Inhibitor of the adrenergic receptor ADRAC2

Abstract

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

Description

[Technical Field]

[0001] The present application relates to novel substituted heterocyclic carboxamides, processes for their preparation, their use alone or in combination for the treatment and / or prevention of diseases, and their use for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of peripheral and cardiovascular disorders, including dyspnea, including sleep-induced dyspnea such as central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, diabetic microangiopathy and disorders of the peripheral and central nervous system, such as neurodegenerative and neuroinflammatory disorders. [Background technology]

[0002] Alpha-2-adrenergic receptors (alpha-2-ARs) belong to the family of G protein-coupled receptors. They are activated by the pertussis toxin-sensitive inhibitory G protein G i and G0, reducing adenylate cyclase activity. They are involved in mediating diverse physiological effects in various tissues after stimulation by endogenous catecholamines (adrenaline, noradrenaline), which are released into synapses or reach their sites of action via the blood. α2-ARs play important physiological roles primarily in the cardiovascular system and in the central nervous system. Biochemical, physiological, and pharmacological studies have identified three α2-AR subtypes (α1-AR) in many cardiovascular-related and neuronal target cells and tissues, in addition to various α1-AR subtypes. 2A , α 2B and α 2C), making them promising targets for therapeutic intervention. However, due to the lack of highly selective ligands and / or antagonists for individual α2-ARs, elucidating the precise physiological functions of receptor subtypes has remained difficult to date [Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The α2-Adrenergic Receptors: Adrenergic Receptors in the 21st Century / Receptors, 2005, 241-265].

[0003] Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction.

[0004] During breathing, the patency of the upper airway is ensured by the interaction of two opposing forces. The dilator action of the upper airway musculature counteracts the negative intraluminal pressure that constricts the lumen. Active contraction of the diaphragm and other accessory respiratory muscles generates negative pressure in the airway and constitutes the driving force for breathing. Upper airway stability is substantially determined by the coordination and contractile properties of the dilator muscles of the upper airway.

[0005] It is hypothesized that in OSA, collapse of the upper airway occurs early during sleep because reduced activity of some upper airway dilator muscles means that the anatomically sensitive airway can no longer maintain an open state. However, some upper airway dilator muscles, such as the genioglossus, the most important upper airway extensor innervated by the hypoglossal nerve, increase their activity during sleep in response to respiratory stimuli, possibly counteracting some of these changes early in sleep. Patients with OSA have been observed to have apnea-free periods in which genioglossus activity is only 25–40% higher compared to sleep phases 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]. Noradrenaline is a neuromodulator of hypoglossal motoneuron activity [Horner RL Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196]. It is speculated that a decrease in noradrenergic stimulation leads to a sleep-induced decrease in the excitability of hypoglossal motoneurons, resulting in decreased activity of the dilator muscles of the upper airway, particularly the genioglossus.

[0006] Patients with obstructive sleep apnea experience high mortality and morbidity as a result of cardiovascular disorders such as hypertension, myocardial infarction, and stroke [Vrints et al., Acta Clin Belg., 68 , 169-78 (2013)].

[0007] α 2CAlpha-adrenergic receptors regulate the release of noradrenaline from central noradrenergic neurons. They are autoreceptors involved in the inhibition of presynaptic feedback of noradrenaline [Hein L. et al, Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402 (6758): 181-184].

[0008] Increasing the activity of hypoglossal motor neurons through α2c adrenergic receptor antagonism can stabilize the upper airway and protect it from collapse and obstruction. Furthermore, stabilizing the upper airway may also suppress snoring.

[0009] In primary snoring, there is no obstruction of the upper airway. However, the upper airway contracts, increasing the inspiratory and expiratory flow. This, combined with the relaxation of muscular tissue, causes the soft tissues of the mouth and pharynx to vibrate with the airflow. This gentle vibration produces the typical snoring sound.

[0010] Obstructive snoring (upper airway resistance syndrome, loud snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This results in increased airway resistance and therefore increased work of breathing with considerable fluctuations in intrathoracic pressure. During inspiration, negative intrathoracic pressure can reach values ​​similar to those resulting from complete airway obstruction during obstructive sleep apnea. The pathophysiological consequences for the heart, circulation, and sleep quality are comparable to those of obstructive sleep apnea. As with obstructive sleep apnea, the etiology is presumed to be impaired activity of the pharyngeal dilator muscles during inspiration during sleep. Very often, obstructive snoring is a precursor to obstructive sleep apnea [Hollandt et al., HNO, 48 , 628-634(2000)].

[0011] Central sleep apnea (CSA) occurs when brain function or respiratory control is impaired. CSA is characterized by a lack of respiratory stimulation during sleep, resulting in repeated episodes of insufficient breathing or apnea and impaired gas exchange. CSA has a variety of manifestations, including high altitude periodic breathing, idiopathic CSA (ICSA), opiate-induced central apnea, hypoventilation syndrome (OHS), and Cheyne-Stokes respiration (CSB). While the exact mechanisms underlying different types of CSA vary considerably, one of the primary features is unstable respiratory stimulation during sleep [Eckert DJ et al., Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131 (2): 595-607].

[0012] Dysphagia is difficulty swallowing, which can have various causes. The complex regulation of swallowing is carried out by various brain structures. There are bidirectional connections between the cerebral cortex, the corticobulbar tract, the brainstem, and the peripheral swallowing musculature. Five cranial nerves (trigeminal (V), facial (VII), glossopharyngeal (IX), vagus (X), and hypoglossal (XII)) and more than 25 muscle pairs are involved in the control and execution of the swallowing act [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].

[0013] Dysphagia can have very different causes, such as structural disorders of the oral cavity and / or larynx, psychogenic causes, neurological diseases (neurogenic dysphagia), such as Parkinson's disease, myotonic dystrophy, amyotrophic lateral sclerosis, cerebral infarction, traumatic brain injury, brainstem disorders, muscular atrophy and neuromuscular disorders, among others [Karkos PD, Current evaluation of the dysphagic patient. Hippokratia. 2009 Jul;13(3):141-6].

[0014] Noradrenergic neurons and α2-ARs play a role in coordinating swallowing and respiration [Yamanishi T., Alpha2-adrenoceptors coordinate swallowing and respiration. J Dent Res 2010, 89 (3): 258-2639].

[0015] α2-ARs also play an important role in cardiovascular changes. For example, cardiac contractility is primarily controlled by central regulation of sympathetic efferent nerves. Furthermore, sympathetic efferent nerves also exert direct effects on smooth muscle cells and vascular endothelial cells. Thus, the sympathetic nervous system is involved not only in regulating cardiac output performance but also in regulating local perfusion in various vascular beds. This is also regulated via α2-ARs, which are involved in the control of peripheral resistance. Therefore, blood vessels are innervated by sympathetic nerve fibers running through the adventitia, which terminate in varicose veins that release norepinephrine. The released norepinephrine regulates local vascular tone via α2-ARs on endothelial and smooth muscle cells.

[0016] In addition to effects on sympathetic efferent nerves, peripheral cardiovascular function is also regulated by pre- and postsynaptic α2-ARs. Smooth muscle cells and endothelial cells express different α2-AR subtypes. α2-ARs on smooth muscle cells 2A , α 2B and α 2CActivation of the receptors results in constriction, which in turn leads to vasoconstriction [Kanagy, Clinical Science 109:431-437, (2005)]. However, the distribution of individual receptor subtypes varies in different vascular beds, among species, and across different vessel diameters. 2A -AR appears to be expressed virtually exclusively in the aorta, and α 2B -AR contributes more to vascular tone in small arteries and veins. 2B ARα may play a role in salt-induced hypertension [Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. 2C The role of ARα is not yet fully understood. 2C Receptors appear to mediate venous vasoconstriction. They are also involved in cold-induced enhancement of adrenoceptor-induced 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., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. Cold temperature and other factors (e.g., tissue proteins, estrogen) activate ARα 2C regulates the functional coupling of cAMP to intracellular signaling pathways [Chotani et al., Distinct cAMP signaling pathways differentially regulate α 2Cadrenenoxceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol 288: H69-H76, (2005)].

[0017] Under pathophysiological conditions, the adrenergic system may be activated, resulting in, for example, hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disorders, stroke, and sexual dysfunction. Thus, for example, the pathophysiology of Raynaud's syndrome and scleroderma is poorly understood but is related to altered adrenergic activity. Thus, for example, patients with spastic Raynaud's syndrome show significantly increased expression of ARα2 receptors on platelets. This may be related to 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)].

[0018] The possibility of treating such disorders by targeting the regulation of the activated adrenergic system in the organism is a promising approach, as it is expected to be highly efficient and have a low level of side effects. In particular, in diabetic patients, who often have high catecholamine levels, peripheral circulatory disorders (microangiopathy) such as diabetic retinopathy, nephropathy, or significant wound healing disorders (diabetic foot ulcers) are important. In peripheral occlusive disease, diabetes is one of the most important comorbidities and also plays a very important role in the progression of the disease (microvascular and macrovascular disorders). Adrenergic receptor α associated with high catecholamine levels 2C Higher expression of the receptor may be involved in these pathophysiological processes in diabetic patients. [Prior art documents] [Non-patent literature]

[0019]

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[0020] In 2011, there were 350 million people with diabetes worldwide (approximately 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 diabetic patients. Diabetic patients have a 15% to 25% lifetime risk of developing a diabetic foot ulcer, and 15% of all diabetic foot ulcers result in amputation. Globally, 40% to 70% of all non-traumatic amputations are performed in diabetic patients. Risk factors for diabetic foot ulcers include trauma, poor metabolic control, sensory, motor, and autonomic polyneuropathy, inappropriate footwear, infection, and peripheral arterial disease. Treatment of diabetic foot ulcers requires a multidisciplinary team and uses a multifactorial approach, including weight loss, revascularization (in cases of peripheral arterial occlusive disease, PAOD), improved metabolic control, debridement, bandaging, dalteparin, Regranex (PDGF), and amputation. The cost of treating one diabetic foot ulcer (without amputation) is US$7,000-10,000. 33% of all diabetic foot ulcers do not heal within two years, and recurrence rates are high (34% within one year and 61% at three years).

[0021] The compound of the present invention is α 2C -by activation of adrenergic receptors or activated α 2C -Diseases caused by adrenergic receptors, and α 2C - Suitable for the prevention and treatment of diseases secondary to adrenoceptor-related damage.

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

[0023] Therefore, the object of the present invention is to 2C The present invention aims to provide novel substances which act as potent and selective antagonists of -adrenergic receptors and are therefore suitable for the treatment and / or prevention 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 (microangiopathy), such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers). [Means for solving the problem]

[0024] The present invention provides compounds of the following general formula (I), as well as salts, solvates and solvates of the salts thereof: [ka] During the ceremony, X represents S, N or O; Y represents N, S or O; If X represents S, then Y represents N; When X represents O, Y represents N; Z represents CR4, O or NR4; When X represents N and Y represents N, Z represents O; When X represents S, Z represents CR4 or NR4; R1 represents a 5- or 6-membered heteroaryl, phenyl; The 5-6-membered heteroaryl may be substituted by 1-2 substituents, each independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; (C1-C4)-alkyl may be up to three-substituted by halogen; (C1-C4)-alkoxy may be up to three-substituted by halogen; Phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; (C1-C4)-alkyl may be up to three-substituted by halogen; R2 represents hydrogen, (C1-C4)-alkyl; (C1-C4)-alkyl may be up to three-substituted by halogen; or together with the carbon atom to which R2 is attached, form a (C3-C4)-cycloalkyl ring, R3 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkyl may be up to three-substituted by halogen; R4 is CR4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, halogen; (C1-C4)-alkyl may be up to three times substituted by halogen, phenyl may be substituted by halogen, NR4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl; (C1-C4)-alkyl may be up to three times substituted by halogen, phenyl may be substituted by halogen, R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; R6 is a group of the following formula a), b), c), d), e), f) or g): [ka] represents *** indicates a bond to the adjacent piperidine ring, R7 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, phenyl; (C1-C4)-Alkyl may be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy and may be up to trisubstituted by halogen; (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and may be up to three times substituted by halogen; (C3-C4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and may be up to disubstituted by halogen; (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and may be up to three times substituted by halogen; (C3-C4)-cycloalkyl may be mono- or disubstituted by halogen; (C3-C4)-cycloalkoxy may be up to disubstituted by halogen; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; (C1-C4)-Alkyl may be substituted by (C1-C4)-alkoxy, n represents 0 or 1; m represents 0, 1 or 2; p represents 0, 1 or 2; q represents 0, 1 or 2.

[0025] The present invention provides compounds of the following general formula (I), as well as salts, solvates and solvates of the salts thereof: [ka] During the ceremony, X represents S, N, or O; Y represents N, S, or O; If X represents S, then Y represents N; Z represents C, O, or N; When X represents N and Y represents N, Z represents O; R1 represents a 5- or 6-membered heteroaryl, phenyl; The 5-6-membered heteroaryl may be substituted by 1-2 substituents, each independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; (C1-C4)-alkyl may be up to three-substituted by halogen; (C1-C4)-alkoxy may be up to three-substituted by halogen; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; (C1-C4)-alkyl may be up to three-substituted by halogen; R2 represents hydrogen, (C1-C4)-alkyl; (C1-C4)-alkyl may be up to three-substituted by halogen; or together with the carbon atom to which R2 is attached, form a (C3-C4)-cycloalkyl ring, R3 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkyl may be up to three-substituted by halogen; R4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, halogen; (C1-C4)-alkyl may be up to three times substituted by halogen, phenyl may be substituted by halogen, R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; R6 is a group of the following formula a), b), c), d), e), f) or g): [ka] represents *** indicates a bond to the adjacent piperidine ring, R7 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, phenyl; (C1-C4)-Alkyl may be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy and may be up to trisubstituted by halogen; (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and may be up to three times substituted by halogen; (C3-C4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen; (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to three times by halogen; (C3-C4)-cycloalkyl may be mono- or disubstituted by halogen; (C3-C4)-cycloalkoxy may be up to disubstituted by halogen; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; (C1-C4)-Alkyl may be substituted by (C1-C4)-alkoxy, n represents 0 or 1; m represents 0, 1 or 2; p represents 0, 1 or 2; q represents 0, 1 or 2. DETAILED DESCRIPTION OF THE INVENTION

[0026] The compounds of the present invention are compounds of formula (I) and the salts, solvates and solvates of salts thereof, compounds encompassed by formula (I) and of the formulae mentioned below and the salts, solvates and solvates of salts thereof, and compounds encompassed by formula (I) and mentioned below, if they are not already salts, solvates or solvates of salts, and the compounds encompassed by formula (I) and cited below as examples and the salts, solvates and solvates of salts thereof.

[0027] Compounds of the invention also include the N-oxides and S-oxides of compounds of formula (I) and their salts, solvates and solvates of the salts.

[0028] In the context of the present invention it is preferred salt is a physiologically acceptable salt of the compound according to the invention. Also included are salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolating, purifying or storing the compound of the invention.

[0029] Suitable pharmaceutically acceptable salts of the compounds of the invention may, for example, be acid addition salts of compounds of the invention having a sufficiently basic nitrogen atom in the chain or in the ring, such as acid addition salts with inorganic or "mineral acids", for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid, or with organic acids, 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, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, Examples of the acid addition salts include those with pamoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, para-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, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and thiocyanic acid.

[0030] Further suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium, magnesium or strontium salts, or aluminum or zinc salts, or salts of ammonia or organic primary, secondary or tertiary amines having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine ... Ammonium salts derived from phosphorus, arginine, lysine, 1,2-ethylenediamine, 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 salts with quaternary ammonium ions having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butylammonium), N-benzyl-N,N,N-trimethylammonium, choline, or benzalkonium.

[0031] Those skilled in the art will further appreciate that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali metal and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds with the appropriate base via a variety of known methods.

[0032] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

[0033] Whenever a compound is referred to herein, particularly in the experimental section, in connection with the synthesis of an intermediate or example of the present invention, as a salt form with a corresponding base or acid, the exact stoichiometry of the salt form obtained by a particular preparation and / or purification method is in most cases unknown.

[0034] Unless otherwise specified, the term "hydrochloride", "trifluoroacetate", "sodium salt" or "xHCl", "xCF3COOH", "xNa + " or the like attached to a chemical name or structural formula related to a salt refers to the salt form and does not refer to the stoichiometry of this salt. This also applies when a synthetic intermediate or an example compound or a salt thereof is obtained as a solvate, for example, as a hydrate, by the described preparation and / or purification method.

[0035] In the context of the present invention solvate are described as forms of the compounds according to the invention which form a complex in solid or liquid form by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination is with water. Preferred solvates in the context of the present invention are hydrates.

[0036] Depending on their structure, the compounds of the present invention can exist in different stereoisomeric forms, i.e., in the form of configurational isomers, or, where appropriate, as conformational isomers (including enantiomers and / or diastereomers, atropisomers). The present invention therefore encompasses enantiomers and diastereomers, as well as their individual mixtures. Stereomerically homogeneous components can be isolated from such mixtures of enantiomers and / or diastereomers by known methods. Chromatographic methods, particularly HPLC chromatography on achiral or chiral separating phases, are preferred for this purpose. In the case of carboxylic acids as intermediates or final products, separation is also possible via diastereomeric salts using chiral amine bases.

[0037] In the context of the present invention, the term "enantiomerically pure" should be understood to mean that 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 in this case by evaluating an HPLC analytical chromatogram on a chiral phase using the following formula:

number

[0038] Where compounds of the invention can exist in tautomeric forms, the present invention encompasses all tautomeric forms.

[0039] The present invention also encompasses all suitable isotopic forms of the compounds of the present invention. An isotopic form of a compound according to the present invention is understood herein to mean a compound in which at least one atom in the compound of the present invention is replaced with another atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly occurring in nature ("unnatural proportion"). The expression "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 context are 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 according to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, e.g. 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, 123I, 124 I, 129 I and 131 I. Certain isotopic forms of the compounds according to the invention, especially those incorporating one or more radioisotopes, may be useful, for example, to study the mechanism of action or distribution of the active ingredient in the body; these are relatively easy to prepare and detect, and are therefore particularly 3 H or 14 Compounds labeled with a C isotope are suitable for this purpose. In addition, the incorporation of an isotope, such as deuterium, can increase the metabolic stability of the compound, thereby providing certain therapeutic advantages, such as an increased half-life in the body or a reduced required active dose. Therefore, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention. With regard to the treatment and / or prevention of the disorders specified herein, isotopic forms of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). 3 H or 14 Isotopic forms of compounds of general formula (I), into which one or more radioactive isotopes, such as C, are incorporated, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for their ease of incorporation and detectability. 18 F or 11 It is possible to incorporate positron-emitting isotopes, such as C, into compounds of general formula (I). These isotopic forms of compounds of general formula (I) are suitable for use in in vivo imaging applications. Deuterium-containing and 13 C-containing compounds can be used for mass spectrometry in preclinical or clinical studies (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic forms of the compounds of the present invention can be prepared by commonly used methods known to those skilled in the art, for example, by using corresponding isotopic modifications of the respective reagents and / or starting compounds by the methods described further below and the procedures described in the Examples.

[0040] Isotopic forms of compounds of general formula (I) can generally be prepared by methods known to those skilled in the art, as described in the schemes and / or examples herein, by substituting an isotopic form of the reagent, preferably a deuterium-containing reagent, for the reagent. Depending on the desired deuteration site, deuterium from DO can optionally be incorporated directly into the compound or into a reagent that can be used to synthesize such a compound (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Photochemical deuteration and tritiation methods have also been reported (YY Loh et al., Science 10.1126 / science.aap9674(2017)). Another reagent useful for incorporating deuterium into molecules is deuterium gas. A rapid route to deuterium incorporation is the catalytic deuteration of olefinic bonds (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; JR 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). Direct exchange of hydrogen for deuterium in functionalized hydrocarbons can also be achieved using metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas (JG Atkinson et al., U.S. Patent 3,966,781). A variety of deuterated reagents and synthesis units 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.Further information relating to the prior art regarding deuterium-hydrogen exchange can be found, for example, 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.

[0041] 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 are replaced by one or more deuterium atoms, and the frequency of deuterium at any deuteration position in the compound of general formula (I) is higher than the natural frequency of deuterium (about 0.015%). Specifically, in a deuterium-containing compound of general formula (I), the frequency of deuterium at any deuteration position in the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% at this or those positions, preferably higher than 90%, 95%, 96%, or 97%, and even more preferably higher than 98% or 99%. It will be apparent that the frequency of deuterium at any deuteration position is independent of the frequency of deuterium at other deuteration positions.

[0042] The selective incorporation of one or more deuterium atoms into the compound of general formula (I) can affect the physicochemical properties of the molecule (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 metabolic profile may be altered, resulting in changes in the parent compound:metabolite ratio or the amount of metabolite produced. Such conversion may be desirable under certain circumstances, as it may confer certain therapeutic benefits. Decreased rates of metabolic switching, which alter metabolism and metabolite ratios, have been reported (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to parent compounds and metabolites may have important consequences for the pharmacodynamics, tolerability, and efficacy of deuterium-containing compounds of general formula (I).In some cases, deuterium substitution reduces or eliminates the production of undesirable or toxic metabolites and promotes the production of desirable metabolites (e.g., nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9, 1862; efavirenz: AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to decrease the systemic clearance rate, thereby increasing the biological half-life of the compound. Potential clinical benefits may include the ability to maintain similar systemic exposure while decreasing peak levels and increasing trough levels. This may result in reduced side effects and increased efficacy, depending on the pharmacokinetic / pharmacodynamic relationship of the particular compound. Indiplon (AJ Morales et al., Abstract 285, The 15. thExamples of this deuterium effect include ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208), and odanacativ (K. Kassahun et al., WO2012 / 112363). Further cases have been reported in which a decrease in metabolic rate increases drug exposure without altering systemic clearance (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 this effect may reduce dosing requirements (e.g., fewer doses or lower doses to achieve the desired effect) and / or result in a reduced metabolic burden. Compounds of general formula (I) may have multiple potential metabolic sites. To optimize the above effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) may be selected that have one or more deuterium-hydrogen exchange patterns. In particular, the deuterium atoms of deuterium-containing compounds of general formula (I) may be bonded to carbon atoms and / or to other molecules, such as cytochrome P. 450 The compound of general formula (I) is located at a position that is the attack site of metabolic enzymes such as

[0043] The present invention further encompasses prodrugs of the compounds of the present invention. The term "prodrug," as used herein, refers to a compound that may itself be biologically active or inactive, but that is converted into a compound of the present invention while present in the body, for example, by a metabolic or hydrolytic pathway.

[0044] In the context of the present invention, unless otherwise specified, the substituents are defined as follows:

[0045] In the context of the present invention Alkyl is a straight or branched chain alkyl group having the particular number of carbon atoms specified. 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.

[0046] In the context of the present invention Alkoxy is a straight 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.

[0047] In the context of the present invention cycloalkoxy is a cyclic alkoxy group having 3 to 4 carbon atoms. Examples include cyclopropoxy or cyclobutoxy.

[0048] In the context of the present invention cycloalkyl or carbocyclic ringis a monocyclic, polycyclic, or spirocyclic, preferably monocyclic or bicyclic, carbocyclic ring having a total of 3 to 8 ring atoms. Monocyclic saturated carbocyclic rings are referred to synonymously as cycloalkyl. 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, and the like. Monocyclic cycloalkyls having 3 to 5 carbon atoms are preferred. Examples include cyclopropyl, cyclobutyl, and cyclopentyl.

[0049] In the context of the present invention 5- or 6-membered heteroaryl is a monocyclic aromatic heterocycle (heteroaromatic) having a total of 5 or 6 ring atoms and containing up to 3 identical or different ring heteroatoms from the series N, O and / or S, bonded 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.

[0050] In general, and unless otherwise specified, heteroaryl groups include all possible isomers, such as tautomers and positional isomers with respect to the point of attachment to the rest of the molecule, so the term pyridyl includes, by way of non-limiting example, 2-pyridyl, 3-pyridyl, and 4-pyridyl, or the term thienyl includes 2-thienyl and 3-thienyl.

[0051] In the context of the present invention halogen includes fluorine, chlorine, bromine and iodine, preferably chlorine or fluorine.

[0052] When a group in the compound of the present invention is substituted, the group may be mono-substituted or poly-substituted unless otherwise specified.In the context of the present invention, all groups that occur multiple times are defined independently of each other.When a group in the compound of the present invention is substituted, the group may be mono-substituted or poly-substituted unless otherwise specified.Substitution by one substituent or two identical or different substituents is preferred.

[0053] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, checking, mitigating, attenuating, limiting, reducing, suppressing, warding off or curing a disease, condition, disorder, injury or health problem, or of the development, course or progression of such a condition and / or symptoms of such a condition. Herein, the term "therapy" is understood to be synonymous with the term "treatment."

[0054] The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and refer to avoiding or reducing the risk of contracting, experiencing, suffering from or having a disease, condition, disorder, injury or health problem, or developing or progressing such a condition and / or symptoms of such a condition.

[0055] The treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.

[0056] Preferred in the context of the present invention are X represents S or N; Y represents N, S or O, If X represents S, then Y represents N; Z represents CR4, N or O; When X represents N and Y represents N, Z represents O; When X represents S, Z represents N or CR4; R1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, pyrazolyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, thiazolyl may be substituted by 1 to 2 substituents independently selected from the group consisting of fluorine and chlorine; thienyl may be substituted by 1 to 2 substituents independently selected from the group consisting of fluorine and chlorine; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R2, represents hydrogen, (C1-C2)-alkyl, or Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring, R3 represents hydrogen, (C1-C2)-alkyl; R4 represents hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl; The phenyl may be substituted with a halogen; R5 represents hydrogen, (C1-C2)-alkyl, methoxy, fluorine; R6 is a group of the following formula a), b), c) or e): [ka] represents *** indicates the bond to the adjacent piperidine ring, R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine, methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl; cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine, R8 and R'8 independently represent hydrogen or fluorine, R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine, chlorine; n represents 0 or 1; m represents 1 or 2; q represents 0 or 2 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0057] Preferred in the context of the present invention are X represents S, N; Y represents N, S, or O; If X represents S, then Y represents N; Z represents C or O; When X represents N and Y represents N, Z represents O; R1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, pyrazolyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, thiazolyl may be substituted by 1 to 2 substituents independently selected from the group consisting of fluorine and chlorine; thienyl may be substituted by 1 to 2 substituents independently selected from the group consisting of fluorine and chlorine; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R2, represents hydrogen, (C1-C2)-alkyl, or Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring, R3 represents hydrogen, (C1-C2)-alkyl; R4 represents hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl; The phenyl may be substituted with a halogen; R5 represents hydrogen, (C1-C2)-alkyl, methoxy, fluorine; R6 is a group of the following formula a), b), c) or e): [ka] represents *** indicates the bond to the adjacent piperidine ring, R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine, methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl; cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine, R8 and R'8 independently represent hydrogen or fluorine, R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine, chlorine; n represents 0 or 1; m represents 1 or 2; q represents 0 or 2 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0058] In the context of the present invention, preference is given to X, Y, and Z are each a group having a structure in which the aromatic five-membered ring has the following structural formula h), i), j), k), or (r): [ka] is selected to have * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, pyrazolyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, thiazolyl may be substituted by chlorine; thienyl may be substituted by fluorine; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R2, represents hydrogen, methyl, or Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring, R3 represents hydrogen, (C1-C2)-alkyl; R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted by chlorine; R5 represents hydrogen or fluorine; R6 is a group of the following formula a), b'), b"), c'), c") or e): [ka] represents *** indicates the bond to the adjacent piperidine ring, R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, (C1-C4)-alkyl optionally substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine, methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl; cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine, R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine; n represents 0 or 1; m represents 1 or 2 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0059] In the context of the present invention, preference is given to X, Y and Z are groups of formula h), i), j), k) or (r): [ka] represents * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, pyrazolyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, thiazolyl may be substituted by chlorine; thienyl may be substituted by fluorine; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R2, represents hydrogen, methyl, or Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring, R3 represents hydrogen, (C1-C2)-alkyl; R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted by chlorine; R5 represents hydrogen or fluorine; R6 is a group of the following formula a), b'), b"), c'), c") or e): [ka] represents *** indicates the bond to the adjacent piperidine ring, R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, (C1-C4)-alkyl optionally substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine, methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl; cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine, R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine; n represents 0 or 1; m represents 1 or 2 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0060] In the context of the present invention, preference is given to X, Y, and Z are each a group having a structure in which the aromatic five-membered ring has the following structural formula h′), i′), j′), or k): [ka] is selected to have R1 is pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl nyl, 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; R2 represents hydrogen or methyl; R3 represents hydrogen or methyl; R4 represents hydrogen, ethyl, or trifluoromethyl; R5 represents hydrogen or fluorine; R6 is a group of the following formula a), c′) or c″): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 and R'7 are each independently 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 0 or 1; m represents 1 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0061] Preferred in the context of the present invention are X, Y, and Z represent 1,3-thiazolyl, 1,3-oxazolyl, or 1,2,4-oxadiazolyl; R1 is pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl nyl, 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; R2 represents hydrogen or methyl; R3 represents hydrogen or methyl; R4 represents hydrogen, methyl, ethyl, or trifluoromethyl; R5 represents hydrogen or fluorine; R6 is a group of the following formula a), c′) or c″): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 and R'7 are each independently 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 0 or 1; m represents 1 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0062] In the context of the present invention, preference is given to X, Y and Z are each a 5-membered aromatic ring represented by the following formula h'): [ka] is selected to have R1 is pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl nyl, 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; R2 represents hydrogen or methyl; R3 represents hydrogen; R5 represents hydrogen or fluorine; R6 is a group of the following formula a), c′) or c″): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 and R'7 are each independently 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 0 or 1; m represents 1 Compounds of formula (I) and salts, solvates and solvates of salts thereof.

[0063] A particular embodiment of the present invention comprises: X, Y, and Z are each a group having a structure in which the aromatic five-membered ring has the following structural formula h), i), j), k), or (r): [ka] is selected to have; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted with chlorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0064] A particularly preferred embodiment of the present invention comprises: X, Y and Z are represented by the following formula (h) or (i): [ka] represents a group of; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted with chlorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0065] A particularly preferred embodiment of the present invention comprises: X, Y, and Z are each a compound in which the aromatic five-membered ring is represented by the following structural formula (h) or (i): [ka] is selected to have; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted with chlorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0066] A very particularly preferred embodiment of the present invention is X, Y and Z are represented by the following formula (h): [ka] represents a group of; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen, methyl, ethyl, or trifluoromethyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0067] A very particularly preferred embodiment of the present invention is X, Y, and Z are each a group having the following structural formula h): [ka] is selected to have; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen, methyl, ethyl, or trifluoromethyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0068] A very particularly preferred embodiment of the present invention is X, Y, and Z are each a group having the following structural formula h): [ka] is selected to have; * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R4 represents hydrogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0069] A particular embodiment of the present invention comprises: R1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, pyrazolyl may be substituted by 1 to 2 substituents independently selected from the group consisting of methyl and chlorine; thiazolyl may be substituted by chlorine; thienyl may be substituted by fluorine; The phenyl may be substituted by 1 to 2 substituents, each independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0070] A particularly preferred embodiment of the present invention comprises: R1 represents pyridinyl or phenyl; pyridinyl may be substituted by 1 to 2 substituents independently selected from the group consisting of methyl, ethyl, fluorine, chlorine, trifluoromethyl, and trifluoromethoxy; The phenyl may be substituted with 1 to 2 substituents independently selected from the group consisting of methyl, cyclopropyl, methoxy, cyano, hydroxy, fluorine, chlorine, and trifluoromethyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0071] A very particularly preferred embodiment of the present invention is R1 is a group of the following formula (f): [ka] represents; # is adjacent to -[CHR2] n Shows bond to NR3CO- group It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0072] A particular embodiment of the present invention comprises: R2, represents hydrogen, (C1-C4)-alkyl; (C1-C4)-alkyl may be up to three-substituted by halogen; or Together with the carbon atom to which R2 is attached, it forms a (C3-C4)-cycloalkyl ring. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0073] A particularly preferred embodiment of the present invention comprises: R2 represents hydrogen, methyl, or forms a cyclopropyl ring together with the carbon atom to which R2 is attached. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0074] A very particularly preferred embodiment of the present invention is R2 represents hydrogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0075] A particular embodiment of the present invention comprises: R3 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-Alkyl may be up to three-substituted by halogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0076] A particularly preferred embodiment of the present invention comprises: R3 represents hydrogen or methyl It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0077] A very particularly preferred embodiment of the present invention is R3 represents hydrogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0078] A particular embodiment of the present invention comprises: R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted with chlorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0079] A particularly preferred embodiment of the present invention comprises: R4 represents hydrogen, methyl, ethyl, or trifluoromethyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0080] A very particularly preferred embodiment of the present invention is R4 represents hydrogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0081] A particular embodiment of the present invention comprises: R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0082] A particularly preferred embodiment of the present invention comprises: R5 represents hydrogen or fluorine It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0083] A very particularly preferred embodiment of the present invention is R5 represents hydrogen It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0084] A particular embodiment of the present invention comprises: R6 is a group of the following formula a), b'), b") or c'), c") or e): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 represents hydrogen or methyl; 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, or fluorine; R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0085] A particularly preferred embodiment of the present invention comprises: R6 is a group of the following formula a), c′) or c″): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 represents hydrogen; 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, or fluorine. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0086] A very particularly preferred embodiment of the present invention is R6 is a group of formula a): [ka] represents; *** indicates the bond to the adjacent piperidine ring, R7 represents hydrogen; 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, cyclobutyloxymethyl, cyclopropylmethoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 3-fluorobutyloxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, 2-fluoroethyl, cyclopropyl, cyclobutyl, 2-methoxyethyl, or tert-butyl. It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0087] A particular embodiment of the present invention comprises: n represents 0 or 1 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0088] A particularly preferred embodiment of the present invention comprises: n represents 1 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0089] A particular embodiment of the present invention comprises: m represents 1 or 2 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0090] A particularly preferred embodiment of the present invention comprises: m represents 1 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0091] A particular embodiment of the present invention comprises: p represents 0, 1 or 2 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0092] A particularly preferred embodiment of the present invention comprises: It relates to compounds of formula (I) in which p represents 1.

[0093] A particular embodiment of the present invention comprises: q represents 0 or 2 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0094] A particularly preferred embodiment of the present invention comprises: q represents 2 It relates to compounds of formula (I) and to salts, solvates and solvates of salts thereof.

[0095] The definitions of the individual groups specified in each or preferred combination of groups may also be replaced as desired by the definitions of the groups in other combinations, independently of the individual combinations of groups specified.

[0096] Very particular preference is given to combinations of two or more of the above preferred ranges.

[0097] The present invention further provides a method for preparing a compound of formula (I), or a salt thereof, a solvate thereof, or a solvate of a salt thereof, comprising the steps of: [A] A compound of the following formula (II): [ka] [In the formula, X, Y, Z, R1, R2, R3 and R4 and n have the meanings given above, Hal represents a leaving group, preferably chlorine, bromine, iodine or methylsulfonyl.] in the presence of a base to give a compound of formula (III): [ka] [In the formula, R5, R6 and m have the meanings given above.] to give a compound of formula (IA): [ka] get, or [B] A compound of the following formula (IV): [ka] [In the formula, X, Y, Z, R1, R2, R3, R4 and R5 and n and m have the meanings given above. A compound of formula (V): [ka] [In the formula, R6 has the meaning given above.] and Reaction in the presence of a reducing agent and optionally an acid, preferably an alkali metal borohydride and acetic acid, to give a compound of formula (IB): [ka] get, or [C] A compound of formula (VI): [ka] [In the formula, X, Y, Z, R4, R5 and R6 and n and m have the meanings given above. A compound of formula (VII): [ka] [In the formula, R1, R2, R3 and n have the same meanings as above.] in the presence of a condensing agent or an activating agent, preferably a phosphorus compound, to give a compound of the following formula (IC): [ka] get, The compounds of formula (IA), (IB), (IC) thus obtained can be optionally separated into their enantiomers and / or diastereomers and / or converted into solvates, salts and / or solvates of salts thereof, optionally with a suitable (i) solvent and / or (ii) acid.

[0098] Process Step [A] The reaction of compound (II) with compound (III) to give compound (IA) is carried out by replacing the Hal group in compound (II) with the nitrogen atom of the piperidine ring of compound (III), and the reaction can be carried out, for example, by heating in a solvent or dispersant, depending on the reactivity in the individual case.

[0099] Suitable bases for process step [A] are, in particular, alkali metal carbonates such as sodium carbonate, potassium carbonate, or cesium carbonate, and 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-o-phenanthroline, or 4-N,N-dimethylaminopyridine (DMAP). The base used is preferably sodium carbonate, potassium carbonate, or cesium carbonate. The addition of an alkylation catalyst, such as lithium bromide, sodium iodide, potassium iodide, tetra-n-butylammonium bromide, copper(I) iodide, or benzyltriethylammonium chloride, may be advantageous.

[0100] The base is preferably used in an equimolar amount or an excess amount, usually 1 to 5 times, preferably 5 times, the molar amount.

[0101] Furthermore, the reaction can be palladium-catalyzed using Pd2(dba)3, cesium carbonate as auxiliary base and the following ligands: 1,1'-[1,1'-naphthalene]-2,2'-diylbis[1,1-diphenylphosphine] or 1,1'-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine] (see documents WO2008052934 or WO2015017305).

[0102] Suitable inert solvents for process 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 polar 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-methylpyrrolidinone (NMP). Mixtures of such solvents can also be used. Preferably, acetonitrile or dimethylformamide is used.

[0103] The reaction (II)+(III)→(IA) is generally carried out in the temperature range of 0°C to +150°C, preferably +20°C to +100°C.

[0104] Process Step [B]The reaction of compound (IV) with (V) to obtain compound (IB) in the above is a reductive amination. Suitable reducing agents for reductive amination are alkali metal borohydrides, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, which are common for such purposes; preferably, sodium triacetoxyborohydride is used. The addition of an acid, in particular acetic acid, and / or a dehydrating agent, such as molecular sieves or trimethyl orthoformate or triethyl orthoformate, can be advantageous in these reactions.

[0105] Suitable solvents for these reactions are, in particular, 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, preferably tetrahydrofuran. The reactions are generally carried out in the temperature range from 0°C to +50°C.

[0106] The protecting group PG used in compound (XI) or (XI') can be a standard amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z), or (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc), preferably tert-butoxycarbonyl (Boc). Removal of the protecting group in this process step is carried out by known methods. Thus, the tert-butoxycarbonyl group is typically cleaved by treatment with a strong acid, such as hydrogen chloride, hydrogen bromide, or trifluoroacetic acid, in an inert solvent, such as diethyl ether, 1,4-dioxane, dichloromethane, or acetic acid. In the case of benzyloxycarbonyl as the protecting group, it is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst, such as palladium on activated carbon. The (9H-fluoren-9-ylmethoxy)carbonyl group is generally removed using a secondary amine such as diethylamine or piperidine [see, e.g., TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; PJ Kocienski, Protective Groups, 3 rd edition, Thieme, 2005.]

[0107] Process Step [B]The reaction (VI) + (VII) → (IC) [amide formation] is carried out by known methods using a condensing agent or an activating agent. Suitable such agents include, for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate, or 2-tert-butyl-5-methylisoxazolium 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-methylmorpholinium chloride, phosphorus compounds such as n-propanephosphonic anhydride (PPA, T3P (registered trademark) )), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorophosphate. O-(1H-1-chlorobenzotriazol-1-yl)-1,1,3,3-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)-pyridyl)-1,1,3,3-Tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with further auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), suitable bases are alkali metal carbonates such as sodium carbonate or potassium carbonate, or tertiary amine bases such as triethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), DIPEA, pyridine, or 4-N,N-dimethylaminopyridine (DMAP). A preferred condensing or activating agent is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in combination with N,N-diisopropylethylamine as the base.

[0108] Suitable inert solvents for these amide-forming reactions include, 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; halohydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene, or chlorobenzene; or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU), or N-methylpyrrolidinone (NMP); mixtures of such solvents can also be used. Preferably, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, or mixtures of these solvents are used. The reaction is generally carried out within a temperature range of -20°C to +60°C, preferably 0°C to +40°C.

[0109] For their part, compounds of formula (II) can be prepared by methods known from the literature [amide formation] from the following amines (VII): [ka] [In the formula, R1, R2 and R3 and n have the meanings given above. Under the influence of a condensing agent or an activating agent, a compound of formula (X): [ka] [In the formula, X, Y, Z, R4 and Hal have the meanings given above, A compound of formula (II): [ka] It can be produced by obtaining

[0110] Compounds of formula (III) can be prepared by a method known from the literature [amide formation] from the following amines (V): [ka] [In the formula, R6 has the meaning given above. A protected piperidine derivative of formula (XI): [ka] [In the formula, R5 and m have the meanings given above, PG represents a suitable amino protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, or (9H-fluoren-9-ylmethoxy)carbonyl, A compound of formula (III′): [ka] wherein PG, R5, R6 and m have the meanings given above, Next, the protecting group PG is removed to give a compound of the following formula (III): [ka] It can be produced by obtaining

[0111] Compounds of formula (IV) can be prepared by a method known from the literature [alkylation] to give compounds of formula (II): [ka] wherein X, Y, Z, R1, R2, R3 and R4, Hal and n have the meanings given above, In the presence of a base, a compound of formula (XII): [ka] wherein R5 and m have the meanings given above, Cleavage under acidic conditions then gives a compound of formula (IV): [ka] It can be produced by obtaining

[0112] For their part, compounds of formula (VI) can be converted by methods known from the literature [alkylation] to compounds of formula (XIII): [ka] wherein X, Y, Z, R4 and Hal have the meanings given above, T1 represents -O-(C1-C4)-alkyl. In the presence of a base, a compound of formula (III): [ka] wherein R5, R6 and m have the meanings given above, By hydrolysis under conditions known from the literature, compounds of formula (VI): [ka] It can be produced by obtaining

[0113] The hydrolysis of the ester group T1 is carried out by conventional methods by treating the ester with an acid or a base in an inert solvent; in the latter case, the salt formed initially is converted to the corresponding carboxylic acid by treatment with an acid. In the case of tert-butyl esters, the ester hydrolysis is preferably carried out with an acid.

[0114] Suitable inert solvents for these reactions are water or organic solvents commonly used in 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, it is preferred to use mixtures of water with dioxane, tetrahydrofuran, methanol, ethanol, and / or dimethylformamide. In the case of the reaction with trifluoroacetic acid, it is preferred to use dichloromethane, and in the case of the reaction with hydrogen chloride, it is preferred to use tetrahydrofuran, diethyl ether, dioxane, or water.

[0115] Suitable bases are the usual inorganic bases. These include, in particular, 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.

[0116] Suitable acids for ester hydrolysis are usually 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.

[0117] Ester hydrolysis is generally carried out within a temperature range of -20°C to +120°C, preferably 0°C to +80°C.

[0118] The preparation of the compounds according to the invention can be illustrated by way of example by the following reaction schemes.

[0119] Diagram 1 [ka]

[0120] Diagram 2 [ka]

[0121] Diagram 3 [ka]

[0122] The compounds of the present invention have valuable pharmacological properties and can be used in the prevention and treatment of diseases in humans and animals.

[0123] The compounds according to the present invention are 2C - a potent and selective antagonist of adrenergic receptors, and therefore, is effective in the treatment of disorders and pathological processes, especially those caused by or activated by α 2C - those triggered by adrenergic receptors and α 2C-Suitable for the treatment and / or prevention of diseases secondary to adrenoceptor-related damage.

[0124] The compounds according to the invention are used in a method for the treatment and / or prevention of respiratory distress, swallowing disorders, peripheral and cardiovascular disorders and disorders of the peripheral and central nervous system.

[0125] The compounds according to the invention may also be used in methods 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 disorders of the peripheral and central nervous system, including neurodegenerative and neuroinflammatory disorders.

[0126] In the context of the present invention, these include, in particular, disorders such as, for example, dyspnea and sleep-induced dyspnea, in particular obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome), central sleep apnea, Schein-Stokes respiration, primary sleep apnea of ​​early childhood, central sleep apnea as a result of an obvious life-threatening event, the use of medicines or the use of other substances, obesity hypoventilation syndrome, disturbances of the 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 high-altitude adaptation, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0127] The compounds according to the invention are preferably used in a method for the treatment and / or prevention of 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, Shine-Stokes respiration, primary sleep apnea of ​​early childhood, central sleep apnea as a result of an obvious life-threatening event, the use of medicines or the use of other substances, obesity hypoventilation syndrome, disturbances of central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during high altitude adaptation, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0128] In the context of the present invention, peripheral and cardiovascular disorders include diabetic microangiopathy, especially diabetic ulcers of the extremities for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolism and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0129] Also preferably, the compounds according to the invention are used in a method for the treatment and / or prevention of peripheral and cardiovascular disorders, including diabetic microangiopathy, in particular diabetic ulcers of the limbs for the promotion of wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolism and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0130] Furthermore, the compounds according to the invention may be used to treat dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHS), Tourette's syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm and other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by alterations in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease. The compounds may be used in methods for the treatment and / or prevention of disorders of the peripheral and central nervous system, such as progressive supranuclear palsy, corticobasal degeneration, tauopathy, chromosome 17-linked frontotemporal dementia and parkinsonism, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedreich's ataxia, dentate-papillary-gel atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxial dystrophy, neurodegeneration associated with brain iron accumulation, ubiquitin-proteasome system-mediated frontotemporal lobar degeneration, and familial encephalopathy associated with neuroserpin inclusion.

[0131] The compounds according to the invention are preferably used in a method for the treatment and / or prevention of disorders of the peripheral and central nervous system such as dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHS), Tourette's syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm and other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by alterations in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0132] The compounds according to the invention may be used to treat dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity, Tourette's syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm and other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by alterations in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease. It is also used in methods for the treatment and / or prevention of disorders of the peripheral and central nervous system such as progressive supranuclear palsy, corticobasal degeneration, tauopathies, chromosome 17-linked frontotemporal dementia and parkinsonism, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedreich's ataxia, dentate-papillary-colloid atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxial dystrophy, neurodegeneration associated with brain iron accumulation, ubiquitin-proteasome system-mediated frontotemporal lobar degeneration, and familial encephalopathy associated with neuroserpin inclusion.

[0133] The compounds of the present invention may further be used to treat cardiovascular disorders such as cardiac arrhythmias, atrial and ventricular rhythm disorders and conduction disorders, e.g. atrioventricular block of degree I to III, supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes tachycardia, premature atrial and ventricular extrasystoles, premature atrioventricular junctional beats, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, high blood pressure (hypertension), 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 disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, shock, e.g. cardiogenic shock, septic shock They can be used for the treatment and / or prevention of shock and anaphylactic shock, etc., further for the treatment and / or prevention of thromboembolic disorders and ischemia, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, pre-eclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasm, edema formation, such as pulmonary edema, cerebral edema, renal edema or edema due to heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial dysfunction, endothelial dysfunction, microvascular and macrovascular damage (vasculitis), etc., and also for the prevention of, for example, thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, restenosis after bypass surgery, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH).

[0134] In the context of the present invention, the term "heart failure" includes both acute and chronic forms of heart failure, and also specific or related disease forms thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valve regurgitation, combined heart valve defects, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure.

[0135] The compounds of the invention may also be used for the treatment and / or prevention of various severe asthmatic disorders of an intermittent or persistent nature (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, asthmatic asthma), bronchiectasis, pneumonia, farmer's lung and related diseases, coughs and colds (chronic inflammatory cough, ectopic cough), inflammation of the nasal mucosa (rhinitis medicamentosa, vasomotor rhinitis and seasonal allergic rhinitis, e.g., hay fever) and polyps.

[0136] Furthermore, the compounds of the present invention are also suitable for treating and / or preventing renal disorders, especially renal insufficiency and renal failure.In the context of the present invention, the term "renal insufficiency" and "renal failure" refer to both acute and chronic manifestations thereof, as well as underlying renal disorders or related renal disorders, such as renal blood flow reduction, dialysis hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephropathic disorders such as primary and congenital kidney disease, nephritis, immune-mediated kidney disorders such as renal transplant rejection and immune complex-induced kidney disorders, toxic substance-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, These conditions include pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, which can be diagnostically characterized by, for example, abnormally low creatinine and / or water excretion, abnormally elevated blood levels of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes, such as glutamyl synthetase, altered urine osmolality or volume, elevated microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the present invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.

[0137] In addition, the compounds according to the invention are suitable for the treatment and / or prevention of disorders of the urogenital system, such as benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract symptoms (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 also erectile dysfunction and female sexual dysfunction.

[0138] The compounds of the present invention are further suitable for the treatment and / or prevention of inflammatory and autoimmune disorders, such as, for example, rheumatic 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 (e.g. smoking-induced emphysema), cystic fibrosis (CF), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, and also for the treatment and / or prevention of fibrotic disorders of internal organs, such as the lungs, heart, kidneys, bone marrow and especially the liver, as well as dermatological fibrosis and ocular fibrotic disorders. In the context of the present invention, the term "fibrotic disorders" includes, inter alia, disorders such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic lesions caused by diabetes, myelofibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (e.g., sarcoidosis). The compounds of the present invention can also be used cosmetically to promote wound healing, for example, to inhibit postoperative scarring after glaucoma surgery, and for aging or keratinized skin.

[0139] Moreover, the compounds of the present invention are suitable for the treatment and / or prevention of neoplastic diseases, such as skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

[0140] Furthermore, the compounds of the present invention are useful in the treatment of arteriosclerosis, disorders of lipid metabolism and dyslipidemia (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined dyslipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, adiposity, obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, gestational diabetes mellitus, hyperinsulinemia, insulin resistance, impaired glucose tolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), anemias such as hemolytic anemia, hemoglobinopathies such as sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, and the like. anemia due to blood, acute hemorrhagic anemia, replacement 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, liver cirrhosis, pancreatitis and cholecystitis), disorders of the central nervous system and neurodegenerative disorders (stroke, epilepsy, depression), immune disorders, thyroid disorders (hyperthyroidism), skin disorders (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, as well as keratitis, bullous diseases, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian syndrome syndrome, scar formation, wart formation, chilblains), ocular inflammatory diseases (sarcoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (due to influenza, adeno- and coronaviruses, e.g., HPV, HCMV, HIV, SARS), disorders of the skeletal bones and joints and skeletal muscles, inflammatory changes of the arteries (various forms of arteritis, e.g., endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arteritis, arteritis deformans, arteritis temporalis, arteritis cranialis, arteritis gigantocellularis, and arteritis granulomatousgranulomatosa, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), Muckle-Wells syndrome, Kikuchi's disease, polychondritis, dermatosclerosis, and other disorders with an inflammatory or immune component, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sézary syndrome and paraneoplastic syndromes, in rejection after organ transplantation, and in wound healing and angiogenesis, especially in the case of chronic wounds.

[0141] Due to their property profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of respiratory distress, including central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders including diabetic microangiopathy, disorders of the peripheral and central nervous system, including neurodegenerative and neuroinflammatory disorders.

[0142] The well-characterized diseases described above in humans can occur in other mammals with comparable etiologies and can likewise be treated with the compounds of the present invention.

[0143] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, checking, mitigating, attenuating, limiting, reducing, suppressing, warding off or curing a disease, condition, disorder, injury or health problem, or of the development, course or progression of such a condition and / or symptoms of such a condition. Herein, the term "therapy" is understood to be synonymous with the term "treatment."

[0144] The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and refer to avoiding or reducing the risk of contracting, experiencing, suffering from or having a disease, condition, disorder, injury or health problem, or developing or progressing such a condition and / or symptoms of such a condition.

[0145] The treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.

[0146] Accordingly, the present invention further provides the use of the compounds of the invention for the treatment and / or prevention of disorders, especially the disorders mentioned above.

[0147] The present invention further provides the use of the compounds of the invention for the preparation of a medicament for the treatment and / or prevention of disorders, especially the disorders mentioned above.

[0148] The present invention further provides medicaments comprising at least one compound of the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0149] The present invention further provides the use of the compounds of the invention in a method for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above.

[0150] The present invention further provides a method for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above, using an effective amount of at least one compound of the invention.

[0151] The compounds of the present invention can be used alone or, if necessary, in combination with one or more pharmacologically active substances, provided that this combination does not lead to undesirable or unacceptable side effects. Thus, the present invention further provides medicaments comprising at least one compound of the present invention and one or more other active ingredients, in particular for the treatment and / or prevention of the above-mentioned disorders. Examples of suitable combinations of active ingredients in this regard include the following:

[0152] TASK1 channel and TASK3 channel blockers, such as, by way of example and preferably, those disclosed in WO2017 / 097792A1, WO2017 / 097671A1, WO2018 / 015196A1, WO2018 / 228907A1, WO2018 / 228909A1; P2X3 receptor antagonists, such as, by way of example and preferably, gefapixant; Respiratory stimulants such as, by way of example and preferably, theophylline, doxapram, nikethamide, caffeine; Psychostimulants, for example and preferably modafinil, armodafinil; Amphetamine and amphetamine derivatives, by way of example and preferably amphetamine, methamphetamine, methylphenidate; Serotonin reuptake inhibitors, by way of example and preferably fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine, trazodone; Serotonin precursors, for example and preferably L-tryptophan; Selective serotonin-noradrenaline reuptake inhibitors, for example and preferably venlafaxine, duloxetine; noradrenergic and specific serotonergic antidepressants, for example and preferably mirtazapine; Selective noradrenaline reuptake inhibitors, by way of example and preferably atomoxetine, reboxetine; Muscarinic receptor antagonists, for example and preferably oxybutynin; Tricyclic antidepressants, by way of example and preferably, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine, desipramine; GABAergic drugs, for example and preferably baclofen; alpha sympathomimetics, by way of example and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrizoline, tramazoline; Glucocorticoids, by way of example and preferably, fluticasone, budesonide, beclomethasone, mometasone, tixocortol pivalate, triamcinolone acetonide; ·Cannabinoid receptor agonists and antagonists; Carboanhydrase inhibitors, by way of example and preferably acetazolamide, methazolamide, diclofenamid; Opioid and benzodiazepine receptor antagonists, by way of example and preferably flumazenil, naloxone, naltrexone; Cholinesterase inhibitors, by way of example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine, rivastigmine; N-methyl-D-aspartate and glutamate antagonists, by way of example and preferably amantadine, memantine, sabeluzole; Nicotinic receptor agonists; Leukotriene receptor antagonists, by way of example and preferably, montelukast, tripelukast; Dopamine receptor antagonists, by way of example and preferably dromperidone, metoclopramide, benzamides, butyrophenones, phenothiazines; Appetite suppressants, by way of example and preferably sibutramine, topiramate, lipase inhibitors, cannabinoid receptor antagonists, phentermine; Proton pump inhibitors, by way of example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole; antihypertensive compounds, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists and diuretics; active compounds which alter lipid metabolism, by way of example and preferably thyroid receptor agonists, cholesterol synthesis inhibitors, by way of example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPARα, PPARγ and / or PPARδ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists; Azo organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; 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, in particular PDE5 inhibitors (sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, miclodenfil or rhodenafil; NO- and heme-independent activators of soluble guanylate cyclase (sGC), such as, in particular, the compounds described in WO01 / 19355, WO01 / 19776, WO01 / 19778, WO01 / 19780, WO02 / 070462 and WO02 / 070510; NO-independent but heme-dependent stimulators of soluble guanylate cyclase (sGC), such as, in particular, riociguat and the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301, WO03 / 095451, WO2011 / 147809, WO2012 / 004258, WO2012 / 028647 and WO2012 / 059549; Compounds that affect cardiac energy metabolism, by way of example and preferably etomoxir, dichloroacetate, ranolazine, or trimetazidine; antithrombotic agents, for example and preferably from the group consisting of platelet aggregation inhibitors, anticoagulants, and antifibrinolytic substances; anti-obstructive agents used, for example, in the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, such as, by way of example and preferably, from the group of inhaled or systemically administered beta-adrenergic receptor agonists (betamimetics) and inhaled antimuscarinic agents; anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, for example and preferably systemically or inhaled corticosteroids, further dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferon, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tripelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN-γ, pirfenidone or etanercept; compounds that inhibit signal transduction cascades, by way of example and preferably from the group of kinase inhibitors, in particular tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazupanib, vatanib, gefitinib, erlotinib, lapatinib, canatinib, lestaurtinib, peritinib, semixanib or tandoctinib; prostacyclin analogues and IP receptor agonists, by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol or selexipag; Endothelin receptor antagonists, by way of example and preferably bosentan, darzentan, ambrisentan or sitaxsentan; compounds that inhibit human neutrophil elastase (HNE), for example and preferably sivelestat or DX-890 (Reltran); compounds that inhibit the degradation and alteration of the extracellular matrix, by way of example and preferably inhibitors of matrix metalloproteinases (MMPs), in particular stromelysins, collagenases, gelatinases and aggrecanases (in this context in particular MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastases (MMP-12); Compounds that inhibit the binding of serotonin to receptors, for example and preferably 5-HT, such as PRX-08066 2B receptor antagonists; antagonists of growth factors, cytokines and chemokines, by way of example and preferably TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrin antagonists; Rho kinase inhibitor compounds, for example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; and / or Antifibrotic agents, by way of example and preferably, pirfenidone, lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF- antagonists.

[0153] In a particularly preferred embodiment of the invention, the compounds of the invention are administered in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulants, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

[0154] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a β-adrenergic receptor agonist, for example and preferably albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0155] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antimuscarinic agonist, for example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0156] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid, for example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

[0157] Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

[0158] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

[0159] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, for example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or clexane.

[0160] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a GPIIb / IIIa antagonist, for example and preferably tirofiban or abciximab.

[0161] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV803, SSR-126512 or SSR-128428.

[0162] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0163] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin.

[0164] Antihypertensive agents are preferably understood to mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

[0165] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0166] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, for example and preferably prazosin.

[0167] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a β-receptor blocker, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, calazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0168] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

[0169] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0170] In a preferred embodiment of the invention, the inventive compounds are administered in combination with an endothelin antagonist, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.

[0171] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, for example and preferably aliskiren, SPP-600 or SPP-800.

[0172] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably spironolactone, eplerenone or finerenone.

[0173] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic, for example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerin, isosorbide, mannitol, amiloride or triamterene.

[0174] Lipid metabolism modifiers are preferably understood to mean compounds from the group of 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 sequestrants, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0175] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, for example and preferably torcetrapib (CP-529414), JJT-705 or CETP vaccine (Avant).

[0176] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist, for example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or axityrom (CGS26214).

[0177] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of the statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0178] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.

[0179] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, for example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0180] In a preferred embodiment of the invention, the inventive compounds are administered in combination with an MTP inhibitor, for example and preferably implitapide, BMS-201038, R-103757 or JTT-130.

[0181] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a PPAR-γ agonist, for example and preferably pioglitazone or rosiglitazone.

[0182] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a PPAR-δ agonist, for example and preferably GW501516 or BAY68-5042.

[0183] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a cholesterol absorption inhibitor, for example and preferably ezetimibe, tiqueside or pamaqueside.

[0184] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a lipase inhibitor, by way of example and preferably orlistat.

[0185] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent, for example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0186] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid reabsorption inhibitor, for example and preferably an ASBT (=IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0187] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, for example and preferably gemcabene calcium (CI-1027) or nicotinic acid.

[0188] Particularly preferred is the combination of the compounds of the present invention with one or more further active compounds selected from the group of respiratory stimulants, psychostimulants, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulators, immunosuppressants and cytotoxic agents.

[0189] If necessary, the compounds of the present invention can be used in combination with one or more other medical means, provided that the combination does not cause undesirable and unacceptable side effects. Preferred examples of medical means suitable for this purpose include:

[0190] Devices for positive airway pressure ventilation, for example and preferably CPAP (continuous positive airway pressure) devices, BiPAP (bilayer positive airway pressure) devices, and IPPV (intermittent positive pressure ventilation) devices Hypoglossal nerve stimulator Intraoral devices, for example and preferably protrusion braces Disposable nasal valves Nasal stents.

[0191] The present invention further provides medicaments comprising at least one compound of the invention, typically together with one or more inert, non-toxic pharmaceutically suitable excipients, and their use for the above purposes.

[0192] The compounds of the invention can act systemically and / or locally, and in this respect they can be administered in any suitable way, for example orally, parenterally, pulmonary, nasal, pharyngeal, sublingual, lingual, buccal, rectal, cutaneous, transdermal, conjunctival or otic, or as an implant or stent.

[0193] The compounds of the present invention can be administered in dosage forms suitable for these administration routes.

[0194] Dosage forms suitable for oral administration are dosage forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolving form which function according to conventional techniques to provide rapid and / or modified release of the compounds of the invention, such as tablets (uncoated tablets or uncoated or coated tablets which control the release of the compounds of the invention, e.g. gastric acid resistant or slow-dissolving or insoluble), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0195] Parenteral administration can bypass the absorption step (for example, intravenous, arterial, intracardiac, intraspinal, or intralumbar) or include absorption (for example, by inhalation, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Suitable dosage forms for parenteral administration include injectable and infusible preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0196] For other routes of administration, suitable examples are inhalable pharmaceutical forms (powder inhalers, nebulizers, metered dose aerosols, etc.), nasal drops, solutions or sprays, throat sprays, tablets for lingual, sublingual or buccal administration, films / wafers or capsules, suppositories, ear or ocular preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents.

[0197] Oral, parenteral and topical administration are preferred, especially oral, intravenous, intranasal and pharyngeal administration.

[0198] The compounds of the present invention can be converted into the above-mentioned dosage forms by mixing them with inert, non-toxic, pharmaceutically suitable excipients in a manner known per se. These excipients include:

[0199] The compounds of the present invention can be converted into the mentioned dosage forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, inter alia, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxide), and flavorings and / or odor correctors.

[0200] In general, it has been found advantageous to achieve effective results by administering about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg, for parenteral administration. For oral administration, the dose is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, and most preferably about 0.1 to 10 mg / kg. For pulmonary administration, the amount is usually about 0.1 to 50 mg per inhalation.

[0201] Nevertheless, in some cases it may be necessary to deviate from the amounts mentioned above, in particular depending on the body weight, the route of administration, the individual's response to the active ingredient, the nature of the formulation and the time or interval of administration. Thus, in some cases it may be sufficient to manage with amounts less than the minimum amounts mentioned above, while in other cases the upper limit mentioned above must be exceeded. When administering relatively large amounts, it may be advisable to divide these into several individual doses over the course of a day.

[0202] The following examples are illustrative of the present invention, but are not intended to limit the scope of the present invention.

[0203] A. Working Example Abbreviations and Acronyms Abs.: Pure Ac: Acetyl aq.: aqueous, aqueous solution Boc: tert-butoxycarbonyl br.: broad (in NMR signal) Example: Example Bu: butyl c: Concentration cat.:catalyst CI: Chemical ionization (with MS) d: doublet (in NMR) d:day DCI: Direct Chemical Ionization (MS) dd: double doublet (NMR) diamix: a mixture of diastereomers DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide dq: double quartet (in NMR) dt: double triplet (in NMR) ot: theoretical value (chemical yield) EI: Electron impact ionization (MS) eq.: equivalent ESI: Electrospray ionization (MS) Et: Ethyl h: time HATU:O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt: 1-hydroxy-1H-benzotriazole hydrate HPLC: High-Pressure High-Performance Liquid Chromatography iPr: Isopropyl Conc.: Concentrated (in the case of a solution) LC: liquid chromatography LC-MS: Liquid chromatography-coupled mass spectrometry lit.: Literature (References) m: multiplet (in NMR) Me: Methyl min:minutes MS: Mass spectrometry NMR: nuclear magnetic resonance spectroscopy Ph: Phenyl Pr: Propyl q: quartet (in NMR) quant: quantitative (chemical yield) RP: reversed phase (HPLC) RT: room temperature R t : Retention time (HPLC, LC-MS) s: singlet (in NMR) t: triplet (in NMR) tBu: tert-butyl TFA: Trifluoroacetic acid THF: tetrahydrofuran UV: Ultraviolet spectroscopy v / v: volume ratio (of solution) tog.:Together.

[0204] LC-MS, GC-MS and HPLC methods Method 1 (LC-MS): 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 L water + 0.01% formic acid; mobile phase B: 1 L 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.

[0205] Method 2 (LC-MS): MS instrument type: Waters TOF instrument; UPLC instrument type: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Mobile phase A: 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.

[0206] Method 3 (GC-MS): Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; Column: Restek RTX-35MS, 15 m x 200 μm x 0.33 μm; Helium constant flow: 1.20 mL / min; Oven: 60 °C; Inlet: 220 °C; Gradient: 60 °C, 30 °C / min → 300 °C (hold for 3.33 min).

[0207] Method 4 (LC-MS): Apparatus: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Mobile phase A: 1 L water + 0.25 mL 99% strength formic acid, Mobile phase B: 1 L acetonitrile + 0.25 mL 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.

[0208] Method 5 (LC-MS): Apparatus: Waters Single Quad MS System; Apparatus: Waters UPLC Acquity; Column: Waters BEH C18 1.7μ 50 × 2.1 mm; Mobile phase A: 1 L water + 1.0 mL (25% strength ammonia) / L, Mobile phase B: 1 L 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.

[0209] Method 6 (LC-MS): MS instrument: Waters SQD2 HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm × 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.

[0210] Method 7 (preparative HPLC): Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm.

[0211] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume). Total flow rate: 80 mL / min, room temperature, wavelength: 200-400 nm, at-column injection (complete injection).

[0212] Gradient profile: Mobile phase A 0 to 2 min 47 mL, mobile phase B 0 to 2 min 23 mL, mobile phase A2 to 10 min 47 mL to 23 mL and mobile phase B2 3 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 had a constant flow rate of 5 mL / min over the entire run time.

[0213] Method 8 (preparative HPLC): Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm.

[0214] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume). Total flow rate: 80 mL / min, room temperature, wavelength: 200-400 nm, at-column injection (complete injection).

[0215] Gradient profile: Mobile phase A 0 to 2 min 63 mL, mobile phase B 0 to 2 min 7 mL, mobile phase A2 to 10 min 63 mL to 39 mL and mobile phase B 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 each had a constant flow rate of 5 mL / min over the entire run time.

[0216] Method 9 (preparative HPLC): Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm.

[0217] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume). Total flow rate: 80 mL / min, room temperature, wavelength: 200-400 nm, at-column injection (complete injection).

[0218] Gradient profile: Mobile phase A 0 to 2 min 55 mL, mobile phase B 0 to 2 min 15 mL, mobile phase A2 to 10 min 55 mL to 31 mL and mobile phase B 15 mL to 39 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 had a constant flow rate of 5 mL / min over the entire run time.

[0219] Method 10 (preparative HPLC): Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm.

[0220] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume). Total flow rate: 80 mL / min, room temperature, wavelength: 200-400 nm, at-column injection (complete injection).

[0221] Gradient profile: Mobile phase A 0 to 2 min 39 mL, mobile phase B 0 to 2 min 31 mL, mobile phase A2 to 10 min 39 mL to 15 mL and mobile phase B 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 each had a constant flow rate of 5 mL / min over the entire run time.

[0222] Method 11 (preparative HPLC): Apparatus: Abimed Gilson 305; Column: Reprosil C18 10 μm, 250 mm × 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.

[0223] Method 12 (LC-MS): Apparatus: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Mobile phase A: 1 L water + 0.25 mL 99% strength formic acid, Mobile phase B: 1 L acetonitrile + 0.25 mL 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.

[0224] Further details: below 1 Descriptions of coupling patterns for H NMR signals are based on the visual appearance of the signal and do not necessarily correspond to a strict physical interpretation. Generally, chemical shifts reported refer to the center of the signal of interest, and intervals are usually reported in the case of broad multiplets.

[0225] 1 All values ​​in the H NMR spectrum indicate chemical shifts δ [ppm] in ppm.

[0226] provided in the paragraphs below 1 The multiplicity of proton signals in H NMR spectra indicates the signal shape observed in each case, and does not take into account higher-order signal phenomena. Generally, chemical shift descriptions are relative to the center of the signal of interest. Signals that are obscured by solvent or water are tentatively assigned or not listed. Signals that are highly broadened, for example, by rapid rotation of parts of the molecule or due to proton exchange, are likewise tentatively assigned (often called broad multiplets or broad singlets) or not listed.

[0227] Selected Synthetic Intermediates and Examples 1 H NMR data in some cases 1The peaks are written in the form of a H-NMR peak list. For each signal peak, the δ value (in ppm) is listed first, followed by the signal intensity in parentheses. Pairs of δ [ppm] value / signal intensity numbers for different signal peaks are listed, separated from each other by commas. Thus, the peak list in one example has the following form: δ [ppm] 1 (intensity 1), δ [ppm] 2 (intensity 2), ..., δ [ppm] i (strength i ), ..., δ [ppm] n (strength n ).

[0228] The intensity of a sharp signal correlates with the signal height in a printout of the NMR spectrum in cm, and shows the true ratio of signal intensities compared to other signals. For broad signals, several peaks or the center of the signal and their relative intensities compared to the most intense signal in the spectrum can be shown. 1 The list of H NMR peaks is 1 As it is similar to a 1 H NMR printout, it usually contains all the peaks listed in the traditional NMR interpretation. 1 Like H NMR prints, they may show solvent signals, signals of stereoisomers of the target compound (also provided by the present invention) and / or signals of impurity peaks. The peaks of stereoisomers of the target compound and / or peaks of impurities usually have generally lower intensities than the peaks of the target compound (e.g., purity >90%). Such stereoisomers and / or impurities may be representative of a particular manufacturing method. Therefore, these peaks may be useful in this case to check the reproducibility of our manufacturing method by referring to the "by-product fingerprint". Experts who calculate the peaks of the target compound by known methods (MestreC, ACD simulations, or using empirically evaluated expectation values) can separate the peaks of the target compound using different intensity filters as needed. This separation is not possible with traditional methods. 1 It is believed to be similar to the selection of peaks of interest in 1 H NMR interpretation.

[0229] A detailed description of the display of NMR data in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (Research Disclosure Database Number 605005, 2014, August 1, 2014 or see http: / / www.researchdisclosure.com / searching-disclosures). In the peak selection routine described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be set to 1%-4%. Depending on the type of chemical structure and / or the concentration of the compound being analyzed, it may be desirable to set the parameter "MinimumHeight" to a value <1%.

[0230] Melting points and melting point ranges, when given, are uncorrected.

[0231] When the reaction products were obtained by grinding, stirring, or recrystallization, it was often possible to isolate additional amounts of product from the respective mother liquors by chromatography, which will not be discussed further below, except in cases where a significant portion of the total yield can be isolated only at this stage.

[0232] Any reactant or reagent whose preparation is not expressly described below was purchased commercially from a publicly accessible source. For all other reactants or reagents whose preparation is also not described below and which were not commercially available or obtained from sources that were not publicly accessible, reference is made to published literature describing their preparation.

[0233] Starting materials and intermediates: Example 1A 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] 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 74.4 mL (124.98 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was added dropwise to the reaction solution. After the addition was complete, the reaction solution was allowed to warm to room temperature and stirred at this temperature for 4 h. Approximately 250 mL of water was added to the solution. The resulting aqueous phase was extracted three times with ethyl acetate. The combined organic phases were then filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was triturated with diethyl ether and air-dried. This gave 27.3 g (81.7 mmol, 85% of theory) of the target product as a pale beige solid. The collected 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 over 15 CV (CV = column volume) → cyclohexane / ethyl acetate 1:1). This gave an additional 2.1 g (6.28 mmol, 6.5% of theory) of the target compound as a white solid.

[0234] 1 H-NMR (600 MHz, DMSO-d6, 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).

[0235] LC-MS (Method 1):R t =1.38 min; m / z=333 / 335(M+H) + .

[0236] In analogy to Example 1A, the following compounds Examples 2A to 8A were prepared from the starting materials indicated in each case.

[0237] [Table 1] TIFF0007748938000054.tif198159TIFF0007748938000055.tif73159

[0238] Example 9A N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-thiazole-5-carboxamide [ka] 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. 1.29 g (8.98 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane was weighed into the reaction solution, which was then stirred overnight at reflux. After cooling, the reaction mixture was directly loaded 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 over 15 CV (CV = column volume) → ethyl acetate). The resulting 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 pale beige solid.

[0239] 1H-NMR (600 MHz, DMSO-d6, 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).

[0240] LC-MS (Method 2):R t =0.73min;m / z=397(M+H) + .

[0241] Example 10A N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide [ka] 2.3 g (5.80 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-thiazole-5-carboxamide was dissolved in 15 mL of acetone, and 15 mL of semi-concentrated aqueous hydrochloric acid was added. The reaction solution was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator and then taken up in water. The aqueous solution was adjusted to pH 7 with saturated sodium bicarbonate solution. The resulting precipitate was filtered off with suction, washed repeatedly with water, and dried under reduced pressure. This gave 1.96 g (5.49 mmol, 95% of theory) of the target compound as a white solid.

[0242] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 2.48-2.56 (t, 4H, partially obscured 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).

[0243] LC-MS (Method 1):Rt =1.09min;m / z=353(M+H) + .

[0244] Example 11A 3-[(3,3-difluorocyclobutyl)methoxy]pyridine [ka] 2 g (21.03 mmol) of pyridin-3-ol was dissolved in 40 mL of THF, and 7.17 g (27.34 mmol) of triphenylphosphine was added. The clear solution was cooled to 0 °C. To the resulting suspension, an additional 30 mL of THF was added. 5.53 g (27.34 mmol) of diisopropyl azodicarboxylate was added to the suspension, and the mixture was stirred at this temperature for 5 minutes. 3.34 g (27.34 mmol) of (difluorocyclobutyl)methanol dissolved in 10 mL of THF was added dropwise, and after the addition was complete, the ice bath was removed. After stirring at room temperature for approximately 1 hour, a clear yellow solution was formed, which was stirred at this temperature overnight. Water was added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, separated, filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was stirred with approximately 150 mL of cyclohexane. The precipitated triphenylphosphine oxide was filtered off with suction and washed repeatedly with cyclohexane. The filtrates were combined and concentrated to dryness under reduced pressure. This gave 3.69 g (18.52 mmol, 88% of theory) of the target compound as a yellow oil. The target compound was used in further reactions without further purification.

[0245] 1H-NMR (600 MHz, DMSO-d6, δ / ppm): 2.42-2.55 (m, 2H, partially obscured 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).

[0246] LC-MS (Method 1):R t =1.12 min; m / z=200(M+H) + .

[0247] Example 12A 3-[(3,3-Difluorocyclobutyl)methoxy]piperidine acetate (1:1) (racemic) [ka] 2.5 g (12.55 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy]pyridine was dissolved in 20 mL of glacial acetic acid and hydrogenated using an H-Cube (ThalesNano H-Cube Pro™-1.7).

[0248] Reaction conditions: Catalyst: Pd / C 10%; Solvent: Glacial acetic acid; Cartridge pressure: 80 bar hydrogen; Flow rate: 1 mL / min; Temperature: 80°C.

[0249] After the reaction was completed, the reaction mixture was concentrated to dryness.The obtained residue was dried under reduced pressure at room temperature overnight.This gave 4.2 g of the target compound as a yellow oil.The target compound was used in further reactions without further purification.

[0250] GC-MS (method 3):R t =3.87min;m / z=205(M-C2H4O2) + .

[0251] Example 13A Benzyl 3-(difluoromethyl)[1,4'-bipiperidine]-1'-carboxylate (racemic) [ka] 1 g (4.29 mmol) of benzyl 4-oxopiperidine-1-carboxylate, 883 mg (5.14 mmol) of 3-(difluoromethyl)piperidine hydrochloride (1:1), and 0.9 mL (5.14 mmol) of N,N-diisopropylethylamine (a small amount of 4 Å molecular sieves was added to the reaction solution) in 15 mL of dichloromethane were stirred at room temperature for 1 hour. 1.363 g (6.43 mmol) of sodium acetoxyborohydride was added, and the reaction mixture was continued to stir at room temperature overnight. The molecular sieves were filtered off and washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This gave 1.39 g (3.54 mmol, 89% purity, 83% of theory) of the target compound as a clear, colorless oil, which was used in further reactions without further purification.

[0252] LC-MS (Method 1):R t =1.04 min; m / z=353(M+H) + .

[0253] In a similar manner to Example 13A, the following compounds Examples 14A to 17A were prepared from the starting materials indicated in each case.

[0254] [Table 2] TIFF0007748938000062.tif161159

[0255] Example 18A rac-Benzyl 3-(hydroxymethyl)[1,4'-bipiperidine]-1'-carboxylate [ka] Acetic acid (1.8 mL, 32 mmol) was added to a solution of rac-benzyl 4-oxopiperidine-1-carboxylate (5.00 g, 21.4 mmol) and piperidin-3-ylmethanol (4.94 g, 42.9 mmol) in dichloromethane (50 mL), and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (5.45 g, 25.7 mmol) was added to the reaction mixture, and stirring at room temperature was continued. After 2 hours, saturated NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration under suction, the filtrate was concentrated, and the residue was applied to Isolute®. The mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 100 g; DCM / MeOH gradient: 2% MeOH - 20% MeOH; flow rate 100 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum, which gave 4.37 g of the target compound (100% pure, 61% of theory).

[0256] LC-MS (Method 1):R t =0.92min;MS(ESIpos):m / z=333[M+H] + .

[0257] Example 19A rac-Benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, rac-benzyl 3-(hydroxymethyl)[1,4′-bipiperidine]-1′-carboxylate (5.42 g, 16.3 mmol) was initially added to 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 stirred at 0 °C for 15 min, after which the ice bath was removed and stirring continued at room temperature. After 15 min, the reaction mixture was diluted with dichloromethane and washed successively with 1 N hydrochloric acid, saturated NaHCO3 solution, and saturated NaCl solution. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was dried under high vacuum and further reacted without further purification. This yielded 6.16 g of the target compound (100% pure, 92% of theory).

[0258] LC-MS (Method 12):R t =1.39min;MS(ESIpos):m / z=411[M+H] + .

[0259] Example 20A rac-Benzyl 3-(methoxymethyl)[1,4'-bipiperidine]-1'-carboxylate [ka] Sodium methoxide solution (840 μL, 25% solution in methanol, 3.7 mmol) was added to a solution of rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (500 mg, 1.22 mmol) in DMF (10 mL), and the mixture was stirred at 50° C. overnight. The solvent was removed on a rotary evaporator, and the residue was taken up in ethyl acetate and washed successively with water and saturated NaCl solution. The organic phase was dried over NaSO, filtered, and concentrated. The residue was applied to an Isolute® column, and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 25 g; DCM / MeOH gradient: 2% MeOH-20% MeOH; flow rate 75 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 146 mg of the target compound (100% pure, 35% of theory).

[0260] LC-MS (Method 4):R t =0.59min;MS(ESIpos):m / z=347[M+H] + .

[0261] Example 21A Diastereomeric mixture - benzyl (3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylate [ka] Acetic acid (1.71 mL, 29.85 mmol) was added to a solution of rac-benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (5 g, 19.9 mmol) and (3R)-3-methylpiperidine (5.4 g, 39.8 mmol) in dichloromethane (200 mL), and the mixture was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (5.06 g, 23.88 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was applied to Isolute® and purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 100 g; DCM / MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 5.13 g of the target compound (55% pure, 42% of theory).

[0262] LC-MS (Method 1):R t =1.05min;MS(ESIpos):m / z=335[M+H] + .

[0263] Example 22A Diastereomeric mixture - tert-butyl (3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylate [ka] (3R)-3-Methylpiperidine hydrochloride (6.24 g, 46.0 mmol) was first added to 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-tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate (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 hours. Sodium triacetoxyborohydride (5.85 g, 27.6 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% v / 20% v); 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 A2 10 min: 47 mL to 23 mL, and mobile phase B2 2 min: 3 mL to 47 mL, and mobile phase C 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 over the entire run time). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 5.30 g of the target compound (100% pure, 77% of theory).

[0264] LC-MS (Method 4):R t =0.52 min;MS(ESIpos):m / z=301[M+H] + .

[0265] Example 23A rac-Benzyl 3-[(2,2,2-trifluoroethoxy)methyl][1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, 2,2,2-trifluoroethanol (66 μL, 910 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 h, 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 Na2SO4, filtered, and concentrated. The residue was dried under high vacuum. This yielded 218 mg of the target compound (81% purity, 70% of theory).

[0266] LC-MS (Method 1):R t =1.33min;MS(ESIpos):m / z=415[M+H] + .

[0267] Example 24A rac-Benzyl 3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate [ka] Under argon, [1-(fluoromethyl)cyclopropyl]methanol (95.1 mg, 913 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C overnight. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over NaSO, filtered, and concentrated. The residue was dried under high vacuum. This yielded 204 mg of the target compound (40% purity, 32% of theory).

[0268] LC-MS (Method 1):R t =1.36min;MS(ESIpos):m / z=419[M+H] + .

[0269] Example 25A rac-Benzyl 3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate [ka] Under argon, [1-(difluoromethyl)cyclopropyl]methanol (112 mg, 913 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 h, 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 Na2SO4, filtered, and concentrated. The residue was dried under high vacuum. This yielded 197 mg of the target compound (51% purity, 37% of theory).

[0270] LC-MS (Method 1):R t =1.41 min;MS(ESIpos):m / z=437[M+H] + .

[0271] Example 26A rac-Benzyl 3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate [ka] Under argon, [1-(trifluoromethyl)cyclopropyl]methanol (128 mg, 913 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 h, 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 Na2SO4, filtered, and concentrated. The residue was dried under high vacuum. This yielded 212 mg of the target compound (58% purity, 44% of theory).

[0272] LC-MS (Method 1):R t =1.48min;MS(ESIpos):m / z=455[M+H] + .

[0273] Example 27A Benzyl 3,3-dimethyl[1,4'-bipiperidine]-1'-carboxylate [ka] 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 dichloromethane (7 mL), and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (218 mg, 1.03 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO 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 NaSO. The drying agent was removed by filtration, the filtrate was concentrated, and the residue was dried under high vacuum. This gave 280 mg of the target compound (81% purity, 80% of theory).

[0274] LC-MS (Method 1):R t =1.18 min;MS(ESIpos):m / z=331[M+H] + .

[0275] Example 28A Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate [ka] 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 dichloromethane (10 mL), and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (327 mg, 1.54 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over NaSO. The drying agent was removed by filtration, the filtrate was concentrated, and the residue was dried under high vacuum. This gave 368 mg of the target compound (40% purity, 35% of theory).

[0276] LC-MS (Method 1):R t=1.12 min;MS(ESIpos):m / z=329[M+H] + .

[0277] Example 29A rac-Benzyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate [ka] 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 (354 mg, 1.93 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (327 mg, 1.54 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration, the filtrate was concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 405 mg of the target compound (61% purity, 53% of theory).

[0278] LC-MS (Method 1):R t =1.14 min;MS(ESIpos):m / z=365[M+H] + .

[0279] Example 30A rac-Benzyl 3-hydroxy[1,4′-bipiperidine]-1′-carboxylate [ka] Triethylamine (1.8 mL, 13 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 piperidin-3-ol (1.73 g, 17.1 mmol) in dichloromethane (100 mL), and the mixture was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 48 hours. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 50 g; DCM / MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 1.87 g of the target compound (100% pure, 68% of theory).

[0280] LC-MS (Method 1):R t =0.88min;MS(ESIpos):m / z=319[M+H] + .

[0281] Example 31A rac-Benzyl 3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, rac-benzyl 3-hydroxy[1,4′-bipiperidine]-1′-carboxylate (250 mg, 785 μmol) was first added to 5 mL of THF, and the mixture was cooled to 0°C in 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 min. Next, (bromomethyl)cyclopropane (110 μL, 1.2 mmol) was added, and the reaction 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 h. The product was then isolated by preparative HPLC (Column: Chromatorex C18 10 μm, 250 × 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 product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 68.0 mg of the target compound (68% pure, 16% of theory).

[0282] LC-MS (Method 1):R t =1.25min;MS(ESIpos):m / z=373[M+H] + .

[0283] Example 32A rac-Benzyl 3-[(cyclobutyloxy)methyl][1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, cyclobutanol (72 μL, 910 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C overnight. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was dried under high vacuum. This yielded 290 mg of the target compound (46% purity, 57% of theory).

[0284] LC-MS (Method 4):R t =0.73min;MS(ESIpos):m / z=387[M+H] + .

[0285] Example 33A rac-Benzyl 3-[(cyclopropylmethoxy)methyl][1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, sodium hydride (268 mg, 60% purity, 6.70 mmol) was first added to 25 mL of DMF, and the mixture was cooled to 0 °C in an ice bath. At this temperature, cyclopropylmethanol (540 μL, 6.7 mmol) was added, and the mixture was stirred at room temperature for 30 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (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 h. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over NaSO, filtered, and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: Phenomenex Kinetex C18 5 μm 100 × 30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength aqueous formic acid, mobile phase D: acetonitrile / water (80% by volume / 20% by volume); total flow rate: 80 mL / min; room temperature, wavelength 200-400 nm, complete injection; gradient profile: 63 mL of mobile phase A from 0 to 2 min, 7 mL of mobile phase B from 0 to 2 min, 63 mL to 39 mL of mobile phase A from 10 min, and 7 mL to 31 mL of mobile phase B 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, constant flow rates of 5 mL / min each over the entire run time). The product-containing fractions were combined and lyophilized. This yielded 241 mg of the target compound (78% purity, 8% of theory).

[0286] LC-MS (Method 1):R t =1.27min;MS(ESIpos):m / z=387[M+H] + .

[0287] Example 34A tert-Butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate [ka] 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 dichloromethane (5 mL), and the mixture was stirred at room temperature. After 5 h, sodium triacetoxyborohydride (214 mg, 1.01 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO solution was then added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over NaSO. The drying agent was removed by filtration with suction, the filtrate was concentrated on a rotary evaporator, and the residue was dried under high vacuum. This yielded 215 mg of a mixture, which was further reacted without further purification or analysis.

[0288] Example 35A Diastereomeric mixture - benzyl 3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, rac-(2,2-difluorocyclopropyl)methanol (98.7 mg, 913 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (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 Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was dried under high vacuum. This yielded 343 mg of the target compound (56% purity, 74% of theory).

[0289] LC-MS (Method 1):R t=1.32min;MS(ESIpos):m / z=423[M+H] + .

[0290] Example 36A rac-Benzyl 3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, (3,3-difluorocyclobutyl)methanol (112 mg, 913 μmol) was first added to 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 min. Next, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added, and the reaction mixture was stirred at 60 °C. After 6 h, 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 Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was dried under high vacuum. This yielded 287 mg of the target compound (33% purity, 36% of theory).

[0291] LC-MS (Method 1):R t =1.44min;MS(ESIpos):m / z=437[M+H] + .

[0292] Example 37A 3-(Difluoromethyl)-1,4'-bipiperidine dihydrochloride (racemic form) [ka] 1.35 g (3.83 mmol) of benzyl 3-(difluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (racemic form) was dissolved in 100 mL of ethanol and hydrogenated using an H-Cube (Thales Nano H-Cube Pro™-1.7).

[0293] Reaction conditions: Catalyst: Pd / C 10%; Solvent: ethanol; Cartridge pressure: 1 bar hydrogen; Flow rate: 1 mL / min; Temperature: 50°C.

[0294] After the conversion was complete, 4N HCl (solution 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 used in further reactions without further purification.

[0295] GC-MS (method 3):R t =4.87 min; m / z=218(M-2HCl) + .

[0296] Example 38A 3-[(3,3-difluorocyclobutyl)methoxy]-1,4′-bipiperidine (racemic) [ka] 2.7 g (6.39 mmol) of benzyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidine]-1′-carboxylate (racemic form) was dissolved in 90 mL of ethanol and hydrogenated using an H-Cube (Thales Nano H-Cube Pro™-1.7).

[0297] Reaction conditions: Catalyst: Pd / C 10%; Solvent: ethanol; Cartridge pressure: 50 bar hydrogen; Flow rate: 1 mL / min; Temperature: 50°C.

[0298] 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 gave 1.27 g (4.40 mmol, 69% of theory) of the target compound as a yellow oil. The target compound was used in further reactions without further purification.

[0299] GC-MS (method 3):R t =6.42min;m / z=288(M) + .

[0300] In a similar manner to Examples 37A and 38A, the compounds of the following Examples 39A to 41A were prepared from the starting materials indicated in each case.

[0301] [Table 3]

[0302] Example 42A rac-3-(Methoxymethyl)-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-(methoxymethyl)[1,4'-bipiperidine]-1'-carboxylate (145 mg, 419 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of hydrochloric acid in diethyl ether (310 μL, 2.0 M, 630 μmol) was added to the filtrate, and the precipitated solid was filtered off with suction, washed with diethyl ether, and dried under high vacuum. This gave 92.0 mg of the target compound (76% pure, 59% of theory).

[0303] GC-MS (method 3):R t =5.45min;MS(ESIpos):m / z=212[M-HCl] + .

[0304] Example 43A Diastereomeric mixture - (3R)-3'-fluoro-3-methyl-1,4'-bipiperidine dihydrochloride [ka] Synthesis method 1: The diastereomeric mixture - benzyl (3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylate (5.13 g, 55% purity, 8.40 mmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 with suction, washed with dichloromethane, and dried under high vacuum. This gave 2.31 g (100% of theory) of the target compound.

[0305] LC-MS (Method 4): MS (ESIpos): m / z=200[M-2HCl] + .

[0306] Synthesis method 2: 4M hydrochloric acid / dioxane (22 mL, 4.0 M, 88 mmol) was added to a solution of the diastereomeric mixture tert-butyl (3R)-3'-fluoro-3-methyl[1,4'-bipiperidine]-1'-carboxylate (5.30 g, 17.6 mmol) in dichloromethane (250 mL), and the mixture was stirred at room temperature for 48 hours. The precipitated solid was filtered off with suction, washed with dichloromethane, and dried overnight at 40 °C in a vacuum drying cabinet. This gave 3.47 g of the target compound (100% pure, 72% of theory).

[0307] GC-MS (method 3): MS (ESIpos): m / z=200[M-2HCl] + .

[0308] Example 44A rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate (218 mg, 81% purity, 526 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 of the target compound (74% purity, 66% of theory).

[0309] GC-MS (method 3):R t =5.26 minutes; MS (complete ms): m / z=280[M-2HCl] + .

[0310] Example 45A rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (204 mg, 40% purity, 487 μmol) was first added to 10 mL of THF, and palladium (58 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 2 hours, the catalyst was filtered off through diatomaceous earth and washed with THF. A solution of 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 or analysis.

[0311] Example 46A rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (197 mg, 51% purity, 451 μmol) was first added to 10 mL of THF, and palladium (54 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 h, the catalyst was filtered off through diatomaceous earth and washed with THF. A solution of 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 or analysis.

[0312] Example 47A rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (212 mg, 58% purity, 466 μmol) was first added to 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 h, the catalyst was filtered off through diatomaceous earth and washed with THF. A solution of 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 further reacted without further purification or analysis.

[0313] Example 48A 3,3-Dimethyl-1,4′-bipiperidine dihydrochloride [ka] Benzyl 3,3-dimethyl[1,4′-bipiperidine]-1′-carboxylate (260 mg, 81% purity, 637 μmol) was first added to 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. A solution of 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 further reacted without further purification or analysis.

[0314] Example 49A 5-(Piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride [ka] Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (368 mg, 40% purity, 1.12 mmol) was first added to 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 off through diatomaceous earth and washed with THF. A solution of 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 filtered off with suction, washed with dichloromethane, and dried under high vacuum. This gave 185 mg of a mixture, which was further reacted without further purification or analysis.

[0315] Example 50A rac-1,1-Difluoro-5-(piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride [ka] rac-Benzyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (405 mg, 61% purity, 1.11 mmol) was first added to 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 off through diatomaceous earth and washed with THF. A solution of 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 further reacted without further purification or analysis.

[0316] Example 51A rac-3-(cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylate (68.0 mg, 68% purity, 124 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 further reacted without further purification or analysis.

[0317] Example 52A rac-3-[(cyclobutyloxy)methyl]-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-[(cyclobutyloxy)methyl][1,4′-bipiperidine]-1′-carboxylate (290 mg, 46% purity, 386 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 yielded 225 mg of a mixture, which was further reacted without further purification or analysis.

[0318] Example 53A rac-3-[(cyclopropylmethoxy)methyl]-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate (241 mg, 78% purity, 486 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 yielded 155 mg of a mixture, which was further reacted without further purification or analysis.

[0319] Example 54A 4-[(3R)-3-Methylpiperidin-1-yl]azepane dihydrochloride [ka] 4 M hydrochloric acid / dioxane (2.2 mL, 4.0 M, 8.6 mmol) was added to a solution of tert-butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate (215 mg) in dichloromethane (5.4 mL), 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 further reacted without further purification or analysis.

[0320] Example 55A Diastereomeric mixture - 3-[(3-fluorobutoxy)methyl]-1,4′-bipiperidine dihydrochloride [ka] The diastereomeric mixture - benzyl 3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4'-bipiperidine]-1'-carboxylate (343 mg, 56% purity, 446 μmol) was first added to 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 diatomaceous earth and washed with THF. A solution of 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 the mixture, which was further reacted without further purification or analysis.

[0321] Example 56A rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}-1,4′-bipiperidine dihydrochloride [ka] rac-Benzyl 3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (287 mg, 33% purity, 217 μmol) was first added to 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 off through diatomaceous earth and washed with THF. A solution of 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 or analysis.

[0322] Example 57A Methyl 2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylate [ka] 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 were heated to boiling point (oil bath temperature approximately 100 °C) in 30 mL of 2-propanol and stirred at this temperature overnight. After cooling the reaction mixture, the solution was concentrated to dryness using a rotary evaporator. This gave 14.29 g of the target product and triethylamine salt (crude product, approximately 34% purity). The mixture was used for further reactions without further purification.

[0323] LC-MS (Method 4):R t =0.51 min; m / z=324(M+H) + .

[0324] Example 58A 2-[(3R)-3-Methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride [ka] 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. A brown oil separated, which was dissolved by adding 50 mL of THF. The reaction mixture was then heated to 60 °C and stirred at this temperature for 1 h. After the reaction mixture was cooled to room temperature, the solution was concentrated to dryness on a rotary evaporator, taken up in water, and acidified with concentrated hydrochloric acid. The resulting solution was then concentrated to dryness once more. This yielded 20.54 g of a beige solid, which was purified by column chromatography.

[0325] Conditions: Separations were performed using 1 g aliquots. RP column Chromatorex C18, 10 μm; 125 × 30 mm, gradient over 20 min from acetonitrile / water (+0.05% formic acid) 5 / 95 to acetonitrile / water (+0.05% formic acid) 95 / 5, flow rate 75 mL / min.

[0326] Finally, the product-containing fractions were combined, concentrated to dryness under reduced pressure and dried, which gave 4.75 g (12.42 mmol, 83% of theory) of the target compound as a pale beige solid.

[0327] LC-MS (Method 1):R t =0.54 min; m / z=310(M+H-2HCl) + .

[0328] Example 59A 3-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,2,4-oxadiazole-5-carboxylic acid [ka] 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 min, the reaction mixture was acidified with 2 N hydrochloric acid and purified by preparative HPLC (Column: Chromatorex C18 10 μm, 250 × 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). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 25 mg of the target compound (60% purity, 11% of theory).

[0329] LC-MS (Method 1):R t =0.47min;MS(ESIpos):m / z=295[M+H] + .

[0330] Example 60A rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride [ka] Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in THF (25 mL), 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. Next, a solution of rac-2,2-difluorocyclopropanemethanol (1.00 g, 9.25 mmol) in THF (5 mL) was added dropwise to the mixture. 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 NaSO, 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 (4N in 1.4-dioxane) was added. The precipitated solid was filtered off with suction, washed with MTBE, and dried under high vacuum. This gave 698 mg of the target compound (93% pure, 41% of theory).

[0331] LC-MS (Method 4):R t =0.40min;MS(ESIpos):m / z=186[M-HCl] + .

[0332] Example 61A Diastereomeric mixture -3-[(2,2-difluorocyclopropyl)methoxy]piperidine sulfate hydrochloride [ka] Under argon, rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride (698 mg, 93% purity, 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 under a hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and washed with ethanol. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 761 mg of the target compound (74% of theory).

[0333] LC-MS (Method 5): MS (ESIpos): m / z=192[M-HCl-H2SO4] + .

[0334] Example 62A 3-(Cyclobutyloxy)pyridine hydrochloride [ka] Triphenylphosphine (7.17 g, 27.3 mmol) was added to a solution of pyridin-3-ol (2.00 g, 21.0 mmol) in THF (70 mL), 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. Next, a solution of cyclobutanol (2.1 mL, 27 mmol) in THF (10 mL) was added dropwise to the mixture. 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, dried over NaSO, filtered, and concentrated. The oily residue was stirred with 150 mL of cyclohexane for 30 minutes. The solid was removed by filtration, 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 with suction, washed with MTBE and dried under high vacuum, which gave 2.02 g of the target compound (51% pure, 26% of theory).

[0335] LC-MS (Method 5):R t =1.34 min;MS(ESIpos):m / z=150[M-HCl] + .

[0336] Example 63A rac-3-(Cyclobutyloxy)piperidine sulfate hydrochloride [ka] Under argon, 3-(cyclobutyloxy)pyridine hydrochloride (2.0 g, 51% purity, 5.51 mmol) was dissolved in 95 mL of ethanol. Sulfuric acid (550 μL, 10 mmol) and platinum(IV) oxide (612 mg, 2.6 mmol) were added, and the mixture was hydrogenated under a hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and washed with ethanol. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 2.52 g of the target compound (157% of theory).

[0337] LC / MS (Method 4): MS (ESIpos): m / z=156[M-HCl-H2SO4] + .

[0338] Example 64A 3-[(3,3-difluorocyclobutyl)oxy]pyridine hydrochloride [ka] Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in THF (25 mL), 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. Next, a solution of 3,3-difluorocyclobutanol (1.00 g, 9.25 mmol) in THF (5 mL) was added dropwise to the mixture. 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 extracted with water and ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over NaSO, filtered, and concentrated. The oily residue was stirred with 150 mL of cyclohexane for 30 minutes. The precipitated solid was removed by filtration, and the filtrate was concentrated to give a residue. The residue was dissolved in 100 mL of MTBE and 5 mL of hydrochloric acid (4N in 1.4-dioxane) was added. The precipitated solid was filtered off with suction, washed with MTBE, and dried under high vacuum. This gave 289 mg of the target compound (94% pure, 17% of theory).

[0339] LC-MS (Method 4):R t=1.01 min;MS(ESIpos):m / z=186[M-HCl] + .

[0340] Example 65A rac-3-[(3,3-difluorocyclobutyl)oxy]piperidine sulfate hydrochloride [ka] 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 h. The catalyst was removed by filtration through Celite and washed with ethanol. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 297 mg of the target compound (68% of theory).

[0341] LC / MS (Method 4): MS (ESIpos): m / z=192[M-HCl-H2SO4] + .

[0342] Example 66A 2-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide [ka] N,N-Diisopropylethylamine (680 μL, 3.9 mmol) and propylphosphonic anhydride (1.0 mL, 50% solution in ethyl acetate, 1.7 mmol) were added 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 acetonitrile (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was applied to Isolute®, and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA-66% EA; flow rate 36 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum to give 193 mg of the target compound (46% of theory, 84% purity), which was used in further reactions without further purification.

[0343] LC-MS (Method 1):R t =1.32min;MS(ESIpos):m / z=274[M+H] + .

[0344] Example 67A 2-Bromo-N-(5-chloro-2-fluorobenzyl)-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (630 μL, 3.6 mmol) and propylphosphonic anhydride (930 μL, 50% solution 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 acetonitrile (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was applied to Isolute®, and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA-66% EA; flow rate 36 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum, which gave 106 mg of the target compound (96% pure, 24% of theory).

[0345] LC-MS (Method 1):R t =1.85 min;MS(ESIpos):m / z=348[M+H] + .

[0346] Example 68A Benzyl (3R)-3-hydroxy[1,4'-bipiperidine]-1'-carboxylate [ka] 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 dichloromethane (100 mL), and the mixture was stirred at room temperature for 1 hour. Next, 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 NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was applied to Isolute®, and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 50 g; DCM / MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 1.79 g of the target compound (100% pure, 66% of theory).

[0347] LC-MS (Method 1):R t =0.87min;MS(ESIpos):m / z=319[M+H] + .

[0348] Example 69A Benzyl (3R)-3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylate [ka] Under argon, benzyl (3R)-3-hydroxy[1,4′-bipiperidine]-1′-carboxylate (1.79 g, 5.62 mmol) was first added to 40 mL of THF, and the mixture was cooled to 0°C in 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. Next, (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. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution and dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The product was purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: Phenomenex Kinetex C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% strength aqueous formic acid; mobile phase D: acetonitrile / water (80% by volume / 20% by volume); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 63 mL; mobile phase B from 0 to 2 min: 7 mL; mobile phase A from 10 min: 63 mL to 39 mL and mobile phase B from 7 mL to 31 mL; mobile phase C and mobile phase D 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, constant flow rates of 5 mL / min each over the entire run time). The product-containing fractions were combined and lyophilized. This yielded 100.0 mg of the target compound (100% pure, 4.8% of theory).

[0349] LC-MS (Method 1):R t =1.19min;MS(ESIpos):m / z=373[M+H] + .

[0350] Example 70A (3R)-3-(Cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride [ka] Benzyl (3R)-3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-carboxylate (100 mg, 268 μmol) was initially added to 7.5 mL of THF, and palladium (32.1 mg; 10% on activated carbon) was added under argon. The mixture was hydrogenated under a hydrogen atmosphere for 2 hours. The catalyst was filtered off through diatomaceous earth and washed with THF. A solution of hydrochloric acid in diethyl ether (200 μL, 2.0 M, 400 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 66 mg of a mixture, which was further reacted without further purification or analysis.

[0351] Example 71A rac-2-Bromo-N-[1-(2,5-difluorophenyl)ethyl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (630 μL, 3.6 mmol) and propylphosphonic anhydride (930 μL, 50% solution 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)ethanamine (189 mg, 1.20 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was applied to Isolute®, and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy / EA gradient: 8% EA-66% EA; flow rate 36 mL / min). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum, which gave 148 mg of the target compound (100% pure, 35% of theory).

[0352] LC-MS (Method 1):R t =1.81 min;MS(ESIpos):m / z=346[M+H] + .

[0353] Example 72A Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylate [ka] 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 in sodium carbonate solution (870 μL, 2.0 M, 1.7 mmol) at 120 °C for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over NaSO, filtered, and the filtrate was concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 199 mg of the target compound (95% pure, 98% of theory).

[0354] LC-MS (Method 1):R t =1.34min;MS(ESIpos):m / z=449[M+H] + .

[0355] Example 82A Diastereomeric mixture -5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride [ka] 4M hydrochloric acid / 1,4-dioxane (720 μL, 4.0 M, 2.9 mmol) was added to a solution of the diastereomeric mixture - tert-butyl 4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate (179 mg, 573 μmol) in dichloromethane (8 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 162 mg of the mixture, which was further reacted without further purification or analysis.

[0356] Example 73A 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid [ka] 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. To the solution was added aqueous sodium hydroxide (4 mL, 2.0 M, 8 mmol), and the mixture was stirred at room temperature for 5 days. The 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 of the target compound (98% pure, 84% of theoretical).

[0357] LC-MS (Method 1):R t =0.97min;MS(ESIpos):m / z=420[M+H] + .

[0358] Example 74A 4-Bromo-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxylic acid [ka] 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. The reaction mixture was then concentrated to dryness and stirred with DCM / MeOH 5:1. Insoluble salts were filtered off with suction. The filtrate was concentrated by evaporation, and the residue was dried under high vacuum. This gave 240 mg of the target compound (100% pure, 118% of theory).

[0359] LC-MS (Method 1):R t =0.70min;MS(ESIpos):m / z=388[M+H] + .

[0360] Example 75A 2-Bromo-4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (720 μL, 4.1 mmol) and propylphosphonic anhydride (800 μL, 50% solution 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 acetonitrile (14 mL), 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 NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dried under high vacuum. This gave 250 mg of the target compound (purity 95%, 62% of theory).

[0361] LC-MS (Method 1):R t =1.79min;MS(ESIpos):m / z=367[M+H] + .

[0362] Example 76A 2-Bromo-4-cyclopropyl-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (560 μL, 3.2 mmol) and propylphosphonic anhydride (620 μL, 50% solution 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 acetonitrile (11 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed with saturated NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dried under high vacuum. This gave 239 mg of the target compound (78% pure, 62% of theory).

[0363] LC-MS (Method 1):R t =1.87min;MS(ESIpos):m / z=373[M+H] + .

[0364] Example 77A 2-Bromo-4-ethyl-1,3-thiazole-5-carboxylic acid [ka] Methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate (150 mg, 600 μmol) was dissolved in 3 mL of THF. Aqueous sodium hydroxide (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 of the target compound (98% pure, 69% of theoretical).

[0365] LC-MS (Method 1):R t =1.30min;MS(ESIpos):m / z=235[M+H] + .

[0366] Example 78A 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-ethyl-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (300 μL, 1.7 mmol) and propylphosphonic anhydride (330 μL, 50% solution in ethyl acetate, 550 μmol) were added 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 acetonitrile (5.7 mL), 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 NaHCO3 solution, water, and saturated NaCl solution. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dried under high vacuum. This yielded 150 mg of the target compound (95% pure, 93% of theory).

[0367] LC-MS (Method 4):R t =0.86min;MS(ESIpos):m / z=364[M+H] + .

[0368] Example 79A Diastereomeric mixture - tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate [ka] N,N-Diisopropylethylamine (570 μL, 3.3 mmol) was added to a solution of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (600 mg, 3.27 mmol) in 1,2-dichloroethane (15 mL), and the mixture was stirred for 5 minutes. After that, rac-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (355 mg, 1.63 mmol) and acetic acid (140 μL, 2.5 mmol) were added to the mixture. The mixture was stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: Phenomenex Kinetex C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% strength aqueous formic acid; mobile phase D: acetonitrile / water (80% by volume / 20% by volume); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 70 mL; mobile phase B from 0 to 2 min: 0 mL; mobile phase A from 10 min: 70 mL to 55 mL and mobile phase B from 0 mL to 15 mL; mobile phase A from 10 to 12 min: 0 mL; and mobile phase B from 10 to 12 min: 0 mL; mobile phase C and mobile phase D, each with a constant flow rate of 5 mL / min over the entire run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 264 mg of the target compound (100% pure, 46% of theory).

[0369] LC-MS (Method 4):R t=0.56 min;MS(ESIpos):m / z=349[M+H] + .

[0370] Example 80A Diastereomeric mixture - 1,1-difluoro-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride [ka] 4M hydrochloric acid / 1,4-dioxane (950 μL, 4.0 M, 3.8 mmol) was added to a solution of the diastereomeric mixture - tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate (264 mg, 760 μmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 246 mg of the mixture, which was further reacted without further purification or analysis.

[0371] Example 81A Diastereomeric mixture - tert-butyl 4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate [ka] 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 1,2-dichloroethane (10 mL). The mixture was stirred for 5 minutes, and 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 stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: Phenomenex Kinetex C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% strength aqueous formic acid; mobile phase D: acetonitrile / water (80% by volume / 20% by volume); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 70 mL; mobile phase B from 0 to 2 min: 0 mL; mobile phase A from 10 min: 70 mL to 55 mL and mobile phase B from 0 mL to 15 mL; mobile phase A from 10 to 12 min: 0 mL; and mobile phase B from 10 to 12 min: 0 mL; mobile phase C and mobile phase D, each with a constant flow rate of 5 mL / min over the entire run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 179 mg of the target compound (100% pure, 48% of theory).

[0372] LC-MS (Method 4):R t =0.53min;MS(ESIpos):m / z=313[M+H] + .

[0373] Example 82A Ethyl 5-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3,4-thiadiazole-2-carboxylate [ka] 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, and the mixture was heated to 80 °C and stirred at this temperature overnight. After cooling the reaction mixture, the solution was diluted with ethyl acetate and washed with water. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This gave 1.29 g (3.81 mmol, 90% of theory) of the target compound as a red solid.

[0374] 1 H NMR (600 MHz, DMSO-d6) 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 obscured by DMSO), 2.74 (br. t, 2H), 3.24 (td, 2H), 3.98 (br. d, 2H), 4.34 (q, 2H).

[0375] LC-MS (Method 1):R t =0.82min;m / z=339(M+H) + .

[0376] Example 83A 5-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3,4-thiadiazole-2-carboxylic acid [ka] 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 5 mL of water was added to the reaction solution. The reaction solution was stirred at room temperature for several hours. After the conversion was complete, the reaction solution was adjusted to pH 7 with 1N HCl and concentrated to dryness on a rotary evaporator. This yielded 2.95 g of an amber oil, which was purified by column chromatography.

[0377] Conditions: Separations were performed using approximately 1 g of each. RP column Chromatorex C18, 10 μm; 125×30 mm, gradient over 38 min from acetonitrile / water 10 / 90 to acetonitrile / water 90 / 10, flow rate 75 mL / min.

[0378] Finally, the product-containing fractions were combined, concentrated to dryness under reduced pressure and dried, which gave 487 mg (1.57 mmol, 35% of theory) of the target compound as a white solid.

[0379] LC-MS (Method 1):R t =0.39min;m / z=311(M+H) + .

[0380] Example 84A rac-tert-butyl 4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate [ka] To the initial solution of 5-azaspiro[2.5]octane hydrochloride (346 mg, 2.34 mmol) in 7 mL of 1,2-dichloroethane, N,N-diisopropylethylamine (410 μL, 2.3 mmol) was added. The mixture was stirred for 5 minutes, followed by the addition of tert-butyl 4-oxoazepane-1-carboxylate (250 mg, 1.17 mmol) and acetic acid (100 μL, 1.8 mmol). The mixture was then stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (298 mg, 1.41 mmol) was then added to the mixture, which was then stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution and water. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System, column: Phenomenex Kinetex C18 5 μm 100 × 30 mm, eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile / water (80% v / 20% v), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, on-column injection (full injection). Gradient profile: 2 min from eluent A0 to 70 mL, 2 min from eluent B0 to 0 mL, 10 min from eluent A2 to 70 mL to 0 mL and eluent B to 70 mL, 10 to 12 min from 0 mL eluent A and 70 mL eluent B. Eluent C and eluent D constant flow rate of 5 mL / min in each case over the entire run time). After complete solvent removal, 140 mg (39% of theory) of the title compound was obtained.

[0381] LC-MS (Method 4): MS (ESIpos): m / z=309[M+H] + .

[0382] Example 85A rac-5-(azepan-4-yl)-5-azaspiro[2.5]octane hydrochloride [ka] rac-tert-Butyl 4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (140 mg, 454 μmol) was dissolved in 4 mL of dichloromethane, and HCl / dioxane (570 μL, 4.0 M, 2.3 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dried under high vacuum. 139 mg of the target compound (125% of theoretical yield) was obtained.

[0383] LC-MS (Method 4): MS (ESIpos): m / z=208[M-HCl] + .

[0384] Example 86A Diastereomeric mixture - tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate [ka] To the initial solution of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (500 mg, 2.72 mmol) in 10 mL of 1,2-dichloroethane, N,N-diisopropylethylamine (470 μL, 2.7 mmol) was added. The mixture was stirred at room temperature for 5 minutes, followed by the addition of tert-butyl 4-oxoazepane-1-carboxylate (290 mg, 1.36 mmol) and acetic acid (120 μL, 2.0 mmol). The mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (346 mg, 1.63 mmol) was then added to the mixture, which was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution and water. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; eluent A: water; eluent B: acetonitrile; eluent C: 2% formic acid in water; eluent D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: 2 min from eluent A0 to 70 mL; 2 min from eluent B0 to 0 mL; 10 min from eluent A2 to 70 mL and eluent B to 70 mL; 10 to 12 min from 0 mL eluent A and 70 mL eluent B; eluent C and eluent D constant flow rate of 5 mL / min in each case over the entire run time). The product-containing fractions were combined and lyophilized. 292 mg of the target compound (62% of theory) was obtained.

[0385] LC-MS (Method 4): MS (ESIpos): m / z=345[M+H] + .

[0386] Example 87A Diastereomeric mixture -5-(azepan-4-yl)-1,1-difluoro-5-azaspiro[2.5]octane dihydrochloride [ka] To a solution of diastereomeric mixture - tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (292 mg, 848 μmol) in dichloromethane (8 mL), HCl / dioxane (1.1 mL, 4.0 M, 4.2 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. 194 mg (72% of theoretical) of the target compound was obtained.

[0387] LC-MS (Method 4): MS (ESIpos): m / z=245[M-2HCl] + .

[0388] Example 88A Diastereomeric mixture - tert-butyl (3R)-2',3-dimethyl[1,4'-bipiperidine]-1'-carboxylate [ka] To (3R)-3-methylpiperidine hydrochloride (318 mg, 2.34 mmol) in 1,2-dichloroethane (5.8 mL) was added N,N-diisopropylethylamine (410 μL, 2.3 mmol). The mixture was stirred at room temperature for 5 minutes, and then rac-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (250 mg, 1.17 mmol) and acetic acid (100 μL, 1.8 mmol) were added. The mixture was then stirred overnight at room temperature. Sodium triacetoxyborohydride (298 mg, 1.41 mmol) was then added to the mixture, which was stirred at room temperature for another 5 hours. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution and water. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The residue (340 mg) was further converted without analysis.

[0389] Example 89A Diastereomeric mixture - (3R)-2',3-dimethyl-1,4'-bipiperidine dihydrochloride [ka] The diastereomeric mixture tert-butyl (3R)-2',3-dimethyl[1,4'-bipiperidine]-1'-carboxylate (340 mg, 1.15 mmol) was dissolved in 16 mL of dichloromethane, HCl / dioxane (1.4 mL, 4.0 M, 5.7 mmol) was added, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, and the residue was dried under high vacuum. The residue (290 mg) was further transformed without analysis.

[0390] Example 90A N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide [ka] 1 g (2.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide was added to 40 mL of water and mixed with 1.9 g (17.96 mmol) of sodium carbonate. 538 mg (3.29 mmol) of 3-ethylpiperidin-4-one hydrochloride was metered into the reaction solution, which was then stirred overnight at reflux. After cooling, the reaction mixture was extracted with dichloromethane. The resulting organic phase was washed with sodium bicarbonate solution, separated, and filtered through a water-repellent filter (MN616WA 1 / 4 pleated filter, D = 12.5 cm). The resulting filtrate was concentrated on a rotary evaporator and dried under reduced pressure. 1.1 g (2.89 mmol, 97% of theory) of the target compound were obtained as an amorphous solid, which was separated into its enantiomers by chiral preparative HPLC without further purification.

[0391] LC-MS (Method 1):R t =1.42min;m / z=381(M+H) + .

[0392] Example 91A and Example 92A N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2) [ka] 1.1 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 its enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm (SFC); eluent: CO / 2-propanol 55:45; pressure: 90 bar; flow rate: 95 g / min; UV detection: 210 nm; temperature: 40 °C].

[0393] Example 91A (Enantiomer 1): N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide Yield: 487mg R t = 4.02 min; chemical purity >99%; >97% ee [Column: Chiraltek AY-3, 3 μm, 100 mm × 4.6 mm; eluent: CO₂ / ethanol 90:10; flow rate: 3 mL / min; pressure: 130 bar; temperature: 40 °C; UV detection: 210 nm].

[0394] LC-MS (Method 1):R t =1.41 min; m / z=381(M+H) + .

[0395] 1H-NMR (600 MHz, DMSO-d6, 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 obscured 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).

[0396] [α] D 20 =-14.69° (c=0.440, methanol).

[0397] Example 92A (Enantiomer 2): N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide Yield: 476mg R t = 5.98 min; chemical purity > 99%; > 97% ee [Column: Chiraltek AY-3, 3 μm, 100 mm × 4.6 mm; eluent: CO₂ / ethanol 90:10; flow rate: 3 mL / min; pressure: 130 bar; temperature: 40 °C; UV detection: 210 nm].

[0398] LC-MS (Method 1):R t =1.41 min; m / z=381(M+H) + .

[0399] 1H-NMR (600 MHz, DMSO-d6, 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 obscured 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).

[0400] [α] D 20 = +11.64° (c = 0.435, methanol).

[0401] Example 93A Diastereomeric mixture - cis-benzyl (3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate [ka] To the initial (3R)-3-methylpiperidine hydrochloride (1000 mg, 4.04 mmol) in 25 mL of dichloromethane, N,N-diisopropylethylamine (1.41 mL, 8.1 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. After that, 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. Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was then added to the mixture, which was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with saturated NaHCO3 solution and water. The organic phase was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated. The resulting residue was dissolved in 18 mL of a mixture of acetonitrile and MeOH and purified by preparative HPLC.

[0402] Method: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5μm 100×30mm.

[0403] Eluent A: water, eluent B: acetonitrile, eluent C: 1% aqueous ammonia; total flow rate: 80 mL / min, 40°C, wavelength: 210 nm.

[0404] Gradient profile: 25% eluent A (0-4 min), 70% eluent B (0-4 min), 5% eluent C (0-4 min). 0% eluent A (4-4.71 min), 95% eluent B (4-4.71 min), 5% eluent C (4-4.71 min). 25% eluent A (4.71-4.78 min), 70% eluent B (4.71-4.78 min), 5% eluent C (4.71-4.78 min).

[0405] After complete solvent removal, 716 mg (2.13 mmol, 98% purity, 53% of theory) of the title compound was obtained.

[0406] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, including (d, 3H) of 0.82), 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).

[0407] Example 94A and Example 95A cis-Benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate (Diastereomers 1 and 2) [ka] The cis-benzyl(3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate (716 mg, 2.17 mmol) was separated into the cis-diastereomers 1 and 2 by preparative HPLC on a chiral phase (column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 15 mL / min; UV detection: 220 nm; temperature: 30 °C).

[0408] Example 94A (cis diastereomer 1): cis-benzyl (3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate Yield: 287mg R t =7.44min;Chemical purity>99%;>99%de [Column: Chiralpak AY-H, 5 μm, 250 mm × 4.6 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 1 mL / min; temperature: 30 °C; UV detection: 220 nm].

[0409] LC-MS (Method 1):R t =1.02 min; m / z=331(M+H) + .

[0410] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, including (d, 3H) of 0.82), 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).

[0411] Example 95A (cis diastereomer 2): cis-benzyl (3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate Yield: 135mg R t =8.06min;Chemical purity>99%;>99%de [Column: Chiralpak AY-H, 5 μm, 250 mm × 4.6 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 1 mL / min; temperature: 30 °C; UV detection: 220 nm].

[0412] LC-MS (Method 1):R t =1.02 min; m / z=331(M+H) + .

[0413] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.89 (m, 4H, including (d, 3H) of 0.83), 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).

[0414] Example 96A Cis-(3R)-3,3′-Dimethyl-1,4′-bipiperidine dihydrobromide (Diastereomer 1) [ka] 280 mg (0.85 mmol) of cis-benzyl (3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate (diastereomer 1; Example 94A) was dissolved in 5 mL of an HBr / glacial acetic acid mixture with ice cooling and stirred at 0 °C for 15 min. The ice bath was then removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was mixed with diethyl ether, and the resulting precipitate was filtered off with suction, washed repeatedly with diethyl ether, and dried under high vacuum. 260 mg (0.73 mmol, 86% of theory) of the title compound was obtained, which was further transformed without further analysis.

[0415] Example 97A Cis-(3R)-3,3′-Dimethyl-1,4′-bipiperidine dihydrobromide (diastereomer 2) [ka] 130 mg (0.39 mmol) of cis-benzyl (3R)-3,3'-dimethyl[1,4'-bipiperidine]-1'-carboxylate (diastereomer 2; Example 95A) was dissolved in 3 mL of an HBr / glacial acetic acid mixture while cooling with ice and stirred at 0 °C for 15 min. The ice bath was then removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was mixed with diethyl ether, and the resulting precipitate was filtered off with suction, washed repeatedly with diethyl ether, and dried under high vacuum. 124 mg (0.35 mmol, 88% of theory) of the title compound was obtained, which was further transformed without further analysis.

[0416] Working Example: Example 1 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 8.51 g (38.91 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 13 g (38.91 mmol) of (3R)-3-methyl-1,4′-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry Number 1799475-27-6), and 20.62 g (194.53 mmol) of sodium carbonate in 200 mL of water were heated to 120 °C and stirred at this temperature overnight. After cooling the reaction mixture, the solution was extracted with ethyl acetate. The separated organic phase was then filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The residue obtained was taken up in acetonitrile and heated to 80 °C, and slowly cooled back to room temperature while stirring. The precipitated solid was filtered off by suction and washed with acetonitrile. The residue was then taken up once more in acetonitrile and recrystallized again. This gave 10.75 g (24.68 mmol, 63% of theory) of the target compound as a pale beige solid. The two mother liquors were combined and concentrated to dryness on a rotary evaporator. The residue obtained was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column, mobile phase: dichloromethane → gradient over 20 CV (CV = column volume) → dichloromethane / methanol 9:1). The product fractions obtained were combined, concentrated on a rotary evaporator, and recrystallized from acetonitrile. This gave a further 3.28 g (7.48 mmol, 19% of theory) of the target compound as a pale beige solid.

[0417] 1H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76–0.86 (m, 4H, including 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 obscured 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).

[0418] LC-MS (Method 4):R t =0.50min;m / z=436(M+H) + .

[0419] [α] D 20 =-8.06° (c=0.430, methanol).

[0420] Example 2 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide [ka] In a sealed vessel, 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 and stirred at this temperature for 30 minutes. After cooling, water was added, and the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The residue obtained was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column, mobile phase: ethyl acetate → gradient over 5 CV (CV = column volume) → ethyl acetate / methanol 95:5). The resulting product fractions were 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.

[0421] 1 H-NMR (600 MHz, DMSO-d6, 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).

[0422] LC-MS (Method 1):R t =0.97min;m / z=470(M+H) + .

[0423] Example 3 2-[3-(cyclopropylmethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemic) [ka] In a sealed vessel, 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 22 mg (0.10 mmol), 32 mg (0.10 mmol) of 3-(cyclopropylmethyl)-1,4′-bipiperidine (racemic), and 31 mg (0.29 mmol) of sodium carbonate were heated to 120°C in 1 mL of water and stirred at this temperature for 30 min. After cooling the reaction mixture, the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D=12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The resulting residue was purified using the following method.

[0424] Method 7: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 47 mL, mobile phase B 0 to 2 min 23 mL, mobile phase A2 to 10 min 47 mL to 23 mL and mobile phase B2 3 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 had a constant flow rate of 5 mL / min over the entire run time.

[0425] This gave 40.8 mg (0.09 mmol, 88% of theory) of the target compound as a white lyophilizate.

[0426] 1H-NMR (400 MHz, DMSO-d6, 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 obscured 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).

[0427] LC-MS (Method 1):R t =1.13min;m / z=476(M+H) + .

[0428] In a similar manner to Examples 1 to 3, the compounds of the following Examples 4 to 14 were prepared from the starting materials indicated in each case.

[0429] [Table 4] TIFF0007748938000144.tif229159TIFF0007748938000145.tif186159TIFF0007748938 000146.tif197159TIFF0007748938000147.tif197159TIFF0007748938000148.tif98159

[0430] Example 15 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methoxy[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 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. 72 mg (0.34 mmol) of sodium acetoxyborohydride was weighed in, and the reaction solution was stirred overnight at room temperature. The reaction mixture was then diluted with dichloromethane and washed with sodium bicarbonate solution. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0431] Method 8: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 63 mL, mobile phase B 0 to 2 min 7 mL, mobile phase A2 to 10 min 63 mL to 39 mL and mobile phase B 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 each had a constant flow rate of 5 mL / min over the entire run time.

[0432] This gave 62 mg (0.14 mmol, 48% of theory) of the target compound as a white lyophilizate.

[0433] 1H-NMR (600 MHz, DMSO-d6, 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 obscured 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).

[0434] LC-MS (Method 1):R t =0.83min;m / z=452(M+H) + .

[0435] Example 16 2-[3-(Difluoromethoxy)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemic) [ka] 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 86 mg (0.57 mmol) of 3-(difluoromethoxy)piperidine (racemic) and 24 μL (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride was weighed in, and the reaction solution was stirred overnight at room temperature. The reaction mixture was then diluted with dichloromethane and washed with sodium bicarbonate solution. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0436] Method 9: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 55 mL, mobile phase B 0 to 2 min 15 mL, mobile phase A2 to 10 min 55 mL to 31 mL and mobile phase B 15 mL to 39 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 had a constant flow rate of 5 mL / min over the entire run time.

[0437] This gave 60 mg (0.12 mmol, 44% of theory) of the target compound as a white lyophilizate.

[0438] 1H-NMR (600 MHz, DMSO-d6, 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).

[0439] LC-MS (Method 1):R t =0.91 min; m / z=488(M+H) + .

[0440] Example 17 N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl[1,4'-bipiperidin]-1'-yl)-1,3-thiazole-5-carboxamide (racemic) [ka] 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 64 mg (0.57 mmol) and 24 μL (0.43 mmol) of 3-ethylpiperidine (racemic) glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride was weighed in, and the reaction solution was stirred overnight at room temperature. The reaction mixture was then diluted with dichloromethane and washed with sodium bicarbonate solution. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0441] Method 7: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 47 mL, mobile phase B 0 to 2 min 23 mL, mobile phase A2 to 10 min 47 mL to 23 mL and mobile phase B2 3 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 had a constant flow rate of 5 mL / min over the entire run time.

[0442] This gave 46 mg (0.10 mmol, 36% of theory) of the target compound as a white lyophilizate.

[0443] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.87 (m, 4H, including at 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 obscured 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).

[0444] LC-MS (Method 1):R t =0.99min;m / z=450(M+H) + .

[0445] Example 18 2-[(3R)-3-Methyl[1,4'-bipiperidin]-1'-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-5-carboxamide [ka] 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 a 50% strength solution (0.58 mmol) of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate (0.34 mL) was added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred at room temperature overnight. The reaction mixture was extracted with water and dichloromethane. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D=12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0446] Method 7: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 47 mL, mobile phase B 0 to 2 min 23 mL, mobile phase A2 to 10 min 47 mL to 23 mL and mobile phase B2 3 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 had a constant flow rate of 5 mL / min over the entire run time.

[0447] This gave 55 mg (0.12 mmol, 23% of theory) of the target compound as a white lyophilizate.

[0448] 1 H-NMR (400 MHz, DMSO-d6, δ / ppm): 0.74-0.89 (m, 4H, including 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 obscured 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).

[0449] LC-MS (Method 1):R t =1.05 min; m / z=469(M+H) + .

[0450] Example 19 2-[(3R)-3-Methyl[1,4'-bipiperidin]-1'-yl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide [ka] 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride was dissolved in 10 mL of dichloromethane, and 56 mg (0.42 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine was added. The mixture was stirred at room temperature for 30 minutes. Next, 60 μL of pyridine was added, followed by 46 mg (0.26 mmol) of 1-[3-(trifluoromethyl)phenyl]methanamine. The mixture was stirred overnight at room temperature. 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 (pleated filter MN616WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0451] Method 11: Apparatus: Abimed Gilson 305; Column: Reprosil C18 10 μm, 250 mm × 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.

[0452] This gave 45 mg (0.10 mmol, 37% of theory) of the target compound.

[0453] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.78-0.91 (m, 4H, including (d, 3H) of 0.83), 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).

[0454] LC-MS (Method 1):R t =1.31 min; m / z=467(M+H) + .

[0455] Example 20 N-[(3-fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 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 acetonitrile (10 mL), and 0.17 mL (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction mixture at room temperature. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and dichloromethane. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D=12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0456] Method 9: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 55 mL, mobile phase B 0 to 2 min 15 mL, mobile phase A2 to 10 min 55 mL to 31 mL and mobile phase B 15 mL to 39 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 had a constant flow rate of 5 mL / min over the entire run time.

[0457] This gave 5.4 mg (0.01 mmol, 5% of theory) of the target compound as a white lyophilizate.

[0458] 1 H-NMR (400 MHz, DMSO-d6, 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 obscured 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).

[0459] LC-MS (Method 4):R t =0.48min;m / z=418(M+H) + .

[0460] Example 21 N-(5-chloro-2-fluorobenzyl)-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 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'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 46 mg (0.29 mmol) of 1-(5-chloro-2-fluorophenyl)methanamine in acetonitrile (10 mL), and 0.17 mL (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction mixture at room temperature. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and dichloromethane. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D=12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0461] Method 7: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 47 mL, mobile phase B 0 to 2 min 23 mL, mobile phase A2 to 10 min 47 mL to 23 mL and mobile phase B2 3 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 had a constant flow rate of 5 mL / min over the entire run time.

[0462] This gave 45 mg of a mixture, which was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column; mobile phase: cyclohexane / ethyl acetate 8:2 → gradient over 15 CV (CV = column volume) → cyclohexane / ethyl acetate 2:8), which gave 16 mg (0.04 mmol, 14% of theory) of the target compound as a beige solid.

[0463] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76–0.87 (m, 4H, including 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 obscured 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).

[0464] LC-MS (Method 4):R t =0.68 min; m / z=451 / 453(M+H) + .

[0465] Example 22 2-[(3R)-3-Methyl[1,4'-bipiperidin]-1'-yl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide [ka] 0.22 mL (1.23 mmol) of N,N-diisopropylethylamine was added to 200 mg (0.31 mmol, 59% purity) of 2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 59 mg (0.34 mmol) of 1-[4-(trifluoromethyl)phenyl]methanamine in acetonitrile (10 mL), and 0.2 mL (0.34 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was metered into the reaction mixture at room temperature. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and dichloromethane. The organic phase was finally separated, and the resulting organic solution was filtered through a hydrophobic filter (pleated filter MN616WA1 / 4, D=12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified using the following method.

[0466] Method 10: Apparatus: Waters Prep LC / MS System, Column: XBridge C18 5 μm 100 × 30 mm Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% aqueous ammonia, mobile phase D: acetonitrile / water (80% by volume / 20% by volume), total flow rate: 80 mL / min, room temperature, wavelength: 200-400 nm, at-column injection (complete injection). Gradient profile: Mobile phase A 0 to 2 min 39 mL, mobile phase B 0 to 2 min 31 mL, mobile phase A2 to 10 min 39 mL to 15 mL and mobile phase B 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 each had a constant flow rate of 5 mL / min over the entire run time.

[0467] This gave 25 mg (0.05 mmol, 17% of theory) of the target compound as a white lyophilizate.

[0468] 1H-NMR (400 MHz, DMSO-d6, 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 obscured 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).

[0469] LC-MS (Method 1):R t =1.27min;m / z=467(M+H) + .

[0470] In a manner analogous to Examples 18-22, the compounds of the following Examples 23-37 were prepared from the starting materials indicated in each case.

[0471] [Table 5] TIFF0007748938000158.tif185159TIFF0007748938000159.tif230159TIFF0007748938000160.tif186159 TIFF0007748938000161.tif191159TIFF0007748938000162.tif180159TIFF0007748938000163.tif186159

[0472] Examples 38 and 39 2-[3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2) [ka] 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 its enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×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.].

[0473] Example 38 (Enantiomer 1): 2-[(3S)-3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] Yield: 97mg R t = 4.93 min; chemical purity > 99%; > 99% ee [Column: Chiraltek AY-3, 3 μm, 100 mm × 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].

[0474] LC-MS (Method 5):R t =1.52 min; m / z=472(M+H) + .

[0475] Example 39 (Enantiomer 2): 2-[(3R)-3-(Difluoromethyl)[1,4'-bipiperidin]-1'-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] Yield: 101mg R t= 6.03 min; chemical purity >96%; >94% ee [Column: Chiraltek AY-3, 3 μm, 100 mm × 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].

[0476] LC-MS (Method 5):R t =1.52 min; m / z=472(M+H) + .

[0477] 1 H-NMR (600 MHz, DMSO-d6, 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 obscured 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).

[0478] Examples 40 and 41 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (enantiomers 1 and 2) [ka] 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 its enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IG, 5 μm, 250 mm×20 mm; mobile phase: ethanol; flow rate: 15 mL / min; UV detection: 220 nm; temperature: 70° C.].

[0479] Example 40 (Enantiomer 1): N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3S)-3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] Yield: 71 mg R t = 10.94 min; chemical purity 99%; 99% ee [Column: Daicel Chiralcel IG, 5 μm, 250 mm × 4.6 mm; Mobile phase: Ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 40 °C; UV detection: 235 nm].

[0480] LC-MS (Method 1):R t =0.85min;m / z=454(M+H) + .

[0481] Example 41 (Enantiomer 2): N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-(fluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] Yield: 70mg R t = 12.21 min; chemical purity 99%; 99% ee [Column: Daicel Chiralcel IG, 5 μm, 250 mm × 4.6 mm; Mobile phase: Ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 40 °C; UV detection: 235 nm].

[0482] LC-MS (Method 1):R t =0.84min;m / z=454(M+H) + .

[0483] 1 H-NMR (400 MHz, DMSO-d6, 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 obscured 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).

[0484] Examples 42 and 43 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2) [ka] 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 its enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IG, 5 μm, 250 mm×20 mm; mobile phase: ethanol; flow rate: 15 mL / min; UV detection: 220 nm; temperature: 40° C.].

[0485] Example 42 (Enantiomer 1): N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3S)-3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] Yield: 67mg R t = 11.22 min; chemical purity 99%; 99% ee [Column: Daicel Chiralcel IG, 5 μm, 250 mm × 4.6 mm; Mobile phase: Ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 50 °C; UV detection: 235 nm].

[0486] LC-MS (Method 1):R t =0.97min;m / z=490(M+H) + .

[0487] Example 43 (Enantiomer 2): N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-(trifluoromethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] Yield: 67mg R t = 11.87 min; chemical purity 99%; >96% ee [Column: Daicel Chiralcel IG, 5 μm, 250 mm × 4.6 mm; Mobile phase: Ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 50 °C; UV detection: 235 nm].

[0488] LC-MS (Method 1):R t =0.96min;m / z=490(M+H) + .

[0489] 1 H-NMR (500 MHz, DMSO-d6, 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).

[0490] Examples 44 and 45 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) [ka] 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 its enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OD-H, 5 μm, 250 mm × 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.].

[0491] Example 44 (Enantiomer 1): 2-{(3R)-3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] Yield: 93mg R t = 1.50 min; chemical purity > 99%; 99% ee [Column: Phenomenex Cellulose-1, 3 μm, 50 mm × 4.6 mm; Mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); Flow rate: 1 mL / min; Temperature: 25 °C; UV detection: 220 nm].

[0492] LC-MS (Method 4):R t =0.63min;m / z=542(M+H) + .

[0493] Example 45 (Enantiomer 2): 2-{(3S)-3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidin]-1'-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide [ka] Yield: 86mg R t = 2.21 min; chemical purity > 99%; 99% ee [Column: Phenomenex Cellulose-1, 3 μm, 50 mm × 4.6 mm; Mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); Flow rate: 1 mL / min; Temperature: 25 °C; UV detection: 220 nm].

[0494] LC-MS (Method 4):R t =0.62min;m / z=542(M+H) + .

[0495] 1 H-NMR (400 MHz, DMSO-d6, 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 obscured 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 obscured by H2O), 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).

[0496] Examples 46 and 47 N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (diastereomers 1 and 2) [ka] Diastereomeric mixture N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]-1,3-thiazole-5-carboxamide (Example 30), 51 mg (0.11 mmol), was separated into diastereomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H 5 μm, 250 mm × 20 mm; mobile phase: n-heptane / ethanol 50:50; flow rate: 20 mL / min; UV detection: 220 nm; temperature: 40 °C].

[0497] Example 46 (Diastereomer 1): Yield: 20 mg R t = 1.32 min; chemical purity > 99%; 99% ee [Column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 25 °C; UV detection: 220 nm].

[0498] LC-MS (Method 1):R t =1.22 min; m / z=449(M+H) + .

[0499] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.87 (m, 4H, including 0.82 (d, 3H)), 1.34-1.66 (m, 9H, including 1.42 (d, 3H)), 1.70-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.56 (m, 1H, partially obscured 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).

[0500] Example 47 (Diastereomer 2): Yield: 19 mg R t = 1.78 min; chemical purity > 99%; 99% ee [Column: Daicel Chiralpak OX-3, 3 μm, 50 mm × 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine; Flow rate: 1 mL / min; Temperature: 25 °C; UV detection: 220 nm].

[0501] LC-MS (Method 1):R t =1.19 min; m / z=449(M+H) + .

[0502] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.89 (m, 4H, including 0.82 (d, 3H)), 1.34-1.67 (m, 9H, including 1.42 (d, 3H)), 1.72-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.60 (m, 1H, partially obscured 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).

[0503] Example 48 rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 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, 75% purity, 285 μmol) were combined and stirred in 2 mL of sodium carbonate solution (2.0 mL, 2.0 M, 4.0 mmol) at 120° C. for 1 hour. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 55 mL, mobile phase B from 0 to 2 min: 15 mL, mobile phase A from 10 min: 55 mL to 31 mL and mobile phase B from 15 mL to 39 mL, mobile phase C from 10 to 12 min: 0 mL mobile phase A and 70 mL mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 60.0 mg of the target compound (100% pure, 35% of theory).

[0504] LC-MS (Method 4):R t =0.51 min;MS(ESIpos):m / z=466[M+H] + .

[0505] 1H-NMR (600 MHz, DMSO-d6) 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).

[0506] Example 49 N-[(3,5-difluoropyridin-2-yl)methyl]-3-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,2,4-oxadiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (44 μL, 250 mmol) and propylphosphonic anhydride (66 μL, 50% solution in ethyl acetate, 110 μmol) were added to a solution of 3-[(3R)-3-methyl[1,4′-bipiperidine]-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 acetonitrile (1 mL), 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 (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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: 47 mL to 23 mL and mobile phase B 2 to 47 mL, mobile phase C and mobile phase D 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 at a constant flow rate of 5 mL / min over the entire run). The product-containing fractions were combined and lyophilized. This gave 7.00 mg of the target compound (100% pure, 20% of theory).

[0507] LC-MS (Method 1):R t =0.96min;MS(ESIpos):m / z=421[M+H] + .

[0508] 1H-NMR (600 MHz, DMSO-d6) 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).

[0509] Example 50 Diastereomeric mixture -N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3'-fluoro-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 μmol) and the diastereomeric mixture (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 concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 55 mL, mobile phase B from 0 to 2 min: 15 mL, mobile phase A from 10 min: 55 mL to 31 mL and mobile phase B from 15 mL to 39 mL, mobile phase C from 10 to 12 min: 0 mL mobile phase A and 70 mL mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 192 mg of the target compound (100% pure, 70% of theory).

[0510] LC-MS (Method 4):R t =0.54 min;MS(ESIpos):m / z=454[M+H] + .

[0511] 1H-NMR (600 MHz, DMSO-d6) 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).

[0512] Example 51 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) [ka] 190 mg of the diastereomeric mixture -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 Daicel® Chiralpak IA, 5 μm, 250 × 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 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 mL / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60 ° C; detection: 220 nm) was collected. Removal of the solvent gave 88 mg (99% ee) of the title compound.

[0513] LC-MS (Method 1):R t =0.93min;MS(ESIpos):m / z=454[M+H] + .

[0514] 1H.NMR (500 MHz, DMSO-d6) 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).

[0515] Example 52 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) [ka] 190 mg of the diastereomeric mixture -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 Daicel® Chiralpak IA, 5 μm, 250 × 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 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 mL / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60 ° C; detection: 220 nm) was collected. Removal of the solvent gave 91 mg (99% ee) of the title compound.

[0516] LC-MS (Method 1):R t=0.93min;MS(ESIpos):m / z=454[M+H] + .

[0517] 1 H.NMR (500 MHz, DMSO-d6) 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).

[0518] Example 53 rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (49 μL, 280 μmol) and acetic acid (9.7 μL, 170 μmol) were added sequentially 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 dichloromethane (2.5 mL), and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (45.1 mg, 213 μmol) was then added, and the mixture was continued stirring at room temperature. After 2 h, saturated NaHCO 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 (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A: 47 mL from 0 to 2 min; mobile phase B: 23 mL from 0 to 2 min; mobile phase A: 47 mL from 10 min to 23 mL and mobile phase B: 3 mL from 47 mL from 10 min to 12 min; mobile phase C and mobile phase D: 0 mL of mobile phase A and 70 mL of mobile phase B, respectively; constant flow rates of 5 mL / min for the entire run). The product-containing fractions were combined and lyophilized. This gave 43.0 mg of the title compound (100% pure, 67% of theory).

[0519] LC-MS (Method 1):R t =0.98min;MS(ESIpos):m / z=450[M+H] + .

[0520] 1H-NMR (600 MHz, DMSO-d6) 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).

[0521] Example 54 rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(3-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (49 μL, 280 μmol) and acetic acid (9.7 μL, 170 μmol) were added sequentially 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 dichloromethane (2.5 mL), and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (45.1 mg, 213 μmol) was then added, and the mixture was continued stirring at room temperature. After 2 h, saturated NaHCO 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 (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A: 47 mL from 0 to 2 min; mobile phase B: 23 mL from 0 to 2 min; mobile phase A: 47 mL from 10 min to 23 mL and mobile phase B: 3 mL from 47 mL from 10 min to 12 min; mobile phase C and mobile phase D: 0 mL of mobile phase A and 70 mL of mobile phase B, respectively; constant flow rates of 5 mL / min for the entire run). The product-containing fractions were combined and lyophilized. This gave 40.0 mg of the target compound (100% pure, 63% of theory).

[0522] LC-MS (Method 1):R t =0.97min;MS(ESIpos):m / z=450[M+H] +

[0523] 1 H-NMR (600 MHz, DMSO-d6) 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).

[0524] Example 55 Diastereomeric mixture - N-[1-(3,5-difluoropyridin-2-yl)ethyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (182 μL, 105 μmol) and propylphosphonic anhydride (86 μL, 50% solution 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 rac-1-(3,5-difluoropyridin-2-yl)ethanamine (45.5 mg, 288 μmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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 A2 to 10 min: 47 mL to 23 mL and mobile phase B2 to 47 mL, mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 12.0 mg of the target compound (100% pure, 10% of theory).

[0525] LC-MS (Method 1):R t =1.02min;MS(ESIpos):m / z=450[M+H] + .

[0526] 1H-NMR (600 MHz, DMSO-d6) 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).

[0527] Example 56 N-[(5-chloro-1,3-thiazol-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (230 μL, 1.3 mmol) and propylphosphonic anhydride (86 μL, 50% solution 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 acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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 A2 to 10 min: 47 mL to 23 mL and mobile phase B2 to 47 mL, mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 14.0 mg of the target compound (100% pure, 12% of theory).

[0528] LC-MS (Method 1):R t =1.00min;MS(ESIpos):m / z=440[M+H] + .

[0529] 1H-NMR (400 MHz, DMSO-d6) 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).

[0530] Example 57 N-[(5-fluoro-2-thienyl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (180 μL, 1.0 mmol) and propylphosphonic anhydride (86 μL, 50% solution in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidine]-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 acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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 A2 to 10 min: 47 mL to 23 mL and mobile phase B2 to 47 mL, mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 12.0 mg of the target compound (100% pure, 11% of theory).

[0531] LC-MS (Method 1):R t =1.09min;MS(ESIpos):m / z=423[M+H] + .

[0532] 1H-NMR (600 MHz, DMSO-d6) 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).

[0533] Example 58 2-[(3R)-3-Methyl[1,4'-bipiperidin]-1'-yl]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide [ka] N,N-Diisopropylethylamine (180 μL, 1.0 mmol) and propylphosphonic anhydride (86 μL, 50% solution 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 acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; wavelength: 200-400 nm; full injection; gradient profile: mobile phase A from 0 to 2 min: 55 mL, mobile phase B from 0 to 2 min: 15 mL, mobile phase A from 10 min: 55 mL to 31 mL and mobile phase B from 15 mL to 39 mL, mobile phase C from 10 to 12 min: 0 mL mobile phase A and 70 mL mobile phase B, mobile phase C and mobile phase D, constant flow rate of 5 mL / min each over the entire run). The product-containing fractions were combined and lyophilized. This gave 7.00 mg of the target compound (100% pure, 7% of theory).

[0534] LC-MS (Method 1):R t =0.48min;MS(ESIneg):m / z=398[MH] - .

[0535] 1H-NMR (400 MHz, DMSO-d6) 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).

[0536] Example 59 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 [ka] 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, 75% purity, 348 μmol) were combined and stirred in 2 mL of sodium carbonate solution (2 mL, 2.0 M, 4 mmol) at 120° C. for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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: 47 mL to 23 mL and mobile phase B 2 to 47 mL; mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, respectively; constant flow rates of 5 mL / min for mobile phase C and mobile phase D over the entire run time). The product-containing fractions were combined and lyophilized. This yielded 56.0 mg of the target compound (100% pure, 30% of theoretical).

[0537] LC-MS (Method 5):R t =1.64 min;MS(ESIpos):m / z=534[M+H] + .

[0538] 1H-NMR (600 MHz, DMSO-d6) 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).

[0539] Example 60 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 [ka] 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 in 2 mL of sodium carbonate solution (2 mL, 2.0 M, 4 mmol) at 120° C. for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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: 47 mL to 23 mL and mobile phase B 2 to 47 mL; mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, respectively; constant flow rates of 5 mL / min for the entire run). The product-containing fractions were combined and lyophilized. This yielded 10.5 mg of the target compound (100% pure, 9% of theoretical).

[0540] LC-MS (Method 5):R t =1.65 min;MS(ESIpos):m / z=538[M+H] + .

[0541] 1H-NMR (600 MHz, DMSO-d6) 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).

[0542] Example 61 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 [ka] 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) were combined and stirred in 2 mL of sodium carbonate solution (2 mL, 2.0 M, 4 mmol) at 120° C. for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); 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: 47 mL to 23 mL and mobile phase B 2 to 47 mL; mobile phase C and mobile phase D 10 to 12 min: 0 mL of mobile phase A and 70 mL of mobile phase B, mobile phase C and mobile phase D, constant flow rates of 5 mL / min each over the entire run time). The product-containing fractions were combined and lyophilized. This yielded 49.8 mg of the target compound (100% pure, 30% of theoretical).

[0543] LC-MS (Method 5):R t =1.71 min;MS(ESIpos):m / z=556[M+H] + .

[0544] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.608 (6.75), 0.611 (6.72), 0.725 (3.50), 0.733 (9.17), 0.735 (8.79), 0.743 (2.54), 0.904 (0.57), 0.921 (1.21), 0.936 (1.35), 0.955 (0.59), 1.372 (0.53), 1.391 (1.17), 1.411 (1.22), 1.437 (0.65), 1.444 (0.72), 1.456 (1.67), 1.466 (1.85), 1.476 (2.47), 1.485 (1.95), 1.496 (1.74), 1.515 (0.52), 1.587 (2.51), 1.592 (2.61), 1.599 (2.32), 1.722 (1.44), 1.739 (1.01), 1.759 (2.61), 1.781 (2.25), 1.909 (1.70), 1.926 (2.76), 1.943 (1.48), 2.109 (1.17), 2.125 (2.16), 2.142 (1.16), 2.486 (1.43), 2.522 (1.19), 2.699 (1.73), 2.718 (1.60), 2.791 (1.81), 2.806 (1.75), 3.029 (2.22), 3.050 (4.07), 3.071 (2.19), 3.237 (7.84), 3.248 (8.49), 3.384 (0.66), 3.403 (16.00), 3.422 (0.65), 3.922 (3.21), 3.943 (3.05), 4.524 (6.21), 4.533 (6.24), 5.805 (2.61), 5.901 (5.22), 5.996 (2.47), 7.824 (12.56), 7.878 (1.45), 7.882 (1.55), 7.897 (2.60), 7.910 (1.53), 7.914 (1.57), 8.458 (5.72), 8.462 (5.73), 8.666 (1.94), 8.675 (3.99), 8.684 (2.01).

[0545] Example 62 rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide [ka] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (110 mg, 329 μmol) and rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride (129 mg) were combined and stirred in 2 mL of sodium carbonate solution (2 mL, 2.0 M, 4 mmol) at 120° C. for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (apparatus: Waters Prep LC / MS System; column: XBridge C18 5 μm 100 × 30 mm; mobile phase A: water; mobile phase B: acetonitrile; mobile phase C: 2% aqueous ammonia; mobile phase D: acetonitrile / water (80% v / 20% v); total flow rate: 80 mL / min; room temperature; ...

Claims

1. A compound of the following general formula (I) or a salt of said compound, or a solvate of the compound of formula (I) or a salt of said compound: 【Chemical 1】 [In the formula, The aromatic five-membered ring having X, Y, and Z has the following structural formula h), i), j), k), or (r): 【Chemistry 2】 selected to have where: * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R １ represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; Pyridinyl is independently (C １ -C ２ )-optionally substituted by 1 to 2 substituents selected from the group consisting of alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy; The pyrazolyls are each independently (C １ -C ２ )-optionally substituted by 1 to 2 substituents selected from the group consisting of alkyl, fluorine, chlorine, trifluoromethyl; thiazolyl may be substituted by chlorine; thienyl may be substituted by fluorine; Phenyl is independently (C １ -C ２ )-alkyl, (C ３ -C ４ )--optionally substituted by 1 to 2 substituents selected from the group consisting of cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, and trifluoromethyl; R ２ but, represents hydrogen, methyl, or R ２ together with the carbon atom to which it is attached form a cyclopropyl ring, R ３ is hydrogen, (C １ -C ２ )-alkyl; R ４ represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted by chlorine; R ５ represents hydrogen or fluorine; R ６ is a group of the following formula a), b'), b"), c'), c") or e): 【Chemistry 3】 represents *** indicates a bond to the adjacent piperidine ring, R ７ or R' ７ are each independently hydrogen, (C １ -C ４ )-alkyl, (C ３ -C ４ )-cycloalkyl, (C １ -C ２ )-alkoxy, (C ３ -C ４ )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl; (C １ -C ４ )-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy, and may be up to disubstituted by fluorine; methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl is optionally substituted by monofluoromethyl, difluoromethyl, trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C １ -C ２ )-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl, and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C ３ -C ４ )-cycloalkoxy may be up to disubstituted by fluorine; R ９ represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine; n represents 0 or 1, and m represents 1 or 2.

2. The aromatic five-membered ring having X, Y, and Z has the following structural formula h'), i'), j'), or k): 【Chemistry 4】 is selected to have R １ pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, 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 or methyl; R ４ represents hydrogen, ethyl, or trifluoromethyl; R ５ represents hydrogen or fluorine; R ６ is a group of formula a), c') or c"): 【Chemistry 5】 represents *** indicates a bond to the adjacent piperidine ring, R ７ and R' ７ are each independently 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy or trifluoromethylcyclopropylmethoxy; n represents 0 or 1, and m represents 1 2. A compound of formula (I) according to claim 1, or a salt of said compound, or a solvate of said compound of formula (I) or a salt of said compound.

3. The aromatic five-membered ring having X, Y, and Z has the following structural formula h': 【Chemistry 6】 is selected to have R １ pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, 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 or fluorine; R ６ is a group of formula a), c') or c"): 【Chemistry 7】 represents *** indicates a bond to the adjacent piperidine ring, R ７ and R' ７ represent each independently 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, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy or trifluoromethylcyclopropylmethoxy; n represents 0 or 1, and m represents 1 2. A compound of formula (I) according to claim 1, or a salt of said compound, or a solvate of said compound of formula (I) or a salt of said compound.

4. N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide represented by the following formula or a salt of the compound, or a solvate of the compound or the salt of the compound: 【Chemistry 19】

5. 2-[4-(5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide represented by the following formula, or a salt of the compound, or a solvate of the compound or a salt of the compound: 【Chemistry 20】

6. ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide (enantiomer 2) represented by the following formula or a salt of the compound, or a solvate of the compound or a salt of the compound: 【Chemical 21】

7. 4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide represented by the following formula, or a salt of the compound, or a solvate of the compound or a salt of the compound: 【Chemical 22】

8. N-[1-(3,5-difluoropyridin-2-yl)cyclopropyl]-2-[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl]-1,3-thiazole-5-carboxamide represented by the following formula, or a salt of the compound, or a solvate of the compound or a salt of the compound: 【Chemical 23】

9. A method for producing a compound of the following general formula (I) or a salt of said compound, or a solvate of a compound of the following general formula (I) or a salt of said compound, comprising: 【Chemistry 24】 [In the formula, The aromatic five-membered ring having X, Y, and Z has the following structural formula h), i), j), k), or (r): 【Chemistry 25】 selected to have where: * indicates a bond to a carbonyl group, ** indicates a bond to a nitrogen atom of an adjacent piperidine ring, R 1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, or phenyl; pyridinyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy; pyrazolyl is optionally substituted by 1 to 2 substituents, independently of one another, selected from the group (C 1 -C 2 )-alkyl, fluorine, chlorine, trifluoromethyl; thiazolyl may be substituted by chlorine; thienyl may be substituted by fluorine; phenyl may be substituted by 1 to 2 substituents, independently of one another, selected from the group (C 1 -C 2 )-alkyl, (C 3 -C 4 )-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R 2 is represents hydrogen, methyl, or together with the carbon atom to which R 2 is attached, form a cyclopropyl ring; R 3 represents hydrogen, (C 1 -C 2 )-alkyl; R 4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; The phenyl may be substituted by chlorine; R 5 represents hydrogen or fluorine; R 6 is a group of the following formula a), b′), b″), c′), c″) or e): ​ represents *** indicates a bond to the adjacent piperidine ring, R 7 or R′ 7 are independently hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 1 -C 2 )-alkoxy, (C 3 -C 4 )-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl; (C 1 -C 4 )-alkyl optionally substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine; methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl; cyclopropyl is optionally substituted by monofluoromethyl, difluoromethyl, trifluoromethyl; cyclobutyl may be up to disubstituted by fluorine; n-butoxy may be up to disubstituted by fluorine; (C 1 -C 2 )-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl, and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; (C 3 -C 4 )-cycloalkoxy may be up to disubstituted by fluorine; R 9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine or chlorine; n represents 0 or 1, and m represents 1 or 2; where: [A] A compound of the following formula (II): 【Chemical 27】 [In the formula, X, Y, Z, R １ , R ２ , R ３ and n has the meaning given above, Hal represents a leaving group. ] in the presence of a base to give a compound of the following formula (III): 【Chemical formula 28】 [In the formula, R ５ and R ６ and m has the meaning given above, to give a compound of formula (IA): 【Chemical 29】 and or [B] A compound of the following formula (IV): 【Chemistry 30】 [In the formula, X, Y, Z, R １ , R ２ , R ３ and R ５ and n and m have the meanings given above. A compound of formula (V): 【Chemical 31】 [In the formula, R ６ has the meaning given above], and Reacting in the presence of a reducing agent and optionally an acid produces a compound of formula (IB): 【Chemical Formula 32】 and or [C] A compound of the following formula (VI): 【Chemical 33】 [In the formula, X, Y, Z, R ５ and R ６ and m has the meaning given above. A compound of formula (VII): 【Chemical 34】 [In the formula, R １ , R ２ and R ３ and n has the same meaning as above.] in the presence of a condensing agent or an activating agent to obtain a compound of the following formula (IC): 【Chemical 35】 and and optionally separating the compounds of formula (IA), (IB), (IC) thus obtained into their enantiomers and / or diastereomers, and / or converting them into solvates, salts, and / or solvates of salts thereof with an appropriate (i) solvent and / or (ii) acid.

10. A compound as defined in any one of claims 1 to 8 for the treatment and / or prevention of diseases.

11. A compound as defined in any one of claims 1 to 8 for use in a method for the treatment and / or prevention of respiratory distress, swallowing disorders, peripheral and cardiovascular disorders and disorders of the peripheral and central nervous system.

12. 10. A compound as defined in any one of claims 1 to 8 for use in a method for the treatment and / or prevention of dyspnea, including sleep-induced dyspnea, including central and obstructive sleep apnea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiovascular disorders including diabetic microangiopathy, and disorders of the peripheral and central nervous system, including neurodegenerative and neuroinflammatory disorders.

13. 10. A compound as defined in any one of claims 1 to 8 for use in a method for the treatment and / or prevention of dyspnea, including in particular sleep-induced dyspnea such as obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome), central sleep apnea, Shine-Stokes respiration, primary sleep apnea of ​​early childhood, central sleep apnea as a result of an obvious life-threatening event, the use of medicines or the use of other substances, obesity hypoventilation syndrome, disturbances of central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, post-operative hypoxia and apnea, muscular respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during high altitude adaptation, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

14. 10. A compound as defined in any one of claims 1 to 8 for use in a method for the treatment and / or prevention of peripheral and cardiovascular disorders including diabetic microangiopathy, in particular diabetic ulcers of the limbs for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular disorders, thromboembolism and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic sclerosis, CREST syndrome, microcirculatory disorders and intermittent claudication.

15. 9. A compound as defined in any one of claims 1 to 8 for use in a method for the treatment and / or prophylaxis of disorders of the peripheral and central nervous system such as dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity, Tourette's syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm and other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by alterations in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease.

16. A medicament comprising a compound as defined in any one of claims 1 to 8 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

17. 9. A medicament comprising a compound as defined in any one of claims 1 to 8 in combination with one or more further active compounds selected from the group consisting of 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.

18. 18. A medicament according to claim 16 or 17 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 disorders of the peripheral and central nervous system including neurodegenerative and neuroinflammatory disorders.

19. 10. Use of a compound as defined in any one of claims 1 to 8 for the preparation of a medicament 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 disorders of the peripheral and central nervous system, including neurodegenerative and neuroinflammatory disorders, in humans and animals.

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