Adrenergic receptor ADRAC2 antagonists

Abstract

The present application relates to adrenergic receptor ADRAC2 antagonists, to novel substituted heterocyclic carboxamides, to a method for the production thereof, to the use thereof alone or in combination for the treatment and / or prophylaxis of diseases and to the use thereof for producing medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of dyspnea, including sleep-induced dyspnea, including sleep-induced dyspnea, including sleep-induced dyspnea, including sleep-induced dyspnea, including sleep-induced dyspnea, including sleep-induced dyspnea. Such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

Description

[0001] This application is a divisional application of the Chinese patent application with the application number 202080091881.6 and the invention title "Adrenergic Receptor ADRAC2 Antagonist", which was filed on November 5, 2020.

[0002] This application relates to novel substituted heterocyclic carboxamides, methods for their preparation, their use alone or in combination for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

[0003] The α2-adrenergic receptors (α2-ARs) belong to the G protein-coupled receptor family. They bind to the pertussis toxin-sensitive inhibitory G proteins G1 and G0 and reduce adenylate cyclase activity. They are involved in the mediation of several different physiological actions in different tissues when stimulated by endogenous catecholamines (epinephrine, norepinephrine) released via synapses or reaching the site of action via the blood. α2-ARs play important physiological roles, mainly in the cardiovascular system and the central nervous system. Biochemical, physiological and pharmacological studies have shown that, in addition to various α1-AR subtypes, there are three α2-AR subtypes (α2A, α2B and α2C) in many cardiovascular-related target cells and tissues as well as neuronal target cells and tissues, which makes them attractive target proteins for therapeutic intervention. However, due to the lack of highly selective ligands and / or antagonists for the corresponding α2-ARs, the interpretation of the precise physiological tasks of the receptor subtypes remains difficult [Gyires et al., α 2 -Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The α2-Adrenergic Receptors: Adrenergic Receptors in the 21st Century / Receptors, 2005, 241-265].

[0004] Obstructive sleep apnea (OSA) is a sleep-related respiratory disorder characterized by recurrent upper airway obstruction.

[0005] During inspiration, the interaction between two opposing forces ensures the patency of the upper airway. The dilatory action of the upper airway muscles counteracts the negative intraluminal pressure and causes the lumen to contract. The active contraction of the diaphragm and other accessory respiratory muscles generates a negative pressure in the airway, which constitutes the driving force for breathing. The stability of the upper airway essentially depends on the coordination and contractile properties of the upper airway dilator muscles.

[0006] It is thought that upper airway collapse in OSA occurs early in sleep because of reduced activity of some upper airway dilator muscles, which results in the loss of patency of the anatomically sensitive airway. However, certain upper airway dilator muscles, including the genioglossus, are the most important of the upper airway abductors and are innervated by the hypoglossal nerve, and can increase their activity during sleep in response to respiratory stimuli, which may counteract some of the changes in early sleep. It has been observed that patients with OSA have apnea-free intervals during which genioglossus muscle activity is increased by only 25 - 40% compared with sleep with frequent obstructive apneas [Jordan AS, White DP, Lo YL et al., Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32 (3):361 - 8]. Norepinephrine is one of the most potent neuromodulators of hypoglossal motoneuron activity [Horner R.L., Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1 - 2):179 - 196]. It is thought that reduced noradrenergic stimulation leads to a decrease in the excitability of sleep - induced hypoglossal motoneurons, which results in a decrease in the activity of the upper airway dilator muscles, particularly the genioglossus muscle.

[0007] Patients with obstructive sleep apnea have high mortality and morbidity due to cardiovascular disorders such as hypertension, myocardial infarction, and stroke [Vrints et al., Acta Clin Belg., 68 , 169 - 78(2013].

[0008] The α2C - adrenergic receptors regulate the release of norepinephrine by central noradrenergic neurons and are autoreceptors involved in the presynaptic feedback inhibition of norepinephrine. [Hein L. et al., Two functionally distinct alpha2 - adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402 (6758): 181 - 184].

[0009] The increased activity of hypoglossal motoneurons through α2c - adrenergic receptor antagonism can stabilize the upper airway and protect it from collapse and obstruction. In addition, snoring can be inhibited by stabilizing the upper airway.

[0010] In the case of primary snoring, the upper airway is not obstructed. However, due to the constriction of the upper airway, the flow rate of the inhaled and exhaled air increases. This, combined with relaxed muscle tissue, causes the soft tissues of the oral cavity and pharynx to vibrate in the air stream. This slight vibration then produces the typical snoring noise.

[0011] Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This leads to an increase in airway resistance and, consequently, an increase in the work of breathing, accompanied by significant fluctuations in intrathoracic pressure. During inspiration, the development of negative intrathoracic pressure can reach values similar to those encountered due to complete airway obstruction during obstructive sleep apnea. The pathophysiological effects on the heart, blood circulation, and sleep quality are comparable to those in obstructive sleep apnea. As in obstructive sleep apnea, the pathogenesis is thought to be the reduced activity of pharynx - dilating muscles during inspiration while sleeping. Usually, obstructive snoring is the initial stage of obstructive sleep apnea [Hollandt et al., HNO, 48, 628 - 634 (2000)].

[0012] Central sleep apnea (CSA) occurs when brain function or respiratory control is impaired. CSA is characterized by a lack of respiratory drive during sleep, leading to recurrent episodes of inadequate breathing or apnea and impaired gas exchange. CSA has multiple manifestations. These include high-altitude periodic breathing, idiopathic CSA (ICSA), central apnea induced by anesthetics, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes breathing (CSB). The exact mechanisms in different types of CSA can vary widely; however, a major feature is unstable respiratory drive during sleep [Eckert D.J. et al., Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607].

[0013] Dysphagia is difficulty in swallowing that can have various causes. The complex regulation of swallowing occurs in various structures of the brain. This is a bidirectional connection between the cerebral cortex, corticobulbar tract, brainstem, and peripheral swallowing muscle tissues. The regulation and execution of swallowing behavior essentially involve five pairs of cranial nerves (trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII)) and more than 25 muscle pairs [Arens C., Position paper of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German Society of Phoniatrics and Pediatric Audiology - current state of clinical and endoscopic diagnostics, evaluation, and therapy of swallowing disorders in children and adults. Laryngorhinootologie, 2015 Mar; 94 Suppl 1: 306-54].

[0014] Dysphagia can have very different causes, such as structural disorders of the oral cavity and / or larynx, psychological causes, and neurological disorders (neurogenic dysphagia), for example, including Parkinson's disease, myotonic dystrophy, amyotrophic lateral sclerosis, cerebral infarction, craniocerebral injury, brainstem injury, myositis, and neuromuscular disorders [Karkos PD, Current evaluation of the dysphagic patient. Hippokratia. 2009 Jul; 13(3): 141-6].

[0015] Noradrenergic neurons and α2 -ARs play a role in the coordination of swallowing and respiration [Yamanishi T., Alpha2-adrenoceptors coordinate swallowing and respiration. J Dent Res 2010, 89(3): 258-2639].

[0016] α2-ARs also play an important role in cardiovascular changes. For example, the regulation of cardiac contractility is first regulated by the central modulation of sympathetic efferent nerves. In addition, the sympathetic efferent system also regulates the direct effects on smooth muscle cells and vascular endothelial cells. Therefore, the sympathetic nervous system is involved in the regulation of cardiac output performance and the control of local perfusion of various vascular beds. This is also controlled by α2-ARs involved in the regulation of peripheral resistance. Therefore, blood vessels are innervated by sympathetic nerve fibers located in the adventitia and having varicosities at their ends for the release of norepinephrine. The released norepinephrine regulates the respective local vascular tone via α2-ARs in endothelial cells and smooth muscle cells.

[0017] In addition to the effects on sympathetic efferent nerves, peripheral cardiovascular function is also regulated by presynaptic and postsynaptic α2-ARs. Smooth muscle cells and endothelial cells express different α2-AR subtypes. Activation of the α 2A 、α 2B and α 2C receptors leads to contraction and thus to vasoconstriction [Kanagy, Clinical Science 109: 431-437, (2005)]. However, the distribution of each receptor subtype changes among different vascular beds, between species, and between different vascular sizes. Therefore, α2A-ARs appear to be expressed almost exclusively in large arteries, while α2B-ARs contribute more to vascular tone in arterioles and veins. ARα 2BAppears to play a role in salt-induced hypertension[Gyires et al., α 2 -Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. The role of ARα2C in hemodynamics has not been fully understood; however, the ARα2C receptor appears to mediate venous vasoconstriction. They are also involved in the cold-induced enhancement of adrenergic receptor-evoked vasoconstriction [Chotani et al., Silent α 2C adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol 278:H1075-H1083, 2000; Gyires et al., α 2 -Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. Cold and other factors (such as tissue proteins, estrogen) regulate ARα2C function coupled to intracellular signaling pathways [Chotani et al., Distinct cAMP signaling pathways differentially regulate α2C adrenenoxceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol 288:H69-H76, (2005)].

[0018] Under pathophysiological conditions, the adrenergic system can be activated, which can lead to, for example, hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disturbances, stroke, and sexual dysfunction. Thus, for example, the pathophysiology of Raynaud's syndrome and scleroderma is largely unknown, but is associated with altered adrenergic activity. Thus, patients with spastic Raynaud's syndrome show, for example, a significantly increased expression of, e.g., ARα2 on their platelets. This may be associated with the vasospastic attacks observed in these patients [Keenan and Porter, α2-Adrenergic receptors in platelets from patients with Raynaud′s syndrome, Surgery, V94(2),(1983)].

[0019] Due to the expected high efficiency and low side effect levels, possible therapies for such conditions directed at the regulation of the activated adrenergic system in the organism are promising approaches. Especially in diabetic patients, who often have elevated catecholamine levels, peripheral circulatory disturbances (microangiopathy) such as diabetic retinopathy, nephropathy, or significant wound healing disorders (diabetic foot ulcers) play a major role. In peripheral occlusive diseases, diabetes is one of the most important comorbidities and also plays a decisive role in the progression of the disease (micro- and macroangiopathy). A higher expression of the adrenergic receptor α2C receptor, which is associated with elevated catecholamine levels, may be involved in these pathophysiological processes in diabetic patients.

[0020] In 2011, there were 350 million diabetics worldwide (about 6.6% of the population), and this number is expected to double by 2028. Diabetic foot ulcers are the most common cause of hospitalization among diabetics. The risk of developing a diabetic foot ulcer during a diabetic's lifetime is 15 - 25%, and 15% of all diabetic foot ulcers result in amputation. 40 - 70% of all non-traumatic amputations worldwide are performed on diabetics. Risk factors for diabetic foot ulcers are trauma, poor metabolic control, sensory, motor, and autonomic polyneuropathy, improper footwear, infection, and peripheral arterial disease. The treatment of diabetic foot ulcers requires an interdisciplinary team and the use of a multi-factorial approach: weight loss, revascularization (in the case of peripheral arterial occlusive disease, PAOD), improved metabolic control, debridement, dressing, dalteparin, Regranex (PDGF), and amputation. The treatment cost for each diabetic foot ulcer (without amputation) is 7000 - 10000 USD. 33% of all diabetic foot ulcers do not heal within 2 years, and the recurrence rate is high (34% in the first year, 61% over 3 years).

[0021] The compounds of the present application are suitable for preventing and treating diseases caused by activated or activation of α 2C -adrenergic receptors, as well as diseases secondary to injuries related to α 2C -adrenergic receptors.

[0022] Disorders that may be mentioned in this context are in particular dyspnea, sleep-induced dyspnea such as central and obstructive sleep apnea, mixed sleep apnea, Cheyne-Stokes respiration, snoring (primary and obstructive snoring), interrupted central respiratory drive, sudden infant death, postoperative hypoxia and apnea, muscular respiratory disorder, respiratory disorders following long-term ventilation, respiratory disorders during adaptation in high mountains, dysphagia, acute and chronic pulmonary diseases with hypoxia and hypercapnia, peripheral circulatory disorders (microangiopathies) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers), disorders of the peripheral and central nervous system, in particular dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHD), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0023] Accordingly, it is an object of the present invention to provide a new substance which acts as a potent and selective antagonist of the α2C-adrenergic receptor and is thus suitable for the treatment and / or prophylaxis of dyspnea, sleep-induced dyspnea such as obstructive and central sleep apnea, snoring, dysphagia, disorders of the peripheral and central nervous system and peripheral circulatory disorders (microangiopathies) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers).

[0024] The present invention provides compounds of general formula (I)

[0025]

[0026] wherein

[0027] X represents S, N or O;

[0028] Y represents N, S or O;

[0029] wherein, if X represents S, then Y represents N;

[0030] Wherein, if X represents O, then Y represents N;

[0031] Z represents CR 4 , O or NR 4 ,

[0032] Wherein, if X represents N and Y represents N, then Z represents O;

[0033] Wherein, if X represents S, then Z represents CR 4 or NR 4

[0034] R 1 represents a 5- or 6-membered heteroaryl, phenyl,

[0035] wherein the 5- to 6-membered heteroaryl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;

[0036] Wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times,

[0037] Wherein (C 1 -C 4 )-alkoxy may be substituted by halogen up to three times,

[0038] Wherein phenyl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 4 )-alkyl, (C 3 -C 5 )-cycloalkyl, (C 1 -C 4 )-alkoxy, cyano, hydroxy, halogen;

[0039] Wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times,

[0040] R 2 represents hydrogen, (C 1 -C 4 )-alkyl;

[0041] Wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times,

[0042] or

[0043] together with R 2The connected carbon atoms together form a (C 3 -C 4 )-cycloalkyl ring,

[0044] R 3 represents hydrogen, (C 1 -C 4 )-alkyl,

[0045] wherein the (C 1 -C 4 )-alkyl may be substituted up to three times by halogen,

[0046] R 4 in CR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl, halogen;

[0047] wherein the (C 1 -C 4 )-alkyl may be substituted up to three times by halogen and the phenyl may be substituted by halogen,

[0048] in NR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl;

[0049] wherein the (C 1 -C 4 )-alkyl may be substituted up to three times by halogen and the phenyl may be substituted by halogen,

[0050] R 5 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen,

[0051] R 6 represents a group of formula a), b), c), d), e), f) or g)

[0052]

[0053] wherein * marks the connection to the adjacent piperidine ring,

[0054] wherein R 7 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4)-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, phenyl,

[0055] wherein (C 1 -C 4 )-alkyl may be substituted by (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy,

[0056] (C 3 -C 4 )-cycloalkoxy and is substituted by halogen at most trisubstituted,

[0057] wherein (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and is substituted by halogen at most trisubstituted,

[0058] wherein (C 3 -C 4 )-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and is substituted by halogen at most disubstituted,

[0059] wherein (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and is substituted by halogen at most trisubstituted,

[0060] wherein (C 3 -C 4 )-cycloalkyl may be substituted by halogen monosubstituted or disubstituted,

[0061] wherein (C 3 -C 4 )-cycloalkoxy may be substituted by halogen at most disubstituted,

[0062] wherein R 8 represents hydrogen or fluorine,

[0063] wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;

[0064] wherein (C 1 -C 4 )-alkyl may be substituted by (C 1-C 4 )-alkoxy-substituted,

[0065] n represents 0 or 1,

[0066] m represents 0, 1 or 2,

[0067] p represents 0, 1 or 2 and

[0068] q represents 0, 1 or 2,

[0069] and its salts, solvates and solvates of salts.

[0070] The present invention provides a compound of general formula (I)

[0071]

[0072] wherein

[0073] X represents S, N, O;

[0074] Y represents N, S, O,

[0075] wherein, if X represents S, then Y represents N;

[0076] Z represents C, O, N,

[0077] wherein, if X represents N and Y represents N, then Z represents O;

[0078] R 1 represents a 5- or 6-membered heteroaryl, phenyl,

[0079] wherein the 5- to 6-membered heteroaryl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;

[0080] wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times,

[0081] wherein (C 1 -C 4 )-alkoxy may be substituted by halogen up to three times,

[0082] wherein phenyl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 4 )-alkyl, (C 3 -C 5 )-cycloalkyl, (C 1 -C 4 )-alkoxy, cyano, hydroxy, halogen;

[0083] wherein the (C 1 -C 4 )-alkyl group may be substituted by halogen up to three times,

[0084] R 2 represents hydrogen, (C 1 -C 4 )-alkyl;

[0085] wherein the (C 1 -C 4 )-alkyl group may be substituted by halogen up to three times,

[0086] or

[0087] together with the carbon atom to which R 2 is attached forms a (C 3 -C 4 )-cycloalkyl ring,

[0088] R 3 represents hydrogen, (C 1 -C 4 )-alkyl,

[0089] wherein the (C 1 -C 4 )-alkyl group may be substituted by halogen up to three times,

[0090] R 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl, halogen;

[0091] wherein the (C 1 -C 4 )-alkyl group may be substituted by halogen up to three times and the phenyl group may be substituted by halogen,

[0092] R 5 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen,

[0093] R 6 represents a group of formula a), b), c), d), e), f) or g)

[0094]

[0095] wherein *** indicates the connection to the adjacent piperidine ring,

[0096] wherein R 7represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, phenyl,

[0097] wherein (C 1 -C 4 )-alkyl may be substituted by (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy,

[0098] (C 3 -C 4 )-cycloalkoxy and trisubstituted at most by halogen,

[0099] wherein (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and trisubstituted at most by halogen,

[0100] wherein (C 3 -C 4 )-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and disubstituted at most by halogen,

[0101] wherein (C 1 -C 4 )-alkoxy may be substituted by (C 3 -C 4 )-cycloalkyl and trisubstituted at most by halogen,

[0102] wherein (C 3 -C 4 )-cycloalkyl may be monosubstituted or disubstituted by halogen,

[0103] wherein (C 3 -C 4 )-cycloalkoxy may be disubstituted at most by halogen,

[0104] wherein R 8 represents hydrogen or fluorine,

[0105] wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen;

[0106] wherein the (C 1 -C 4 )-alkyl may be substituted by (C 1 -C 4 )-alkoxy,

[0107] n represents 0 or 1,

[0108] m represents 0, 1 or 2,

[0109] p represents 0, 1 or 2 and

[0110] q represents 0, 1 or 2,

[0111] and their salts, solvates and solvates of salts.

[0112] The compounds of the present invention are the compounds of formula (I) and their salts, solvates and solvates of salts, the compounds of the formula included in formula (I) and having the formula mentioned hereinafter and their salts, solvates and solvates of salts, and the compounds included in formula (I) and mentioned hereinafter as working examples and their salts, solvates and solvates of salts, even if the compounds included in formula (I) and mentioned hereinafter are not yet salts, solvates and solvates of salts.

[0113] The compounds of the present invention are also the N-oxides and S-oxides of the compounds of formula (I) and their salts, solvates and solvates of salts.

[0114] In the present invention, the salts are preferably physiologically acceptable salts of the compounds according to the present invention. Also included are salts that are not suitable for pharmaceutical use per se but can be used, for example, for the separation, purification or storage of the compounds of the present invention.

[0115] Pharmaceutically acceptable salts of suitable compounds of the present invention can be, for example, acid addition salts of compounds of the present invention having a nitrogen atom with sufficient basicity in the chain or ring, such as acid addition salts with inorganic acids or "mineral acids" or with organic acids. The inorganic acids are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid; the organic acids are, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, glucaric acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, palmitic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid or thiocyanic acid.

[0116] In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention having sufficient acidity is an alkali metal salt, such as a sodium or potassium salt; an alkaline earth metal salt, such as a calcium, magnesium or strontium salt; or an aluminum or zinc salt; or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1-20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethanediamine, N-methylpiperidine, N-methylglucamine, N,N-dimethylglucamine, N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol; or a salt with a quaternary ammonium ion having 1-20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium chloride.

[0117] Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with a suitable base using a variety of known methods.

[0118] The present invention includes all possible salts of the compounds of the present invention, as a single salt or any mixture of said salts in any proportion.

[0119] In the present context, particularly in the experimental section, for the synthesis of the intermediates and examples of the present invention, when a compound is mentioned in the form of a salt with a corresponding base or acid as obtained by the respective preparation and / or purification methods, in most cases, the exact stoichiometric composition of the salt form is unknown. Unless otherwise stated, the suffixes of chemical names or structural formulas related to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF3COOH", "x Na+", for example, are meant to refer to the salt form, while the stoichiometry of its salt form is not specified. This similarly applies to cases where the synthetic intermediates or the exemplified compounds or their salts obtained by the described preparation and / or purification methods are in the form of solvates (such as hydrates).

[0120] Solvates are described in the context of the present invention as those forms of the compounds of the present invention that form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination occurs with water. The preferred solvates in the context of the present invention are hydrates.

[0121] Depending on their structure, the compounds of the present invention can exist in different stereoisomeric forms, i.e., as configurational isomers or optionally as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention thus includes enantiomers and diastereomers and their respective mixtures. Stereoisomerically homogeneous components can be separated from such mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, chromatography is preferably used, especially HPLC chromatography on non-chiral or chiral separation phases. In the case of carboxylic acids as intermediates or end products, chiral amine bases can also be used for separation via diastereomeric salts.

[0122] In the present invention, the term "enantiomerically pure" is understood as follows: the compound in question is present in an enantiomeric excess of greater than 95%, preferably greater than 98%, with respect to the absolute configuration of the chiral center. The enantiomeric excess ee is calculated here by evaluating the analytical chromatogram of HPLC on a chiral phase using the following formula:

[0123]

[0124] If the compounds of the present invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

[0125] The present invention also includes all suitable isotopic variants of the compounds of the present invention. Isotopic variants of the compounds of the present invention are understood herein to mean compounds in which at least one atom within the compounds of the present invention has been replaced by another atom having the same atomic number but an atomic mass different from the atomic mass that is normally or predominantly present in nature. The phrase "unnatural proportion" is understood to mean a proportion of such an isotope that is higher than its natural frequency. The natural frequencies of the isotopes used in this regard can be found in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Specific isotopic variants of the compounds of the present invention, especially those in which one or more radioactive isotopes have been incorporated, may be useful, for example, in examining the mechanism of action or the distribution of the active ingredient in the body; due to their relatively easy preparation and detection, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this use. In addition, the incorporation of an isotope, such as deuterium, can confer specific therapeutic benefits due to the greater metabolic stability of the compound, such as an extended half-life in the body or a reduced required active dose; such modifications of the compounds of the present invention may therefore also optionally constitute preferred embodiments of the present invention. With regard to the treatment and / or prevention of the disorders defined herein, the (one or more) isotopic variants of the compounds of formula (I) preferably contain deuterium ("deuterium-containing compounds of formula (I)"). Isotopic variants of the compounds of formula (I) in which one or more radioactive isotopes such as 3 H or 14 C have been incorporated are useful, for example, in pharmaceutical and / or substrate tissue distribution studies. These isotopes are particularly preferred because of their ease of incorporation and detection. Positron-emitting isotopes such as 18 F or11 C incorporated into the compounds of formula (I). These isotopic variants of the compounds of formula (I) are suitable for in vivo imaging applications. Deuterium-containing and 13 13C-containing compounds of formula (I) can be used in the context of preclinical or clinical studies in mass spectrometry (H.J. Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compounds of the present invention can be prepared by conventional methods known to those skilled in the art, such as according to the procedures reported in the methods and examples further described below, by using the corresponding isotopic modifications of various reagents and / or starting compounds.

[0126] Isotopic variants of the compounds of formula (I) are generally prepared by replacing the reagent with an isotopic variant of the reagent, preferably a deuterium-containing reagent, by methods known to those skilled in the art as described in the schemes and / or examples herein. Depending on the desired deuteration site, in some cases, deuterium from D2O can be directly incorporated into the compound or into the reagents that can be used to synthesize such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Photochemical deuteration and tritiation methods have also been described (Y.Y. Loh et al., Science 10.1126 / science.aap9674 (2017)). Another useful reagent for incorporating deuterium into molecules is deuterium gas. A rapid route for incorporating deuterium is the catalytic deuteration of olefinic bonds (H.J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J.R. Morandi et al., J. Org. Chem., 1969, 34(6), 1889) and acetylenic bonds (N.H. Khan, J. Am. Chem. Soc., 1952, 74(12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). To directly replace hydrogen in a functionalized hydrocarbon with deuterium, a metal catalyst (i.e., Pd, Pt, and Rh) can also be used in the presence of deuterium gas (J.G. Atkinson et al., US Patent 3966781). Various deuteration reagents and synthesis apparatuses are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0127] Further information related to the prior art on deuterium-hydrogen exchange was found, e.g., in Hanzlik et al., J. Org. Chem., 1990, 55, 3992-3997; R.P. Hanzlik et al., Biochem. Biophys. Res. Commun., 1989, 160, 844; P.J. Reider et al., J. Org. Chem., 1987, 52, 3326-3334; M. Jarman et al., Carcinogenesis, 1993, 16(4), 683-688; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem. Soc, Chem. Commun., 1519-1520; K. Kassahun et al., WO2012 / 112363.

[0128] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms have been replaced by one or more deuterium atoms and in which the deuterium frequency at each deuterated position in the compound of general formula (I) is higher than the natural frequency of deuterium (which is approximately 0.015%). In particular, in the deuterium-containing compound of general formula (I), the deuterium frequency at each deuterated position in the compound of general formula (I) is at this position or these positions higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, and even more preferably higher than 98% or 99%. It is obvious that the deuterium frequency at each deuterated position is independent of the deuterium frequencies at other deuterated positions.

[0129] The selective incorporation of one or more deuterium atoms into a compound of general formula (I) can alter the physicochemical properties (e.g., acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; C. L. Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or the metabolic profile of the molecule and result in a change in the ratio of the parent compound to the metabolite or the amount of metabolite formed. Such changes may confer specific therapeutic benefits and are thus preferred in certain circumstances. Reduced metabolic rates and metabolic switching have been reported, in which the ratio of metabolites is altered (D. J. Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure relative to the parent compound and metabolites have important implications for the pharmacodynamics, tolerability, and potency of the deuterated compound of general formula (I). In some cases, the formation of unwanted or toxic metabolites is reduced or eliminated due to deuterium substitution and the formation of the desired metabolite is enhanced (e.g., Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the systemic clearance rate. Consequently, the biological half-life of the compound is increased. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak concentrations and increased trough concentrations. Depending on the pharmacokinetic / pharmacodynamic relationship of the respective compound, this can lead to lower side effects and enhanced potency.Examples of such deuterium effects are Indiplon (A. J. Morales et al., Abstract 285, The 15th North American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12 - 16, 2008), ML - 337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208), and Odanacatib (K. Kassahun et al., WO2012 / 112363). Other situations have been reported where a reduced metabolic rate results in increased drug exposure without changing the systemic clearance rate (e.g., Rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs that exhibit such effects may have a reduced dose requirement (e.g., a lower number of doses or a lower dose to achieve the desired effect) and / or may produce a lower metabolite burden.

[0130] Compounds of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above effects on physicochemical properties and metabolic profiles, deuterated compounds of general formula (I) with a specific pattern of one or more deuterium - hydrogen exchanges can be selected. In particular, one deuterium atom / multiple deuterium atoms of the (one or more) deuterated compounds of general formula (I) are attached to carbon atoms and / or are located at those positions of the compounds of general formula (I) that are sites of attack for metabolic enzymes, such as cytochrome P450.

[0131] The present invention further includes prodrugs of the compounds of the present invention. The term "prodrug" as used herein refers to a compound that may be biologically active or inactive in itself but is converted in vivo (e.g., by metabolic or hydrolysis pathways) into a compound of the present invention.

[0132] In the context of the present invention, unless otherwise specified, substituents have the following meanings:

[0133] In the context of the present invention, Alkylis a straight-chain or branched-chain alkyl group having a specific number of carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4,4-dimethylpentyl, and 1,4,4-trimethylpentyl.

[0134] In the context of the present invention, Alkoxy is a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0135] In the context of the present invention, Cycloalkoxy is a cyclic alkoxy group having 3 to 4 carbon atoms. Examples include: cyclopropoxy or cyclobutoxy.

[0136] In the context of the present invention, Cycloalkyl or Carbocyclic ring is a monocyclic, polycyclic or spiro ring having a total of 3 to 8 ring atoms, preferably a monocyclic or bicyclic saturated carbon ring. A monocyclic saturated carbon ring is synonymously referred to as a cycloalkyl group. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, tricyclo[3.3.1.13,7]decyl. Preferred is a monocyclic cycloalkyl group having 3 to 5 carbon atoms. Examples include: cyclopropyl, cyclobutyl or cyclopentyl.

[0137] In the context of the present invention, 5- or 6-membered heteroaryl is a monocyclic aromatic heterocycle (heteroaromatic compound) having a total of 5 or 6 ring atoms, which contains at most three identical or different ring heteroatoms selected from N, O and / or S, and is connected via a ring carbon atom or optionally via a ring nitrogen atom. Examples include: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0138] In general, unless otherwise specified, heteroaryl includes all possible isomeric forms, such as tautomers and positional isomers related to the point of attachment to the rest of the molecule. Thus, by way of non-limiting example, the term pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl, or the term thienyl includes 2-thienyl and 3-thienyl.

[0139] In the context of the present invention, Halogen include fluorine, chlorine, bromine and iodine. Chlorine or fluorine is preferred.

[0140] When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or poly-substituted. In the present invention, all groups that occur more than once are defined independently of one another. When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or poly-substituted. It is preferably substituted by one substituent or two identical or different substituents.

[0141] In the context of the present invention, the term "treat" or "treatment" includes inhibiting, delaying, preventing, alleviating, attenuating, limiting, reducing, arresting, repelling or curing a disease, condition, disorder, injury or health problem, or the development, course or progression of such a condition and / or the symptoms of such a condition. The term "therapy" is understood herein to be synonymous with the term "treatment".

[0142] The terms "prevent", "prevention" or "preventive measure" are used synonymously in the present invention and refer to avoiding or reducing the risk of infection, occurrence, being afflicted with or suffering from a disease, condition, symptom, injury or health problem or the development or progression of such a condition and / or the symptoms of such a condition.

[0143] The treatment or prevention of a disease, condition, symptom, injury or health problem may be achieved partially or completely.

[0144] In the context of the present invention, compounds of formula (I) are preferred

[0145] wherein X represents S or N;

[0146] Y represents N, S or O,

[0147] wherein, if X represents S, then Y represents N;

[0148] Z represents CR 4 , N or O,

[0149] wherein, if X represents N and Y represents N, then Z represents O;

[0150] wherein, if X represents S, then Z represents N or CR 4

[0151] R 1represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0152] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0153] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,

[0154] wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine, chlorine,

[0155] wherein the thienyl group may be substituted by 1 to 2 substituents independently selected from fluorine, chlorine,

[0156] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0157] R 2 represents hydrogen, (C 1 -C 2 )-alkyl,

[0158] or

[0159] together with the carbon atom to which R 2 is attached forms a cyclopropyl ring,

[0160] R 3 represents hydrogen, (C 1 -C 2 )-alkyl;

[0161] R 4 represents hydrogen, (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl;

[0162] wherein the phenyl group may be substituted by halogen,

[0163] R 5 represents hydrogen, (C 1 -C 2 )-alkyl, methoxy, fluorine;

[0164] R 6A group of formula a), b), c) or e),

[0165]

[0166] wherein * marks the linkage to the adjacent piperidine ring,

[0167] wherein R 7 or R‘ 7 each independently represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,

[0168] wherein the (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine at most disubstituted,

[0169] wherein methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,

[0170] wherein cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl, wherein cyclobutyl may be substituted by fluorine at most disubstituted,

[0171] wherein n-butoxy may be substituted by fluorine at most disubstituted,

[0172] wherein the (C 1 -C 2 )-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and

[0173] wherein cyclopropyl and cyclobutyl may be substituted by fluorine at most disubstituted,

[0174] wherein the (C 3 -C 4 )-cycloalkoxy may be substituted by fluorine at most disubstituted,

[0175] wherein R 8 or R‘ 8 each independently represents hydrogen or fluorine,

[0176] wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 2 )-alkoxy, methoxyethyl, fluorine, chlorine;

[0177] n represents 0 or 1 and

[0178] m represents 1 or 2,

[0179] q represents 0 or 2,

[0180] and their salts, solvates and solvates of salts.

[0181] In the context of the present invention, compounds of formula (I) are preferred, wherein

[0182] X represents S, N;

[0183] Y represents N, S, O,

[0184] wherein, if X represents S, then Y represents N;

[0185] Z represents C, O,

[0186] wherein, if X represents N and Y represents N, then Z represents O;

[0187] R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0188] wherein the pyridyl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0189] wherein the pyrazolyl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,

[0190] wherein the thiazolyl may be substituted by 1 to 2 substituents independently selected from fluorine, chlorine,

[0191] wherein the thienyl may be substituted by 1 to 2 substituents independently selected from fluorine, chlorine,

[0192] wherein the phenyl may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0193] R 2 represents hydrogen, (C 1 -C 2 )-alkyl,

[0194] or

[0195] together with R2 The carbon atoms to which they are attached together form a cyclopropyl ring,

[0196] R 3 represents hydrogen, (C 1 -C 2 )-alkyl;

[0197] R 4 represents hydrogen, (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl;

[0198] wherein the phenyl may be substituted by halogen,

[0199] R 5 represents hydrogen, (C 1 -C 2 )-alkyl, methoxy, fluorine;

[0200] R 6 represents a group of formula a), b), c) or e),

[0201]

[0202] wherein *** indicates the connection to the adjacent piperidine ring,

[0203] wherein R 7 or R‘ 7 each independently represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,

[0204] wherein (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine up to disubstituted,

[0205] wherein methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,

[0206] wherein cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,

[0207] wherein cyclobutyl may be substituted by fluorine up to disubstituted,

[0208] wherein the n-butoxy group may be substituted by fluorine up to two times,

[0209] wherein the (C 1 -C 2 )-alkoxy group may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl

[0210] and

[0211] wherein the cyclopropyl and cyclobutyl groups may be substituted by fluorine up to two times,

[0212] wherein the (C 3 -C 4 )-cycloalkoxy group may be substituted by fluorine up to two times,

[0213] wherein R 8 or R‘ 8 each independently represents hydrogen or fluorine,

[0214] wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 2 )-alkoxy, methoxyethyl, fluorine, chlorine;

[0215] n represents 0 or 1 and

[0216] m represents 1 or 2,

[0217] q represents 0 or 2,

[0218] and its salts, solvates and solvates of salts.

[0219] In the context of the present invention, the compounds of formula (I) are preferably

[0220] wherein

[0221] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k) or (r),

[0222]

[0223] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0224] R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0225] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0226] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,

[0227] wherein the thiazolyl group may be substituted by chlorine,

[0228] wherein the thienyl group may be substituted by fluorine,

[0229] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0230] R 2 represents hydrogen, methyl,

[0231] or

[0232] together with the carbon atom to which R 2 is attached forms a cyclopropyl ring,

[0233] R 3 represents hydrogen, (C 1 -C 2 )-alkyl;

[0234] R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0235] wherein the phenyl group may be substituted by chlorine,

[0236] R 5 represents hydrogen, fluorine;

[0237] R 6 represents a group in formula a), b'), b"), c'), c") or e),

[0238]

[0239] wherein the * marks the connection to the adjacent piperidine ring,

[0240] wherein R 7 or R 7 each independently represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4)-cycloalkyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,

[0241] wherein (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine at most disubstituted,

[0242] wherein methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,

[0243] wherein cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,

[0244] wherein cyclobutyl may be substituted by fluorine at most disubstituted,

[0245] wherein n-butoxy may be substituted by fluorine at most disubstituted,

[0246] wherein (C 1 -C 2 )-alkyloxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluorometh

[0247] yl and

[0248] wherein cyclopropyl and cyclobutyl may be substituted by fluorine at most disubstituted,

[0249] wherein (C 3 -C 4 )-cycloalkyloxy may be substituted by fluorine at most disubstituted,

[0250] wherein R 9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, chlorine;

[0251] n represents 0 or 1 and

[0252] m represents 1 or 2,

[0253] and its salts, solvates and solvates of salts.

[0254] In the context of the present invention, the preferred compound of formula (I)

[0255] wherein

[0256] X, Y and Z represent the groups in h), i), j), k) or (r),

[0257]

[0258] wherein * marks the connection to the carbonyl group and the connection to the nitrogen atom of the adjacent piperidine ring and

[0259] R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0260] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0261] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl,

[0262] wherein the thiazolyl group may be substituted by chlorine,

[0263] wherein the thienyl group may be substituted by fluorine,

[0264] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl,

[0265] R 2 represents hydrogen, methyl,

[0266] or

[0267] together with the carbon atom to which R 2 is attached forms a cyclopropyl ring,

[0268] R 3 represents hydrogen, (C 1 -C 2 )-alkyl;

[0269] R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0270] wherein the phenyl group may be substituted by chlorine,

[0271] R 5 represents hydrogen, fluorine;

[0272] R 6 represents a group in formula a), b), b), c), c) or e),

[0273]

[0274] wherein the * marks the connection to the adjacent piperidine ring,

[0275] wherein R 7 or R‘ 7 each independently represents hydrogen, (C 1 -C 4)-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,

[0276] where (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine up to disubstituted,

[0277] where methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,

[0278] where cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,

[0279] where cyclobutyl may be substituted by fluorine up to disubstituted,

[0280] where n-butoxy may be substituted by fluorine up to disubstituted,

[0281] where (C 1 -C 2 )-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl

[0282] and

[0283] where cyclopropyl and cyclobutyl may be substituted by fluorine up to disubstituted,

[0284] where (C 3 -C 4 )-cycloalkoxy may be substituted by fluorine up to disubstituted,

[0285] where R 9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, chlorine;

[0286] n represents 0 or 1 and

[0287] m represents 1 or 2,

[0288] and its salts, solvates and solvates of salts.

[0289] In the context of the present invention, the preferred compound of formula (I)

[0290] where

[0291] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h'), i'), j') or k),

[0292]

[0293] R 1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0294] R 2 represents hydrogen or methyl;

[0295] R 3 represents hydrogen, methyl;

[0296] R 4 represents hydrogen, ethyl, trifluoromethyl;

[0297] R 5 represents hydrogen, fluorine;

[0298] R 6 represents a group in formula a), c') or c");

[0299]

[0300] where *** marks the connection to the adjacent piperidine ring,

[0301] where R 7 and R' 7 each independently represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0302] n represents 0 or 1 and

[0303] m represents 1,

[0304] and its salts, solvates and solvates of salts.

[0305] In the context of the present invention, compounds of formula (I) are preferred, wherein

[0306] X, Y and Z represent 1,3-thiazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl;

[0307] R 1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0308] R 2 represents hydrogen or methyl;

[0309] R 3 represents hydrogen, methyl;

[0310] R 4 represents hydrogen or methyl, ethyl, trifluoromethyl;

[0311] R 5 represents hydrogen, fluorine;

[0312] R 6 represents a group in formula a), c') or c");

[0313]

[0314] wherein * marks the connection to the adjacent piperidine ring,

[0315] wherein R 7 and R' 7Each independently represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0316] n represents 0 or 1 and

[0317] m represents 1,

[0318] and its salts, solvates and solvates of salts.

[0319] In the context of the present invention, preferably the compound of formula (I) wherein

[0320] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h')

[0321]

[0322] R 1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0323] R 2 represents hydrogen or methyl;

[0324] R 3 represents hydrogen;

[0325] R 5 represents hydrogen, fluorine;

[0326] R 6 The group in formula (a), c') or c'')

[0327]

[0328] wherein *** indicates the connection to the adjacent piperidine ring,

[0329] wherein R 7 and R' 7 each independently represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0330] n represents 0 or 1 and

[0331] m represents 1,

[0332] and their salts, solvates and solvates of salts.

[0333] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0334] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h), (i), (j), (k) or (r);

[0335]

[0336] wherein * indicates the connection to the carbonyl group and ** indicates the connection to the nitrogen atom of the adjacent piperidine ring and

[0337] R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0338] wherein the phenyl group may be substituted by chlorine,

[0339] and their salts, solvates and solvates of salts.

[0340] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0341] X, Y and Z represent the groups in formula (h) or (i);

[0342]

[0343] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0344] R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0345] wherein the phenyl group may be substituted by chlorine,

[0346] and its salts, solvates and solvates of salts.

[0347] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0348] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h) or (i);

[0349]

[0350] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0351] R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0352] wherein the phenyl group may be substituted by chlorine,

[0353] and its salts, solvates and solvates of salts.

[0354] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0355] X, Y and Z represent a group of formula (h);

[0356]

[0357] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0358] R 4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0359] and its salts, solvates and solvates of salts.

[0360] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0361] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h);

[0362]

[0363] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0364] R 4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0365] and its salts, solvates and solvates of salts.

[0366] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0367] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h);

[0368]

[0369] wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0370] R 4 represents hydrogen,

[0371] and its salts, solvates and solvates of salts.

[0372] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0373] R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl;

[0374] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0375] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from methyl, chlorine,

[0376] wherein the thiazolyl group may be substituted by chlorine,

[0377] wherein the thienyl group may be substituted by fluorine,

[0378] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0379] and its salts, solvates and solvates of salts.

[0380] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0381] R 1 represents pyridyl, phenyl,

[0382] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from methyl, ethyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy;

[0383] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from methyl, cyclopropyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0384] and its salts, solvates and solvates of salts.

[0385] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0386] R 1 represents the group in formula (f);

[0387]

[0388] where # marks the connection to the adjacent -[CHR 2 nNR 3 CO-group, and its salts, solvates and solvates of salts.

[0389] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 2 represents hydrogen, (C 1 -C 4 )-alkyl;

[0390] wherein the (C 1 -C 4 )-alkyl may be substituted by halogen up to three times,

[0391] or together with the carbon atom to which R 2 is attached forms a (C 3 -C 4 )-cycloalkyl ring, and its salts, solvates and solvates of salts.

[0392] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein R 2 represents hydrogen, methyl or together with the carbon atom to which R 2 is attached forms a cyclopropyl ring; and its salts, solvates and solvates of salts.

[0393] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein R 2 represents hydrogen;

[0394] and its salts, solvates and solvates of salts.

[0395] A particular embodiment of the invention relates to a compound of formula (I) wherein R 3 represents hydrogen, (C 1 -C 4 )-alkyl,

[0396] wherein (C 1 -C 4 )-alkyl may be substituted up to three times with halogen,

[0397] and its salts, solvates and solvates of salts.

[0398] A particularly preferred embodiment of the invention relates to a compound of formula (I) wherein R 3 represents hydrogen, methyl;

[0399] and its salts, solvates and solvates of salts.

[0400] A very particularly preferred embodiment of the invention relates to a compound of formula (I) wherein R 3 represents hydrogen;

[0401] and its salts, solvates and solvates of salts.

[0402] A particular embodiment of the invention relates to a compound of formula (I) wherein R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl;

[0403] wherein phenyl may be substituted with chlorine,

[0404] and its salts, solvates and solvates of salts.

[0405] A particularly preferred embodiment of the invention relates to a compound of formula (I) wherein R 4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0406] and its salts, solvates and solvates of salts.

[0407] A very particularly preferred embodiment of the invention relates to a compound of formula (I) wherein R 4 represents hydrogen,

[0408] and its salts, solvates and solvates of salts.

[0409] A particular embodiment of the invention relates to a compound of formula (I) wherein R 5 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C4 ) - alkoxy, halogen, and their salts, solvates, and solvates of salts.

[0410] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein R 5 represents hydrogen, fluorine,

[0411] and their salts, solvates, and solvates of salts.

[0412] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein R 5 represents hydrogen,

[0413] and their salts, solvates, and solvates of salts.

[0414] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 6 represents a group in formula a), b‘), b“), or c‘), c“), or e),

[0415]

[0416] wherein *** marks the connection to the adjacent piperidine ring and

[0417] R 7 represents hydrogen or methyl,

[0418] R‘ 7 represents hydrogen, methyl, ethyl, n - propyl, isopropyl, tert - butyl, 2 - fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3 - difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3 - fluorobutoxymethyl, 3,3 - difluorocyclobutylmethoxymethyl, 2,2,2 - trifluoroethoxy, 2,2,2 - trifluoroethoxymethyl, 2,2 - difluorocyclopropylmethoxy, cyclobutoxy, 3,3 - difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine,

[0419] R 9 represents hydrogen, methyl, tert - butyl, methoxy, methoxymethyl, fluorine, chlorine;

[0420] and their salts, solvates, and solvates of salts.

[0421] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0422] R 6 represents a group in formula a), c‘), or c“),

[0423]

[0424] where *** indicates the connection to the adjacent piperidine ring and

[0425] R 7 represents hydrogen,

[0426] R 7 represents hydrogen, methyl, ethyl, n - propyl, isopropyl, tert - butyl, 2 - fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3 - difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3 - fluorobutoxymethyl, 3,3 - difluorocyclobutylmethoxymethyl, 2,2,2 - trifluoroethoxy, 2,2,2 - trifluoroethoxymethyl, 2,2 - difluorocyclopropylmethoxy, cyclobutoxy, 3,3 - difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluoro,

[0427] and its salts, solvates and solvates of salts.

[0428] A very particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0429] R 6 represents the group in formula (a),

[0430]

[0431] where *** indicates the connection to the adjacent piperidine ring and

[0432] R 7 represents hydrogen,

[0433] R‘ 7 represents methyl, ethyl, isopropyl, propyl, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3 - difluorocyclobutylmethoxy, 2,2,2 - trifluoroethoxymethyl, cyclopropylmethyl, 1 - fluoromethylcyclopropylmethoxymethyl, 1 - difluoromethylcyclopropylmethoxymethyl, 1 - trifluoromethylcyclopropylmethoxymethyl, cyclobutylmethoxy, cyclopropylmethoxy, cyclobutoxymethyl, cyclopropylmethoxymethyl, 3,3 - difluorocyclobutylmethoxymethyl, 3 - fluorobutoxymethyl, 2,2 - difluorocyclopropylmethoxy, cyclobutoxy, 3,3 - difluorocyclobutoxy, 2 - fluoroethyl, cyclopropyl, cyclobutyl, 2 - methoxyethyl, tert - butyl, and its salts, solvates and solvates of salts.

[0434] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0435] n represents 0 or 1,

[0436] and its salts, solvates and solvates of salts.

[0437] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0438] n represents 1,

[0439] and its salts, solvates and solvates of salts.

[0440] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0441] m represents 1 or 2,

[0442] and its salts, solvates and solvates of salts.

[0443] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0444] m represents 1,

[0445] and its salts, solvates and solvates of salts.

[0446] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0447] p represents 0, 1 or 2,

[0448] and its salts, solvates and solvates of salts.

[0449] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0450] p represents 1.

[0451] A particular embodiment of the present invention relates to a compound of formula (I) wherein

[0452] q represents 0 or 2,

[0453] and its salts, solvates and solvates of salts.

[0454] A particularly preferred embodiment of the present invention relates to a compound of formula (I) wherein

[0455] q represents 2,

[0456] and its salts, solvates and solvates of salts.

[0457] The definitions of the various groups specified in the binding or preferred binding of each group are independent of the binding of each specified group and may also be replaced by other defined groups of binding as required.

[0458] It is very particularly preferred to combine two or more of the above preferred ranges.

[0459] The present invention further provides a process for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof, wherein

[0460] [A] a compound of formula (II)

[0461]

[0462] wherein

[0463] X, Y, Z, R 1 , R 2 , R 3 and R 4 and n have the meanings given above,

[0464] Hal represents a leaving group, preferably chlorine, bromine, iodine or mesyl,

[0465] is reacted with a compound of formula (III) in the presence of a base

[0466]

[0467] wherein

[0468] R 5 and R 6 and m have the meanings given above,

[0469] to produce a compound of formula (I-A)

[0470]

[0471] or

[0472] [B] a compound of formula (IV)

[0473]

[0474] wherein

[0475] X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 and n and m have the meanings given above,

[0476] is reacted with a compound of formula (V)

[0477] H-R 6 (V),

[0478] wherein

[0479] R6 has the meaning given above,

[0480] react in the presence of a reducing agent and optionally an acid, preferably an alkali metal borohydride and acetic acid, to form a compound of formula (I-B)

[0481]

[0482] or

[0483] [C] a compound of formula (VI)

[0484]

[0485] wherein

[0486] X, Y, Z, R 4 , R 5 and R 6 and n and m have the meaning given above, with a compound of formula (VII)

[0487]

[0488] wherein

[0489] R 1 , R 2 and R 3 and n have the meaning given above,

[0490] react in the presence of a condensing agent or activator, preferably a phosphorus compound, to form a compound of formula (I-C)

[0491]

[0492] and the compounds of formula (I-A), (I-B), (I-C) thus obtained are optionally separated into their enantiomers and / or diastereoisomers and / or optionally converted into their solvates, their salts and / or their salt solvates with a suitable (i) solvent and / or (ii) acid.

[0493] In Method step [A] , the reaction of compound (II) with compound (III) to form compound (I-A) is the replacement of the Hal group in compound (II) by the nitrogen atom of the piperidine ring of compound (III), and this reaction can be carried out, for example, by heating in a solvent or dispersant, depending on the reactivity in each case.

[0494] Suitable bases for process step [A] are, in particular, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, tertiary amine bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,10-phenanthroline or 4-N,N-dimethylaminopyridine (DMAP). The base used is preferably sodium carbonate, potassium carbonate or cesium carbonate. It may be advantageous to add an alkylation catalyst, such as lithium bromide, sodium iodide, potassium iodide, tetra-n-butylammonium bromide, copper(I) iodide or benzyltriethylammonium chloride.

[0495] The base is preferably used in an equimolar amount or in excess, usually 1 to 5 times the molar amount, preferably 5 times.

[0496] Furthermore, the reaction can also be carried out by palladium catalysis using Pd 2 (dba) 3 , cesium carbonate as auxiliary base and the following ligands: 1,1'-[1,1'-binaphthalene]-2,2'-diylbis[1,1-diphenylphosphine] or 1,1'-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine] (see the literature WO 2008052934 or WO 2015017305).

[0497] Suitable inert solvents for step [A] 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, heptane, cyclohexane or mineral oil fractions, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of such solvents can also be used. Acetonitrile or dimethylformamide is preferably used.

[0498] The reaction (II) + (III) → (I-A) is generally carried out in the temperature range from 0 °C to +150 °C, preferably from +20 °C to +100 °C.

[0499] In Method step [B] , the reaction of compound (IV) with (V) to form compound (I-B) is reductive amination. Suitable reducing agents for reductive amination are alkali metal borohydrides commonly used for this purpose, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; sodium triacetoxyborohydride is preferably used. It may be advantageous to add an acid, such as in particular acetic acid, and / or a dehydrating agent, such as molecular sieve or trimethyl orthoformate or triethyl orthoformate, in these reactions.

[0500] Suitable solvents for these reactions are especially alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of such solvents; tetrahydrofuran is preferably used. The reaction is generally carried out in the temperature range from 0 °C to +50 °C.

[0501] The protecting group PG used in compound (XI) or (XI') can be a conventional amino protecting group such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Z) or (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc); tert-butoxycarbonyl (BOC) is preferably used. The removal of the protecting group in process step [B] (V) → (VI) is carried out by known methods. Thus, tert-butoxycarbonyl is generally cleaved by treatment with a strong acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid in an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane or acetic acid. In the case of benzyloxycarbonyl as the protecting group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst such as palladium on activated carbon. (9H-Fluoren-9-ylmethoxy)carbonyl is generally removed with a secondary amine base such as diethylamine or piperidine [see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; P.J. Kocienski, Protecting Groups, 3 rd edition, Thieme, 2005].

[0502] Method step [B] (VI) + (VII) → (I-C) [amide formation] is carried out by known methods with the aid of a condensing agent or activator. Suitable such reagents 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 N,N'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines such as 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, phosphorus compounds such as n-propylphosphonic anhydride (PPA, ) Diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), bis-(2-oxo-3-oxazolidinyl)phosphinyl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), or an uronium compound such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(1H-1-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-(2-oxo-1-(2H)-pyridinyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), which is optionally combined with other adjuvants such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and a suitable base is an alkali metal carbonate such as sodium carbonate or potassium carbonate, or a tertiary amine base such as triethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), DIPEA, pyridine or 4-N,N-dimethylaminopyridine (DMAP). The condensing agent or activator used is preferably O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) combined with N,N-diisopropylethylamine as the base.

[0503] Suitable inert solvents for these amide formation reactions are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, chloroform, 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), N,N'-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of such solvents can also be used. Dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide or mixtures of these solvents are preferably used. The reaction is generally carried out in the temperature range from -20 °C to +60 °C, preferably from 0 °C to +40 °C.

[0504] For them, the compounds of formula (II) can be prepared by methods known in the literature [amide formation], by reacting the amine (VII)

[0505]

[0506] wherein

[0507] R 1 、R 2 and R 3 and n have the meanings given above,

[0508] react with a compound of formula (X) under the influence of a condensing agent or activator

[0509]

[0510] wherein

[0511] X, Y, Z, R 4 and Hal have the meanings given above,

[0512] to produce a compound of formula (II)

[0513]

[0514] The compound of formula (III) can be prepared by a method known in the literature [reductive amination], by reacting an amine (V)

[0515] H-R 6 (V),

[0516] wherein

[0517] R 6 has the meaning given above,

[0518] with a protected piperidine derivative of formula (XI)

[0519]

[0520] wherein

[0521] R 5 and m have the meanings given above and

[0522] PG represents a suitable amino protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl

[0523] to produce a compound of formula (III')[[]]

[0524]

[0525] wherein PG and R 5 and R 6 and m have the meanings given above,

[0526] and then removing the protecting group PG to produce a compound of formula (III)

[0527]

[0528] The compound of formula (IV) can be prepared by methods known in the literature [alkylation] by reacting a compound of formula (II)

[0529]

[0530] wherein X, Y, Z, R 1 , R 2 , R 3 and R 4 and Hal and n have the meanings given above,

[0531] with a compound of formula (XII) in the presence of a base

[0532]

[0533] wherein R 5 and m have the meanings given above,

[0534] and then cleaving under acidic conditions to give the compound (IV)

[0535]

[0536] For them, the compound of formula (VI) can be prepared by methods known in the literature [alkylation] by reacting a compound of formula (XIII)

[0537]

[0538] wherein X, Y, Z, R 4 and Hal have the meanings given above and

[0539] T 1 represents -O-(C 1 -C 4 )-alkyl,

[0540] with a compound of formula (III) in the presence of a base

[0541]

[0542] wherein R 5 , R 6 and m have the meanings given above,

[0543] and hydrolyzing under conditions known in the literature to give the compound of formula (VI)

[0544]

[0545] the ester group T 1The hydrolysis is carried out by conventional methods by treating the ester with an acid or a base in an inert solvent. In a later variant, the initially formed salt is converted to the free carboxylic acid by treatment with an acid. In the case of tert-butyl esters, the hydrolysis of the ester is preferably carried out with an acid.

[0546] Suitable inert solvents for these reactions are water or organic solvents common for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide or dimethyl sulfoxide. Mixtures of these solvents can also be used. In the case of basic ester hydrolysis, a mixture of water with dioxane, tetrahydrofuran, methanol, ethanol and / or dimethylformamide is preferably used. In the case of reaction with trifluoroacetic acid, dichloromethane is preferably used, and in the case of reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane or water is preferably used.

[0547] Suitable bases are the usual inorganic bases. These particularly include alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate or calcium carbonate. Lithium hydroxide, sodium hydroxide or potassium hydroxide are preferred.

[0548] Suitable acids for ester hydrolysis are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0549] Ester hydrolysis is generally carried out in the temperature range from -20 °C to +120 °C, preferably from 0 °C to +80 °C.

[0550] The preparation of the compounds of the invention can be illustrated, for example, by the following reaction scheme:

[0551] Scheme 1

[0552]

[0553] Scheme 2

[0554]

[0555] Scheme 3

[0556]

[0557] The compounds of the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0558] The compounds according to the invention are potent and selective antagonists of the α 2C -adrenergic receptor and are thus suitable for the treatment and / or prevention of disorders and pathological processes, in particular those caused by activation or by activated α2C-adrenergic receptors, as well as diseases secondary to α2C-adrenergic receptor-related lesions.

[0559] The compounds of the invention are used in methods for the treatment and / or prevention of dyspnea, dysphagia, peripheral and cardiovascular disorders and disorders of the peripheral and central nervous systems.

[0560] The compounds according to the invention are also used in methods for the treatment and / or prevention of the following disorders: dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

[0561] In the context of the present invention, these include in particular the following disorders: such as dyspnea and sleep-induced dyspnea, such as in particular obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome), central sleep apnea, Cheyne-Stokes respiration, primary sleep apnea in infants, apparent life-threatening events, central sleep apnea due to the use of drugs or other substances, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during altitude acclimatization, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0562] The compounds according to the invention are preferably used in methods for the treatment and / or prophylaxis of the following disorders: dyspnea, including sleep-induced dyspnea, such as in particular obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome), central sleep apnea, Cheyne-Stokes respiration, primary sleep apnea of infancy, apparent life-threatening events, central sleep apnea due to the use of drugs or other substances, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during altitude acclimatization, acute and chronic pulmonary diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0563] In the context of the present invention, peripheral and cardiovascular disorders include diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0564] Equally preferably, the compounds according to the invention are used in methods for the treatment and / or prophylaxis of peripheral and cardiovascular disorders including diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0565] In addition, the compounds according to the invention can be used in methods for the treatment and / or prevention of the following disorders: disorders of the peripheral and central nervous systems such as dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHD), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, tauopathies, frontotemporal dementia with parkinsonism linked to chromosome 17, multiple system atrophy, spinocerebellar ataxia, Kennedy's spinal and bulbar muscular atrophy, Friedreich's ataxia, dentatorubral-pallidoluysian atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal degeneration with ubiquitin proteasome system and familial encephalopathy with neuroserpin inclusions.

[0566] The compounds according to the invention are preferably used in methods for the treatment and / or prevention of the following disorders: disorders of the peripheral and central nervous systems, including dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHD), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0567] The compounds according to the invention are also used in methods for treating and / or preventing the following disorders: disorders of the peripheral and central nervous systems, such as dementia, depression, schizophrenia, attention deficit hyperactivity disorder (ADHD) with or without hyperactivity, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, tauopathies, frontotemporal dementia with parkinsonism linked to chromosome 17, multisystem atrophy, spinocerebellar ataxia, Kennedy's spinal bulbar muscular atrophy, Friedrich's ataxia, dentatorubral-pallidoluysian atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal degeneration with ubiquitin proteasome system and familial encephalopathy with neuroserpin inclusions.

[0568] In addition, the compounds of the present invention are also suitable for the treatment and / or prevention of cardiovascular disorders such as arrhythmias, atrial and ventricular arrhythmias and impaired conduction such as degrees I-III atrioventricular block, supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsade de pointes tachycardia, atrial and ventricular premature contractions, AV-junctional extrasystoles, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, hypertension (high blood pressure), heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), boxer dog cardiomyopathy, aneurysm, shock such as cardiogenic shock, septic shock and anaphylactic shock, and are also used for the treatment and / or prevention of thromboembolic disorders and ischemia such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, coronary and peripheral arterial spasm, edema formation such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial dysfunction, endothelial dysfunction, microvascular and macrovascular damage (vasculitis), and the prevention of restenosis such as restenosis after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH).

[0569] In the context of the present invention, the term "heart failure" includes acute and chronic forms of heart failure, and its specific or related disease types such as acute decompensated heart failure, right heart failure, left heart failure, congestive heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, cardiac valve defects, heart failure associated with cardiac valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, combined cardiac valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure.

[0570] The compounds of the present invention can also be used for treating and / or preventing asthma conditions of varying severity with intermittent or persistent characteristics (refractory asthma, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, drug- or dust-induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis in chickens, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related conditions, coughs and colds (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis such as hay fever), and polyps.

[0571] In addition, the compounds of the present invention are also suitable for treating and / or preventing kidney diseases, in particular renal insufficiency and renal failure. In the present invention, the terms "renal insufficiency" and "renal failure" include their acute and chronic manifestations as well as underlying or related kidney diseases such as renal hypoperfusion, hypotension during dialysis, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, kidney diseases such as primary and congenital kidney diseases, nephritis, immune kidney diseases such as kidney transplant rejection and immune complex-induced kidney diseases, kidney diseases induced by toxic substances, contrast agent-induced kidney diseases, diabetic and non-diabetic kidney diseases, pyelonephritis, renal cysts, renal sclerosis, hypertensive renal sclerosis, and nephrotic syndrome, the diagnostic features of which may lie, for example, in abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes such as glutamine synthetase, altered urine osmolality or urine volume, elevated urinary microalbumin, massive albuminuria, glomerular and arteriolar lesions, tubule dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the present invention for treating and / or preventing the sequelae of renal insufficiency such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (such as hyperkalemia, hyponatremia), and bone and carbohydrate metabolism disorders.

[0572] Furthermore, the compounds of the present invention are suitable for treating and / or preventing diseases of the urogenital system such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, and erectile dysfunction and female sexual dysfunction.

[0573] The compounds of the present invention are also suitable for the treatment and / or prevention of inflammatory and autoimmune disorders, such as rheumatoid disorders, inflammatory eye diseases, sepsis (SIRS), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 antitrypsin deficiency (AATD), emphysema (such as emphysema caused by cigarette smoke), cystic fibrosis (CF), multiple organ failure (MODS, MOF), renal inflammatory disorders, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, and are also suitable for the treatment and / or prevention of fibrotic disorders of internal organs such as the lung, heart, kidney, bone marrow and especially the liver, as well as fibrotic disorders of the skin and the eye. In the context of the present invention, the term "fibrotic disorder" particularly includes disorders such as hepatic fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, morphea, keloid, hypertrophic scar, nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (such as sarcoidosis). The compounds of the present invention can also be used for promoting wound healing, for controlling postoperative scar formation (such as after glaucoma surgery) and for cosmetic use for aged or keratinized skin.

[0574] In addition, the compounds of the present invention are suitable for the treatment and / or prevention of neoplastic disorders, such as skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

[0575] In addition, the compounds of the present invention can be used for the treatment and / or prevention of arteriosclerosis, impaired fat metabolism and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier disease, lipomatosis, obesity, metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and sequelae of diabetes such as retinopathy, nephropathy and neuropathy), anemias such as hemolytic anemia, hemoglobinopathies (such as sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, anemia attributable to acute blood loss, myelopathic anemia and aplastic anemia), gastrointestinal and abdominal disorders (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritus ani, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis and cholecystitis), central nervous system diseases and neurodegenerative disorders (stroke, epilepsy, depression), immune disorders, thyroid diseases (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, as well as keratitis, bullous diseases, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, Sweet syndrome, Weber-Christian syndrome, scar formation, wart formation, chilblains), inflammatory eye diseases (sarcoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmia), viral diseases (caused by influenza virus, adenovirus and coronavirus, such as HPV, HCMV, HIV, SARS), disorders of bones and joints and skeletal muscles, inflammatory changes of arteries (various forms of arteritis, such as endarteritis, medial arteritis, periarteritis, systemic arteritis, rheumatic arteritis, degenerative arteritis, temporal arteritis, cranial arteritis, giant cell arteritis and granulomatous arteritis as well as Horton syndrome, Churg-Strauss syndrome and Takayasu arteritis), Muckle-Well syndrome, Kikuchi disease, polychondritis, scleroderma and other diseases with an inflammatory or immune component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndromes, for the rejection reaction after organ transplantation and for wound healing and angiogenesis, especially in the case of chronic wounds).

[0576] Due to its performance profile, the compound of the present invention is particularly suitable for the treatment and / or prevention of dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

[0577] The above fully characterized diseases in humans can also occur in other mammals with comparable etiologies and can be treated with the compounds of the present invention as well therein.

[0578] In the present invention, the term "treatment" ("treatement", "treating") includes inhibiting, delaying, preventing, alleviating, attenuating, restricting, reducing, suppressing, repelling, or curing a disease, symptom, disorder, injury, or health problem, or the development, process, or progression of such a condition and / or the symptoms of such a condition. The term "therapy" is understood herein to be synonymous with the term "treatment".

[0579] The terms "prevent", "prevention", or "block" are used synonymously in the present invention and refer to avoiding or reducing the risk of infection, occurrence, being afflicted with, or developing a disease, disorder, impairment, injury, or health problem or the development or progression of such a condition and / or the symptoms of such a condition.

[0580] The treatment or prevention of a disease, condition, disorder, injury, or health problem can be partial or complete.

[0581] The present invention thus also provides the use of the compounds of the present invention for the treatment and / or prevention of diseases, particularly the above-mentioned diseases.

[0582] The present invention also provides the use of the compounds of the present invention for the preparation of a medicament for the treatment and / or prevention of a condition, particularly the above-mentioned condition.

[0583] The present invention also provides a medicament comprising at least one compound of the present invention for the treatment and / or prevention of a condition, particularly the above-mentioned condition.

[0584] The present invention also provides the use of the compounds of the present invention in a method for the treatment and / or prevention of a condition, particularly the above-mentioned condition.

[0585] The present invention also provides a method for treating and / or preventing a condition, particularly the above-mentioned condition, using an effective amount of at least one compound of the present invention.

[0586] The compounds of the present invention can be used alone or, if desired, in combination with one or more other pharmacologically active substances, provided that such combination does not cause undesirable and unacceptable side effects. Thus, the present invention also provides a medicament containing at least one compound of the present invention and one or more active ingredients, which is particularly used for the treatment and / or prevention of the above-mentioned diseases. Preferred examples of the combination active ingredients suitable for this purpose include:

[0587] ·TASK1 channels and channel blockers, such as and preferably those disclosed in WO 2017 / 097792 A1, WO 2017 / 097671 A1, WO 2018 / 015196 A1, WO 2018 / 228907 A1, WO 2018 / 228909 A1;

[0588] ·P2X3 receptor antagonists, such as and preferably gefapixant;

[0589] ·Respiratory stimulants, such as and preferably theophylline, doxapram, nikethamide, caffeine;

[0590] ·Psychostimulant compounds, such as and preferably modafinil, armodafinil;

[0591] ·Amphetamines and amphetamine derivatives, such as and preferably amphetamine, methylphenidate;

[0592] ·Serotonin reuptake inhibitors, such as and preferably fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine, trazodone;

[0593] ·Serotonin precursors, such as and preferably L-tryptophan;

[0594] ·Selective serotonin-norepinephrine reuptake inhibitors, such as and preferably venlafaxine, duloxetine;

[0595] ·Noradrenergic and specific serotonergic antidepressants, such as and preferably mirtazapine;

[0596] ·Selective norepinephrine reuptake inhibitors, such as and preferably atomoxetine and reboxetine;

[0597] ·Muscarinic receptor antagonists such as and preferably oxybutynin;

[0598] ·Tricyclic antidepressants, such as and preferably amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine, desipramine;

[0599] ·GABA agonists, such as and preferably baclofen;

[0600] ·Alpha adrenergic agonists, such as and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrahydrozoline, tramazoline;

[0601] ·Glucocorticoids, such as and preferably fluticasone, budesonide, beclomethasone, mometasone, tixocortol pivalate, triamcinolone acetonide;

[0602] ·Cannabinoid receptor agonists and antagonists;

[0603] · Carbonic anhydrase inhibitors, such as and preferably acetazolamide, methazolamide and dichlorphenamide;

[0604] · Opioid and benzodiazepine receptor antagonists, such as and preferably flumazenil, naloxone, naltrexone;

[0605] · Cholinesterase inhibitors, such as and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine, rivastigmine;

[0606] · N-methyl-D-aspartic acid and glutamate antagonists, such as and preferably amantadine, memantine, sabril;

[0607] · Nicotinic receptor agonists;

[0608] · Leukotriene receptor antagonists, such as and preferably montelukast, tranilast;

[0609] · Dopamine receptor antagonists, such as and preferably domperidone, metoclopramide, benzamide, butyrophenone, phenothiazine;

[0610] · Appetite suppressants, such as and preferably topiramate, lipase inhibitors, cannabinoid receptor antagonists, phentermine;

[0611] · Proton pump inhibitors, such as and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;

[0612] · Hypotensive active ingredients, such as and preferably selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α receptor blockers, β receptor blockers, mineralocorticoid receptor antagonists and diuretics;

[0613] · Active compounds for regulating lipid metabolism, such as and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, such as and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists;

[0614] · Azoorganic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 and inhaled NO;

[0615] · Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4, and / or 5, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dasenafil, avanafil, milanafil, or lodenafil;

[0616] · NO- and heme-independent soluble guanylate cyclase (sGC) activators, especially for example the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462, and WO 02 / 070510;

[0617] · NO-independent but heme-dependent soluble guanylate cyclase (sGC) stimulators, especially for example riociguat and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO2012 / 004258, WO 2012 / 028647, and WO 2012 / 059549;

[0618] · Compounds that affect cardiac energy metabolism, such as and preferably etomoxir, dichloroacetate, ranolazine, or trimetazidine;

[0619] · Antithrombotic agents, such as and preferably selected from platelet aggregation inhibitors, anticoagulants, and profibrinolytisch substances;

[0620] · Antiasthmatic agents, such as for example used in the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, such as and preferably selected from inhaled or systemic β-adrenergic receptor agonists (β-mimetics) and inhaled antimuscarinic substances;

[0621] · Anti-inflammatory, immunomodulatory, immunosuppressive, and / or cytotoxic agents, such as and preferably selected from corticosteroids administered systemically or by inhalation, as well as dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferons, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, zafirlukast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, IFN-γ, pirfenidone, or etanercept;

[0622] · Compounds that inhibit signal transduction cascades, such as and preferably selected from kinase inhibitors, particularly preferably tyrosine kinase and / or serine / threonine kinase inhibitors, such as and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brigatinib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, samuraciclib or tandutinib;

[0623] · Prostacyclin analogues and IP receptor agonists, such as and preferably iloprost, beraprost, treprostinil, epoprostenol or selexipag;

[0624] · Endothelin receptor antagonists, such as and preferably bosentan, darusentan, ambrisentan or sitaxentan;

[0625] · Compounds that inhibit human neutrophil elastase (HNE), such as and preferably sivelestat or DX-890 (Reltran);

[0626] · Compounds that inhibit the degradation and alteration of the extracellular matrix, such as and preferably inhibitors of matrix metalloproteinases (MMPs), particularly inhibitors of matrilysin, collagenase, gelatinase and aggrecanase (in this context especially MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastase (MMP-12);

[0627] · Compounds that block the binding of serotonin to its receptors, such as and preferably antagonists of 5-HT 2B receptors, such as PRX-08066;

[0628] · Antagonists of growth factors, cytokines and chemokines, such as and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

[0629] · Rho kinase inhibitory compounds, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; and / or

[0630] · Antifibrotic agents, such as and preferably pirfenidone, lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists;

[0631] In a particularly preferred embodiment of the present invention, the compounds of the present invention are administered in combination with one or more other active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

[0632] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a β-adrenergic receptor agonist such as, and preferably, salbutamol, isoprenaline, orciprenaline, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0633] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an antimuscarinic substance such as, and preferably, ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0634] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a corticosteroid such as, and preferably, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

[0635] Antithrombotic agents are preferably understood to mean compounds selected from platelet aggregation inhibitors, anticoagulants and plasminogen substances.

[0636] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a platelet aggregation inhibitor such as, and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0637] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a thrombin inhibitor such as, and preferably, ximelagatran, melagatran, dabigatran, bivalirudin or enoxaparin.

[0638] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a GPIIb / IIIa antagonist such as, and preferably, tirofiban or abciximab.

[0639] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a factor Xa inhibitor, such as and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0640] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0641] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a vitamin K antagonist, such as and preferably coumarin.

[0642] The antihypertensive agent is preferably understood to mean a compound selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-blockers, β-blockers, mineralocorticoid receptor antagonists and diuretics.

[0643] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0644] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an α-1-blocker, such as and preferably prazosin.

[0645] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a β-blocker, such as and preferably propranolol, atenolol, timolol, indolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carteolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adalimumab, landiolol, nebivolol, epanolol or bucindolol.

[0646] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an angiotensin AII antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embusartan.

[0647] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trandolapril.

[0648] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an endothelin antagonist, such as and preferably bosentan, darusentan, ambrisentan or sitaxentan.

[0649] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a renin inhibitor, such as and preferably aliskiren, SPP-600 or SPP-800.

[0650] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a mineralocorticoid receptor antagonist, such as and preferably spironolactone, eplerenone or finerenon.

[0651] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a diuretic, such as and preferably furosemide, bumetanide, torasemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0652] The lipid metabolism regulator is preferably understood to mean a compound selected from CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0653] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a CETP inhibitor, such as and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

[0654] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a thyroid receptor agonist, such as and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or axitirole (CGS26214).

[0655] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an HMG-CoA reductase inhibitor selected from the statins, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0656] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a squalene synthase inhibitor, such as and preferably BMS-188494 or TAK-475.

[0657] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an ACAT inhibitor, such as and preferably avasimibe, mevinamide, pactimibe, eflucimibe or SMP-797.

[0658] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an MTP inhibitor, such as and preferably implitapide, BMS-201038, R-103757 or JTT-130.

[0659] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a PPAR-γ agonist, such as and preferably pioglitazone or rosiglitazone.

[0660] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a PPAR-δ agonist, such as and preferably GW 501516 or BAY 68-5042.

[0661] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tiquian or pamaquine.

[0662] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a lipase inhibitor, such as and preferably orlistat.

[0663] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a polymeric bile acid adsorbent, such as and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimid.

[0664] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a bile acid reabsorption inhibitor, such as and preferably an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0665] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a lipoprotein(a) antagonist, such as and preferably gemcabene calcium (CI-1027) or niacin.

[0666] Particularly preferred is the combination of the compounds of the present invention with one or more other active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

[0667] If desired, the compounds of the present invention can be used in combination with one or more other medical means, provided that the combination does not produce undesirable and unacceptable side effects. Preferred examples of medical means suitable for this purpose include:

[0668] · Devices for positive pressure ventilation of the respiratory tract, such as and preferably CPAP (continuous positive airway pressure) devices, BiPAP (bilevel positive airway pressure) devices and IPPV (intermittent positive pressure ventilation) devices;

[0669] · A nerve stimulator for the hypoglossal nerve;

[0670] · Intraoral auxiliary devices, such as and preferably a protruding dental brace;

[0671] · A disposable nasal valve;

[0672] · A nasal stent.

[0673] The present invention also provides a medicament comprising at least one compound of the present invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the above purposes.

[0674] The compounds of the present invention can act systemically and / or locally. To this end, they can be administered in a suitable manner, for example, orally, parenterally, by the pulmonary, nasal, pharyngeal, sublingual, lingual, oral, rectal, dermal, transdermal, conjunctival, otic or as implants or stents.

[0675] The compounds of the present invention can be administered in dosage forms suitable for these administration routes.

[0676] Dosage forms suitable for oral administration are those that work according to the prior art and release the compounds of the present invention rapidly and / or in a controlled manner and contain the compounds of the present invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, for example, with an anti-gastric acid or delayed dissolution or insoluble coating that controls the release of the compounds of the present invention), tablets or films / discs that rapidly disintegrate in the mouth, films / freeze-dried products, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

[0677] Parenteral administration can bypass the reabsorption step (for example, intravenous, intra-arterial, intracardiac, intraspinal or intralumbar) or include reabsorption (for example, inhalation, intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Dosage forms suitable for parenteral administration include, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, freeze-dried products or sterile powders.

[0678] For other administration routes, suitable examples are inhalable dosage forms (including powder inhalers, sprays, metered aerosols), nasal drops, nasal solutions or sprays, throat sprays, tablets, films / discs or capsules for lingual, sublingual or oral administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example, patches), emulsions, pastes, foams, dusting powders, implants or stents.

[0679] Oral, parenteral and local administrations are preferred, especially oral, intravenous, intranasal and pharyngeal administrations.

[0680] The compounds of the invention can be converted into the stated dosage forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include in particular carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersing or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleat), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) and taste and / or odor correctors.

[0681] It is generally found to be advantageous in the case of parenteral administration to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight, to achieve an effective result. In the case of oral administration, the dose is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, most preferably 0.1 to 10 mg / kg body weight. In the case of pulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.

[0682] However, in some cases it may be necessary to deviate from the stated amounts, especially depending on body weight, route of administration, individual response to the active ingredient, nature of the formulation and time or time interval at which administration is carried out. Thus, in some cases less than the above minimum amount may be sufficient, while in other cases the upper limit mentioned must be exceeded. In the case of administering larger amounts, it may be advisable to divide them into several single doses within a day.

[0683] The following working examples illustrate the invention. The invention is not limited to these examples.

[0684] A. Example

[0685] Abbreviations and acronyms:

[0686] abs. absolute value

[0687] Ac acetyl

[0688] aq. aqueous, aqueous solution

[0689] Boc tert-butoxycarbonyl

[0690] br. broad (in NMR signals)

[0691] Bsp. example

[0692] Bu butyl

[0693] c concentration

[0694] cat. Catalysis

[0695] CI Chemical ionization (in MS)

[0696] d Doublet (in NMR)

[0697] d Day

[0698] DCI Direct chemical ionization (in MS)

[0699] dd Double doublet (in NMR)

[0700] diamix Diastereoisomer mixture

[0701] DMF N,N-Dimethylformamide

[0702] DMSO Dimethyl sulfoxide

[0703] dq Double quartet (in NMR)

[0704] dt Double triplet (in NMR)

[0705] o.t. Theoretical (in chemical yield)

[0706] EI Electron impact ionization (in MS)

[0707] eq. Equivalent

[0708] ESI Electrospray ionization (in MS)

[0709] Et Ethyl

[0710] h Hour

[0711] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0712] HOBt 1-Hydroxy-1H-benzotriazole hydrate

[0713] HPLC High pressure high performance liquid chromatography

[0714] iPr Isopropyl

[0715] konz Concentrated (in the case of a solution)

[0716] LC Liquid chromatography

[0717] LC-MS Liquid chromatography - Mass spectrometry combination

[0718] Lit. Literature (reference)

[0719] m Multiplet (in NMR)

[0720] Me Methyl

[0721] min Minute

[0722] MS Mass spectrometry

[0723] NMR Nuclear magnetic resonance spectroscopy

[0724] Ph Phenyl

[0725] Pr Propyl

[0726] q Quartet (in NMR)

[0727] quant. Quantitative (in chemical yield)

[0728] RP Reverse phase (in HPLC)

[0729] RT Room temperature

[0730] R t Retention time (in HPLC, LC / MS)

[0731] s Singlet (in NMR)

[0732] t Triplet (in NMR)

[0733] tBu tert-Butyl

[0734] TFA Trifluoroacetic acid

[0735] THF Tetrahydrofuran

[0736] UV Ultraviolet spectroscopy

[0737] v / v (volume / volume ratio of solution)

[0738] tog. Together

[0739] LC-MS, GC-MS and HPLC methods

[0740] Method 1 (LC-MS):

[0741] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 μm; mobile phase A: 1 liter of water + 0.01% formic acid; mobile phase B: 1 liter of acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; oven: 50 °C; flow rate: 0.90 ml / min; UV detection: 210 nm / optimal integration path 210 - 300 nm.

[0742] Method 2 (LC-MS):

[0743] MS instrument type: Waters Tinstrument; UPLC instrument type: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Mobile phase: 1 liter of water + 0.100 ml of 99% strength formic acid; Mobile phase B: 1 liter of acetonitrile + 0.100 ml of 99% strength formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50°C; Flow rate: 0.40 ml / min; UV detection: 210 nm.

[0744] Method 3 (GC-MS):

[0745] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; Column: Restek RTX-35MS, 15m x 200μm x 0.33μm; Constant helium flow rate: 1.20 ml / min; Oven: 60°C; Injection port: 220°C; Gradient: 60°C, 30°C / min → 300°C (hold for 3.33 min).

[0746] Method 4 (LC-MS):

[0747] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Mobile phase: 1 liter of water + 0.25 ml of 99% strength formic acid, Mobile phase B: 1 liter of acetonitrile + 0.25 ml of 99% strength formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50°C; Flow rate: 0.40 ml / min; UV detection: 210 nm.

[0748] Method 5 (LC-MS):

[0749] Instrument: Waters Single Quad MS system; instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7μ 50x 2.1mm; Mobile phase A: 1 liter of water + 1.0 ml (25% strength ammonia) / l, Mobile phase B: 1 liter of acetonitrile; Gradient: 0.0 min 92% A → 0.1 min 92% A → 1.8 min 5% A → 3.5 min 5% A; Oven: 50 °C; Flow rate: 0.45 ml / min; UV detection: 210 nm.

[0750] Method 6 (LC-MS):

[0751] MS instrument: Waters SQD2 HPLC instrument: Waters UPLC; Column: Z or bax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 μm; Mobile phase A: water + 0.025% formic acid, Mobile phase B: acetonitrile (ULC) + 0.025% formic acid; Gradient: 0.0 min 98% A - 0.9 min 25% A - 1.0 min 5% A - 1.4 min 5% A - 1.41 min 98% A - 1.5 min 98% A; Oven: 40 °C; Flow rate: 0.600 ml / min; UV detection: DAD; 210 nm.

[0752] Method 7 (Preparative HPLC):

[0753] Instrument: Waters Prep LC / MS system, Column: XBridge C18 5μm 100x30mm.

[0754] Mobile phase A: water, Mobile phase B: acetonitrile, Mobile phase C: 2% ammonia in water, Mobile phase D: acetonitrile / water (80 vol% / 20 vol%); Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, headspace injection (complete injection).

[0755] Gradient overview: Mobile phase A 0 to 2 min 47 ml, Mobile phase B 0 to 2 min 23 ml, Mobile phase A 2 to 10 min from 47 ml to 23 ml and Mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Mobile phase C and Mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time.

[0756] Method 8 (Preparative HPLC):

[0757] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm.

[0758] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the column head (complete injection).

[0759] Gradient overview: For mobile phase A, from 0 to 2 min is 63 ml, for mobile phase B, from 0 to 2 min is 7 ml. For mobile phase A, from 2 to 10 min it changes from 63 ml to 39 ml and for mobile phase B from 7 ml to 31 ml. From 10 to 12 min, mobile phase A is 0 ml and mobile phase B is 70 ml. Mobile phase C and mobile phase D each have a constant flow rate of 5 ml / min throughout the run time.

[0760] Method 9 (Preparative HPLC):

[0761] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm.

[0762] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the column head (complete injection).

[0763] Gradient overview: For mobile phase A, from 0 to 2 min is 55 ml, for mobile phase B, from 0 to 2 min is 15 ml. For mobile phase A, from 2 to 10 min it changes from 55 ml to 31 ml and for mobile phase B from 15 ml to 39 ml. From 10 to 12 min, mobile phase A is 0 ml and mobile phase B is 70 ml. Mobile phase C and mobile phase D each have a constant flow rate of 5 ml / min throughout the run time.

[0764] Method 10 (Preparative HPLC):

[0765] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm.

[0766] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the column head (complete injection).

[0767] Gradient overview: Mobile phase A: 39 ml from 0 to 2 min, Mobile phase B: 31 ml from 0 to 2 min, Mobile phase A: from 39 ml to 15 ml and Mobile phase B: from 31 ml to 55 ml from 2 to 10 min, 0 ml of Mobile phase A and 70 ml of Mobile phase B from 10 to 12 min. Mobile phase C and Mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time.

[0768] Method 11 (Preparative HPLC):

[0769] Instrument: Abimed Gilson 305; Column: Reprosil C18 10μm, 250mm x 30mm; Mobile phase: water, Mobile phase 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 rate: 50 ml / min; Room temperature; UV detection: 210 nm.

[0770] Method 12 (LC-MS):

[0771] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50 x 1mm; Mobile phase: 1 liter of water + 0.25 ml of 99% strength formic acid, Mobile phase B: 1 liter of acetonitrile + 0.25 ml of 99% strength formic acid; Gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A; Oven: 50°C; Flow rate: 0.35 ml / min; UV detection: 210 nm.

[0772] Other details:

[0773] The following descriptions of the coupling patterns of 1H NMR signals are based on the visual appearance of the signals involved and do not necessarily correspond to a strict, physically correct interpretation. Generally speaking, the chemical shift mentioned refers to the center of the signal involved; in the case of a broad multiplet, an interval is given.

[0774] All numbers in the 1H NMR spectrum indicate the chemical shift δ [ppm] = in ppm.

[0775] The multiplicity of the proton signals in the 1H NMR spectra given in the following paragraphs indicates the signal shape observed in each case, and higher order signal phenomena are not considered. In general, the chemical shift assignment is related to the center of the relevant signal. In the case of broad multiplets, an interval is given. Signals masked by solvent or water or signals that are tentatively assigned or not listed. For example, signals significantly broadened by rapid rotation of molecular moieties or due to proton exchange are also tentatively assigned (usually referred to as broad multiplets or broad singlets) or not listed.

[0776] The 1H NMR data for the selected synthetic intermediates and examples are listed in the form of a 1H-NMR peak list. For each signal peak, the δ [ppm] value in ppm is listed first, followed by the signal intensity in parentheses. The δ [ppm] / signal intensity numerical pairs for different signal peaks are listed separated from each other by commas. Thus, the peak list for an example takes the following form: δ [ppm] 1 (intensity 1 ), δ [ppm] 2 (intensity 2 ),......, δ [ppm] i (intensity i ),...,,,, δ [ppm] n (intensity n ).

[0777] The intensity of the sharp signals is associated with the signal height (in cm) in the printout example of the NMR spectrum and shows the true ratio of the signal intensity compared to other signals. In the case of broad signals, the center of multiple peaks or signals can be shown and their relative intensity compared to the strongest signal in the spectrum. The list of 1H-NMR peaks is similar to a conventional 1H-NMR printout and thus usually contains all the peaks listed in a conventional NMR interpretation. In addition, similar to a conventional 1H-NMR printout, they can show solvent signals, signals of stereoisomers of the target compound, which is also the subject of the present invention, and / or peaks of impurities. The peaks of stereoisomers of the target compound and / or peaks of impurities usually have an intensity that is on average lower than the peaks of the target compound (e.g., having a purity of >90%). Such stereoisomers and / or impurities may be typical for a particular preparation method. Thus, their peaks here help to identify the reproducibility of our preparation method with reference to the "by-product fingerprint". A person skilled in the art calculating the peaks of the target compound by known methods (MestReC, ACD simulation or using empirically evaluated expected values) can separate the peaks of the target compound as needed, optionally using an additional intensity filter. This separation is similar to the peak picking involved in a conventional 1H-NMR interpretation. A detailed description of the NMR data shown in the form of a peak list can be found in the publication "Citation NMR Peaklist Data within Patent Applications" (see Research Disclosure Database Number 605005, August 1, 2014 or http: / / www.researchdisclosure.com / searching-disclosures). In the peak picking convention described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be set between 1% and 4%. Depending on the type of chemical structure and / or the concentration of the compound to be analyzed, it may be reasonable to set the parameter "MinimumHeight" to a value <1%.

[0778] Melting points and melting ranges, if given, are uncorrected.

[0779] In cases where the reaction product is obtained by grinding, stirring or recrystallization, often more amounts of the product can be separated from the respective mother liquor by chromatographic separation. However, unless most of the total yield can be separated only in this step, the description of such chromatography will be omitted hereinafter.

[0780] For all reactants or reagents whose preparation is not explicitly described below, they are purchased from generally available sources. For all other reactants or reagents that are also not described below and are not commercially available or obtained from sources that are not generally available, refer to the published literature that describes their preparation.

[0781] Starting materials and intermediates:

[0782] Example 1A

[0783] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[0784]

[0785] 50.24 ml (288.41 mmol) of N,N-diisopropylethylamine was added to a solution of 20 g (96.14 mmol) of 2-bromo-1,3-thiazole-5-carboxylic acid and 29.21 g (134.59 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride in 450 ml of acetonitrile. The mixture was cooled to 0 °C using an ice bath, and then a solution of 74.4 ml (124.98 mmol) of 50% strength T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide) in ethyl acetate was added dropwise to the reaction solution. After the addition was complete, the reaction solution was warmed to room temperature and stirred at this temperature for 4 hours. Then approximately 250 ml of water was added to the solution. The resulting aqueous phase was then extracted 3 times with ethyl acetate. The combined organic phases were subsequently filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was triturated with diethyl ether and then air-dried. This yielded 27.3 g (81.7 mmol, 85% of theory) of the target product as a light beige solid. The recovered mother liquor was evaporated to dryness under reduced pressure, and the resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column; mobile phase: cyclohexane / ethyl acetate 9:1 → gradient 15 CV (CV = column volume) → cyclohexane / ethyl acetate 1:1). This yielded an additional 2.1 g (6.28 mmol, 6.5% of theory) of the target compound as a white solid.

[0786] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 4.59 (d, 2H), 7.90 - 7.95 (m, 1H), 8.27 (S, 1H), 8.48 (d, 1H), 9.32 (br.t, 1H).

[0787] LC-MS (Method 1): R t = 1.38 min; m / z = 333 / 335 (M+H) + 。

[0788] Similar to Example 1A, the following Compound Examples 2A to 8A were prepared from the starting materials described in each case:

[0789]

[0790]

[0791]

[0792] Example 9A

[0793] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxamide

[0794]

[0795] 2 g (5.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide was dissolved in 30 ml of THF, and 4.88 g (14.96 mmol) of cesium carbonate was added. Then 1.29 g (8.98 mmol) of 1,4-dioxo-8-azaspiro[4.5]decane was metered into the reaction solution, and it was then stirred overnight at the reflux temperature. After cooling, the reaction mixture was applied directly onto silica gel and purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 50 g column; mobile phase: cyclohexane / ethyl acetate 85:15 → gradient 15 CV (CV = column volume) → ethyl acetate). Then the obtained product fractions were combined, concentrated on a rotary evaporator and dried under reduced pressure. This gave 1.40 g (3.53 mmol, 99% of theory) of the target compound as a light beige solid.

[0796] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 1.71 (t, 4H), 3.56 (t, 4H), 3.92 (S, 4H), 4.53 (br.d, 2H), 7.84 (S, 1H), 7.89 - 7.94 (m, 1H), 8.47 (d, 1H), 8.74 (t, 1H).

[0797] LC-MS (Method 2): Rt = 0.73 min; m / z = 397 (M+H) + 。

[0798] Example 10A

[0799] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[0800]

[0801] Dissolve 2.3 g (5.80 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxamide in 15 ml of acetone, and add 15 ml of semi-concentrated aqueous hydrochloric acid solution. Then stir the reaction solution at room temperature overnight. Then concentrate the reaction mixture on a rotary evaporator and then place it in water. Then adjust the aqueous solution to pH 7 with saturated sodium bicarbonate solution. Filter the resulting precipitate by suction, wash it repeatedly with water and dry it under reduced pressure. This gives 1.96 g (5.49 mmol, 95% of theory) of the target compound as a white solid.

[0802] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 2.48 - 2.56 (t, 4H, partially masked by DMSO), 3.82 (t, 4H), 4.54 (br.d, 2H), 7.89 (S, 1H), 7.90 - 7.94 (m, 1H), 8.48 (d, 1H), 8.78 (t, 1H).

[0803] LC-MS (Method 1): Rt = 1.09 min; m / z = 353 (M+H) + 。

[0804] Example 11A

[0805] 3-[(3,3-Difluorocyclobutyl)methoxy]pyridine

[0806]

[0807] Dissolve 2 g (21.03 mmol) of pyridin-3-ol in 40 ml of THF, and add 7.17 g (27.34 mmol) of triphenylphosphine. Then cool the clear solution to 0 °C. Add 30 ml of THF to the resulting suspension. Add 5.53 g (27.34 mmol) of diisopropyl azodicarboxylate to this suspension, and stir the mixture at this temperature for 5 minutes. Then add dropwise 3.34 g (27.34 mmol) of (difluorocyclobutyl)methanol dissolved in 10 ml of THF, and remove the ice bath after the addition is complete. After stirring at room temperature for about one hour, a clear yellow solution is formed, and stir overnight at this temperature.

[0808] Then add water, and extract the reaction solution three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, separated and filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. Stir the resulting residue with about 150 ml of cyclohexane. Then filter off the precipitated triphenylphosphine by suction, and wash it repeatedly with cyclohexane. Combine the resulting filtrates, and concentrate to dryness under reduced pressure. This gives 3.69 g (18.52 mmol, 88% of theory) of the target compound as a yellow oil. The resulting target compound is reacted further without further purification.

[0809] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 2.42 - 2.55 (m, 2H, partially masked by DMSO), 2.55 - 2.64 (m, 1H), 2.68 - 2.78 (m, 2H). 4.11 (d, 2H), 7.30 - 7.36 (m, 1H), 7.37 - 7.43 (m, 1H), 8.18 (dd, 1H), 8.30 (d, 1H).

[0810] LC-MS (method 1): R t = 1.12 min; m / z = 200 (M+H) + .

[0811] Example 12A

[0812] 3-[(3,3-Difluorocyclobutyl)methoxy]piperidine acetate (1:1) (racemate)

[0813]

[0814] Dissolve 2.5 g (12.55 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy]pyridine in 20 ml of glacial acetic acid, and hydrogenate using an H-Cube (ThalesNano H-Cube ProTM - 1.7).

[0815] Reaction conditions:

[0816] Catalyst: Pd / C 10%; Solvent: glacial acetic acid; Cylinder pressure: 80 bar hydrogen; Flow rate: 1 ml / min; Temperature: 80 °C.

[0817] After the reaction was completed, the reaction mixture was concentrated to dryness. The resulting residue was dried under reduced pressure at room temperature overnight. This produced 4.2 g of the target compound as a yellow oil. The target compound was further reacted without further purification.

[0818] GC-MS (Method 3): R t = 3.87 min; m / z = 205 (M - C 2 H 4 O 2 ).

[0819] Example 13A

[0820] Benzyl 3-(difluoromethyl)[1,4'-bipiperidine]-1'-carboxylate (racemate)

[0821]

[0822] 1 g (4.29 mmol) of benzyl 4-oxopiperidine-1-carboxylate, 883 mg (5.14

[0823] mmol) of 3-(difluoromethyl)piperidine hydrochloride (1:1) and 0.9 ml (5.14 mmol) of N,N-diisopropylethylamine in 15 ml of dichloromethane (a small amount of molecular sieve was additionally added to the reaction solution) were stirred at room temperature for 1 hour. Then 1.363 g (6.43 mmol) of sodium acetylborohydride was added, and then the reaction mixture was stirred at room temperature overnight. Then the molecular sieve was filtered off, washed with dichloromethane, and the resulting filtrate was washed twice with a sodium bicarbonate solution and once with a saturated sodium chloride solution. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This produced 1.39 g (3.54 mmol, purity 89%, 83% of the theoretical value) of the target compound as a colorless transparent oil. The target compound was further reacted without further purification.

[0824] LC-MS (Method 1): R t = 1.04 min; m / z = 353 (M + H) + .

[0825] Similar to Example 13A, the following compounds of Examples 14A to 17A were prepared from the starting materials described in each case:

[0826]

[0827]

[0828] Example 18A

[0829] rac-3-(Hydroxymethyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0830]

[0831] Acetic acid (1.8 ml, 32 mmol) was added to a solution of rac-4-oxopiperidine-1-carboxylic acid benzyl ester (5.00 g, 21.4 mmol) and piperidin-3-ylmethanol (4.94 g, 42.9 mmol) in 50 ml of dichloromethane, and the mixture was stirred overnight at room temperature. Then sodium triacetoxyborohydride (5.45 g, 25.7 mmol) was added to the reaction, and stirring was continued at room temperature. After 2 hours, saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 4. The desiccant was filtered off by suction, and the filtrate was concentrated. The residue was applied to Then the mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 100 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 100 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 4.37 g (purity 100%, 61% of theory) of the target compound.

[0832] LC-MS (Method 1): R t = 0.92 min; MS (ESIpos): m / z = 333 [M+H] + .

[0833] Example 19A

[0834] rac-3-{[(Methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0835]

[0836] Under argon, rac-3-(hydroxymethyl)[1,4'-bipiperidine]-1'-carbobenzyloxide (5.42 g, 16.3 mmol) was initially loaded in 65 ml of dichloromethane, triethylamine (3.0 ml, 21 mmol) was added, and the mixture was cooled to 0 °C. At this temperature, methanesulfonyl chloride (1.5 ml, 20 mmol) was added dropwise. The mixture was then stirred at 0 °C for 15 minutes, after which the ice bath was removed and stirring was continued at room temperature. After 15 minutes, the reaction mixture was diluted with dichloromethane and washed successively with 1 N hydrochloric acid, saturated NaHCO 3 solution and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered and concentrated. The residue was dried under high vacuum and reacted further without further purification. This gave 6.16 g (purity 100%, 92% of theory) of the target compound.

[0837] LC-MS (method 12): R t = 1.39 min; MS (ESIpos): m / z = 411 [M+H] + .

[0838] Example 20A

[0839] rac-3-(methoxymethyl)[1,4'-bipiperidine]-1'-carbobenzyloxide

[0840]

[0841] Sodium methoxide solution (840 μl, 25% in methanol, 3.7 mmol) was added to a solution of rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carbobenzyloxide (500 mg, 1.22 mmol) in 10 ml of DMF, and the mixture was stirred at 50 °C overnight. The solvent was removed on a rotary evaporator, and the residue was placed in ethyl acetate and washed successively with water and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered and concentrated. The residue was applied to and the mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 25 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 75 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 146 mg (purity 100%, 35% of theory) of the target compound.

[0842] LC-MS (Method 4): Rt = 0.59 min; MS (ESI pos): m / z = 347 [M+H] + 。

[0843] Example 21A

[0844] diamix-(3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0845]

[0846] Acetic acid (1.71 ml, 29.85 mmol) was added to a solution of rac-3-fluoro-4-oxopiperidine-1-carboxylic acid benzyl ester (5 g, 19.9 mmol) and (3R)-3-methylpiperidine (5.4 g, 39.8 mmol) in 200 ml of dichloromethane, and the mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (5.06 g, 23.88 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution, water, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 and filtered and concentrated on a rotary evaporator. The residue was applied to and purified by column chromatography ( Isolera One; column: Snap Ultra 100 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 100 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 5.13 g (purity 55%, 42% of theory) of the target compound.

[0847] LC-MS (Method 1): R t t = 1.05 min; MS (ESI pos): m / z = 335 [M+H].

[0848] Example 22A

[0849] diamix-(3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester

[0850]

[0851] (3R)-3-Methylpiperidine hydrochloride (6.24 g, 46.0 mmol) was initially loaded in 250 ml of 1,2-dichloroethane. N,N-Diisopropylethylamine (8.0 ml, 46 mmol) was added and the mixture was stirred at room temperature for 5 minutes. rac-3-Fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.00 g, 23.0 mmol) and acetic acid (2.0 ml, 35 mmol) were added and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (5.85 g, 27.6 mmol) was added and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution, water and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x 30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 minutes 47 ml, mobile phase B 0 to 2 minutes 23 ml, mobile phase A 2 to 10 minutes from 47 ml to 23 ml, mobile phase B from 23 ml to 47 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min each throughout the run time). The fractions containing the product were combined, concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 5.30 g (purity 100%, 77% of theory) of the target compound.

[0852] LC-MS (method 4): R t = 0.52 min; MS (ESIpos): m / z = 301 [M+H] + .

[0853] Example 23A

[0854] rac-3-[(2,2,2-Trifluoroethoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0855]

[0856] Under argon, 2,2,2-trifluoroethanol (66 μl, 910 μmol) was initially loaded in 5 ml of DMF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 hours, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 dried, filtered and concentrated. The residue was dried under high vacuum. This gave 218 mg (81% purity, 70% of theory) of the target compound.

[0857] LC-MS (method 1): Rt = 1.33 min; MS (ESIpos): m / z = 415 [M+H] + 。

[0858] Example 24A

[0859] rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0860]

[0861] Under argon, [1-(fluoromethyl)cyclopropyl]methanol (95.1 mg, 913 μmol) was initially loaded in 5 ml of DMF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C overnight. Then water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 dried, filtered and concentrated. The residue was dried under high vacuum. This gave 204 mg (40% purity, 32% of theory) of the target compound.

[0862] LC-MS (method 1): Rt = 1.36 min; MS (ESIpos): m / z = 419 [M+H] + 。

[0863] Example 25A

[0864] rac-3-({[1-(Difluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0865]

[0866] Under argon, [1-(difluoromethyl)cyclopropyl]methanol (112 mg, 913 μmol) was initially loaded in 5 ml of DMF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 hours, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 dried, filtered and concentrated. The residue was dried under high vacuum. This gave 197 mg (51% purity, 37% of theory) of the target compound.

[0867] LC-MS (Method 1): R t t = 1.41 min; MS (ESIpos): m / z = 437 [M+H] + .

[0868] Example 26A

[0869] rac-3-({[1-(Trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0870]

[0871] Under argon, [1-(trifluoromethyl)cyclopropyl]methanol (128 mg, 913 μmol) was initially loaded in 5 ml of DMF, and the mixture was cooled to 0 °C with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 hours, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4Dry, filter and concentrate. Dry the residue under high vacuum. This gave 212 mg (58% purity, 44% of theory) of the target compound.

[0872] LC-MS (Method 1): R t = 1.48 min; MS (ESIpos): m / z = 455 [M+H] + .

[0873] Example 27A

[0874] Benzyl 3,3-dimethyl[1,4'-bipiperidine]-1'-carboxylate

[0875]

[0876] Acetic acid (74 μl, 1.3 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (200 mg, 58% purity, 857 μmol) and 3,3-dimethylpiperidine (240 μl, 1.7 mmol) in 7 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (218 mg, 1.03 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, and dried over Na 2 SO 4 4. The desiccant was filtered off, the filtrate was concentrated, and the residue was dried under high vacuum. This gave 280 mg (81% purity, 80% of theory) of the target compound.

[0877] LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m / z = 331 [M+H] + .

[0878] Example 28A

[0879] Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate

[0880]

[0881] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and 5-azaspiro[2.5]octane (286 mg, 2.57 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 . The drying agent was filtered off, the filtrate was concentrated, and the residue was dried under high vacuum. This gave 368 mg (40% purity, 35% of theory) of the target compound.

[0882] LC-MS (method 1): Rt = 1.12 min; MS (ESIpos): m / z = 329 [M+H] + .

[0883] Example 29A

[0884] Benzyl rac-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate

[0885]

[0886] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (300 mg, 1.29 mmol) and rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (354 mg, 1.93 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 . The drying agent was filtered off, the filtrate was concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 405 mg (61% purity, 53% of theory) of the target compound.

[0887] LC-MS (method 1): Rt = 1.14 min; MS (ESIpos): m / z = 365 [M+H] + .

[0888] Example 30A

[0889] rac-3-Hydroxy[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0890]

[0891] Triethylamine (1.8 ml, 13 mmol) and acetic acid (740 μl, 13 mmol) were added to a solution of 4-oxopiperidine-1-carboxylic acid benzyl ester (2.00 g, 8.57 mmol) and piperidin-3-ol (1.73 g, 17.1 mmol) in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added to the reaction, and the mixture was stirred at room temperature for 48 h. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 4. The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to and the mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 50 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 100 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 1.87 g (purity 100%, 68% of theory) of the target compound.

[0892] LC-MS (method 1): Rt = 0.88 min; MS (ESIpos): m / z = 319 [M+H] + .

[0893] Example 31A

[0894] rac-3-(Cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0895]

[0896] Under argon, 3-hydroxy-[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 785 μmol) was initially loaded in 5 ml of THF, and the mixture was cooled to 0 °C using an ice bath. At this temperature, sodium hydride (47.1 mg, 60% purity, 1.18 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl)cyclopropane (110 μl, 1.2 mmol) was added and the mixture was stirred at 60 °C overnight. (Bromomethyl)cyclopropane (110 μl, 1.2 mmol) and sodium hydride (47.1 mg, 60% purity, 1.18 mmol) were added, and the mixture was stirred at 60 °C for an additional 24 hours. Subsequently, the product was separated by preparative HPLC (column: Chromatorex C18 10 μm, 250 x 30 mm, mobile phase A = water, B = acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml / min; 0.1% formic acid). The fractions containing the product were combined, concentrated on a rotary evaporator, and the residue was dried under high vacuum. This yielded 68.0 mg (68% purity, 16% of theory) of the target compound.

[0897] LC-MS (Method 1): Rt = 1.25 min; MS (ESIpos): m / z = 373 [M+H] + 。

[0898] Example 32A

[0899] rac-3-[(Cyclobutoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0900]

[0901] Under argon, cyclobutanol (72 μl, 910 μmol) was initially loaded in 5 ml of DMF, and the mixture was cooled to 0 °C using an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(Methanesulfonyl)oxy]methyl}[1,4’-bipiperidine]-1’-carboxylic acid benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C overnight. Then water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and dried over Na 2 SO 4 2SO4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This yielded 290 mg (46% purity, 57% of theory) of the target compound.

[0902] LC-MS (Method 4): Rt t = 0.73 min; MS (ESI pos): m / z = 387 [M+H] + .

[0903] Example 33A

[0904] rac-3-[(Cyclopropylmethoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0905]

[0906] Under argon, sodium hydride (268 mg, 60% purity, 6.70 mmol) was initially loaded in 25 ml of DMF and the mixture was cooled to 0 °C with an ice bath. At this temperature, cyclopropylmethanol (540 μl, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(Methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (2.50 g, 6.09 mmol) was added and the reaction mixture was stirred at 55 °C overnight. Cyclopropylmethanol (540 μl, 6.7 mmol) and sodium hydride (268 mg, 60% purity, 6.70 mmol) were added and the mixture was stirred at 55 °C for an additional 24 hours. Then water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 241 mg (78% purity, 8% of the theoretical value) of the target compound was obtained by combining the fractions containing the product and lyophilizing. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature, wavelength 200 - 400 nm, full injection; gradient profile: mobile phase A from 63 ml at 0 to 2 minutes, mobile phase B from 7 ml at 0 to 2 minutes, mobile phase A from 63 ml to 39 ml from 2 to 10 minutes, mobile phase B from 7 ml to 31 ml, 0 ml of mobile phase A and 70 ml of mobile phase B from 10 to 12 minutes. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time).

[0907] LC-MS (Method 1): Rt = 1.27 min; MS (ESI pos): m / z = 387 [M+H] + .

[0908] Example 34A

[0909] tert-Butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate

[0910]

[0911] Acetic acid (72 μl, 1.3 mmol) was added to a solution of tert-butyl 4-oxoazepane-1-carboxylate (179 mg, 840 μmol) and (3R)-3-methylpiperidine (167 mg, 1.68 mmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature. After 5 h, sodium triacetoxyborohydride (214 mg, 1.01 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Subsequently, saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 4. The desiccant was filtered off by suction, the filtrate was concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 215 mg of a mixture, which was reacted further without further purification and analysis.

[0912] Example 35A

[0913] diamix-3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylate benzyl ester

[0914]

[0915] Under argon, rac-(2,2-difluorocyclopropyl)methanol (98.7 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled to 0 °C with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added, and the mixture was stirred at room temperature for 30 min. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylate benzyl ester (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 343 mg (56% purity, 74% of theory) of the target compound.

[0916] LC-MS (Method 1): Rt = 1.32 min; MS (ESI pos): m / z = 423 [M+H] + 。

[0917] Example 36A

[0918] rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[0919]

[0920] Under argon, (3,3-difluorocyclobutyl)methanol (112 mg, 913 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0 °C with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methanesulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60 °C. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na 2 SO 4 dried, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 287 mg (33% purity, 36% of theory) of the target compound.

[0921] LC-MS (Method 1): Rt = 1.44 min; MS (ESI pos): m / z = 437 [M+H] + 。

[0922] Example 37A

[0923] 3-(Difluoromethyl)-1,4'-bipiperidine dihydrochloride (racemate)

[0924]

[0925] 1.35 g (3.83 mmol) of 3-(difluoromethyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (racemate) was dissolved in 100 ml of ethanol and hydrogenated using an H-Cube (ThalesNano H-Cube ProTM - 1.7).

[0926] Reaction conditions:

[0927] Catalyst: Pd / C 10%; Solvent: ethanol; Cartridge pressure: 1 bar of hydrogen; Flow rate: 1 ml / min; Temperature: 50 °C

[0928] After complete conversion, 4N HCl (in dioxane) was added and the reaction mixture was concentrated to dryness. The resulting residue was dried under reduced pressure at room temperature overnight. This gave 1.107 g (3.80 mmol, 99% of theory) of the target compound as a white solid. The target compound was reacted further without further purification.

[0929] GC-MS (Method 3): R t = 4.87 min; m / z = 218 (M - 2HCl) + .

[0930] Example 38A

[0931] 3-[(3,3-Difluorocyclobutyl)methoxy]-1,4'-bipiperidine (racemate)

[0932]

[0933] 2.7 g (6.39 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (racemate) was dissolved in 90 ml of ethanol and hydrogenated using an H-Cube (ThalesNano H-Cube ProTM - 1.7).

[0934] Reaction conditions:

[0935] Catalyst: Pd / C 10%; Solvent: ethanol; Cartridge pressure: 50 bar hydrogen; Flow rate: 1 ml / min; Temperature: 50 °C

[0936] After completion of the reaction, the reaction mixture was concentrated to dryness. The resulting residue was dried under reduced pressure at room temperature overnight. This gave 1.27 g (4.40 mmol, 69% of theory) of the target compound as a yellow oil. The target compound was reacted further without further purification.

[0937] GC-MS (Method 3): R t = 6.42 min; m / z = 288 (M) + .

[0938] Analogously to Examples 37A and 38A, the following compounds of Examples 39A to 41A were prepared from the starting materials stated in each case.

[0939]

[0940]

[0941] Example 42A

[0942] rac-3-(Methoxymethyl)-1,4'-bipiperidine dihydrochloride

[0943]

[0944] rac-3-(Methoxymethyl)[1,4'-bipiperidine]-1'-carbobenzyloxy (145 mg, 419 μmol) was initially loaded in 5 ml of THF and palladium (50.0 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (310 μl, 2.0 M, 630 μmol) was added to the filtrate and the precipitated solid was filtered off by suction, washed with diethyl ether and dried under high vacuum. This gave 92.0 mg (76% purity, 59% of theory) of the target compound.

[0945] GC-MS (method 3): Rt = 5.45 min; MS (ESIpos): m / z = 212 [M-HCl] + 。

[0946] Example 43A

[0947] diamix-(3R)-3'-Fluoro-3-methyl-1,4'-bipiperidine dihydrochloride

[0948]

[0949] Synthetic method 1:

[0950] diamix-(3R)-3'-Fluoro-3-methyl[1,4'-bipiperidine]-1'-carbobenzyloxy (5.13 g, 55% purity, 8.40 mmol) was initially loaded in 250 ml of THF and palladium (382 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (6.3 ml, 2.0 M, 13 mmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane and the solid was filtered off by suction, washed with dichloromethane and dried under high vacuum. This gave 2.31 g (100% of theory) of the target compound.

[0951] LC-MS (method 4): MS (ESIpos): m / z = 200 [M-2HCl] + 。

[0952] Synthetic method 2:

[0953] 4 M hydrochloric acid in 1,4-dioxane (22 ml, 4.0 M, 88 mmol) was added to a solution of diamix-(3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (5.30 g, 17.6 mmol) in dichloromethane, and the mixture was stirred at room temperature for 48 h. The precipitated solid was filtered off with suction, washed with dichloromethane, and dried overnight at 40 °C in a vacuum drying oven. This gave 3.47 g (purity 100%, 72% of theory) of the target compound.

[0954] GC-MS (method 3): MS (ESIpos): m / z = 200 [M-2HCl] + 。

[0955] Example 44A

[0956] rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4'-bipiperidine dihydrochloride

[0957]

[0958] rac-3-[(2,2,2-trifluoroethoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (218 mg, purity 81%, 526 μmol) was initially loaded in 12 ml of THF and palladium (63 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 3.5 h, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (390 μl, 2.0 M, 790 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 164 mg (purity 74%, 66% of theory) of the target compound.

[0959] GC-MS (method 3): R t = 5.26 min; MS (full ms): m / z = 280 [M-2HCl] + 。

[0960] Example 45A

[0961] rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4'-bipiperidine dihydrochloride

[0962]

[0963] The rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (204 mg, purity 40%, 487 μmol) was initially loaded in 10 ml of THF, and palladium (58 mg; 10% on activated carbon) was added under argon. Then the mixture was hydrogenated under a hydrogen atmosphere. After 2 hours, the catalyst was filtered off through diatomaceous earth and washed with THF. Hydrochloric acid in diethyl ether (370 μl, 2.0 M, 740 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This gave 133 mg of a mixture which was reacted without further purification and analysis.

[0964] Example 46A

[0965] rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)-1,4'-bipiperidine dihydrochloride

[0966]

[0967] The rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (197 mg, purity 51%, 451 μmol) was initially loaded in 10 ml of THF, and palladium (54 mg; 10% on activated carbon) was added under argon. Then the mixture was hydrogenated under a hydrogen atmosphere. After 1.5 hours, the catalyst was filtered off through diatomaceous earth and washed with THF. Hydrochloric acid in diethyl ether (374 μl, 2.0 M, 680 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This gave 112 mg of a mixture which was reacted without further purification and analysis.

[0968] Example 47A

[0969] rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)-1,4'-bipiperidine dihydrochloride

[0970]

[0971] The rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (212 mg, purity 58%, 466 μmol) was initially loaded in 10 ml of THF, and palladium (56 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 hours, the catalyst was filtered off through diatomaceous earth and washed with THF. Hydrochloric acid in diethyl ether (350 μl, 2.0 M, 700 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This gave 129 mg of a mixture which was reacted further without further purification and analysis.

[0972] Example 48A

[0973] 3,3-Dimethyl-1,4'-bipiperidine dihydrochloride

[0974]

[0975] The 3,3-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (260 mg, purity 81%, 637 μmol) was initially loaded in 18 ml of THF, and palladium (27 mg; 10% on activated carbon, 255 μmol) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through diatomaceous earth and washed with THF. Hydrochloric acid in diethyl ether (478 μl, 2.0 M, 956 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 180 mg of a mixture which was reacted further without further purification and analysis.

[0976] Example 49A

[0977] 5-(Piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[0978]

[0979] Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (368 mg, purity 40%, 1.12 mmol) was initially loaded in 32 ml of THF, and palladium (51 mg, 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered out through celite and washed with THF. Hydrochloric acid in diethyl ether (840 μl, 2.0 M, 1.7 mmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane. The precipitated solid was suction filtered, washed with dichloromethane, and dried under high vacuum. This gave 185 mg of a mixture, which was reacted further without further purification and analysis.

[0980] Example 50A

[0981] rac-1,1-Difluoro-5-(piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[0982]

[0983] Benzyl rac-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (405 mg, purity 61%, 1.11 mmol) was initially loaded in 32 ml of THF, and palladium (51 mg, 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered out through celite and washed with THF. Hydrochloric acid in diethyl ether (840 μl, 2.0 M, 1.7 mmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated on a rotary evaporator and dried under high vacuum. This gave 280 mg of a mixture, which was reacted further without further purification and analysis.

[0984] Example 51A

[0985] rac-3-(Cyclopropylmethoxy)-1,4'-bipiperidine dihydrochloride

[0986]

[0987] The rac-3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (68.0 mg, purity 68%, 124 μmol) was initially loaded in 5 ml of THF, and palladium (22 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (93 μl, 2.0 M, 186 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated, and dried under high vacuum. This gave 51 mg of a mixture which was reacted further without further purification and analysis.

[0988] Example 52A

[0989] rac-3-[(Cyclobutoxy)methyl]-1,4'-bipiperidine dihydrochloride

[0990]

[0991] The rac-3-[(cyclobutoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (290 mg, purity 46%, 386 μmol) was initially loaded in 15 ml of THF, and palladium (41 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (259 μl, 2.0 M, 518 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This gave 225 mg of a mixture which was reacted further without further purification and analysis.

[0992] Example 53A

[0993] rac-3-[(Cyclopropylmethoxy)methyl]-1,4'-bipiperidine dihydrochloride

[0994]

[0995] The rac-3-[(cyclopropylmethoxy)methyl][1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (241 mg, purity 78%, 486 μmol) was initially loaded in 20 ml of THF, and palladium (58 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (360 μl, 2.0 M, 730 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This gave 155 mg of a mixture which was reacted further without further purification and analysis.

[0996] Example 54A

[0997] 4-[(3R)-3-Methylpiperidin-1-yl]azepane dihydrochloride

[0998]

[0999] 4M hydrochloric acid (2.2 ml, 4.0 M, 8.6 mmol) in 1,4-dioxane was added to a solution of tert-butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate (215 mg) in 5.4 ml of dichloromethane, and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 237 mg of a mixture which was reacted further without further purification and analysis.

[1000] Example 55A

[1001] diamix-3-[(3-Fluorobutoxy)methyl]-1,4'-bipiperidine dihydrochloride

[1002]

[1003] diamix-3-({[-2,2-Difluorocyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylate benzyl ester (343 mg, purity 56%, 446 μmol) was initially loaded in 25 ml of THF and palladium (53 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in diethyl ether (330 μl, 2.0 M, 670 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 218 mg of a mixture which was reacted further without further purification and analysis.

[1004] Example 56A

[1005] rac-3-{[(3,3-Difluorocyclobutyl)methoxy]methyl}-1,4'-bipiperidine dihydrochloride

[1006]

[1007] The rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (287 mg, purity 33%, 217 μmol) was initially loaded in 15 ml of THF, and palladium (26 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered out through diatomaceous earth and washed with THF. Hydrochloric acid in diethyl ether (163 μl, 2.0 M, 325 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This yielded 286 mg of a mixture, which was further reacted without further purification and analysis.

[1008] Example 57A

[1009] Methyl 2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylate

[1010]

[1011] 5 g (22.52 mmol) of methyl 2-bromo-1,3-thiazole-5-carboxylate, 4.926 g (22.52 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride, and 9.4 ml (67.55 mmol) of triethylamine in 30 ml of 2-propanol were heated to boiling (oil bath temperature about 100 °C) and stirred at this temperature overnight. After the reaction mixture was cooled, the solution was concentrated to dryness on a rotary evaporator. This yielded 14.29 g (crude product, purity about 34%) of the target product and the triethylamine salt. The mixture was further reacted without further purification.

[1012] LC-MS (method 4): R t = 0.51 min; m / z = 324 (M+H) + .

[1013] Example 58A

[1014] 2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride

[1015]

[1016] A mixture of 14.29 g of methyl 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylate and its triethylamine salt was dissolved in water, and 221 ml of 1N NaOH solution was added. The brown oil was separated out and dissolved in 50 ml of THF. Then the reaction mixture was heated to 60 °C and stirred at this temperature for 1 hour. After the reaction mixture was cooled to room temperature, the solution was concentrated to dryness on a rotary evaporator, placed in water and acidified with concentrated hydrochloric acid. Then the solution was concentrated to dryness again. This produced 20.54 g of a beige solid, which was purified by column chromatography.

[1017] Condition: separation was carried out in 1 g portions. RP column Chromatorex C18, 10 μm; 125 x 30 mm, acetonitrile / water (+0.05% formic acid) 5 / 95 → gradient for 20 minutes → acetonitrile / water (+0.05% formic acid) 95 / 5 flow rate 75 ml / min.

[1018] Finally, the fractions containing the product were combined and concentrated to dryness under reduced pressure and dried. This produced 4.75 g (12.42 mmol, 83% of theory) of the target compound as a light beige solid.

[1019] LC-MS (method 1): R t = 0.54 min; m / z = 310 (M + H - 2HCl) + .

[1020] Example 59A

[1021] 3-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,2,4-oxadiazole-5-carboxylic acid

[1022]

[1023] Ethyl 3-bromo-1,2,4-oxadiazole-5-carboxylate (100 mg, 452 μmol) and (3R)-3-methyl-1,4'-bipiperidine dihydrochloride (173 mg, 679 μmol) were stirred in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4.0 mmol) at 120 °C. After 30 minutes, the reaction mixture was acidified with 2 N hydrochloric acid and purified by preparative HPLC (column: Chromatorex C18 10 μm, 250 x 30 mm, mobile phase A = water, B = acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml / min; 0.1% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 25 mg (purity 60%, 11% of theory) of the target compound.

[1024] LC-MS (method 1): R t = 0.47 min; MS (ESI pos): m / z = 295 [M+H] + 。

[1025] Example 60A

[1026] rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride

[1027]

[1028] Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in 25 ml of THF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, diisopropyl azodicarboxylate (1.3 ml, 9.3 mmol) was added, and the mixture was stirred at 0 °C for 5 minutes. Subsequently, a solution of rac-2,2-difluorocyclopropylmethanol (1.00 g, 9.25 mmol) in 5 ml of THF was added dropwise to the mixture. Then the ice bath was removed, and the mixture was stirred at room temperature overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 4, filtered and concentrated. The oily residue was stirred with 75 ml of cyclohexane for 30 minutes. The precipitated solid was filtered off and the filtrate was concentrated to give a residue. The residue was dissolved in 50 ml of MTBE, and 5 ml of hydrochloric acid (4 N in 1,4-dioxane) was added. The precipitated solid was suction filtered, washed with MTBE and dried under high vacuum. This gave 698 mg (purity 93%, 41% of theory) of the target compound.

[1029] LC-MS (Method 4): R t = 0.40 min; MS (ESIpos): m / z = 186 [M-HCl] + .

[1030] Example 61A

[1031] diamix - 3 - [(2,2-difluorocyclopropyl)methoxy]piperidine sulfate hydrochloride

[1032]

[1033] Under argon, rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride (698 mg, purity 93%, 2.93 mmol) was dissolved in 35 ml of ethanol. Sulfuric acid (168 μl, 3.15 mmol) and platinum(IV) oxide (179 mg, 0.79 mmol) were added, and the mixture was hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through diatomaceous earth and washed with ethanol. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 761 mg (74% of theory) of the target compound.

[1034] LC-MS (Method 5): MS (ESIpos): m / z = 192 [M-HCl-H 2 SO 4 + .

[1035] Example 62A

[1036] 3-(Cyclobutoxy)pyridine hydrochloride

[1037]

[1038] Triphenylphosphine (7.17 g, 27.3 mmol) was added to a solution of pyridin-3-ol (2.00 g, 21.0 mmol) in 70 ml of THF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, diisopropyl azodicarboxylate (3.9 ml, 27 mmol) was added, and the mixture was stirred at 0 °C for 5 minutes. Subsequently, a solution of cyclobutanol (2.1 ml, 27 mmol) in 10 ml of THF was added dropwise to the mixture. Then the ice bath was removed, and the mixture was stirred at room temperature over the weekend. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, over Na 2 SO 4 ​Dry, filter and concentrate. Stir the oily residue with 150 ml of cyclohexane for 30 minutes. Filter off the solid and concentrate the filtrate to give a residue. Dissolve the residue in 100 ml of MTBE and add 5 ml of hydrochloric acid (4 N in 1,4-dioxane). Filter off the precipitated solid by suction, wash with MTBE and dry under high vacuum. This gives 2.02 g (51% purity, 26% of theory) of the target compound.

[1039] LC-MS (Method 5): R t = 1.34 min; MS (ESIpos): m / z = 150 [M-HCl].

[1040] Example 63A

[1041] rac-3-(Cyclobutyloxy)piperidine sulfate hydrochloride

[1042]

[1043] Under argon, dissolve 3-(cyclobutyloxy)pyridine hydrochloride (2.0 g, 51% purity, 5.51 mmol) in 95 ml of ethanol. Add sulfuric acid (550 μl, 10 mmol) and platinum(IV) oxide (612 mg, 2.6 mmol), and hydrogenate the mixture overnight under a hydrogen atmosphere. Filter off the catalyst through diatomaceous earth and wash with ethanol. Concentrate the filtrate by evaporation and dry the residue under high vacuum. This gives 2.52 g (157% of theory) of the target compound.

[1044] LC / MS (Method 4): MS (ESIpos): m / z = 156 [M-HCl-H 2 SO 4 + 。

[1045] Example 64A

[1046] 3-[(3,3-Difluorocyclobutyl)oxy]pyridine hydrochloride

[1047]

[1048] ​Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in 25 ml of THF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, diisopropyl azodicarboxylate (1.3 ml, 9.3 mmol) was added, and the mixture was stirred at 0 °C for 5 minutes. Subsequently, a solution of 3,3-difluorocyclobutanol (1.00 g, 9.25 mmol) in 5 ml of THF was added dropwise to the mixture. Then the ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was stirred at 80 °C for 5 hours and then extracted between water and ethyl acetate. The organic phase was washed with saturated NaCl solution and dried over Na 2 SO 4 , filtered and concentrated. The oily residue was stirred with 150 ml of cyclohexane for 30 minutes. The precipitated solid was filtered off, and the filtrate was concentrated to give a residue. The residue was dissolved in 100 ml of MTBE, and 5 ml of hydrochloric acid (4 N in 1,4-dioxane) was added. The precipitated solid was filtered off by suction, washed with MTBE and dried under high vacuum. This gave 289 mg (94% purity, 17% of theory) of the target compound.

[1049] LC-MS (Method 4): R t = 1.01 min; MS (ESIpos): m / z = 186 [M-HCl] + .

[1050] Example 65A

[1051] rac-3-[(3,3-Difluorocyclobutyl)oxy]piperidine sulfate hydrochloride

[1052]

[1053] Under argon, 3-[(3,3-difluorocyclobutyl)oxy]pyridine hydrochloride (298 mg, 1.34 mmol) was dissolved in 12 ml of ethanol. Sulfuric acid (72 μl, 1.3 mmol) and platinum(IV) oxide (76.3 mg, 336 μmol) were added, and the mixture was hydrogenated under a hydrogen atmosphere for 3 hours. The catalyst was filtered off through diatomaceous earth and washed with ethanol. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 297 mg (68% of theory) of the target compound.

[1054] LC / MS (Method 4): MS (ESIpos): m / z = 192 [M-HCl-H 2 SO 4 + .

[1055] Example 66A ​

[1056] 2-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide

[1057]

[1058] To a solution of 2-bromo-1,3-oxazole-4-carboxylic acid (250 mg, 1.30 mmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (283 mg, 1.30 mmol) in 10 ml of acetonitrile were added N,N-diisopropylethylamine (680 μl, 3.9 mmol) and propylphosphonic anhydride (1.0 ml, 50% in ethyl acetate, 1.7 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 solution, water, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 . The desiccant was filtered off and the filtrate was concentrated. The residue was applied to and the mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA - 66% EA; flow rate 36 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 193 mg (46% of theory, purity 84%) of the target compound, which was reacted further without further purification.

[1059] LC-MS (method 1): R t = 1.32 min; MS (ESIpos): m / z = 274 [M+H] + .

[1060] Example 67A

[1061] 2-Bromo-N-(5-chloro-2-fluorobenzyl)-1,3-thiazole-5-carboxamide

[1062]

[1063] N,N-Diisopropylethylamine (630 μl, 3.6 mmol) and propylphosphonic anhydride (930 μl, 50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and 1-(5-chloro-2-fluorophenyl)methanamine (192 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was placed in ethyl acetate and washed with saturated NaHCO 3 solution, water, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 . The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to and the mixture was purified by column chromatography ([[]] Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA - 66% EA; flow rate 36 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 106 mg (purity 96%, 24% of theory) of the target compound.

[1064] LC-MS (method 1): R t = 1.85 min; MS (ESIpos): m / z = 348 [M+H] + .

[1065] Example 68A

[1066] (3R)-3-Hydroxy[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[1067]

[1068] Triethylamine (3.0 ml, 21 mmol) and acetic acid (740 μl, 13 mmol) were added to a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g, 8.57 mmol) and (3R)-piperidin-3-ol hydrochloride (2.36 g, 17.1 mmol) in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 48 hours. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 . The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to and the mixture was purified by column chromatography ([[]] Purified by Isolera One; column: Snap Ultra 50 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 100 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 1.79 g (purity 100%, 66% of theory) of the target compound.

[1069] LC-MS (method 1): R t = 0.87 min; MS (ESI pos): m / z = 319 [M+H] + 。

[1070] Example 69A

[1071] (3R)-3-(Cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[1072]

[1073] Under argon, (3R)-3-hydroxy[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (1.79 g, 5.62 mmol) was initially loaded in 40 ml of THF, and the mixture was cooled to 0 °C with an ice bath. At this temperature, sodium hydride (337 mg, 60% purity, 8.43 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl)cyclopropane (820 μl, 8.4 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. (Bromomethyl)cyclopropane (820 μl, 8.4 mmol) and sodium hydride (337 mg, 60% purity, 8.43 mmol) were added, and the mixture was stirred at 60 °C for an additional 24 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and passed through Na 2 SO 4Dry. Filter out the desiccant and concentrate the filtrate. Purify the product by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5μm 100x30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, full injection. Gradient profile: mobile phase A 0 to 2 minutes 63 ml, mobile phase B 0 to 2 minutes 7 ml, mobile phase A 2 to 10 minutes from 63 ml to 39 ml, mobile phase B from 7 ml to 31 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time). Combine the fractions containing the product and lyophilize. This yields 100.0 mg (purity 100%, 4.8% of theoretical) of the target compound.

[1074] LC-MS (Method 1): R t = 1.19 min; MS (ESI pos): m / z = 373 [M+H] + 。

[1075] Example 70A

[1076] (3R)-3-(Cyclopropylmethoxy)-1,4'-bipiperidine dihydrochloride

[1077]

[1078] Initially load (3R)-3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (100 mg, 268 μmol) in 7.5 ml of THF and add palladium (32.1 mg; 10% on activated carbon) under argon. Then hydrogenate the mixture under a hydrogen atmosphere for 2 hours. Filter out the catalyst through celite and wash with THF. Add hydrochloric acid in diethyl ether (200 μl, 2.0 M, 400 μmol) to the filtrate and concentrate the mixture on a rotary evaporator. Stir the residue with dichloromethane, concentrate and dry under high vacuum. This yields 66 mg of a mixture which is reacted further without further purification and analysis.

[1079] Example 71A

[1080] rac-2-Bromo-N-[1-(2,5-difluorophenyl)ethyl]-1,3-thiazole-5-carboxamide

[1081]

[1082] N,N-Diisopropylethylamine (630 μl, 3.6 mmol) and propylphosphonic anhydride (930 μl, 50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and rac-1-(2,5-difluorophenyl)ethylamine (189 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was placed in ethyl acetate and washed with saturated NaHCO 3 solution, water, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 . The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to and the mixture was purified by column chromatography ([[]] Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA - 66% EA; flow rate 36 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 148 mg (purity 100%, 35% of theory) of the target compound.

[1083] LC-MS (method 1): R t = 1.81 min; MS (ESIpos): m / z = 346 [M+H] + .

[1084] Example 72A

[1085] Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylate

[1086]

[1087] Ethyl 2-bromo-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate (150 mg, 433 μmol) and (3R)-3-methyl-1,4'-bipiperidine dihydrochloride (166 mg, 649 μmol) were combined and stirred at 120 °C in sodium carbonate solution (870 μl, 2.0 M, 1.7 mmol) for 30 minutes. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na 2 SO 4 and filtered, and the filtrate was concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 199 mg (purity 95%, 98% of theory) of the target compound.

[1088] LC-MS (method 1): Rt = 1.34 min; MS(ESIpos): m / z = 449 [M+H] + 。

[1089] Example 82A

[1090] diamix-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[1091]

[1092] 4M hydrochloric acid in 1,4-dioxane (720 μl, 4.0 M, 2.9 mmol) was added to a solution of diamix-4-(5-azaspiro[2.5]oct-5-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (179 mg, 573 μmol) in 8 ml of dichloromethane, and the mixture was stirred overnight at room temperature. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 162 mg of a mixture which was reacted further without further purification and analysis.

[1093] Example 73A

[1094] 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid

[1095]

[1096] Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylate (199 mg, 444 μmol) was dissolved in 10 ml of THF. Aqueous sodium hydroxide solution (4 ml, 2.0 M, 8 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 days. THF was removed on a rotary evaporator and the residue was acidified with hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gave 160 mg (98% purity, 84% of theory) of the target compound.

[1097] LC-MS (Method 1): R t = 0.97 min; MS(ESIpos): m / z = 420 [M+H] + 。

[1098] Example 74A

[1099] 4-bromo-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid

[1100]

[1101] 2,4-Dibromo-1,3-thiazole-5-carboxylic acid (150 mg, 523 μmol) and (3R)-3-methyl-1,4'-bipiperidine dihydrochloride (133 mg, 523 μmol) were combined and stirred in sodium carbonate solution (1.0 ml, 2.0 M, 2.1 mmol) at 120 °C for 1 h. Subsequently, the reaction mixture was concentrated to dryness and stirred with DCM / MeOH 5:1. The insoluble salts were filtered off with suction. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gave 240 mg (purity 100%, 118% of theory) of the target compound.

[1102] LC-MS (method 1): R t = 0.70 min; MS (ESIpos): m / z = 388 [M+H] + 。

[1103] Example 75A

[1104] 2-Bromo-4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1105]

[1106] N,N-Diisopropylethylamine (720 μl, 4.1 mmol) and propylphosphonic anhydride (800 μl, 50% in ethyl acetate, 1.3 mmol) were added to a solution of 2-bromo-4-chloro-1,3-thiazole-5-carboxylic acid (250 mg, 1.03 mmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (291 mg, 1.34 mmol) in 14 ml of acetonitrile and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 solution, water and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 and the desiccant was filtered off and the filtrate was concentrated. The residue was dried in high vacuum. This gave 250 mg (purity 95%, 62% of theory) of the target compound.

[1107] LC-MS (method 1): R t = 1.79 min; MS (ESIpos): m / z = 367 [M+H] + 。

[1108] Example 76A

[1109] 2-Bromo-4-cyclopropyl-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1110]

[1111] N,N-Diisopropylethylamine (560 μl, 3.2 mmol) and propylphosphonic anhydride (620 μl, 50% in ethyl acetate, 1.0 mmol) were added to a solution of 2-bromo-4-cyclopropyl-1,3-thiazole-5-carboxylic acid (200 mg, 806 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (227 mg, 1.05 mmol) in 11 ml of acetonitrile, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was placed in ethyl acetate and washed with saturated NaHCO 3 solution, water, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 4. The desiccant was filtered off, and the filtrate was concentrated. The residue was dried under high vacuum. This gave 239 mg (purity 78%, 62% of theory) of the target compound.

[1112] LC-MS (Method 1): R t = 1.87 min; MS (ESIpos): m / z = 373 [M+H] + .

[1113] Example 77A

[1114] 2-Bromo-4-ethyl-1,3-thiazole-5-carboxylic acid

[1115]

[1116] Methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate (150 mg, 600 μmol) was dissolved in 3 ml of THF. Aqueous sodium hydroxide solution (3 ml, 2.0 M, 6 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. THF was removed on a rotary evaporator, and the residue was acidified with 2 N hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gave 100 mg (purity 98%, 69% of theory) of the target compound.

[1117] LC-MS (Method 1): R t = 1.30 min; MS (ESIpos): m / z = 235 [M+H] + .

[1118] Example 78A

[1119] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-ethyl-1,3-thiazole-5-carboxamide

[1120]

[1121] To a solution of 2-bromo-4-ethyl-1,3-thiazole-5-carboxylic acid (100 mg, 424 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (120 mg, 550 μmol) in 5.7 ml of acetonitrile were added N,N-diisopropylethylamine (300 μl, 1.7 mmol) and propylphosphonic anhydride (330 μl, 50% in ethyl acetate, 550 μmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was placed in ethyl acetate and washed with saturated NaHCO 3 solution, water and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 4. The desiccant was filtered off, and the filtrate was concentrated. The residue was dried under high vacuum. This gave 150 mg (95% purity, 93% of theory) of the target compound.

[1122] LC-MS (method 4): R t = 0.86 min; MS (ESIpos): m / z = 364 [M+H] + .

[1123] Example 79A

[1124] diamix-4-(1,1-difluoro-5-azaspiro[2.5]oct-5-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester

[1125]

[1126] To a solution of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (600 mg, 3.27 mmol) in 15 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (570 μl, 3.3 mmol), and the mixture was stirred for 5 min, after which rac-3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (355 mg, 1.63 mmol) and acetic acid (140 μl, 2.5 mmol) were added to the mixture. The mixture was then stirred at room temperature. After 5 h, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4Dry. Filter out the desiccant and concentrate the filtrate. Dissolve the residue in DMSO and purify by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5μm 100x30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, full injection. Gradient profile: mobile phase A 70 ml from 0 to 2 minutes, mobile phase B 0 ml from 0 to 2 minutes, mobile phase A from 70 ml to 55 ml from 2 to 10 minutes, mobile phase B from 0 ml to 15 ml, 0 ml mobile phase A and 70 ml mobile phase B from 10 to 12 minutes. Mobile phase C and mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time). Combine the fractions containing the product and concentrate, and dry the residue under high vacuum. This gives 264 mg (purity 100%, 46% of theory) of the target compound.

[1127] LC-MS (method 4): R t = 0.56 min; MS (ESI pos): m / z = 349 [M+H] + 。

[1128] Example 80A

[1129] diamix - 1,1 - difluoro - 5 - (3 - fluoropiperidin - 4 - yl)-5 - azaspiro[2.5]octane dihydrochloride

[1130]

[1131] 4M hydrochloric acid in 1,4 - dioxane (950 μl, 4.0 M, 3.8 mmol) was added to a solution of diamix - tert - butyl 4 - (1,1 - difluoro - 5 - azaspiro[2.5]oct - 5 - yl)-3 - fluoropiperidine - 1 - carboxylate (264 mg, 760 μmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 246 mg of a mixture which was further reacted without further purification and analysis.

[1132] Example 81A

[1133] diamix - tert - butyl 4 - (5 - azaspiro[2.5]oct - 5 - yl)-3 - fluoropiperidine - 1 - carboxylate

[1134]

[1135] N,N-Diisopropylethylamine (410 μl, 2.4 mmol) was added to a solution of 5-azaspiro[2.5]octane hydrochloride (350 mg, 2.37 mmol) in 10 ml of dichloroethane, and the mixture was stirred for 5 minutes. Then, rac-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (257 mg, 1.19 mmol) and acetic acid (100 μl, 1.8 mmol) were added to the mixture. The mixture was then stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. Saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 . The drying agent was filtered off, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 μm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, full injection. Gradient profile: mobile phase A 0 to 2 minutes 70 ml, mobile phase B 0 to 2 minutes 0 ml, mobile phase A 2 to 10 minutes from 70 ml to 55 ml, mobile phase B from 0 ml to 15 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 179 mg (purity 100%, 48% of theory) of the target compound.

[1136] LC-MS (method 4): R t = 0.53 min; MS (ESIpos): m / z = 313 [M+H] + .

[1137] Example 82A

[1138] Ethyl 5-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3,4-thiadiazole-2-carboxylate

[1139]

[1140] 3.67 mL (21.09 mmol) of N,N-diisopropylethylamine was added to 1 g (4.22 mmol) of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate and 1.077 g (4.22 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride in 25 mL of acetonitrile. The mixture was heated to 80 °C and stirred at this temperature overnight. After the reaction mixture was cooled, the solution was diluted with ethyl acetate and washed with water. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This yielded 1.29 g (3.81 mmol, 90% of theory) of the target compound as a red solid.

[1141] 1 H NMR (600 MHz, DMSO-d 6 ) δ [ppm]: 0.77 - 0.87 (m, 4H, including 0.82 (d, 3H)), 1.30 (t, 3H), 1.34 - 1.46 (m, 1H), 1.48 - 1.67 (m, 5H), 1.72 - 1.85 (m, 3H), 2.06 (br.t, 1H), 2.48 - 2.58 (m, 1H, partially masked by DMSO), 2.74 (br.t, 2H), 3.24 (td, 2H), 3.98 (br.d, 2H), 4.34 (q, 2H).

[1142] LC-MS (method 1): R t = 0.82 min; m / z = 339 (M + H) + .

[1143] Example 83A

[1144] 5-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3,4-thiadiazole-2-carboxylic acid

[1145]

[1146] 1.52 g (4.49 mmol) of ethyl 5-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3,4-thiadiazole-2-carboxylate was dissolved in 8 mL of THF, 538 mg (22.45 mmol) of lithium hydroxide was added, and then 5 mL of water was added to the reaction solution. The reaction solution was then stirred at room temperature for several hours. After complete conversion, the reaction solution was adjusted to pH 7 with 1 N hydrochloric acid and concentrated to dryness on a rotary evaporator. This yielded 2.95 g of an amber oil, which was purified by column chromatography.

[1147] Condition: Separation was carried out using approximately 1 g portion. RP column Chromatorex C18, 10 μm; 125 x 30 mm, acetonitrile / water 10 / 90 → gradient for 38 min → acetonitrile / water 90 / 10 flow rate 75 ml / min.

[1148] Finally, the fractions containing the product were combined and concentrated to dryness under reduced pressure and dried. This gave 487 mg (1.57 mmol, 35% of theory) of the target compound as a white solid.

[1149] LC-MS (Method 1): R t = 0.39 min; m / z = 311 (M+H) + .

[1150] Example 84A

[1151] tert-Butyl rac-4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate

[1152]

[1153] To an initial charge of 5-azaspiro[2.5]octane hydrochloride (346 mg, 2.34 mmol) in 7 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (410 μl, 2.3 mmol), and the mixture was stirred for 5 min, then 4-oxoazepane-1-carboxylic acid tert-butyl ester (250 mg, 1.17 mmol) and acetic acid (100 μl, 1.8 mmol) were added. Then the mixture was stirred at room temperature for 5 h. After that, sodium triacetoxyborohydride (298 mg, 1.41 mmol) was added to the mixture and it was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution and water. The organic phase was passed through Na 2 SO 4Dry. Filter off the desiccant and concentrate the filtrate. Dissolve the residue in DMSO and purify by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5μm 100x30mm, eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile / water (80% v / v). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, head injection (full injection). Gradient profile: eluent A 0 - 2 min 70 ml, eluent B 0 - 2 min 0 ml, eluent A 2 - 10 min from 70 ml to 0 ml, eluent B from 0 ml to 70 ml, 10 - 12 min 0 ml, eluent A 70 ml, eluent B, eluent C and eluent D at a constant flow rate of 5 ml / min each throughout the run time). After removing the solvent, 140 mg (39% of theory) of the title compound was obtained.

[1154] LC-MS (method 4): MS (ESIpos): m / z = 309 [M+H] + 。

[1155] Example 85A

[1156] rac-5-(Azepan-4-yl)-5-azaspiro[2.5]octane hydrochloride

[1157]

[1158] Dissolve rac-4-(5-azaspiro[2.5]oct-5-yl)azepane-1-carboxylic acid tert-butyl ester (140 mg, 454 μmol) in 4 ml of dichloromethane, add hydrochloric acid in dioxane (570 μl, 4.0 M, 2.3 mmol), and stir the mixture at room temperature overnight. Concentrate the reaction mixture and dry the residue under high vacuum. 139 mg (125% of theory) of the target compound was obtained.

[1159] LC-MS (method 4): MS (ESIpos): m / z = 208 [M-HCl] + 。

[1160] Example 86A

[1161] diamix-4-(1,1-difluoro-5-azaspiro[2.5]oct-5-yl)azepane-1-carboxylic acid tert-butyl ester

[1162]

[1163] To the initial charge of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (500 mg, 2.72 mmol) in 10 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (470 μl, 2.7 mmol), and the mixture was stirred at room temperature for 5 minutes. Then tert-butyl 4-oxoazepane-1-carboxylate (290 mg, 1.36 mmol) and acetic acid (120 μl, 2.0 mmol) were added. The mixture was stirred at room temperature for 5 hours. Thereafter, sodium triacetoxyborohydride (346 mg, 1.63 mmol) was added to the mixture, and it was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution and water. The organic phase was dried over Na 2 SO 4 . The desiccant was filtered off, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm. Eluent A: water, Eluent B: acetonitrile, Eluent C: 2% formic acid in water, Eluent D: acetonitrile / water (80% v / v), total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, full injection. Gradient profile: Eluent A 70 ml from 0 - 2 minutes, Eluent B 0 ml from 0 - 2 minutes, Eluent A from 70 ml to 0 ml from 2 - 10 minutes, Eluent B from 0 ml to 70 ml, 0 ml of Eluent A and 70 ml of Eluent B from 10 - 12 minutes, Eluent C and Eluent D at a constant flow rate of 5 ml / min each throughout the run time). The fractions containing the product were combined and lyophilized. 292 mg (62% of theory) of the target compound was obtained.

[1164] LC-MS (method 4): MS (ESIpos): m / z = 345 [M+H] + .

[1165] Example 87A

[1166] diamix-5-(azepan-4-yl)-1,1-difluoro-5-azaspiro[2.5]octane dihydrochloride

[1167]

[1168] To a solution of diamix-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylic acid tert-butyl ester (292 mg, 848 μmol) in 8 ml of dichloromethane was added hydrochloric acid (1.1 ml, 4.0 M, 4.2 mmol) in dioxane, and the mixture was stirred overnight at room temperature. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum to afford 194 mg (72% of theory) of the target compound.

[1169] LC-MS (method 4): MS (ESIpos): m / z = 245 [M - 2HCl] + 。

[1170] Example 88A

[1171] diamix-(3R)-2',3-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester

[1172]

[1173] To (3R)-3-methylpiperidine hydrochloride (318 mg, 2.34 mmol) in 5.8 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (410 μl, 2.3 mmol), and the mixture was stirred at room temperature for 5 minutes, then rac-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.17 mmol) and acetic acid (100 μl, 1.8 mmol) were added. Subsequently, the mixture was stirred overnight at room temperature. Then sodium triacetoxyborohydride (298 mg, 1.41 mmol) was added to the mixture, and it was stirred for an additional 5 hours at room temperature. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution and water. The organic phase was dried over Na 2 SO 4 The desiccant was filtered off and the filtrate was concentrated. The residue (340 mg) was further transformed without analysis.

[1174] Example 89A

[1175] diamix-(3R)-2',3-dimethyl-1,4'-bipiperidine dihydrochloride

[1176]

[1177] Dissolve diamix-(3R)-2',3-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (340 mg, 1.15 mmol) in 16 ml of dichloromethane, add hydrochloric acid in dioxane (1.4 ml, 4.0 M, 5.7 mmol), and stir the mixture at room temperature for 5 hours. Concentrate the reaction mixture and dry the residue under high vacuum. The residue (290 mg) was further transformed without analysis.

[1178] Example 90A

[1179] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1180]

[1181] Add 1 g (2.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide to 40 ml of water and mix with 1.9 g (17.96 mmol) of sodium carbonate. Then, meteredly add 538 mg (3.29 mmol) of 3-ethylpiperidin-4-one hydrochloride to the reaction solution, and then stir at reflux temperature overnight. After cooling, extract the reaction mixture with dichloromethane. Wash the resulting organic phase with a sodium bicarbonate solution, separate and filter through a water-repellent filter (MN 616WA 1 / 4 fluted filter, D = 12.5 cm). Then concentrate the resulting filtrate on a rotary evaporator and dry under reduced pressure. Obtain 1.1 g (2.89 mmol, 97% of theory) of the target compound as an amorphous solid, which was separated into enantiomers by chiral preparative HPLC without further purification.

[1182] LC-MS (method 1): R t = 1.42 min; m / z = 381 (M+H) + .

[1183] Example 91A and Example 92A

[1184] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (enantiomers 1 and 2)

[1185]

[1186] 1 g (2.89 mmol) of racemic N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide was separated into enantiomers on a chiral phase by preparative HPLC [column: Daicel Chiralpak AY-H, 5 μm, 250 mm x 20 mm (SFC); eluent: CO2 / 2-propanol 55:45; pressure: 90 bar; flow rate: 95 g / min; UV detection: 210 nm; temperature: 40 °C]:

[1187] Example 91A (Enantiomer 1):

[1188] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1189] Yield: 487 mg

[1190] R t = 4.02 min; chemical purity > 99%; > 97% ee

[1191] [column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; eluent: CO 2 / ethanol) 90:10; flow rate: 3 ml / min; pressure: 130 bar; temperature: 40 °C; UV detection: 210 nm].

[1192] LC-MS (method 1): Rt = 1.41 min; m / z = 381 (M+H) + .

[1193] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.89 (t, 3H), 1.25 - 1.33 (m, 1H), 1.65 - 1.75 (m, 1H), 2.41 - 2.48 (1, 2H), 2.48 - 2.56 (m, 1H, partially masked by DMSO), 2.56 - 2.63 (m, 1H), 3.36 (dd, 1H), 3.60 - 3.67 (m, 1H), 3.96 - 4.04 (m, 1H), 4.05 - 4.11 (m, 1H), 4.55 (br.d, 2H), 7.87 - 7.94 (m, 2H), 7.93 8.47 (d, 1H), 8.76 (t, 1H).

[1194] [α]D 20 = -14.69° (c = 0.440, methanol).

[1195] Example 92A (Enantiomer 2):

[1196] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1197] Yield: 476 mg

[1198] R t = 5.98 min; Chemical purity > 99%; > 97% ee

[1199] [Column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; Eluent: CO 2 / ethanol) 90:10; Flow rate: 3 ml / min; Pressure: 130 bar; Temperature: 40 °C; UV detection: 210 nm].

[1200] LC-MS (Method 1): R t = 1.41 min; m / z = 381 (M+H) + .

[1201] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.89 (t, 3H), 1.25 - 1.33 (m, 1H), 1.65 - 1.75 (m, 1H), 2.42 - 2.48 (1, 2H), 2.48 - 2.56 (m, 1H, partially masked by DMSO), 2.55 - 2.63 (m, 1H), 3.36 (dd, 1H), 3.60 - 3.67 (m, 1H), 3.96 - 4.03 (m, 1H), 4.04 - 4.11 (m, 1H), 4.55 (br.d, 2H), 7.87 - 7.94 (m, 2H), 7.93 8.47 (d, 1H), 8.76 (t, 1H).

[1202] [α]D 20 = +11.64° (c = 0.435, methanol).

[1203] Example 93A

[1204] Diamix - cis-(3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[1205]

[1206] To the initial charge of (3R)-3-methylpiperidine hydrochloride (1000 mg, 4.04 mmol) in 25 ml of dichloromethane was added N,N-diisopropylethylamine (1.41 ml, 8.1 mmol), and the mixture was stirred at room temperature for 5 minutes, then rac-benzyl 3-methyl-4-oxopiperidine-1-carboxylate (1.1 g, 8.1 mmol) and acetic acid (0.35 ml, 6.1 mmol) were added. Then sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added to the mixture, and it was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO 3 solution and water. The organic phase was dried over Na 2 SO 4 The desiccant was filtered off and the filtrate was concentrated. The resulting residue was dissolved in a mixture of 18 ml of acetonitrile + MeOH and purified by preparative HPLC.

[1207] Method: Instrument: Waters Prep LC / MS system, Column: XBridge C18 5μm 100x30 mm.

[1208] Eluent A: water, Eluent B: acetonitrile, Eluent C: 1% ammonia in water; Total flow rate: 80 ml / min, 40 °C, wavelength 210 nm.

[1209] Gradient overview: Eluent A 0 to 4 min 25%, Eluent B 0 to 4 min 70%, Eluent C 0 to 4 min 5%. Eluent A 4 to 4.71 min 0%, Eluent B 4 to 4.71 min 95%, Eluent C 4 to 4.71 min 5%. Eluent A 4.71 to 4.78 min 25%, Eluent B 4.71 to 4.78 min 70%, Eluent C 4.71 to 4.78 min 5%.

[1210] After removal of the solvent, 716 mg (2.13 mmol, purity 98%, 53% of theory) of the title compound was obtained.

[1211] 1 H-NMR (600 MHz, DMSO-d 6, δ / ppm): 0.76 (d, 3H), 0.79 - 0.90 (m, 4H, including 0.82 (d, 3H)), 1.22 - 1.33 (m, 1H), 1.33 - 1.44 (m, 1H), 1.44 - 1.55 (m, 2H), 1.55 - 1.66 (m, 2H), 1.66 - 1.78 (m, 2H), 1.98 - 2.16 (m, 2H), 2.60 - 2.96 (m, 4H), 3.88 (br.d, 1H), 4.07 (br.d, 1H), 5.06 (S, 2H), 7.27 - 7.41 (m, 5H).

[1212] Example 94A and Example 95A

[1213] cis-(3R)-3,3'-Dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (diastereomers 1 and 2)

[1214]

[1215] 716 mg (2.17 mmol) of the cis-diastereomer mixture diamix-cis-(3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester was separated into cis-diastereomers 1 and 2 by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm x 20 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 15 ml / min; UV detection: 220 nm; temperature: 30 °C]:

[1216] Example 94A (cis-Diastereomer 1):

[1217] cis-(3R)-3,3'-Dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[1218] Yield: 287 mg

[1219] R t = 7.44 min; chemical purity > 99%; > 99% de

[1220] [column: Chiralpak AY-H, 5 μm, 250 mm x 4.6 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 1 ml / min;; temperature: 30 °C; UV detection: 220 nm].

[1221] LC-MS (method 1): R t = 1.02 min; m / z = 331 (M+H) + .

[1222] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 (d, 3H), 0.79 - 0.90 (m, 4H, including 0.82 (d, 3H)), 1.22 - 1.33 (m, 1H), 1.33 - 1.44 (m, 1H), 1.44 - 1.55 (m, 2H), 1.55 - 1.66 (m, 2H), 1.66 - 1.78 (m, 2H), 1.98 - 2.16 (m, 2H), 2.60 - 2.96 (m, 4H), 3.88 (br.d, 1H), 4.07 (br.d, 1H), 5.06 (S, 2H), 7.27 - 7.41 (m, 5H).

[1223] Example 95A (cis-Diastereomer 2):

[1224] cis-(3R)-3,3'-Dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester

[1225] Yield: 135 mg

[1226] R t = 8.06 min; Chemical purity > 99%; > 99% de

[1227] [Column: Chiralpak AY-H, 5 μm, 250 mm x 4.6 mm; Eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[1228] LC-MS (Method 1): R t = 1.02 min; m / z = 331 (M + H) + .

[1229] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 (d, 3H), 0.79 - 0.89 (m, 4H, including 0.83 (d, 3H)), 1.22 - 1.32 (m, 1H), 1.33 - 1.43 (m, 1H), 1.46 - 1.55 (m, 2H), 1.55 - 1.67 (m, 2H), 1.67 - 1.76 (m, 2H), 2.00 - 2.15 (m, 2H), 2.62 - 2.99 (m, 4H), 3.88 (br.d, 1H), 4.07 (br.d, 1H), 5.06 (S, 2H), 7.27 - 7.40 (m, 5H).

[1230] Example 96A

[1231] cis-(3R)-3,3'-Dimethyl-1,4'-bipiperidine dihydrobromide (diastereomer 1)

[1232]

[1233] Dissolve 280 mg (0.85 mmol) of cis-(3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (diastereomer 1; Example 94A) in 5 ml of HBr / acetic acid mixture while cooling with ice and stir at 0 °C for 15 minutes. Subsequently, remove the ice bath and stir the reaction mixture at room temperature for 2 hours. Mix the reaction mixture with diethyl ether and suction filter the formed precipitate, wash it repeatedly with diethyl ether and dry it under high vacuum. 260 mg (0.73 mmol, 86% of theory) of the title compound is obtained and is further transformed without further analysis.

[1234] Example 97A

[1235] cis-(3R)-3,3'-Dimethyl-1,4'-bipiperidine dihydrobromide (diastereomer 2)

[1236]

[1237] Dissolve 130 mg (0.39 mmol) of cis-(3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (diastereomer 2; Example 95A) in 3 ml of HBr / acetic acid mixture while cooling with ice and stir at 0 °C for 15 minutes. Subsequently, remove the ice bath and stir the reaction mixture at room temperature for 2 hours. Mix the reaction mixture with diethyl ether and suction filter the formed precipitate, wash it repeatedly with diethyl ether and dry it under high vacuum. 124 mg (0.35 mmol, 88% of theory) of the title compound is obtained and is further transformed without further analysis.

[1238] Working examples:

[1239] Example 1

[1240] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxamide

[1241]

[1242] 13 g (38.91 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 8.51 g (38.91 mmol) of (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (Example 1A of WO2015091420; CAS Registry No. 1799475-27-6) and 20.62 g (194.53 mmol) of sodium carbonate were heated to 120 °C in 200 ml of water and stirred overnight at this temperature. After the reaction mixture was cooled, the solution was extracted with ethyl acetate. The separated organic phase was then filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness on a rotary evaporator. The resulting residue was placed in acetonitrile, heated to 80 °C and slowly cooled back to room temperature with stirring. The precipitated solid was filtered off with suction and washed with acetonitrile. Then the residue was placed in acetonitrile again and recrystallized once more. This gave 10.75 g (24.68 mmol, 63% of theory) of the target compound as a light beige solid. The two mother liquors were combined and concentrated to dryness on a rotary evaporator. The resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column mobile phase: dichloromethane → gradient 20 CV (CV = column volume) → dichloromethane / methanol 9:1). Then the resulting product fractions were combined, concentrated on a rotary evaporator and recrystallized from acetonitrile. This gave an additional 3.28 g (7.48 mmol, 19% of theory) of the target compound as a light beige solid.

[1243] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 - 0.86 (m, 4H, including at 0.82 (d, 3H)), 1.34 - 1.66 (m, 6H), 1.71 - 1.81 (m, 3H), 2.01 - 2.09 (m, 1H), 2.44 - 2.56 (m, 1H, partially masked by DMSO), 2.69 - 2.77 (m, 2H), 3.04 (td, 2H), 3.93 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.88 - 7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1244] LC-MS (method 4): R t = 0.50 min; m / z = 436 (M + H) + .

[1245] [α] D 20= -8.06° (c = 0.430, methanol).

[1246] Example 2

[1247] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1248]

[1249] 60 mg (0.18 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 51 mg (0.18 mmol) of 2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride and 95 mg (0.9 mmol) of sodium carbonate were heated to 160 °C in 1 ml of water in a sealed vessel and stirred at this temperature for 30 minutes. After the reaction mixture was cooled, water was added and the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness on a rotary evaporator. The resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column mobile phase: ethyl acetate → gradient 5 CV (CV = column volume) → ethyl acetate / methanol 95:5). The resulting product fractions were then combined and concentrated to dryness on a rotary evaporator. This gave 62.7 mg (0.13 mmol, 74% of theory) of the target compound as a yellow solid.

[1250] 1 1H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 1.55 - 1.65 (m, 2H), 1.86 - 1.94 (m, 2H), 2.67 - 2.73 (m, 1H), 2.73 - 2.81 (m, 4H), 3.12 (br.t, 2H), 3.70 (s, 2H), 3.97 (br.d, 2H), 4.53 (br.d, 2H), 7.01 - 7.12 (m, 4H), 7.85 (s, 1H), 7.93 (td, 1H), 8.48 (d, 1H), 8.76 (t, 1H).

[1251] LC-MS (method 1): R t = 0.97 min; m / z = 470 (M + H) + .

[1252] Example 3

[1253] 2-[3-(Cyclopropylmethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemate)

[1254]

[1255] 32 mg (0.10 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 22 mg (0.10 mmol) of 3-(cyclopropylmethyl)-1,4'-bipiperidine (racemate) and 31 mg (0.29 mmol) of sodium carbonate were heated to 120 °C in a sealed vessel in 1 ml of water and stirred at this temperature for 30 minutes. After the reaction mixture had cooled, the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness on a rotary evaporator. The resulting residue was purified by the following method.

[1256] Method 7: Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100 x 30 mm

[1257] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the head of the column (full injection)

[1258] Gradient overview: Mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml from 2 to 10 min, 0 ml of mobile phase A and 70 ml of mobile phase B from 10 to 12 min. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1259] This gave 40.8 mg (0.09 mmol, 88% of theory) of the target compound in the form of a white lyophilizate.

[1260] 1 H-NMR (400 MHz, DMSO-d 6, δ / ppm): -0.07 - 0.03 (m, 2H), 0.34 - 0.43 (m, 2H), 0.60 - 0.73 (m, 1H), 0.80 - 0.94 (m, 1H), 0.99 - 1.14 (m, 2H), 1.32 - 1.65 (m, 5H), 1.68 - 1.91 (m, 4H), 2.02 - 2.14 (m, 1H), 2.44 - 2.59 (m, 1H, partially masked by DMSO), 2.73 (br.d, 1H), 2.83 (br.d, 1H), 3.04 (br.t, 2H), 3.94 (br.d, 2H), 4.52 (br.d, 2H), 7.83 (S, 1H), 7.87 - 7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1261] LC-MS (Method 1): R t = 1.13 min; m / z = 476 (M + H) + .

[1262] Similar to Examples 1 to 3, prepared from the starting materials described in each case Examples 4 to 14 the following compounds:

[1263]

[1264]

[1265]

[1266]

[1267]

[1268] Example 15

[1269] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-methoxy[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1270]

[1271] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide was dissolved in 5 ml of dichloromethane, and 65 mg (0.57 mmol) of (3R)-3-methoxypiperidine and 24 μl (0.43 mmol) of glacial acetic acid were added. Then, 72 mg (0.34 mmol) of sodium triacetoxyborohydride was added portionwise, and the reaction solution was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1272] Method 8:

[1273] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5 μm 100 x 30 mm

[1274] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the head of the column (full injection)

[1275] Gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1276] This gave 62 mg (0.14 mmol, 48% of theory) of the target compound as a white lyophilizate.

[1277] 1 H-NMR (600 MHz, DMSO-d 6, δ / ppm): 1.00 - 1.11 (m, 1H), 1.30 - 1.40 (m, 1H), 1.43 - 1.54 (m, 2H), 1.59 - 1.66 (m, 1H), 1.77 (br.d, 2H), 1.86 - 1.93 (m, 1H), 1.98 (t, 1H), 2.11 (t, 1H), 2.47 - 2.58 (m, 1H, partially masked by DMSO), 2.64 (br.d, 1H), 2.94 (br.d, 1H), 3.04 (br.t, 2H), 3.12 - 3.19 (m, 1H), 3.23 (S, 3H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.91 (td, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1278] LC-MS (Method 1): R t = 0.83 min; m / z = 452 (M + H) + .

[1279] Example 16

[1280] 2-[3-(Difluoromethoxy)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemate)

[1281]

[1282] Dissolve 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide in 5 ml of dichloromethane, and add 86 mg (0.57 mmol) of 3-(difluoromethoxy)piperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid. Then, add 72 mg (0.34 mmol) of sodium triacetoxyborohydride portionwise, and then stir the reaction solution at room temperature overnight. Subsequently, dilute the reaction mixture with dichloromethane and wash it with sodium bicarbonate solution. Finally, separate the organic phase, and then filter the resulting organic solution through a hydrophobic filter (folded filter MN616WA 1 / 4, D = 12.5 cm), dry it, and concentrate it to dryness under reduced pressure. The resulting residue was purified by the following method.

[1283] Method 9:

[1284] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30 mm

[1285] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min, at room temperature, wavelength 200 - 400 nm, injection at the column head (complete injection).

[1286] Gradient overview: For mobile phase A, from 0 to 2 min is 55 ml, for mobile phase B, from 0 to 2 min is 15 ml; for mobile phase A, from 2 to 10 min it changes from 55 ml to 31 ml and for mobile phase B from 15 ml to 39 ml; from 10 to 12 min, 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D each have a constant flow rate of 5 ml / min throughout the run time.

[1287] This produced 60 mg (0.12 mmol, 44% of the theoretical value) of the target compound as a white lyophilized product.

[1288] 1 1H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 1.27 - 1.36 (m, 1H), 1.36 - 1.53 (m, 3H), 1.62 - 1.69 (m, 1H), 1.73 - 1.81 (m, 2H), 1.85 - 1.93 (m, 1H), 2.13 - 2.25 (m, 2H), 2.54 - 2.67 (m, 2H), 2.90 (br.d, 1H), 3.05 (br.t, 2H), 3.94 (br.d, 2H), 4.01 - 4.08 (m, 1H), 4.53 (d, 2H), 6.57 - 6.88 (m, 1H), 7.83 (S, 1H), 7.91 (t, 1H), 8.47 (d, 1H), 8.72 (t, 1H).

[1289] LC-MS (method 1): R t = 0.91 min; m / z = 488 (M + H) + .

[1290] Example 17

[1291] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl[1,4'-bipiperidin]-1'-yl)-1,3-thiazole-5-carboxamide (racemate)

[1292]

[1293] Dissolve 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide in 5 ml of dichloromethane, and add 64 mg (0.57 mmol) of 3-ethylpiperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid. Then, add 72 mg (0.34 mmol) of sodium triacetoxyborohydride portionwise, and stir the reaction solution at room temperature overnight. Subsequently, dilute the reaction mixture with dichloromethane and wash it with sodium bicarbonate solution. Finally, separate the organic phase, and filter the resulting organic solution through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dry it, and concentrate it to dryness under reduced pressure. The resulting residue was purified by the following method.

[1294] Method 7:

[1295] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5 μm 100 x 30 mm

[1296] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the head of the column (full injection)

[1297] Gradient overview: Mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D each have a constant flow rate of 5 ml / min throughout the run time.

[1298] This gave 46 mg (0.10 mmol, 36% of theory) of the target compound as a white lyophilized product.

[1299] 1 H-NMR (600 MHz, DMSO-d 6, δ / ppm): 0.76 - 0.87 (m, 4H, including 0.85 (t, 3H)), 1.09 - 1.25 (m, 2H), 1.26 - 1.34 (m, 1H), 1.34 - 1.43 (m, 1H), 1.44 - 1.53 (m, 2H), 1.55 - 1.62 (m, 1H), 1.65 - 1.71 (m, 1H), 1.73 - 1.83 (m, 3H), 2.08 (br.t 1H), 2.46 - 2.56 (m, 1H, partially masked by DMSO), 2.70 - 2.79 (m, 2H), 3.04 (br.t, 2H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 7.82 (S, 1H), 7.89 (br.t, 1H), 8.46 (d, 1H), 8.67 (t, 1H).

[1300] LC-MS (Method 1): R t = 0.99 min; m / z = 450 (M + H) + .

[1301] Example 18

[1302] 2-[(3R)-3-Methyl[1,4'-bipiperidin]-1'-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-5-carboxamide

[1303]

[1304] 0.46 ml (2.62 mmol) of N,N-diisopropylethylamine was added to 200 mg (0.52 mmol) of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 122 mg (0.58 mmol) of 1-[4-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (1:1) in 20 ml of acetonitrile, and then a solution of 0.34 ml (0.58 mmol) of 50% strength T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide) in ethyl acetate was added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred overnight at room temperature. Then the reaction mixture was extracted with water and dichloromethane. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1305] Method 7:

[1306] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30 mm

[1307] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, at room temperature, wavelength 200 - 400 nm, injection at the head of the column (complete injection)

[1308] Gradient profile: For mobile phase A, 47 ml from 0 to 2 min, for mobile phase B, 23 ml from 0 to 2 min. For mobile phase A, from 47 ml to 23 ml and for mobile phase B from 23 ml to 47 ml from 2 to 10 min. 0 ml of mobile phase A and 70 ml of mobile phase B from 10 to 12 min. Mobile phase C and mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time.

[1309] This yielded 55 mg (0.12 mmol, 23% of theory) of the target compound as a white lyophilized solid.

[1310] 1 1H-NMR (400 MHz, DMSO-d 6 , δ / ppm): 0.74 - 0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34 - 1.68 (m, 6H), 1.70 - 1.84 (m, 3H), 1.99 - 2.11 (m, 1H), 2.44 - 2.58 (m, 1H, partially masked by DMSO), 2.69 - 2.80 (m, 2H), 3.06 (td, 2H), 3.95 (br.d, 2H), 4.59 (d, 2H), 7.62 (S, 1H), 7.67 (d, 1H), 7.87 (S, 1H), 8.81 (d, 1H), 8.89 (t, 1H).

[1311] LC-MS (method 1): R t = 1.05 min; m / z = 469 (M+H) + .

[1312] Example 19

[1313] 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[1314]

[1315] Dissolve 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride in 10 ml of dichloromethane, add 56 mg (0.42 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-amine, and stir the mixture at room temperature for 30 minutes. Subsequently, 60 μl of pyridine and then 46 mg (0.26 mmol) of 1-[3-(trifluoromethyl)phenyl]methanamine were metered into the reaction solution, and the mixture was stirred at room temperature overnight. After adding water, the resulting precipitate was filtered off by suction. The resulting biphasic filtrate was separated, and the resulting organic phase was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1316] Method 11:

[1317] Apparatus: Abimed Gilson 305; Column: Reprosil C18 10 μm, 250 mm x 30 mm; Mobile phase A: water, Mobile phase 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 rate: 50 ml / min; Room temperature; UV detection: 210 nm.

[1318] This gave 45 mg (0.10 mmol, 37% of theory) of the target compound.

[1319] 1 1H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.78 - 0.91 (m, 4H, including at 0.83 (d, 3H)), 1.37 - 1.69 (m, 6H), 1.73 - 1.94 (m, 3H), 2.05 - 2.23 (m, 1H), 2.56 - 2.67 (m, 1H), 2.73 - 2.90 (m, 2H), 3.06 (br.t, 2H), 3.96 (br.d, 2H), 4.48 (d, 2H), 7.54 - 7.65 (m, 4H), 7.84 (s, 1H), 8.84 (t, 1H).

[1320] LC-MS (Method 1): Rt = 1.31 min; m / z = 467 (M + H) + .

[1321] Example 20

[1322] N-[(3-Fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1323]

[1324] 0.18 mL (1.05 mmol) of N,N-diisopropylethylamine was added to 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 47 mg (0.29 mmol) of 1-(3-fluoropyridin-2-yl)methanamine hydrochloride (1:1) in 10 mL of acetonitrile, and then a solution of 0.17 mL (0.29 mmol) of 50% strength T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred overnight at room temperature. The reaction mixture was then extracted with water and dichloromethane. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1325] Method 9:

[1326] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5 μm 100 x 30 mm

[1327] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 mL / min, room temperature, wavelength 200 - 400 nm, injection at the head of the column (full injection)

[1328] Gradient overview: Mobile phase A 0 to 2 min 55 mL, mobile phase B 0 to 2 min 15 mL, mobile phase A from 55 mL to 31 mL and mobile phase B from 15 mL to 39 mL from 2 to 10 min, 0 mL of mobile phase A and 70 mL of mobile phase B from 10 to 12 min. Mobile phase C and mobile phase D each had a constant flow rate of 5 mL / min throughout the run time.

[1329] This produced 5.4 mg (0.01 mmol, 5% of theory) of the target compound as a white lyophilized product.

[1330] 1 H-NMR (400 MHz, DMSO-d 6, δ / ppm): 0.75 - 0.89 (m, 4H, including 0.82 (d, 3H)), 1.33 - 1.68 (m, 6H), 1.71 - 1.83 (m, 3H), 2.05 (br.t, 1H), 2.44 - 2.58 (m, 1H, partially masked by DMSO), 2.69 - 2.80 (m, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.56 (dd, 2H), 7.36 - 7.43 (m, 1H), 7.64 - 7.72 (m, 1H), 7.84 (S, 1H), 8.38 (dt, 1H), 8.69 (t, 1H).

[1331] LC-MS (Method 4): Rt = 0.48 min; m / z = 418 (M + H) + .

[1332] Example 21

[1333] N-(5-Chloro-2-fluorobenzyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1334]

[1335] 0.18 ml (1.05 mmol) of N,N-diisopropylethylamine was added to 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 46 mg (0.29 mmol) of 1-(5-chloro-2-fluorophenyl)methanamine in 10 ml of acetonitrile, and then a solution of 0.17 ml (0.29 mmol) of 50% strength T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred overnight at room temperature. Then the reaction mixture was extracted with water and dichloromethane. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1336] Method 7:

[1337] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30 mm

[1338] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, at room temperature, wavelength 200 - 400 nm, injection at the column head (complete injection).

[1339] Gradient overview: For mobile phase A, 47 ml from 0 to 2 min, for mobile phase B, 23 ml from 0 to 2 min. For mobile phase A, from 47 ml to 23 ml and for mobile phase B from 23 ml to 47 ml from 2 to 10 min. 0 ml of mobile phase A and 70 ml of mobile phase B from 10 to 12 min. Mobile phase C and mobile phase D each have a constant flow rate of 5 ml / min throughout the run time.

[1340] This produced 45 mg of a mixture further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column; mobile phase: cyclohexane / ethyl acetate 8:2 → gradient 15 CV (CV = column volume) → cyclohexane / ethyl acetate 2:8). This produced 16 mg (0.04 mmol, 14% of the theoretical value) of the target compound as a beige solid.

[1341] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 - 0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35 - 1.67 (m, 6H), 1.72 - 1.82 (m, 3H), 2.05 (br.t, 1H), 2.45 - 2.57 (m, 1H, partially masked by DMSO), 2.74 (br.t, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.41 (d, 2H), 7.26 (t, 1H), 7.33 - 7.40 (m, 2H), 7.85 (S, 1H), 8.76 (t, 1H).

[1342] LC-MS (method 4): R t = 0.68 min; m / z = 451 / 453 (M+H) + .

[1343] Example 22

[1344] 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[1345]

[1346] 0.22 ml (1.23 mmol) of N,N-diisopropylethylamine was added to 200 mg (0.31 mmol, purity 59%) of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 59 mg (0.34 mmol) of 1-[4-(trifluoromethyl)phenyl]methanamine in 10 ml of acetonitrile. Then, a solution of 0.2 ml (0.34 mmol) of 50% strength T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred overnight at room temperature. The reaction mixture was then extracted with water and dichloromethane. Finally, the organic phase was separated, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1347] Method 10:

[1348] Apparatus: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30 mm

[1349] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%). Total flow rate: 80 ml / min, room temperature, wavelength 200 - 400 nm, injection at the head of the column (full injection)

[1350] Gradient overview: Mobile phase A from 0 to 2 min 39 ml, mobile phase B from 0 to 2 min 31 ml, mobile phase A from 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1351] This yielded 25 mg (0.05 mmol, 17% of theory) of the target compound as a white lyophilizate.

[1352] 1 H-NMR (400 MHz, DMSO-d 6, δ / ppm): 0.74 - 0.89 (m, 4H, including 0.82 (d, 3H)), 1.33 - 1.68 (m, 6H), 1.71 - 1.83 (m, 3H), 2.00 - 2.10 (m, 1H), 2.45 - 2.57 (m, 1H, partially masked by DMSO), 2.70 - 2.79 (m, 2H), 3.06 (td, 2H), 3.94 (br.d, 2H), 4.47 (d, 2H), 7.50 (d, 2H), 7.70 (d, 2H), 7.84 (S, 1H), 8.83 (t, 1H).

[1353] LC-MS (Method 1): R t = 1.27 min; m / z = 467 (M + H) + .

[1354] Similar to Examples 18 to 22, prepared from the starting materials described in each case Examples 23 to 37 of the following compounds:

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361] Example 38 and Example 39

[1362] 2-[3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (enantiomers 1 and 2)

[1363]

[1364] 203 mg (0.43 mmol) of racemic 2-[3-(difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 4) was separated into enantiomers on a chiral phase by preparative HPLC [column: Daicel Chiralpak AY-H, 5 μm, 250 mm x 20 mm; mobile phase: 2-propanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 40 °C]:

[1365] Example 38 (Enantiomer 1):

[1366] 2-[(3S)-3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1367]

[1368] Yield: 97 mg

[1369] Rt = 4.93 min; chemical purity > 99%; > 99% ee

[1370] [Column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; mobile phase: isohexane / 2-propanol + 0.2% diethylamine 20:80; flow rate: 1 ml / min; temperature: 25 °C; UV detection: 220 nm].

[1371] LC-MS (Method 5): Rt = 1.52 min; m / z = 472 (M+H) + .

[1372] Example 39 (Enantiomer 2):

[1373] 2-[(3R)-3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1374]

[1375] Yield: 101 mg

[1376] R t t = 6.03 min; chemical purity > 96%; > 94% ee

[1377] [Column: Chiraltek AY-3, 3μm, 100mm x 4.6mm; Mobile phase: Isohexane / 2-propanol + 0.2% diethylamine 20:80; Flow rate: 1ml / min; Temperature: 25°C; UV detection: 220nm].

[1378] LC-MS (Method 5): R t = 1.52 min; m / z = 472 (M+H) + .

[1379] 1 H-NMR (600MHz, DMSO-d 6 , δ / ppm): 1.11 - 1.22 (m, 1H), 1.37 - 1.54 (m, 3H), 1.62 - 1.72 (m, 2H), 1.73 - 1.81 (m, 2H), 1.88 - 1.99 (m, 1H), 2.10 - 2.21 (m, 2H), 2.47 - 2.60 (m, 1H, partially masked by DMSO), 2.72 (br.d, 1H), 2.79 (br.d, 1H), 3.05 (br.t, 2H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 5.82 - 6.06 (m, 1H), 7.84 (S, 1H), 7.93 (td, 1H), 8.47 (d, 1H), 8.75 (t, 1H).

[1380] Example 40 and Example 41

[1381] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (enantiomers 1 and 2)

[1382]

[1383] 144 mg (0.32 mmol) of racemic N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (Example 6) was separated into enantiomers by preparative HPLC on a chiral phase [Column: Daicel Chiralpak IG, 5μm, 250mm x 20mm; Mobile phase: Ethanol; Flow rate: 15ml / min; UV detection: 220nm; Temperature: 70°C]:

[1384] Example 40 (Enantiomer 1):

[1385] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3S)-3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1386]

[1387] Yield: 71 mg

[1388] R t = 10.94 min; Chemical purity 99%; 99% ee

[1389] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; Mobile phase: ethanol + 0.2% diethylamine; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[1390] LC-MS (Method 1): R t = 0.85 min; m / z = 454 (M+H) + .

[1391] Example 41 (Enantiomer 2):

[1392] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1393]

[1394] Yield: 70 mg

[1395] R t = 12.21 min; Chemical purity 99%; 99% ee

[1396] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; Mobile phase: ethanol + 0.2% diethylamine; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[1397] LC-MS (Method 1): R t = 0.84 min; m / z = 454 (M+H) + .

[1398] 1 H-NMR (400 MHz, DMSO-d 6, δ / ppm): 0.94 - 1.10 (m, 1H), 1.35 - 1.55 (m, 3H), 1.61 (br.d, 2H), 1.72 - 1.92 (m, 3H), 2.03 (t, 1H), 2.16 (br.t, 1H), 2.47 - 2.57 (m, 1H, partially masked by DMSO), 2.65 - 2.76 (m, 1H), 2.80 (br.d, 1H), 3.05 (br.t, 2H), 3.94 (br.d, 2H), 4.19 - 4.29 (m, 1H), 4.31 - 4.41 (m, 1H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.87 - 7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1399] Example 42 and Example 43

[1400] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (enantiomers 1 and 2)

[1401]

[1402] 143 mg (0.29 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (Example 5) was separated into enantiomers by preparative HPLC on a chiral phase [Column: Daicel Chiralpak IG, 5 μm, 250 mm x 20 mm; Mobile phase: ethanol; Flow rate: 15 ml / min; UV detection: 220 nm; Temperature: 40 °C]:

[1403] Example 42 (Enantiomer 1):

[1404] N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3S)-3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1405]

[1406] Yield: 67 mg

[1407] Rt = 11.22 min; Chemical purity 99%; 99% ee

[1408] [Column: Daicel Chiralcel IG, 5μm, 250mm x 4.6mm; Mobile phase: ethanol + 0.2% diethylamine; Flow rate: 1ml / min; Temperature: 50°C; UV detection: 235nm].

[1409] LC-MS (Method 1): R t = 0.97 min; m / z = 490 (M+H) + .

[1410] Example 43 (Enantiomer 2):

[1411] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1412]

[1413] Yield: 67mg

[1414] R t = 11.87 min; Chemical purity 99%; >96% ee

[1415] [Column: Daicel Chiralcel IG, 5μm, 250mm x 4.6mm; Mobile phase: ethanol + 0.2% diethylamine; Flow rate: 1ml / min; Temperature: 50°C; UV detection: 235nm].

[1416] LC-MS (Method 1): R t = 0.96 min; m / z = 490 (M+H) + .

[1417] 1 H-NMR (500MHz, DMSO-d 6 , δ / ppm): 1.14 - 1.27 (m, 1H), 1.39 - 1.57 (m, 3H), 1.65 - 1.73 (m, 1H), 1.74 - 1.82 (m, 2H), 1.82 - 1.88 (m, 1H), 2.06 - 2.20 (m, 2H), 2.32 - 2.44 (m, 1H), 2.61 (br.t, 1H), 2.81 (br.d, 1H), 2.96 (br.d, 1H), 3.05 (td, 2H), 3.95 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.88 - 7.94 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1418] Example 44 and Example 45

[1419] 2-{3-[(3,3-Difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (enantiomers 1 and 2)

[1420]

[1421] 251 mg (0.46 mmol) of 2-{3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 7) was separated into enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OD-H, 5 μm, 250 mm x 20 mm; mobile phase: n-heptane / 2-propanol + 0.2% diethylamine 50:50; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 30 °C]:

[1422] Example 44 (Enantiomer 1):

[1423] 2-{(3R)-3-[(3,3-Difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1424]

[1425] Yield: 93 mg

[1426] R t = 1.50 min; chemical purity > 99%; 99% ee

[1427] [column: Phenomenex Cellulose-1, 3 μm, 50 mm x 4.6 mm; mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); flow rate: 1 ml / min; temperature: 25 °C; UV detection: 220 nm].

[1428] LC-MS (method 4): R t = 0.63 min; m / z = 542 (M+H) + .

[1429] Example 45 (Enantiomer 2):

[1430] 2-{(3S)-3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1431]

[1432] Yield: 86 mg

[1433] R t = 2.21 min; Chemical purity > 99%; 99% ee

[1434] [Column: Phenomenex Cellulose-1, 3 μm, 50 mm x 4.6 mm; Mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); Flow rate: 1 ml / min; Temperature: 25 °C; UV detection: 220 nm].

[1435] LC-MS (Method 4): Rt = 0.62 min; m / z = 542 (M+H) + 。

[1436] 1 H-NMR (400 MHz, DMSO-d 6 , δ / ppm): 1.02 - 1.12 (m, 1H), 1.30 - 1.42 (m, 1H), 1.42 - 1.56 (m, 2H), 1.58 - 1.68 (m, 1H), 1.72 - 1.83 (m, 2H), 1.85 - 1.94 (m, 1H), 1.99 (br.t, 1H), 2.10 (br.t, 1H), 2.21 - 2.38 (m, 3H), 2.48 - 2.62 (m, 3H, partially masked by DMSO), 2.62 - 2.70 (m, 1H), 2.95 (br.d, 1H), 3.04 (br.t, 2H), 3.22 - 3.34 (m, 1H, partially masked by H 2 O masked), 3.40 - 3.51 (m, 2H), 3.95 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.87 - 7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1437] Examples 46 and 47

[1438] N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (diastereomers 1 and 2)

[1439]

[1440] 51 mg (0.11 mmol) of the diastereoisomer mixture N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (Example 30) was separated into the diastereoisomers by preparative HPLC in the chiral phase [column: Daicel Chiralcel OX-H 5 μm, 250 mm x 20 mm; mobile phase: heptane / ethanol 50:50; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 40 °C]:

[1441] Example 46 (Diastereomer 1):

[1442] Yield: 20 mg

[1443] R t = 1.32 min; chemical purity > 99%; 99% ee

[1444] [column: Daicel Chiralpak OX-3, 3 μm, 50 mm x 4.6 mm; mobile phase: heptane / ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 25 °C; UV detection: 220 nm].

[1445] LC-MS (method 1): R t = 1.22 min; m / z = 449 (M+H) + .

[1446] 1 1H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 - 0.87 (m, 4H, including at 0.82 (d, 3H)), 1.34 - 1.66 (m, 9H, including at 1.42 (d, 3H)), 1.70 - 1.84 (m, 3H), 2.00 - 2.12 (m, 1H), 2.44 - 2.56 (m, 1H, partially masked by DMSO), 2.68 - 2.80 (m, 2H), 3.00 - 3.09 (m, 2H), 3.95 (br.t, 2H), 5.21 - 5.29 (m, 1H), 7.09 - 7.16 (m, 1H), 7.19 - 7.25 (m, 2H), 7.92 (S, 1H), 8.56 (d, 1H).

[1447] Example 47 (Diastereomer 2):

[1448] Yield: 19 mg

[1449] R t= 1.78 min; Chemical purity > 99%; 99% ee

[1450] [Column: Daicel Chiralpak OX-3, 3 μm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine; Flow rate: 1 ml / min; Temperature: 25 °C; UV detection: 220 nm].

[1451] LC-MS (Method 1): R t = 1.19 min; m / z = 449 (M+H) + 。

[1452] 1 H-NMR (600 MHz, DMSO-d 6 , δ / ppm): 0.76 - 0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34 - 1.67 (m, 9H, including at 1.42 (d, 3H)), 1.72 - 1.84 (m, 3H), 2.00 - 2.12 (m, 1H), 2.44 - 2.60 (m, 1H, partially masked by DMSO), 2.69 - 2.81 (m, 2H), 3.05 (br.t, 2H), 3.89 - 4.00 (m, 2H), 5.21 - 5.29 (m, 1H), 7.09 - 7.16 (m, 1H), 7.18 - 7.26 (m, 2H), 7.92 (S, 1H), 8.56 (d, 1H).

[1453] Example 48

[1454] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1455]

[1456] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (124 mg, 370 μmol) and rac-3-(methoxymethyl)-1,4'-bipiperidine dihydrochloride (123 mg, purity 75%, 285 μmol) were combined and stirred at 120 °C in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4.0 mmol) for 1 hour. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run). The fractions containing the product were combined and lyophilized. This gave 60.0 mg (purity 100%, 35% of theory) of the target compound.

[1457] LC-MS (method 4): Rt = 0.51 min; MS (ESIpos): m / z = 466 [M+H] + 。

[1458] 1 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.903(0.47), 0.918(0.53), 1.389(0.42), 1.409(0.44), 1.432(0.44), 1.445(0.53), 1.452(0.88), 1.460(0.62), 1.465(0.64), 1.472(0.94), 1.480(0.56), 1.578(1.12), 1.596(1.00), 1.716(0.49), 1.755(1.11), 1.774(0.96), 1.878(0.66), 1.895(1.06), 1.912(0.56), 2.091(0.43), 2.106(0.78), 2.109(0.78), 2.124(0.42), 2.483(0.43), 2.520(0.42), 2.706(0.61), 2.724(0.57), 2.795(0.63), 2.809(0.61), 3.018(0.74), 3.023(0.88), 3.040(1.54), 3.043(1.52), 3.060(0.87), 3.064(0.76), 3.129(0.51), 3.144(1.48), 3.157(1.78), 3.159(1.83), 3.169(1.56), 3.175(0.63), 3.184(0.52), 3.200(16.00), 3.920(1.12), 3.941(1.06), 4.521(2.22), 4.530(2.22), 7.828(5.37), 7.893(0.59), 7.897(0.63), 7.910(0.90), 7.913(0.94), 7.925(0.60), 7.929(0.62), 8.465(2.32), 8.468(2.28), 8.701(0.73), 8.710(1.47), 8.720(0.71).

[1459] Example 49

[1460] N-[(3,5-difluoropyridin-2-yl)methyl]-3-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,2,4-oxadiazole-5-carboxamide

[1461]

[1462] N,N-Diisopropylethylamine (44 μl, 250 mmol) and propylphosphonic anhydride (66 μl, 50% in ethyl acetate, 110 μmol) were added to a solution of 3-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,2,4-oxadiazole-5-carboxylic acid (25.0 mg, 84.9 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (24.0 mg, 110 μmol) in 1 ml of acetonitrile, and the mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 7.00 mg (purity 100%, 20% of theory) of the target compound.

[1463] LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 421 [M+H] + 。

[1464] 1 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.780(0.59), 0.786(0.66), 0.813(14.94), 0.824(16.00), 0.841(0.69), 0.847(0.57), 1.370(0.56), 1.377(0.45), 1.391(1.47), 1.411(1.58), 1.431(1.38), 1.437(1.22), 1.457(2.49), 1.472(2.70), 1.493(1.64), 1.498(1.66), 1.510(1.34), 1.516(1.25), 1.522(1.29), 1.527(1.13), 1.567(1.91), 1.583(1.19), 1.588(1.52), 1.618(1.61), 1.639(1.55), 1.744(2.47), 1.760(5.97), 1.778(4.64), 2.040(1.21), 2.055(2.23), 2.074(1.19), 2.449(1.19), 2.467(2.20), 2.487(1.30), 2.732(2.07), 2.746(3.74), 2.763(1.77), 2.931(2.53), 2.949(4.76), 2.969(2.54), 3.905(3.81), 3.927(3.64), 4.586(6.49), 4.596(6.41), 7.930(1.47), 7.934(1.53), 7.949(2.60), 7.962(1.51), 7.966(1.50), 8.476(5.87), 8.479(5.69), 9.631(1.76), 9.641(3.44), 9.651(1.75).

[1465] Example 50

[1466] diamix - N - [(3,5 - difluoropyridin - 2 - yl)methyl] - 2 - [(3R) - 3'-fluoro - 3 - methyl[1,4'-bipiperidin] - 1'-yl] - 1,3 - thiazole - 5 - carboxamide

[1467]

[1468] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 μmol) and diamix-(3R)-3'-fluoro-3-methyl-1,4'-bipiperidine dihydrochloride (142 mg, 519 μmol) were combined and stirred in 1.2 ml of sodium carbonate solution (1.2 ml, 2.0 M, 2.4 mmol) at 120 °C for 30 minutes. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This yielded 192 mg (purity 100%, 70% of theory) of the target compound.

[1469] LC-MS (method 4): R t = 0.54 min; MS (ESIpos): m / z = 454 [M+H] + 。

[1470] 1 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.807 (8.04), 0.818 (8.54), 0.823 (9.19), 0.833 (9.26), 0.845 (1.26), 0.851 (1.27), 0.865 (0.57), 0.872 (0.48), 1.375 (0.72), 1.396 (0.88), 1.425 (0.72), 1.513 (0.76), 1.524 (0.78), 1.550 (1.22), 1.572 (1.24), 1.578 (1.30), 1.600 (1.01), 1.624 (1.99), 1.639 (1.94), 1.647 (1.92), 1.795 (1.24), 1.817 (0.99), 1.923 (0.96), 1.932 (0.79), 1.940 (1.73), 1.948 (1.32), 1.958 (1.00), 1.964 (0.66), 2.226 (1.04), 2.245 (1.98), 2.264 (1.01), 2.424 (0.59), 2.653 (0.51), 2.730 (2.22), 2.744 (2.48), 2.801 (1.20), 2.813 (1.28), 3.129 (1.00), 3.134 (1.13), 3.154 (1.85), 3.169 (1.17), 3.214 (0.84), 3.226 (1.61), 3.235 (1.14), 3.247 (1.52), 3.261 (0.83), 3.286 (0.43), 3.705 (1.26), 3.726 (1.18), 4.117 (0.76), 4.123 (0.88), 4.136 (1.42), 4.144 (1.43), 4.156 (0.80), 4.162 (0.74), 4.527 (5.54), 4.536 (5.52), 4.691 (0.60), 4.698 (0.88), 4.705 (1.12), 4.713 (0.79), 4.719 (0.57), 4.773 (0.59), 4.779 (0.81), 4.787 (1.13), 4.794 (0.85), 4.801 (0.57), 7.844 (16.00), 7.899 (1.65), 7.903 (1.77), 7.916 (2.25), 7.918 (2.38), 7.931 (1.68), 7.935 (1.72), 8.468 (6.33), 8.472 (6.30), 8.754 (1.79), 8.764 (3.76), 8.773 (1.86).

[1471] Example 51

[1472] ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3'-fluoro-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (enantiomer 1)

[1473]

[1474] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3'-fluoro-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide was separated into stereoisomers by chiral HPLC (preparative HPLC: column Chiralpak IA, 5 μm, 250 x 20 mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 20 ml / min; temperature 60 °C, detection: 220 nm). The stereoisomer with a retention time of 7.873 minutes was collected (HPLC: column Chiralpak IE 5 μm flow rate 1 ml / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60 °C; detection: 220 nm). The solvent was removed to give 88 mg (99% ee) of the title compound.

[1475] LC-MS (method 1): R t = 0.93 min; MS (ESIpos): m / z = 454 [M+H] + .

[1476] 1 H.NMR (500 MHz, DMSO-d 6 ) δ [ppm]: δ 8.72 (t, 1H), 8.47 (d, 1H), 7.94 - 7.89 (m, 1H), 7.82 (S, 1H), 5.10 (d, 1H), 4.53 (d, 2H), 4.18 (m, 1H), 4.00 (m, 1H), 3.32 (dd, 1H), 3.18 - 3.11 (m, 1H), 2.82 (m, 2H), 2.70 - 2.57 (m, 1H), 2.20 - 2.14 (m, 1H), 1.94 - 1.83 (m, 2H), 1.70 - 1.51 (m, 4H), 1.43 - 1.33 (m, 1H), 0.88 - 0.78 (m, 1H), 0.82 (d, 3H).

[1477] Example 52

[1478] ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3'-fluoro-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (enantiomer 2)

[1479]

[1480] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3'-fluoro-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide was separated into stereoisomers by chiral HPLC (preparative HPLC: column Chiralpak IA, 5 μm, 250 x 20 mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 20 ml / min; temperature 60 °C, detection: 220 nm). The stereoisomer with a retention time of 10.179 minutes was collected (HPLC: column Chiralpak IE 5 μm flow rate 1 ml / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60 °C; detection: 220 nm). The solvent was removed to give 91 mg (99% ee) of the title compound.

[1481] LC-MS (method 1): R t = 0.93 min; MS (ESIpos): m / z = 454 [M+H] + .

[1482] 1 H.NMR (500 MHz, DMSO-d 6 ) δ [ppm]: δ 8.72 (t, 1H), 8.47 (d, 1H), 7.94 - 7.89 (m, 1H), 7.82 (S, 1H), 5.10 (d, 1H), 4.53 (d, 2H), 4.18 (m, 1H), 4.00 (m, 1H), 3.32 (dd, 1H), 3.19 - 3.12 (m, 1H), 2.82 (d br, 2H), 2.70 - 2.57 (m, 1H), 2.21 - 2.15 (m, 1H), 1.94 - 1.84 (m, 2H), 1.70 - 1.56 (m, 3H), 1.53 - 1.38 (m, 2H), 0.88 - 0.78 (m, 1H), 0.81 (d, 3H).

[1483] Example 53

[1484] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1485]

[1486] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were successively added to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-4-methylazepane (32.1 mg, 284 μmol) in 2.5 ml of dichloromethane, and the mixture was stirred overnight at room temperature. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added, and the mixture was stirred continuously at room temperature. After 2 hours, saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator, and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This yielded 43.0 mg (purity 100%, 67% of theory) of the title compound.

[1487] LC-MS (method 1): Rt = 0.98 min; MS (ESIpos): m / z = 450 [M+H] + 。

[1488] 1 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.874(16.00), 0.886(15.94), 1.166(1.35), 1.173(2.14), 1.180(1.44), 1.189(2.16), 1.195(1.69), 1.206(1.49), 1.223(2.09), 1.240(2.28), 1.257(1.07), 1.262(0.94), 1.417(1.40), 1.431(3.73), 1.438(3.97), 1.451(4.78), 1.457(4.63), 1.471(3.48), 1.478(2.98), 1.491(1.13), 1.499(0.91), 1.566(1.97), 1.572(1.71), 1.590(2.05), 1.609(1.83), 1.632(4.40), 1.642(4.13), 1.649(3.78), 1.727(2.59), 1.747(4.36), 1.766(2.28), 2.519(3.82), 2.525(2.88), 2.567(1.76), 2.574(1.84), 2.588(3.16), 2.594(2.42), 2.603(2.38), 2.610(2.22), 2.636(3.23), 2.645(6.11), 2.653(6.12), 2.664(4.76), 2.675(3.65), 2.684(1.53), 3.020(3.04), 3.038(5.45), 3.059(3.16), 3.327(0.99), 3.921(4.02), 3.941(3.84), 4.523(7.77), 4.532(7.71), 7.819(13.98), 7.877(1.85), 7.881(1.92), 7.895(3.21), 7.897(3.22), 7.909(1.86), 7.913(1.83), 8.458(6.41), 8.462(6.13), 8.662(2.36), 8.671(4.40), 8.680(2.29).

[1489] Example 54

[1490] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(3-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1491]

[1492] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were successively added to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-methylazepane hydrochloride (42.5 mg, 284 μmol) in 2.5 ml of dichloromethane, and the mixture was stirred overnight at room temperature. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added, and the mixture was stirred continuously at room temperature. After 2 hours, saturated NaHCO 3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator, and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A from 0 to 2 min 47 ml, mobile phase B from 0 to 2 min 23 ml, mobile phase A from 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 0 ml of mobile phase A and 70 ml of mobile phase B from 10 to 12 min. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min each throughout the run time). The fractions containing the product were combined and lyophilized. This yielded 40.0 mg (purity 100%, 63% of theory) of the target compound.

[1493] LC-MS (method 1): R t = 0.97 min; MS (ESIpos): m / z = 450 [M+H] +

[1494] H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.813 (15.55), 0.823 (16.00), 1.127 (0.63), 1.144 (1.47), 1.151 (1.29), 1.168 (1.44), 1.409 (0.90), 1.422 (3.44), 1.428 (3.08), 1.440 (5.99), 1.449 (4.90), 1.461 (3.41), 1.468 (2.80), 1.481 (1.05), 1.561 (1.44), 1.573 (1.70), 1.589 (0.97), 1.610 (3.22), 1.629 (4.80), 1.637 (3.85), 1.648 (2.15), 1.738 (3.86), 1.757 (3.39), 2.188 (2.20), 2.202 (2.24), 2.210 (2.45), 2.224 (2.31), 2.569 (0.93), 2.578 (1.13), 2.591 (2.08), 2.600 (2.09), 2.609 (1.71), 2.630 (1.60), 2.639 (4.89), 2.644 (4.73), 2.660 (4.71), 2.664 (4.78), 2.683 (1.26), 3.018 (2.77), 3.035 (5.01), 3.039 (4.91), 3.056 (2.76), 3.256 (0.45), 3.933 (3.56), 3.953 (3.40), 4.524 (7.13), 4.533 (7.07), 7.819 (13.92), 7.880 (1.63), 7.883 (1.71), 7.896 (2.87), 7.899 (2.96), 7.911 (1.68), 7.915 (1.70), 8.460 (6.36), 8.463 (6.29), 8.662 (2.12), 8.672 (4.27), 8.681 (2.16).

[1495] Example 55

[1496] diamix - N - [1 - (3,5 - difluoropyridin - 2 - yl)ethyl] - 2 - [(3R) - 3 - methyl[1,4'-bipiperidin] - 1'-yl] - 1,3 - thiazole - 5 - carboxamide

[1497]

[1498] N,N-Diisopropylethylamine (182 μl, 105 μmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-

[1499] yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and rac-1-(3,5-difluoropyridin-2-yl)ethylamine (45.5 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 12.0 mg (purity 100%, 10% of theory) of the target compound.

[1500] LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m / z = 450 [M+H] + 。

[1501] 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.788(0.72), 0.811(14.96), 0.822(16.00), 0.843(0.68), 1.389(1.55), 1.409(1.64), 1.440(14.70), 1.452(14.49), 1.480(2.90), 1.502(2.05), 1.564(1.99), 1.586(1.51), 1.615(1.65), 1.636(1.56), 1.735(1.85), 1.753(4.97), 1.779(3.32), 2.032(1.18), 2.049(2.19), 2.069(1.17), 2.423(0.65), 2.466(1.28), 2.653(0.49), 2.716(2.04), 2.731(3.74), 2.748(1.88), 3.015(2.36), 3.036(4.36), 3.057(2.38), 3.224(0.42), 3.249(0.65), 3.316(0.89), 3.913(2.65), 5.317(0.57), 5.329(2.00), 5.341(3.01), 5.353(1.96), 7.861(1.44), 7.876(2.73), 7.893(1.49), 7.912(11.30), 8.468(5.59), 8.531(3.80), 8.543(3.75).

[1502] Example 56

[1503] N-[(5-chloro-1,3-thiazol-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1504]

[1505] N,N-Diisopropylethylamine (230 μl, 1.3 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-chloro-1,3-thiazol-2-yl)methanamine hydrochloride (53.2 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 14.0 mg (purity 100%, 12% of theory) of the target compound.

[1506] LC-MS (method 1): R t = 1.00 min; MS (ESIpos): m / z = 440 [M+H] + 。

[1507] 1 1H-NMR (400 MHz, DMSO-d 6)δ [ppm]: -0.149 (0.78), 0.146 (0.87), 0.811 (14.60), 0.827 (16.00), 1.475 (2.13), 1.498 (2.88), 1.605 (1.71), 1.729 (1.52), 1.756 (3.69), 1.802 (2.53), 2.051 (1.90), 2.366 (1.52), 2.710 (2.65), 3.041 (2.14), 3.067 (3.51), 3.098 (1.95), 3.937 (2.72), 3.966 (2.56), 4.573 (8.03), 4.588 (7.85), 7.731 (15.89), 7.837 (15.31), 9.094 (1.71), 9.108 (3.31), 9.122 (1.68).

[1508] Example 57

[1509] N-[(5-Fluoro-2-thienyl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1510]

[1511] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-fluoro-2-thienyl)methanamine (37.7 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 12.0 mg (purity 100%, 11% of theory) of the target compound.

[1512] LC-MS (method 1): Rt = 1.09 min; MS (ESIpos): m / z = 423 [M+H] + 。

[1513] 1 1H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.783(0.52), 0.790(0.59), 0.813(15.03), 0.824(16.00), 0.843(0.57), 0.850(0.47), 1.370(0.50), 1.391(1.25), 1.411(1.35), 1.431(0.57), 1.454(0.72), 1.474(1.98), 1.494(2.47), 1.511(1.80), 1.529(0.96), 1.540(0.58), 1.565(1.59), 1.571(1.23), 1.582(0.96), 1.587(1.28), 1.616(1.32), 1.637(1.24), 1.737(1.79), 1.754(3.23), 1.771(4.08), 1.788(2.51), 2.036(1.05), 2.050(1.91), 2.054(1.88), 2.069(1.04), 2.471(1.13), 2.477(0.78), 2.722(1.66), 2.734(3.05), 2.752(1.45), 3.031(1.84), 3.035(2.16), 3.052(3.73), 3.055(3.70), 3.072(2.12), 3.077(1.85), 3.257(0.59), 3.278(0.99), 3.927(2.78), 3.948(2.65), 4.394(4.22), 4.398(4.54), 4.404(4.54), 4.408(4.29), 6.512(3.08), 6.516(3.37), 6.518(3.69), 6.522(3.52), 6.660(2.25), 6.666(4.14), 6.672(2.16), 7.780(13.01), 8.786(1.58), 8.796(3.27), 8.806(1.66).

[1514] Example 58

[1515] 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide

[1516]

[1517] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(pyridin-4-yl)methanamine (31.1 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC. (Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength: 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 7.00 mg (purity 100%, 7% of theory) of the target compound.

[1518] LC-MS (method 1): R t = 0.48 min; MS (ESIneg): m / z = 398 [M-H]-.

[1519] 1 1H-NMR (400 MHz, DMSO-d 6)δ [ppm]: 0.776(0.54), 0.796(1.55), 0.812(14.81), 0.828(16.00), 0.855(0.65), 0.865(0.55), 0.950(1.20), 0.966(1.16), 1.356(0.44), 1.387(1.16), 1.417(1.35), 1.446(1.24), 1.474(2.25), 1.499(2.83), 1.525(1.95), 1.534(1.73), 1.563(1.86), 1.604(1.82), 1.645(1.30), 1.731(1.87), 1.758(4.55), 1.783(2.68), 1.796(2.56), 2.030(1.05), 2.052(1.88), 2.058(1.85), 2.080(1.06), 2.366(0.57), 2.473(1.30), 2.725(2.30), 2.741(2.70), 3.031(2.07), 3.057(3.71), 3.088(2.13), 3.932(2.97), 3.965(2.79), 4.401(6.43), 4.416(6.43), 7.269(4.34), 7.280(4.58), 7.849(13.88), 8.505(1.83), 8.800(1.58), 8.815(3.27), 8.830(1.59).

[1520] Example 59

[1521] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4'-bipiperidin]-1'-yl}-1,3-thiazole-5-carboxamide

[1522]

[1523] Combine 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (118 mg, 353 μmol) and rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4'-bipiperidine dihydrochloride (164 mg, purity 75%, 348 μmol), and stir in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) at 120 °C for 1 hour. Then dilute the reaction mixture with water and extract with dichloromethane. Wash the organic phase with Na 2 SO 4Dry, filter off the desiccant, and concentrate the filtrate on a rotary evaporator. Dissolve the residue in DMSO and purify by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D are at a constant flow rate of 5 ml / min each throughout the run time). Combine the product-containing fractions and lyophilize. This yields 56.0 mg (purity 100%, 30% of theory) of the target compound.

[1524] LC-MS (method 5): Rt = 1.64 min; MS (ESIpos): m / z = 534 [M+H] + 。

[1525] 1 H-NMR (600 MHz, DMSO-d 6)δ [ppm]: 0.937 (0.65), 0.955 (1.56), 0.970 (1.59), 0.988 (0.67), 1.381 (0.58), 1.402 (1.31), 1.420 (1.45), 1.431 (1.19), 1.439 (1.22), 1.452 (2.08), 1.458 (1.80), 1.465 (1.92), 1.471 (3.02), 1.478 (1.98), 1.485 (1.91), 1.492 (2.15), 1.505 (0.81), 1.512 (0.59), 1.589 (3.51), 1.605 (3.09), 1.767 (4.45), 1.952 (1.98), 1.969 (3.12), 1.986 (1.74), 2.133 (1.36), 2.148 (2.51), 2.166 (1.33), 2.513 (2.55), 2.689 (1.93), 2.707 (1.83), 2.776 (2.08), 2.791 (2.00), 3.029 (2.57), 3.049 (4.90), 3.070 (2.56), 3.425 (0.45), 3.443 (7.66), 3.454 (8.96), 3.925 (3.82), 3.947 (3.63), 3.976 (3.33), 3.992 (9.56), 4.008 (9.29), 4.023 (3.00), 4.525 (7.17), 4.534 (7.14), 7.824 (16.00), 7.877 (1.74), 7.881 (1.86), 7.897 (2.97), 7.909 (1.76), 7.913 (1.81), 8.458 (6.85), 8.462 (6.81), 8.666 (2.27), 8.676 (4.58), 8.685 (2.26).

[1526] Example 60

[1527] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide

[1528]

[1529] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (75.5 mg, 226 μmol) and rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4'-bipiperidine dihydrochloride (133 mg) were combined and stirred at 120 °C in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na 2 SO4, the desiccant was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%); total flow rate: 80 ml / min; room temperature; wavelength 200 - 400 nm, full injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This yielded 10.5 mg (purity 100%, 9% of theory) of the target compound.

[1530] LC-MS (method 5): Rt = 1.65 min; MS (ESI pos): m / z = 538 [M+H] + 。

[1531] 1 1H-NMR (600 MHz, DMSO-d 6 ) δ [ppm]: 0.500 (0.62), 0.507 (0.85), 0.526 (0.86), 0.531 (1.03), 1.601 (0.40), 3.051 (0.52), 3.242 (1.08), 3.253 (1.11), 3.279 (2.71), 3.289 (16.00), 3.923 (0.41), 3.943 (0.40), 4.219 (0.96), 4.301 (0.97), 4.524 (0.77), 4.533 (0.76), 7.824 (1.56), 8.459 (0.67), 8.463 (0.68), 8.675 (0.48).

[1532] Example 61

[1533] rac-2-[3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1534]

[1535] Combine 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 300 μmol) and rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)-1,4'-bipiperidine dihydrochloride (112 mg), and stir in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mm...

Claims

1. Compounds of formula (I) wherein X represents S, N or O; Y represents N, S or O; wherein if X represents S, then Y represents N; wherein if X represents O, then Y represents N; Z represents CR 4 , O or NR 4 , wherein if X represents N and Y represents N, then Z represents O; Wherein, if X represents S, then Z represents CR 4 or NR 4 R 1 represents a 5- or 6-membered heteroaryl group, phenyl group, wherein the 5- to 6-membered heteroaryl may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, and halogen; wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times, wherein (C 1 -C 4 )-alkoxy may be substituted up to three times by halogen, wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 4 )-alkyl, (C 3 -C 5 )-cycloalkyl, (C 1 -C 4 )-alkoxy, cyano, hydroxy, halogen; wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times, R 2 represents hydrogen, (C 1 -C 4 )-alkyl; wherein (C 1 -C 4 )-alkyl may be substituted up to three times with halogen, or Together with the carbon atom linked to R 2 forms a (C 3 -C 4 )-cycloalkyl ring, R 3 represents hydrogen, (C 1 -C 4 )-alkyl, wherein (C 1 -C 4 )-alkyl may be substituted up to three times by halogen, R 4 In CR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl, halogen; wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times and the phenyl group may be substituted by halogen, In NR 4 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, phenyl; wherein (C 1 -C 4 )-alkyl may be substituted by halogen up to three times and the phenyl group may be substituted by halogen, R 5 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen, R 6 group of formula a), b), c), d), e), f) or g) wherein * marks the connection to the adjacent piperidine ring, wherein R 7 represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, phenyl, Among them, (C 1 -C 4 )-alkyl can be replaced by (C 3 -C 4 )-cycloalkyl, (C 1 -C 4 )-alkoxy, (C 3 -C 4 )-cycloalkyloxy-substituted and trisubstituted at most by halogen, wherein the (C 1 -C 4 )-alkoxy group may be substituted by a (C 3 -C 4 )-cycloalkyl group and is at most trisubstituted by a halogen, wherein the (C 3 -C 4 )-cycloalkyl group may be substituted by a monofluoromethyl, difluoromethyl or trifluoromethyl group and is at most disubstituted by halogen, wherein the (C 1 -C 4 )-alkoxy may be substituted by a (C 3 -C 4 )-cycloalkyl and is substituted by at most three halogens, wherein the (C 3 -C 4 )-cycloalkyl group may be mono- or di-substituted by a halogen, wherein the (C 3 -C 4 )-cycloalkyloxy group may be substituted with halogen up to two times, wherein R 8 represents hydrogen or fluorine, wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, halogen; wherein the (C 1 -C 4 )-alkyl may be substituted by a (C 1 -C 4 )-alkoxy group, n represents 0 or 1, m represents 0, 1 or 2, p represents 0, 1 or 2 and q represents 0, 1 or 2, and their salts, solvates and solvates of salts.

2. The compound of formula (I) according to claim 1, wherein X represents S or N; Y represents N, S or O, wherein if X represents S, then Y represents N; Z represents CR 4 , N or O, wherein if X represents N and Y represents N, then Z represents O; Wherein, if X represents S, then Z represents N or CR 4 R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine; wherein the thiophenyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine; wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluoro, chloro, trifluoromethyl; R 2 represents hydrogen, (C 1 -C 2 )-alkyl, or together with the carbon atom to which it is attached to form a cyclopropyl ring, 2 which, together with the carbon atom to which it is attached, forms a cyclopropyl ring R 3 represents hydrogen, (C 1 -C 2 )-alkyl; R 4 represents hydrogen, (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl; wherein the phenyl group may be substituted by halogen; R 5 represents hydrogen, (C 1 -C 2 )-alkyl, methoxy, fluorine; R 6 a group of formula (a), (b), (c) or (e) wherein *** marks the connection to the adjacent piperidine ring, wherein R 7 or R' 7 each independently represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, wherein (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine at most disubstituted, wherein the methoxy group may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; wherein the cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl; wherein the cyclobutyl group may be substituted by fluorine up to disubstituted; wherein the n-butoxy group may be substituted by fluorine up to disubstituted; Among them, (C 1 -C 2 )-alkoxy can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and wherein the cyclopropyl and cyclobutyl groups may be substituted by fluorine up to disubstituted; wherein (C 3 -C 4 )-cyclanoxy can be substituted with fluorine up to two times, wherein R 8 or R' 8 each independently represents hydrogen or fluorine, wherein R 9 represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 2 )-alkoxy, methoxyethyl, fluorine, chlorine; n represents 0 or 1 and m represents 1 or 2, q represents 0 or 2, and their salts, solvates and solvates of salts.

3. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h), (i), (j), (k) or (r), wherein * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and R 1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by chlorine; wherein the thiophenyl group may be substituted by fluorine; wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from each other from (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluoro, chloro, trifluoromethyl; R 2 represents hydrogen, methyl, or Together with the carbon atom linked to R 2 forms a cyclopropyl ring R 3 represents hydrogen, (C 1 -C 2 )-alkyl; R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl; wherein the phenyl group may be substituted by chlorine; R 5 represents hydrogen, fluorine; R 6 a group in formulae a), b'), b"), c'), c") or e) wherein *** marks the connection to the adjacent piperidine ring, wherein R 7 or R' 7 each independently represents hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, wherein (C 1 -C 4 )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and is substituted by fluorine at most disubstituted, wherein the methoxy group may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; wherein the cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl; wherein the cyclobutyl group may be substituted by fluorine up to disubstituted; wherein the n-butoxy group may be substituted by fluorine up to disubstituted; wherein (C 1 -C 2 )-alkoxy can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and wherein the cyclopropyl and cyclobutyl groups may be substituted by fluorine up to disubstituted; wherein the (C 3 -C 4 )-cyclanoxy group may be substituted with fluorine up to two times, wherein R 9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, chlorine; n represents 0 or 1 and m represents 1 or 2, and their salts, solvates and solvates of salts.

4. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h'), (i'), (j') or (k), R 1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R 2 represents hydrogen or methyl; R 3 represents hydrogen, methyl; R 4 represents hydrogen, ethyl, trifluoromethyl; R 5 represents hydrogen, fluorine; R 6 The group in formula (a), (c') or (c") wherein *** marks the connection to the adjacent piperidine ring, wherein R 7 and R' 7 each independently represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluoro; n represents 0 or 1 and m represents 1, and their salts, solvates and solvates of salts.

5. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula (h') R 1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R 2 represents hydrogen or methyl; R 3 represents hydrogen; R 5 represents hydrogen, fluorine; R 6 Group in formula (a), (c') or (c") wherein *** marks the connection to the adjacent piperidine ring, wherein R 7 and R' 7 each independently represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluoro; n represents 0 or 1 and m represents 1, and their salts, solvates and solvates of salts.

6. A process for preparing a compound of formula (I) or its salt, its solvate or its solvate of salt, wherein [A] A compound of formula (II) wherein X, Y, Z, R 1 , R 2 , R 3 and R 4 and n have the meanings given above, Hal represents a leaving group, is reacted with a compound of formula (III) in the presence of a base wherein R 5 and R 6 and m have the meanings given above, to form a compound of formula (I-A) or [B]Compound of formula (IV) wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 and n and m have the meanings given above, react with a compound of formula (V) in the presence of a reducing agent and optionally an acid H-R 6 (V), wherein R 6 has the meaning given above, to produce a compound of formula (I-B) or [C]Compound of formula (VI) wherein X, Y, Z, R 4 , R 5 and R 6 and n and m have the meanings given above, react with a compound of formula (VII) in the presence of a condensing agent or an activating agent wherein R 1 、R 2 and R 3 and n have the meanings given above, to produce a compound of formula (I-C) and the compounds of formula (I-A), (I-B), (I-C) thus obtained are optionally separated into their enantiomers and / or diastereoisomers and / or optionally converted into their solvates, salts and / or solvate of salts with a suitable (i) solvent and / or (ii) acid.

7. A compound as defined in any one of claims 1 to 5 for use in the treatment and / or prophylaxis of a disease.

8. A compound as defined in any one of claims 1 to 5 for use in a method of treating and / or preventing dyspnoea, dysphagia, peripheral and cardiovascular disorders and disorders of the peripheral and central nervous systems.

9. A compound as defined in any one of claims 1 to 5 for use in a method of treating and / or preventing the following disorders: dyspnoea, including sleep-induced dyspnoea such as central and obstructive sleep apnoea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders including diabetic microangiopathy; and disorders of the peripheral and central nervous systems including neurodegenerative and neuroinflammatory disorders.

10. A compound as defined in any one of claims 1 to 5 for use in a method of treating and / or preventing the following disorders: dyspnoea, including sleep-induced dyspnoea such as in particular obstructive sleep apnoea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnoea syndrome), central sleep apnoea, Cheyne-Stokes respiration, primary sleep apnoea in infants, apparent life-threatening events, central sleep apnoea due to the use of drugs or other substances, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnoea, muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during altitude acclimatization, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

11. A compound as defined in any one of claims 1 to 5 for use in the treatment and / or prophylaxis of peripheral and cardiovascular disorders including diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular disorders, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

12. A compound as defined in any one of claims 1 to 5, for use in a method of treating and / or preventing the following conditions: conditions of the peripheral and central nervous systems, including dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHD), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

13. A pharmaceutical agent comprising a compound as defined in any one of claims 1 to 5 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

14. A pharmaceutical agent comprising a compound as defined in any one of claims 1 to 5 in combination with one or more other active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulators, immunosuppressants and cytotoxic drugs.

15. The pharmaceutical agent according to claim 13 or 14, for use in treating and / or preventing dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and including neurodegeneration; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

16. A method of treating and / or preventing the following conditions in humans and animals: dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions, by administering an effective amount of at least one compound as defined in any one of claims 1 to 5 or a pharmaceutical agent as defined in any one of claims 13 to 15.

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