EA039175B1 - Substituted diazahetero-bicyclic compounds, method for preparing same and use thereof - Google Patents

Abstract

The invention concerns a compound of general formula (I)wherein A, D, Q, R1, R2 have the meanings defined in claim 1, as well as physiologically acceptable salts thereof. Further, the invention concerns methods for preparing said compound, the use thereof in producing a drug for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders, a drug comprising said compound alone or in combinations for the treatment and/or prevention of the above mentioned diseases, as well as a method for the treatment and/or prevention of the above mentioned diseases in humans and animals using said compound or said drug.

Description

(57) The invention relates to a compound of general formula (I)

039175 B1

039175 Bl

R ² -U

Λ (I), in which A, D, Q, R ¹ R ² have the values specified in paragraph 1, as well as its physiologically acceptable salts. The invention further relates to processes for the preparation of said compound, its use in the manufacture of a medicament for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases, a medicament containing said compound alone or in combinations for the treatment and/or or prevention of the above diseases, as well as a method of treating and/or preventing the above diseases in humans and animals using the specified compound or the specified drug.

The present invention relates to new (imidazo[1,2-a]pyridin-3-yl)methyl-substituted diazaheterobicyclic compounds, a method for their preparation, their use in the manufacture of drugs for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases, a medicinal product containing these compounds alone or in combination for the treatment and / or prevention of the above diseases, as well as a method for the treatment and / or prevention of the above diseases in humans and animals using the active amount of these compounds or the specified drug.

Potassium channels are the most abundant membrane proteins involved in a wide variety of physiological processes. They also include regulation of membrane potential and electrical excitability of neurons and muscle cells. Potassium channels are divided into three large groups, which differ in the number of transmembrane domains (2, 4, or 6). A group of potassium channels in which two pore-forming domains of four transmembrane domains are flanked are called K2P channels. Functionally, K2P channels transmit K+ background fluxes well, regardless of time and voltage, and strongly contribute to the preservation of the membrane resting potential. The K2P channel family includes 15 members, which are divided into six subfamilies based on sequence, structure, and function similarity: TWIK, TREK, TASK, TALK, THIK, and TRESK.

Of particular interest are the TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 or K2P9.1) TASK (TWIK-related acid-sensitive K ⁺ channel) subfamilies. These channels are functionally different in that the so-called residual or background flows pass through them while maintaining voltage-independent kinetics, and they respond to a large number of physiological and pathological influences with an increase or decrease in activity. Characteristic of TASK signals is a sensitive response to changes in the extracellular pH value. Channels are inhibited at acidic pH and activated at alkaline pH.

TASK-1 is predominantly expressed in the central nervous system and in the cardiovascular system. Significant expression of TASK-1 can be found in the brain, spinal ganglia, motor neurons Nervus hypoglossus and Nervus trigeminus, heart, Glomus caroticum, pulmonary artery, aorta, lungs, pancreas, placenta, uterus, kidneys, adrenal glands, small intestine and stomach, as well as on T-lymphocytes. TASK-3 is mainly expressed in the central nervous system. Significant expression of TASK-3 can be found in the brain, in Nervus hypoglossus and Nervus trigeminus motor neurons and in Glomus caroticum and lung neuroepithelial cells, as well as on T-lymphocytes. Minor expression can be found in the heart, stomach, testicular tissue, and adrenal glands.

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 (the central respiratory group with the pre-Boetzinger complex), and in the noradrenal Locus caeruleus, as well as in the serotonergic neurons of the raphe nucleus. Due to pH independence, TASK channels take on the function of a sensor that translates intracellular changes in pH into appropriate cellular signals [Bayliss et al., Pflugers Arch. 467, 917-929 (2015)]. Also in Glomus caroticum, a peripheral chemoreceptor that detects the pH, O ₂ and CO ₂ content of the blood and sends signals to the respiratory center in the brainstem to regulate respiration, TASK1 and TASK-3 are expressed. TASK-1 knockout mice have been shown to exhibit a reduced ventilatory response (increased respiratory rate and inspiratory volume) to hypoxia and normoxic hypercapnia [Trapp et al., J. Neurosci. 28, 8844-8850 (2008)]. Further, TASK-1 and TASK-3 channels were found in the motor neurons of Nervus hypoglossus, in the XIIth cranial nerve, which has an important function to keep the upper airways open [Berg et al., J. Neurosci. 24, 6693-6702 (2004)].

In a model of sleep apnea in anesthetized pigs, intranasal administration of a potassium channel blocker, which blocks the TASK-1 channel in the nanomolar region, was performed to prevent contraction of the pharyngeal muscles of the respiratory tract and to sensitize the negative pressure reflex of the upper respiratory tract. It was assumed that the intranasal administration of a potassium channel blocker would depolarize the mechanoreceptors in the upper airways and, by activating the negative pressure reflex, would lead to increased activity of the muscles of the upper airways, which would stabilize the upper airways and prevent collapse. Through this stabilization of the upper airways, blockade of the TASK channel may be of great importance for obstructive sleep apnea and also for snoring [Wirth et al., Sleep 36, 699-708 (2013); Kiper et al., Pflugers Arch. 467, 1081-1090 (2015)].

Obstructive sleep apnea (OAC) is a breathing disorder during sleep that is characterized by recurring episodes of upper airway blockage. During inhalation, the patency of the upper respiratory tract is provided by the interaction of two opposing forces. The expansion effects of the musculature of the upper respiratory tract counteract the negative intraluminal

- 1 039175 pressure narrowing the lumen of the vessel. Active contraction of the diaphragm and other respiratory muscles creates a reduced pressure in the airways and is thus the driving force behind breathing. The stability of the upper airways is largely determined by the coordination and contraction properties of the dilating muscles of the upper airways.

Musculus genioglossus plays a crucial role in the pathogenesis of obstructive sleep apnea. The activity of Musculus genioglossus increases with a decrease in pressure in the pharynx as a dilating compensatory mechanism. Innervated by Nervus hypoglossus, it moves the tongue forward and downward and thus widens the pharyngeal airways [Verse et al., Somnologie 3, 14-20 (1999)]. Tension of the dilating muscles of the upper airways is also modulated by mechano/stretch receptors in the nasopharynx [Bouillette et al., J. Appl. physiol. Respir. Environ. Exerc. physiol. 46, 772-779 (1979)]. During local anesthesia of the upper respiratory tract in patients with severe sleep apnea, an additional decrease in Musculus genioglossus activity during sleep can be observed [Berry et al., Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]. Patients with obstructive sleep apnea have a high risk of mortality and morbidity due to diseases of the cardiovascular system, such as high blood pressure, myocardial infarction and apoplexy [Vrints et al., Ada Clin. Belg. 68, 169-178 (2013)].

With central sleep apnea, episodic delay in respiratory impulses occurs due to impaired brain function or dysregulation of the respiratory tract. Centrally conditioned respiratory disorders lead to mechanical stops of breathing, i.e. during these episodes there is no respiratory activity, all respiratory muscles, including the diaphragm, temporarily stop. Central sleep apnea does not block the upper airways.

During primary snoring, blockage of the upper respiratory tract also does not occur. However, when the airways narrow, the flow rate of inhaled and exhaled air increases. Together with relaxed muscles, this causes fluttering of the soft tissues of the oral cavity and pharynx in the air stream. And this slight vibration creates snoring.

Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by recurring partial blockage of the upper airways during sleep. This leads to an increase in airway resistance and thus to increased respiratory work with significant intrathoracic pressure fluctuations. In this case, the negative intrathoracic pressure development during inspiration can reach the same values as with complete airway obstruction in obstructive sleep apnea. The pathophysiological effects on the heart, circulation, and sleep quality are consistent with those in obstructive sleep apnea. During inspiration, pathogenesis occurs, as in obstructive sleep apnea with a disturbed mechanism of the reflex of the muscles dilating the pharynx during sleep. Obstructive snoring is often the initial stage for obstructive sleep apnea [Hollandt et al., HNO 48, 628-634 (2000)].

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

It is further described that T-lymphocytes express the TASK-1 and TASK-3 channels and blocking of these channels leads to a decrease in cytokine production and proliferation after stimulation of T-lymphocytes. Selective blocking of TASK channels on T-cells improved the course of the disease in an experimental model of multiple sclerosis. Therefore, blockade of TASK channels is also of value in the treatment of autoimmune diseases [Meuth et al., J. Biol. Chem. 283, 14559-14579 (2008)].

TASK-1 and TASK-3 are also expressed in the heart [Rinne et al., J. Mol. cell. cardiol. 81, 71-80 (2015)]. Since TASK-1 is particularly strongly expressed in the conduction system of the heart and in the atrium, this channel could have an impact on impulse conduction disorder or supraventricular arrhythmia. In the heart, TASK-1 promotes background flow, which in turn promotes resting potential, action potential duration, and repolarization [Kim et al., Am. J Physiol. 277, H1669-1678 (1999)]. It has been shown in human myocardial cells that blockade of the TASK-1 ion flux leads to an increase in the action potential [Limberg et al., Cell. physiol. Biochem. 28, 613-624 (2011)]. Also, TASK-1 knockout mice showed an increase in the QT period [Decher et al., Cell. physiol. Biochem. 28, 77-86 (2011)]. Thus, blocking TASK channels could be of great value in the treatment of cardiac arrhythmias, especially atrial fibrillation.

TASK channels also play a role in certain vessels in the regulation of vascular tone. Important expression of TASK-1 can also occur in the smooth muscle of the pulmonary and mesenteric arteries. Studies of human pulmonary artery smooth muscle have shown that TASK-1 plays a role in the regulation of pulmonary vascular tone. TASK-1 may be involved in hypoxic and azido-induced pulmonary vasoconstriction [Tang et al., Am. J. Respir. cell. Mol. Biol. 41, 476-483 (2009)].

In adrenal glomerular cells, TASK-1 promotes potassium conduction [Czirjak et al.,

- 2 039175

Mol. Endocrinol. 14, 863-874 (2000)].

TASK channels may also be important for apoptosis and tumorigenesis. TASK-3 has been found to be highly overexpressed in biopsies of breast, colon, and lung cancer cells, 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 on the TASK-3 channel, which turns on the action of the channel, simultaneously has an antitumor effect (prevents proliferation, tumor growth, resistance to apoptosis) [Mu et al., Cancer Cell 3, 297-302 (2003)]. Overexpression of TASK-3 and TASK-1 in a rat fibroblast cell line (C8 cells) prevents intracellular apoptosis [Liu et al., Brain Res. 1031, 164-173 (2005)]. Therefore, blockade of TASK channels is also important for the treatment of various cancers.

Thus, it is an object of the present invention to provide novel substances that act as potent and selective blockers of the TASK-1 and TASK-3 channels and are particularly suitable for the treatment and/or prevention of respiratory disorders, including sleep-related respiratory disorders such as obstructive sleep apnea. and central sleep apnea, as well as other diseases.

US 2002/0022624 A1 describes various azaindole derivatives, among them also imidazo[1,2a]π pyridines as substance P antagonists for the treatment of diseases of the central nervous system. WO 02/066478 A1 describes substituted imidazo[1,2-a]pyridines as GnRH agonists for the treatment of hormone-dependent diseases of the reproductive system. From WO 2004/035578 A1, 3-(aminomethyl)imidazo[1,2-a]piridine derivatives are known as NO synthase blockers, which can be used to treat various diseases. WO 02/02557 A2 and WO 2009/143156 A2 present 2-phenylimidazo[1,2-a]n-pyridine derivatives which are suitable as GABAA receptor modulators also for the treatment of CNS diseases. WO 2011/113606 A1 and WO 2012/14 796 A2 describe bicyclic imidazole derivatives which are suitable for the treatment of bacterial infections or inflammatory diseases. From EP 2671582 A1 bicyclic imidazole derivatives and their therapeutic applications as T-type potassium channel inhibitors are known. WO 2012/130322 A1 describes 2,6-diaryl-3-(piperazinomethyl)imidazo[1,2-a]piridine derivatives which, due to their HIF-1 inhibitory activity, are particularly suitable for the treatment of inflammatory and hyperproliferative diseases. WO 2014/187922 A1 describes various 2-phenyl3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives as glucose transporter (GLUT) inhibitors that can be used to treat inflammatory, proliferative, metabolic, neurological and/or autoimmune diseases. WO 2015/144605 A1 describes acylated bicyclic amine compounds that are suitable as inhibitors of autotaxin and lysophosphatidic acid products for the treatment of various diseases. WO 2016/084866 A1 and WO 2016/088813 A1 disclose acylated diazabicyclic compounds which can be used due to their orexin receptor antagonistic action in the treatment of neurodegenerative diseases, mental disorders, eating disorders and sleep disorders, especially insomnia.

The subject of the present invention is a compound of general formula (I)

in which the ring Q stands for the diazaheterobicycle of the formula

where * denotes a bond with an adjacent methylene group, ** denotes a bond with a carbonyl group,

A and D are respectively CH, or one of these ring members is CH and the other is N,

R ¹ means chlorine, bromine, isopropyl or cyclopropyl,

R ² means cyclobutyl, cyclopentyl or cyclohexyl, or

R ² means a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d)

- 3 039175

where *** denotes a bond with an adjacent carbonyl group,

R ³ means hydrogen, fluorine or chlorine,

R ⁴ means fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,

R ⁵ means hydrogen, fluorine, chlorine, bromine or methyl,

R ⁶ is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy or cyclobutyloxy,

R ^8A and R ^8b are in each case hydrogen, and

Y means N(CH ₃ ), as well as its physiologically acceptable salts.

Compounds according to the invention are compounds of formula (I) and their salts containing formula (I) compounds of formula (I-A) and their salts, as well as containing formula (I) named in the following as exemplary compounds and their salts, as far as named in the following containing formula (I) compounds are no longer salts.

As salts within the scope of the present invention, physiologically unquestionable salts according to the invention are preferred. Also salts, which are not themselves suitable for pharmaceutical use, but they can be used, for example, to isolate, purify or store the compounds according to the invention.

The physiologically undoubted salts according to the invention contain added salts of mineral acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, fumaric acids. , maleic, lactic, tartaric, malic, citric, glyconic, benzoic and embonic acids.

The compounds according to the invention, depending on their structure, can exist in various stereoisomeric forms, i.e. in the form of configurational isomers or, if necessary, also in the form of conformational isomers (enantiomers and/or diastereoisomers, including atropical isomers). Therefore, this invention contains enantiomers and diastereoisomers and mixtures thereof. From such mixtures of enantiomers and/or diastereoisomers stereoisomerically single constituents are isolated in a known manner; preferably, chromatographic methods are used here, especially high performance liquid chromatography of an achiral or chiral separation phase. In the case of using chiral amines as an intermediate or final product, it is also alternatively possible to carry out the resolution via the diastereometric salt with enantiomerically pure carboxylic acids.

Since the compounds of the invention may occur in tautomeric forms, this invention includes all tautomeric forms.

This invention also contains all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is here understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom with the same atomic number, but with a different atomic mass with the usual or naturally occurring predominant atomic mass. Examples of isotopes that can be included in the compound according to the invention are 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 the compound according to the invention, such as in particular those in which one or more radioactive isotopes are attached, may be useful, for example, for studying the mechanism of action or distribution of the biologically active substance in the body; because of the relatively easy preparation and detection, compounds marked with ³ H or ¹⁴ C isotopes are suitable for this. On this basis, the introduction of isotopes, such as deuterium, can lead to certain therapeutic advantages due to the greater metabolic stability of the compound, such as an increase in the half-life in the body or a reduction in the required effective dose; therefore, such modifications of the compounds according to the invention, if necessary, may also represent a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can also be obtained by conventional methods known to the person skilled in the art, for example, the methods described below and further demonstrated in the described exemplary embodiments, while using the appropriate isotopic modifications of the reagents and/or starting compounds.

- 4 039175

In addition, this invention may also contain prodrugs of the compounds according to the invention. The term "prodrug" here refers to compounds which themselves may be biologically active or inactive, but which, during their exposure in the body, for example, are converted metabolically or hydrolytically into the compounds according to the invention.

Within the scope of the present invention, substituents and residues, unless otherwise indicated, have the following meanings: (C ₄ -C ₆ )-cycloalkyl means within the scope of the invention a monocyclic, saturated cycloalkyl group with 4 to 6 ring carbon atoms. For example, cyclobutyl, cyclopentyl and cyclohexyl should be mentioned.

Halogen within the scope of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.

Within the scope of the present invention, it is valid for all residues that occur several times, the value of which is independent of each other. If residues in the compounds according to the invention are substituted, they may, unless otherwise indicated, be singly or multiply substituted. Substitution with one, or two, or three identical or different substituents is preferred. Particular preference is given to substitution with one substituent.

One preferred embodiment of the present invention relates to a compound of formula (I) wherein ring Q is a diazaheterobicycle of formula

wherein * denotes a bond to an adjacent methylene group, and ** denotes a bond to a carbonyl group as well as its physiologically acceptable salts.

Another particular embodiment of the present invention relates to a compound of formula (I) in which ring Q is a diazaheterobicycle of formula

wherein * denotes a bond to an adjacent methylene group, and ** denotes a bond to a carbonyl group as well as its physiologically acceptable salts.

Yet another particular embodiment of the present invention relates to a compound of formula (I) wherein ring Q is a diazaheterobicycle of formula ♦ G—N ^Z

O--^ -** where * denotes a bond with an adjacent methylene group, and ** denotes a bond with a carbonyl group, as well as its physiologically acceptable salts.

Another particular embodiment of the present invention relates to a compound of formula (I) in which A and D respectively represent CH, as well as physiologically acceptable salts thereof.

Another particular embodiment of the present invention relates to a compound of formula (I) in which A is N and D is CH, as well as physiologically acceptable salts thereof.

Another particular embodiment of the present invention concerns a compound of formula (I) in which R ¹ is chlorine, bromine or isopropyl, as well as physiologically acceptable salts thereof.

Another particular embodiment of the present invention concerns a compound of formula (I) in which R ² is cyclobutyl, cyclopentyl or cyclohexyl, as well as physiologically acceptable salts thereof.

Another particularly preferred embodiment of the present invention includes a compound of formula (I) wherein ring Q is a diazaheterobicycle of formula

where * denotes a bond with an adjacent methylene group, and

- 5 039175 ** denote a bond with a carbonyl group,

A stands for CH or N,

D stands for CH

R ¹ means chlorine, bromine, isopropyl or cyclopropyl,

R ² means cyclobutyl, cyclopentyl or cyclohexyl, or

R ² is a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d)(d) where *** denotes a bond to an adjacent carbonyl group, and

R ³ means hydrogen, fluorine or chlorine,

R ⁴ means fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,

R ⁵ means hydrogen, fluorine, chlorine, bromine or methyl,

R ⁶ is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy or cyclobutyloxy,

R ^8A and R ^8b are respectively hydrogen, and

Y means N(CH ₃ ), as well as its physiologically acceptable salts.

The residue definitions specified in these or preferred combinations of residues individually apply independently of the residue combinations mentioned, also arbitrarily with the aid of the residue definitions of other combinations. Very preferred are combinations of two or more of the above preferred areas.

Another object of the invention is a method for the preparation according to the invention of a compound of formula (I), characterized in that the compound of formula (II) in which A, D and R ¹ have the above meanings, in the presence of a reducing agent selected from an alkali metal borohydride, is reacted with a compound of the formula (III) (III) wherein R ² and ring Q are as defined above, in the presence of a solvent selected from the group consisting of alcohols, ethers, polar aprotic solvents, or mixtures thereof.

Another subject of the invention is a process for the preparation of a compound of formula (IA) wherein A, D, R ¹ and Q are as defined above, and

R ^2A means (C ₄ -C ₆ )-cycloalkyl or means a phenyl group of formula (a), a pyridinyl group of formula (b) or an azole group of formula (d), as described above, characterized in that the compound of formula (II)

- 6 039175 in which A, D and R ¹ have the above meanings, in the presence of a reducing agent selected from an alkali metal borohydride, is subjected to interaction with a protected diazaheterobicycle of formula (IV)

in which ring Q has the above meaning, and

PG is a protecting amino group selected from tert-butoxycarbonyl, benzyloxycarbonyl, or (9H-fluoren-9-ylmethoxy)carbonyl in the presence of a solvent selected from the group consisting of alcohols, ethers, polar aprotic solvents, or mixtures thereof, to give a compound of formula ( v)

in which A, D, PG, R ¹ and ring Q have the above meanings, then the protecting group PG is separated and the resulting compound of formula (VI)

in which A, D, R ¹ and ring Q have the above meanings, then subjected to interaction with the compound of formula (VII)

R ² * OH (VII), in which R ^2A has the above meaning, by activating the carboxylic acid function in (VII) or using the corresponding acid chloride of the formula (VIII)

O

Cl (VIII), in which R ^2A has the above meaning.

The compounds of formula (I) or (I-A) thus obtained are, in a preferred embodiment of the above process, separated into their enantiomers and/or diastereoisomers and/or with appropriate (i) solvents and/or (ii) acids converted into their physiologically acceptable salts.

Alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride are suitable as reducing agents for process steps (II) + (III) ^ (I) and (II) + (IV) ^ (V) [reductive amination]. ; preferably sodium triacetoxyborohydride is used. The addition of an acid, in particular acetic acid, and/or a dehydrating agent, such as, for example, a molecular sieve or trimethyl or triethyl orthoformate, is preferred during these reactions.

Alcohols such as methanol,

- 7 039175 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 Ν,Ν-dimethylformamide ( DMF) or mixtures of these solvents; preferably tetrahydrofuran is used. The reactions are generally carried out at temperatures from 0 to +50°C.

As the protecting group PG in the compound (IV), a conventional amine protecting group such as, for example, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or (9H-fluoren-9ylmethoxy)carbonyl (Fmoc) can be used; preferably tert-butoxycarbonyl (Boc) is used. The separation of the protective group at the stage of the technological stage [B] (V) ^ (VI) is carried out by conventional methods. Thus, the tert-butoxycarbonyl group is usually separated 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. If the protecting group is benzyloxycarbonyl, it is preferably removed by destructive hydrogenation in the presence of a suitable palladium catalyst, such as palladium on activated carbon. The (9Hfluoren-9-ylmethoxy)carbonyl group is generally removed with a secondary amine base such as diethylamine or piperidine [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wylie, New York, 1999 ; PJ ^Kocienski , Protecting Groups, 3rd ed., Thieme, 2005].

Certain compounds of formula (V), in particular those in which PG is t-butoxycarbonyl, also show significant inhibitory activity against TASK1 and/or TASK-3.

The stage of the technological stage (VI) + (VII) ^ (I-A) [amide formation] is carried out according to known methods using a condensing agent or an activator. Suitable agents are, 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 Ν,N'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 -sulfate or 2-tert-butyl-5methylisoxazolium perchlorate, acylamines, such as 2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline, α-chlorenamines, such as 1-chloro-N,N,2-trimethylprop-1-en- 1-amine, 1,3,5triazine derivatives as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, phosphorus compounds as n-propanephosphonic acid anhydride (PPA) , cyanophosphonic acid diethyl ester, diphenylphosphoryl azide (DPPA), bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate ( RuVOP), or uronic compounds like O-( benzotriazol-1-yl)-N,N,N',N'tetramethyluronium tetrafluoroborate (TBTU), O-(1 H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU) , O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or 2-(2oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), if necessary in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or Nhydroxysuccinimide (HOSu), also as a base to an alkali metal carbonate such as sodium or potassium carbonate, or a tertiary amine base such as triethylamine, N,Ndiisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP) , pyridine, or 4-N,Ndimethylaminopyridine (DMAP). Preferably, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is used as the condensation agent or activator in combination with N,N-diisopropylethylamine as base.

An alternative method with carboxylic acid chloride (VIII) [(VI) + (VIII) ^ (I-A)] is usually carried out in the presence of a base, such as sodium carbonate, potassium carbonate, triethylamine, N,Ndiisopropylethylamine, N-methylmorpholine (NMM) , N-methylpiperidine (NMP), pyridine, 2,6dimethylpyridine, 4-N,N-dimethylaminopyridine (DMAP), 1,5-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,8-diazabicyclo[ 4.3.0] non-5-ene (DBN); preferably triethylamine or N,Ndiisopropylethylamine is used.

Suitable inert solvents for these amide-forming reactions are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether , hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile , pyridine, dimethyl sulfoxide (DMSO), Ν,N-dimethylformamide (DMF), Ν,N'-dimethylpropyleneurea (DMPU) or Nmethylpyrrolidinone (NMP); mixtures of these solvents can also be used. Preferably, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide or mixtures thereof are used. The transformations are usually carried out at temperatures of (-20) - (+60)°C, preferably 0 - +40°C.

The amine compound (VI) can be used in process steps (VI) + (VII) or (VIII) ^ (I-A), also in the form of a salt, for example in the form of hydrochloride or triforacetate. In this case, the transformation is carried out in the presence of an increased amount of auxiliary base used.

The previously described method can be carried out at normal, elevated or reduced pressure (for example, in the range of 0.5-5 bar); usually operate at normal pressure.

The separation of the compounds according to the invention into the corresponding enantiomers and/or diastereoisomers can, if necessary, also take place already in the step of the individual compounds (III), (IV), (V) or (VI), depending on the purpose, and these compounds in separated form can then be converted further according to the previously described process steps. This separation of stereoisomers can be carried out by conventional methods known to those skilled in the art. Within the scope of the present invention, the chromatographic method of chiral or achiral separable phases is preferably used; in the case of achiral amines, as intermediates or final products, it is also possible, alternatively, to carry out separation via diastereomeric salts with enantiomeric carboxylic acids.

The compounds of formula (II) for their part can be obtained in a manner known in the literature, by condensing 2-aminopyridine (XI)

C.NH ₂ G ^N (XI) is converted with a base with a compound of formula (XII)

VhTVr ¹

X—' A=D (XII), in which A, D and R ¹ have the above meanings, and

X is a suitable volatile group, such as chlorine, bromine or iodine, is condensed into an imidazo[1,2-a]pyridine derivative of formula (XIII)

in which A, D and R ¹ have the above meanings, and then this composition, together with a mixture of N,N-dimethylformamide and phosphorus oxychloride, is converted into (II).

The condensation reaction (XI) + (XII) ^ (XIII) is usually carried out in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol, in an ether such as diethyl, diisopropyl, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2methoxyethyl) ether, in a dipolar aprotic solvent, such as N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP), or also in water at temperatures of 50-150°C; preferably ethanol or water is used as the solvent.

Suitable bases for these reactions are especially alkali metal hydrogen carbonates or carbonates, such as sodium or potassium hydrogen carbonates, or lithium, sodium, potassium or cesium carbonates, alkali metal hydroxides, such as sodium or potassium hydroxide, or also aluminum oxide; preferably sodium bicarbonate or sodium hydrochloride is used. If necessary, the substitution can be carried out with a corresponding increase in the reaction temperature, also without the addition of a base.

Regioselective formylation (XIII) ^ (II) is carried out under normal Vilsmeier-Haack reaction conditions by treating (XIII) with a pre-prepared mixture of N,N-dimethylformamide and phosphorus oxychloride, which is used in excess and which simultaneously also serves as a solvent. The transformation is carried out, in General, at temperatures of 0-100°C.

Compounds of formulas (III), (IV), (VII), (VIII), (IX), (X), (XI) and (XII) are commercially available or can be prepared according to methods described in the literature, or they can be obtained from other commercially available compounds by conventional methods known to the specialist and described in the literature. Numerous detailed prescriptions and other bibliographic references are also found in the experimental part in the section on preparation of starting and intermediate compounds.

The preparation of the compounds according to the invention can be exemplified using the following reaction schemes.

- 9 039175

Scheme 1

Scheme 2

- 10 039175

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of various diseases in humans and animals.

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

These in the meaning of the present invention, in particular, include diseases from the group of respiratory disorders and respiratory disorders during sleep, such as obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome), central sleep apnea, mixed sleep apnea, Cheyne-Stokes respiration, primary sleep apnea in childhood, sleep apnea of premature babies, central sleep apnea due to medication or other substances, obesity-hypoventilation syndrome, dysfunction of the central respiratory impulse, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, sleep disturbance due to decreased muscle tone, respiratory failure after prolonged lung ventilation, respiratory failure during adaptation in high mountain areas, acute and chronic lung diseases with hypoxia and hypercapnia, non-obstructive alveolar sleep hypoventilation and congenital central alveolar hypoventilation syndrome.

Further, the compounds according to the invention are used in the treatment and/or prevention of neurodegenerative diseases, such as, for example, dementia, dementia with Lewy bodies, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear paresis, corticobasal degeneration, tauopathy, frontal - temporal dementia and parkinsonism associated with a disorder in chromosome 17, multisystem atrophy, spinocerebellar ataxia, spinobulbar muscular atrophy of the Kennedy type, Friedreich's ataxia, dento-rubro-pallido-Lewis atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscle atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with iron deposition in the brain, degeneration of the anterior temporal lobe of the brain with the ubiquitin-proteasome system, and familial encephalopathy with neuroserpin inclusions.

In addition, the compounds according to the invention can be used for the treatment and/or prevention of neuroinflammatory and neuroimmunological diseases of the central nervous system (CNS), such as multiple sclerosis (Encephalomyelitis disseminata), transverse myelitis, neuromyelitis of the optic nerve, acute disseminated encephalomyelitis, optic neuritis , meningitis, encephalitis, demyelinating diseases, and inflammatory diseases of the vessels of the central nervous system.

The compounds of the invention can also be used in the treatment and/or prevention of cancers such as, for example, skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

In addition, the compounds according to the invention are suitable for the treatment and/or prevention of cardiac arrhythmias and arrhythmias, such as, for example, atrial and ventricular arrhythmias, impulse conduction disorders, such as atrioventricular block I-III degree, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter , ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, pirouette tachycardia, atrial and ventricular extrasystoles, extrasystoles from the atrioventricular junction, sick sinus syndrome, syncope and atrioventricular nodal reciprocal tachycardia.

Other cardiovascular diseases for the treatment and/or prevention of which the compounds of the invention are used are, for example, heart failure, vascular disease of the heart, stable and unstable angina, high blood pressure (hypertension), pulmonary arterial hypertension (PAH) and others. forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardiac angiopathy, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysm, shock , cardiogenic shock, septic and anaphylactic shock, further thromboembolic diseases and ischemias such as myocardial ischemia, myocardial infarction, apoplexy, cardiac hypertrophy, transistor ischemic attack, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary and peripheral arteries, the formation of edema, such as e.g. pulmonary edema, from cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, repercussion damage, arterial and venous thrombosis, microalbuminuria, cardiac weakness, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as to prevent restenosis, for example, after treatment of thrombosis, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and coronary bypass surgery.

In the meaning of the present invention, the concept of heart failure includes both acute and chronic manifestations of heart failure, as well as specific or related forms of diseases, such as acute decompensated heart failure, right ventricular failure of the heart, left ventricular failure, complete heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease, valvular heart disease, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined mitral heart disease, myocarditis (inflammation of the myocardium), chronic myocarditis, acute myocarditis, viral myocarditis, heart failure with diabetes diabetes, toxic alcoholic cardiomyopathy, storage diseases, diastolic and systolic heart failure.

The compounds according to the invention can also be used for the treatment and/or prevention of asthmatic diseases of varying severity with intermittent or persistent course (refractive asthma, bronchial asthma, allergic asthma, internal asthma, external asthma, asthma caused by drugs or dust), 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), inflammation of the nasal mucosa (including drug-induced, vasomotor and seasonal, allergic rhinitis, such as hay runny nose) and polyps.

The compounds according to the invention are also suitable for the treatment and/or prevention of kidney diseases, especially kidney failure. In the meaning of the present invention, the concepts of renal failure cover both acute and chronic manifestations of renal failure, as well as their underlying or related diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathy such as primary and congenital kidney diseases, nephritis, immunological kidney diseases, such as kidney transplant rejection and immune complex-induced kidney diseases, nephropathy caused by the action of poisonous substances, nephropathy caused by the use of contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, kidney cyst, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, which can be diagnostically characterized, for example, by abnormally low creatinine and/or water excretion, abnormally high blood levels of urea, nitrogen, potassium and/or creatinine, altered activity of enzymes in the kidneys, such as glutamine synthetase, altered molarity or amount of urine, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and/or the need for dialysis. This invention also includes the use of the compounds according to the invention for the treatment and/or prevention of the consequences of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (eg, hyperkalemia, hyponatremia), impaired bone metabolism and impaired carbohydrate metabolism.

In addition, the compounds according to the invention are suitable for the treatment and/or prevention of diseases of the genitourinary system, such as benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPH), bladder procreation disorder, lower urinary tract syndrome (LUTS), neurogenic overactive bladder (NAB), incontinence such as mixed, urge incontinence, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction in men and sexual dysfunction in women.

Further, the compounds according to the invention are suitable for the treatment and/or prophylaxis of inflammatory and autoimmune diseases, such as rheumatoid diseases, inflammatory eye diseases, acute chronic lung diseases (COPD), acute respiratory distress syndrome (ARDS), acute lung injury syndrome (ALD). , α-1-antitrypsin deficiency (AATD), emphysema (eg, smoking-induced emphysema), cystic fibrosis (CF), sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory lung disease, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, inflammation of the bladder, urethritis, prostatitis, epidymitis, oophoritis, salpingitis and vulvovaginitis, as well as for the treatment and / or prevention of fibrotic diseases of internal organs, such as lungs, heart , kidney, bone marrow and especially liver, dermatological fibrosis and fibrotic eye diseases. The term fibrotic diseases specifically includes such terms as hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic lesions due to diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic diseases, sclero- 12 039175 roderma, localized scleroderma, keloids, hypertrophic scarring, nevus, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue diseases (eg, sarcoidosis). The compounds of the invention are also suitable for promoting wound healing, for combating postoperative wound healing, for example after glaucoma surgery, and for cosmetic purposes after removal of aging and keratinized skin.

In addition, the compounds according to the invention can be used for the treatment and/or prevention of arteriosclerosis, lipid disorders and dyslipidemia (hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity, obesity, metabolic diseases ( metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic consequences of retinopathy, nephropathy and neuropathy), anemia, such as hemolytic anemia, especially hemoglobinopathies, such as drepanocytosis and thalassemia, megaloblastic anemia, anemia caused by iron deficiency, anemia caused by acute blood loss, replacement and aplastic anemia, diseases of the gastrointestinal tract and abdominal cavity (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, itching of the anus, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis and cholecystitis), diseases of the central nervous system (apoplexy, epilepsy, depression), immune diseases, thyroid diseases ( hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, keratitis, epidermolysis bullosa, vasculitis, cellulitis, panniculitis, systemic lupus erythematosus, erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian syndrome, scarring , formation of warts, frostbite), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, choroiditis uveitis, ophthalmitis), viral diseases (caused by group viruses, adeno- and coviruses, such as HPV, HCMV, HIV, SARS), diseases of the bones of the skeleton, joints and skeletal muscles, inflammatory changes in the arteries (various forms of arteritis, such as endarteritis, mesarteritis, periarteritis eryitis, panarteritis, rheumatoid arteritis, arteritis deformans, temporal arteritis, temporal arteritis, giant cell arteritis and granulomatous arteritis, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), Muckle-Wells syndrome, Kikuchi disease, polychondritis, scleroderma, and also other diseases with inflammatory and immunological components, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Cesari syndrome and tumor syndrome, in rejection reactions after organ transplantation and for wound healing and angiogenesis, especially in chronic wounds.

Due to their properties, the compounds according to the invention are preferably suitable for the treatment and/or prevention of respiratory disorders, especially sleep disorders such as obstructive and central sleep apnea, as well as primary and obstructive snoring, for the treatment and/or prevention of cardiac arrhythmias and arrhythmias, as well as for the treatment and/or prevention of neurodegenerative, neuroinflammatory and neuroimmunological diseases.

Previously named, well-described human diseases of comparable etiology may also occur in other mammals and may also be treated with the compounds of the present invention.

In the present invention, the term "treatment" or "treatment" includes curbing, slowing down, delaying, alleviating, attenuating, reducing, reducing, arresting, suppressing or curing a disease, ailment, disease, injury or disorder related to health, development, course or the progression of such a condition and/or the symptoms of such a condition. The concept of therapy is synonymous with the concept of treatment.

The terms prevention or prophylaxis within the scope of the present invention may be used interchangeably and refer to the prevention or reduction of the risk of acquiring, getting, experiencing or having a disease, disease, illness, injury or health-related disorder, development, course or progression of such a condition and/or symptoms. such a state.

The treatment or prevention of a disease, ailment, illness, injury or health-related disorder may be total or partial.

Thus, another object of the present invention is the use of a compound according to the invention for the manufacture of a medicament, for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases.

In a preferred embodiment, the invention relates to the above use of a compound of the invention for the manufacture of a medicament, wherein the respiratory disorders are sleep disorders selected from obstructive sleep apnea syndrome, central sleep apnea syndrome and snoring.

Another object of the present invention is a medicament containing a compound according to the invention in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients for the treatment and/or prevention of cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases. .

In a preferred embodiment, the invention relates to the above drug, where the breathing disorders are breathing disorders during sleep, selected from obstructive sleep apnea syndrome, central sleep apnea syndrome and snoring.

Another object of the present invention is a medicament containing a compound according to the invention, in combination with one or more additional biologically active substances selected from the group consisting of respiratory stimulants, psychostimulant compounds, sGC serotonin recovery stimulants, noradrenergic, serotonergic and tricyclic antidepressants, stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents and cytotoxic agents for the treatment and/or prevention of cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases.

In a preferred embodiment, the invention relates to the above drug, where the breathing disorders are breathing disorders during sleep, selected from obstructive sleep apnea syndrome, central sleep apnea syndrome and snoring.

Another object of the present invention is a method for the treatment and/or prevention of cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases in humans and animals by using an active amount of at least one compound according to the invention or the above drugs.

In a preferred embodiment, the invention relates to the above method for the treatment and/or prevention of the above diseases, where the respiratory disorders are respiratory disorders during sleep, selected from obstructive sleep apnea syndrome, central sleep apnea syndrome and snoring.

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 these combinations do not lead to undesirable and unacceptable side effects. As possible combinations of biologically active substances, for example, respiratory stimulants, such as, for example and preferably, theophylline, doxapram, nikethamide or caffeine;

psychoactive 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 and norepinephrine reuptake inhibitors, such as, for example and preferably, fenlafaxine or duloxetine;

noradrenergic and specific serotonergic antidepressants, such as, for example and preferably, mirtazapine;

selective noradrenaline reuptake inhibitors, such as, and preferably, reboxetine;

tricyclic antidepressants such as, for example and preferably, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine;

α2-adrenergic agonists, such as, for example and preferably, clonidine;

GABA-B receptor agonists, such as, for example and preferably, baclofen α-sympathomimetics, such as, for example and preferably, xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrizoline or tramazolin;

glucocorticoids such as, for example and preferably, fluticasone, budesonide, beclomethasone, mometasone, thixocortol or triamcinolone;

cannabinoid receptor agonists;

carbonic anhydrase inhibitors, such as, for example and preferably, acetazolamide, methazolamide or diclofenamide;

opioid and benzodiazepine receptor agonists such as, for example and preferably, flumazenil, naloxone or naltrexone;

quinolinesterase inhibitors such as, for example and preferably, neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine;

- 14 039175 N-methyl-D-aspartate and glutamate antagonists, such as, for example and preferably, amantadine, memantine or sabeluzole;

nicotinic 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 prevent the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5 inhibitors, 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), as in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 compounds ;

NO-independent as well as heme-independent activators of soluble guanylate cyclase (sGC), such as especially riociguat, vericiguat, as well as those 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 compounds;

prostacyclin analogs and IP receptor agonists, such as, for example and preferably, iloprost, beraprost, treprostinil, epoprostenol or selexipag;

endothelin receptor antagonists such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan;

compounds which inhibit human neurophilic elastase (HNE), such as, for example and preferably, sivelestat or DX-890 (reltran);

compounds which inhibit the breakdown and remodeling of the extracellular matrix, for example and preferably matrix metalloprotease (MMP) inhibitors, especially inhibitors of stromelysin, collagenase, gelatinase and agrecanase (primarily mmP-1, mmP-3, mmP-8, mmP-9, mmP -10, mmP-11 and mmP-13), as well as metal elastase (MMP-12);

compounds which block the binding of serotonin to its receptors, for example and preferably 5-HT2 _B receptor antagonists, such as PRX-08066;

antagonists of growth factors, cytokines and chemokines, for example and preferably, antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

Rho kinase inhibitory compounds such as, for example and preferably, fasudil, Y-27632, SLx2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

compounds affecting the energy metabolism of the heart, such as, for example and preferably, etomoxir, dichloroacetate, ranolazine or trimetazidine;

compounds inhibiting the signal transduction cascade, for example and preferably from the group of kinase inhibitors, especially from the group of tyrosine kinase and/or serine/threonine kinase inhibitors, such as, for example and preferably, 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 which are used, for example, in the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably from the group of inhaled or systemically used β-adrenergic receptor agonists (β-mimetics) and inhaled antimuscarinic substances;

anti-inflammatory, immunomodulatory, 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, immunoglobulin, acetylcysteine, montelukast, tripelukast, azathioprine , cyclophosphamide, hydroxyurea, azithromycin, interferon-γ, pirfenidone, or etanercept;

antithrombotic agents such as, for example and preferably, lysophosphatidic acid (LPA-1) receptor antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists or pirfenidone;

antithrombotic agents, for example and preferably from the group of blockers of platelet aggregation, anticoagulants and profibrinolytic substances;

- 15 039175 biologically active substances that lower blood pressure, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE blockers, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, and also diuretics; and / or biologically active substances that affect fat metabolism, for example and preferably from the group of thyroid receptor antagonists, inhibitors of cholesterol synthesis, such as, for example and preferably, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase or squalene synthase, inhibitors acyl-CoA cholesterol acyltransferase, cholesteryl ester transfer inhibitors, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated α-, γ-, and/or δ-receptor antagonists, cholesterol uptake blockers, lipase inhibitors, polymeric bile acid adsorbers, blockers bile acid reabsorption and lipoprotein(s) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, for example and preferably, spironolactone, eplerenone or finerenon.

Particularly preferred are combinations of the compounds according to the invention with one or more additional biologically active substances selected from the group consisting of respiratory stimulants, psychostimulant compounds, serotonin recovery stimulants, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulating agents , immunosuppressive agents and cytotoxic agents.

The substances according to the invention, if necessary, can also be used together with the use of one or more medico-technical devices or aids, if this does not lead to undesirable and unacceptable effects. For such combined use, medical devices and aids are taken into account, such as, for example and preferably, devices for hyperbaric oxygenation of the respiratory system, such as, for example and preferably, CPAP (continuous positive airway pressure) devices, BiPAP ( bilevel positive airway pressure devices and IPPV devices;

neurostimulators Nervus hypoglossus;

excipients for intraoral administration, such as, for example and preferably, protrusion clamps;

nasal one-way valves; nasal stents.

The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered by any suitable route, such as, for example, oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, eye drops. , ear canal or as an implant or stent.

For these applications, the compounds according to the invention are administered in a suitable application form.

For oral administration according to the prior art, fast-acting and/or modified compounds are suitable in administration forms which contain the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (coated or uncoated tablets, e.g. resistant to the action of gastric juice or slowly soluble or insoluble shells that control the release of the compound according to the invention), rapidly dissolving tablets or films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, substance in granules, granules, powder, emulsions, suspensions, aerosols or solutions.

Parenteral administration can occur regardless of the stage of absorption (for example, intravenous, intraarterial, intracardiac, intravertebral or intralumbar) or including the stage of absorption (for example, by inhalation, intramuscularly, by subcutaneous injection, intradermal injection, transdermal or intraperitoneal injection). Suitable forms of administration and other preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders are suitable for parenteral use.

Suitable for other uses are, for example, inhalation formulations (and other dry powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, tablets, films/wafers or capsules, oral sprays taken by the lingual , sublingual or buccal route, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (regular lotions, suspensions or low-fat lotions), fat-soluble suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, powders, implants or stents.

Oral, intravenous, intranasal and pharyngeal administration is preferred.

According to the form of execution, the application is carried out using intranasal administration. According to the form of execution, intranasal application is carried out using drops or nasal spray. According to the embodiment, intranasal application is carried out using a nasal spray.

The compounds according to the invention can be converted into the indicated application forms. This can be done in a known manner by mixing with inert, non-toxic, pharmaceutically acceptable excipients. These excipients include other excipients (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone) , synthetic and natural polymers (eg, albumin), stabilizers (eg, antioxidants, such as ascorbic acid), colorants (eg, inorganic pigments, such as iron oxide) and substances that improve taste and/or smell.

Preferably, for parenteral administration, an amount of about 0.001-1 mg/kg, particularly preferably 0.01-0.5 mg/kg of body weight, is used to achieve the desired result. For oral administration, the dosage is about 0.01-100 mg/kg, preferably about 0.01-20 mg/kg, and very preferably 0.1-10 mg/kg body weight.

According to the form of execution, the dosage for intranasal administration is approximately 0.1-500 μg per day. According to another form of execution, the dosage for intranasal administration is about 1-250 μg per day. According to another form of execution, the dosage for intranasal administration is about 1-120 μg per day. According to another form of execution, the dosage for intranasal administration is about 0.1-500 micrograms per day, or about 1-250 micrograms per day, or about 1120 micrograms per day, daily at bedtime. According to the form of execution, the dosage is about 0.1500 micrograms per day, or about 1-250 micrograms per day, or about 1-120 micrograms per day, daily, half the dose in each nasal opening. According to the form of execution, the dosage is about 0.1-500 micrograms per day, or about 1-250 micrograms per day, or about 1-120 micrograms per day, daily at bedtime, half the dose in each nasal opening.

Despite this, it is sometimes necessary to deviate from the indicated dosage, namely, depending on the body weight, the method of application, the individual relationship to the biologically active substance, the method of preparation and the time or intervals in which the application is carried out. Thus, in some cases it may be sufficient to use less than the specified minimum amount, while in other cases it is necessary to exceed the specified upper limit. If a larger amount is used, it may be recommended to divide it into more single doses per day.

Obstructive sleep apnea syndrome (OSAS) is caused by decreased muscle activity in the upper airways. Musculus genioglossus (the muscle at the base of the tongue) is the most important dilating muscle of the upper airway and is reflexively activated by negative pressure in the upper airway to counteract upper airway collapse. Pressure-sensitive nerve endings/mechanoreceptors in the pharynx and in the upper airways recognize a set low pressure in the upper airways during a breathing cycle. This mechanoreceptor feedback is responsible for most of the dilating muscle responses in the upper airways.

The following examples clarify the invention. The invention is not limited to the examples.

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A. Examples. Abbreviations abs. and abbreviations. absolutely ace acetyl aq. aqueous, aqueous solution Vos otreoth-butoxycarbonyl br: lat. (with NMR signal) Note. In and Example Butyl With Concentration sa. about, approximately cat. catalytically CI chemical ionization (in MS) d doublet (with NMR) d day(s) DCI direct chemical ionization (in MS) dd doublet doublet (by NMR) DMF MA-dimethylformamide DMSO dq dt dimethyl sulfoxide quartet doublet (by NMR) triplet doublet (by NMR) d. th. theor. exit (during chemical exit) EI electron impact ionization (at MS) eq. ESI equivalent(s) electrospray ionization (at MS) Et ethyl h watch) HATU O-(7-azabenzotriazol-1-yl)-A ^g ,A ^g ,L/',L/'-tetramethyluronium hexafluorophosphate HOBt 1-hydroxy-III-benzotriazole hydrate HPLC HPLC (high pressure liquid chromatography, high performance liquid chromatography)

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IPr isopropyl konz. concentration, (in solution) LC LC (liquid chromatography) LC-MS LC-MS (liquid chromatography coupled with mass spectrometry) Lit. literary source m multiplet (at NMR) Me methyl min minute (minutes) MS MS (mass spectrometry) NMR NMR (nuclear magnetic resonance spectroscopy) Ph phenyl Pr propyl q: means quartet (with NMR) count quantitative yield (during chemical yield) RP reverse phase (reverse phase, HPLC) KT room temperature Rt retention time (for high performance liquid chromatography, LC-MS) sec: t: singlet (by NMR) triplet (by NMR) tBu tert-butyl TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet spectrometry v/v ratio! volume to volume (solution) ZUS. together

LC-MS and HPLC methods.

Method 1 (LC-MS).

Appliance: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 2 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.

Method 2 (LC-MS).

MC instrument: Thermo Scientific FT-MS; UHPLC instrument: Thermo Scientific UltiMate 3000; column: Waters AHSS 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 10% B ^ 1.7 min 95% B ^ 23.5 min 95% B; temperature: 50°C; flow: 0.90 ml/min; UV detection: 210 nm / optimal integration contour 210-300 nm.

Method 3 (LC-MS).

MS instrument: Waters Micromass QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.5 µm, 50 mm x 3.0 mm; eluent A: 1 l water + 0.01 ml ammonium carbonate, eluent B: 1 l acetonitrile; gradient: 0.0 min 98% A ^ 0.2 min 98% A ^ 3.0 min 5% A ^ 4.5 min 5% A; temperature: 40°C; flow: 1.75 ml/min; UV detection: 210 nm.

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Method 4 (LC-MS).

MS instrument: Waters Micromass Quattro Micro; HPLC instrument: Waters UPLC Acquity; column: Waters VEN C18 1.7 µm, 50 mm x 2.1 mm; eluent A: 1 l water + 0.01 ml ammonium formate, eluent B: 1 l acetonitrile; gradient: 0.0 min 95% A ^ 0.1 min 95% A ^ 2.0 min 15% A ^ 2.5 min 15% A ^ 2.51 min 10% A ^ 3.0 min 10% A; temperature: 40°C; flow: 0.5 ml/min; UV detection: 210 nm.

Method 5 (LC-MS).

Instrument: Agilent MS Quad 6150 with Agilent 1290 HPLC; column: Waters Acquity UPLC HSS T3 2.2.1.8 µm 50 mmx1 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.

Method 6 (preparative HPLC).

Device: 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 7 (LC-MS).

MS Tool: 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: diode array detector (DAD) 210 nm.

Other data.

The following descriptions of examples of the connection ^{of 1} H-NMR signals are focused on the external properties of these signals and, if necessary, do not fully comply with a strict, physically correct interpretation. Typically, chemical shift data is relative to the center of a given signal; with a wide multiplet, the data indicate, as a rule, through an interval.

Melting points and melting range, unless otherwise indicated, do not correct.

In cases where reaction products are obtained by kneading, stirring or recrystallization, it has often been possible to isolate a different amount of product from the corresponding mother liquor by chromatography. However, the description of this chromatography is omitted from the following, as most of the total yield can be isolated at this stage.

For all reactants and reagents, the preparation of which is not described in detail below, they are considered to be commercially available substances. For all other reactants and reagents, the preparation of which is also not described below, and which are not commercially available or refer to starting materials that are not publicly available, there is a reference to the published literature that describes their preparation.

Initial and intermediate connections.

Example 1A. 2-(4-Chlorophenyl)umidazo[1,2-a]nirudin

A solution of 20 g (85.65 mmol) of 2-bromo-1-(4-chlorophenyl)ethanone and 8.87 g (94.22 mmol) of pyridine-2-amine in 200 ml of ethanol was mixed with 10.95 g (130 mmol) of sodium bicarbonate and stirred for 5 h at 80°C. Then the initial mixture was first cooled to room temperature and then to 0°C (ice bath). The precipitate formed was filtered off and washed several times with ethanol/water (2:1). Then the solid was dried over night at a temperature of 40°C. Received 19.8 g of the target compound, which was used without further purification in subsequent reactions.

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 6.87-6.94 (m, 1H), 7.23-7.29 (m, 1H), 7.50 (d, 2H), 7.58 (d, 1H), 7.99 (d, 2H), 8.43 (s, 1H), 8.53 (d, 1H).

LC-MS (method 1): R _t = 0.58 min; m/z = 229/231 (M+H) ⁺ .

Example 2A. 2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridine

g (32.14 mmol) of 1-(5-chloropyridin-2-yl)ethanone, 6.96 g (73.92 mmol) of pyridine-2-amine, and 9.79 g (38.56 mmol) of iodine were stirred for 2 h at 120°С. After cooling to room temperature, 15 ml of water and 1.93 g (48 mmol) of sodium hydroxide were added, and then the reaction mixture was again stirred for 1 h at 100°C. After that, the mixture was cooled to room temperature, the precipitate formed was filtered off and washed several times with water. The solid was dissolved in cyclohexane/ethyl acetate (1:1), mixed with silica gel, thickened again to

- 20 039175 dry and purified the residue using silica gel column chromatography (eluent:

cyclohexane/acetic acid ethyl ester 1:1). Received 4.32 g (18.81 mmol, 59% theoretical. out.) of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 6.95 (t, 1H), 7.30 (t, 1H), 7.61 (d, 1H), 8.00 (dd, 1H), 8.12 (d, 1H), 8.50 (s, 1H), 8.59 (d, 1H), 8.65 (d, 1H).

LC-MS (method 1): Rt = 0.50 min; m/z = 230/232 (M+H)+.

Example 3A. 2-(6-Isopropylpyridin-3-yl)imidazo[1,2-a]pyridine

g (30.63 mmol) 1-(6-isopropylpyridin-3-yl)ethanone [CAS registration number 80394-97-4], 6.63 g (70.46 mmol) pyridine-2-amine and 9.33 g (36.76 mmol) iodine were stirred for 2 h at 120°C. After cooling to room temperature, 50 ml of water were added, as well as 46 ml (46 mmol) of 1 M sodium hydroxide solution, and then the reaction mixture was stirred again for 1 hour at 100°C. The mixture was then cooled to room temperature, whereby an oily liquid separated out. The reaction mixture was partitioned between water and ethyl acetate and the organic phase separated. Finally washed twice with water, dried over magnesium sulfate and then thickened. The resulting oil was purified by chromatography with neutral alumina (eluent: cyclohexane/ethyl acetate 1:1). The resulting material was then purified twice by silica gel column chromatography (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl acetate 1:2). We obtained 1.62 g (6.83 mmol, 22% of theoretical yield) of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.27 (d, 6H), 2.98-3.12 (m, 1H), 6.91 (t, 1H), 7.27 (t, 1H), 7.35 ( d, 1H), 7.60 (d, 1H), 8.22 (dd, 1H), 8.45 (s, 1H), 8.54 (dd, 1H), 9.06 (d, 1H).

LC-MS (method 2): R _t = 0.86 min; m/z = 238 (M+H) ⁺ .

By analogy with example 1A, the following compounds were obtained from the corresponding indicated educts:

Example Name/structure/educt Analytical data 4A 2-(4-bromophenyl)imidazo[1,2-a]pyridine 1 Λ V V— Br \_/ from 2-bromo-1-(4-bromophenyl)ethanone and pyridine-2-amine 'H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 6.88-6.94 (m, 1H), 7.23-7.29 (m, 1H), 7.58 (d, 1H), 7.63 (d, 2H), 7.92 (d, 2H), 8.44 (s, 1H), 8.53 (d, 1H). LC-MS (Method 1): Rt = 0.63 min; m/z = 273/275 (M+H) ⁺ . 5A 2-(4-isopropylphenyl)imidazo[1,2-a]pyridine \/ ^CH3 \_/ X _CH3 from 2-bromo-1-(4-isopropylphenyl)ethanone and pyridine-2-amine 'H-NMR (400 MHz, DMSO4, δ/ppm): 1.23 (d, 6H), 2.85-2.96 (m, 1H), 6.88 (t, 1H), 7.19-7.26 (m, 1H), 7.31 (d , 2H), 7.56 (d, 1H), 7.88 (d, 2H), 8.34 (s, 1H), 8.51 (d, 1H). LC-MS (Method 1): Rt = 0.68 min; m/z = 237 (M+H) ⁺ .

Example 6A. 2-(4-Chlorophenyl)imidazo[1,2-a]nurudin-3-carbaldehyde

300 ml DMF was cooled to 0°C. Then 44 ml (470.08 mmol) of phosphorus oxychloride were slowly added dropwise. The reaction mixture was then warmed to room temperature and stirred at this temperature for one hour. Then 43 g (188.03 mmol) of 2-(4-chlorophenyl)imidazo[1,2a]pyridine was added in portions. While the reaction solution was heated to 35°C. After completion of the addition, the reaction mixture was heated to 80°C and stirred for 2 hours at this temperature. After cooling to room temperature, the solution was slowly poured into 3 liters of ice water. The solid formed was evacuated, washed several times with water and dried overnight in a high vacuum oven at 40°C. Received 39.6 g (154.27 mmol, 82% theoretical. Yield) of the target compound.

- 21 039175 ^-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 7.37 (t, 1H), 7.63 (d, 2H), 7.78 (t, 1H), 7.90-7.99 (m, 3H), 9.58(d,

1H), 10.02 (s, 1H).

LC-MS (method 1): R _t = 0.97 min; m/z = 257/259 (M+H) ⁺ .

Example 7A. 2-(5-Chloropyridin-2-yl)imidazo[1,2-а]pyridine-3-carbaldehyde

ml DMF was cooled to 0°C. Then 4.4 ml (47.02 mmol) of phosphorus oxychloride were slowly added dropwise. The reaction mixture was then warmed to room temperature and stirred at this temperature for one hour. Then 4.32 g (18.81 mmol) of 2-(5-chloropyridine-2yl)imidazo[1,2-a]pyridine was added in portions. After completion of the addition, the reaction mixture was heated to 80° C. and stirred for 1 hour at this temperature. After cooling to room temperature, the solution was slowly poured into ice water. Acetic acid ethyl ester was added, shaken well and the organic phase separated. The residue was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (solvent: cyclohexane/ethyl acetate 2:1). Received 4.46 g (17.31 mmol, 92% theoretical. out.) of the target compound.

^-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 7.36 (td, 1H), 7.76 (ddd, 1H), 7.94 (d, 1H), 8.15 (dd, 1H), 8.35 (d, 1H ), 8.81 (d, 1H), 9.60 (d, 1H), 10.87 (s, 1H).

LC-MS (method 1): R _t = 0.92 min; m/z = 258/260 (M+H) ⁺ .

Example 8A. 2-(6-Isopropylpyridin-3-yl)imidazo[1,2-а]pyridine-3-carbaldehyde

ml DMF was cooled to 0°C. Then 1.6 ml (17.07 mmol) of phosphorus oxychloride was slowly added dropwise. The reaction mixture was then warmed to room temperature and stirred at this temperature for one hour. Then 1.62 g (6.83 mmol) of 2-(6-isopropylpyridin-3yl)imidazo[1,2-a]pyridine was added in portions. After completion of the addition, the reaction mixture was heated to 80° C. and stirred for 1 hour at this temperature. After cooling to room temperature, the solution was slowly poured into ice water. With slow stirring and addition of 1M sodium hydroxide, the pH of the solution was changed from pH 1 to pH 4. The solution was then extracted several times with ethyl acetate and the combined organic phases were dried over magnesium sulfate and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl acetate 1:1). Thus, two fractions of the target compound were isolated. Fraction 1: 850 mg (pure), fraction 2: 640 mg (not yet purified). The last fraction was purified again under the same chromatographic conditions, whereby a further 350 mg of pure title compound was obtained. A total of 1.20 g (4.52 mmol, 66% of theor. out) of the target compound was obtained.

LC-MS (method 2): R _t = 1.37 min; m/z = 266 (M+H) ⁺ .

By analogy with example 6A, the following compounds were obtained from the corresponding indicated educts: _______________________________________________________________________________

Example Name/structure/educt Analytical data 9A 2-(4-bromophenyl)imidazo[1,2-а]pyridine _- 3 carbaldehyde _ουΑо Ln from 2-(4-bromophenyl)imidazo[1,2-а]pyridine Ή-NMR (400 MHz, DMSO-t/b, δ/ppm): 7.35 (t, 1H), 7.72-7.80 (m, 3H), 7.85-7.95 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H). LC-MS (Method 2): Rt = 1.76 min; m/z = 301/303 (M+H) ⁺ .

-22039175

10A 2-(4-isopropylphenyl)imidazo[1,2a]pyridine-3-carbald egide X _CH3 Λ—H O from 2-(4-isopropylphenyl)imidazo[1,2a]pyridine 'H-NMR (400 MHz, DMSO-t/b, δ/ppm): 1.27 (d, 6H), 2.93-3.05 (m, 1H), 7.33 (t, 1H), 7.44 (d, 2H), 7.74 (t, 1H), 7.85 (d, 2H), 7.91 (d, 1H), 9.58 (d, 1H), 10.03 (s, 1H). LC-MS (Method 1): Rt = 1.03 min; m/z = 265 (M+H) ⁺ .

Example 11A. 2-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane dihydrochloride (enantiomer 1)

2.64 g (5.83 mmol) tert-butyl-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane-2- carboxylate (enantiomer 1) was mixed with stirring with 14.6 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 3.55 g of a solid was obtained, which was used without further purification in subsequent reactions.

LC-MS (method 5): Rt = 0.44 min; m/z = 353/355 (M+H)+.

Example 12A. 2-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5-diazabicyclo [2.2.2]octane dihydrochloride (enantiomer 1)

450 mg (0.99 mmol) tert-butyl-5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2] octane-2-carboxylate (enantiomer 1) was mixed with stirring with 1.49 ml of a 4M solution of hydrogen chloride in dioxane, and also with another 5 ml of dioxane. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 464 mg of a solid were obtained, which was used without further purification in subsequent reactions.

LC-MS (method 2): Rt = 0.70 min; m/z = 354 (M+H) ⁺ .

Example 13A. 2-{[2-(6-Isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane dihydrochloride (racemate)

820 mg (1.78 mmol) tert-butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (racemate) was mixed with stirring with 4.44 ml of a 4M solution of hydrogen chloride in dioxane, and also with another 10 ml of dioxane. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 883 mg of a solid were obtained, which was used without further purification in subsequent reactions.

LC-MS (method 1): Rt = 0.40 min; m/z = 362 (M+H) ⁺ .

Example 14A. 7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrudin-3-yl]methyl}-3-oxa-7,9-diazabicyclo

[3.3.1 ]nonane dihydrochloride

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1.87 g (3.99 mmol) tert-butyl-7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9diazabicyclo[3.3.1] nonane-9-carboxylate was mixed with 10 ml of a 4M solution of hydrogen chloride in dioxane with stirring. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 1.99 g of a solid compound was obtained, which was used without further purification in subsequent reactions.

LC-MS (method 4): Rt = 1.30 min; m/z = 369/371 (M+H)+.

By analogy with examples 11A-14A, the following compounds were obtained from the corresponding indicated educts:

Example Name/structure/educt Analytical data 15A 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-2,5-diazabicyclo[2.2.2]octanedihydrochloride (enantiomer 2) νΔζ ^{x 2HC |} n' from ot/?ot-butyl-5-{[2-(4chlorophenyl)imidazo[1,2-а]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]octane-2carboxylate ( enantiomer 2) LC-MS (Method 5): Rt = 0.40 min; m/z = 353/355 (M+H) ⁺ .

- 24 039175

16A 2-{[2-(4-isopropylphenyl)imidazo[1,2a]pyridin-3-yl]methyl } -2,5 diazabicyclo[2.2.2]octane-dihydrochloride (enantiomer 7) / ^CH3 ua-Ct-q ^{x 2 NS|} from threot-butyl-5-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2]octane-2-carboxylate (enantiomer 1) LC-MS (Method 1): Rt = 0.48 min; m/z = 361 (M+H) ⁺ . 17A 2-{[2-(4-isopropylphenyl)imidazo[1,2а]pyridin-3-yl]methyl } -2,5 diazabicyclo[2.2.2]octane dihydrochloride (enantiomer 2) aAn: ^{x 2 HC |} n ^ζ from t/?eot-butyl-5-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2]octane-2 carboxylate ( enantiomer 2) LC-MS (Method 1): Rt = 0.49 min; m/z = 361 (M+H) ⁺ . 18A 8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-3,8-diazabicyclo[3.2.1]octane dihydrochloride nSz ^{x 2HC|} n' from threot-butyl-8-{[2-(4bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]octane-3 carboxylate LC-MS (Method 1): Rt = 0.48 min; m/z = 397/399 (M+H) ⁺ .

-25 039175

19A 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-3,8-diazabicyclo[3.2.1]octanedihydrochloride l-th N-Sz ^{x 2HC|} H' from ot/?eot-butyl-8-{[2-(4chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]octane-3 carboxylate LC-MS (Method 4): Rt = 1.24 min; m/z = 353/355 (M+H) ⁺ . 20A 8-{[2-(4-isopropylphenyl)imidazo[1,2а]pyridin-3-yl]methyl}-3,8diazabicyclo[3.2.1]octane-dihydrochloride l·™ nSz ^{x 2HC|} n ^z from ot/?eot-butyl-8-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]octane-3 carboxylate LC-MS (Method 4): Rt = 1.41 min; m/z = 361 (M+H) ⁺ . 21A 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl}-3,6-diazabicyclo[3.1.1]heptane dihydrochloride OSH-nA/ ^{x 2HC|} from ot/?eot-Butyl-3-{[2-(4chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptane-6carboxylate LC-MS (Method 4): Rt = 1.22 min; m/z = 339/341 (M+H) ⁺ .

- 26 039175

22A 3-{[2-(4-isopropylphenyl)imidazo[1,2а]pyridin-3-yl]methyl}-3,6diazabicyclo[3.1.1]heptane dihydrochloride caw: /•N GL/ x 2 HCI from tert-butyl 3-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptane-6carboxylate LC-MS (Method 4): Rt = 1.33 min; m/z = 347 (M+H) ⁺ . 23A 3 - {[2-(4-chlorophenyl) imidazo [ 1,2-a] pyridin3 -yl] methyl } -3,8-diazabicyclo [3.2.1] octane dihydrochloride JSC ΖΓ~ν ^ζ ' _N 7 / X 2 HCl n ^ from ot/?eot-butyl-3-{[2-(4chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8carboxylate LC-MS (Method 4): Rt = 1.23 min; m/z = 353/355 (M+H) ⁺ . 24A ^from from /?eo-butyl-3-{[2-(4bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]octane-8carboxylate LC-MS (Method 1): Rt = 0.46 min; m/z = 397/399 (M+H) ⁺ .

- 27 039175

25A 3-{[2-(4-isopropylphenyl)imidazo[1,2a]pyridin-3-yl]methyl }-3,8diazabicyclo[3.2.1]octane-dihydrochloride σρ&ρ. yar™ N IT ^{x 2 HCI} from tert-butyl-3 -{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl} -3,8-diazabicyclo[3.2.1]octane-8carboxylate LC-MS (Method 4): Rt = 1.38 min; m/z = 361 (M+H) ⁺ . 26A 3 - {[2-(5-chloropyridin-2-yl) imidazo[ 1,2a] pyridin-3 -yl] methyl } -3,8 diazabicyclo[3.2.1] octane dihydrochloride N ^{x 2 HC |} from tert-butyl-3-{[2-(5-chloropyridin-2yl)imidazo[1,2-a]pyridin-3-yl]methyl }-3,8diazabicyclo[3.2.1]octane-8-carboxylate LC-MS (Method 2): Rt = 0.74 min; m/z = 354 (M+H) ⁺ . 27A 2- {[2-(5-chloropyridin-2-yl) imidazo[ 1,2a] pyridin-3 -yl] methyl } -2,5 diazabicyclo[2.2.2] octane-dihydrochloride (Racemate) ΖΓ'Ν ^/ νΔζ ^{x 2NS|} η' from tert-butyl-5-{[2-(5-chloropyridin-2yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2.5d iazabicyclo[2.2.2]octane-2 -carboxylate (racemate) LC-MS (Method 4): Rt = 1.27 min; m/z = 354/356 (M+H) ⁺ .

- 28 039175

28A 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2а]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2) an> LC-MS (Method 2): Rt = 0.70 min; m/z = 354 (M+H) ⁺ . □ N 'x ^{x 2HC1} n ^z from tert-butnl-5-{[2-(5-chloropyridin-2yl)imidazo[1,2-a]pyridin-3-yl]methyl } -2.5 d iazabicyclo[2.2 .2] octane-2-carboxylate (enantiomer 2) 29A 7-{[2-(5-chloropyridin-2-yl)imidazo[ 1,2- LC-MS (Method 2): a] pyridin-3 -yl] methyl } -3 -oxa-7,9- Rt = 0.71 min; MS (ESIpos): diazabicyclo[3.3.1]nonane-dihydrochloride onu-G-N ^Z IV x 2 HCl from tert-butnl-7-{[2-(5-chloropyridin-2yl)imide azo[1,2-a]pyridine-3 - yl] methyl } -3 oxa-7,9-diazabicyclo[3.3.1 ]nonane-9carboxylate m/z = 370 [M+H] ⁺ . ZOA 3 - (3, 8-diazabicyclo[3.2.1 ]oct-3 -ylmethyl) -2- LC-MS (Method 2): (b-isopropylpyr idin-3 -yl)imidazo[1,2- Rt = 0.64 min; MS (ESIpos): a] pyridine-dihydrochloride okk: Z>N ^/ N X ^{x 2 HC1} n' ^X from tert-butal-3-{[2-(6-isopropylpyridin3-yl)imide azo[1,2-a]pyridin-3 -yl] methyl } 3,8-diazabicyclo[3.2.1]octane-8-carboxylate m/z = 362 [M+H] ⁺ . 31A 2-(4-bromophenyl)-3 -(2,5- LC-MS (Method 5): diazabicyclo[2.2.2]oct-2- Rt = 0.61 min; MS (ESIpos): ylmethyl)imidazo[1,2-a]pyridinedihydrochloride (Racemate) N ^{X 2HC1} n' from /u/?e/u-butyl-5-{[2-(4bromophenyl)imidazo[1,2-a]pyridin-3yl ] methyl } -2,5-diazabicyclo[2.2.2]octane-2carboxylate (Racemate) m/z = 397 [M+H] ⁺ .

Example 32A. 2-{[2-(6-Isopropylpyridin-3-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane dihydrochloride (enantiomer 1)

- 29 039175

1090 mg (2.36 mmol) tert-butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (enantiomer 1) was mixed with stirring with 8.86 ml of a 4M solution of hydrogen chloride in dioxane, and also with another 10 ml of dioxane. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 1195 mg of a solid were obtained, which was used without further purification in subsequent reactions.

LC-MS (method 2): Rt = 0.61 min; m/z = 362 (M+H)+.

Example 33A. 2-{[2-(6-Isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane dihydrochloride (enantiomer 2)

1010 mg (2.19 mmol) tert-butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (enantiomer 2) was mixed with stirring with 8.86 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred overnight at room temperature. Then pumped out the resulting solid, washed several times with diethyl ether and dried in high vacuum at 40°C. 1050 mg of a solid were obtained, which was used without further purification in subsequent reactions.

LC-MS (method 2): Rt = 0.63 min; m/z = 362 (M+H) ⁺ .

Implementation examples.

Example 1 tert-Butyl 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate)

5 g (19.48 mmol) of 2-(4chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde in 100 ml of THF was dissolved in an argon atmosphere at room temperature and mixed with 8.27 g (38.96 mmol) of tert-butyl-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (racemate) and 2.23 ml (38.96 mmol) acetic acid. Then, 6.19 g (29.22 mmol) of sodium triacetoxyborohydride was added in portions, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: possible gas formation) and then mixed with ethyl acetate. The resulting organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo on a rotary evaporator to dry matter. The resulting residue was taken up on silica gel and purified by silica gel column chromatography (solvent: cyclohexane/ethyl acetate 1:1). Received 6.58 g (13.70 mmol, 70% theoretical. out.) of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.36 (2 s, 9H), 1.43-1.54 (m, 1H), 1.57-1.73 (m, 2H), 1.79-1.89 (m, 1H), 2.61-2.78 (m, 3H), 3.13 (br. t, 1H), 3.50 (br. t, 1H), 3.81 (br. d, 1H), 4.16-4.27 (m, 2H), 6.97 ( t, 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.82–7.90 (m, 2H), 8.57 (d, 1H).

LC-MS (method 2): Rt = 1.50 min; m/z = 453/455 (M+H) ⁺ .

Example 2 tert-Butyl-5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane-2 -carboxylate (racemate)

- 30 039175

1.1 g (4.27 mmol) of 2-5-chloropyridin-2yl)imidazo[1,2-a]nurudin-3-carbaldehyde was dissolved in 35 ml of THF in an argon atmosphere at room temperature and mixed with 1.36 g (6.40 mmol) of tert-butyl -2,5diazabicyclo[2.2.2]octane-2-carboxylate (racemate) and 0.49 ml (8.54 mmol) acetic acid. Then, 1.36 g (6.40 mmol) of sodium triacetoxyborohydride was added in portions, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: possible gas formation) and then mixed with ethyl acetate. The resulting organic phase was separated off 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 in vacuo on a rotary evaporator to dryness. The resulting residue was purified by silica gel column chromatography (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl acetate 1:1). Received 1.57 g (3.46 mmol, 81% theoretical. out.) of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.39 (2 s, 9H), 1.44-1.58 (m, 1H), 1.70 (br. t, 2H), 1.85-2.01 (m, 1H), 2.70 (br. s, 0.5H), 2.78 (br. s, 0.5H), 2.82-2.96 (m, 2H), 3.14 (br. d, 1H), 3.63 (br. dd, 1H), 3.81 (br. s, 0.5H), 3.87 (br. s, 0.5H), 4.55-4.71 (m, 2H), 6.99 (t, 1H), 7.35 (t, 1H), 7.62 (d, 1H), 8.01 (br. d, 1H), 8.21 (d, 1H), 8.48 (d, 1H), 8.63 (dd, 1H).

LC-MS (method 2): Rt = 1.27 min; m/z = 454/456 (M+H)+.

Example 3 tert-Butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane-2 -carboxylate (racemate)

670 mg (2.53 mmol) of 2-(6isopropylpyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde in 15 ml of THF was dissolved in an argon atmosphere at room temperature and mixed with 643 mg (3.03 mmol) of tert- butyl-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (racemate) and 0.29 ml (5.05 mmol) acetic acid. Then, 803 mg (3.79 mmol) of sodium riacetoxyborohydride was added in portions, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: possible gas formation) and then mixed with ethyl acetate. The resulting organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo on a rotary evaporator to dry matter. The residue was taken up in dichloromethane and filtered off. The resulting filtrate was again thickened to dryness. The residue thus formed was purified by silica gel column chromatography (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl acetate 1:1). Received 720 mg (1.56 mmol, 62% theoretical. out.) of the target compound.

¹ H-NMR (4OO MHz, DMSO-d6, δ/ppm): 1.28 (d, 6H), 1.36 (2 s, 9H), 1.43-1.55 (m, 1H), 1.57-1.75 (m, 2H), 1.78-1.91 (m, 1H), 2.65-2.82 (m, 3H), 3.01-3.19 (m, 2H), 3.53 (dd, 1H), 3.81 (br. d, 1H), 4.17-4.28 (m, 2H ), 6.98 (t, 1H), 7.31 (t, 1H), 7.38 (d, 1H), 7.61 (d, 1H), 8.13 (dt, 1H), 8.58 (d, 1H), 8.92 (dd, 1H) .

LC-MS (method 2): R _t = 1.41 min; m/z = 462 (M+H) ⁺ .

Example 4 tert-Butyl-7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane -9-carboxylate

- 31 039175

1.406 g (5.48 mmol) of 2-(4chlorophenyl)umidazo[1,2-a]nurudin-3-carbaldehyde was dissolved in 25 ml of THF in an argon atmosphere at room temperature and mixed with 1.5 g (6.57 mmol) of tert-butyl-3-oxa- 7,9-diazabicyclo[3.3.1]nonane-9-carboxylate and 0.63 ml (10.95 mmol) acetic acid. Then, 1.74 g (8.21 mmol) of sodium triacetoxyborohydride was added in portions, and the reaction solution was stirred overnight at room temperature. Water was then slowly and carefully added dropwise (caution: possible gas formation) and then mixed with ethyl acetate. The resulting organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo on a rotary evaporator to dry matter. The resulting residue was purified by silica gel column chromatography (Biotage SNAPCartridge KP-NH column; eluent: cyclohexane/ethyl acetate 1:1).

Received 1.87 g (3.99 mmol, 73% theoretical. out.) of the target compound.

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.35-1.46 (m, 9H), 2.43 (br. d, 2H), 2.85 (br. d, 2H), 3.57 (br. d, 2H), 3.71 (d, 2H), 3.81-3.92 (m, 4H), 6.93 (td, 1H), 7.30 (ddd, 1H), 7.51 (d, 2H), 7.60 (d, 1H), 7.97 (d , 2H), 8.81 (d, 1H).

LC-MS (method 2): Rt = 1.52 min; m/z = 469/471 (M+H)+.

By analogy with examples 1-4, the following compounds were obtained from the corresponding indicated educts:

- 32 039175

Example Name/structure/educt Analytical data 5 ot/?eot-butyl-8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } -3,8-d iazabiciklo[3.2.1]octane3-carboxylate o © ^H s ^c CH ₃ ° ¹ H-NMR (400 MHz, DMSO-J ₆ , δ/ppm): 1.36 (s, 9H), 1.42-1.50 (m, 2H), 1.78-1.91 (m, 2H), 2.63-2.75 (m, 1H ), 2.76-2.88 (m, 1H), 3.003.14 (m, 2H), 3.44-3.61 (m, 2H), 3.98 (s, 2H), 6.98 (td, 1H), 7.32 (ddd, 1H), 7.60 (d, 1H), 7.67 (d, 2H), 7.81 (d, 2H), 8.64 (d, 1H). LC-MS (Method 2): Rt = 1.64 min; m/z = 497/499 (M+H) ⁺ . 6 ot/?eot-butyl-8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl }-3,8-d iazabicyclo[3.2.1]octane3-carboxylate H3C from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine- _{3carbaldehyde} and ^from /? ^eot -butyl-3,8-diazabicyclo[3.2.1]octane-3- carboxylate 'H-NMR (400 MHz, DMSO-J ₆ , δ/ppm): 1.35 (s, 9H), 1.46 (q, 2H), 1.79-1.89 (m, 2H), 2.63-2.76 (m, 1H), 2.77-2.88 (m, 1H), 3.00-3.14 (m, 2H), 3.42-3.61 (m, 2H), 3.98 (s, 2H), 6.98 (td, 1H), 7.32 (ddd, 1H), 7.53 ( d, 2H), 7.60 (d, 1H), 7.87 (d, 2H), 8.64 (d, 1H). LC-MS (Method 1): Rt = 0.84 min; m/z = 453/455 (M+H) ⁺ . 7 threot-butyl-8-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-d andazabicyclo[3.2.1]octane-3 carboxylate ΟφΌ-C . © ⁿ » ^with CH, ° from 2-(4-isopropylphenyl)imidazo[1,2-a]pyridine-3carbaldehyde and from/?eot-butyl-3,8-diazabicyclo-[3.2.1]octane-3-carboxylate 'H-NMR (400 MHz, DMSO-J ₆ , δ/ppm): 1.24 (d, 6H), 1.35 (s, 9H), 1.46 (q, 2H), 1.78-1.89 (m, 2H), 2.65- 2.75 (m, 1H), 2.77-2.87 (m, 1H), 2.87-3.01 (m, 1H), 3.04-3.17 (m, 2H), 3.43-3.62 (m, 2H), 3.98 (s, 2H), 6.96 (t, 1H), 7.29 (t, 1H), 7.34 (d, 2H), 7.58 (d, 1H), 7.74 (d, 2H), 8.64 (d, 1H). LC-MS (Method 2): Rt = 1.63 min; m/z = 461 (M+H) ⁺ .

- 33 039175 mpem-Butyl-3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} -3,6-d iazabicyclo[3.1.1]heptan-6- carboxylate

¹ H-NMR (400 MHz, DMSO-J ₆ , δ/ppm): 1.27 (s, 9H), 1.62 (d, 1H), 2.20 (q, 1H), 2.57-3.04 (m, 4H), 3.83- 3.98 (m, 2H), 4.09-4.26 (m, 2H), 6.98 (t, 1H), 7.31 (t, 1H), 7.51 (d, 2H), 7.61 (d, 1H), 7.82 (d, 2H) , 8.47(d, 1H).

LC-MS (Method 1):

Rt = 0.87 min; m/z = 439/441 (M+H) ⁺ .

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3carbaldehyde and t/?eot-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate mpem-Butyl-3 -{[ 2-(4isopropylphenyl)imidazo[1,2-а]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptane-6carboxylate

¹ H-NMR (400 MHz, DMSO-tA, δ/ppm): 1.25 (d, 6H), 1.28 (s, 9H), 1.65 (d, 1H), 2.20 (q, 1H), 2.563.02 (m , 5H), 3.81-4.03 (m, 2H), 4.05-4.24 (m, 2H), 6.94 (t, 1H), 7.24-7.35 (m, 3H), 7.59 (d, 1H), 7.71 (d, 2H ), 8.44 (d, 1H).

LC-MS (Method 1):

Rt = 0.88 min; m/z = 447 (M+H) ⁺ .

from 2-(4-isopropylphenyl)imidazo[1,2-а]pyridine-3carbaldehyde and /u/?e/u-butyl-3,6-diazabicyclo____________[3,1,1]heptane-6-carboxylate____________ mpem-Butyl -3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } -3,8-d iazabicyclo[3.2.1]octane8-carboxylate

¹ H-NMR (400 MHz, DMSO-tA, δ/ppm): 1.39 (s, 9H), 1.64 (br. s, 4H), 2.27 (br. d, 2H), 2.48-2.58 (m, 2H, partially hidden by the DMSO signal), 3.97 (br. s, 2H), 4.03 (br. s, 2H), 6.99 (t, 1H), 7.31 (t, 1H), 7.53 (d, 2H), 7.60 (d, 1H ), 7.92 (d, 2H), 8.58 (d, 1H). LC-MS (Method 2):

Rt= 1.81 min; m/z = 453/455 (M+H) ⁺ .

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3carbaldehyde and t/?eot-butyl-3,8-diazabicyclo[3,2,1]octane-8-carboxylate

- 34 039175 from / eeot-Butyl-3 - {[2- (4-bromophenyl) imidazo [ 1,2-a] pyridin-3 -yl] methyl } -3,8-d iazabicyclo[3.2.1] octane8- carboxylate

¹ H-NMR (400 MHz, DMSO®, δ/ppm): 1.39 (s, 9H), 1.64 (br. s, 4H), 2.27 (br. d, 2H), 2.46-2.58 (m, 2H, hidden DMSO signal), 3.97 (s, 2H), 4.03 (br. s, 2H), 6.99 (td, 1H), 7.31 (ddd, 1H), 7.60 (d, 1H), 7.67 (d, 2H), 7.85 ( d, 2H), 8.58 (d, 1H).

LC-MS (Method 2):

Rt = 1.86 min; m/z = 497/499 (M+H) ⁺ .

from 2-(4-bromophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and t/eeot-butyl-3,8-diazabicyclo__________[3,2,1]octane-8-carboxylate__________otreot-Butyl-3 - {[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-d andazabicyclo[3.2.1]octane-8carboxylate

'H-NMR (400 MHz, DMSO®, δ/ppm): 1.25 (d, 6H), 1.39 (s, 9H), 1.65 (br. s, 4H), 2.26 (br. d, 2H), 2.46- 2.59 (m, 2H, partially hidden by DMSO), 2.883.01 (m, 1H), 3.97 (s, 2H), 4.03 (br. s, 2H), 6.96 (t, 1H), 7.28 (t, 1H) , 7.34 (d, 2H), 7.58 (d, 1H), 7.79 (d, 2H), 8.55 (d, 1H).

LC-MS (Method 2):

Rt = 1.74 min; m/z = 461 (M+H) ⁺ .

from 2-(4-isopropylphenyl)imidazo[1,2-a]pyridine-3carbaldehyde and t/eeot-butyl-3,8-diazabicyclo___________[3,2,1]octane-8-carboxylate___________ otreot-Butyl-5-{ [2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-d andazabicyclo[2.2.2]octane-2carboxylate (Racemate)

¹ H-NMR (400 MHz, DMSO®, δ/ppm): 1.25 (d, 6H), 1.36 (2 s, 9H), 1.43-1.56 (m, 1H), 1.58-1.76 (m, 2H), 1.77 -1.93 (m, 1H), 2.642.82 (m, 3H), 2.87-3.01 (m, 1H), 3.13 (br. t, lH), 3.52 (br. d, 1H), 3.82 (br. d, 1H), 4.21 (s, 2H), 6.95 (t, 1H), 7.28 (t, 1H), 7.34 (d, 2H), 7.58 (d, 1H), 7.70-7.79 (m, 2H), 8.55 (d , 1H).

LC-MS (Method 2):

Rt = 1.60 min; m/z = 461 (M+H) ⁺ .

from 2-(4-isopropylphenyl)imidazo[1,2-a]pyridine-3carbaldehyde and t/eeot-butyl-2,5-diazabicyclo_____[2,2,2]octane-2-carboxylate (Racemate)_____ mpem-Butyl -3 - {[2-(5-chloropyride in-2yl)imidazo[1,2-a]pyridin-3-yl]methyl} -3,8diazabicyclo[3.2.1]octane-8-carboxylate

from 2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridine-3carbaldehyde and threot-Butyl-3,8diazabicyclo[3,2,1]octane-8-carboxylate ¹ H-NMR (400 MHz , DMSO®, δ/ppm): 1.38 (s, 9H), 1.62 (br. s, 4H), 2.25 (br. d, 2H), 2.45-2.59 (m, 2H, partially obscured by DMSO signal), 3.98 ( br. s, 2H), 4.45 (s, 2H), 7.01 (td, 1H), 7.34 (t, 1H), 7.62 (d, 1H), 8.00 (dd, 1H), 8.20 (d, 1H), 8.54 (d, 1H), 8.65 (d, 1H).

LC-MS (Method 2):

Rt= 1.50 min; m/z = 454/456 (M+H) ⁺ .

Examples 15 and 16 tert-Butyl-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5 diazabicyclo[2.2.2]octane-2- carboxylate (enantiomers 1 and 2)

- 35 039175

5.86 g (12.94 mmol) racemic tert-butyl-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2 -carboxylates (example 1) using preparative HPLC chiral phase was separated into enantiomers [column: Daicel Chiralpak IC, 5 μm, 250 mm x 20 mm; eluent: isohexane/ethanol 80:20; flow: 15 ml/min; UV detection: 220 nm; temperature: 30°C].

Example 15 (enantiomer 1): yield: 2640 mg;

Rt = 9.85 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/ethanol 80:20; flow: 1 ml/min; temperature: 30°C; UV detection: 220 nm];

LC-MS (method 2): Rt = 1.52 min; m/z = 453/455 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.36 (2 s, 9H), 1.43-1.54 (m, 1H), 1.57-1.72 (m, 2H), 1.78-1.91 (m, 1H), 2.61-2.79 (m, 3H), 3.13 (br. t, 1H), 3.50 (br. t, 1H), 3.80 (br. d, 1H), 4.16-4.27 (m, 2H), 6.97 ( t, 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.82–7.90 (m, 2H), 8.57 (d, 1H).

Example 16 (enantiomer 2): yield: 2430 mg;

_Rt = 10.62 min; chemical purity >99%;>99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/ethanol 80:20; flow: 1 ml/min; temperature: 30°C; UV detection: 220 nm].

LC-MS (method 1): Rt = 0.81 min; m/z = 453/455 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.36 (2 s, 9H), 1.42-1.55 (m, 1H), 1.59-1.72 (m, 2H), 1.78-1.90 (m, 1H ), 2.61-2.79 (m, 3H), 3.13 (br. t, 1H), 3.50 (br. t, 1H), 3.81 (br. d, 1H), 4.16-4.26 (m, 2H), 6.97 (t , 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.82–7.91 (m, 2H), 8.57 (d, 1H).

Examples 17 and 18 tert-Butyl 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane-2-carboxylate (enantiomers 1 and 2)

3.91 g (14.79 mmol) racemic tert-butyl-5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]octane-2 α-carboxylate (Example 13) was separated by preparative supercritical liquid chromatography (SFC) of the chiral phase into enantiomers [column: Daicel Chiralpak ID-H, 5 μm, 250 mm x 20 mm; eluent: carbon dioxide/ethanol 67:33 (v/v); flow: 175 ml/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38°C].

Example 17 (enantiomer 1): yield: 1889 mg;

_Rt = 3.39 min; chemical purity >99%;>99% her

[column: Daicel Chiralpak IAD-H, 3 µm, 50 mm x 4.6 mm; eluent: carbon dioxide/methanol 55:95 ^ 50:50 (v/v); flow: 3 ml/min; pressure: 130 bar; temperature: 40°C; UV detection: 220 nm].

LC-MS (method 1): R _t = 0.88 min; m/z = 461 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.25 (d, 6H), 1.36 (2 s, 9H), 1.43-1.56 (m, 1H), 1.58-1.76 (m, 2H), 1.77-1.93 (m, 1H), 2.64-2.82 (m, 3H), 2.87-3.01 (m, 1H), 3.13 (br. t, 1H), 3.52 (br. d, 1H), 3.82 (br. d , 1H), 4.21 (s, 2H), 6.95 (t, 1H), 7.28 (t, 1H), 7.34 (d, 2H), 7.58 (d, 1H), 7.70-7.79 (m, 2H), 8.55 ( d, 1H).

Example 18 (enantiomer 2): yield: 1860 mg;

Rt = 33.72 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IAD-H, 3 µm, 50 mm x 4.6 mm; eluent: carbon dioxide/methanol 55:95 ^ 50:50 (v/v); flow: 3 ml/min; pressure: 130 bar; temperature: 40°C; UV detection: 220 nm].

LC-MS (method 1): R _t = 0.87 min; m/z = 461 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.25 (d, 6H), 1.36 (2 s, 9H), 1.44-1.56 (m, 1H), 1.58-1.75 (m, 2H) ,

- 36 039175

1.79-1.92 (m, 1H), 2.64-2.83 (m, 3H), 2.87-3.00 (m, 1H), 3.13 (br. t, 1H), 3.52 (br. d, 1H), 3.82 (br. d , 1H), 4.21 (s, 2H), 6.95 (t, 1H), 7.28 (t, 1H), 7.34 (d, 2H), 7.58 (d, 1H), 7.71-7.78 (m, 2H), 8.55 ( d, 1H).

Examples 19 and 20 tert-Butyl-5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane -2-carboxylate (enantiomers 1 and 2)

950 mg (2.09 mmol) racemic tert-butyl-5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2 ]octane-2-carboxylate (Example 2) was separated by preparative HPLC of the chiral phase into enantiomers [column: YMC Cellulose SC, 5 μm, 250 mm x 20 mm; eluent: isohexane/isopropanone 50:50 + 0.2% diethylamine; flow: 15 ml/min; UV detection: 220 nm; temperature: 40°C].

Example 19 (enantiomer 1): yield: 450 mg;

Rt= 6.48 min; chemical purity >99%; >99% her

[column: YMC Cellulose SC, 5 µm, 250 mm x 4.6 mm; eluent: n-heptane/isopropanol 70:30 + 0.2% diethylamine; flow: 1 ml/min; temperature: 40°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.39 (2 s, 9H), 1.44-1.58 (m, 1H), 1.70 (br. t, 2H), 1.86-2.00 (m, 1H ), 2.70 (br. s, 0.5H), 2.78 (br. s, 0.5H), 2.82-2.95 (m, 2H), 3.14 (br. d, 1H), 3.63 (br. dd, 1H), 3.81 (br. s, 0.5H), 3.87 (br. s, 0.5H), 4.55-4.72 (m, 2H), 6.99 (t, 1H), 7.35 (t, 1H), 7.62 (d, 1H), 8.01 (dt, 1H), 8.22 (d, 1H), 8.48 (d, 1H), 8.63 (dd, 1H).

LC-MS (method 1): R _t = 0.71 min; m/z = 454/456 (M+H) ⁺ .

Example 20 (enantiomer 2): yield: 448 mg;

_Rt = 7.70 min; chemical purity >99%;>99% her

[column: YMC Cellulose SC, 5 µm, 250 mm x 4.6 mm; eluent: n-heptane/isopropanol 70:30 + 0.2% diethylamine; flow: 1 ml/min; temperature: 40°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.39 (2 s, 9H), 1.44-1.58 (m, 1H), 1.70 (br. t, 2H), 1.85-2.01 (m, 1H), 2.70 (br. s, 0.5H), 2.78 (br. s, 0.5H), 2.82-2.96 (m, 2H), 3.14 (br. d, 1H), 3.63 (br. dd, 1H), 3.81 (br. s, 0.5H), 3.87 (br. s, 0.5H), 4.55-4.71 (m, 2H), 6.99 (t, 1H), 7.35 (t, 1H), 7.62 (d, 1H), 8.01 (dd, 1H), 8.21 (d, 1H), 8.48 (d, 1H), 8.63 (dd, 1H).

LC-MS (method 1): R _t = 0.71 min; m/z = 454/456 (M+H) ⁺ .

Example 21 (-)-[(1S,4S)-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo [2.2. 2]oct-2-yl](6-methoxypyridin-2-yl)methanone (enantiomer 1)

mg (0.39 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 2 ml of DMF, mixed with 201 mg (0.53 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3 -tetramethyluronium-hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 150 mg (0.35 mmol) of 2-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-dihydrochloride ( enantiomer 1), as well as 307 µl (1.76 mmol) of Ν,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 100 mg (0.2 mmol, 58% thor. y.) of the title compound was obtained.

LC-MS (method 1): R _t = 0.73 min; m/z = 488/490 (M+H) ⁺ . [a] ^D20 = _-40.83 ° (c = 0.320, methanol).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.47-1.99 (m, 4H), 2.64 (br. s, 0.25H), 2.71 (dd, 0.75H), 2.822.92 (m , 2H), 3.38 (dd, 0.75H), 3.47 (dd, 0.25H), 3.70-3.78 (m, 3H), 3.80 (s, 0.75H), 3.92 (br. d, 0.25H), 3.98 (br . s, 0.75H), 4.21-4.33 (m, 2H), 4.38 (br. s, 0.25H), 6.84-7.02 (m, 2H), 7.17 (d, 0.75H), 7.25-7.36 (m, 1.25 H), 7.44-7.55 (m, 2H), 7.60 (d, 1H), 7.75-7.91 (m, 3H), 8.54-8.64 (m, 1H).

- 37 039175

The absolute configuration of the compound was determined using circular dichroism vibrational spectroscopy (VCD) [cf. Kuppens, T., Bultinck, P., Langenaeker, W., Determination of absolute configuration via vibrational circular dichroism, Drug Discovery Today: Technologies 1 (3), 269-275 (2004); Stephens, P. J, Vibrational circular dichroism spectroscopy: A new tool for the stereochemical characterization of chiral molecules, Computational Medicinal Chemistry for Drug Discovery, 699-725 (2004)].

Example 22 (-)-(3-Chloro-6-methoxypyridin-2-yl)[(18.48)-5-{[2-(4-chlorophenyl)imidazo[1,2a]pyridin-3-yl] methyl} -2,5-diazabicyclo[2.2.2]oct-2-yl]methanone (enantiomer 1)

363 mg (1.94 mmol) of 3-chloro-6-methoxypyridine-2-carboxylic acid was dissolved in 10 ml of DMF, mixed with 1005 mg (2.64 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 750 mg (1.76 mmol) of 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-dihydrochloride ( enantiomer 1), as well as 1.53 ml (8.8 mmol) Kfdiisopropylethylamine, and the mixture was stirred overnight at room temperature. Then, the reaction solution was poured into ice water, the precipitated solid was pumped out, washed several times with water, and then dried under high vacuum at 40°C. The aqueous phase was extracted several times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. Pre-purify the residue with the resulting solid, then carried out subsequent purification using column chromatography on silica gel (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl ester of acetic acid 1:1). In this way, 685 mg (1.24 mmol, 70% th. y.) of the title compound were obtained. One part (100 mg) was again purified by preparative HPLC (method 6) and the specific optical rotation of this sample was determined.

LC-MS (method 2): R _t = 1.38 min; m/z = 522/523/524 (M+H)+. [a] ^D20 = _-62.64 ° (c = 0.455, methanol).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.51-1.99 (m, 4H), 2.61 (br. d, 0.7H), 2.65-2.77 (m, 1H), 2.81 (br . s, 0.6H), 2.93-3.00 (m, 1H), 3.20 (br. s, 0.7H), 3.37 (br. d, 0.3H), 3.42 (br. d, 0.7H), 3.71-3.85 ( m, 3.7H), 4.16-4.42 (m, 2.3H), 6.85-7.02 (m, 2H), 7.31 (br. t, 1H), 7.46-7.64 (m, 3H), 7.77-7.99 (m, 3H ), 8.53-8.65 (m, 1H).

Example 23 (-)-[(1S,4S)-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo [2.2. 2]oct-2-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1)

332 mg (1.94 mmol) of 3-fluoro-6-methoxypyridine-2-carboxylic acid was dissolved in 10 ml of DMF, mixed with 1005 mg (2.64 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 750 mg (1.76 mmol) of 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-dihydrochloride ( enantiomer 1), as well as 1.53 ml (8.8 mmol) of N,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. Then, the reaction solution was poured into ice water, the precipitated solid was pumped out, washed several times with water, and then dried under high vacuum at 40°C. The aqueous phase was extracted several times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. Pre-purify the residue with the resulting solid, then carried out subsequent purification using column chromatography on silica gel (Biotage SNAP-Cartridge KP-NH-column; eluent: cyclohexane/ethyl ester of acetic acid 1:1). In this way, 581 mg (1.15 mmol, 65% thor.) of the title compound were obtained. One part (100 mg) was again purified by preparative HPLC (method 6) and the specific optical rotation of this sample was determined.

LC-MS (method 1): Rt = 0.74 min; m/z = 505/506 (M+H)+. [a] ^D20 = _-47.17 ° (c = 0.460, methanol).

1Н-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.51-2.10 (m, 4H), 2.63-2.72 (m, 2H), 2.77-2.86 (m, 1H), 2.872.92 (m , 1H), 3.42 (br. d, 1H), 3.48 (br. s, 1H), 3.73 (s, 3H), 4.22-4.41 (m, 2H), 6.89-7.04 (m, 2H), 7.26-7.35 (m,

1H), 7.47-7.56 (m, 2H), 7.60 (d, 1H), 7.74 (t, 1H), 7.82-7.91 (m, 2H), 8.54-8.63 (m, 1H).

Example 24 (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo [2.2.2]oct-2- yl)(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1)

mg (0.24 mmol) of 3-fluoro-6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 123 mg (0.32 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.22 mmol) 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane- dihydrochloride (enantiomer 1), as well as 188 μl (1.08 mmol) of N,Ndiisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 79 mg (0.16 mmol, 72% th. y.) of the title compound were obtained.

LC-MS (method 2): Rt= 1.13 min; m/z = 507/509 (M+H) ⁺ .

[a] ^D20 = _-77.15 ° (c = 0.270, methanol).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.52-2.09 (m, 4H), 2.76 (br. s, 0.3H), 2.83-3.08 (m, 2.7H), 3.15 ( br. d, 0.3H), 3.42 (br. d, 0.7H), 3.50 (br. s, 0.7H), 3.73-3.89 (m, 4H), 4.42 (br. s, 0.3H), 4.58-4.75 (m, 2H), 6.93 (dd, 0.7H), 6.96-7.05 (m, 1.3H), 7.30-7.39 (m, 1H), 7.58-7.66 (m, 1H), 7.76 (t, 0.7H), 7.84 (t, 0.3H), 7.96-8.04 (m, 1H), 8.17-8.26 (m, 1H), 8.44-8.53 (m, 1.3H), 8.66 (d, 0.7H).

Example 25 (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2.5 -diazabicyclo[2.2.2]oct-2-yl)methanone (enantiomer 1)

mg (0.24 mmol) of 3-chloro-6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 123 mg (0.32 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.22 mmol) 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane- dihydrochloride (enantiomer 1), as well as 188 μl (1.08 mmol) of N,Ndiisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. Received 84 mg (0.16 mmol, 74% theoretical. out.) specified in the title compound.

LC-MS (method 2): Rt = 1.21 min; m/z = 523/524/525 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.51-2.08 (m, 4H), 2.74 (br. s, 0.3H), 2.83 (br. d, 0.7H), 2.903. 08 (m, 2.3H), 3.24 (br. s, 0.7H), 3.44 (br. d, 0.7H) 3.66 (br. d, 0.3H), 3.76 (s, 2.3H), 3.82-3.90 (m , 1.4H), 4.43 (br. s, 0.3H), 4.62-4.74 (m, 2H), 6.90 (d, 0.7H), 6.94-7.06 (m, 1.3H), 7.30-7.39 (m, 1H) , 7.58-7.67 (m, 1H), 7.85 (d, 0.7H), 7.95 (d, 0.3H), 7.97-8.05 (m, 1H), 8.16-8.27 (m, 1H), 8.44 (d, 0.3H ), 8.46-8.53 (m, 1H), 8.65 (d, 0.7H).

Example 26 (-)-(5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo [2.2.2] oct-2-yl)(6-methoxypyridin-2-yl)methanone (enantiomer 1)

- 39 039175

Mixture 1. 40 mg (0.26 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 1.7 ml of DMF, mixed with 137 mg (0.36 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 111 mg (0.24 mmol) 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane- dihydrochloride (enantiomer 1), as well as 210 µl (1.20 mmol) of N,Ndiisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. Due to column losses during purification, only 16 mg (0.03 mmol, 14% of th. y.) of the title compound was obtained.

LC-MS (method 2): Rt = 1.12 min; m/z = 489/491 (M+H)+. [a]D ²⁰ = -74.46° (c = 0.295, methanol).

Mixture 2: 36 mg (0.24 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 123 mg (0.32 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 100 mg (0.22 mmol) 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]octane- dihydrochloride (enantiomer 1), as well as 188 μl (1.08 mmol) of N,Ndiisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. Received 87 mg (0.18 mmol, 82% theoretical. output.) specified in the title compound.

LC-MS (method 2): Rt = 1.14 min; m/z = 489/491 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.50-2.07 (m, 4H), 2.68-2.73 (m, 0.3H), 2.85-2.94 (m, 1.4H), 2.99- 3.09 (m, 1.3H), 3.37 (dd, 0.7H), 3.49 (dd, 0.3H), 3.77 (s, 2.3H), 3.81-3.89 (m, 1.4H), 4.01 (br. s, 0.7H ), 4.08 (br. d, 0.3H), 4.42 (br. s, 0.3H), 4.57-4.76 (m, 2H), 6.89 (d, 0.7H), 6.94 (d, 0.3H), 6.96-7.04 (m, 1H), 7.21 (d, 0.7H), 7.30-7.39 (m, 1.3H), 7.58-7.65 (m, 1H), 7.77-7.89 (m, 1H), 7.97-8.04 (m, 1H) , 8.17-8.25 (m, 1H), 8.43 (d, 0.3H), 8.47-8.53 (m, 1H), 8.63 (d, 0.7H).

Example 27 (5-{[2-(6-Isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2- yl) (6-methoxypyridin-2-yl) methanone (racemate)

mg (0.51 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 2.5 ml of DMF, mixed with 266 mg (0.70 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3 -tetramethyluronium-hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 220 mg (0.47 mmol) 2-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2] was added octane dihydrochloride (racemate), as well as 410 μl (2.34 mmol) of N,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 150 mg (0.30 mmol, 65% of theor. yield) of the title compound were obtained.

LC-MS (method 2): R _t = 1.18 min; m/z = 497 (M+H)+.

Example 28 (3-Fluoro-6-methoxypyridin-2-yl)(5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2a]pyridin-3-yl]methyl} -2.5 -diazabicyclo [2.2.2]oct-2-yl) methanone (racemate)

mg (0.51 mmol) -fluoro-6-methoxypyridine-2-carboxylic acid was dissolved in 2.5 ml of DMF, mix

- 40 039175 shawl with 266 mg (0.70 mmol) 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 min at room temperature . Then 220 mg (0.47 mmol) 2-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2] was added octane-dihydrochloride (racemate), as well as 410 μl (2.34 mmol) of K,K-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 147 mg (0.29 mmol, 61% of theor. yield) of the title compound were obtained.

LC-MS (method 2): R _t = 1.19 min; m/z = 515 (M+H)+.

Example 29 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo

[3.3.1]non-9-yl)(6-methoxypyridin-2-yl)methanone

mg (0.23 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 119 mg (0.31 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3 -tetramethyluronium-hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 100 mg (0.21 mmol) 7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1] was added nonane dihydrochloride, as well as 150 µl (0.84 mmol) of K,K-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 71 mg (0.14 mmol, 67% th. y.) of the title compound were obtained.

LC-MS (method 1): R _t = 0.72 min; m/z = 504/506 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.56-2.69 (m, 2H), 2.90 (br. d, 1H), 3.04 (br. d, 1H), 3.66-3.78 ( m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.94 (s, 2H), 4.21 (br. s, 1H), 4.46 (br. s, 1H), 6.89-6.97 (m, 2H), 7.26-7.33 (m, 2H), 7.51 (d, 2H), 7.60 (d, 1H), 7.83 (dd, 1H), 7.98 (d, 2H), 8.83 (d, 1H).

Example 30 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo [3.3.1]non-9- yl)(3-fluoro-6-methoxypyridin-2-yl)methanone

mg (0.243 mmol) of 3-fluoro-6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 119 mg (0.31 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.21 mmol) of 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9diazabicyclo[3.3.1]nonan- dihydrochloride, as well as 146 μl (0.84 mmol) of K,K-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC into its components [equipment: 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 at 10% B, 22.2 min at 30% B, 2.2-7 min at 70% B, 7-7.5 min at 92% B, 7.5-9 min at 92% B; flow: 65 ml/min; in addition, constantly 5 ml/min 2% ammonia in water; room temperature; UV detection: 200-400 nm]. In this way, 77 mg (0.15 mmol, 71% th. y.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.33 min; m/z = 522/524 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47-2.62 (m, 2H, partially covered by DMSO signal), 2.88 (br. d, 1H), 3.04 (br. d, 1H) , 3.59-3.76 (m, 4H), 3.80 (s, 3H), 3.88 (d, 1H), 3.94 (s, 2H), 4.47 (br. s, 1H), 6.90-7.01 (m, 2H), 7.30 (ddd, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.80 (t, 1H), 7.97 (d, 2H), 8.82 (d, 1H).

Example 31 (7-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]non-9- yl)[6-(cyclobutyloxy)pyridin-2-yl]methanone

- 41 039175

mg (0.23 mmol) of 6-(cyclobutyloxy)pyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 119 mg (0.31 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1, 3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.21 mmol) of 7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}-3-oxa-7,9diazabicyclo[3.3.1]nonan- dihydrochloride, as well as 146 µl (0.84 mmol) of Ν,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC into its components [equipment: 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 at 10% B, 22.2 min at 30% B, 2.2-7 min at 70% B, 7-7.5 min at 92% B, 7.5-9 min at 92% B; flow: 65 ml/min; in addition, constantly 5 ml/min 2% ammonia in water; room temperature; UV detection: 200-400 nm]. In this way, 79 mg (0.14 mmol, 69% th. y.) of the title compound were obtained.

LC-MS (method 2): R _t = 1.60 min; m/z = 544/546 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.45-1.61 (m, 1H), 1.68-1.80 (m, 1H), 1.93-2.10 (m, 2H), 2.232.38 (m , 2H), 2.57-2.65 (m, 2H), 2.87 (br. d, 1H), 3.07 (br. d, 1H), 3.63-3.77 (m, 3H), 3.87-4.01 (m, 3H), 4.14 (br. s, 1H), 4.46 (br. s, 1H), 4.98-5.09 (m, 1H), 6.87 (dd, 1H), 6.93 (td, 1H), 7.26 (dd, 1H), 7.31 (td , 1H), 7.51 (d, 2H), 7.60 (d, 1H), 7.82 (dd, 1H), 7.99 (d, 2H), 8.84 (d, 1H).

Example 32 (3-Chloro-6-methoxypyridin-2-yl)(7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl} -3-oxa-7.9 -diazabicyclo[3.3.1]non-9-yl)methanone

mg (0.23 mmol) of 3-chloro-6-methoxypyridine-2-carboxylic acid was dissolved in 1.4 ml of DMF, mixed with 119 mg (0.31 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1.1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.21 mmol) of 7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}-3-oxa-7,9diazabicyclo[3.3.1]nonan- dihydrochloride, as well as 182 µl (1.05 mmol) of Ν,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 86 mg (0.16 mmol, 76% of theor. yield) of the title compound were obtained.

LC-MS (method 2): Rt = 1.39 min; m/z = 538/539/540 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.46-2.60 (m, 2H, partially covered by DMSO signal), 2.86 (br. d, 1H), 3.04 (br. d, 1H), 3.34 (br. s, 1H), 3.59-3.76 (m, 3H), 3.82 (s, 3H), 3.88 (d, 1H), 3.94 (s, 2H), 4.46 (br. s, 1H), 6.89- 6.98 (m, 2H), 7.30 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.90 (d, 1H), 7.97 (d, 2H), 8.81 (d, 1H).

Example 33 (3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,8-diazabicyclo

[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanone

- 42 039175 mg (0.26 mmol) of 6-methoxypyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 134 mg (0.35 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1, 3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg (0.23 mmol) 3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,8-diazabicyclo [3.2.1] was added octane dihydrochloride, as well as 200 μl (1.17 mmol) of N,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 93 mg (0.19 mmol, 81% of theor. yield) of the title compound were obtained.

LC-MS (method 2): Rt = 1.31 min; m/z = 489/491 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.62-1.80 (m, 4H), 2.40 (br. d, 1H), 2.46-2.69 (m, 2H, partially covered by DMSO signal) , 2.76 (br. d, 1H), 3.72 (s, 3H), 4.44-4.64 (m, 4H), 6.91 (d, 1H), 7.02 (td, 1H), 7.30-7.39 (m, 2H), 7.62 (d, 1H), 7.80 (dd, 1H), 8.00 (dd, 1H), 8.19 (d, 1H), 8.57 (d, 1H), 8.66 (d, 1H).

By analogy with examples 21 and 33, the following compounds were obtained from the corresponding indicated educts: _______________________________________________________________________________

Example Name/structure/educt Analytical data 34 (+)-[(17?,47?)-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyride in-3-yl]methyl } -2,5 - diazabicycle o[2.2 .2] οκτ-2-yl] (6-methoxypyride in-2-yl) methanone (enantiomer 2) Oyo ^-H3C 9 O from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridine -3 yl] methyl } -2,5 -d-iazabicyclo[2.2.2] octane dihydrochloride (enantiomer 2) and 6-methoxypyridine-2-carboxylic acid 'H-NMR (400 MHz, DMSO-r7): δ [ppm] = 1.48-2.00 (m, 4H), 2.64 (br. s, 0.25H), 2.71 (dd, 0.75H), 2.81-2.93 (m , 2H), 3.38 (dd, 0.75H), 3.47 (dd, 0.25H), 3.70-3.78 (m, 3H), 3.80 (s, 0.75H), 3.92 (br. d, 0.25H), 3.98 (br s, 0.75H), 4.21-4.32 (m, 2H), 4.38 (br. s, 0.25H), 6.85-7.02 (m, 2H), 7.17 (d, 0.75H), 7.25-7.35 (m, 1.25 H), 7.46-7.56 (m, 2H), 7.60 (d, 1H), 7.75-7.92 (m, 3H), 8.55-8.63 (m, 1H). [a] and ²⁰ = +46.13° (c = 0.250, methanol). LC-MS (Method 1): Rt = 0.73 min; m/z = 488/490 (M+H) ⁺ . The absolute configuration was tuned using vibrational circular dichroism spectroscopy (cf. Example 21) 35 (-)-(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3 -yl] methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)(2fluorophenyl )Methanone (enantiomer 7) 0QU sch® V° aus 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-2,5-diazabicycle o[2.2.2]octanedihydrochloride (enantiomer 1) and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSCWe): δ [ppm] = 1.48-1.97 (m, 4H), 2.63-2.71 (m, 1H), 2.74-2.88 (m, 1.25H), 2.90 (br. s, 0.75H), 3.01 (d, 0.25H), 3.27-3.36 (m, 0.75H, partially obscured by the H2O signal), 3.42 (br. d, 1H), 3.76 (br. d, 0.75H), 4.17-4.32 (m , 2H), 4.39 (br. s, 0.25H), 6.93-7.02 (m, 1H), 7.20-7.39 (m, 4H), 7.42-7.63 (m, 4H), 7.84 (d, 0.5H), 7.88 (d, 1.5H), 8.54-8.63 (m, 1H). [a] and ²⁰ = -29.87° (c = 0.250, methanol). LC-MS (Method 1): Rt = 0.75 min; m/z = 475/477 (M+H) ⁺ . 36 (+)-(5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-2,5-diazabicyclo[2.2.2]oct-2-yl)(2fluorophenyl )Methanone (enantiomer 2) from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]octanedihydrochloride (enantiomer 2) and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSO^): δ [ppm] = 1.48-1.97 (m, 4H), 2.62-2.71 (m, 1H), 2.74-2.88 (m, 1.25H), 2.90 (br. s , 0.75H), 3.01 (d, 0.25H), 3.27-3.36 (m, 0.75H, partially obscured by the H2O signal), 3.42 (br. d, 1H), 3.76 (br. d, 0.75H), 4.17-4.32 ( m, 2H), 4.39 (br. s, 0.25H), 6.93-7.02 (m, 1H), 7.20-7.39 (m, 4H), 7.41-7.63 (m, 4H), 7.83 (d, 0.5H), 7.88 (d, 1.5H), 8.54-8.63 (m, 1H). [a] and ²⁰ = +19.64° (c = 0.275, methanol). LC-MS (Method 1): Rt = 0.74 min; m/z = 475/477 (M+H) ⁺ .

- 43 039175

37 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl)(cyclopentyl)methanone (enantiomer one) a# sch® o from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 1) and cyclopentanecarboxylic acid Ή-NMR (400 MHz, DMSOWc): δ [ppm] = 1.39-1.79 (m, 11H), 1.811.95 (m, 1H), 2.63-2.86 (m, 4H), 3.18 (dd, 0.5H), 3.36 (br. d, 0.5H), 3.54 (br. d, 0.5H), 3.73 (br. d, 0.5H), 3.93 (br. s, 0.5H), 4.15-4.29 (m, 2.5H), 6.97 (t, 1H), 7.25-7.36 (m, 1H), 7.53 (d, 2H), 7.59 (d, 1H), 7.86 (d, 2H), 8.54-8.62 (m, 1H). LC-MS (Method 1): Rt = 0.74 min; m/z = 449/451 (M+H) ⁺ . 38 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl)(cyclopentyl)methanone (enantiomer 2) coolant O from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 2) and cyclopentanecarboxylic acid Ή-NMR (400 MHz, DMSOWc): δ [ppm] = 1.38-1.78 (m, 11H), 1.801.95 (m, 1H), 2.64-2.86 (m, 4H), 3.18 (dd, 0.5H), 3.36 (br. d, 0.5H), 3.54 (br. d, 0.5H), 3.73 (br. d, 0.5H), 3.93 (br. s, 0.5H), 4.16-4.30 (m, 2.5H), 6.97 (t, 1H), 7.25-7.35 (m, 1H), 7.53 (d, 2H), 7.59 (d, 1H), 7.86 (d, 2H), 8.53-8.62 (m, 1H). LC-MS (Method 1): Rt = 0.75 min; m/z = 449/451 (M+H) ⁺ . 39 (-)-(5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3 methoxyphenyl) methanone (enantiomer 1) ⁿ ' ^c ~ 9 / A o from 2- {[2- (4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5 -d iazabicyclo[ 2.2.2] octane dihydrochloride (enantiomer 1) and 3-methoxybenzoic acid Ή-NMR (400 MHz, DMSOWc): δ [ppm] = 1.46-1.67 (m, 1.75H), 1.691.98 (m, 2.25H), 2.68 (br. d, 1H), 2.81 (br. d, 1H), 2.88 (br. s, 0.75H), 2.92 (br. d, 0.25H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75 H), 3.62 (br. d, 0.25H), 3.67-3.82 (m, 3.75H), 4.194.32 (m, 2.25H), 6.80-6.87 (m, 1.5H), 6.91-7.06 (m, 2.5 H), 7.26-7.40 (m, 2H), 7.46-7.64 (m, 3H), 7.83-7.92 (m, 2H), 8.56-8.63 (m, 1H). [a] ^D20 = _-36.15 ° (c = 0.260, methanol). LC-MS (Method 1): Rt = 0.75 min; m/z = 487/489 (M+H) ⁺ .

-44039175 (+)-(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3-yl]methyl }-2,5-diazabicyclo[2.2.2]oct-2-yl) (3 methoxyphenyl) methanone (enantiomer 2)

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 2) and 3-methoxy______benzoic acid____________ ( 2-chloro-5-fluorophenyl)(5-{[2-(4chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl } 2,5-diazabicyclo[2.2.2]oct-2-yl )Methanone (enantiomer 7)

'H-NMR (400 MHz, DMSO4/ ₆ ):

δ [ppm] = 1.46-1.67 (m, 1.75H), 1.701.97 (m, 2.25H), 2.68 (br. d, 1H), 2.81 (br. d, 1H), 2.88 (br. s, 0.75 H), 2.92 (br. d, 0.25H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.53 (br. s, 0.75H), 3.62 (br. d, 0.25 H), 3.68-3.82 (m, 3.75H), 4.204.32 (m, 2.25H), 6.80-6.87 (m, 1.5H), 6.92-7.06 (m, 2.5H), 7.26-7.39 (m, 2H ), 7.47-7.63 (m, 3H), 7.84-7.92 (m, 2H), 8.56-8.64 (m, 1H).

[oc]d ²⁰ = +43.73° (c = 0.250, methanol).

LC-MS (Method 1):

Rt = 0.75 min; m/z = 487/489 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-cA):

δ [ppm] = 1.46-1.99 (m, 4H), 2.56-3.01 (m, 3.6H), 3.14 (br. s, 0.4H), 3.23 (br. s, 0.4H), 3.41 (br. t, 0.6H), 3.77 (br. t, 0.6H), 4.17-4.33 (m, 2H), 4.39 (br. s, 0.4H), 6.92-7.03 (m, 1H), 7.14-7.38 (m, 3H) , 7.46-7.64 (m, 4H), 7.77-7.93 (m, 2H), 8.53-8.64 (m, 1H).

LC-MS (Method 1):

Rt = 0.79 min; m/z = 509/511 (M+H) ⁺ .

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 1) and 2-chloro-5__________fluorobenzoic acids __________ (5-{ [2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5-diazabicyclo[2.2.2] οκτ-2-yl) (cyclohexyl) methanone ( enantiomer 1)

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and cyclohexanecarboxylic acid 'H- NMR (400 MHz, DMSO4/ ₆ ): δ [ppm] = 1.04-1.38 (m, 5H), 1.42-1.78 (m, 8H), 1.79-1.94 (m, 1H), 2.23-2.45 (m, 1H) , 2.61-2.84 (m, 3H), 3.16 (dd, 0.6H), 3.27-3.39 (m, 0.4H, partially H2O-hidden signal), 3.51 (d, 0.6H), 3.72 (d, 0.4H), 3.89 (br. s, 0.6H), 4.154.29 (m, 2.4H), 6.97 (t, 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.827.90 (m, 2H), 8.57 (d, 1H).

LC-MS (Method 1):

Rt = 0.77 min; m/z = 463/465 (M+H) ⁺ .

- 45 039175

43 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl)(sus1obutyl)methanone (enantiomer /) sch® O from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer /) and cyclobutanecarboxylic acid 'H-NMR (400 MHz, DMSO4Z ₆ ): δ [ppm] = 1.41-1.55 (m, 1H), 1.56-2.18 (m, 9H), 2.64-2.83 (m, 3H), 3.10-3.24 (m, 2H), 3.48-3.60 (m, 1H), 3.63 (br. s, 0.6H), 4.15-4.28 (m, 2.4H), 6.97 (t, 1H), 7.31 (t, 1H), 7.53 (d, 2H), 7.59 (d, 1H), 7.81-7.90 (m, 2H), 8.57 (d, 1H). LC-MS (Method 1): Rt = 0.69 min; m/z = 435/437 (M+H) ⁺ . 44 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)(2methoxyphenyl)methanone (enantiomer 7) Ολο-CA® H ₃ c ^z from 2- {[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3 yl]methyl} -2,5-d iazabiciklo[2.2.2] octanedihydrochloride (enantiomer 7) and 2-methoxybenzoic acid 'H-NMR (400 MHz, DMSO-d/): δ [ppm] = 1.45-1.67 (m, 2.2H), 1.691.95 (m, 1.8H), 2.46-2.84 (m, 3H, partially obscured by signal DMSO), 2.90 (br. s, 1H), 3.18 (br. s, 0.8H), 3.283.47 (m, 1H, partially hidden by the H2O signal), 3.58 (br. _s , 1.2H), 3.74 (br s, 1.8H), 4.17-4.30 (m, 2H), 4.33-4.39 (m, 0.2H), 6.86-7.14 (m, 4H), 7.26-7.41 (m, 2H), 7.47-7.63 (m, 3H), 7.79-7.94 (m, 2H). LC-MS (Method 2): Rt = 1.33 min; m/z = 487/489 (M+H) ⁺ . 45 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)(5fluoro-2- methoxyphenyl) methanone (enantiomer 7) H ₃ c ^z from 2- {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5 -d iazabicyclo[2.2.2] octane dihydrochloride (enantiomer 7) and 5-fluoro-2-methoxybenzoic acid 'H-NMR (400 MHz, DMSOW4 δ [ppm] = 1.47-1.97 (m, 4H), 2.69 (br. d, 1H), 2.77-2.92 (m, 2H), 3.03 (br. d, 0.25H) , 3.34-3.48 (m, 1.75H), 3.68-3.80 (m, 3.75H), 4.17-4.30 (m, 2H), 4.38 (br. s, 0.25H), 6.80-6.91 (m, 1H), 6.93 -7.05 (m, 2H), 7.13-7.25 (m, 1H), 7.27-7.35 (m, 1H), 7.46-7.57 (m, 2H), 7.57-7.63 (m, 1H), 7.81-7.92 (m, 2H), 8.54-8.63 (m, 1H) LC-MS (Method 2): Rt = 1.41 min, m/z = 505/507 (M+H) ⁺ .

- 46 039175

46 (5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)(2methylphenyl)methanone (enantiomer 1) yYau sch® ° CH ₃ from 2- {[2- (4-chlorophenyl) imidazo [ 1,2-a] pyridin-3 yl] methyl } -2,5-d iazabiciklo[2.2.2] octanedihydrochloride (enantiomer 1) and 2-methylbenzoic acid 'H-NMR (400 MHz, DMSO-όΑ): δ [ppm] = 1.46-1.97 (m, 4H), 2.00-2.22 (m, ZN), 2.56-2.69 (m, 1.5H), 2.73-2.80 ( m, 0.5H), 2.86 (br. t, 0.5H), 2.94 (br. s, 0.75H), 3.12-3.27 (m, 1H), 3.40 (d, 0.75H), 3.80 (br. d, 0.75 H), 4.16-4.30 (m, 2H), 4.40 (br. s, 0.25H), 6.91-7.02 (m, 1.3H), 7.09-7.36 (m, 4.7H), 7.467.63 (m, 3H) , 7.79-7.91 (m, 2H), 8.528.62 (m, 1H). LC-MS (Method 2): Rt = 1.40 min; m/z = 471/473 (M+H) ⁺ . 47 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)(5fluoro-2- methylphenyl) methanone (enantiomer D) LLC %® SN ₃ from 2- {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5 -d iazabicyclo[2.2.2 ] octane dihydrochloride (enantiomer 7) and 5-fluoro-2-methylbenzoic acid 'H-NMR (400 MHz, DMSO-rA): δ [ppm] = 1.48-1.96 (m, 4H), 1.97-2.20 (m, 3H), 2.57-2.69 (m, 1.4H), 2.74-3.01 ( m, 2H), 3.13-3.29 (m, 1H), 3.40 (dd, 0.7H), 3.78 (br. d, 0.6H), 4.16-4.31 (m, 2H), 4.39 (br. s, 0.3H) , 6.90-7.17 (m, 3H), 7.21-7.35 (m, 2H), 7.47-7.56 (m, 2H), 7.56-7.63 (m, 1H), 7.81-7.92 (m, 2H), 8.53-8.63 ( m, 1H). LC-MS (Method 2): Rt = 1.45 min; m/z = 489/491 (M+H) ⁺ . 48 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl) [3(trifluoromethoxy)phenyl ] methanone (enantiomer 7) GO "X® about from 2-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and 3(trifluoromethoxy)benzoic acids 'H-NMR (400 MHz, DMSO-rA): δ [ppm] = 1.46-1.99 (m, 4H), 2.63-2.72 (m, 1H), 2.84 (br. d, 1H), 2.87-2.97 (m , 1H), 3.18 (br. d, 0.3H), 3.39 (dd, 0.7H), 3.47 (br. s, 0.7H), 3.63 (br. d, 0.3H), 3.74 (br. d, 0.7H ), 4.20-4.35 (m, 2.3H), 6.92-7.02 (m, 1H), 7.26-7.37 (m, 2.4H), 7.40-7.63 (m, 5.6H), 7.83-7.92 (m, 2H), 8.56-8.64 (m, 1H). LC-MS (Method 4): Rt = 2.09 min; m/z = 541/543 (M+H) ⁺ .

-47 039175 (3-chlorophenyl)(5-{[2-(4chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl } 2,5-diazabicyclo[2.2.2]oct-2-yl )Methanone (enantiomer 7)

Ή-NMR (400 MHz, DMSOV ₆ ): δ [ppm] = 1.48-1.98 (m, 4H), 2.62-2.70 (m, 1H), 2.83 (br. d, 1H), 2.87-2.95 (m, 1H ), 3.17 (br. d, 0.3H), 3.38 (dd, 0.7H), 3.49 (br. s, 0.7H), 3.65 (br. d, 0.3H), 3.73 (br. d, 0.7H), 4.19-4.32 (m, 2.3H), 6.93-7.02 (m, 1H), 7.22-7.63 (m, 8H), 7.84-7.92 (m, 2H), 8.56-8.64 (m, 1H).

LC-MS (Method 4):

Rt = 2.00 min; m/z = 491/493 (M+H) ⁺ .

from 2-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 1) and 3-chloro____________benzoic acid______ ( 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl} -2,5-diazabicyclo[2.2.2]οκτ-2-yl)[3-(trifluoromethyl)phenyl ]methanone (enantiomer /)

Ή-NMR (400 MHz, DMSOV ₆ ): δ [ppm] = 1.47-1.99 (m, 4H), 2.63-2.71 (m, 1H), 2.80-2.99 (m, 2H), 3.19 (br. d, 0.3 H), 3.41 (d, 0.7H), 3.47 (br. s, 0.7H), 3.63 (br. d, 0.3H), 3.75 (br. d, 0.7H), 4.19-4.36 (m, 2.3H) , 6.92-7.03 (m, 1H), 7.26-7.35 (m, 1H), 7.45-7.73 (m, 5H), 7.76-7.92 (m, 4H), 8.56-8.65 (m, 1H).

LC-MS (Method 4):

Rt = 2.05 min; m/z = 525/527 (M+H) ⁺ .

from 2-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]octanedihydrochloride (enantiomer G) and 3-(Trifluoro__________methyl) benzoic acid__________ (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2] οκτ-2-yl)(pyridin-2 -yl) methanone (enantiomer 7)

Ή-NMR (400 MHz, DMSOV ₆ ): δ [ppm] = 1.47-1.99 (m, 4H), 2.68 (dd, 1H), 2.81-2.94 (m, 2H), 3.34-3.45 (m, 1H), 3.71-3.81 (m, 1H), 3.87 (br. s, 0.75H), 4.20-4.33 (m, 2H), 4.39 (br. s, 0.25H), 6.92-7.02 (m, 1H), 7.26-7.35 (m, 1H), 7.41-7.66 (m, 5H), 7.81-7.97 (m, 3H), 8.50-8.64 (m, 2H).

LC-MS (Method 1):

Rt = 0.64 min; m/z = 458/460 (M+H) ⁺ .

from 2-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and pyridine2-carboxylic acid

- 48 039175 (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl)( 1 methyl - 1//-imidazol-2-yl) methanone (enantiomer

'H-NMR (400 MHz, DMSO4A): δ [ppm] = 1.48-1.98 (m, 4H), 2.64-2.93 (m, 3H), 3.36 (dd, 1H), 3.66-3.81 (m, 3.75H) , 4.09 (d, 0.25H), 4.19-4.31 (m, 2H), 4.38 (br. s, 0.25H), 4.74 (br. s, 0.75H), 6.87-7.02 (m, 2H), 7.23-7.35 (m, 2H), 7.46-7.56 (m, 2H), 7.60 (d, 1H), 7.82-7.92 (m, 2H), 8.60 (d, 1H).

LC-MS (Method 1):

Rt = 0.61 min; m/z = 461/463 (M+H) ⁺ .

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 1) and 1-methyl-\ H_______imidazole-2-carboxylic acid_______ (5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2-yl) (3 methylphenyl) methanone (enantiomer 7)

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and 3-methylbenzoic acid' H-NMR (400 MHz, DMSO<7 ₆ ): δ [ppm] = 1.45-1.98 (m, 4H), 2.30 (s, 2H), 2.35 (s, 1H), 2.62-2.69 (m, 1H), 2.75-2.84 (m, 1H), 2.86-2.94 (m, 1H), 3.16 (br. d, 0.3H), 3.37 (br. d, 0.7H), 3.52 (br. d, 0.7H), 3.62 ( br. d, 0.3H), 3.74 (br. d, 0.7H), 4.20-4.32 (m, 2.3H), 6.92-7.13 (m, 2.4H), 7.18-7.36 (m, 3.6H), 7.46- 7.64 (m, 3H), 7.83-7.92 (m, 2H), 8.56-8.63 (m, 1H).

LC-MS (Method 2):

Rt = 1.41 min; m/z = 471/473 (M+H) ⁺ .

(5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl)(3-ethoxyphenyl)methanone (enantiomer 7)

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and 3ethoxybenzoic acid 'H- NMR (400 MHz, DMSO4/ ₆ ): δ [ppm] = 1.22-1.38 (m, SA), 1.44-1.96 (m, 4H), 2.62-2.97 (m, SA), 3.16 (br. d, 0.3H ), 3.36 (br. d, 0.7H), 3.52 (br. s, 0.7H), 3.63 (br. d, 0.3H), 3.73 (br. d, 0.7H), 3.95-4.10 (m, 2H) , 4.17-4.32 (m, 2.3H), 6.77-6.85 (m, 1.4H), 6.91-7.03 (m, 2.6H), 7.23-7.38 (m, 2H), 7.46-7.63 (m, 3H), 7.82 -7.92(m, 2H), 8.55-8.64(m, 1H).

LC-MS (Method 2):

Rt= 1.43 min; m/z = 501/503 (M+H) ⁺ .

- 49 039175 (5- {[2-(4-chlorophenyl)imidazo[1,2-a] pyridin-3 yl] methyl } -2,5-diazabicyclo[2.2.2] οκτ-2-yl) (pyridin- 4-yl) methanone (enantiomer 7)

from 2-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-d-iazabicyclo[2.2.2]octanedihydrochloride (enantiomer 7) and isonicotinic acid (-) -(2-fluorophenyl)(5-{[2-(4isopropylphenyl)imidazo[1,2-а]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2]oct-2yl)methanone (enantiomer 7 )

from 2-{[2-(4-isopropylphenyl)imide azo[1,2-a]pyride in-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-dihydrochloride (enantiomer 7) and 2 -fluorobenzoic acid (+)-(2-fluorophenyl)(5-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -2,5-diazabicyclo[2.2.2] oct- 2yl) methanone (enantiomer 2)

from 2-{[2-(4-isopropylphenyl)imide azo[1,2-a]pyride in-3-yl]methyl}-2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2) and 2 -fluorobenzoic acid 'H-NMR (400 MHz, DMSO4A): δ [ppm] = 1.47-1.99 (m, 4H), 2.61-2.70 (m, 1H), 2.78-2.87 (m, 1H), 2.91 (br. s, 1H), 3.14 (br. d, 0.3H), 3.36-3.46 (m, 1.4H), 3.58 (br. d, 0.3H), 3.74 (br. d, 0.7H), 4.18-4.36 (m , 2.3H), 6.92-7.02 (m, 1H), 7.25 (m, 2.5H), 7.38-7.44 (m, 0.5H), 7.47-7.63 (m, 3H), 7.81-7.91 (m, 2H), 8.55-8.64 (m, 2.5H), 8.65-8.70 (m, 0.5H).

LC-MS (Method 2):

Rt = 1.06 min; m/z = 458/460 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-c/b): δ [ppm] = 1.20-1.30 (m, 6H), 1.49-1.99 (m, 4H), 2.65-2.73 (m, 1H), 2.76-2.88 (m, 1.25H), 2.88-3.06 (m, 2H), 3.273.36 (m, 0.75H, partially obscured by the H2O signal), _3.39-3.49 (m, 1H), 3.77 (br. d, 0.75H) , 4.22 (s, 0.5H), 4.26 (s, 1.5H), 4.40 (br. s, 0.25H), 6.91-7.00 (m, 1H), 7.18-7.39 (m, 6H), 7.41-7.53 (m , 1H), 7.55-7.62 (m, 1H), 7.73 (d, 0.5H), 7.76 (d, 1.5H), 8.52-8.61 (m, 1H).

[oc] _D ²⁰ = -27.07° (c = 0.250, methanol). LC-MS (Method 1):

Rt = 0.81 min; m/z = 483 (M+H) ⁺ .

^-NMR (400 MHz, DMSOW4 δ [ppm] = 1.20-1.30 (m, 6H), 1.48-1.97 (m, 4H), 2.63-2.74 (m, 1H), 2.75-2.88 (m, 1.25H), 2.89-3.05 (m, 2H), 3.253.36 (m, 0.75H, partially hidden by the H2O signal), _3.38-3.51 (m, 1H), 3.77 (br. d, 0.75H), 4.22 (s, 0.5H ), 4.26 (s, 1.5H), 4.40 (br. s, 0.25H), 6.90-7.00 (m, 1H), 7.17-7.40 (m, 6H), 7.40-7.53 (m, 1H), 7.54-7.61 (m, 1H), 7.73 (d, 0.5H), 7.76 (d, 1.5H), 8.51-8.61 (m, 1H).

[a] _D20 = + ^26.29 ° (c = 0.265, methanol). LC-MS (Method 4):

Rt = 2.02 min; m/z = 483 (M+H) ⁺ .

- 50 039175

(-)-(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl } -2.5d iazabicyclo[2.2.2]oct-2-yl) (3 methoxyphenyl) methanone (enantiomer /) n ₃ s.

o from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl }-2,5-diazabicyclo[2.2.2]octane-dihydrochloride (enantiomer 7) and 3 -methoxybenzoic acid

(+)-(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl } -2.5d iazabicyclo[2.2.2]oct-2-yl) (3 methoxyphenyl) methanone (enantiomer 2)

o from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl }-2,5e azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2) and 3- methoxybenzoic acid (-)-(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3 -yl] methyl } -2.5 d iazabicyclo[2.2.2] oct-2- yl)(6-methoxypyride in2-yl)methanone (enantiomer 7)

o from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl}-2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 7) and 6 -methoxypyridine-2carboxylic acid 'H-NMR (400 MHz, DMSO4Z ₆ ): δ [ppm] = 1.20-1.30 (m, 6H), 1.47-1.69 (m, 1.75H), 1.71-1.98 (m, 2.25H) , 2.662.74 (m, 1H), 2.82 (br. d, 1H), 2.88-3.01 (m, 2H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.54 ( br. s, 0.75H), 3.64 (br. d, 0.25H), 3.70-3.82 (m, 3.75H), 4.22 (s, 0.5H), 4.26 (s, 1.5H), 4.31 (br. s, 0.25H), 6.80-6.87 (m, 1.5H), 6.90-7.06 (m, 2.5H), 7.24-7.39 (m, 4H), 7.54-7.62 (m, 1H), 7.73-7.80 (m, 2H) , 8.53-8.62 (m, 1H).

[a]o ²⁰ = -27.50° (c = 0.280, methanol).

LC-MS (Method 1):

Rt = 0.81 min; m/z = 495 (M+H) ⁺ . 'H-NMR (400 MHz, DMS(W ₆ ): δ [ppm] = 1.19-1.30 (m, 6H), 1.47-1.69 (m, 1.75H), 1.71-1.98 (m, 2.25H), 2.662. 74 (m, 1H), 2.82 (br. d, 1H), 2.87-3.02 (m, 2H), 3.17 (br. d, 0.25H), 3.37 (br. d, 0.75H), 3.54 (br. s , 0.75H), 3.64 (br. d, 0.25H), 3.69-3.82 (m, 3.75H), 4.22 (s, 0.5H), 4.26 (s, 1.5H), 4.31 (br. s, 0.25H) , 6.80-6.87 (m, 1.5H), 6.89-7.05 (m, 2.5H), 7.23-7.39 (m, 4H), 7.53-7.61 (m, 1H), 7.71-7.82 (m, 2H), 8.53- 8.62(m, 1H).

[a]o ²⁰ = +30.79° (c = 0.275, methanol).

LC-MS (Method 4):

Rt = 2.02 min; m/z = 495 (M+H) ⁺ . 'H-NMR (400 MHz, DMSO-t/e): δ [ppm] = 1.24 (d, 6H), 1.49-2.00 (m, 4H), 2.67-2.78 (m, 1H), 2.84-3.01 (m , 3H), 3.39 (dd, 0.75H), 3.46 (d, _0.25H ), 3.71-3.78 (m, 3H), 3.82 (s, 0.75H), m, 2H), 4.39 (br. s, 0.25H), 6.85-7.00 (m, 2H), 7.17 (d, 0.75H), 7.24-7.38 (m, 3.25H), 7.58 (d, 1H), 7.70 -7.86 (m, 3H), 8.548.61 (m, 1H).

[a]o ²⁰ = -32.98° (c = 0.285, methanol).

LC-MS (Method 2):

Rt = 1.34 min; m/z = 496 (M+H) ⁺ .

- 51 039175 (+) - (5-{[2- (4-isopropylphenyl) imidazo [1,2-a] pyride in-3 -yl] methyl } -2.5d iazabicyclo[2.2.2] oct-2- yl)(6-methoxypyride in2-yl)methanone (enantiomer 2)

from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl}-2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2) and 6- methoxypyridine-2carboxylic acid

Cyclopentyl (5 - {[2- (4isopropylphenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5 -diazabicyclo[2.2.2] oct-2yl) methanone (enantiomer /) 'H-NMR (400 MHz, DMSO®): δ [ppm] = 1.24 (d, 6H), 1.49-2.01 (m, 4H), 2.68-2.78 (m, 1H), 2.84-3.01 (m, 3H), 3.39 (dd , 0.75H), 3.46 (d, 0.25H), 3.71-3.78 (m, 3H), 3.82 (s, 0.75H), 3.94-4.03 (n ₅ s), 4.22-4.31 (m, 2H), 4.39 ( br. s, 0.25H), 6.85-7.00 (m, 2H), 7.17 (d, 0.75H), 7.23-7.38 (m, 3.25H), 7.58 (d, 1H), 7.70-7.85 (m, 3H) , 8.548.61 (m, 1H).

[a] ^D20 = + _36.23 ° (c = 0.265, methanol). LC-MS (Method 4):

Rt = 2.02 min; m/z = 496 (M+H) ⁺ .

from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl}-2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer /) and cyclopentanecarboxylic ' H-NMR (400 MHz, DMSO®): δ [ppm] = 1.25 (d, 6H), 1.39-1.79 (m, 11H), 1.80-1.96 (m, 1H), 2.64-2.86 (m, 4H), 2.88-3.01 (m, 1H), 3.19 (dd, 0.5H), 3.27-3.38 (m, 0.5H, partially hidden by the H2O signal), 3.55 (br. d, 0.5H), 3.73 (br. d, 0.5 H), 3.94 (br. s, 0.5H), 4.174.30 (m, 2.5H), 6.95 (t, 1H), 7.28 (t, 1H), 7.34 (d, 2H), 7.58 (dd, 1H) , 7.717.79 (m, 2H), 8.56 (d, 1H).

LC-MS (Method 2): Rt = 1.44 min; m/z = 457 (M+H) ⁺ .

acids

Cyclopentyl (5 - {[2- (4isopropylphenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -2,5 -diazabicyclo[2.2.2] oct-2yl) methanone (enantiomer 2)

from 2-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl}-2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2) and cyclopentanecarboxylic acid 'H-NMR (400 MHz, DMSO®): δ [ppm] = 1.25 (d, 6H), 1.38-1.80 (m, PN), 1.80-1.96 (m, 1H), 2.64-2.86 (m, 4H) , 2.88-3.01 (m, 1H), 3.19 (dd, 0.5H), _3.27-3.38 (m, 0.5H, partially hidden by H2O signal), 3.55 (br. d, 0.5H), 3.73 (br. d, 0.5H), 3.94 (br. s, 0.5H), 4.174.30 (m, 2.5H), 6.95 (t, 1H), 7.28 (t, 1H), 7.34 (d, 2H), 7.58 (dd , 1H), 7.707.79 (m, 2H), 8.56 (d, 1H).

LC-MS (Method 4):

Rt = 2.10 min; m/z = 457 (M+H) ⁺ .

(-)-(5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl } -2.5 d azabicyclo[2.2.2] oct- 2-yl)(2fluorophenyl)methanone (enantiomer /)

from 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl} -2.5 d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 7 ) and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSO®): δ [ppm] = 1.49-1.93 (m, 3.3H), 1.942.07 (m, 0.7H), 2.65-2.73 (m, 0.3 H), 2.87 (br. d, 0.7H), 2.91-3.09 (m, 2.3H), 3.36 (br. s, 0.7H), 3.43 (dd, 0.7H), 3.73 (br. d, 0.3H) , 3.85 (br. d, 0.7H), 4.43 (br. s, 0.3H), 4.53-4.75 (m, 2H), 6.947.05 (m, 1H), 7.21-7.40 (m, 3.7H), 7.41 -7.57 (m, 1.3H), 7.58-7.66 (m, 1H), 7.94-8.05 (m, 1H), 8.19 (d, 0.3H), 8.22 (d, 0.7H), 8.41 (d, 0.3H) , 8.45-8.52 (m, 1H), 8.66 (d, 0.7H).

[a] ^D20 = _-55.55 ° (c = 0.270, methanol). LC-MS (Method 2):

Rt = 1.13 min; m/z = 476/478 (M+H) ⁺ .

-52039175 (+)-(5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl } -2.5d iazabicyclo[2.2.2] oct -2-yl)(6-methoxypyride in2-yl)methanone (enantiomer 2)

from 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl } -2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2 ) and 6-methoxypyridine-2___________carboxylic acid___________ (5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3 -yl]methyl } -2.5 diazabicyclo[2.2.2 ]oct-2-yl)(3-fluoro-6methoxypyridin-2-yl)methanone (enantiomer 2)

from 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl } -2.5d azabicyclo[2.2.2]octane-dihydrochloride (enantiomer 2 ) and 3-fluoro-6-methoxypyridine-2-carboxylic acid

Ή-NMR (400 MHz, DMSOV ₆ ): δ [ppm] = 1.50-2.07 (m, 4H), 2.68-2.72 (m, 0.3H), 2.85-2.95 (m, 1.4H), 3.003.09 (m , 1.3H), 3.37 (dd, 0.7H), 3.49 (dd, 0.3H), 3.77 (s, 2.3H), 3.81-3.89 (m, 1.4H), 4.01 (br. s, 0.7H), 4.08 (br. d, 0.3H), 4.42 (br. s, 0.3H), 4.57-4.76 (m, 2H), 6.89 (d, 0.7H), 6.94 (d, 0.3H), 6.96-7.04 (m, 1H), 7.21 (d, 0.7H), 7.317.39 (m, 1.3H), 7.57-7.65 (m, 1H), 7.77-7.89 (m, 1H), 7.97-8.04 (m, 1H), 8.17- 8.25 (m, 1H), 8.43 (d, 0.3H), 8.478.53 (m, 1H), 8.63 (d, 0.7H). [α]π ²⁰ = +76.24° (c = 0.275, methanol). LC-MS (Method 2):

Rt = 1.16 min; m/z = 489/491 (M+H) ⁺ .

Ή-NMR (400 MHz, DMSOV ₆ ): δ [ppm] = 1.53-2.08 (m, 4H), 2.76 (br. s, 0.3H), 2.87 (dd, 0.7H), 2.91-3.09 (m, 2H ), 3.15 (br. d, 0.3H), 3.42 (dd, 0.7H), 3.50 (br. s, 0.7H), 3.72-3.89 (m, 4H), 4.42 (br. s, 0.3H), 4.58 -4.76 (m, 2H), 6.93 (dd, 0.7H), 6.96-7.04 (m, 1.3H), 7.31-7.39 (m, 1H), 7.59-7.65 (m, 1H), 7.76 (t, 0.7H ), 7.84 (t, 0.3H), 7.96-8.04 (m, 1H), 8.16-8.25 (m, 1H), 8.44-8.52 (m, 1.3H), 8.65 (d, 0.7H).

LC-MS (Method 2): Rt= 1.13 min; m/z = 507/509 (M+H) ⁺ .

- 53 039175

(3-chloro-6-methoxypyride in-2-yl)(5 - {[2-(5 chloropyridin-2-yl)imidazo[1,2-a]pyridin-3yl]methyl)-2,5-diazabicyclo[ 2.2.2] oct-2yl) methanone (enantiomer 2)

ci

ci ' from 2-{[2-(5-chloropyridin-2-yl)-imidazo[1,2-a] pyride in-3-yl] methyl)-2,5d and azabicyclo[2.2.2] octane-dihydrochloride (enantiomer 2) and 3-chloro-6-methoxypyridine-2____________carboxylic acid____________ (2-fluorophenyl)(5-{[2-(6-isopropylpyridin-3yl)imidazo[1,2-а]pyridin-3-yl]methyl)-2 ,5d iazabicyclo[2.2.2]oct-2-yl)methanone (Racemate)

'H-NMR (400 MHz, DMSO^A): δ [ppm] = 1.51-2.08 (m, 4H), 2.74 (br.

s, 0.3H), 2.83 (dd, 0.7H), 2.91-3.08 (m, 2.3H), 3.24 (br. s, 0.7H), 3.44 (br. d, 0.7H), 3.66 (br. d, 0.3H), 3.76 (s, 2.3H), 3.82-3.90 (m, 1.4H), 4.43 (br. s, 0.3H), 4.62-4.74 (m, 2H), 6.90 (d, 0.7H), 6.937 .06 (m, 1.3H), 7.30-7.39 (m, 1H), 7.58-7.67 (m, 1H), 7.85 (d, 0.7H), 7.95 (d, 0.3H), 7.97-8.05 (m, 1H ), 8.16-8.27 (m, 1H), 8.44 (d, 0.3H), 8.46-8.53 (m, 1H), 8.65 (d, 0.7H).

LC-MS (Method 2):

Rt= 1.21 min; m/z = 523/524/525 (M+H) ⁺ .

LC-MS (Method 2):

Rt = 1.19 min; m/z = 484 (M+H) ⁺ .

from 2-{[2-(6-isopropylpyridin-3yl)imidazo[1,2-a]pyridin-3-yl]methyl } -2,5 diazabicyclo[2.2.2]octane-d and hydrochloride a (Racemate) and 2 -fluorobenzoic acid (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl) -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl) (2-fluorophenyl) methanone o

Cl ¹ H-NMR (400 MHz, DMSO A δ/ppm): 2.45 (br. d, 1H), 2.57 (br. d, 1H, partially obscured by the DMSO signal), 2.86 (br. d, 1H), 3.00 ( br. d, 1H), 3.39 (br. s, 1H), 3.59 (br. d, 1H), 3.70 (br. t, 2H), 3.86 (d, 1H), 3.93 (s, 2H), 4.49 ( br. s, 1H), 6.93 (td, 1H), 7.25-7.35 (m, 3H), 7.41-7.55 (m, 4H), 7.59 (d, 1H), 7.96 (d, 2H), 8.82 (d, 1H). LC-MS (Method 1):

Rt = 0.73 min; m/z = 491/493 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3yl]methyl)-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 2-fluorobenzoic acid

- 54 039175 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1] non-9yl) (3-methoxyphenyl) methanone

Ή-NMR (400 MHz, DMSOA δ/ppm): 2.46-2.57 (m, 1H, masked by DMSO signal), 2.61 (br. d, 1H), 2.83 (br. d, 1H), 2.96 (br. d, 1H), 3.563.75 (m, 4H), 3.77 (s, 3H), 3.84 (d, 1H), 3.94 (s, 2H), 4.41 (br. s, 1H), 6.88-7.06 (m, 4H) , 7.30 (t, 1H), 7.36 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.98 (d, 2H), 8.83 (d, 1H).

LC-MS (Method 1):

Rt = 0.74 min; m/z = 503/505 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 3-methoxybenzoic acid ( 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1] non-9yl)(cyclopentyl)methanone

¹ H-NMR (400 MHz, DMSO-tA, δ/ppm): 1.43-1.81 (m, 8H), 2.40 (br. d, 1H), 2.45-2.57 (m, 1H, partially obscured by DMSO signal), 2.83 -2.96 (m, 3H), 3.51 (br. d, 1H), 3.60 (br. d, 1H), 3.76 (dd, 2H), 3.85-3.95 (m, 2H), 4.05 (br. s, 1H) , 4.34 (br. s, 1H), 6.93 (td, 1H), 7.30 (ddd, 1H), 7.51 (d, 2H), 7.60 (d, 1H), 7.98 (d, 2H), 8.82 (d, 1H ). LC-MS (Method 1):

Rt = 0.74 min; m/z = 465/467 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and cyclopentanecarboxylic acid (7- {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl)[3-(trifluoromethoxy) phenyl] methanone

¹ H-NMR (400 MHz, DMSO-iA, δ/ppm): 2.47-2.58 (m, 1H, partially obscured by DMSO signal), 2.64 (br. d, 1H), 2.83 (br. d, 1H), 2.96 (br. d, 1H), 3.53 (br. s, 1H), 3.63-3.77 (m, 3H), 3.84 (d, 1H), 3.95 (s, 2H), 4.42 (br. s, 1H), 6.93 (td, 1H), 7.30 (dd, 1H), 7.40-7.55 (m, 5H), 7.56-7.64 (m, 2H), 7.97 (d, 2H), 8.82 (d, 1H).

LC-MS (Method 2):

Rt = 1.60 min; m/z = 557/559 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 3-(trifluoromethoxy) benzoic acid

-55039175 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl)( 2-isopropylphenyl) methanone ζ—l ci • Ν

CH ₃

IACHj from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 2-isopropylbenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.11-1.26 (m, 6H), 2.26 (br. d, 0.5H), 2.46-2.59 (m, 1H, partially obscured by DMSO signal), 2.62 (br .d, 0.5H), 2.77-2.89 (m, 1H), 2.90-3.05 (m, 2H), 3.25-3.35 (m, 1H, partially hidden by the H2O signal), 3.44 (br. d, 0.5H), 3.61-3.76 (m, 2.5H), 3.78-3.88 (m, 1H), 3.88-4.01 (m, 2H), 4.52 (br. s, 1H), 6.94 (td, 1H), 7.15-7.26 (m, 2H), 7.30 (ddd, 1H), 7.35-7.45 (m, 2H), 7.51 (t, 2H), 7.60 (d, 1H), 7.93 (d, 1H), 7.98 (d, 1H), 8.76 (d , 0.5H), 8.83 (d, 0.5H).

LC-MS (Method 2):

Rt= 1.60 min; m/z = 515/517 (M+H) ⁺ .

(2-chloro-5-methoxyphenyl)(7-{[2-(4chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl } 3-oxa-7,9-diazabicyclo [3.3.1] non-9-yl) methanone g—l ci

Cl

CH.

o' 'H-NMR (400 MHz, DMSOA δ/ppm): 2.47-2.60 (m, 1.5H, partially obscured by DMSO signal), 2.65 (br. d, 0.5H), 2.77-2.92 (m, 1H), 2.92-3.04 (m, 1H), 3.26 (br. d, 1H), 3.62-3.98 (m, 9H), 4.46 (br. s, 1H), 6.93 (t, 1H), 7.01 (d, 2H), 7.30 (t, 1H), 7.42 (d, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.97 (t, 2H), 8.82 (t, 1H).

LC-MS (Method 2):

Rt= 1.44 min; m/z = 537/538/539 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 2-chloro-5 -methoxybenzoic acid (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1] non-9yl) (5-fluoro-2-methoxyphenyl) methanone g—l

N

Cl•CH.

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 5-fluoro-2- methoxybenzoic acid (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl)( 3-isopropylphenyl) methanone

Cl

CH ₃

CH ₃ from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 3-isopropylbenzoic acid 'H-NMR (400 MHz, DMSO-tA, δ/ppm): 2.38-2.60 (m, 2H, partially obscured by DMSO signal), 2.75-2.89 (m, 1H), 2.89-3.04 (m, 1H), 3.26 (br. s, 1H), 3.47-3.97 (m, 9H), 4.44 (br. s, 1H), 6.94 (t, 1H), 7.05-7.18 (m, 2H), 7.23 (tt, 1H), 7.30 (t, 1H), 7.52 (d, 2H), 7.59 (d, 1H), 7.96 (d, 2H), 8.82 (d, 1H).

LC-MS (Method 2):

Rt= 1.35 min; m/z = 521/523 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-rA δ/ppm): 1.19 (d, 6H), 2.47-2.57 (m, 1H, hidden by DMSO), 2.63 (br. d, 1H), 2.80-3.00 (m , 3H), 3.55-3.75 (m, 4H), 3.84 (br. d, 1H), 3.94 (s, 2H), 4.42 (br. s, 1H), 6.93 (td, 1H), 7.20-7.39 (m , 5H), 7.52 (d, 2H), 7.59 (d, 1H), 7.98 (d, 2H), 8.83 (d, 1H).

LC-MS (Method 2):

Rt = 1.62 min; m/z = 515/517 (M+H) ⁺ .

- 56 039175 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl) [6-(2,2,2-trifluoroethoxy)pyridin-2-yl]methanone

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 6-(2, 2,2Trifluoroethoxy)pyridine-2-carboxylic acid (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3-oxa-7,9-diazabicycle o[3.3 .1] non-9yl)(tetrahydrofuran-3-yl)methanone

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and tetrahydrofuran____________3-carboxylic acid____________ ( 3-chlorophenyl)(7-{[2-(4-chlorophenyl)imidazo[1,2a]pyridin-3-yl]methyl }-3-oxa-7,9diazabicyclo[3.3.1]non-9-yl)methanone

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 3-chlorobenzoic acid ¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 2.58-2.69 (m, 2H), 2.87 (br. d, 1H), 3.07 (br. d, 1H), 3.66-3.76 (m, 3H), 3.87-4.00 (m, 3H), 4.16 (br. s, 1H), 4.47 (br. s, 1H), 4.92 (q, 2H), 6.92 (td, 1H), 7.11 (d, 1H) , 7.30 (ddd, 1H), 7.42 (d, 1H), 7.51 (d, 2H), 7.60 (d, 1H), 7.91–8.01 (m, 3H), 8.84 (d, 1H).

LC-MS (Method 2):

Rt = 1.60 min; m/z = 572/574 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.73-2.16 (m, 4H), 2.42 (br. t, 1H), 2.46-2.59 (m, 1H, partially obscured by DMSO signal), 2.91 (br .d, 2H), 3.47-3.58 (m, 1H), 3.64 (br. d, 1H), 3.68-3.82 (m, 4H), 3.84-3.96 (m, 2H), 4.09 (br. s, 1H) , 4.28 (br. s, 1H), 4.60 (td, 1H), 6.93 (td, 1H), 7.30 (ddd, 1H), 7.51 (dd, 2H), 7.60 (d, 1H), 7.938.02 (m , 2H), 8.82 (d, 1H).

LC-MS (Method 2):

Rt = 1.13 min; m/z = 467/469 (M+H) ⁺ .

'H-NMR (400 MHz, DMSOA δ/ppm): 2.46-2.58 (m, 1H, partially obscured by DMSO signal), 2.63 (d, 1H), 2.83 (br. d, 1H), 2.96 (br. d, 1H), 3.56 (br. s, 1H), 3.62-3.76 (m, 3H), 3.84 (d, 1H), 3.95 (s, 2H), 4.41 (br. s, 1H), 6.93 (t, 1H) , 7.30 (t, 1H), 7.39 (d, 1H), 7.457.56 (m, 5H), 7.60 (d, 1H), 7.97 (d, 2H), 8.83 (d, 1H).

LC-MS (Method 2):

Rt = 1.54 min; m/z = 507/508/509 (M+H) ⁺ .

- 57 039175 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl) [6-(trifluoromethoxy)pyridin-2-yl]methanone

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 2.56-2.64 (m, 2H), 2.88 (br. d, 1H), 3.03 (br. d, 1H), 3.64-3.79 (m , 3H), 3.88 (d, 1H), 3.93 (s, 2H), 4.01 (br. s, 1H), 4.46 (br. s, 1H), 6.93 (t, 1H), 7.31 (t, 1H), 7.41 (d, 1H), 7.51 (d, 2H), 7.60 (d, 1H), 7.73 (d, 1H), 7.97 (d, 2H), 8.18 (t, 1H), 8.81 (d, 1H).

LC-MS (Method 2):

Rt = 1.47 min; m/z = 558/560 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 6-(trifluoromethoxy) pyridine___________2-carboxylic acid___________ (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl} -3-oxa-7,9-diazabicycle o[3.3.1]non-9yl )(6-methoxy-3-methylpyridin-2-yl) methanone

'H-NMR (400 MHz, DMSOA δ/ppm): 2.21 (s, 3H), 2.46-2.61 (m, 2H, partially obscured by DMSO signal), 2.86 (br. d, 1H), 3.03 (br. d, 1H), 3.38 (br. s, 1H), 3.57-3.74 (m, 3H), 3.77 (s, 3H), 3.87 (d, 1H), 3.93 (s, 2H), 4.48 (br. s, 1H) , 6.79 (d, 1H), 6.93 (td, 1H), 7.30 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.64 (d, 1H), 7.97 (d, 2H), 8.81(d, 1H).

LC-MS ((Method 1):

Rt = 0.75 min; m/z = 518/520 (M+H) ⁺ .

from 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3-oxa-7,9-diazabicycle o[3.3.1] nonanedihydrochloride and 6-methoxy-3 -methylpyridine-2____________carboxylic acid____________ (8-{[2-(4-bromophenyl)imidazo[1,2-а]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]oct-3-yl)( 2fluorophenyl) methanone

'H-NMR (400 MHz, DMSO^, δ/ppm): 1.33-1.60 (m, 2H), 1.78-1.97 (m, 2H), 2.79 (br. d, 1H), 2.99 (br. d, 1H ), 3.05 (br. s, 1H), 3.12 (br. d, 1H), 3.21 (br. s, 1H), 3.93-4.05 (m, 2H), 4.16 (br. d, 1H), 6.99 (t , 1H), 7.25 (t, 2H), 7.32 (t, 2H), 7.46 (q, 1H), 7.60 (d, 1H), 7.66 (d, 2H), 7.80 (d, 2H), 8.67 (d, 1H). LC-MS (Method 1):

Rt = 0.80 min; m/z = 519/521 (M+H) ⁺ .

from 8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-fluorobenzoic acid

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83 (8-{[2-(4-bromophenyl)imidazo[1,2-а]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]oct-3-yl)(6methoxypyridin-2-yl ) methanone about from 8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-d-iazabicyclo[3.2.1]octanedihydrochloride and 6-methoxypyridine2-carboxylic acid ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.49-1.60 (m, 1H), 1.62-1.71 (m, 1H), 1.79-1.98 (m, 2H), 2.81 (d, 1H), 3.05 (br. s, 1H), 3.11 (br. d, 1H), 3.23 (br. s, 1H), 3.39 (br. d, 1H), 3.80 (s, 3H), 3.93-4.07 (m, 2H) , 4.13 (br. d, 1H), 6.85 (d, 1H), 6.99 (t, 1H), 7.09 (d, 1H), 7.32 (t, 1H), 7.60 (d, 1H), 7.66 (d, 2H ), 7.77 (t, 1H), 7.81 (d, 2H), 8.68 (d, 1H). LC-MS (Method 2): Rt = 1.41 min; m/z = 532/534 (M+H) ⁺ . 84 (8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]oct-3-yl)(3methoxyphenyl) methanone ⁿ ' ^c ~9 /G ^ o from 8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]octanedihydrochloride and 3 -methoxybenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.33-1.47 (m, 1H), 1.49-1.63 (m, 1H), 1.77-1.95 (m, 2H), 2.77 (br. d, 1H), 3.05 (br. s, 1H), 3.16 (br. s, 3H), 3.75 (s, 3H), 3.98 (br. s, 2H), 4.16 (br. d, 1H), 6.80-6.89 (m, 2H ), 6.92-7.02 (m, 2H), 7.26-7.36 (m, 2H), 7.60 (d, 1H), 7.66 (d, 2H), 7.80 (d, 2H), 8.66 (d, 1H). LC-MS (Method 2): Rt= 1.46 min; m/z = 531/533 (M+H) ⁺ . 85 (8-{[2-(4-Bromophenyl)imidazo[1,2-а]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl)(cyclopentyl)methanone αλο- O from 8-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]octanedihydrochloride and cyclopentanecarboxylic acids 'H-NMR (400 MHz, DMSOA δ/ppm): 1.29-1.39 (m, 1H), 1.39-1.92 (m, 11H), 2.44-2.61 (m, 1H, partially obscured by DMSO signal), 2.78-2.90 ( m, 1H), 3.01 (br. d, 1H), 3.08 (br. s, 1H), 3.13 (br. s, 1H), 3.58 (br. d, 1H), 3.95 (br. d, 1H), 4.01 (s, 2H), 6.99 (t, 1H), 7.32 (t, 1H), 7.60 (d, 1H), 7.67 (d, 2H), 7.82 (d, 2H), 8.66 (d, 1H). LC-MS (Method 2): Rt = 1.48 min; m/z = 493/495 (M+H) ⁺ .

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86 (8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-3-yl)(cyclopentyl)methanone l^ ⁷ O from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl} -3,8-diazabicyclo[3.2.1]octanedihydrochloride and cyclopentanecarboxylic acid ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.31-1.38 (m, 1H), 1.41-1.68 (t, 8H), 1.69-1.78 (t, 1H), 1.78-1.89 (t, 2H) , 2.57 (br. d, 1H), 2.80-2.88 (t, 1H), 3.01 (br. d, 1H), 3.08 (br. s, 1H), 3.13 (br. s, 1H), 3.58 (br. d, 1H), 3.95 (br. d, 1H), 4.01 (s, 2H), 6.99 (td, 1H), 7.32 (ddd, 1H), 7.53 (d, 2H), 7.60 (d, 1H), 7.87 (d, 2H), 8.66 (d, 1H). LC-MS (Method 1): Rt = 0.80 min; m/z = 449/451 (M+H) ⁺ . 87 (8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl }-3,8-diazabicyclo[3.2.1]oct-3-yl)(2fluorophenyl)methanone l- */ V ⁰ from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.38-1.49 (m, 1H), 1.50-1.59 (m, 1H), 1.77-1.95 (m, 2H), 2.79 (br. d, 1H), 2.99 (br. d, 1H), 3.05 (br. s, 1H), 3.12 (br. d, 1H), 3.21 (br. d, 1H), 4.00 (q, 2H), 4.15 (br. d, 1H ), 6.99 (td, 1H), 7.25 (br. t, 2H), 7.32 (ddd, 2H), 7.42 (m, 1H), 7.53 (d, 2H), 7.60 (d, 1H), 7.85 (d, 2H), 8.66 (d, 1H). LC-MS (Method 1): Rt = 0.78 min; m/z = 475/477 (M+H) ⁺ . 88 (8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl }-3,8-diazabicyclo[3.2.1]oct-3-yl)(5fluoro-2- methylphenyl) methanone SN ₃ from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl] methyl } -3,8-diazabicyclo[3.2.1] octanedihydrochloride and 2-methyl-5 -fluorobenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.27-1.41 (m, 0.5H), 1.41-1.66 (m, 1.5H), 1.77-1.97 (m, 2H), 2.04 (br. s, 1.5 H), 2.21 (br. s, 1.5H), 2.79 (br. d, 1H), 2.87 (br. s, 1H), 3.02 (br. s, 1.5H), 3.09-3.19 (m, 0.5H) , 3.22 (br. s, 1H), 3.92-4.07 (m, 2H), 4.14 (br. d, 1H), 6.93-7.06 (m, 2H), 7.10 (td, 1H), 7.207.37 (m, 2H), 7.52 (d, 2H), 7.60 (d, 1H), 7.86 (d, 2H), 8.65 (d, 1H). LC-MS (Method 1): Rt = 0.85 min; m/z = 489/491 (M+H) ⁺ .

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(8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)(5fluoro-2- methoxyphenyl) methanone

ci

O

H ₃ c ^z from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl)-3,8-d iazabiciklo[3.2.1]octanedihydrochloride and 2-methoxy-5- fluorobenzoic acid

Ή-NMR (400 MHz, DMSO A δ/ppm): 1.32-1.43 (m, 0.5H), 1.53 (br. d, 1H), 1.60-1.70 (m, 0.5H), 1.74-1.95 (m, 2H ), 2.75 (br. d, 1H), 2.82-2.94 (m, 1H), 2.95-3.08 (m, 2H), 3.20 (br. s, 1H), 3.70 (br. s, 1.6H), 3.77 ( br. s, 1.4H), 3.93-4.02 (m, 2H), 4.05 (br. d, 0.5H), 4.12 (br. d, 0.5H), 6.93-7.11 (m, 3H), 7.13-7.24 ( m, 1H), 7.32 (br. t, 1H), 7.53 (d, 2H), 7.60 (d, 1H), 7.81-7.90 (m, 2H), 8.65 (d, 1H).

LC-MS (Method 1):

Rt = 0.81 min; m/z = 505/506 (M+H) ⁺ .

(8-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3 yl]methyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)(2methylphenyl)methanone

Cl

sn ₃ ' from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl] methyl)-3,8-d iazabiciklo[3.2.1] octanedihydrochloride and 2-methylbenzoic acid (8- {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)(2methoxyphenyl)methanone

Ή-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.28-1.42 (m, 0.5H), 1.42-1.65 (m, 1.5H), 1.76-1.97 (m, 2H), 2.08 (br. s, 1.5H), 2.24 (br. s, 1.5H), 2.78 (br. d, 1H), 2.88 (br. d, 1H), 2.96-3.15 (m, 2H), 3.22 (br. s, 1H ), 3.92-4.07 (m, 2H), 4.17 (br. d, 1H), 6.99 (t, 1H), 7.02-7.29 (m, 4H), 7.32 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.85 (d, 2H), 8.65 (d, 1H).

LC-MS (Method 1):

Rt = 0.82 min; m/z = 471/473 (M+H) ⁺ .

Cl from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-d-iazabicyclo[3.2.1]octanedihydrochloride and 2-methoxybenzoic acid

Ή-NMR (400 MHz, DMSO A δ/ppm): 1.27-1.41 (m, 0.5H), 1.53 (br. t, 1H), 1.61-1.72 (m, 0.5H), 1.73-1.95 (m, 2H ), 2.69-2.80 (m, 1H), 2.82-3.08 (m, 3H), 3.19 (br. s, 1H), 3.71 (s, 1.7H), 3.78 (s, 1.3H), 3.92-4.05 (m , 2H), 4.08 (br. d, 0.5H), 4.18 (br. d, 0.5H), 6.897.08 (m, 3.5H), 7.18 (br. d, 0.5H), 7.277.39 (m, 2H), 7.52 (d, 2H), 7.60 (d, 1H), 7.80-7.90 (m, 2H), 8.65 (d, 1H).

LC-MS (Method 1):

Rt = 0.78 min; m/z = 487/489 (M+H) ⁺ .

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92 (8-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]oct-3-yl)(6methoxypyridin-2-yl ) methanone H ₃ C-l) A® 0 from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl} -3,8-d iazabiciklo[3.2.1] octanedihydrochloride and 6-methoxypyridine2-carboxylic acid Ή-NMR (400 MHz, DMSOA δ/ppm): 1.50-1.60 (m, 1H), 1.62-1.71 (m, 1H), 1.79-1.97 (m, 2H), 2.81 (br. d, 1H), 3.05 (br. s, 1H), 3.11 (br. d, 1H), 3.23 (br. s, 1H), 3.39 (br. d, 1H), 3.80 (s, 3H), 3.96-4.06 (m, 2H) , 4.13 (br. d, 1H), 6.85 (d, 1H), 6.99 (t, 1H), 7.09 (d, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.60 (d, 1H ), 7.77 (t, 1H), 7.87 (d, 2H), 8.68 (d, 1H). LC-MS (Method 1): Rt = 0.75 min; m/z = 488/490 (M+H) ⁺ . 93 (8-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl)(cyclohexyl)methanone about from 8-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-d andazabicyclo[3.2.1]octanedihydrochloride and cyclohexanecarboxylic acids Ή-NMR (400 MHz, DMSO^A, δ/ppm): 1.04-1.41 (m, 6H), 1.42-1.55 (m, 2H), 1.55-1.72 (m, 4H), 1.76-1.89 (m, 2H ), 2.39-2.48 (m, 1H), 2.48-2.58 (br. d, 1H, partially obscured by the DMSO signal), 3.03 (br. d, 1H), 3.10 (br. d, 2H), 3.55 (br. d , 1H), 3.94 (br. d, 1H), 4.01 (s, 2H), 6.99 (td, 1H), 7.32 (ddd, 1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.87 ( d, 2H), 8.66 (d, 1H). LC-MS (Method 1): Rt = 0.81 min; m/z = 463/465 (M+H) ⁺ . 94 (2-fluorophenyl)(8-{[2-(4isopropylphenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct- _3yl )methanone CH3%® from 8-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl}-3,8diazabicyclo[3.2.1]octane-dihydrochloride and 2fluorobenzoic acid Ή-NMR (400 MHz, DMSO-tA, δ/ppm): 1.24 (d, 6H), 1.36-1.61 (m, 2H), 1.76-1.97 (m, 2H), 2.80 (br. d, 1H), 2.87-3.04 (m, 2H), 3.05-3.18 (m, 2H), 3.20-3.27 (m, 1H), 3.93-4.06 (m, 2H), 4.16 (br. d, 1H), 6.97 (td, 1H ), 7.20-7.39 (m, 6H), 7.42-7.51 (m, 1H), 7.58 (d, 1H), 7.73 (d, 2H), 8.66 (d, 1H). LC-MS (Method 2): Rt = 1.46 min; m/z = 483 (M+H) ⁺ .

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(8-{[2-(4-isopropylphenyl)imidazo[1,2-а]pyride in-3-yl]methyl}-3,8d iazabicyclo[3.2.1]oct-3-yl)(6-methoxypyride in2 -yl) methanone

'3 '3

O from 8-{[2-(4-isopropylphenyl)imidazo[1,2-а]pyride in-3-yl]methyl}-3,8diazabicyclo[3.2.1]octane-dihydrochloride and 6methoxypyridine-2-carboxylic acid ( 3 - {[2-(4-bromophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] οκτ-8-yl) (cyclopentyl) methanone

Br about

from 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-d-iazabicyclo[3.2.1]octanedihydrochloride and cyclopentanecarboxylic acid 'H-NMR (400 MHz, DMSO A δ/ppm): 1.24 (d, 6H), 1.50-1.60 (t, 1H), 1.63-1.72 (t, 1H), 1.79-1.97 (t, 2H), 2.81 (br. d, 1H), 2.87-3.00 (t, 1H), 3.06-3.15 (t, 2H), 3.22-3.28 (t, 1H), 3.40 (br. d, 1H), 3.80 (s, 3H), 4.01 (s, 2H), 4.13 (br. d, 1H), 6.95 (dd, 1H), 6.97 (td, 1H), 7.09 (dd, 1H), 7.26-7.37 (m, 3H), 7.34 (d, 2H), 7.59 (d, 1H), 7.74 (d, 2H), 7.78 (d, 1H), 8.67 (d, 1H).

LC-MS (Method 2):

Rt = 1.45 min; m/z = 496 (M+H) ^{+ 1} H-NMR (400 MHz, DMSO A δ/ppm): 1.43-1.67 (m, 7H), 1.67-1.80 (m, 5H), 2.27 (br. dd, 2H), 2.55 (br. d, 1H, partially obscured by the DMSO signal), 2.61 (br. d, 1H), 2.80-2.91 (m, 1H), 3.92-4.04 (m, 2H), 4.29 (br. s, 1H), 4.42 (br. d, 1H), 6.99 (td, 1H), 7.31 (ddd, 1H), 7.60 (d, 1H), 7.67 (d, 2H), 7.87 (d, 2H), 8.61 (d , 1H).

LC-MS (Method 1):

Rt = 0.89 min; m/z = 493/495 (M+H) ⁺ .

(3 - {[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(2fluorophenyl)methanone

Br 'H-NMR (400 MHz, DMSO^, δ/ppm): 1.63-1.80 (m, 4H), 2.26 (br. d, 1H), 2.43 (br. d, 1H), 2.55 (br. d, 1H, partially hidden by DMSO signal), 2.66 (br. d, 1H), 3.67 (br. s, 1H), 4.02 (s, 2H), 4.60 (br. d, 1H), 6.99 (td, 1H), 7.24 -7.34 (m, 3H), 7.41-7.54 (m, 2H), 7.60 (d, 1H), 7.67 (d, 2H), 7.86 (d, 2H), 8.60 (d, 1H).

LC-MS (Method 1):

Rt = 0.86 min; m/z = 519/521 (M+H) ⁺ from 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-d iazabicyclo[3.2.1 ]octanedihydrochloride and 2-fluorobenzoic acid

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98 (3 - {[2-(4-bromophenyl)imidazo[1,2-а]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(6methoxypyridin-2-yl ) methanone ΟλΦ 0 from 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-d-iazabicyclo[3.2.1]octanedihydrochloride and 6-methoxypyridine2-carboxylic acid ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.65-1.84 (m, 4H), 2.46 (br. d, 1H), 2.60 (s, 2H), 2.73 (dd, 1H), 3.77 (s , 3H), 4.04 (s, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 6.99 (td, 1H), 7.27-7.38 (m, 2H), 7.61 (d, 1H), 7.67 (d, 2H), 7.82 (t, 1H), 7.87 (d, 2H), 8.62 (d, 1H). LC-MS (Method 1): Rt = 0.86 min; m/z = 532/534 (M+H) ⁺ . 99 (3 - {[2-(4-bromophenyl)imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] oct-8-yl)(3 methoxyphenyl) methanone H ₃ C-l) o from 3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl] methyl } -3,8-d azabicyclo[3.2.1] octanedihydrochloride and 3-methoxybenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.64-1.79 (m, 4H), 2.36-2.69 (m, 4H, partially obscured by DMSO signal), 3.78 (s, 3H), 3.94 (br. s, 1H), 4.03 (s, 2H), 4.56 (br. s, 1H), 6.94-7.06 (m, 4H), 7.27-7.39 (m, 2H), 7.60 (d, 1H), 7.67 (d, 2H) , 7.87 (d, 2H), 8.62 (d, 1H). LC-MS (Method 1): Rt = 0.86 min; m/z = 531/533 (M+H) ⁺ . 100 (3 - {[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(2methylphenyl)methanone cX sn ₃ ⁰ out of 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-methylbenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.62-1.80 (m, 4H), 2.20-2.29 (m, 4H), 2.24 (s, 3H), 2.43 (br. d, 1H), 2.53 ( br. d, 1H), 2.66 (br. d, 1H), 3.52 (br. s, 1H), 4.02 (s, 2H), 4.60 (br. s, 1H), 6.99 (t, 1H), 7.19- 7.33 (m, 5H), 7.54 (d, 2H), 7.60 (d, 1H), 7.92 (d, 2H), 8.60 (d, 1H). LC-MS (Method 1): Rt = 0.83 min; m/z = 471/473 (M+H) ⁺ .

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101 (3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] οκτ-8-yl) (cycl butyl) methanone 0 %® about from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and cyclobutanecarboxylic acids ¹ H-NMR (400 MHz, DMSO®, δ/ppm): 1.51-1.79 (m, 5H), 1.81-1.96 (m, 1H), 1.97-2.13 (m, 3H), 2.17-2.30 (m, 3H ), 2.48-2.63 (m, 2H, partially hidden by the DMSO signal), 3.21-3.34 (m, 1H, partially hidden by the H2O signal), _3.92-4.03 (m, 2H), 4.06 (br. s, 1H), 4.38 (br. d, 1H), 6.98 (td, 1H), 7.31 (ddd, 1H), 7.53 (d, 2H), 7.60 (d, 1H), 7.92 (d, 2H), 8.59 (d, 1H). LC-MS (Method 2): Rt = 1.46 min; m/z = 435/437 (M+H) ⁺ . 102 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(2fluorophenyl)methanone From® from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSO®, δ/ppm): 1.63-1.79 (m, 4H), 2.26 (br. d, 1H), 2.43 (br. d, 1H), 2.46-2.59 (m, 1H , partially hidden by the DMSO signal), 2.66 (br. d, 1H), 3.66 (br. s, 1H), 4.03 (s, 2H), 4.60 (br. s, 1H), 6.99 (td, 1H), 7.23- 7.35 (m, 3H), 7.40-7.51 (m, 2H), 7.54 (d, 2H), 7.60 (d, 1H), 7.92 (d, 2H), 8.60 (d, 1H). LC-MS (Method 2): Rt = 1.50 min; m/z = 475/477 (M+H) ⁺ . 103 (3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] oct-8-yl) (5 fluoro-2- methoxyphenyl) methanone oto H ₃ C ^Z from 3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8 -d iazabiciklo[3.2.1] octanedihydrochloride and 5 -fluoro-2-methoxybenzoic acid 'H-NMR (400 MHz, DMSO®, δ/ppm): 1.61-1.77 (m, 4H), 2.26 (br. d, 1H), 2.40 (br. d, 1H), 2.46-2.54 (m, 1H , partially hidden by the DMSO signal), 2.63 (br. d, 1H), 3.54 (br. s, 1H), 3.75 (s, 3H), 4.01 (s, 2H), 4.55 (br. s, 1H), 6.99 ( td, 1H), 7.05-7.16 (m, 2H), 7.22 (td, 1H), 7.31 (ddd, 1H), 7.54 (d, 2H), 7.60 (d, 1H), 7.92 (d, 2H), 8.59 (d, 1H). LC-MS (Method 1): Rt = 0.81 min; m/z = 505/507 (M+H) ⁺ .

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104 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(6methoxypyridin-2-yl ) methanone about from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and 6-methoxypyridine2-carboxylic acid ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.62-1.82 (m, 4H), 2.45 (br. d, 1H), 2.57-2.64 (m, 2H), 2.73 (dd, 1H), 3.78 (s, 3H), 4.04 (s, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 6.99 (td, 1H), 7.32 (ddd, 1H), 7.35 (d, 1H), 7.54 (d, 2H), 7.60 (d, 1H), 7.82 (dd, 1H), 7.93 (d, 2H), 8.62 (d, 1H). LC-MS (Method 2): Rt = 1.52 min; m/z = 488/490 (M+H) ⁺ . 105 (3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3, 8-diazabicyclo[3.2.1] οκτ-8-yl) (cyclohexyl) methanone O from 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and cyclohexanecarboxylic acids 'H-NMR (400 MHz, DMSOA δ/ppm): 1.02-1.46 (m, 5H), 1.50-1.79 (m, 9H), 2.25 (br. dd, 2H), 2.38-2.48 (m, 1H), 2.48-2.65 (m, 2H, partially obscured by the DMSO signal), 3.93-4.06 (m, 2H), 4.26 (br. s, 1H), 4.41 (br. d, 1H), 6.99 (td, 1H), 7.32 ( ddd, 1H), 7.53 (d, 2H), 7.60 (d, 1H), 7.93 (d, 2H), 8.61 (d, 1H). LC-MS (Method 2): Rt = 1.65 min; m/z = 463/465 (M+H) ⁺ . 106 (2-chloro-5-fluorophenyl)(3-{[2-(4chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl } 3,8-diazabicyclo[3.2.1]oct-8- yl) methanone CI ⁰ from 3 - {[2-(4-chlorophenyl)imidazo[ 1,2-a] pyridin-3 yl]methyl}-3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-chloro-5 -fluorobenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.64-1.86 (m, 4H), 2.34 (br. d, 1H), 2.44 (br. d, 1H), 2.47-2.57 (m, 1H, hidden DMSO signal), 2.64 (br. d, 1H), 3.55 (br. s, 1H), 4.03 (s, 2H), 4.58 (br. s, 1H), 7.00 (t, 1H), 7.27-7.35 (m , 2H), 7.36-7.49 (m, 1H), 7.51-7.63 (m, 4H), 7.91 (d, 2H), 8.59 (d, 1H). LC-MS (Method 2): Rt= 1.61 min; m/z = 509/510/511 (M+H) ⁺ .

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107 (3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] oct-8-yl) (5 fluoro-2- methylphenyl) methanone SN ₃ ° from 3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8 -d iazabicyclo[3.2.1] octanedihydrochloride and 5-fluoro -2-methylbenzoic acid ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.64-1.81 (m, 4H), 2.20 (s, 3H), 2.29 (br. d, 1H), 2.44 (br. d, 1H), 2.54 (br. d, 1H), 2.63 (br. d, 1H), 3.54 (br. s, 1H), 4.03 (s, 2H), 4.58 (br. s, 1H), 7.00 (td, 1H), 7.09 -7.18 (m, 2H), 7.27-7.34 (m, 2H), 7.54 (d, 2H), 7.60 (d, 1H), 7.93 (d, 2H), 8.60 (d, 1H). LC-MS (Method 1): Rt = 0.84 min; m/z = 489/491 (M+H) ⁺ . 108 ^{n ,c} ~° 2 o from 3 - {[2-(4-chlorophenyl)imidazo[ 1,2-a]pyridin-3 yl] methyl } -3,8-d azabicyclo[3.2.1] octanedihydrochloride and 3-methoxybenzoic acids 'H-NMR (400 MHz, DMSOA δ/ppm): 1.62-1.79 (m, 4H), 2.35-2.69 (m, 4H, partially obscured by DMSO signal), 3.78 (s, 3N), 3.94 (br. s, 1H), 4.04 (s, 2H), 4.56 (br. s, 1H), 6.94-7.07 (m, 4H), 7.26-7.38 (m, 2H), 7.54 (d, 2H), 7.60 (d, 1H) , 7.94 (d, 2H), 8.62 (d, 1H). LC-MS (Method 2): Rt = 1.51 min; m/z = 487/489 (M+H) ⁺ . 109 (3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] oct-8-yl) (2 methoxyphenyl) methanone H ₃ c ^z from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]octanedihydrochloride and 2-methoxybenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.57-1.80 (m, 4H), 2.17-2.30 (m, 1H), 2.39 (br. d, 1H), 2.43-2.57 (m, 1H, partially hidden by DMSO signal), 2.65 (br. d, 1H), 3.52 (br. s, 1H), 3.76 (s, 3H), 4.01 (s, 2H), 4.56 (br. s, 1H), 6.93–7.02 ( m, 2H), 7.06 (d, 1H), 7.17-7.26 (m, 1H), 7.27-7.41 (m, 2H), 7.54 (d, 2H), 7.60 (d, 1H), 7.91 (d, 2H) , 8.59(d, 1H). LC-MS (Method 2): Rt = 1.46 min; m/z = 487/489 (M+H) ⁺ .

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HO (2-fluorophenyl)(3-{[2-(4isopropylphenyl)imidazo[1,2-а]pyridin-3yl]methyl)-3,8-diazabicyclo[3.2.1]oct-8yl)methanone

¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.25 (d, 6H), 1.66-1.80 (t, 4H), 2.27 (br. d, 1H), 2.42 (br. d, 1H), 2.58 (br. d, 1H), 2.67 (br. d, 1H), 2.883.01 (m, 1H), 3.68 (br. s, 1H), 4.02 (s, 2H), 4.60 (br. s, 1H) , 6.97 (td, 1H), 7.24-7.32 (m, 3H), 7.35 (d, 2H), 7.427.54 (m, 2H), 7.58 (d, 1H), 7.80 (d, 2H), 8.58 (d , 1H).

LC-MS (Method 2):

Rt = 1.46 min; m/z = 483 (M+H) ⁺ .

111 from 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3 -yl]methyl)-3,8diazabicyclo[3.2.1]octane-dihydrochloride and 2_________fluorobenzoic acid_________ (3 -{[ 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl } -3,8diazabicyclo[3.2.1]oct-8-yl)(2fluorophenyl)methanone

from 3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl)-3,8-diazabicyclo[3.2.1]octane-dihydrochloride and 2- fluorobenzoic acid

112 (3 -{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl)-3,8diazabicyclo[3.2.1]oct-8-yl)( 3-methoxyphenyl) methanone

from 3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-dihydrochloride and 3- methoxybenzoic acid 'H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.61-1.77 (m, 4H), 2.23 (br. d, 1H), 2.39 (br. d, 1H), 2.57 (br .d, 1H), 2.71 (dd, 1H), 3.63 (br. s, 1H), 4.50 (s, 2H), 4.57 (br. s, 1H), 7.01 (td, 1H), 7.24-7.31 (m , 2H), 7.34 (ddd, 1H), 7.42 (td, 1H), 7.45-7.52 (m, 1H), 7.60 (d, 1H), 7.99 (dd, 1H), 8.20 (d, 1H), 8.53 ( d, 1H), 8.68 (d, 1H).

LC-MS (Method 2):

Rt = 1.47 min; m/z = 476/478 (M+H) ⁺ .

' H-NMR (400 MHz, DMSO A δ/ppm): 1.60-1.76 (m, 4H), 2.28-2.45 (m, 2H), 2.55-2.76 (m, 2H), 3.77 (s, 3H), 3.91 (br. s, 1H), 4.51 (br. s, 3H), 6.95 dd, 1H), 6.97-7.05 (m, 3H), 7.34 (t, 2H), 7.62 (d, 1H), 7.99 (dd, 1H), 8.20 (d, 1H), 8.55 (d, 1H), 8.68 (d, 1H).

LC-MS (Method 2):

Rt = 1.45 min; m/z = 488/490 (M+H) ⁺ .

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(3 -{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl } -3,8diazabicyclo[3.2.1]oct-8-yl)(cyclopentyl ) methanone

ci o

from 3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyride in-3-yl]methyl }-3,8-diazabicyclo[3.2.1]octane-dihydrochloride and cyclopentanecarboxylic acid (3-chlorophenyl)(3-{[2-(4chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}3,6-diazabicyclo[3.1.1]hept-6-yl)methanone

Cl about

from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]heptane dihydrochloride and 3-chlorobenzoic acid (3-{[2 -(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl }-3,6-diazabicyclo[3.1.1]hept-6-yl)(tetrahydrofuran-2-yl)methanone (Racemate)

Cl about

from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptane dihydrochloride and tetrahydrofuran2-carboxylic acid (Racemate) 'H- NMR (400 MHz, DMSOA δ/ppm): 1.43-1.78 (m, 12H), 2.16-2.28 (m, 2H), 2.55-2.67 (m, 2H), 2.83 (quin, 1H), 4.25 (br. s , 1H), 4.38 (br. d, 1H), 4.42-4.52 (m, 2H), 7.02 (td, 1H), 7.35 (ddd, 1H), 7.60 (d, 1H), 7.99 (dd, 1H), 8.20 (d, 1H), 8.56 (d, 1H), 8.66 (d, 1H).

LC-MS (Method 2):

Rt = 1.39 min; m/z = 450/452 (M+H) ⁺ .

'H-NMR (400 MHz, DMSOA δ/ppm): 1.70 (d, 1H), 2.47-2.60 (m, 1H, partially obscured by DMSO signal), 2.73 (br. d, 1H), 2.79 (br. d, 1H), 3.25 (br. d, 1H), 3.28-3.34 (m, 1H, partially hidden by the H2O signal), 4.20 (s, 2H), 4.32 (br. s, 1H), 4.47 (br. s, 1H ), 6.97 (t, 1H), 7.31 (t, 1H), 7.41 (d, 1H), 7.447.55 (m, 5H), 7.59 (d, 1H), 7.85 (d, 2H), 8.44 (d, 1H).

LC-MS (Method 1):

Rt = 0.82 min; m/z = 477/479 (M+H) ⁺ .

'H-NMR (400 MHz, DMSOA δ/ppm): 1.65-2.05 (m, 5H), 2.29-2.42 (m, 1H), 2.70-2.93 (m, 3.5H), 3.01 (br. d, 0.5H ), 3.61-3.75 (m, 2H), 4.13-4.22 (m, 3.5H), 4.26 (dd, 0.5H), 4.41-4.50 (m, 1H), 6.96 (td, 1H), 7.31 (t, 1H ), 7.49-7.56 (m, 2H), 7.60 (d, 1H), 7.827.92 (m, 2H), 8.51 (d, 1H).

LC-MS (Method 1):

Rt = 0.64 min; m/z = 437/439 (M+H) ⁺ .

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116 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]hept-6-yl)(cyclopentyl)methanone O of 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1. 1]heptane dihydrochloride and cyclopentanecarboxylic acids ¹ H-NMR (400 MHz, DMSO A δ/ppm): 1.34-1.62 (m, 7H), 1.65-1.77 (m, 2H), 2.27-2.36 (m, 1H), 2.41-2.52 (m, 1H, partially hidden by the DMSO signal), 2.70-2.82 (m, 3H), 2.97 (br. d, 1H), 4.08-4.24 (m, 3H), 4.29-4.37 (m, 1H), 6.96 (td, 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.86 (d, 2H), 8.48 (d, 1H). LC-MS (Method 1): Rt = 0.76 min; m/z = 435/437 (M+H) ⁺ . 117 (3 - {[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3 yl]methyl } -3,6-diazabicyclo[3.1.1 ]hept-6-yl)(2fluorophenyl)methanone from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]heptanedihydrochloride and 2-fluorobenzoic acid 'H-NMR (400 MHz, DMSOA δ/ppm): 1.82 (d, 1H), 2.39-2.48 (m, 2H), 2.70 (dd, 1H), 2.89 (dd, 1H), 3.14 (d, 1H) , 4.07 (br. s, 1H), 4.15-4.27 (m, 2H), 4.37 (br. s, 1H), 6.98 (t, 1H), 7.157.27 (m, 2H), 7.27-7.39 (m, 2H), 7.437.56 (m, 3H), 7.60 (d, 1H), 7.85 (d, 2H), 8.49 (d, 1H). LC-MS (Method 1): Rt = 0.75 min; m/z = 461/463 (M+H) ⁺ . 118 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]hept-6-yl)(cyclohexyl)methanone about from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]heptane dihydrochloride and cyclohexanecarboxylic acids 'H-NMR (400 MHz, DMSOA δ/ppm): 1.01-1.40 (m, 6H), 1.52-1.67 (m, 4H), 1.71 (d, 1H), 1.95-2.06 (m, 1H), 2.28 ( q, 1H), 2.65 (br. d, 1H), 2.74-2.83 (m, 2H), 2.91 (br. d, 1H), 4.09 (br. s, 1H), 4.12-4.25 (m, 2H), 4.33 (br. s, 1H), 6.96 (td, 1H), 7.31 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H), 7.85 (d, 2H), 8.48 (d, 1H) . LC-MS (Method 1): Rt = 0.80 min; m/z = 449/451 (M+H) ⁺ .

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119 (2-chloro-5-fluorophenyl)(3-{ [2-(4- Ή-NMR (400 MHz, DMSO A chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl } 3,6-diazabicyclo[3.1.1 ]hept-6-yl)methanone CI° from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptanedihydrochloride and 2-chloro-5-fluorobenzoic acids δ/ppm): 1.92 (d, 1H), 2.40-2.52 (m, 2H, partially obscured by DMSO signal), 2.74 (dd, 1H), 2.95 (dd, 1H), 3.09 (d, 1H), 3.99 (br . s, 1H), 4.25 (s, 2H), 4.41 (br. s, 1H), 6.97 (t, 1H), 7.26-7.36 (t, 3H), 7.49-7.58 (t, 3H), 7.60 (d , 1Н), 7.88 (d, 2Н), 8.52 (d, 1Н). LC-MS (Method 1): Rt = 0.79 min; m/z = 495/497 (M+H) ⁺ . 120 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl] methyl } -3,6-d iazabicyclo[3.1.1]hept-6-yl) [3 (trifluoromethoxy) phenyl] methanone Τ'/άΉ about of 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1. 1]heptane dihydrochloride and 3-(trifluoromethoxy)benzoic acids Ή-NMR (400 MHz, DMSO A δ/ppm): 1.73 (d, 1H), 2.47-2.60 (t, 2H, partially obscured by DMSO signal), 2.74 (br. d, 1H), 2.82 (br. d, 1H), 3.26 (br. d, 1H), 4.14-4.25 (m, 2H), 4.35 (br. s, 1H), 4.47 (br. s, 1H), 6.95 (t, 1H), 7.30 (t, 1H), 7.41-7.61 (m, 7H), 7.85 (d, 2H), 8.46 (d, 1H). LC-MS (Method 1): Rt = 0.90 min; m/z = 527/529 (M+H) ⁺ . 121 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl}-3,6-diazabicyclo[3.1.1]hept-6-yl)(cycl butyl)methanone s+et /-ίτ about from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1.1]heptanedihydrochloride and cyclobutanecarboxylic acids Ή-NMR (400 MHz, DMSO A δ/ppm): 1.62-1.89 (m,4H), 1.91-2.13 (m, 3H), 2.31 (q, 1H), 2.66 (dd, 1H), 2.70-2.81 ( m, 2H), 2.87-3.02 (m, 2H), 4.08-4.24 (m, 4H), 6.95 (t, 1H), 7.30 (t, 1H), 7.52 (d, 2H), 7.60 (d, 1H) , 7.86 (d, 2H), 8.46 (d, 1H). LC-MS (Method 1): Rt = 0.71 min; m/z = 421/423 (M+H) ⁺ . 122 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl }-3,6-diazabicyclo[3.1.1]hept-6-yl)(3-ethoxyphenyl)methanone „ oh O of 3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,6-diazabicyclo[3.1. 1]heptane dihydrochloride and 3-ethoxybenzoic acid Ή-NMR (400 MHz, DMSO A δ/ppm): 1.30 (t, 3H), 1.72 (d, 1H), 2.472.61 (m, 2H, partially obscured by DMSO signal), 2.73 (br. d, 1H) , 2.81 (br. d, 1H), 3.27 (br. d, 1H), 3.833.99 (dq, 2H), 4.11-4.23 (m, 2H), 4.31 (br. s, 1H), 4.43 (br. s, 1H), 6.91-7.02 (m, 3H), 7.07 (d, 1H), 7.23-7.33 (m, 2H), 7.50 (d, 2H), 7.58 (d, 1H), 7.87 (d, 2H) , 8.49(d, 1H). LC-MS (Method 2): Rt = 1.56 min; m/z = 487/489 (M+H) ⁺ . 123 Cyclopentyl (3 - {[2- (4isopropylphenyl) imidazo [ 1,2-a] pyridin-3 yl] methyl } -3,6-diazabicyclo [3.1.1] hept-6yl) methanone orc: about from 3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyride in-3-yl]methyl }-3,6-diazabicyclo[3.1.1]heptane dihydrochloride and cyclopentanecarboxylic acid Ή-NMR (400 MHz, DMSO A δ/ppm): 1.25 (d, 6H), 1.35-1.63 (m, 7H), 1.66-1.79 (m, 2H), 2.31 (q, 1H), 2.42-2.57 ( m, 1H, partially hidden by the DMSO signal), 2.70–2.83 (m, ZN), 2.87–3.01 (m, 2H), 4.07–4.24 (m, 3H), 4.34 (br. s, 1H), 6.93 (t, 1H), 7.28 (t, 1H), 7.33 (d, 2H), 7.58 (d, 1H), 7.75 (d, 2H), 8.44 (d, 1H). LC-MS (Method 2): Rt = 1.48 min; m/z = 443 (M+H) ⁺ .

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Examples 124 and 125 (5-{[2-(6-Isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5diazabicyclo[2.2.2]oct-2- yl)(6-methoxypyridin-2-yl)methanone (enantiomers 1 and 2)

139 mg (0.28 mmol) racemate 2-yl)(6-methoxypyridin-2-yl)methanone (Example 27) was separated by preparative HPLC of the chiral phase into enantiomers [column: YMC Cellulose SC, 5 μm, 250 mm x 20 mm; eluent: n-heptane/isopropanol 25:75 + 0.2% diethylamine; flow: 15 ml/min; UV detection: 220 nm; temperature: 55°C].

Example 124 (enantiomer 1): yield: 65 mg;

Rt = 14.77 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanone 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.28 (d, 6H), 1.47-2.00 (m, 4H), 2.74 (br. d, 1H), 2.82-2.95 (m, 2H ), 3.07 (dt, 1H), 3.39 (br. d, 0.7H), 3.50 (br. d, 0.3H), 3.71-3.81 (m, 3H), 3.84 (s, 0.7H), 3.99 (br. s, 1H), 4.224.34 (m, 2H), 4.39 (br. s, 0.3H), 6.84-7.03 (m, 2H), 7.17 (d, 0.7H), 7.27-7.41 (m, 2.3H) , 7.62 (d, 1H), 7.73-7.85 (m, 1H), 8.09-8.18 (m, 1H), 8.55-8.65 (m, 1H), 8.88-8.98 (m, 1H).

LC-MS (method 2): Rt = 1.19 min; m/z = 497 (M+H) ⁺ .

Example 125 (enantiomer 2): yield: 66 mg;

Rt = _19.54 min; chemical purity >99%;>99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanone 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

Ή-NMR (400 MHz, DMSO-d6, δ/ppm): 1.28 (d, 6H), 1.48-2.00 (m, 4H), 2.74 (br. d, 1H), 2.82-2.96 (m, 2H), 3.08 (dt, 1H), 3.39 (br. d, 0.7H), 3.50 (br. d, 0.3H), 3.71-3.81 (m, 3H), 3.84 (s, 0.7H), 4.00 (br. s, 1H), 4.224.34 (m, 2H), 4.39 (br. s, 0.3H), 6.85-7.03 (m, 2H), 7.17 (d, 0.7H), 7.27-7.42 (m, 2.3H), 7.62 (d, 1H), 7.74-7.85 (m, 1H), 8.08-8.18 (m, 1H), 8.56-8.65 (m, 1H), 8.88-8.98 (m, 1H).

LC-MS (method 2): Rt = 1.19 min; m/z = 497 (M+H) ⁺ .

Examples 126 and 127 (3-Fluoro-6-methoxypyridin-2-yl)(5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl} -2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (enantiomers 1 and 2)

134 mg (0.26 mmol) racemic (3-fluoro-6-methoxypyridin-2-yl)(5-{[2-(6-isopropylpyridin-3yl)imidazo[1,2-a]pyridin-3-yl]methyl} -2,5-diazabicyclo[2.2.2]oct-2-yl)methanone (Example 28) was separated by preparative HPLC of the chiral phase into enantiomers [column: YMC Cellulose SC, 5 μm, 250 mm x 20 mm; eluent: n-heptane/isopropanol 25:75 + 0.2% diethylamine; flow: 15 ml/min; UV detection: 220 nm; temperature: 55°C].

Example 126 (enantiomer 1): yield: 60 mg;

Rt = 15.10 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanone 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

Ή-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.22-1.31 (m, 6H), 1.50-1.99 (m, 4H), 2.65-2.77 (m, 1H), 2.772.87 (m, 1.3H), 2.94 (br. s, 0.7H), 3.01-3.18 (m, 1.3H), 3.39-3.51 (m, 1.4H), 3.60 (br. d, 0.3H), 3.68-3.85 (m, 3.7H), 4.20-4.35 (m, 2H), 4.40 (br. s, 0.3H), 6.87-7.03 (m, 2H), 7.27-7.42 (m, 2H), 7.62 (d, 1H), 7.70- 7.83 (m, 1H), 8.07-8.18 (m, 1H), 8.55-8.64 (m, 1H), 8.86-8.98 (m, 1H).

LC-MS (method 2): Rt = 1.22 min; m/z = 515 (M+H) ⁺ .

Example 127 (enantiomer 2): yield: 57 mg;

_Rt = 20.80 min; chemical purity >99%;>99% her

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[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanone 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.21-1.33 (m, 6H), 1.50-1.99 (m, 4H), 2.65-2.77 (m, 1H), 2.772.88 (m , 1.3H), 2.94 (br. s, 0.7H), 3.01-3.18 (m, 1.3H), 3.39-3.51 (m, 1.4H), 3.60 (br. d, 0.3H), 3.69-3.86 (m , 3.7H), 4.19-4.34 (m, 2H), 4.39 (br. s, 0.3H), 6.88-7.04 (m, 2H), 7.27-7.41 (m, 2H), 7.62 (d, 1H), 7.70 -7.83 (m, 1H), 8.07-8.18 (m, 1H), 8.56-8.64 (m, 1H), 8.87-8.98 (m, 1H).

LC-MS (method 2): Rt = 1.22 min; m/z = 515 (M+H) ⁺ .

The non-enantiomeric compound of Example 126 (enantiomer 1) could be prepared by an alternative method as follows: 80 mg (0.26 mmol) of fluoro-6-methoxypyridine-2-carboxylic acid was dissolved in 2 ml of DMF, mixed with 242 mg (0.64 mmol) of 2- (7-aza-1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 min at room temperature. Then 200 mg (0.43 mmol) of 2-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2а]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane- dihydrochloride (enantiomer 1; example 32A), as well as 370 μl (2.12 mmol) K®-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components.

126 mg (0.24 mmol, 57% th. y.) of the title compound were obtained.

[a] ^D20 = _-92.16 ° (c = 0.285, methanol).

LC-MS (method 2): Rt = 1.27 min; m/z = 515 (M+H) ⁺ .

Examples 128 and 129 (2-Fluorophenyl)(5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2 ]oct-2-yl)methanone (enantiomers 1 and 2)

121 mg (0.25 mmol) racemic (2-fluorophenyl)(5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2 .2]oct-2-yl)methanone (Example 68) was separated into enantiomers by preparative HPLC of the chiral phase [column: YMC Cellulose SC, 5 μm, 250 mm x 20 mm; eluent: n-heptane/isopropanol 25:75 + 0.2% diethylamine; flow: 15 ml/min; UV detection: 220 nm; temperature: 55°C].

Example 128 (enantiomer 1): yield: 57 mg;

Rt= 14.26 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanol 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.24-1.32 (m, 6H), 1.48-1.98 (m, 4H), 2.65-2.89 (m, 2.3H), 2.94 (br. s , 0.7H), 3.00-3.16 (m, 1.3H), 3.28-3.36 (m, 0.7H, partially obscured by water signal), 3.39-3.50 (m, 1H), 3.78 (br. d, 0.7H), 4.20 -4.33 (m, 2H), 4.39 (br. s, 0.3H), 6.94-7.03 (m, 1H), 7.19-7.53 (m, 6H), 7.58-7.65 (m, 1H), 8.08-8.18 (m , 1H), 8.55-8.64 (m, 1H), 8.90 (d, 0.3H), 8.94 (d, 0.7H).

LC-MS (method 1): Rt = 0.68 min; m/z = 484 (M+H) ⁺ .

Example 129 (enantiomer 2): yield: 60 mg;

Rt = 23.23 min; chemical purity >99%; >99% her

[column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanol 25:75 + 0.2% diethylamine; flow: 1 ml/min; temperature: 55°C; UV detection: 235 nm].

1H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.22-1.32 (m, 6H), 1.52-1.97 (m, 4H), 2.65-2.89 (m, 2.3H), 2.94 (br. s , 0.7H), 3.01-3.14 (m, 1.3H), 3.27-3.36 (m, 0.7H, partially hidden by water signal), 3.39-3.49 (m, 1H), 3.78 (br. d, 0.7H), 4.21 -4.33 (m, 2H), 4.39 (br. s, 0.3H), 6.93-7.04 (m, 1H), 7.18-7.53 (m, 6H), 7.58-7.65 (m, 1H), 8.08-8.18 (m , 1H), 8.55-8.64 (m, 1H), 8.90 (d, 0.3H), 8.94 (d, 0.7H).

LC-MS (method 1): Rt = 0.67 min; m/z = 484 (M+H) ⁺ .

By analogy with examples 1-4, the following compounds were obtained from the corresponding indicated educts:

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Example

Name/structure/educt

Analytical data

tert-T>utal-7 _{[2-(5-chloropyridin-2yl)imide azo[1,2-a]pyridin-3-yl]methyl } -3-oxa-7,9d iazabicyclo[3.3.1 ]nonane-9-carboxylate o

CI

o ° aus 2-(5-chloropyridin-2-yl)imidazo[1,2-а]pyridine-3-carbaldehyde and ot/?ot-butyl-3-oxa7,9-diazabicyclo[3.3.1]nonane-9 -carboxylate from /? eot-Butyl-3 - {[2- (6-isopropyl pyridin-3 yl) imide azo [ 1,2-a] pyridin-3 -yl] methyl} -3,8 diazabicyclo [3.2.1] octane-8-carboxylate ^! h

h ₃ ⁿ s ^ CH ₃ aus octane-3-carboxylate /i/?et-Butyl-5-{[2-(4-bromophenyl)imidazo[1,2-a]pyride in-3-yl]methyl } -2,5 diazabicyclo[2.2.2 ]octane-2-carboxylate (Racemate)

Br ^H 3*- CH ₃ aus 2-(4-bromophenyl)imidazo[1,2-a]pyridine-3carbaldehyde and carboxylate (racemate) 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.39 (s, 9H), 2.38 (br. s, 2H), 2.85 (br. d, 2H), 3.49-3.59 (m , 2H), 3.60-3.70 (m, 2H), 3.83 (br. d, 2H), 4.42 (s, 2H), 6.93 (td, 1H), 7.33 (ddd, 1H), 7.61 (d, 1H), 8.00 (dd, 1H), 8.21 (d, 1H), 8.67 (dd, 1H), 8.83 (d, 1H).

LC-MS (Method 2):

Rt= 1.22 min; MS (ESIpos): m/z = 470 [M+H] ⁺ .

LC-MS (Method 2): Rt = 1.68 min; MS (ESIpos): m/z = 462 [M+H] ⁺ .

'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.13-1.25 (m, 1Η), 1.33-1.40 (m, 9H), 1.50 (br. d, 1H), 1.66 (br. s, 2H ), 1.85 (br. s, 1H), 2.52-2.55 (m, 4H), 2.62-2.77 (m, 3H), 3.13 (br. t, 1H), 3.46-3.54 (m, 1H), 4.17-4.25 (m, 2H), 6.97 (t, 1H), 7.31 (t, 1H), 7.58-7.69 (m, 3H), 7.74-7.83 (m, 2H), 8.57 (d, 1H).

LC-MS (Method 5): Rt = 1.16 min; MS (ESIpos): m/z = 497 [M+H] ⁺ .

Examples 133 and 134 tert-Butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2 ]octane-2-carboxylate (enantiomers 1 and 2)

4700 mg (10.38 mmol) racemic tert-butyl-5-{[2-(6-isopropylpyridin-3-yl)imidazo[1,2a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2 ]octane-2-carboxylate (Example 3) was separated by preparative HPLC of the chiral phase into enantiomers [column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; eluent: isohexane/isopropanone 50:50 + 0.2% diethylamine; flow: 15 ml/min; UV detection: 220 nm; temperature: 50°C].

Example 133 (enantiomer 1): yield: 2310 mg;

_Rt = 8.97 min; chemical purity >99%;>99% her

[column: Daicel Chiralpak IF, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanol 60:40 + 0.2% diethylamine; flow: 1 ml/min; temperature: 40°C; UV detection: 235 nm].

- 74 039175

1H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.28 (d, 6H), 1.36 (2s, 9H), 1.43-1.56 (m, 1H), 1.57-1.74 (m, 2H),

1.79-1.92 (m, 1H), 2.65-2.82 (m, 3H), 3.01-3.19 (m, 2H), 3.53 (dd, 1H), 3.81 (br. d, 1H), 4.17-4.28 (m, 2H ),

6.98 (t, 1H), 7.31 (t, 1H), 7.38 (d, 1H), 7.61 (d, 1H), 8.09-8.16 (m, 1H), 8.58 (d, 1H), 8.92 (dd, 1H) .

LC-MS (method 2): Rt = 1.44 min; m/z = 462 (M+H)+. [a] _D20 = + ^8.89 ° (c = 0.270, methanol).

Example 134 (enantiomer 2): yield: 2110 mg;

_Rt = 7.28 min; chemical purity >99%;>99% her

[column: Daicel Chiralpak IF, 5 µm, 250 mm x 4.6 mm; eluent: isohexane/isopropanol 60:40 + 0.2% diethylamine; flow: 1 ml/min; temperature: 40°C; UV detection: 235 nm].

¹ H-NMR (400 MHz, DMSO-d ₆ , δ/ppm): 1.28 (d, 6H), 1.36 (2s, 9H), 1.43-1.56 (m, 1H), 1.57-1.74 (m, 2H), 1.79-1.92 (m, 1H), 2.65-2.82 (m, 3H), 3.01-3.19 (m, 2H), 3.53 (dd, 1H), 3.81 (br. d, 1H), 4.17-4.28 (m, 2H ), 6.98 (t, 1H), 7.31 (t, 1H), 7.38 (d, 1H), 7.61 (d, 1H), 8.09–8.16 (m, 1H), 8.58 (d, 1H), 8.92 (dd, 1H).

LC-MS (method 2): R _t = 1.44 min; m/z = 462 (M+H) ⁺ . [a] ^D20 = _-10.53 ° (c = 0.285, methanol).

By analogy with examples 21 and 33, the following compounds were obtained from the corresponding indicated educts:

Example Name/structure/educt Analytical data 135 (7-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin3 -yl] methyl } -3-oxa-7,9-d iazabicyclo [3.3.1] non-9yl) [6-(trifluoromethoxy)pyridin-2-yl]methanone Mr. o-sAv ^F from 7-{[2-(5-chloropyride in-2-yl)imidazo[1,2-а]pyridin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonan- dihydrochloride and 6(grifluoromethoxy)pyridine-2-carboxylic acid ¹ H-NMR (400 MHz, DMSOde): δ [ppm] = 2.87 (br. d, lH), 3.07 (br. d, 1H), 3.593.73 (m, 3H), 3.84 (d, 1H), 3.95 (br. s, 1H), 4.39-4.53 (m, 3H), 6.94 (t, 1H), 7.33 (t, 1H), 7.39 (d, 1H), 7.61 (d, 1H), 7.71 (d, 1H), 7.96-8.03 (m, 1H), 8.11-8.24 (m, 2H), 8.66 (d, 1H), 8.82 (d, 1H). LC-MS (Method 2): Rt= 1.36 min; MS (ESIpos): m/z = 559 [M+H] ⁺ . 136 (3-chloro-6-methoxypyride in-2-yl)(7 - {[2-(5 chloropyridin-2-yl)imidazo[1,2-a]pyridin-3yl]methyl } -3-oxa-7 ,9-diazabicycle o[3.3.1] non-9-yl)methanone H z ^CH ' from 7-{[2-(5-chloropyride in-2-yl)imidazo[1,2-a]pyridin-3 -yl] methyl } -3-oxa-7,9-diazabicyclo[3.3.1]nonane-dihydrochloride and 3-chloro-6methoxypyridine-2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 3.57 (br. t, 1H), 3.67 (br. t, 1H), 3.74-3.85 (m, 3H), 3.88 (s, 3H), 3.92-4.02 (m, 2H), 4.10 (br. d, 1H), 4.25 (br. d, 1H), 4.82 (br. s, 1H), 4.93-5.10 (m, 2H), 7.02 (d, 1H ), 7.20 (t, 1H), 7.48 (t, 1H), 7.78 (d, 1H), 7.96 (d, 1H), 8.19–8.31 (m, 2H), 8.72 (d, 1H), 8.90 (d, 1H). LC-MS (Method 2): Rt= 1.21 min; MS (ESIpos): m/z = 539 [M+H] ⁺ .

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137 5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]οκτ-2-yl] (6methoxy-3-methylpyridin- 2-yl) methanone (enantiomer /) H ₃ C^ _P / CH ₃ from 3 -[2,5-diazabicyclo[2.2.2]οκτ-2-ylmethyl]-2-(4isopropylphenyl)imidazo[ 1,2-a ] pyridine dihydrochloride (enantiomer /) and 6-methoxy-3-methylpyridine-2-carboxylic acid LC-MS (Method 2): Rt = 1.49 min; MS (ESIpos): m/z = 510 [M+H] ⁺ . 138 5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } -2,5-diazabicyclo[2.2.2]οκτ-2-yl] (6-methoxy3-methylpyridine -2-yl)methanone (enantiomer /) CH ₃ from 2-(4-chlorophenyl)-3 -(2,5-diazabicyclo[2.2.2]oct-2 ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride (enantiomer 7) and 6-methoxy-3-methylpyridine-2-carboxylic acid ¹ H-NMR (400 MHz, DMSOde): δ [ppm] = 1.50-1.97 (m, 4H), 2.02-2.11 (m, 3H), 2.592.86 (m, 2.3H), 2.89-3.00 (m, 1H), 3.23 (br. s, 0.7H), 3.333.45 (m, 1H), 3.66-3.82 (m, 3.75H), 4.16-4.31 (m, 2H), 4.39 (m, 0.25H), 6.71 -6.80 (m, 1H), 6.92-7.02 (m, 1H), 7.26-7.35 (m, 1H), 7.45-7.65 (m, 4H), 7.79-7.91 (m, 2H), 8.53-8.62 (m, 1H). LC-MS (Method 2): Rt= 1.39 min; MS (ESIpos): m/z = 502/504 [M+H] ⁺ . 139 (3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(3-chloro- 6methoxypyridin-2-yl)methanone 1 -V 7 - Br \_/ H ₃ C^ _P ) CI ⁰ from 2-(4-bromophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl) imidazo[1,2-a]pyridine-dihydrochloride and 3-chloro-6-methoxypyridine-2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.62-1.82 (m, 4H), 2.37-2.55 (m, 3H, partially obscured by DMSO signal), 2.73 (m, 1H), 3.63 (br. s, 1H), 3.79 (s, 3H), 4.04 (s, 2H), 4.60 (br. s, 1H), 6.92 (d, 1H), 6.99 (t, 1H), 7.31 (dd, 1H), 7.60 (d, 1H), 7.67 (d, 2H), 7.86 (t, 3H), 8.59 (d, 1H). LC-MS (Method 2): Rt= 1.58 min; MS (ESIpos): m/z = 566/568/569 [M+H] ⁺ .

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140 (3-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluoro- 6methoxypyridin-2-yl)methanone from* %® from 2-(4-bromophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3 ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride and 3-fluoro-6-methoxypyridine-2-carboxylic acids ¹ H-NMR (400 MHz, DMSOde): δ [ppm] = 1.25 (br. d, 1H), 1.63-1.82 (m, 4H), 2.412.54 (m, ZN, partially obscured by DMSO signal), 2.70- 2.79 (m, 1H), 3.76 (s, 3H), 3.92 (br. s, 1H), 3.99-4.10 (m, 2H), 4.61 (br. s, 1H), 6.93-7.01 (m, 2H), 7.31 (t, 1H), 7.60 (d, 1H), 7.65-7.70 (m, 2H), 7.77 (t, 1H), 7.83-7.88 (m, 2H), 8.61 (d, 1H). LC-MS (Method 2): Rt= 1.50 min; MS (ESIpos): m/z = 550 [M+H] ⁺ . 141 (3 - {[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(2isopropylphenyl)methanone SA® \ o H ₃ L ^CH3 from 2-(4-bromophenyl)-3 -(3,8-diazabicyclo[3.2.1]oct-3 ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride and 2-isopropylbenzoic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.16 (br. d, 6H), 1.51-1.83 (m, 4H), 2.252.57 (m, ZN, partially obscured by DMSO signal), 2.67 ( br. s, 1H), 2.78-3.15 (m, 1H), 3.50 (br. s, 1H), 4.02 (br. s, 2H), 4.62 (br. s, 1H), 6.99 (t, 1H), 7.22 (br. s, 1H), 7.257.42 (m, 4H), 7.57-7.72 (m, 3H), 7.84 (br. s, 2H), 8.59 (br. d, 1H). LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 545 [M+H] ⁺ . 142 (3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,6-diazabicyclo[3.1.1]hept-6-yl)(6methoxy-3-methylpyridin- 2-yl) methanone cj- ^H,C A /-v ί%® CH ₃ ° from 2-(4-chlorophenyl)-3 -(3,6-d iazabiciklo[3.1.1]hept3-ylmethyl)imidazo[1 ,2-а]pyridine-dihydrochloride and 6-methoxy-3-methylpyridine-2-carboxylic acid 'H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.89 (d, 1H), 2.26 (s, 3H), 2.32-2.47 (m, 1H), 2.71-2.79 (m, 1H), 2.812 .88 (m, 1H), 2.96-3.04 (m, 2H), 3.63 (s, 3H), 4.17-4.26 (m, 2H), 4.34-4.41 (m, 2H), 6.80 (d, 1H), 6.93 (t, 1H), 7.29 (t, 1H), 7.50 (d, 2H), 7.59 (d, 2H), 7.84 (d, 2H), 8.52 (d, 1H). LC-MS (Method 1): Rt = 0.77 min; MS (ESIpos): m/z = 488/490 [M+H] ⁺ .

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143 (8 - {[2-(4-chlorophenyl) imide azo[1,2-a] pyridin-3 -yl] methyl } -3,8-diazabicyclo[3.2.1] oct-3 -yl) (6- methoxy-3-methylpyridin-2-yl)methanone H ₃ C^ _P ) A® CH ₃ from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-8ylmethyl)imidazo[ 1 ,2-a]pyridine-dihydrochloride and 6-methoxy-3-methylpyridine-2-carboxylic acid Ή-NMR (400 MHz, DMSOde): δ [ppm] = 1.49-1.70 (m, 2H), 1.79-1.97 (m, 2H), 2.09 (s, 3H), 2.78-2.92 (m, 2H), 2.98 -3.07 (m, 2H), 3.24 (br. d, 1H), 3.76 (s, 3H), 3.94-4.05 (m, 2H), 4.14 (br. d, 1H), 6.74 (d, 1H), 6.99 (td, 1H), 7.32 (ddd, 1H), 7.53 (d, 2H), 7.567.63 (m, 2H), 7.86 (d, 2H), 8.66 (d, 1H). LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 502/504 [M+H] ⁺ . 144 (8-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]oct-3-yl)(6methoxy-3-methylpyridine- ^and _{_} 6-methoxy-3-methylpyridine2-carboxylic acid Ή-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.24 (d, 6H), 1.49-1.70 (m, 2H), 1.80-1.97 (m, 2H), 2.09 (s, 3H), 2.81 ( br. d, 1H), 2.87-2.97 (m, 2H), 3.01-3.08 (m, 2H), 3.27 (m, lH), 3.76(s, 3H), 3.94-4.05 (m, 2H), 4.14 ( br. d, 1H), 6.74 (d, 1H), 6.97 (td, 1H), 7.257.37 (m, 3H), 7.58 (d, 2H), 7.73 (d, 2H), 8.66 (d, 1H) . LC-MS (Method 1): Rt = 0.81 min; MS (ESIpos): m/z = 510 [M+H] ⁺ . 145 (3 -{[2-(4-isopropylphenyl)imidazo[1,2-а]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(6methoxy-3-methylpyridine -2-yl) methanone as much as '%® SN ₃ ⁰ from 3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)-2-(4isopropylphenyl)imidazo[1,2-a]pyridinedihydrochloride and 6 -methoxy-3-methylpyridine2-carboxylic acid Ή-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.25 (d, 6H), 1.61-1.84 (m, 4H), 2.17 (s, 3H), 2.43 (br. d, 2H), 2.472. 56 (m, 1H, masked by DMSO signal), 2.75 (dd, 1H), 2.883.01 (m, 1H), 3.70 (s, 1H), 3.97-4.09 (m, 2H), 4.62 (br. s, 1H ), 6.77 (d, 1H), 6.97 (td, 1H), 7.34 (d, 2H), 7.60 (t, 2H), 7.80 (d, 2H), 8.57 (d, 1H). LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 510 [M+H] ⁺ .

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146 (3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl } -3,8-diazabicyclo[3.2.1]oct-8-yl)(4isopropyl-1,3 - thiazol-2-yl)methanone ot-1-S \ 7) ^H 3CH n ₃ co from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl)imidazo[ 1 ,2-а]pyridine-dihydrochloride and 4-isopropyl-1,3-thiazole-2-carboxylic acid ' H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.24 (d, 6H), 1.67-1.78 (m, 2H), 1.79-1.90 (m, 2H), 2.44 (br. d, 1H) , 2.48-2.56 (m, 1H, masked by DMSO signal), 2.64 (br. d, 1H), 2.74 (br. d, 1H), 2.983.12 (m, 1H), 4.03 (s, 2H), 4.60 ( br. s, 1H), 5.59 (br. s, 1H), 6.99 (t, 1H), 7.32 (t, 1H), 7.52 (d, 2H), 7.57 (s, 1H), 7.61 (d, 1H) , 7.94 (d, 2H), 8.63 (d, 1H). LC-MS (Method 2): Rt= 1.93 min; MS (ESIpos): m/z = 506/508 [M+H] ⁺ . 147 (3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-3,8-diazabicyclo[3.2.1]οκτ-8-yl)(1,3-thiazol- 2-yl) methanone O from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride and 1,3-thiazole-2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.67-1.92 (m, 4H), 2.42-2.57 (m, 1H, partially obscured by DMSO signal), 2.70 (br. t, 2H), 4.03 ( s, 2H), 4.62 (br. s, 1H), 5.62 (br. s, 1H), 6.99 (t, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.61 (d, 1H) , 7.95 (d, 2H), 8.02 (q, 2H), 8.63 (d, 1H). LC-MS (Method 2): Rt = 1.49 min; MS (ESIpos): m/z = 464/466 [M+H] ⁺ . 148 (3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(4methyl-1,3 - thiazol-2-yl)methanone 00-0- ^H 3 ^C ^0® ^N o from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl)imidazo[ 1,2 -a]pyridine-dihydrochloride and 4-methyl-1,3-thiazole-2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.67-1.77 (m, 2H), 1.79-1.92 (m, 2H), 2.41 (s, 3H), 2.42-2.57 (m, 2H, partially hidden by DMSO signal), 2.64 (br. d, 1H), 2.72 (br. d, 1H), 4.03 (s, 2H), 4.59 (br. s, 1H), 5.64 (br. s, 1H), 6.99 ( t, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.57 (s, 1H), 7.61 (d, 1H), 7.95 (d, 2H), 8.63 (d, 1H). LC-MS (Method 2): Rt=1.69 min; MS (ESIpos): m/z = 478/480 [M+H] ⁺ .

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149 (3 -{[2-(4-chlorophenyl )imidazo[ 1,2-a]pyridin-3yl] methyl } -3,8-diazabicyclo[3.2.1] oct-8-yl)(5 methyl-1,3 -thiazol-2-yl)methanone Οΰ-Ό- n ₃ with Qu o from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl)imidazo[ 1,2-a ]pyridine-dihydrochloride and 5-methyl-1,3-thiazole-2-carboxylic acid ¹ H-NMR (400 MHz, DMSOde): δ [ppm] = 1.64-1.90 (m, 4Η), 2.40-2.57 (m, 5H, partially obscured by DMSO signal), 2.68 (br. t, 2H), 4.02 ( s, 2Н), 4.59 (br. s, 1Н), 5.59 (br. s, 1H), 6.99 (td, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.61 (d, 1H) , 7.69 (d, 1H), 7.95 (d, 2H), 8.62 (d, 1H). LC-MS (Method 2): Rt= 1.68 min; MS (ESIpos): m/z = 478/480 [M+H] ⁺ . 150 (3 -{[2-(4-chlorophenyl )imidazo[ 1,2-a]pyridin-3yl] methyl } -3,8-diazabicyclo[3.2.1] οκτ-8-yl)(4,5-dimethyl- 1,3-thiazol-2-yl) methanone O from 2-(4-chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride and 4,5-Dimethyl-1,3-thiazol- 2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.65-1.89 (m, 4H), 2.29 (s, 3H), 2.38 (s, 3H), 2.43 (br. d, 2H), 2.602. 75 (m, 2H), 4.02 (s, 2H), 4.57 (br. s, 1H), 5.62 (br. s, 1H), 6.99 (t, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.95 (d, 2H), 8.63 (d, 1H). LC-MS (Method 2): Rt= 1.75 min; MS (ESIpos): m/z = 492/494 [M+H] ⁺ . 151 5-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl}-2,5-diazabicyclo[2.2.2]οκτ-2-yl] (6methoxypyridin-2-yl) methanone (racemate) K® o from 2-(4-bromophenyl)-3-(2,5-d-iazabicyclo[2.2.2]oct-2ylmethyl)imidazo[1,2-a]pyridinedihydrochloride (Racemate) and 6-methoxypyridine-2-carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.46-1.99 (m, 4H), 2.62-2.75 (m, 1H), 2.812.93 (m, 2H), 3.35-3.50 (m, 1H ), 3.70-3.82 (m, 3.75H), 3.89-4.01 (m, 1H), 4.20-4.41 (m, 2.25H), 6.83-7.02 (m, 2H), 7.17 (d, 0.75H), 7.257. 35 (m, 1.25H), 7.55-7.70 (m, 3H), 7.73-7.86 (m, 3H), 8.54-8.64 (m, 1H). LC-MS (Method 2): Rt= 1.39 min; MS (ESIpos): m/z = 532/534 [M+H] ⁺ .

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5-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3yl]methyl }-2,5-diazabicyclo[2.2.2]οκτ-2-yl](2fluorophenyl)methanone (Racemate)

Br

from 2-(4-bromophenyl)-3 -(2,5-d and azabicyclo[2.2.2] oct-2ylmethyl)imidazo[1,2-a]pyridine-dihydrochloride ______(Racemate) and 2-fluorobenzoic acid______ 5-{ [2-(4-bromophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -2,5-d iazabicyclo[2.2.2] οκτ-2-yl] yl) methanone (racemate)

Br from 2-(4-bromophenyl)-3-(2,5-d-iazabicyclo[2.2.2]oct-2ylmethyl)imidazo[1,2-a]pyridinedihydrochloride (Racemate) and 3-fluoro-6-methoxypyridine -2carboxylic acid 'H-NMR (400 MHz, DMSOde): δ [ppm] = 1.48-1.97 (m, 4H), 2.61-3.04 (m, 4H), 3.42 (br. d, 1H), 3.76 (br. d, 0.75H), 4.16-4.29 (m, 2H), 4.39 (br. s, 0.25H), 6.92-7.02 (m, 1H), 7.20-7.39 (m, 4H), 7.41-7.54 (m, 1H ), 7.56-7.72 (m, 3H), 7.74-7.86 (m, 2H), 8.54-8.63 (m, 1H).

LC-MS (Method 5): Rt= 1.06 min; MS (ESIpos): m/z = 519 [M+H] ⁺ .

' H-NMR (400 MHz, DMSOde): δ [ppm] = 1.51-2.00 (m, 4H), 2.63-2.73 (m, 1H), 2.772.85 (m, 1H), 2.91 (br. s, 0.75 H), 3.14 (br. d, 0.25H), 3.38-3.59 (m, 2H), 3.69-3.83 (m, 3.75H), 4.17-4.32 (m, 2H), 4.39 (br. s, 0.25H) , 6.877.03 (m, 2H), 7.31 (dd, 1H), 7.56-7.69 (m, 3H), 7.71-7.86 (m, 3H), 8.54-8.64 (m, 1H). LC-MS (Method 5): Rt= 1.07 min; MS (ESIpos): m/z = 550/552 [M+H] ⁺ .

Example 154 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-isopropyl-3,8-diazabicyclo [3.2.1]octane-8-carboxamide

8.5 mg (0.10 mmol) of isopropyl isocyanate was placed into the wells of a 96-well microtiter plate and cooled to 0°C. Separately, 42.6 mg (0.10 mmol) of 3-{[2-(4chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-dihydrochloride was dissolved in 0.8 ml 1,2-dichloroethane, mixed with 0.052 ml (0.3 mmol) N,N-diisopropylethylamine and cooled to 8°C. Both solutions were combined on a microtiter plate and first shaken for 1 hour at 0°C. Then left to warm to room temperature and shaken further overnight at room temperature. The solvent was then completely removed using a centrifugal dryer. The residue was dissolved in 0.6 ml DMF, filtered, and the filtrate was separated by preparative LC-MS using one of the following methods into components.

MS instrument: Waters, HPLC instrument: Waters; Column: Waters X-Bridge C18, 19 mm x 50 mm, 5 µm; eluent A: water + 0.375% ammonia, eluent B: acetonitrile + 0.375% ammonia, with eluent gradient; flow: 40 ml/min; UV detection: diode array detector (DAD) 210-400 nm. or MS instrument: Waters, HPLC instrument: Waters; column: Phenomenex Luna 5 µm C 18(2) 100A, AXIA Tech., 50 mm x 21.2 mm; eluent A: water + 0.0375% formic acid, eluent B: acetonitrile + 0.0375% formic acid, with eluent gradient; flow: 40 ml/min; UV detection: diode array detector (DAD) 210-400 nm.

In this way, 2.8 mg (6% th. y., 100% pure) of the title compound were obtained.

LC-MS (method 7, ESIpos): R _t = 0.85 min; m/z = 438 (M+H) ⁺ .

Analogously to example 154, the following compounds were prepared in a parallel-synthetic manner from 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane -dihydrochloride (examples 155-167 and 170-187) or 7-{[2-(4-chlorophenyl)imidazo[1,2-a]niridin-3-yl]methyl}-3-oxa7,9-diazabicyclo[ 3.3.1] nonane dihydrochloride (for examples 168, 169 and 188-198) and the corresponding isocyanate, carbamoyl chloride or chloroformate:

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Example Name/structure (yield; purity) LC-MS (Method 7) 155 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}^-(2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8carboxamide /^n ^/ F Η ⁰ (38% theoretical yield; 97% purity) Rt = 0.91 min; m/z = 490 (M+H) ⁺ 156 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}7V-(2,6-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-8carboxamide z?~n ^/ Cl H fY ° (8% th. y.; 96% purity) Rt = 0.93 min; m/z = 540 (M+H) ⁺ 157 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}L-(2,6-dimethylphenyl)-3,8-diazabicyclo[3.2.1]octane-8carboxamide n ₃ s n yGu ° ν^ϊ/^CH3 (14% theoretical yield; 100% purity) Rt = 0.92 min; m/z = 500 (M+H) ⁺ 158 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}Λ - pentyl-3,8-Diazabicyclo[3.2.1]octane-8-carboxamide zq-n ^/ n H3C^^^^ ° (15% theoretical yield; purity 100%) Rt = 0.93 min; m/z = 466 (M+H) ⁺

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159 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}U-(2-methylphenyl)-3,8-diazabicyclo[3.2.1]octane-8carboxamide n ₃ s n nSl/ ΛΥ ° (8% th. y.; 96% purity) Rt = 0.92 min; m/z = 486 (M+H) ⁺ 160 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N- [2-chloro-5-(trifluoromethyl)phenyl]-3,8diazabicyclo[3.2.1 ] octane-8-carboxamide ОШ- /~-Ν ^Ζ Cl Н \ N__✓ ° CF ₃ (45% of theoretical yield; 92% purity) Rt = 1.06 min; m/z = 574 (M+H) ⁺ 161 А-(4-chlorophenyl)-3 -{[2-(4-chlorophenyl)imidazo[1,2а]pyridin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8carboxamide n ° sg (50% th. y.; 100% purity) Rt = 0.98 min; m/z = 506 (M+H) ⁺

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162 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N -(2-ethyl-6-methylphenyl)-3,8-diazabicyclo[3.2.1 ] octane-8 carboxamide zan ^z Ho C- 1 1 M ³ \ Η Ν / fY ° (15% theoretical yield; 97% purity) Rt = 0.96 min; m/z = 514(M+H) ⁺ 163 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}L-(2,5-d imethylphenyl)-3,8-diazabicyclo[3.2.1]octane- 8carboxamide ζγ'ν^ n ^Η 3^ o \^/^sn ₃ (19% theoretical yield; 100% purity) Rt = 0.96 min; m/z = 500 (M+H) ⁺ 164 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}A-cy clohexyl-3,8-diazabicyclo[3.2.1]octane-8 carboxamide Χ^Ν ^Ζ n ^O (35% theoretical yield; 100% purity) Rt = 0.93 min; m/z = 478 (M+H) ⁺

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165 A-(2-chloro-6-methylphenyl)-3-{[2-(4chlorophenyl)imide azo[1,2-а]pyridin-3-yl]methyl}-3,8diazabicyclo[3.2.1]octane-8 -carboxamide Cl Η \ Ν^ζ fY° (37% th. y.; 97% purity) Rt = 0.93 min; m/z = 520 (M+H) ⁺ 166 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}A-(2,6-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8carboxamide HG'N F H nJ/ \ N^Z fY° (23% th. y.; 100% purity) Rt = 0.90 min; m/z = 508 (M+H) ⁺ 167 3-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl}?/-(2,4-dimethylphenyl)-3,8-diazabicyclo[3.2.1]octane- 8carboxamide ΟλΟ- H ₃ C H ³ \ N_z ° n ₃ c ^x (5% theoretical yield; purity 100%) Rt = 0.96 min; m/z = 500 (M+H) ⁺

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168 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl }Λ-isopropyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9carboxamide G— N ^Z V ⁱ ' n d sn ₃ (16% th. y.; 94% purity) Rt = 0.77 min; m/z = 454 (M+H) ⁺ 169 A-(2-chloro-6-methylphenyl)-7-{[2-(4chlorophenyl)imide azo[1,2-a]pyridin-3-yl]methyl } -3-oxa7,9-diazabicyclo[3.3.1 ]nonane-9-carboxamide CAO G—-Ν ^{Ζ Cl H} \ 2 H ₃ C (2% theoretical yield; 93% purity) Rt = 0.82 min; m/z = 536 (M+H) ⁺ 170 ⁰ (4% th. y.; 100% purity) Rt = 0.79 min; m/z = 436 (M+H) ⁺

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171 PM2-chlorophenyl)-3 -1[2-(4-chlorophenyl)imidazo[1,2а]pyridin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octane-8carboxamide /BUT Cl Η ΛΥ° (6% th. y.; 97% purity) Rt = 0.93 min; m/z = 506 (M+H) ⁺ 172 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}A-methyl-A-phenyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide azh H ₃ C\\\cy ⁰ (38% th. y.; 100% purity) Rt = 0.95 min; m/z = 486 (M+H) ⁺ 173 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } 3,8-diazabicyclo[3.2.1]oct-8-yl)(morpholin-4-yl ) methanone ζαΆ θ' \ uyy about (6% th. y.; 98% purity) Rt = 0.81 min; m/z = 466 (M+H) ⁺

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174 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N,N-diisopropyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide CH ₃ H ₃ f \\ \ N__/ n ₃ s-f L \ O cn ₃ (20% theoretical output; 100% purity) Rt = 0.98 min; m/z = 480 (M+H) ⁺ 175 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N-cyclohexyl-Λ-ethyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide οχ Н ₃ C^ \ \ Ν-φΖ N^Z ° (44% theoretical yield; 100% purity) Rt = 1.04 min; m/z = 506 (M+H) ⁺ 176 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } 3,8-diazabicyclo[3.2.1]oct-8-yl)(pyrrolidin-1yl) methanone OP ΖΤ~ν ^ζ / \ N-JZ O (6% theoretical yield; 93% purity) Rt = 0.87 min; m/z = 450 (M+H) ⁺

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177 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}A-ethyl-A-phenyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide H ₃ C^ f \ \ \ cx ° (40% of theor. out.; 100% purity) Rt = 0.98 min; m/z = 500 (M+H) ⁺ 178 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}A-isopropyl-A-methyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide Z^ N ^Z n ₃ s \ N__/ n ₃ s ^/ A \ O CH ₃ (2% theoretical yield; 100% purity) Rt = 0.90 min; m/z = 452 (M+H) ⁺ 179 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } 3,8-diazabicyclo[3.2.1]oct-8-yl)(piperide in-1yl) methanone x?-n ^z ( λ O (19% theoretical yield; purity 97%) Rt = 0.92 min; m/z = 464 (M+H) ⁺ 180 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N,N-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide n ₃ c \ N^JZ n ₃ c ^{x 3} O (11% theoretical yield; 100% purity) Rt = 0.83 min; m/z = 424 (M+H) ⁺

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181 3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}Λ-ethyl-A-(4-methylphenyl)-3,8-diazabicyclo[3.2.1]octane -8 carboxamide OYO Rt = 1.02 min; m/z = 514(M+H) ⁺ H ₃ C^ f \ \ \ ° H ₃ C (38% th. y.; 95% purity) 182 А-(4-chlorophenyl)-3 -{[2-(4-chlorophenyl)imidazo[1,2a]pyridin-3 -yl]methyl} -Λ -isopropyl-3,8diazabicyclo[3.2.1]octane-8- carboxamide CH ₃ Z>N ^Z H ₃ cY \ SU ⁰ cr (19% theoretical yield; 99% purity) Rt = 1.05 min; m/z = 548 (M+H) ⁺ 183 (3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } 3,8-diazabicyclo[3.2.1]oct-8-yl)(thiomorpholin-4yl)methanone OTO- /u™ S ^Z ~\ O (22% of theor. yield; 100% purity) Rt = 0.89 min; m/z = 482 (M+H) ⁺

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184 Methyl-3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin-3 yl] methyl } -3,8-diazabicyclo[3.2.1] octane-8-carboxylate z>n ^x nV' o ^ / h ₃ c ^z A ³ 0 (7% theoretical output; purity 100%) Rt = 0.85 min; m/z = 411 (M+H) ⁺ 185 Ethyl-3 -{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3 yl]methyl } -3,8-diazabicyclo[3.2.1]octane-8-carboxylate eV ZQN ^Z Ν__X О__/ H ₃ C^/L O (15% theoretical yield; 100% purity) Rt = 0.89 min; m/z = 425 (M+H) ⁺ 186 Cyclopentyl-3 - {[2-(4-chlorophenyl) imidazo[ 1,2-a] pyridin3 -yl] methyl } -3,8-diazabicyclo[3.2.1] octane-8-carboxylate nV' ° (12% th. y.; 99% purity) Rt = 0.98 min; m/z = 465 (M+H) ⁺ 187 Cyclohexyl-3 - {[2-(4-chlorophenyl)imidazo[1,2-a]pyridin3 -yl]methyl} -3,8-diazabicyclo[3.2.1]octane-8-carboxylate XX N ^Z nV' ⁰ ( 8% theoretical yield, 100% purity Rt = 1.02 min; m/z = 479 (M+H) ⁺

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188 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N,N-diethyl-3-oxa-7,9-d iazabicyclo[3.3.1] nonan- 9carboxamide si Ν - Ν ^Ζ ' CH ₃ Ν ^ / ³ CH ₃ (35% theoretical yield; 100% purity) Rt = 0.78 min; m/z = 468 (M+H) ⁺ 189 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} 3-oxa-7,9-diazabicyclo [3.3.1]non-9-yl)(morphol in-4yl) methanone O# r—R JLl θ 0 (27% th. y.; 97% purity) Rt = 0.72 min; m/z = 482 (M+H) ⁺ 190 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}N,N-diisopropyl-3-oxa-7,9-diazabicyclo[3.3.1] nonan-9carboxamide Г—Ν ^Ζ \ sn ₃ Ν^Ζ ³ H ₃ C__/ Λ ' s ₃ CH ₃ ³ (27% of theor. output; purity 100%) Rt = 0.84 min; m/z = 496 (M+H) ⁺

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191 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}TV-cycle o hexyl-A-ethyl-3-oxa-7,9diazabicyclo[3.3.1]nonane -9-carboxamide Г—N ^Z SN ₃ (43% theoretical yield; 100% purity) Rt = 0.90 min; m/z = 522 (M+H) ⁺ 192 (7-{[2-(4-Chlorophenyl)imidazo[1,2-а]pyridin-3-yl]methyl } 3-oxa-7,9-diazabicyclo [3.3.1]non-9-yl)(pyrrolide in-1 yl)methanone G—N ^Z Jul θ (27% th. y.; 96% purity) Rt = 0.76 min; m/z = 466 (M+H) ⁺ 193 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } A-ethyl-A-phenyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane -9carboxamide 03%- r—lT Al o <ό CH ₃ (30% of theor. yield; 99% purity) Rt = 0.86 min; m/z = 516(M+H) ⁺

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194 7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl } A-isopropyl-A-methyl-3-oxa-7,9diazabicyclo[3.3.1]nonan-9 -carboxamide Rt = 0.78 min; m/z = 468 (M+H) ⁺ θ Vz ^CH 3 bn ₃ (44% theoretical yield; 100% purity) 195 Ethyl-7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridine-3 - Rt = 0.79 min; m/z = yl] methyl} -3-oxa-7,9-diazabicycle o[3.3.1] nonane-9-carboxylate 07^-g-N ^Z o O^/ ^CH3 (9% theoretical y.; 100% purity) 441 (M+H) ⁺ 196 Cyclopentyl-7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridine- Rt = 0.87 min; m/z = 3 -yl] methyl } -3 -oxa-7,9-d iazabicyclo[3.3.1] nonane-9carboxylate Ν ^Ζ θ ο^Ζ ⁴ ^ (6% theoretical yield; 100% purity) 481 (M+H) ⁺ 197 Propyl-7-{[2-(4-chlorophenyl)imidazo[1,2-а]pyridine-3 - Rt = 0.83 min; m/z = yl] methyl } -3 -oxa-7,9-d iazabicycle o[3.3.1] nonane-9carboxylate Γ-N o O^^CH ₃ (7% theoretical yield; 100% purity) 455 (M+H) ⁺ 198 (7-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} - Rt = 0.79 min; m/z = 3-oxa-7,9-diazabicyclo[3.3.1 ]non-9-yl)(piperidin-1 yl)methanone r-bg Li Oh (7% th. y.; 98% purity) 480 (M+H) ⁺

By analogy with examples 21 and 33, the following compound was obtained from the indicated educts:

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At

Name/structure/educt

Analytical data -6-methoxypyridin-2-yl) methanone (Racemate)

from 2-(4-bromophenyl)-3-(2,5diazabicyclo[2.2.2]oct-2ylmethyl)imidazo[1,2-a]pyridinedihydrochloride (Racemate) and 3-chloro-6methoxypyridine-2-carboxylic acid

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.51-1.98 (m, 4H), 2.60 (dd, 0.75H), 2.69-2.77 (m, 1H), 2.80 (br. s, 0.5H), 2.92-3.00 (m, 1H), 3.20 (br. s, 0.5H), 3.353.46 (m, 1.25H), 3.71-3.85 (m, 3.75H), 4.18-4.35 (m, 2H ), 4.38 (br. s, 0.25H), 6.85-7.02 (m, 2H), 7.27-7.35 (m, 1H), 7.56-7.70 (m, 3H), 7.72-7.94 (m, 3H), 8.538. 62(m, 1H).

LC-MS (Method 2):

Rt= 1.54 min; MS (ESIpos): m/z = 566/567/568/569 [M+H] ⁺ .

Example 200 (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo

[2.2.2]oct-2-yl)[6-(difluoromethoxy)pyridin-2-yl]methanone (enantiomer 1)

mg (0.24 mmol) of 6-(difluoromethoxy)pyridine-2-carboxylic acid was dissolved in 1.5 ml of DMF, mixed with 123 mg (0.32 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1, 3,3-tetramethyluronium hexafluorophosphate (HATU) and stirred for 30 minutes at room temperature. Then 100 mg of 2-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]octane-dihydrochloride ( enantiomer 1), as well as 190 µl (1.08 mmol) of N,N-diisopropylethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was then immediately separated by HPLC (method 6) into components. 79 mg (0.15 mmol, 70% of theor. yield) of the title compound were obtained.

LC-MS (method 2): Rt = 1.29 min; m/z = 525/527 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.51-2.08 (m, 4H), 2.73 (br. s, 0.25H), 2.85-2.94 (m, 1.5H), 2.98-3.10 (m, 1.25H), 3.38 (dd, 0.75H), 3.49 (d, 0.25H), 3.78-4.05 (m, 1.75H), 4.41 (br. s, 0.25H), 4.56-4.79 (m, 2H ), 6.94-7.05 (m, 1H), 7.15-7.25 (m, 1H), 7.30-7.39 (m, 1.25H), 7.45-7.87 (m, 2.75H), 7.95-8.12 (m, 2H), 8.17 -8.26 (m, 1H), 8.45 (d, 0.25H), 8.47-8.53 (m, 1H), 8.65 (d, 0.75H).

B. Analysis of pharmacological efficacy.

The pharmacological activity of the compounds according to the invention can be demonstrated by in vitro and in vivo studies, which are known to the skilled person. The following application examples describe the biological action of the compounds according to the invention without limiting the invention to these examples.

IN 1. In vitro electrophysiological analysis of the TASK-1 and TASK-3 channels using a two-electrode voltage-clamp technique in maturing Xenopus laevis oocytes.

Mature Xenopus laevis eggs are selected as described in [Decher et al., FEBS Lett. 492, 84-89 (2001)]. Then, a 0.5-5 ng cRNA solution that encodes TASK-1 or TASK-3 is injected into the eggs. For electrophysical analysis of egg-expressed channel proteins, a two-electrode voltage-clamp method was used [Stuhmer, Methods Enzymol. 207, 319-339 (1992)]. The measurements were carried out as described in [Decher et al., FEBS Lett. 492, 84-89 (2001)] at room temperature (21-22°C) with a Turbo-TEC-10CD amplifier (NPI), with 2 kHz acceptance and 0.4 kHz filtering. The use of substances was carried out using a gravitational perfusion system. In this case, the eggs were in the measuring chamber and were treated with a solution flow of 10 ml/min. The level of the measuring chamber was controlled and regulated by pumping out the solution with a peristaltic pump.

In the next table. 1 shows the half-maximal inhibition of the human TASK-1 and TASK-3 channels (1C ₅₀ -value) determined during this test, based on exemplary embodiments of the invention.

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Table 1

Example No. TASK-1 1C ₅ o [nm] TASK-3 1C ₅ o [nm] 21 27.3 ± 5.4 16.3±0.9 24 31.2 ± 5.8 26 54.0± 16.1 12.0±3.3 34 18.6±4.3 10.3±0.9 86 17.1±3.5 58.4 ± 12.1 92 13.5 ± 1.2 5.9± 1.8 102 8.7±3.6 4.3±3.5 104 60.7 ± 12.0 4.2 ± 1.0 115 22.8±3.7 186.2 ± 5.4 126 127.4±8.5 714.2±0.9

From the data in Table. 1 shows that both TASK-1 and TASK-3 blockades have been achieved. Thus, the results in Table. 1 confirm the mechanism of action of the compounds according to the invention as dual inhibitors of TASK-1/3.

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

Inhibition studies of the TASK-1 and TASK-3 recombinant channels were performed 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 using the method detailed 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-kitsl. The activity of the test substances was defined as their ability to inhibit depolarization induced in recombinant cells by 40 mM potassium chloride. The concentration that can block this depolarization by half is designated as IC ₅₀ .

In the next table. 2 shows the average IC ₅₀ values obtained on the basis of individual embodiments of the invention from this test (partially as averages of multiple independent individual values).

table 2

Example No. TASK-1 1C ₅ o [nm] TASK-3 1C ₅ o [nm] four 560 43 5 200 150 6 394 410 ten 1090 230 And 1400 940 12 3000 8300 fourteen 5100 860 fifteen 397 82 16 1300 600 21 240 60 22 170 13 23 790 170 24 140 4.5 25 120 5.6 26 690 42 29 460 fifty

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thirty 770 21 31 310 26 32 270 9.6 33 140 26 34 855 84 35 350 200 36 670 250 37 350 63 38 790 380 39 640 370 40 533 104 41 76 3.9 42 880 17 43 320 8.9 44 130 3.3 45 340 13

46 73 5 47 70 fifteen 48 390 17 49 740 12 51 290 34 52 170 ten 53 140 34 54 470 76 55 2000 320 57 1400 240 60 610 61 680 87 62 2800 760 63 490 140 64 280 17 65 2000 460 66 1100 110 67 990 220 69 870 101 70 1900 160 71 130 24 72 2000 120 73 160 9.6 74 330 23 75 380 thirty 76 240 fourteen 77 810 44 78 1600 65 79 1000 190 80 310 fifteen 81 520 25 82 230 420 83 134 fourteen 84 1100 400 85 520 53 86 331 126 87 583 160 88 766 210 89 827 220 90 958 79 91 1350 89 92 895 29 93 2300 510 94 530 130 95 1700 350 96 240 4.5 97 390 7.8 98 450 fourteen

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99 470 16 100 250 17 101 370 7.2 102 277 56 103 540 twenty 104 255 32 105 830 twenty 106 870 110 107 1000 33 108 1100 95 109 693 92 110 780 300 111 110 25 112 200 29 FROM 89 21 114 480 340 115 4240 2400 116 535 340 117 635 520 118 860 1000 119 1100 1500 120 1100 180 121 1700 2800 122 1100 120 123 2000 1600 126 17900 713 127 9450 670 135 4100 160 136 9300 44 137 190 fourteen 138 75 6.8 139 290 eighteen 140 160 21 141 250 59 142 240 98 143 130 fourteen 144 180 27 145 280 27 146 920 340 147 12 fifteen 148 23 2.7 149 3000 300 150 2700 210 151 72 1.8 152 2900 75 153 1000 34 154 130 29 155 610 210

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156 1200 fifteen 157 24 7.4 158 760 110 159 2900 220 160 7600 1000 161 7700 1000 162 53 13 163 1400 160 164 3100 1000 165 25 166 990 44 167 3000 350 168 1400 130 169 3600 110 170 1200 64 171 1800 26 172 5200 80 173 1700 32 174 91 13 175 43 200 176 49 ten 177 4000 130 178 290 17 179 270 2.9 180 220 23 181 4100 1000 182 6100 1000 183 450 26 184 2900 72 185 120 186 730 44 187 3800 200 188 60 5.9 189 8300 520 190 170 19 191 9500 190 192 870 73 193 7100 100 194 3000 290 195 230 8.1 196 440 52 197 150 13 198 810 60 199 33 1.8 200 877 75

From the data in Table. 2 shows that both TASK-1 and TASK-3 blockades have been achieved. Thus, the results in Table. 2 confirm the mechanism of action of the compounds according to the invention as dual inhibitors of TASK-1/3.

AT 3. An experimental model of obstructive sleep apnea in pigs.

The use of negative pressure on anesthetized, spontaneously breathing pigs can cause collapse and thus blockage of the upper airways [Wirth et al., Sleep 36, 699-708 (2013)].

Locally bred German pigs were used for the model. The pigs were anesthetized and had a tracheotomy. A cannula was inserted into the rostral and caudal trachea, respectively. The rostral cannula was connected with a T-piece on one side to a device that generates negative pressure and on the other side to the caudal cannula. The caudal cannula is connected via a T-piece to the rostral cannula, as well as to a soft tube, which bypasses the upper airway and allows spontaneous breathing. With appropriate closure and opening of the soft tube, pigs were able to transition from normal nasal breathing to caudal cannula breathing by isolating the upper airway and connecting to a negative pressure machine. Muscle activity of Musculus genioglossus was recorded using an electromyogram (EMG).

At certain time points, the condition of the collapse of the upper airways was checked, at which time the pig breathed through the caudal cannula and a reduced pressure was created in the upper airways from -50, -100 to -150 cm of water column (cm H ₂ O). Thus, the upper respiratory tract weakened, as evidenced by the stoppage of air flows and a decrease in pressure in the system.

- 99 039175 hoses. This test was carried out before the administration of the test substance and at certain intervals after the administration of the test substance. An appropriately active test substance can prevent this collapse of the upper airways during the inspiratory phase.

After changing from nasal breathing to breathing through the caudal cannula, EMG activity of Musculus genioglossus was no longer observed in anesthetized pigs. Then, as another test, reduced pressure was determined, during which EMG activity was used again. This threshold value shifted in the positive direction under the action of the test substance. The test was also carried out before the administration of the test substance and at certain intervals after the administration of the test substance. The test substance was administered intranasally, intravenously, subcutaneously, intraperitoneally or intragastrically.

AT 4. Electrophysiological determination of the washout rate of compounds In vitro after coupling to the human TASK-1 channel using the two-electrode voltage clamp method in Xenopus laevis oocytes.

Xenopus laevis oocytes were obtained from animals that were anesthetized with tricaine. The ovaries were treated with collagenase (1 mg/ml, Worthington kit, type II), placed in an OR2 solution (82.5 mM NaCl, 2 mM KCl, 1 mm mg Cl ₂ , 5 mM HEPES; pH 7.4) for 120 min and then stored in analyzed solution of ND96 (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl ₂ , 1 mm mg Cl ₂ , 5 mM HEPES; pH 7.5) with additional sodium pyruvate (275 mg/l), theophylline (90 mg/l) and gentamicin (50 mg/l) at 18°C. hTASK-1 and hTASK-3 were subcloned into the pSGEM vector and cRNA was obtained after linearization with NHEI and in vitro transcription with T7 polymerase. The ovaries were separately injected with 5-20 ng of cRNA solution, which encodes hTASK-1. Spent the standard method of clamping the voltage with two electrodes [Stuhmer, Methods Enzymol. 207, 319-339 (1992)] at room temperature (21-22°C) with a TEC-10CD turbo booster (NPI) as previously described [Decher et al., FEBS Lett. 492, 84-89 (2001)]. The measurement interval was 2 kHz, and the data were filtered at 0.4 kHz. The application of the substance was carried out using gravity through the electrolyte, and ND96 was used. Xenopus laevis oocytes were then selected as described above, injected with TASK-1-cRNA, and subjected to electrophysiological analysis using the two-electrode voltage clamp method.

TASK-1 channels were previously inhibited by administering a compound of the invention to a value of about 40%. At the same time, the following in the table were installed. 3 concentrations that were determined in advance during the analysis of the respective IC ₅₀ -values. The recovery of TASK-1-mediated membrane flux was then recorded for at least an hour by voltage clamping. This recovery is caused by a washout of the corresponding TASK-1 channel connection.

At least 6 oocytes were examined per compound. Trigger clamp measurements were continued for at least 1.5 h (inhibitor administration plus subsequent one hour washout measurement). Oocytes that leaked during measurements were discarded; presented in table. 3, the results included only those oocytes that remained stable throughout the measurement process.

Table 3

Example No. concentration [nm] number of measurements used washout rate [% h ¹ ] 21 thirty 6/6 40 26 60 6/7 17 29 45 5/6 17 33 80 5/6 55

C. Examples of pharmaceutical compositions.

Compounds according to the invention can be converted in the following way into pharmaceutical preparations.

Tablets.

Composition: 100 mg of a compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of cornstarch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, arch radius 12 mm.

Manufacturing.

A mixture of a compound according to the invention, lactose and starch is granulated with a 5% (m/m) solution of PVP in water. After drying, the granulate is mixed with magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (see above for tablet size). A press force of 15 kN is used as a guide value for pressing.

Orally administered suspensions.

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

A single dose of 100 mg of a compound according to the invention corresponds to 10 ml of oral suspension.

- 100 039175

Manufacturing.

Rhodigel is made into a suspension in ethanol, the compound according to the invention is added to the suspension. Water is added while stirring. Finally, the swollen Rhodigel is stirred for about 6 hours.

Orally administered solutions.

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

Manufacturing.

The compound according to the invention is made into a suspension in a mixture of polyethylene glycol and polysorbate with stirring. The mixing process is continued until the compound according to the invention is completely dissolved.

intravenous solution.

The compound according to the invention at a concentration less than the saturated solubility is dissolved in a physiologically compatible solvent (for example, isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is filtered under sterile conditions and dispensed into sterile and non-pyrogenic injection vessels.

Nasally applied solutions.

A compound of the invention at a concentration less than the saturated solubility is dissolved in a physiologically compatible solvent (eg purified water, phosphate buffer, citrate buffer). The solution may contain other additives for isotonization, preservation, pH adjustment, solubility improvement and/or stabilization.

Claims (13)

1. Compound of formula (I) in which ring Q denotes a diazaheterobicycle of the formula wherein * denotes a bond to an adjacent methylene group, ** denotes a bond to a carbonyl group, A and D, respectively, are CH, or one of these ring members is CH and the other is N, R ¹ means chlorine, bromine, isopropyl or cyclopropyl, R ² is cyclobutyl, cyclopentyl or cyclohexyl, or R ² is a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d) where *** denotes a bond with an adjacent carbonyl group, R ³ means hydrogen, fluorine or chlorine, R ⁴ means fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy, R ⁵ means hydrogen, fluorine, chlorine, bromine or methyl, R ⁶ is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy or cyclobutyloxy, R ^8A and R ^8b are in each case hydrogen, and Y means N(CH ₃ ), as well as its physiologically acceptable salts. - 101 039175 2. The compound of formula (I) according to claim 1, wherein ring Q is a diazaheterobicycle of formula where * denotes a bond with an adjacent methylene group, ** denotes a bond with a carbonyl group, A stands for CH or N, D stands for CH R ¹ means chlorine, bromine, isopropyl or cyclopropyl, R ² is cyclobutyl, cyclopentyl or cyclohexyl, or R ² is a phenyl group of formula (a), a pyridyl group of formula (b) or an azole group of formula (d) where *** denotes a bond with an adjacent carbonyl group, R ³ means hydrogen, fluorine or chlorine, R4 means fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy, R ⁵ means hydrogen, fluorine, chlorine, bromine or methyl, R ⁶ is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy or cyclobutyloxy, R ^8A and R ^8b are hydrogen, respectively, and Y means N(CH ₃ ), as well as its physiologically acceptable salts. 3. A process for the preparation of a compound of formula (I) as defined in claim 1 or 2, characterized in that the compound of formula (II) in which A, D and R ¹ have the meanings of claim 1 or 2, in the presence of a reducing agent selected from an alkali metal borohydride, reacted with a compound of formula (III) N / in which R ² and ring Q are as defined in claim 1 or 2, in the presence of a solvent selected from the group consisting of alcohols, ethers, polar aprotic solvents or mixtures thereof. 4. Process for the preparation of a compound of formula (I-A) in which A, D, R ¹ and Q have the meaning specified in claim 1 or 2, and R ^2A means (C ₄ -C ₆ )-cycloalkyl or means a phenyl group of formula (a), a pyridinyl group of formula (b) or an azole a group of formula (d) as described in claim 1 or 2, characterized in that the compound of formula (II) - 102 039175 in which A, D and R ¹ have the meanings specified in claim 1 or 2, in the presence of a reducing agent selected from an alkali metal borohydride, subjected to interaction with a protected diazaheterobicycle of formula (IV) in which the ring Q has the meaning specified in claim 1 or 2, and PG means a protective amino group selected from tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl, in the presence of a solvent selected from the group consisting of alcohols, ethers, polar aprotic solvents, or mixtures thereof, to give a compound of formula (V) in which A, D, R ¹ and ring Q have the above meanings, then reacted with a carboxylic acid compound of formula (VII) O _r 2 ^a x*4 ₀ h (VII), in which R ^2A has the above meanings, by activating the carboxylic acid function in (VII) or by using the corresponding acid chloride of the formula (VIII) R^^CI (VIII), in which R ^2A has the above meanings. 5. The method according to claim 3 or 4, wherein the further obtained compound of formula (I) or (I-A) is separated into its enantiomers and/or diastereoisomers and/or the corresponding (i) solvents and/or (ii) acids are converted into its physiologically acceptable salts. 6. The use of a compound as defined in one of claims 1, 2 for the manufacture of a medicament for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases. 7. Use according to claim 6, wherein the respiratory disorders are sleep disorders selected from obstructive sleep apnea syndrome, central sleep apnea syndrome and snoring. 8. A medicinal product containing a compound as defined in one of claims 1, 2, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases. - 103 039175 9. The medicament of claim 8, wherein the respiratory disorders are sleep disorders selected from obstructive sleep apnea syndrome, central sleep apnea syndrome, and snoring. 10. A drug containing a compound as defined in one of claims 1, 2, in combination with one or more additional biologically active substances selected from the group consisting of respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents, and cytotoxic agents for the treatment and/or prevention of respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases, and neuroimmunological diseases. 11. The medicament of claim 10, wherein the respiratory disorders are sleep disorders selected from obstructive sleep apnea syndrome, central sleep apnea syndrome, and snoring. 12. A method of treating and/or preventing respiratory disorders, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmunological diseases in humans and animals using an active amount of at least one compound as defined in one of claims 1, 2, or medicinal product, as defined in one of claims 8, 9. 13. The method of treatment and/or prevention according to claim 12, wherein the respiratory disorders are sleep disorders selected from obstructive sleep apnea syndrome, central sleep apnea syndrome, and snoring.