd, 1H), 7.55 (d, 2H), 7.97 (d, 2H), 8.60 (dd, 1H), 8.79 (s, 1H), 9.06 (dd, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 4-(Trifluormethyl)-1,3-thiazol-2-carbonsäure LC-MS (Methode 2): R t = 2.00 min; MS (ESIpos): m / z = 533 / 535 [M+H] +< . 61 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(1,3-thiazol-4-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.75 (br. d, 4H), 2.44 (br. t, 2H), 2.66 (br. t, 2H), 4.03 (s, 2H), 4.62 (br. s, 1H), 5.02 (br. s, 1H), 7.14 (dd, 1H), 7.56 (d, 2H), 7.97 (d, 2H), 8.27 (d, 1H), 8.59 (dd, 1H), 9.06 (dd, 1H), 9.15 (d, 1H). aus 2-(4-Chlorphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 1,3-Thiazol-4-carbonsäure LC-MS (Methode 5): R t = 1.07 min; MS (ESIpos): m / z = 465 / 467 [M+H] +< . 62 (3-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]oct-8-yl)[6-(methylamino)pyridin-2-yl]-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.64-1.81 (m, 4H), 2.41 (br. d, 1H), 2.58 (br. s, 1.75H), 2.65-2.76 (m, 4.25H), 2.88-3.01 (m, 1H), 3.98-4.09 (m, 2H), 4.60 (br. s, 1H), 4.76 (br. s, 1H), 6.51 (d, 1H), 6.65 (q, 1H), 6.80 (d, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.74 (d, 1H), 7.84 (d, 2H), 8.56 (dd, 1H), 9.02 (dd, 1H). aus 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 6-(Methylamino)pyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.58 min; MS (ESIpos): m / z = 496 [M+H] +< . 63 (3-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.66-1.84 (m, 4H), 2.44 (br. d, 1H), 2.56-2.66 (m, 2H), 2.74 (dd, 1H), 2.95 (quin, 1H), 3.77 (s, 3H), 3.99-4.11 (m, 2H), 4.64 (br. s, 1H), 4.69 (br. s, 1H), 6.93 (d, 1H), 7.12 (dd, 1H), 7.31-7.40 (m, 3H), 7.77-7.88 (m, 3H), 8.57 (dd, 1H), 9.03 (dd, 1H). aus 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 5): R t = 1.24 min; MS (ESIpos): m / z = 497 [M+H] +< . 64 (2-Fluorphenyl)(3-{[2-(4-isopropylphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 1.64-1.81 (m, 4H), 2.26 (br. d, 1H), 2.42 (br. d, 1H), 2.58 (br. d, 1H), 2.68 (br. d, 1H), 2.96 (quin, 1H), 3.67 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.23-7.32 (m, 2H), 7.38 (d, 2H), 7.41-7.54 (m, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). aus 3-(3,8-Diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Methode 5): R t = 1.23 min; MS (ESIpos): m / z = 484 [M+H] +< . 65 (3-{1-[2-(4-Chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]ethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluor-6-methoxypyridin-2-yl)methanon ( Racemat ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.41-1.60 (m, 4H), 1.61-1.75 (m, 1H), 1.76-1.90 (m, 1H), 2.01 (br. d, 0.5H), 2.06-2.24 (m, 2.5H), 2.34 (br. d, 1H), 3.12 (br. d, 0.5H), 3.23 (br. dd, 0.5H), 3.59 (s, 1.5H), 3.75 (br. d, 0.5H), 3.85 (s, 1.5H), 4.04 (br. d, 0.5H), 4.07-4.17 (m, 1H), 4.43 (br. d, 0.5H), 4.71 (br. d, 0.5H), 6.89 (dd, 0.5H), 6.98 (dd, 0.5H), 7.08-7.15 (m, 1H), 7.52-7.61 (m, 2H), 7.66-7.84 (m, 3H), 8.53-8.63 (m, 1H), 9.27 (d, 1H). aus 2-(4-Chlorphenyl)-3-[1-(3,8-diazabicyclo-[3.2.1]oct-3-yl)ethyl]imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Racemat ) und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.77 min; MS (ESIpos): m / z = 521 / 523 [M+H] +< . 66 (7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]non-9-yl)(6-methoxypyridin-2-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 2.44-2.65 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.86-3.00 (m, 2H), 3.05 (br. d, 1H), 3.66-3.82 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.94-4.06 (m, 2H), 4.20 (br. s, 1H), 4.45 (br. s, 1H), 6.92 (d, 1H), 7.06 (dd, 1H), 7.29 (d, 1H), 7.36 (d, 2H), 7.75-7.87 (m, 3H), 8.55 (dd, 1H), 9.28 (dd, 1H). aus 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.82 min; m / z = 513 (M+H) +< . 67 (3-Chlor-6-methoxypyridin-2-yl)(7-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 2.44-2.57 (m, 2H, verdeckt durch DMSO-Signal), 2.84-3.00 (m, 2H), 3.06 (br. d, 1H), 3.34 (br. s, 1H, teilweise verdeckt H 2 O-Signal), 3.61-3.75 (m, 3H), 3.82 (s, 3H), 3.88 (d, 1H), 3.99 (s, 2H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.05 (dd, 1H), 7.36 (d, 2H), 7.80 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). aus 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 3-Chlor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.88 min; m / z = 547 / 549 (M+H) +< . 68 (2-Fluorphenyl)(7-{[2-(4-isopropylphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.26 (d, 6H), 2.41 (br. d, 1H), 2.46-2.58 (m, 1H, verdeckt durch DMSO-Signal), 2.84-3.06 (m, 3H), 3.37 (br. s, 1H), 3.59 (br. d, 1H), 3.71 (br. t, 2H), 3.87 (d, 1H), 3.99 (s, 2H), 4.47 (br. s, 1H), 7.05 (dd, 1H), 7.24-7.33 (m, 2H), 7.37 (d, 2H), 7.42-7.54 (m, 2H), 7.79 (d, 2H), 8.55 (dd, 1H), 9.28 (dd, 1H). aus 7-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo-[3.3.1]nonan-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Methode 1): R t = 0.84 min; m / z = 500 (M+H) +< . 69 (3-Chlor-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.19-1.31 (m, 6H), 1.52-2.00 (m, 4H), 2.62 (br. dd, 0.75H), 2.70-2.85 (m, 1.5H), 2.89-3.03 (m, 2H), 3.21 (br. s, 0.75H), 3.43 (br. d, 1H), 3.70-3.86 (m, 3.75H), 4.22-4.35 (m, 2H), 4.38 (br. s, 0.25H), 6.85-6.96 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.86 (m, 2.7H), 7.90 (d, 0.3H), 8.56 (dd, 1H), 8.94-9.04 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 3-Chlor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.73 min; m / z = 531 / 533 (M+H) +< . 70 (5-Cyclopropyl-1,3-oxazol-4-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.81-0.95 (m, 2H), 0.96-1.09 (m, 2H), 1.25 (d, 6H), 1.49-1.63 (m, 1H), 1.66-2.00 (m, 3H), 2.44-2.57 (m, 0.7H, teilweise verdeckt durch DMSO-Signal), 2.57-2.65 (m, 0.3H), 2.73-3.02 (m, 4H), 3.36 (dd, 0.7H), 3.63-3.76 (m, 1H), 4.04 (br. d, 0.3H), 4.22-4.33 (m, 2H), 4.36 (br. s, 0.3H), 4.59 (br. s, 0.7H), 7.06-7.14 (m, 1H), 7.31-7.40 (m, 2H), 7.75-7.83 (m, 2H), 8.12-8.19 (m, 1H), 8.53-8.60 (m, 1H), 8.98-9.06 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 5-Cyclopropyl-1,3-oxazol-4-carbonsäure LC-MS (Methode 2): R t = 1.52 min; m / z = 497 (M+H) +< . 71 (3-Fluor-6-methoxypyridin-2-yl)(5-{ [2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.30 (m, 6H), 1.50-2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.88 (m, 1.25H), 2.90-3.01 (m, 1.75H), 3.13 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.84 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.70-7.83 (m, 3H), 8.52-8.60 (m, 1H), 8.96-9.06 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.62 min; m / z = 515 (M+H) +< . 72 (3-Fluor-6-methoxypyridin-2-yl)(5-{ [2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.31 (m, 6H), 1.51-2.01 (m, 4H), 2.69 (br. dd, 0.75H), 2.74 (br. s, 0.25H), 2.77-2.87 (m, 1.25H), 2.89-3.02 (m, 1.75H), 3.14 (br. d, 0.25H), 3.39-3.52 (m, 1.5H), 3.61 (d, 0.25H), 3.69-3.83 (m, 3.75H), 4.21-4.35 (m, 2H), 4.36-4.42 (m, 0.25H), 6.88-6.98 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.41 (m, 2H), 7.70-7.84 (m, 3H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.63 min; m / z = 515 (M+H) +< . 73 (5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-oct-2-yl)(6-methoxypyridin-2-yl)methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.83-3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.86 (m, 3.75H), 3.93-4.04 (m, 1H), 4.23-4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.95 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.26-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.06 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.56 min; m / z = 497 (M+H) +< . 74 (5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-2,5-diazabicylo[2.2.2]-oct-2yl)(6-methoxypyridin-2-yl)methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.49-2.01 (m, 4H), 2.69-2.76 (m, 1H), 2.82-3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.70-3.85 (m, 3.75H), 3.93-4.02 (m, 1H), 4.23-4.35 (m, 2H), 4.39 (br. s, 0.25H), 6.84-6.94 (m, 1H), 7.05-7.14 (m, 1H), 7.17 (d, 0.75H), 7.25-7.40 (m, 2.25H), 7.73-7.85 (m, 3H), 8.52-8.60 (m, 1H), 8.97-9.05 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 6-Methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.55 min; m / z = 497 (M+H) +< . 75 [6-(Difluormethoxy)pyridin-2-yl](5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.29 (m, 6H), 1.50-2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.83-3.01 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.34 (m, 2H), 4.39 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.22 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.48-7.71 (m, 1H), 7.75-7.82 (m, 2H), 7.97-8.09 (m, 1H), 8.53-8.60 (m, 1H), 8.96-9.05 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 6-(Difluormethoxy)pyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.68 min; m / z = 533 (M+H) +< . 76 [6-(Difluormethoxy)pyridin-2-yl](5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.30 (m, 6H), 1.50-2.01 (m, 4H), 2.71 (dd, 0.75H), 2.75 (br. s, 0.25H), 2.82-3.02 (m, 3H), 3.39 (dd, 0.75H), 3.47 (br. d, 0.25H), 3.73 (d, 0.75H), 3.93 (br. s, 1H), 4.23-4.35 (m, 2H), 4.38 (br. s, 0.25H), 7.05-7.13 (m, 1H), 7.14-7.23 (m, 1H), 7.31-7.41 (m, 2.25H), 7.45 (d, 0.75H), 7.49-7.71 (m, 1H), 7.75-7.83 (m, 2H), 7.97-8.09 (m, 1H), 8.52-8.60 (m, 1H), 8.96-9.07 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 6-(Difluormethoxy)pyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.69 min; m / z = 533 (M+H) +< . 77 (5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-oct-2-yl) (6-methoxy-3 -methylpyridin-2-yl) - methanon ( Enantiomer 2 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.20-1.31 (m, 6H), 1.51-2.00 (m, 4H), 2.03-2.12 (m, 3H), 2.63 (dd, 0.75H), 2.70-2.77 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.34 (m, 2H), 4.37-4.43 (m, 0.25H), 6.71-6.80 (m, 1H), 7.06-7.14 (m, 1H), 7.29-7.41 (m, 2H), 7.54-7.65 (m, 1H), 7.72-7.83 (m, 2H), 8.52-8.60 (m, 1H), 8.95-9.05 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 2 ) und 6-Methoxy-3-methylpyridin-2-carbonsäure LC-MS (Methode 6): R t = 1.68 min; m / z = 511 (M+H) +< . 78 (5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-oct-2-yl) (6-methoxy-3 -methylpyridin-2-yl) - methanon ( Enantiomer 1 ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.19-1.31 (m, 6H), 1.51-2.00 (m, 4H), 2.02-2.14 (m, 3H), 2.63 (dd, 0.75H), 2.69-2.78 (m, 1H), 2.81 (d, 0.5H), 2.89-3.03 (m, 2H), 3.24 (br. s, 0.75H), 3.42 (br. d, 1H), 3.65-3.84 (m, 3.75H), 4.20-4.35 (m, 2H), 4.37-4.43 (m, 0.25H), 6.70-6.80 (m, 1H), 7.06-7.15 (m, 1H), 7.30-7.40 (m, 2H), 7.54-7.64 (m, 1H), 7.72-7.83 (m, 2H), 8.53-8.60 (m, 1H), 8.94-9.05 (m, 1H). aus 3-(2,5-Diazabicyclo[2.2.2]oct-2-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Enantiomer 1 ) und 6-Methoxy-3-methylpyridin-2-carbonsäure LC-MS (Methode 6): R t = 1.68 min; m / z = 511 (M+H) +< . 79 (5-{[2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(2-fluorphenyl)methanon ( Racemat ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.45-2.01 (m, 4H), 2.44-2.57 (m, 0.5H), 2.59-2.86 (m, 2.5H), 2.89-3.07 (m, 1H), 3.36-3.49 (m, 1H), 3.77 (br. d, 0.7H), 4.17-4.43 (m, 2.3H), 7.04-7.19 (m, 1H), 7.18-7.39 (m, 3H), 7.40-7.58 (m, 1H), 7.62-7.75 (m, 2H), 7.76-7.91 (m, 2H), 8.54-8.63 (m, 1H), 8.96-9.07 (m, 1H). aus 2-(4-Bromphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Racemat ) und 2-Fluorbenzoesäure LC-MS (Methode 2): R t = 1.54 min; m / z = 520 / 522 (M+H) +< . 80 (5-{[2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(cyclopentyl)methanon (Racemat) aus 2-(4-Bromphenyl)-3-(2,5-diazabicyclo[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid ( Racemat ) und Cyclopentancarbonsäure 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = -0.149 (0.54), -0.008 (4.35), 0.008 (3.57), 0.146 (0.49), 1.468 (2.71), 1.487 (3.20), 1.501 (3.94), 1.516 (4.35), 1.528 (4.98), 1.538 (4.91), 1.552 (4.91), 1.578 (3.45), 1.589 (3.88), 1.605 (4.88), 1.624 (5.35), 1.643 (3.91), 1.685 (3.00), 1.707 (4.06), 1.726 (3.25), 1.750 (1.24), 1.876 (1.41), 2.328 (0.63), 2.646 (0.95), 2.671 (2.30), 2.714 (7.31), 2.746 (4.33), 2.775 (1.34), 2.793 (1.64), 2.822 (3.00), 3.172 (2.01), 3.199 (2.37), 3.359 (1.56), 3.382 (1.69), 3.527 (1.95), 3.558 (1.66), 3.731 (1.41), 3.757 (1.20), 3.926 (2.76), 4.199 (1.20), 4.236 (6.26), 4.243 (9.84), 4.251 (6.91), 4.287 (1.22), 7.110 (4.45), 7.120 (4.69), 7.127 (4.62), 7.138 (4.61), 7.680 (11.67), 7.701 (16.00), 7.815 (8.75), 7.818 (11.65), 7.836 (7.72), 7.839 (7.96), 8.585 (4.37), 8.591 (4.13), 8.595 (4.20), 9.014 (3.08), 9.018 (5.06), 9.023 (2.68), 9.031 (3.23), 9.036 (4.89), 9.040 (2.42). LC-MS (Methode 2): R t = 1.45 min; m / z = 494 / 496 (M+H) +< . 81 (5-{[2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-(3-fluor-6-methoxypyridin-2-yl)methanon ( Racemat ) 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.52-1.99 (m, 4H), 2.67 (dd, 0.75H), 2.72 (br. s, 0.25H), 2.77-2.86 (m, 1.25H), 2.93 (br. s, 0.75H), 3.15 (br. d, 0.25H), 3.43 (dd, 0.75H), 3.48 (br. s, 0.75H), 3.57 (br. d, 0.25H), 3.70-3.83 (m, 3.75H), 4.22-4.34 (m, 2H), 4.36-4.41 (m, 0.25H), 6.89-6.99 (m, 1H), 7.08-7.17 (m, 1H), 7.64-7.88 (m, 5H), 8.57-8.62 (m, 1H), 9.00-9.08 (m, 1H). aus 2-(4-Bromphenyl)-3-(2,5-diazabicyclo-[2.2.2]oct-2-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid ( Racemat ) und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 2): R t = 1.55 min; m / z = 551 / 553 (M+H) +< . 82 (3-{ [2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(3-fluor-6-methoxypyridin-2-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.60-1.83 (m, 4H), 2.39-2.58 (m, 3H, teilweise verdeckt durch DMSO-Signal), 2.75 (dd, 1H), 3.76 (s, 3H), 3.91 (br. s, 1H), 4.00-4.13 (m, 2H), 4.60 (br. s, 1H), 6.95 (dd, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.77 (t, 1H), 7.89 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). aus 2-(4-Bromphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.93 min; m / z = 551 / 553 (M+H) +< . 83 (3-{[2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(2-fluorphenyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.64-1.81 (m, 4H), 2.24 (br. d, 1H), 2.42 (br. d, 1H), 2.47-2.60 (m, 1H, teilweise verdeckt durch DMSO-Signal), 2.68 (br. d, 1H), 3.66 (br. s, 1H), 4.04 (s, 2H), 4.59 (br. s, 1H), 7.14 (dd, 1H), 7.24-7.32 (m, 2H), 7.40-7.55 (m, 2H), 7.70 (d, 2H), 7.88 (d, 2H), 8.59 (dd, 1H), 9.04 (dd, 1H). aus 2-(4-Bromphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Methode 1): R t = 0.93 min; m / z = 520 / 522 (M+H) +< . 84 (3-{[2-(4-Bromphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(cyclopentyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.44-1.66 (m, 7H), 1.66-1.80 (m, 5H), 2.26 (br. dd, 2H), 2.46-2.65 (m, 2H, teilweise verdeckt durch DMSO-Signal), 2.80-2.91 (m, 1H), 3.95-4.05 (m, 2H), 4.28 (br. s, 1H), 4.37-4.44 (m, 1H), 7.14 (dd, 1H), 7.70 (d, 2H), 7.90 (d, 2H), 8.59 (dd, 1H), 9.05 (dd, 1H). aus 2-(4-Bromphenyl)-3-(3,8-diazabicyclo-[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidin-Dihydrochlorid und Cyclopentancarbonsäure LC-MS (Methode 1): R t = 0.97 min; m / z = 494 / 496 (M+H) +< . Beispiel 85 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,4-difluorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid

[0319]

[0320] 15.5 mg (0.10 mmol) of 2,4-difluorophenyl isocyanate was placed in a well of a 96-well multititer plate and cooled to 0°C. Separately, 46.3 mg of 2-(4-chlorophenyl)-3-(3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride was dissolved in 0.8 ml of 1,2-dichloroethane, with 0.052 ml (0.3 mmol) N,N Diisopropylethylamine was added and cooled to 8°C. The two solutions were combined on the multititer plate, mixed with 4Å molecular sieves, and shaken at 0°C for 1 h. The solution was then allowed to warm to RT and shaken at RT overnight. The solvent was then completely removed using a centrifuge dryer. The residue was dissolved in 0.6 ml of DMF, filtered, and the filtrate was separated into its components by preparative LC-MS using one of the following methods: MS instrument: Waters, HPLC instrument: Waters; Column: Phenomenex Luna 5µ C18(2) 100A, AXIA Tech., 50 mm x 21.2 mm; Eluent A: water, Eluent B: acetonitrile, with eluent gradient; Flow: 38.5 ml / min + 1.5 ml / min 10% aq. formic acid; UV detection: DAD, 210-400 nm or MS instrument: Waters, HPLC instrument: Waters; Column: Phenomenex Luna 5µ C18(2) 100A, AXIA Tech., 50 mm x 21.2 mm; Eluent A: water, Eluent B: methanol, with eluent gradient; Flow: 38.5 ml / min + 1.5 ml / min 10% ammonia in water; UV detection: DAD, 210-400 nm.

[0321] Thus, 17.9 mg (35% of theory, purity 100%) of the title compound were obtained.

[0322] LC-MS (Method 7, ESIpos): R t = 1.14 min; m / z = 509 (M+H) +< .

[0323] In a parallel synthetic manner analogous to Example 85, the following compounds were prepared starting from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride and the corresponding isocyanate, carbamoyl chloride, or chloroformate: Beispiel Name / Struktur (Ausbeute, Reinheit) LC-MS (Methode 7) 86 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -isopropyl-3,8-diazabicyclo-[3.2.1]octan-8-carboxamid R t = 1.03 min; m / z = 439 [M+H] +< 11.1 mg (90% purity, 23% of theory) 87 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -cyclopropyl-3,8-diazabicyclo-[3.2.1]octan-8-carboxamid R t = 0.99 min; m / z = 437 [M+H] +< 900 µg (100% purity, 2% of theory) 88 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,5-dichlor-4-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.22 min; m / z = 571 [M+H] +< 8.3 mg (90% purity, 13% of theory) 89 N -(3-Chlorphenyl)-3-{[2-(4-chlorphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.19 min; m / z = 507 [M+H] +< 9.7 mg (100% purity, 19% of theory) 90 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,6-difluorbenzyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.14 min; m / z = 523 [M+H] +< 17.2 mg (100% purity, 33% of theory) 91 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,6-dichlorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.15 min; m / z = 541 [M+H] +< 16.4 mg (98% purity, 30% of theory) 92 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,6-dimethylphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.14 min; m / z = 501 [M+H] +< 18.5 mg (99% purity, 37% of theory) 93 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2-fluorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.13 min; m / z = 491 [M+H] +< 24.8 mg (98% purity, 49% of theory) 94 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,3-dichlorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.24 min; m / z = 541 [M+H] +< 20.8 mg (99% purity, 38% of theory) 95 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2-ethylphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.17 min; m / z = 501 [M+H] +< 6.0 mg (100% purity, 12% of theory) 96 N -(2-Chlorphenyl)-3-{[2-(4-chlorphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.17 min; m / z = 507 [M+H] +< 600 µg (100% purity, 1% of theory) 97 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -[2-chlor-5-(trifluormethyl)-phenyl]-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.29 min; m / z = 575 [M+H] +< 26.9 mg (99% purity, 47% of theory) 98 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2-ethyl-6-methylphenyl)-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.18 min; m / z = 515 [M+H] +< 7.8 mg (97% purity, 15% of theory) 99 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl] methyl} - N -(2, 5-dimethylphenyl)-3 , 8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.17 min; m / z = 501 [M+H] +< 16.1 mg (94% purity, 30% of theory) 100 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -cyclohexyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.14 min; m / z = 479 [M+H] +< 27.3 mg (100% purity, 57% of theory) 101 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -isobutyl-3,8-diazabicyclo-[3.2.1]octan-8-carboxamid R t = 1.09 min; m / z = 453 [M+H] +< 5.1 mg (100% purity, 11% of theory) 102 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(3,4-dimethoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.07 min; m / z = 533 [M+H] +< 14.6 mg (90% purity, 25% of theory) 103 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -{4-[(trifluormethyl)sulfanyl]-phenyl}-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.27 min; m / z = 573 [M+H] +< 2.0 mg (100% purity, 3% of theory) 104 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(3-fluorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.16 min; m / z = 491 [M+H] +< 26.2 mg (97% purity, 52% of theory) 105 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2,6-difluorphenyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.10 min; m / z = 509 [M+H] +< 12.8 mg (100% purity, 25% of theory) 106 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -[4-chlor-2-(trifluormethyl)-phenyl]-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.25 min; m / z = 575 [M+H] +< 20.6 mg (92% purity, 33% of theory) 107 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(2-methylbenzyl)-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.16 min; m / z = 501 [M+H] +< 20.1 mg (100% purity, 40% of theory) 108 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -methyl-N-phenyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.22 min; m / z = 487 [M+H] +< 16.6 mg (100% purity, 34% of theory) 109 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N,N -diethyl-3,8-diazabicyclo-[3.2.1]octan-8-carboxamid R t = 1.16 min; m / z = 453 [M+H] +< 21.3 mg (100% purity, 47% of theory) 110 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(morpholin-4-yl)methanon R t = 1.03 min; m / z = 467 [M+H] +< 2.7 mg (100% purity, 6% of theory) 111 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N,N -diisopropyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.23 min; m / z = 481 [M+H] +< 2.4 mg (100% purity, 5% of theory) 112 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-N-cyclohexyl- N -ethyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.30 min; m / z = 507 [M+H] +< 16.8 mg (100% purity, 33% of theory) 113 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(pyrrolidin-1-yl)methanon R t = 1.10 min; m / z = 451 [M+H] +< 22.8 mg (98% purity, 50% of theory) 114 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -ethyl- N -phenyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.25 min; m / z = 501 [M+H] +< 14.9 mg (100% purity, 30% of theory) 115 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -isopropyl- N -methyl-3,8-diaza-bicyclo[3.2.1]octan-8-carboxamid R t = 1.14 min; m / z = 453 [M+H] +< 4.3 mg (100% purity, 9% of theory) 116 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(piperidin-1-yl)methanon R t = 1.16 min; m / z = 465 [M+H] +< 3.0 mg (100% purity, 6% of theory) 117 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -ethyl- N -(4-methylphenyl)-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.30 min; m / z = 515 [M+H] +< 5.2 mg (98% purity, 10% of theory) 118 N -(4-Chlorphenyl)-3-{[2-(4-chlorphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -isopropyl-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.33 min; m / z = 549 [M+H] +< 3.4 mg (100% purity, 6% of theory) 119 3-{ [2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N,N- dimethyl-3,8-diazabicyclo-[3.2.1]octan-8-carboxamid R t = 1.05 min; m / z = 425 [M+H] +< 6.6 mg (100% purity, 16% of theory) 120 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(4-ethoxyphenyl)- N -methyl-3,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.26 min; m / z = 531 [M+H] +< 35.4 mg (100% purity, 67% of theory) 121 3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- N -(3-methoxybenzyl)- N -methyl-3 ,8-diazabicyclo[3.2.1]octan-8-carboxamid R t = 1.23 min; m / z = 531 [M+H] +< 35.0 mg (96% purity, 63% of theory) 122 (3-{[2-(4-Chlorphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)-(thiomorpholin-4-yl)methanon R t = 1.13 min; m / z = 483 [M+H] +< 5.4 mg (100% purity, 11% of theory) 123 Methyl-3-{[2-(4-chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat R t = 1.10 min; m / z = 412 [M+H] +< 20.7 mg (100% purity, 50% of theory) 124 Ethyl-3-{[2-(4-chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat R t = 1.15 min; m / z = 426 [M+H] +< 17.8 mg (98% purity, 41% of theory) 125 Cyclopentyl-3-{[2-(4-chlorphenyl)imidazo-[1,2-a]pyrimidin-3-yl]methyl}-3,8-diaza-bicyclo[3.2.1]octan-8-carboxylat R t = 1.26 min; m / z = 466 [M+H] +< 19.7 mg (100% purity, 42% of theory) 126 Propyl-3-{[2-(4-chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat R t = 1.21 min; m / z = 440 [M+H] +< 22.5 mg (98% purity, 50% of theory) 127 Cyclohexylmethyl-3-{ [2-(4-chlorphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-carboxylat R t = 1.35 min; m / z = 494 [M+H] +< 11.7 mg (92% purity, 22% of theory) 128 Cyclohexyl-3-{[2-(4-chlorphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat R t = 1.30 min; m / z = 480 [M+H] +< 4.0 mg (91% purity, 8% of theory) 129 2,2-Dimethylpropyl-3- { [2-(4-chlorphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-carboxylat R t = 1.29 min; m / z = 468 [M+H] +< 10.9 mg (96% purity, 22% of theory) Beispiel 130 tert. -Butyl-3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat

[0324]

[0325] Under argon at room temperature, 2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (700 mg, 2.64 mmol) was dissolved in 14 ml of THF, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (672 mg, 3.17 mmol) was added. Sodium triacetoxyborohydride (839 mg, 3.96 mmol) was then added portionwise, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: gas evolution) and subsequently ethyl acetate was added. The resulting organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness in a rotary evaporator under vacuum.The resulting residue was purified by column chromatography (Biotage Isolera, Biotage SNAP-KP-NH column, eluent: cyclohexane / ethyl acetate gradient). 896 mg (1.94 mmol, 74% of theory) of the target compound were obtained.

[0326] LC-MS (Method 2): R t = 2.14 min; m / z = 462 (M+H) +< .

[0327] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.25 (d, 6H), 1.39 (s, 9H), 1.65 (br. s, 4H), 2.26 (br. d, 2H), 2.47-2.60 (m, 2H, partially obscured by DMSO signal), 2.95 (quin, 1H), 3.98 (s, 2H), 4.02 (br. s, 2H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.83 (d, 2H), 8.56 (dd, 1H), 8.99 (dd, 1H). Beispiel 131 (5-Cyclopropyl-1,3-oxazol-4-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone

[0328]

[0329] 5-Cyclopropyl-1,3-oxazole-4-carboxylic acid (39 mg, 0.26 mmol) was dissolved in 1.5 ml of DMF, treated with 2-(7-aza-1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (121 mg, 0.32 mmol) was added and stirred at room temperature for 30 min. Subsequently, 3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N Diisopropylethylamine (190 µl, 1.06 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then separated into its components directly by preparative HPLC (Method 9). 65 mg (0.13 mmol, 61% of theory) of the title compound were obtained.

[0330] LC-MS (Method 2): R t = 1.81 min; MS (ESIpos): m / z = 497 [M+H] +< .

[0331] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.85-0.99 (m, 2H), 1.01-1.13 (m, 2H), 1.25 (d, 6H), 1.63-1.85 (m, 4H), 2.35-2.45 (m, 2H), 2.60-2.74 (m, 3H), 2.88-3.01 (m, 1H), 4.03 (s, 2H), 4.53-4.64 (m, 1H), 5.12 (br. s, 1H), 7.12 (dd, 1H), 7.37 (d, 2H), 7.85 (d, 2H), 8.17 (s, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H). Beispiel 132 tert .-Butyl-3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo-[3.2.1]octan-8-carboxylat

[0332]

[0333] Unter Argon wurden bei Raumtemperatur 1090 mg (2.19 mmol) tert .-Butyl 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 15 ml of toluene and 3 ml of water was placed in a 30 ml microwave vessel, followed by cyclopropylboronic acid (376 mg, 4.37 mmol), potassium phosphate (1625 mg, 7.65 mmol), palladium(II) acetate (49 mg, 0.22 mmol), and tricyclohexylphosphine (123 mg, 0.44 mmol). The microwave vessel was then sealed, and the mixture was heated to 120°C and stirred overnight. After cooling to room temperature, the reaction mixture was filtered through kieselguhr, and the residue was washed portionwise with ethyl acetate. A further amount of ethyl acetate and water were added to the resulting filtrate, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to dryness. The residue was then triturated with diethyl ether.After filtration, the resulting solid was dried overnight under high vacuum. 667 mg (1.36 mmol, 62% of theory) of the target compound were obtained.

[0334] LC-MS (Method 2): R t = 2.00 min; m / z = 460 (M+H) +< .

[0335] 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.69-0.77 (m, 2H), 0.95-1.03 (m, 2H), 1.39 (s, 9H), 1.65 (br. s, 4H), 1.93-2.03 (m, 1H), 2.24 (br. d, 2H), 2.45-2.61 (m, 2H, partially obscured by DMSO signal), 3.97 (s, 2H), 4.02 (br. s, 2H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 8.99 (dd, 1H).

[0336] Analogously to Examples 13-29, the following compounds were prepared from the indicated starting materials: Beispiel Name / Struktur / Edukte Analytische Daten 133 (3-{[2-(4-Cyclopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]-octan-8-yl)(2-fluorphenyl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.70-0.77 (m, 2H), 0.95-1.02 (m, 2H), 1.65-1.79 (m, 4H), 1.93-2.02 (m, 1H), 2.24 (br. d, 1H), 2.41 (br. d, 1H), 2.56 (dd, 1H), 2.68 (dd, 1H), 3.66 (br. s, 1H), 4.03 (s, 2H), 4.59 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.25-7.32 (br. s, 1H), 7.41-7.53 (m, 2H), 7.78 (d, 2H), 8.55 (dd, 1H), 9.00 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und 2-Fluorbenzoesäure LC-MS (Methode 1): R t = 0.87 min; m / z = 482 (M+H) +< . 134 Cyclopentyl(3-{[2-(4-cyclopropylphenyl)-imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.68-0.79 (m, 2H), 0.94-1.03 (m, 2H), 1.44-1.68 (m, 7H), 1.68-1.78 (m, 5H), 1.97 (tt, 1H), 2.18-2.30 (m, 2H), 2.53-2.65 (m, 2H), 2.80-2.90 (m, 1H), 3.94-4.03 (m, 2H), 4.28 (br. s, 1H), 4.41 (br. d, 1H), 7.11 (dd, 1H), 7.20 (d, 2H), 7.79 (d, 2H), 8.56 (dd, 1H), 9.01 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und Cyclopentancarbonsäure LC-MS (Methode 1): R t = 0.90 min; m / z = 456 (M+H) +< . 135 (3-{[2-(4-Cyclopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]-octan-8-yl)(3-fluor-6-methoxypyridin-2-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.69-0.78 (m, 2H), 0.95-1.04 (m, 2H), 1.63-1.84 (m, 4H), 1.93-2.02 (m, 1H), 2.43 (br. t, 2H), 2.52-2.57 (m, 1H), 2.76 (dd, 1H), 3.75 (s, 3H), 3.91 (br. s, 1H), 3.99-4.09 (m, 2H), 4.61 (br. s, 1H), 6.95 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.73-7.81 (m, 3H), 8.56 (dd, 1H), 9.01 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und 3-Fluor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.86 min; m / z = 513 (M+H) +< . 136 (3-Chlor-6-methoxypyridin-2-yl)(3-{[2-(4-cyclo-propylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.68-0.78 (m, 2H), 0.94-1.03 (m, 2H), 1.62-1.83 (m, 4H), 1.93-2.02 (m, 1H), 2.33-2.44 (m, 2H), 2.45-2.56 (m, 1H, teilweise verdeckt durch DMSO-Signal), 2.75 (dd, 1H), 3.62 (br. s, 1H), 3.78 (s, 3H), 3.99-4.10 (m, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 7.12 (dd, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.87 (d, 1H), 8.56 (dd, 1H), 9.00 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und 3-Chlor-6-methoxypyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.90 min; m / z = 529 / 531 (M+H) +< . 137 (3-{[2-(4-Cyclopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]-octan-8-yl)(6-methoxypyridin-2-yl)methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.65-0.79 (m, 2H), 0.94-1.04 (m, 2H), 1.65-1.82 (m, 4H), 1.93-2.01 (m, 1H), 2.43 (br. d, 1H), 2.55-2.64 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 3.98-4.09 (m, 2H), 4.63 (br. s, 1H), 4.69 (br. s, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.35 (dd, 1H), 7.75-7.85 (m, 3H), 8.56 (dd, 1H), 9.02 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und 6-Methoxy-pyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.87 min; m / z = 495 (M+H) +< . 138 (3-{[2-(4-Cyclopropylphenyl)imidazo[1,2-a]-pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]-octan-8-yl)[6-(difluormethoxy)pyridin-2-yl]-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.68-0.76 (m, 2H), 0.94-1.02 (m, 2H), 1.67-1.83 (m, 4H), 1.92-2.01 (m, 1H), 2.42 (br. d, 1H), 2.53-2.59 (m, 1H), 2.60-2.66 (m, 1H), 2.72 (dd, 1H), 4.04 (s, 2H), 4.57 (br. s, 1H), 4.64 (br. s, 1H), 7.11 (dd, 1H), 7.16-7.24 (m, 3H), 7.44 (s, 0.25H), 7.56-7.64 (m, 1.5H), 7.73 (s, 0.25H), 7.79 (d, 2H), 8.05 (t, 1H), 8.57 (dd, 1H), 9.03 (dd, 1H). aus 2-(4-Cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidin-Dihydrochlorid und 6-(Difluor-methoxy)pyridin-2-carbonsäure LC-MS (Methode 1): R t = 0.91 min; m / z = 531 (M+H) +< . 139 (5-Cyclopropyl-1,3-oxazol-4-yl)(3-{[2-(4-cyclo-propylphenyl)imidazo[1,2-a]pyrimidin-3-yl]-methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanon 1< H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.69-0.77 (m, 2H), 0.87-1.01 (m, 4H), 1.02-1.12 (m, 2H), 1.61-1.85 (m, 4H), 1.92-2.01 (m, 1H), 2.39 (br. t, 2H), 2.60-2.74 (m, 3H), 4.01 (s, 2H), 4.59 (br. d, 1H), 5.11 (br. s, 1H), 7.12 (dd, 1H), 7.20 (d, 2H), 7.80 (d, 2H), 8.17 (s, 1H), 8.56 (dd, 1H), 9.02 (dd, 1H). LC-MS (Method 1): from 2-(4-cyclopropylphenyl)-3-(3,8-diaza-bicyclo[3.2.1]octan-3-ylmethyl)imidazo[1,2-a]-pyrimidine dihydrochloride and 5-cyclopropyl-1,3-oxazole-4-carboxylic acid R t = 0.87 min; m / z = 495 (M+H) +< . B. Assessment of pharmacological efficacy

[0337] The pharmacological activity of the compounds according to the invention can be in vitro and in vivo -tests known to the person skilled in the art. The following application examples describe the biological action of the compounds according to the invention without limiting the invention to these examples. B-1. In vitro -electrophysiological analysis of human TASK-1 and TASK-3 channels via Two-electrode voltage clamp technique in Xenopus laevis -Oocytes

[0338] Xenopus laevisOocytes were selected as described elsewhere [Decher et al., FEBS Lett. 492, 84-89 (2001)]. Subsequently, the oocytes were injected with 0.5-5 ng of cRNA encoding TASK-1 or TASK-3. The two-electrode voltage clamp technique was used for electrophysiological analysis of the channel proteins expressed in the oocytes [Stühmer, Methods Enzymol. 207, 319-339 (1992)]. The measurements were performed as described [Decher et al., FEBS Lett. 492, 84-89 (2001)] at room temperature (21-22°C) with a Turbo-TEC-10CD amplifier (NPI), recorded at 2 kHz, and filtered at 0.4 kHz. The substance was administered using a gravity-driven perfusion system. The oocyte is placed in a measuring chamber and exposed to a solution flow of 10 ml / min. The level in the measuring chamber is controlled and regulated by aspirating the solution with a peristaltic pump.

[0339] The following Table 1 lists the half-maximal inhibition of human TASK-1 and TASK-3 channels (IC50 value) determined in this test by representative embodiments of the invention: Table 1 Example No. TASK-1 IC50 [nM] TASK-3 IC50 [nM] 19 239.4 ± 2.7 774.2 ± 67.1 21 19.2 ± 4.3 32.9 ± 6.0 26 31.2 ± 5.8 140.0 ± 34.6 27 17.9 ± 2.2 367.1 ± 67.6 28 20.5 ± 2.7 6.6 ± 0.8 29 21.0 ± 4.1 42.7 ± 8.4 41 44.4 ± 4.4 71.8 ± 15.5 51 21.7 ± 4.6 35.9 ± 8.2

[0340] The data in Table 1 demonstrate that blockade is achieved at both TASK-1 and TASK-3. The results in Table 1 thus demonstrate the mechanism of action of the compounds of the invention as dual TASK-1 / 3 inhibitors. B-2. Inhibition of recombinant TASK-1 and TASK-3 in vitro

[0341] The inhibition studies of recombinant TASK-1 and TASK-3 channels were carried out on stably transfected CHO cells. The compounds of the invention were tested using 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 Fluorometric Imaging Plate Reader (FLIPR ®< ) systems, http: / / www.moleculardevices.com / reagentssupplies / assay-kits / ion-channels / flipr-membrane-potential-assay-kits]. The activity of the test substances was determined as their ability to inhibit depolarization induced in the recombinant cells by 40 mM potassium chloride.The concentration that can block half of this depolarization is called IC 50.

[0342] The following Table 2 lists the IC50 values ​​determined for individual embodiments of the invention from this assay (partly as averages from several independent individual determinations): Table 2 Example No. TASK-1 IC50 [nM] TASK-3 IC50 [nM] 1 1700 400 4 470 97 5 17000 1300 6 1400 41 7 8600 570 10 2200 130 11 2500 16 12 220 13 13 1500 33 14 7600 170 15 1100 19 16 670 12 17 1200 33 18 910 8.6 19 22000 59 20 160 38 21 140 4.2 22 340 5.2 23 1600 100 24 410 102 25 1100 71 26 1400 16 27 1200 10 28 290 3.2 29 280 1.8 30 3500 85 31 7100 140 32 370 29 33 190 130 34 76 29 35 6700 1500 36 310 80 37 1500 140 38 9600 320 39 1400 160 40 5700 210 41 1500 100 42 1000 340 43 1000 320 44 1000 190 45 1800 120 46 7600 140 47 2800 110 48 400 23 49 260 12 50 3300 430 51 250 8.7 52 1300 52 53 620 19 54 860 13 55 2900 170 56 5600 54 57 6400 57 58 1600 17 59 3000 39 60 670 430 61 3000 640 62 6900 70 63 1700 15 64 1100 8.4 65 3500 670 66 3700 20 67 1200 17 68 9400 87 69 2800 22 70 1900 20 71 14000 110 72 2100 29 73 9100 81 74 3400 61 75 3800 51 76 13000 56 77 720 4.9 78 3800 24 81 820 21 82 670 37 83 250 14 84 93 4.6 85 30000 1000 86 7700 430 89 30000 850 91 20000 410 92 15000 270 93 12000 260 94 30000 160 95 3000 41 97 31000 450 98 9000 160 99 30000 750 100 19000 630 101 19000 510 103 30000 690 104 19000 460 106 30000 89 107 30000 750 108 7000 90 109 24 1.5 110 13000 230 111 6300 290 112 15000 130 113 1100 62 114 6700 140 115 7400 330 116 2700 65 118 19000 220 119 5300 210 120 15000 230 121 12000 120 122 5000 120 123 14000 230 124 790 17 125 230 27 126 280 14 128 2000 110 130 1700 210 131 3500 410 132 1700 410 133 1600 180 134 770 97 135 420 34 136 320 41 137 1100 180 138 3200 290 139 4500 470

[0343] The data in Table 2 demonstrate that blockade is achieved at both TASK-1 and, in particular, TASK-3. The results in Table 2 thus demonstrate the mechanism of action of the compounds of the invention as dual TASK-1 / 3 inhibitors. B-3. Animal model of obstructive sleep apnea in pigs

[0344] The use of negative pressure can induce collapse and thus closure of the upper airway in anesthetized, spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

[0345] German Landpigs are used for the model. The pigs are anesthetized and tracheotomy performed. A cannula is inserted into the rostral and caudal portions of the trachea. The rostral cannula is connected to a device that generates negative pressures and to the caudal cannula via a T-piece. The caudal cannula is connected to the rostral cannula via a T-piece and to a tube that allows spontaneous breathing while bypassing the upper airways. By appropriately closing and opening the tubes, the pig can switch from normal nasal breathing to breathing via the caudal cannula, while the upper airways are isolated and connected to the device that generates negative pressures. The muscle activity of the Genioglossus muscle is recorded using an electromyogram (EMG).

[0346] At specific time points, the collapsibility of the upper airway is tested by having the pig breathe through the caudal cannula and applying negative pressures of -50, -100, and -150 cm water column (cmH2O) to the upper airway. This causes the upper airway to collapse, which is indicated by an interruption of airflow and a drop in pressure in the tubing system. This test is performed before administration of the test substance and at specific intervals after administration of the test substance. A sufficiently effective test substance can prevent this collapse of the airways during the inspiratory phase.

[0347] After switching from nasal breathing to breathing through the caudal cannula, no EMG activity of the Genioglossus musclemeasurable in an anesthetized pig. A further test is then used to determine the negative pressure at which EMG activity resumes. This threshold is shifted to more positive values ​​if a test substance is effective. The test is also performed before administration of the test substance and at specific times after administration. The test substance can be administered intranasally, intravenously, subcutaneously, intraperitoneally, or intragastrically. C. Examples of pharmaceutical compositions

[0348] The compounds according to the invention can be converted into pharmaceutical preparations as follows: Tablet: Composition:

[0349] 100 mg of the compound according to the invention, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

[0350] Tablet weight 212 mg. Diameter 8 mm, curvature radius 12 mm. Production:

[0351] The mixture of the compound of the invention, lactose, and starch is granulated with a 5% w / w solution of PVP in water. After drying, the granules are mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a standard tablet press (see tablet format above). A compression force of 15 kN is used as a guideline for compression. Oral suspension: Composition:

[0352] 1000 mg of the compound according to the invention, 1000 mg ethanol (96%), 400 mg Rhodigel ®< (xanthan gum from FMC, Pennsylvania, USA) and 99 g water.

[0353] A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension. Production:

[0354] The Rhodigel is suspended in ethanol, and the compound of the invention is added to the suspension. The water is added while stirring. Stirring is continued for approximately 6 hours until the Rhodigel has completely swelled. Oral solution: Composition:

[0355] 500 mg of the compound according to the invention, 2.5 g polysorbate and 97 g polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution. Production:

[0356] The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate while stirring. Stirring is continued until the compound of the invention is completely dissolved. iv solution;

[0357] The compound according to the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline solution, 5% glucose solution, and / or 30% PEG 400 solution). The solution is sterile filtered and filled into sterile, pyrogen-free injection containers. Nasal applicable solution:

[0358] The compound according to the invention is dissolved in a physiologically acceptable solvent (e.g., purified water, phosphate buffer, citrate buffer) at a concentration below saturation solubility. The solution may contain further additives for isotonication, preservation, pH adjustment, solubility improvement, and / or stabilization.

Claims

1. Compound of the formula (I) in which the ring Q represents a diazaheterobicyclic system of the formula or in which * denotes the bond to the adjacent CHR2 group and ** the bond to the carbonyl group, A represents CH or N, R1 represents halogen, cyano, (C1-C4)-alkyl, cyclopropyl or cyclobutyl, where (C1-C4)-alkyl may be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine, R2 represents hydrogen or methyl, and R3 represents (C4-C6) -cycloalkyl in which a ring CH2 group may be replaced by -O-, or R3 represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f) in which *** marks the bond to the adjacent carbonyl group and R4 represents hydrogen, fluorine, chlorine, bromine or methyl, R5 represents hydrogen, fluorine, chlorine, bromine, cyano, (C1-C3) -alkyl or (C1-C3)-alkoxy, where (C1-C3)-alkyl and (C1-C3)-alkoxy may each be up to trisubstituted by fluorine, R6 represents hydrogen, fluorine, chlorine, bromine or methyl, R7 represents hydrogen, (C1-C3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C1-C3)-alkylamino, di-(C1-C3)- alkylamino or (C1-C3)-alkylsulfanyl, where (C1-C3)-alkoxy may be up to trisubstituted by fluorine, R8 represents hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl or (C1-C3)-alkoxy, R9A and R9B are identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, (C1-C3)-alkyl, cyclopropyl or (C1-C3)-alkoxy, where (C1-C3)-alkyl and (C1-C3)-alkoxy may each be up to trisubstituted by fluorine, and Y represents O or S, or R3 represents an -OR10 or -NR11R12 group in which R10 represents (C1-C6)-alkyl, (C4-C6)-cycloalkyl or [(C3-C6)-cycloalkyl]methyl, R11 represents hydrogen or (C1-C3)-alkyl and R12 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or benzyl, where (C1-C6)-alkyl may be up to trisubstituted by fluorine, and where phenyl and the phenyl group in benzyl may be up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl, or R11 and R12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, and the salts, solvates and solvates of the salts thereof.

2. Compound of the formula (I) according to Claim 1, in which the ring Q represents a diazaheterobicyclic system of the formula in which * denotes the bond to the adjacent CHR2 group and ** the bond to the carbonyl group, A represents CH, R1 represents fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, R2 represents hydrogen, and R3 represents cyclobutyl, cyclopentyl or cyclohexyl, or R3 represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f) in which *** marks the bond to the adjacent carbonyl group and R4 represents hydrogen, fluorine or chlorine, R5 represents fluorine, chlorine, cyano, (C1-C3)-alkyl, (C1-C3)-alkoxy or trifluoromethoxy, R6 represents hydrogen, fluorine, chlorine, bromine or methyl, R7 represents (C1-C3)-alkoxy, cyclobutyloxy or (C1-C3)-alkylsulfanyl, where (C1-C3)-alkoxy may be up to trisubstituted by fluorine, R9A and R9B are identical or different and independently of one another represent hydrogen, chlorine, bromine, (C1-C3)-alkyl or cyclopropyl, where (C1-C3)-alkyl may be up to trisubstituted by fluorine, and Y represents O or S, and the salts, solvates and solvates of the salts thereof.

3. Compound of the formula (I) according to Claim 1 or 2, in which the ring Q represents a diazaheterobicyclic system of the formula in which * denotes the bond to the adjacent CHR2 group and ** the bond to the carbonyl group, A represents CH, R1 represents chlorine, bromine, isopropyl or cyclopropyl, R2 represents hydrogen, and R3 represents cyclopentyl or cyclohexyl, or R3 represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f) in which *** marks the bond to the adjacent carbonyl group and R4 represents hydrogen, fluorine or chlorine, R3 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy, R6 represents hydrogen, fluorine, chlorine, bromine or methyl, R7 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl, R9A and R9B are identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl, and Y represents O or S, and the salts, solvates and solvates of the salts thereof.

4. Compound of the formula (I) according to Claim 1, with the systematic name (5{ [2- (4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]-oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2) and the structural formula 5. Compound of the formula (I) according to Claim 1, with the systematic name (3-fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone and the structural formula 6. Compound of the formula (I) according to Claim 1, with the systematic name ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone and the structural formula 7. Compound of the formula (I) according to Claim 1, with the systematic name (3-chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (enantiomer 2) and the structural formula 8. Compound of the formula (I) according to Claim 1, with the systematic name (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone and the structural formula 9. Process for preparing a compound of the formula (I) as defined in Claims 1 to 3 in which the radical R2 represents hydrogen, characterized in that a compound of the formula (II) in which A and R1 have the definitions given in Claims 1 to 3 is reacted in the presence of a suitable reducing agent either [A] with a compound of the formula (III) in which R3 and the ring Q have the definitions given in Claims 1 to 3 to give a compound of the formula (I-A) in which A, R1, R3 and the ring Q have the meanings given above or [B] with a protected diazaheterobicyclic system of the formula (IV) in which the ring Q has the definition given in Claims 1 to 3 and PG represents a suitable amino protecting group, for example tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy) carbonyl at first to give a compound of the formula (V) in which A, PG, R1 and the ring Q have the meanings given above, then the protecting group PG is cleaved and the resulting compound of the formula (VI) in which A, R1 and the ring Q have the meanings given above is then reacted, depending on the specific definition of the R3 radical, [B-1] with a carboxylic acid of the formula (VII) in which R3A represents (C4-C6)-cycloalkyl in which a ring CH2 group may be replaced by -O-, or represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e) or (f), as described in Claims 1 to 3, with activation of the carboxylic acid function in (VII), or is reacted with the corresponding acid chloride of the formula (VIII) in which R3A has the meaning given above to give a compound of the formula (I-B) in which A, R1, R3A and the ring Q have the meanings given above or [B-2] with a chloroformate or carbamoyl chloride of the formula (IX) in which R3B represents the -OR10 or -NR11AR12 group in which R10 and R12 have the definitions specified in Claims 1 to 3 and R11A has the definition of R11 specified in Claims 1 to 3, but is not hydrogen, to give a compound of the formula (I-C) in which A, R1, R3B and the ring Q have the meanings given above or [B-3] with an isocyanate of the formula (X)         R12-N=C=O     (X), in which R12 has the definition specified in Claims 1 to 3 to give a compound of the formula (I-D) in which A, R1, R12 and the ring Q have the meanings given above and the compounds of the formulae (I-A), (I-B), (I-C) and (I-D) thus obtained are optionally separated into their enantiomers and / or diastereomers and / or optionally converted with the appropriate (i) solvents and / or (ii) acids to the solvates, salts and / or solvates of the salts thereof.

10. Compound as defined in any of Claims 1 to 8 for treatment and / or prevention of diseases.

11. Compound as defined in any of Claims 1 to 8 for use in a method for the treatment and / or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders.

12. Use of a compound as defined in any of Claims 1 to 8 for preparing a medicament for the treatment and / or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders.

13. Medicament comprising a compound as defined in any of Claims 1 to 8 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

14. Medicament comprising a compound as defined in any of Claims 1 to 8 in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin re-uptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.

15. Medicament according to Claim 13 or 14 for treatment and / or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders.