Adrenergic receptor ADRAC2 antagonist

Abstract

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

Description

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

[0002] α2-adrenergic receptors (α2-AR) belong to the G protein coupled receptor family. They bind to pertussis toxin-sensitive inhibitory G proteins G1 and G0 and reduce adenylate cyclase activity. When stimulated by endogenous catecholamines (epinephrine, norepinephrine) released through synapses or reaching the site of action via the blood, they participate in the mediation of several different physiological effects in different tissues. α2-AR plays an important physiological role, mainly in the cardiovascular system and the central nervous system. Biochemical, physiological and pharmacological studies have shown that in many cardiovascular-related target cells and tissues and neuronal target cells and tissues, in addition to various α1-AR subtypes, there are three α2-AR subtypes (α2A, α2B and α2C), which makes them attractive target proteins for therapeutic intervention. However, due to the lack of highly selective ligands and / or antagonists for the corresponding α2-AR, the interpretation of the precise physiological tasks of receptor subtypes remains difficult [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 respiratory disorder characterized by recurrent episodes of upper airway obstruction.

[0004] During inspiration, the interaction of two opposing forces ensures upper airway patency. The dilation of the upper airway muscles counteracts the negative pressure within the airway lumen, causing it to contract. Active contraction of the diaphragm and other accessory respiratory muscles generates negative pressure within the airway, which serves as the driving force for respiration. Upper airway stability essentially depends on the coordination and contractile properties of the upper airway dilator muscles.

[0005] It is thought that upper airway collapse in OSA occurs in early sleep because some upper airway dilator muscles become less active, which results in the physiologically sensitive airway no longer remaining open. However, some upper airway dilator muscles, including the genioglossus, which is the most important of the upper airway extensors and is innervated by the hypoglossal nerve, may increase in activity during sleep in response to respiratory stimuli, potentially offsetting some of the changes in early sleep. It has been observed that patients with OSA have apnea-free intervals during which genioglossus activity is only 25-40% higher than in sleep with recurrent obstructive apnea [Jordan AS, White DP, Lo YL et al. Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32 (3): 361-8]. Norepinephrine is one of the most effective neuromodulators of hypoglossal motor neuron activity [HornerR.L.Neuromodulation of hypoglossal motoneurons during sleep.Respir PhysiolNeurobiol 2008, 164 (1-2): 179-196]. It is thought that reduced noradrenergic stimulation leads to a decrease in sleep-induced hypoglossal motor neuron excitability, resulting in reduced activity of the dilator muscles of the upper airway, particularly the genioglossus muscle.

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

[0007] α2C-adrenergic receptors regulate norepinephrine release from central noradrenergic neurons and are autoreceptors involved in presynaptic feedback inhibition of norepinephrine. [Hein L. et al., Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402 (6758): 181-184].

[0008] Increased activity of the hypoglossal nerve's motor neurons, through α2c-adrenergic receptor antagonism, stabilizes the upper airway and protects it from collapse and obstruction. Furthermore, snoring can be suppressed by stabilizing the upper airway.

[0009] In cases of primary snoring, the upper airway is not obstructed. However, due to the constriction of the upper airway, the flow rate of air being inhaled and exhaled increases. This, combined with the relaxed muscle tissue, causes the soft tissues of the mouth and pharynx to vibrate in the air flow. This gentle vibration subsequently produces the typical snoring noise.

[0010] Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This leads to increased airway resistance and therefore an increase in the work of breathing, accompanied by significant fluctuations in intrathoracic pressure. During inspiration, the development of negative intrathoracic pressure can reach values ​​similar to those encountered due to complete airway obstruction during obstructive sleep apnea. The pathophysiological effects on the heart, blood circulation and sleep quality are comparable to those in obstructive sleep apnea. As in obstructive sleep apnea, the pathogenesis is believed to be impaired pharyngeal dilator muscle activity during inspiration during sleep. Typically, obstructive snoring is the initial stage of 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 recurrent episodes of inadequate breathing or no breathing and impaired gas exchange. CSA has various manifestations. These include high altitude periodic breathing, idiopathic CSA (ICSA), central apnea caused by anesthetics, hypopnea syndrome (OHS), and Cheyne-Stokes breathing (CSB). The exact mechanisms in different types of CSA can vary greatly; however, a key feature 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 a difficulty in swallowing that may have various causes. The complex regulation of swallowing occurs in various structures of the brain. This is a bidirectional connection between the cerebral cortex, cortical brainstem bundles, brainstem and peripheral swallowing muscle tissue. The regulation and execution of swallowing behavior essentially involve five pairs of cranial nerves (trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X) and hypoglossal nerve (XII)) and more than 25 muscle pairs [Arens C., Position paper of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German Societyof Phoniatrics and Pediatric Audiology-current state of clinical and endoscopic diagnostics, evaluation, and therapy of swallowing disorders in children and adults. Laryngo-hinootologie, 2015 Mar; 94 Suppl 1: 306-54].

[0013] Dysphagia can have very different causes, such as structural disorders of the mouth and / or larynx, psychological causes and neurological disorders (neurogenic dysphagia), for example, Parkinson's disease, myotonic dystrophy, amyotrophic lateral sclerosis, cerebral infarction, head injury, brainstem injury, myositis and neuromuscular disorders [Karkos PD, Current evaluation of the dysphagic patient. Hippokratia. 2009 Jul;13(3):141-6].

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

[0015] α2-AR also plays an important role in cardiovascular changes. For example, the regulation of cardiac contractility is primarily regulated by central modulation of sympathetic efferent nerves. In addition, the sympathetic efferent system also regulates direct effects on smooth muscle cells and vascular endothelial cells. Therefore, the sympathetic nervous system is involved in the regulation of cardiac output performance and the control of local perfusion of various vascular beds. This is also controlled by α2-ARs that participate in the regulation of peripheral resistance. Therefore, blood vessels are innervated by sympathetic nerve fibers located in the adventitia and having varicose veins at their ends for the release of norepinephrine. The released norepinephrine regulates the local vascular tone of each via α2-ARs in endothelial cells and smooth muscle cells.

[0016] In addition to its effects on sympathetic efferent nerves, peripheral cardiovascular function is also regulated by presynaptic and postsynaptic α2-ARs. Smooth muscle cells and endothelial cells express different α2-AR subtypes. 2A , α 2B and α 2C Activation of the receptor leads to contraction and therefore vasoconstriction [Kanagy, Clinical Science 109: 431-437, (2005)]. However, the distribution of each receptor subtype varies in different vascular beds, between species, and between different vessel sizes. Thus, α2A-AR appears to be expressed almost exclusively in large arteries, while α2B-AR contributes more to vascular tone in small arteries and veins. ARα 2B Appears to play a role in salt-induced hypertension [Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. The role of ARα2C on hemodynamics is not fully understood; however, ARα2C receptors appear to mediate venous vasoconstriction. They are also involved in the cold-induced enhancement of adrenergic receptor-induced vasoconstriction [Chotani et al., Silent α 2CAdrenergic 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 and other factors (such as tissue proteins, estrogen) regulate ARα2C function coupled to intracellular signaling pathways [Chotani et al., Distinct cAMPsignaling pathways differentially regulate α 2C adrenenoxceptor expression: rolein serum induction in human arteriolar smooth muscle cells. Am J Physiol HeartCirc Physiol 288: H69-H76, (2005)].

[0017] Under pathophysiological conditions, the adrenergic system can be activated, which can lead to, for example, hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disturbances, stroke and sexual dysfunction. Thus, for example, the pathophysiology of Raynaud's syndrome and scleroderma is largely unknown but is associated with altered adrenergic activity. Thus, patients with spastic Raynaud's syndrome show, for example, a significantly increased expression of ARα2 on their platelets. This may be associated with the vasospasm episodes observed in these patients [Keenan and Porter, α2-Adrenergic receptors in platelets from patients with Raynaud's syndrome, Surgery, V94(2), (1983)].

[0018] Due to the expected high efficiency and low side effect level, the possible therapy for such diseases that is regulated by the activated adrenergic system in the organism is a promising method. Particularly in diabetic patients who often have elevated catecholamine levels, peripheral circulatory disorders (microangiopathy) such as diabetic retinopathy, nephropathy or significant wound healing disorders (diabetic foot ulcers) play a great role. Among peripheral occlusive diseases, diabetes is one of the most important comorbidities and also plays a decisive role in the progression of the disease (microvascular and macrovascular lesions). In these pathophysiological processes in diabetic patients, the higher expression of adrenergic receptor α2C receptors associated with elevated catecholamine levels may be involved.

[0019] 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 patients with diabetes. The lifetime risk of a diabetic foot ulcer is 15-25%, and 15% of all diabetic foot ulcers result in amputation. 40-70% of all non-traumatic amputations worldwide occur in patients with diabetes. Risk factors for diabetic foot ulcers are trauma, poor metabolic control, sensory, motor, and autonomic polyneuropathy, inadequate footwear, infection, and peripheral arterial disease. Treatment of diabetic foot ulcers requires an interdisciplinary team approach using a multifactorial approach: weight loss, revascularization (in the setting of peripheral arterial occlusive disease (PAOD), improved metabolic control, debridement, bandaging, dalteparin, Regranex (PDGF), and amputation. The cost of treating each diabetic foot ulcer (without amputation) is US$7,000-10,000. 33% of all diabetic foot ulcers fail to heal within 2 years, and recurrence rates are high (34% within the first year and 61% within 3 years).

[0020] The compounds of the present application are suitable for preventing and treating α 2C -Diseases caused by adrenergic receptors and secondary to α 2C - Diseases involving damage to adrenergic receptors.

[0021] Disorders which may be mentioned in this context are, in particular, dyspnea, sleep-induced dyspnea such as central and obstructive sleep apnea, mixed sleep apnea, Cheyne-Stokes breathing, snoring (primary and obstructive snoring), interrupted central respiratory drive, sudden infant death, postoperative hypoxia and apnea, muscular respiratory disorders, respiratory disorders following long-term ventilation, respiratory disorders during adaptation in high mountains, dysphagia, acute and chronic lung diseases with hypoxia and hypercapnia, peripheral circulatory disorders (microangiopathy) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers), disorders of the peripheral and central nervous system, in particular dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity hyperaktivity)(ADHS), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0022] The object of the present invention was therefore to provide novel substances which act as potent and selective antagonists of α2C-adrenoceptors 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).

[0023] The present invention provides compounds of general formula (I)

[0024]

[0025] in

[0026] X represents S, N or O;

[0027] Y represents N, S or O;

[0028] Where, if X represents S, then Y represents N;

[0029] Where, if X represents O, then Y represents N;

[0030] Z represents CR4, O or NR4,

[0031] Where, if X represents N and Y represents N, then Z represents O;

[0032] Where, if X represents S, then Z represents CR4 or NR4

[0033] R1 represents a 5- or 6-membered heteroaryl group, a phenyl group,

[0034] wherein the 5- to 6-membered heteroaryl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen;

[0035] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0036] wherein the (C1-C4)-alkoxy radical may be up to three times substituted by halogen,

[0037] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen;

[0038] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0039] R2 represents hydrogen, (C1-C4)-alkyl;

[0040] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0041] or

[0042] Together with the carbon atom to which R2 is attached, it forms a (C3-C4)-cycloalkyl ring,

[0043] R3 represents hydrogen, (C1-C4)-alkyl,

[0044] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0045] R4 in CR4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, halogen;

[0046] wherein (C1-C4)-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen,

[0047] NR4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl;

[0048] wherein (C1-C4)-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen,

[0049] R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen,

[0050] R6 represents a group of formula a), b), c), d), e), f) or g)

[0051]

[0052] where ** indicates the connection to the adjacent piperidine ring,

[0053] wherein R7 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, phenyl,

[0054] wherein (C1-C4)-alkyl may be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy and up to three times by halogen,

[0055] wherein (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to three times by halogen,

[0056] where (C3-C4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen,

[0057] where (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to trisubstituted by halogen,

[0058] Wherein (C3-C4)-cycloalkyl may be mono- or disubstituted by halogen,

[0059] wherein the (C3-C4)-cycloalkoxy radical may be up to disubstituted by halogen,

[0060] wherein R8 represents hydrogen or fluorine,

[0061] wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen;

[0062] where (C1-C4)-alkyl may be substituted by (C1-C4)-alkoxy,

[0063] n represents 0 or 1,

[0064] m represents 0, 1 or 2,

[0065] p represents 0, 1 or 2 and

[0066] q represents 0, 1, or 2,

[0067] and salts, solvates and solvates of salts thereof.

[0068] The present invention provides compounds of general formula (I)

[0069]

[0070] in

[0071] X represents S, N, O;

[0072] Y represents N, S, O,

[0073] Where, if X represents S, then Y represents N;

[0074] Z represents C, O, N,

[0075] Where, if X represents N and Y represents N, then Z represents O;

[0076] R1 represents a 5- or 6-membered heteroaryl group or a phenyl group,

[0077] wherein the 5- to 6-membered heteroaryl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen;

[0078] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0079] wherein the (C1-C4)-alkoxy radical may be up to three times substituted by halogen,

[0080] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen;

[0081] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0082] R2 represents hydrogen, (C1-C4)-alkyl;

[0083] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0084] or

[0085] Together with the carbon atom to which R2 is attached, it forms a (C3-C4)-cycloalkyl ring,

[0086] R3 represents hydrogen, (C1-C4)-alkyl,

[0087] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0088] R4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, halogen;

[0089] wherein (C1-C4)-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen,

[0090] R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen,

[0091] R6 represents a group of formula a), b), c), d), e), f) or g)

[0092]

[0093] where ** indicates the connection to the adjacent piperidine ring,

[0094] wherein R7 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, phenyl,

[0095] wherein (C1-C4)-alkyl may be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy and up to three times by halogen,

[0096] wherein (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to three times by halogen,

[0097] where (C3-C4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen,

[0098] wherein (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to three times by halogen,

[0099] Wherein (C3-C4)-cycloalkyl may be mono- or disubstituted by halogen,

[0100] Wherein (C3-C4)-cycloalkoxy can be substituted by halogen up to two times,

[0101] wherein R8 represents hydrogen or fluorine,

[0102] wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen;

[0103] where (C1-C4)-alkyl may be substituted by (C1-C4)-alkoxy,

[0104] n represents 0 or 1,

[0105] m represents 0, 1 or 2,

[0106] p represents 0, 1 or 2 and

[0107] q represents 0, 1, or 2,

[0108] and salts, solvates and solvates of salts thereof.

[0109] The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of salts thereof, compounds encompassed by formula (I) and having the formula mentioned below and salts, solvates and solvates of salts thereof, and compounds encompassed by formula (I) and mentioned below as working examples and salts, solvates and solvates of salts thereof, even if the compounds encompassed by formula (I) and mentioned below are not yet salts, solvates and solvates of salts.

[0110] The compounds of the invention are likewise N-oxides and S-oxides of the compounds of formula (I) and their salts, solvates and solvates of their salts.

[0111] In the present invention, salts are preferably physiologically acceptable salts of the compounds according to the invention. Salts which are not suitable for pharmaceutical use per se but can be used, for example, for the isolation, purification or storage of the compounds according to the invention are also included.

[0112] Suitable pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of compounds of the present invention having a nitrogen atom in a chain or ring which is sufficiently basic, such as acid addition salts with inorganic acids or "mineral acids", such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid, or with organic acids such as 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, palmitic ... benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid Palmitic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0113] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium, magnesium or strontium salt; or an aluminum or zinc salt; or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine , 1,2-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 a salt with a quaternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium chloride.

[0114] Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base using a variety of known methods.

[0115] The present invention includes all possible salts of the compounds of the present invention, as single salts or as any mixture of said salts in any ratio.

[0116] In this article, in particular in the experimental part, for the synthesis of the intermediates and examples of the present invention, when the compound is mentioned as a salt form with the corresponding base or acid obtained by the respective preparation and / or purification method, in most cases, the exact stoichiometric composition of the salt form is unknown. Unless otherwise indicated, the suffixes of the chemical name or structural formula related to the salt, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF3COOH", "x Na+", for example, mean the salt form, and the stoichiometry of its salt form is not specified. This is similarly applicable to the case where the synthetic intermediate or its example compound or its salt has been obtained as a solvate (such as a hydrate) by the described preparation and / or purification method.

[0117] Solvates are described in the context of the present invention as those forms of the compounds of the invention which form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination occurs with water. Preferred solvates in the context of the present invention are hydrates.

[0118] According to their structure, the compounds of the present invention may exist in different stereoisomeric forms, i.e. as configurational isomers or optionally as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore includes enantiomers and diastereomers and their respective mixtures. Stereoisomers can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, preferably chromatography is used, in particular HPLC chromatography on an achiral or chiral separation phase. In the case of carboxylic acids as intermediates or end products, separation via diastereomeric salts can also be achieved using chiral amine bases.

[0119] For the purposes of the present invention, the term "enantiomerically pure" is understood as follows: the compound in question is present in an enantiomeric excess of greater than 95%, preferably greater than 98%, with respect to the absolute configuration of the chiral center. The enantiomeric excess (ee) is calculated by evaluating the chromatogram of the HPLC analysis on a chiral phase using the following formula:

[0120]

[0121] If the compounds according to the invention can exist in tautomeric forms, the present invention comprises all tautomeric forms.

[0122] The present invention also includes all suitable isotopic variants of the compounds of the present invention. An isotopic variant of a compound of the present invention is understood herein to mean a compound in which at least one atom in the compound of the present invention has been replaced by another atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly present in nature. The phrase "unnatural proportion" is understood to mean a proportion of such isotopes that is higher than their natural frequency. The natural frequencies of isotopes used in this context can be found in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F.36 Cl, 82 Br, 123 I. 124 I. 129 I and 131 I. Certain isotopic variations of the compounds of the present invention, especially those into which one or more radioactive isotopes have been incorporated, may be useful, for example, in examining the mechanism of action or the distribution of the active ingredient in vivo; 3 H or 14 Compounds labeled with a C isotope are particularly suitable for this purpose. In addition, the incorporation of isotopes, such as deuterium, may bring specific therapeutic benefits due to the greater metabolic stability of the compound, such as an extension of the half-life in vivo or a reduction in the required active dose; such modifications of the compounds of the invention may therefore also optionally constitute a preferred embodiment of the invention. With regard to the treatment and / or prevention of the disorders specified herein, the (one or more) isotopic variants of the compounds of formula (I) preferably contain deuterium ("deuterated compounds of formula (I)"). In which one or more radioactive isotopes such as 3 H or 14 Isotopic variants of compounds of formula (I) having a cation of formula (I) ... 18 F or 11 C is incorporated into the compound of formula (I). These isotopic variants of the compound of formula (I) are suitable for in vivo imaging applications. 13 Compounds of this invention can be used in the context of preclinical or clinical studies in mass spectrometry analysis (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compounds of the invention can be prepared by conventional methods known to those skilled in the art, for example according to the methods described further below and the procedures reported in the Examples, by using various reagents and / or corresponding isotopic modifications of the starting compounds.

[0123] Isotopic variants of compounds of formula (I) are generally prepared by methods known to those skilled in the art as described in the schemes and / or examples herein by replacing the reagent with an isotopic variant of the reagent, preferably a deuterated reagent. Depending on the desired deuteration site, in some cases, deuterium from D2O may be incorporated directly into the compound or into reagents useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Photochemical deuteration and tritiation methods have also been described (YY Loh et al., Science 10.1126 / science.aap9674 (2017). Another useful reagent for incorporating deuterium into molecules is deuterium gas. A rapid route for incorporating deuterium is the olefinic bond (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; JR Morandi et al., J. Org. Chem., 1969, 34 ( 6), 1889) and acetylenic bonds (NH Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). In order to directly exchange hydrogen in hydrocarbons containing functional groups for deuterium, metal catalysts (i.e., Pd, Pt, and Rh) can also be used in the presence of deuterium gas (JG Atkinson et al., US Patent 3966781). Various deuteration reagents and synthesis equipment can be purchased from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0124] Further information relating to the prior art on deuterium-hydrogen exchange is found, for example, in Hanzlik et al., J. Org. Chem., 1990, 55, 3992-3997; RP Hanzlik et al., Biochem. Biophys. Res. Commun., 1989, 160, 844; PJ 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., WO 2012 / 112363.

[0125] The term "deuterated compound of formula (I)" is defined as a compound of formula (I) in which one or more hydrogen atoms have been replaced by one or more deuterium atoms and in which the deuterium frequency at each deuterated position in the compound of formula (I) is higher than the natural frequency of deuterium, which is about 0.015%. In particular, in a deuterated compound of formula (I), the deuterium frequency at each deuterated position in the compound of formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% at this position or these positions, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99%. Obviously, the deuterium frequency of each deuterated position is independent of the deuterium frequency of the other deuterated positions.

[0126] The selective incorporation of one or more deuterium atoms into the compounds of general formula (I) can change the physicochemical properties (e.g. acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; CL Perrin in Advances in Physical Organic Chemistry, 44, 144; CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19 (3), 271]) and / or the metabolic status of the molecule and lead to a change in the ratio of parent compound to metabolite or the amount of metabolite formed. Such changes may bring specific therapeutic benefits and are therefore preferred in specific cases. Reduced metabolic rates and metabolic conversions have been reported, wherein the ratio of metabolites changes (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes exposed relative to the parent compound and metabolites have an important impact on the pharmacodynamics, tolerability and effectiveness of the compounds of the general formula (I) containing deuterium. In some cases, deuterium substitution reduces or eliminates the formation of unwanted or toxic metabolites and enhances the formation of desired 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: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the systemic clearance rate. Therefore, the biological half-life of the compound is improved. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak concentrations and increased trough concentrations. Depending on the pharmacokinetic / pharmacodynamic relationship of the respective compound, this can result in lower side effects and enhanced efficacy.Examples of such deuterium effects are Indiplon (AJ Morales et al., Abstract 285, The 15th North American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12-16, 2008), ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO 2012 / 112363). Other cases have been reported where reduced metabolic rates lead to increased 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 such effects may have reduced dosing requirements (eg, a lower number of doses or a lower dose to achieve the desired effect) and / or may produce a lower metabolite burden.

[0127] Compounds of formula (I) may have multiple potential attack sites for metabolism. In order to optimize the above-mentioned effects on physicochemical properties and metabolic status, deuterated compounds of formula (I) with specific patterns of one or more deuterium-hydrogen exchanges may be selected. In particular, the deuterium atom / deuterium atoms of the deuterated compound (s) of formula (I) are attached to carbon atoms and / or are located at positions of the compound of formula (I) that are attack sites for metabolic enzymes, such as cytochrome P450.

[0128] The present invention further includes prodrugs of the compounds of the present invention. The term "prodrug" herein refers to a compound which itself may be biologically active or inactive but which is converted into a compound of the present invention when present in vivo (eg by metabolic or hydrolytic pathways).

[0129] In the context of the present invention, unless otherwise specified, substituents have the following meanings:

[0130] In the context of the present invention, alkylis a straight or branched chain alkyl group having a specific number of carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4,4-dimethylpentyl, and 1,4,4-trimethylpentyl.

[0131] In the context of the present invention, Alkoxy is a straight-chain or branched alkoxy group having 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0132] In the context of the present invention, Cycloalkoxy is a cyclic alkoxy group having 3 to 4 carbon atoms. Examples include: cyclopropyloxy or cyclobutyloxy.

[0133] In the context of the present invention, Cycloalkyl or carbon ring For monocyclic, polycyclic or spirocyclic rings with a total of 3 to 8 ring atoms, preferably monocyclic or bicyclic saturated carbocyclic rings. Monocyclic saturated carbocyclic rings are synonymously referred to 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. Preferably, monocyclic cycloalkyl rings with 3 to 5 carbon atoms are used. Examples include: cyclopropyl, cyclobutyl or cyclopentyl.

[0134] In the context of the present invention, 5- or 6-membered heteroaryl is a monocyclic aromatic heterocycle (heteroaromatic compound) having a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms selected from N, O and / or S and is linked 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, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0135] In general, unless otherwise indicated, heteroaryl includes all possible isomeric forms, such as tautomers and positional isomers with respect to the point of attachment to the rest of the molecule. Thus, as non-limiting examples, the term pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl, or the term thienyl includes 2-thienyl and 3-thienyl.

[0136] In the context of the present invention, halogen These include fluorine, chlorine, bromine and iodine, preferably chlorine or fluorine.

[0137] When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or polysubstituted. In the present invention, all groups occurring more than once are defined independently of one another. When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or polysubstituted. Preferably, it is substituted by one substituent or by two identical or different substituents.

[0138] In the context of the present invention, the term "treat" or "treatment" includes inhibiting, delaying, preventing, alleviating, attenuating, limiting, reducing, arresting, repelling or curing the development, course or progress of a disease, condition, disorder, injury or health problem, or such states and / or symptoms of such states. The term "therapy" is understood herein to be synonymous with the term "treatment."

[0139] The terms "prevent," "prevention," or "prophylaxis" are used synonymously herein and refer to avoiding or reducing the risk of contracting, developing, becoming afflicted with, or developing a disease, condition, symptom, injury, or health problem, or the development or progression of such states and / or symptoms of such states.

[0140] Treatment or prevention of a disease, condition, symptom, injury or health problem may be achieved partially or completely.

[0141] In the context of the present invention, preferred compounds of formula (I)

[0142] Where X represents S or N;

[0143] Y represents N, S or O,

[0144] Where, if X represents S, then Y represents N;

[0145] Z represents CR4, N or O,

[0146] Where, if X represents N and Y represents N, then Z represents O;

[0147] Where, if X represents S, then Z represents N or CR4

[0148] R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0149] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0150] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl,

[0151] wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine,

[0152] wherein the thienyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine,

[0153] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0154] R2 represents hydrogen, (C1-C2)-alkyl,

[0155] or

[0156] Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring,

[0157] R3 represents hydrogen, (C1-C2)-alkyl;

[0158] R4 represents hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl;

[0159] The phenyl group may be substituted by halogen.

[0160] R5 represents hydrogen, (C1-C2)-alkyl, methoxy, or fluorine;

[0161] R6 represents a group of formula a), b), c) or e),

[0162]

[0163] where ** indicates the connection to the adjacent piperidine ring,

[0164] wherein 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,

[0165] wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and up to disubstituted by fluorine,

[0166] The methoxy group can be substituted by cyclopropyl, cyclobutyl, or trifluoromethyl.

[0167] The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl.

[0168] wherein the cyclobutyl group may be up to disubstituted by fluorine,

[0169] The n-butoxy group may be substituted with fluorine up to two times.

[0170] wherein the (C1-C2)-alkoxy group may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and

[0171] Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times,

[0172] Wherein (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine,

[0173] wherein R8 or R'8 independently represent hydrogen or fluorine,

[0174] wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine, chlorine;

[0175] n represents 0 or 1 and

[0176] m represents 1 or 2,

[0177] q represents 0 or 2,

[0178] and salts, solvates and solvates of salts thereof.

[0179] In the context of the present invention, compounds of formula (I) are preferred, wherein

[0180] X represents S, N;

[0181] Y represents N, S, O,

[0182] Where, if X represents S, then Y represents N;

[0183] Z represents C, O,

[0184] Where, if X represents N and Y represents N, then Z represents O;

[0185] R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0186] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0187] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl,

[0188] wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine,

[0189] wherein the thienyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine,

[0190] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0191] R2 represents hydrogen, (C1-C2)-alkyl,

[0192] or

[0193] Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring,

[0194] R3 represents hydrogen, (C1-C2)-alkyl;

[0195] R4 represents hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl;

[0196] The phenyl group may be substituted by halogen.

[0197] R5 represents hydrogen, (C1-C2)-alkyl, methoxy, or fluorine;

[0198] R6 represents a group of formula a), b), c) or e),

[0199]

[0200] where ** indicates the connection to the adjacent piperidine ring,

[0201] wherein 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,

[0202] wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and up to disubstituted by fluorine,

[0203] The methoxy group can be substituted by cyclopropyl, cyclobutyl, or trifluoromethyl.

[0204] The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl.

[0205] wherein the cyclobutyl group may be up to disubstituted by fluorine,

[0206] The n-butoxy group may be substituted with fluorine up to two times.

[0207] wherein the (C1-C2)-alkoxy group may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and

[0208] Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times,

[0209] Wherein (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine,

[0210] wherein R8 or R'8 independently represent hydrogen or fluorine,

[0211] wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine, chlorine;

[0212] n represents 0 or 1 and

[0213] m represents 1 or 2,

[0214] q represents 0 or 2,

[0215] and salts, solvates and solvates of salts thereof.

[0216] In the context of the present invention, preferred compounds of formula (I)

[0217] in

[0218] X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h), i), j), k) or (r),

[0219]

[0220] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0221] R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0222] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0223] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl,

[0224] The thiazolyl group may be substituted by chlorine,

[0225] The thienyl group may be substituted by fluorine.

[0226] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0227] R2 represents hydrogen or methyl,

[0228] or

[0229] Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring,

[0230] R3 represents hydrogen, (C1-C2)-alkyl;

[0231] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0232] The phenyl group may be substituted by chlorine.

[0233] R5 represents hydrogen or fluorine;

[0234] R6 represents a group of formula a), b'), b", c'), c") or e),

[0235]

[0236] where ** indicates the connection to the adjacent piperidine ring,

[0237] wherein R7 or R7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl,

[0238] wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and up to disubstituted by fluorine,

[0239] The methoxy group can be substituted by cyclopropyl, cyclobutyl, or trifluoromethyl.

[0240] The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl.

[0241] wherein the cyclobutyl group may be up to disubstituted by fluorine,

[0242] The n-butoxy group may be substituted with fluorine up to two times.

[0243] wherein the (C1-C2)-alkoxy group may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and

[0244] Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times,

[0245] Wherein (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine,

[0246] wherein R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine;

[0247] n represents 0 or 1 and

[0248] m represents 1 or 2,

[0249] and salts, solvates and solvates of salts thereof.

[0250] In the context of the present invention, preferred compounds of formula (I)

[0251] in

[0252] X, Y and Z represent a group in h), i), j), k) or (r),

[0253]

[0254] Where * marks the connection to the carbonyl group and * marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0255] R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl,

[0256] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0257] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl,

[0258] The thiazolyl group may be substituted by chlorine,

[0259] The thienyl group may be substituted by fluorine.

[0260] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl,

[0261] R2 represents hydrogen or methyl,

[0262] or

[0263] Together with the carbon atom to which R2 is attached, it forms a cyclopropyl ring,

[0264] R3 represents hydrogen, (C1-C2)-alkyl;

[0265] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0266] The phenyl group may be substituted by chlorine.

[0267] R5 represents hydrogen or fluorine;

[0268] R6 represents a group in formula a), b), b), c), c) or e),

[0269]

[0270] where ** indicates the connection to the adjacent piperidine ring,

[0271] wherein 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,

[0272] wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and up to disubstituted by fluorine,

[0273] The methoxy group can be substituted by cyclopropyl, cyclobutyl, or trifluoromethyl.

[0274] The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl.

[0275] wherein the cyclobutyl group may be up to disubstituted by fluorine,

[0276] The n-butoxy group may be substituted with fluorine up to two times.

[0277] wherein the (C1-C2)-alkoxy group may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and

[0278] Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times,

[0279] Wherein (C3-C4)-cycloalkoxy may be up to disubstituted by fluorine,

[0280] wherein R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine;

[0281] n represents 0 or 1 and

[0282] m represents 1 or 2,

[0283] and salts, solvates and solvates of salts thereof.

[0284] In the context of the present invention, preferred compounds of formula (I)

[0285] in

[0286] X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h'), i'), j') or k),

[0287]

[0288] R1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0289] R2 represents hydrogen or methyl;

[0290] R3 represents hydrogen or methyl;

[0291] R4 represents hydrogen, ethyl, or trifluoromethyl;

[0292] R5 represents hydrogen or fluorine;

[0293] R6 represents a group in formula a), c') or c")

[0294]

[0295] where ** indicates the connection to the adjacent piperidine ring,

[0296] wherein R7 and R'7 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0297] n represents 0 or 1 and

[0298] m represents 1,

[0299] and salts, solvates and solvates of salts thereof.

[0300] In the context of the present invention, preferred are compounds of formula (I) wherein

[0301] X, Y and Z represent 1,3-thiazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl;

[0302] R1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0303] R2 represents hydrogen or methyl;

[0304] R3 represents hydrogen or methyl;

[0305] R4 represents hydrogen or methyl, ethyl or trifluoromethyl;

[0306] R5 represents hydrogen or fluorine;

[0307] R6 represents a group in formula a), c') or c")

[0308]

[0309] where ** indicates the connection to the adjacent piperidine ring,

[0310] wherein R7 and R'7 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0311] n represents 0 or 1 and

[0312] m represents 1,

[0313] and salts, solvates and solvates of salts thereof.

[0314] In the context of the present invention, preferred compounds of formula (I) wherein

[0315] X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h')

[0316]

[0317] R1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl;

[0318] R2 represents hydrogen or methyl;

[0319] R3 represents hydrogen;

[0320] R5 represents hydrogen or fluorine;

[0321] R6 represents a group in formula a), c') or c")

[0322]

[0323] where ** indicates the connection to the adjacent piperidine ring,

[0324] wherein R7 and R'7 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine;

[0325] n represents 0 or 1 and

[0326] m represents 1,

[0327] and salts, solvates and solvates of salts thereof.

[0328] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0329] X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h), i), j), k) or (r);

[0330]

[0331] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0332] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0333] The phenyl group may be substituted by chlorine.

[0334] and salts, solvates and solvates of salts thereof.

[0335] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0336] X, Y and Z represent a group in formula (h) or (i);

[0337]

[0338] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0339] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0340] The phenyl group may be substituted by chlorine.

[0341] and salts, solvates and solvates of salts thereof.

[0342] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0343] X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula (h) or i);

[0344]

[0345] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0346] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0347] The phenyl group may be substituted by chlorine.

[0348] and salts, solvates and solvates of salts thereof.

[0349] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0350] X, Y and Z represent a group of formula (h);

[0351]

[0352] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0353] R4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0354] and salts, solvates and solvates of salts thereof.

[0355] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0356] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h);

[0357]

[0358] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0359] R4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0360] and salts, solvates and solvates of salts thereof.

[0361] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0362] X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h);

[0363]

[0364] where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and

[0365] R4 represents hydrogen,

[0366] and salts, solvates and solvates of salts thereof.

[0367] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0368] R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, or phenyl;

[0369] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0370] wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from methyl and chlorine,

[0371] The thiazolyl group may be substituted by chlorine,

[0372] The thienyl group may be substituted by fluorine.

[0373] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl;

[0374] and salts, solvates and solvates of salts thereof.

[0375] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0376] R1 represents pyridyl or phenyl,

[0377] wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from methyl, ethyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy,

[0378] wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from methyl, cyclopropyl, methoxy, cyano, hydroxy, fluorine, chlorine, and trifluoromethyl;

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

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

[0381] R1 represents a group in formula (f);

[0382]

[0383] Where # indicates the connection to the adjacent -[CHR2]nNR3CO- group,

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

[0385] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0386] R2 represents hydrogen, (C1-C4)-alkyl;

[0387] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

[0388] or together with the carbon atom to which R2 is attached, forms a (C3-C4)-cycloalkyl ring,

[0389] and salts, solvates and solvates of salts thereof.

[0390] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0391] R2 represents hydrogen, methyl or forms a cyclopropyl ring together with the carbon atom to which R2 is attached;

[0392] and salts, solvates and solvates of salts thereof.

[0393] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0394] R2 represents hydrogen;

[0395] and salts, solvates and solvates of salts thereof.

[0396] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0397] R3 represents hydrogen, (C1-C4)-alkyl,

[0398] wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen,

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

[0400] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0401] R3 represents hydrogen or methyl;

[0402] and salts, solvates and solvates of salts thereof.

[0403] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0404] R3 represents hydrogen;

[0405] and salts, solvates and solvates of salts thereof.

[0406] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0407] R4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl;

[0408] The phenyl group may be substituted by chlorine.

[0409] and salts, solvates and solvates of salts thereof.

[0410] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0411] R4 represents hydrogen, methyl, ethyl, trifluoromethyl,

[0412] and salts, solvates and solvates of salts thereof.

[0413] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0414] R4 represents hydrogen,

[0415] and salts, solvates and solvates of salts thereof.

[0416] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0417] R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen,

[0418] and salts, solvates and solvates of salts thereof.

[0419] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0420] R5 represents hydrogen or fluorine,

[0421] and salts, solvates and solvates of salts thereof.

[0422] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0423] R5 represents hydrogen,

[0424] and salts, solvates and solvates of salts thereof.

[0425] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0426] R6 represents a group of formula a), b'), b") or c'), c") or e),

[0427]

[0428] where ** indicates the connection to the adjacent piperidine ring and

[0429] R7 represents hydrogen or methyl,

[0430] 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-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine,

[0431] R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine or chlorine;

[0432] and salts, solvates and solvates of salts thereof.

[0433] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0434] R6 represents a group in formula a), c') or c"),

[0435]

[0436] where ** indicates the connection to the adjacent piperidine ring and

[0437] R7 represents hydrogen,

[0438] R7 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-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine,

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

[0440] A very particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0441] R6 represents a group in formula a),

[0442]

[0443] where ** indicates the connection to the adjacent piperidine ring and

[0444] R7 represents hydrogen,

[0445] 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-fluorobutoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, 2-fluoroethyl, cyclopropyl, cyclobutyl, 2-methoxyethyl, tert-butyl, and salts, solvates and solvates of salts thereof.

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

[0447] n represents 0 or 1,

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

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

[0450] n represents 1,

[0451] and salts, solvates and solvates of salts thereof.

[0452] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0453] m represents 1 or 2,

[0454] and salts, solvates and solvates of salts thereof.

[0455] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0456] m represents 1,

[0457] and salts, solvates and solvates of salts thereof.

[0458] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0459] p represents 0, 1 or 2,

[0460] and salts, solvates and solvates of salts thereof.

[0461] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0462] p means 1.

[0463] A particular embodiment of the present invention relates to compounds of formula (I) wherein

[0464] q represents 0 or 2,

[0465] and salts, solvates and solvates of salts thereof.

[0466] A particularly preferred embodiment of the present invention relates to compounds of formula (I) wherein

[0467] q represents 2,

[0468] and salts, solvates and solvates of salts thereof.

[0469] The individual radical definitions specified in the individual radical combinations or preferred combinations can, independently of the individual radical combinations specified, also be replaced by radical definitions from other combinations as required.

[0470] Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

[0471] 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, wherein

[0472] [A] Compound of formula (II)

[0473]

[0474] in

[0475] X, Y, Z, R1, R2, R3 and R4 and n have the meanings given above,

[0476] Hal represents a leaving group, preferably chlorine, bromine, iodine or methanesulfonyl,

[0477] In the presence of a base, react with a compound of formula (III)

[0478]

[0479] in

[0480] R5 and R6 and m have the meanings given above,

[0481] To generate the compound of formula (IA)

[0482]

[0483] or

[0484] [B] Compound of formula (IV)

[0485]

[0486] in

[0487] X, Y, Z, R1, R2, R3, R4 and R5 and n and m have the meanings given above,

[0488] Reaction with a compound of formula (V)

[0489] H-R6 (V),

[0490] in

[0491] R6 has the meaning given above,

[0492] In the presence of a reducing agent and optionally an acid, preferably an alkali metal borohydride and acetic acid, to produce a compound of formula (IB)

[0493]

[0494] or

[0495] [C] Compound of formula (VI)

[0496]

[0497] in

[0498] X, Y, Z, R4, R5 and R6 and n and m have the meanings given above, and are the same as the compound of formula (VII)

[0499]

[0500] in

[0501] R1, R2 and R3 and n have the meanings given above,

[0502] In the presence of a condensing agent or activating agent, preferably a phosphorus compound, to produce a compound of formula (IC)

[0503]

[0504] The compounds of formula (IA), (IB), (IC) thus obtained are optionally separated into their enantiomers and / or diastereomers and / or optionally converted into their solvates, their salts and / or solvates of their salts using an appropriate (i) solvent and / or (ii) acid.

[0505] exist Method steps [A] In the reaction of compound (II) with compound (III) to form compound (IA), the Hal group in compound (II) is replaced by the nitrogen atom of the piperidine ring of compound (III), wherein the reaction depends on the reactivity in each case and can be carried out, for example, by heating in a solvent or dispersant.

[0506] Suitable bases for process step [A] are, in particular, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, tertiary amine bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,10-phenanthroline or 4-N,N-dimethylaminopyridine (DMAP). The base used is preferably sodium carbonate, potassium carbonate or cesium carbonate. It may be advantageous to add an alkylation catalyst such as lithium bromide, sodium iodide, potassium iodide, tetra-n-butylammonium bromide, copper(I) iodide or benzyltriethylammonium chloride.

[0507] The base is preferably used in an equimolar amount or in excess, usually 1 to 5 times, preferably 5 times the molar amount.

[0508] In addition, the reaction can also be carried out by palladium catalysis using Pd2(dba)3, cesium carbonate as an auxiliary base and the following ligands: 1,1′-[1,1′-binaphthyl]-2,2′-diylbis[1,1-diphenylphosphine] or 1,1′-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine] (for literature, see WO 2008052934 or WO 2015017305).

[0509] Suitable inert solvents for step [A] are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or mineral oil fractions, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of such solvents can also be used. Preference is given to using acetonitrile or dimethylformamide.

[0510] The reaction (II)+(III)→(IA) is generally carried out in a temperature range of 0°C to +150°C, preferably at +20°C to +100°C.

[0511] exist Method steps [B] In the reaction of compound (IV) with (V) to form compound (IB) is a reductive amination. Suitable reducing agents for reductive amination are alkali metal borohydrides commonly used for this purpose, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; sodium triacetoxyborohydride is preferably used. In these reactions, it may be advantageous to add an acid, such as, in particular, acetic acid, and / or a dehydrating agent, such as molecular sieves or trimethyl or triethyl orthoformate.

[0512] 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; preference is given to using tetrahydrofuran. The reaction is generally carried out at a temperature in the range of 0°C to +50°C.

[0513] The protecting group PG used in compound (XI) or (XI') can be a conventional amino protecting group, such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Z) or (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc); tert-butoxycarbonyl (BOC) is preferably used. The removal of the protecting group in process step [B] (V) → (VI) is carried out by known methods. Thus, the tert-butoxycarbonyl group is usually cleaved by treatment with a strong acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid in an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane or acetic acid. In the case of a benzyloxycarbonyl protecting group, this 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 typically removed with the aid of a secondary amine base such as diethylamine or piperidine [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; PJ Kocienski, Protecting Groups, 3 rd edition, Thieme, 2005].

[0514] Method steps [B] (VI) + (VII) → (IC) [amide formation] is carried out by known methods with the aid of condensing agents or activating agents. Suitable reagents of this type are, for example, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2- Oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines such as 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, phosphorus compounds such as n-propylphosphonic anhydride (PPA, ), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(1H-1-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with other auxiliaries, such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and suitable bases are alkali metal carbonates, for example 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). The condensing agent or activating agent used is preferably O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in combination with N,N-diisopropylethylamine as base.

[0515] Suitable inert solvents for these amide-forming reactions are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of such solvents can also be used. Preference is given to using dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide or mixtures of these solvents. The reaction is generally carried out at a temperature ranging from -20°C to +60°C, preferably from 0°C to +40°C.

[0516] For their part, the compounds of formula (II) can be prepared by methods known from the literature [amide formation], by reacting the amine (VII)

[0517]

[0518] in

[0519] R1, R2 and R3 and n have the meanings given above,

[0520] reacting with a compound of formula (X) under the influence of a condensing agent or an activating agent

[0521]

[0522] in

[0523] X, Y, Z, R4 and Hal have the meanings given above,

[0524] To generate a compound of formula (II)

[0525]

[0526] The compound of formula (III) can be prepared by methods known in the literature [reductive amination], wherein the amine (V)

[0527] H-R6 (V),

[0528] in

[0529] R6 has the meaning given above,

[0530] Reaction with a protected piperidine derivative of formula (XI)

[0531]

[0532] in

[0533] R5 and m have the meanings given above and

[0534] PG represents a suitable amino protecting group, preferably tert-butyloxycarbonyl, benzyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl

[0535] To generate a compound of formula (III')

[0536]

[0537] wherein PG and R5 and R6 and m have the meanings given above,

[0538] The protecting group PG is then removed to produce a compound of formula (III)

[0539]

[0540] The compound of formula (IV) can be prepared by methods known in the literature [alkylation], whereby the compound of formula (II)

[0541]

[0542] wherein X, Y, Z, R1, R2, R3 and R4 and Hal and n have the meanings given above,

[0543] In the presence of a base, react with a compound of formula (XII)

[0544]

[0545] wherein R5 and m have the meanings given above,

[0546] Then, it is cleaved under acidic conditions to generate compound (IV)

[0547]

[0548] For their part, the compounds of formula (VI) can be prepared by methods known in the literature [alkylation], whereby the compounds of formula (XIII)

[0549]

[0550] wherein X, Y, Z, R4 and Hal have the meanings given above and

[0551] T1 represents -O-(C1-C4)-alkyl,

[0552] In the presence of a base, react with a compound of formula (III)

[0553]

[0554] wherein R5, R6 and m have the meanings given above,

[0555] and hydrolyzed under conditions known in the literature to produce a compound of formula (VI)

[0556]

[0557] The hydrolysis of the ester group T1 is carried out in a conventional manner by treating the ester with an acid or base in an inert solvent. In the latter variant, the initially formed salt is converted into the free carboxylic acid by treatment with an acid. In the case of tert-butyl esters, the hydrolysis of the ester is preferably carried out with an acid.

[0558] Suitable inert solvents for these reactions are water or organic solvents commonly used for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide or dimethyl sulfoxide. Mixtures of these solvents can also be used. In the case of alkaline ester hydrolysis, mixtures of water with dioxane, tetrahydrofuran, methanol, ethanol and / or dimethylformamide are preferably used. In the case of reaction with trifluoroacetic acid, dichloromethane is preferably used, and in the case of reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane or water are preferably used.

[0559] 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.

[0560] Suitable acids for ester hydrolysis are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid are preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0561] The ester hydrolysis is generally carried out in a temperature range of from -20°C to +120°C, preferably at 0°C to +80°C.

[0562] The preparation of the compounds of the present invention can be illustrated, for example, by the following reaction scheme:

[0563] Solution 1

[0564]

[0565] Option 2

[0566]

[0567] Option 3

[0568]

[0569] The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0570] The compounds according to the invention are α 2C-potent and selective antagonists of α2C-adrenergic receptors and are therefore suitable for the treatment and / or prevention of disorders and pathological processes, in particular those which are caused by or by activated α2C-adrenergic receptors, as well as diseases which are secondary to α2C-adrenergic receptor-related impairments.

[0571] The compounds of the present invention are used in a method for the treatment and / or prevention of dyspnea, dysphagia, peripheral and cardiovascular disorders and disorders of the peripheral and central nervous systems.

[0572] The compounds according to the invention are also useful in a method for the treatment and / or prevention of the following disorders: dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

[0573] In the context of the present invention, these include, in particular, conditions such as dyspnea and sleep-induced dyspnea, such as, in particular, obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome), central sleep apnea, Cheyne-Stokes breathing, primary sleep apnea in infants, apparent life-threatening events, central sleep apnea due to medication or other substance use, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscle breathing disorders, respiratory disorders after long-term ventilation, respiratory disorders during acclimatization at high altitude, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0574] The compounds according to the invention are preferably used in a method for the treatment and / or prevention of the following disorders: dyspnea, including sleep-induced dyspnea, such as, in particular, obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome), central sleep apnea, Cheyne-Stokes respiration, primary sleep apnea in infants, apparent life-threatening events, central sleep apnea due to the use of medications or other substances, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscle breathing disorders, respiratory disorders after long-term ventilation, respiratory disorders during acclimatization to high altitude, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0575] In the context of the present invention, peripheral and cardiovascular disorders include diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0576] Also preferably, the compounds of the present invention are used in a method for the treatment and / or prevention of peripheral and cardiovascular disorders including diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0577] Furthermore, the compounds according to the invention can be 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 syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychoses, temporal lobe epilepsy with psychoses, panic disorders, disorders caused by changes in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, ta U-proteinopathy, chromosome 17-related frontotemporal dementia with parkinsonism, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedrich's ataxia, dentatorubral pallidum hypothalamic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal lobar degeneration with ubiquitin-proteasome system involvement, and familial encephalopathy with neurogenic serpin inclusions.

[0578] 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, including dementia, depression, schizophrenia, attention deficit disorder with or without hyperactivity (ADHS), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychoses, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by changes in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0579] The compounds according to the invention are also 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 syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychoses, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by changes in sex hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, tau protein Leukopathy, chromosome 17-related frontotemporal dementia with parkinsonism, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedrich's ataxia, dentatorubral pallidum hypothalamic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakob disease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal lobar degeneration with ubiquitin-proteasome system involvement, and familial encephalopathy with neurogenic serpin inclusions.

[0580] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of cardiovascular disorders, for example arrhythmias, atrial and ventricular arrhythmias and conduction impairments, for example atrioventricular block of the I-III degree, supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes tachycardia, atrial and ventricular premature contractions, AV-junctional extrasystoles, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, hypertension (hypertension), heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular disorders, Wolff-Parkinson-White syndrome, syndrome), acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, shock, such as cardiogenic shock, septic shock and anaphylactic shock, in addition to being used for the treatment and / or prevention of thromboembolic disorders and ischemia, such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient and ischemic attacks, pre-eclampsia, inflammatory cardiovascular diseases, coronary and peripheral artery spasm, edema formation, For example, pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and macrovascular damage (vasculitis), and prevention of restenosis, such as restenosis after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH).

[0581] In the context of the present invention, the term "heart failure" includes acute and chronic forms of heart failure, and specific or related disease types thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global heart 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 stenosis, pulmonary regurgitation, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure.

[0582] The compounds of the present invention can also be used to treat and / or prevent asthma conditions of varying severity with intermittent or persistent characteristics (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug- or dust-induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related conditions, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, such as hay fever) and polyps.

[0583] Furthermore, the compounds according to the invention are also suitable for the treatment and / or prevention of renal diseases, in particular renal insufficiency and renal failure. In the present invention, the terms "renal insufficiency" and "renal failure" include acute and chronic manifestations thereof as well as underlying or related renal diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, renal diseases such as primary and congenital renal diseases, nephritis, immune renal diseases such as renal transplant rejection and immune complex-induced renal diseases, renal diseases induced by toxic substances, contrast agent-induced renal diseases, Diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically, for example, by abnormally decreased creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, such as glutamyl synthetase, altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis. The present invention also includes the use of the compounds of the present invention for the treatment and / or prevention of the sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia) and disorders of bone and carbohydrate metabolism.

[0584] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system, for example benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence, for example mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain and erectile dysfunction and female sexual dysfunction.

[0585] The compounds according to the invention are also suitable for the treatment and / or prevention of inflammatory and autoimmune disorders, for example rheumatoid disorders, inflammatory eye diseases, sepsis (SIRS), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 antitrypsin deficiency (AATD), emphysema (e.g. caused by cigarette smoke), cystic fibrosis (CF), multiple organ failure (MODS, MOF), inflammatory disorders of the kidneys, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, and for the treatment and / or prevention of fibrotic disorders of internal organs such as the lungs, heart, kidneys, bone marrow and, in particular, the liver, as well as skin fibrosis and fibrotic disorders of the eye. In the context of the present invention, the term "fibrotic disorders" particularly includes disorders such as hepatic fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal 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 (such as sarcoidosis). The compounds of the invention are also useful for promoting wound healing, for controlling postoperative scarring (e.g. after glaucoma surgery) and for cosmetic use in aged or keratinized skin.

[0586] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of neoplastic disorders, for example skin cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

[0587] Furthermore, the compounds of the present invention can be used for the treatment and / or prevention of arteriosclerosis, impaired lipid metabolism and dyslipidemia (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier disease, excess fat, obesity, metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), anemia such as hemolytic anemia, hemoglobinopathies (such as sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, anemia due to acute blood loss, myeloid anemia and aplastic anemia), gastrointestinal and abdominal disorders (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, anal itching, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis and cholecystitis), central nervous system diseases and neurodegenerative disorders (stroke, epilepsy, depression), immune disorders, thyroid disease (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, as well as keratitis, bullous diseases, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, Sweet syndrome, Weber-Christian syndrome, scarring, wart formation, chilblains), inflammatory eye diseases (sarcoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (caused by influenza viruses, adenoviruses and coronaviruses, such as HPV, HCMV, HIV, SARS), disorders of bones and joints and skeletal muscles, inflammatory changes in arteries (various forms of arteritis, such as endarteritis, medial arteritis, arteriosclerosis), Peripheral arteritis, systemic arteritis, rheumatic arteritis, deforming arteritis, temporalis arteritis, cranial arteritis, giant cell arteritis and granulomatous arteritis, as well as Horton syndrome, Churg-Strauss syndrome and Takayasu's arteritis), Muckle-Well syndrome, Kikuchi disease, polychondritis, scleroderma and other diseases with an inflammatory or immune component, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sézary syndrome and paraneoplastic syndromes, for rejection reactions after organ transplantation and for wound healing and angiogenesis, especially in the case of chronic wounds.

[0588] Due to their profile of properties, the compounds of the present invention are particularly suitable for the treatment and / or prevention of dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular disorders, including diabetic microangiopathy; and peripheral and central nervous system disorders, including neurodegenerative and neuroinflammatory disorders.

[0589] The above-described well-characterized diseases in humans may also occur with comparable etiology in other mammals and similarly be treated therein with the compounds of the present invention.

[0590] As used herein, the terms "treatement" or "treating" include inhibiting, delaying, preventing, alleviating, attenuating, limiting, reducing, suppressing, repelling, or curing a disease, symptom, disorder, injury, or health problem, or the development, course, or progress of such conditions and / or symptoms of such conditions. The term "therapy" is understood herein to be synonymous with the term "treatment."

[0591] The terms "prevent," "preventing," or "blocking" are used synonymously herein and refer to avoiding or reducing the risk of contracting, developing, becoming afflicted with, or developing a disease, condition, disorder, injury, or health problem, or the development or progression of such conditions and / or symptoms of such conditions.

[0592] Treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.

[0593] The present invention therefore also provides the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the diseases mentioned above.

[0594] The present invention further provides the use of the compounds according to the invention for the preparation of a medicament for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0595] The present invention further provides medicaments comprising at least one compound according to the invention for the treatment and / or prophylaxis of disorders, in particular the disorders mentioned above.

[0596] The present invention further provides the use of the compounds according to the invention in a method for the treatment and / or prophylaxis of disorders, in particular the disorders mentioned above.

[0597] The present invention further provides a method for the treatment and / or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one compound according to the invention.

[0598] The compounds of the invention can be used alone or, if desired, in combination with one or more other pharmacologically active substances, provided that such combination does not cause undesirable and unacceptable side effects. The present invention therefore also provides medicaments containing at least one compound of the invention and one or more active ingredients, which are particularly useful for the treatment and / or prevention of the above-mentioned diseases. Preferred examples of active ingredients suitable for this purpose include:

[0599] TASK1 channels and channel blockers, for example and preferably those disclosed in WO 2017 / 097792 A1, WO 2017 / 097671 A1, WO 2018 / 015196 A1, WO 2018 / 228907 A1, WO 2018 / 228909 A1;

[0600] P2X3 receptor antagonists, for example and preferably gefapixen;

[0601] Respiratory irritants, for example and preferably theophylline, doxapram, nikethamide, caffeine;

[0602] Psychostimulant compounds, for example and preferably modafinil, armofinil;

[0603] amphetamine and amphetamine derivatives, for example and preferably amphetamine, methamphetamine, methylphenidate;

[0604] serotonin reuptake inhibitors, for example and preferably fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine, trazodone;

[0605] serotonin precursors, for example and preferably L-tryptophan;

[0606] Selective serotonin norepinephrine reuptake inhibitors, for example and preferably venlafaxine, duloxetine;

[0607] noradrenergic and specific serotonergic antidepressants, for example and preferably mirtazapine;

[0608] Selective norepinephrine reuptake inhibitors, for example and preferably atomoxetine and reboxetine;

[0609] Muscarinic receptor antagonists such as, and preferably, oxybutynin;

[0610] tricyclic antidepressants, for example and preferably amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine, desipramine;

[0611] GABA agonists, for example and preferably baclofen;

[0612] alpha-synergistic agents, for example and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrahydrozoline, tramazoline;

[0613] Glucocorticoids, for example and preferably fluticasone, budesonide, beclomethasone, mometasone, tixocortol pivalate, triamcinolone acetonide;

[0614] Cannabinoid receptor agonists and antagonists;

[0615] carbonic anhydrase inhibitors, for example and preferably acetazolamide, methazolamide and dichlorphenamide;

[0616] Opioid and benzodiazepine receptor antagonists, for example and preferably flumazenil, naloxone, naltrexone;

[0617] Cholinesterase inhibitors, for example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine, rivastigmine;

[0618] N-methyl-D-aspartate and glutamate antagonists, for example and preferably amantadine, memantine, sabeluzole;

[0619] Nicotinic receptor agonists;

[0620] Leukotriene receptor antagonists, for example and preferably montelukast, triprolactone;

[0621] dopamine receptor antagonists, for example and preferably domperidone, metoclopramide, benzamide, butyrophenone, phenothiazines;

[0622] Appetite suppressants, for example and preferably sibutramine, topiramate, lipase inhibitors, cannabinoid receptor antagonists, phentermine;

[0623] proton pump inhibitors, for example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;

[0624] blood pressure lowering active ingredients, for example and preferably selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics;

[0625] active compounds which regulate lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists;

[0626] azoorganic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomide, or SIN-1 and inhaled NO;

[0627] Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dasenafil, avanafil, milonafil or lodenafil;

[0628] NO- and heme-independent soluble guanylate cyclase (sGC) activators, in particular compounds such as those described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;

[0629] NO-independent but heme-dependent soluble guanylate cyclase (sGC) stimulators, such as, in particular, riociguat and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549;

[0630] Compounds which influence cardiac energy metabolism, for example and preferably etolimus, dichloroacetate, ranolazine or trimetazidine;

[0631] antithrombotic agents, for example and preferably selected from the group consisting of platelet aggregation inhibitors, anticoagulants and fibrinolytic substances;

[0632] anti-obstructive agents, for example for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably selected from inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics) and inhaled antimuscarinic substances;

[0633] anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, for example and preferably selected from systemically or inhaled corticosteroids and dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferons, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tralukast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, IFN-γ, pirfenidone or etanercept;

[0634] Compounds that inhibit signal transduction cascades, for example and preferably selected from kinase inhibitors, in particular from tyrosine kinase and / or serine / threonine kinase inhibitors, for example and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, simanib or tandutinib;

[0635] Prostacyclin analogs and IP receptor agonists, for example and preferably iloprost, beraprost, treprostinil, epoprostenol or selexipag;

[0636] endothelin receptor antagonists, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;

[0637] Compounds which inhibit human neutrophil elastase (HNE), for example and preferably sivelestat or DX-890 (Reltran);

[0638] compounds which inhibit the degradation and modification of the extracellular matrix, for example and preferably inhibitors of matrix metalloproteinases (MMPs), in particular inhibitors of stromelysins, collagenases, gelatinases and aggrecanases (in the present context in particular MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastase (MMP-12);

[0639] Compounds that block the binding of serotonin to its receptors, such as and preferably 5-HT 2B Receptor antagonists, such as PRX-08066;

[0640] Antagonists of growth factors, cytokines and chemokines, for example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

[0641] Rho kinase inhibiting compounds, for example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; and / or

[0642] antifibrotic agents, for example and preferably pirfenidone, lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists;

[0643] In a particularly preferred embodiment of the invention, the compounds according to the invention are administered in combination with one or more additional 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.

[0644] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist, for example and preferably albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0645] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antimuscarinic substance, such as for example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0646] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as for example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

[0647] Antithrombotic agents are preferably understood to mean compounds selected from the group consisting of platelet aggregation inhibitors, anticoagulants and plasminogen substances.

[0648] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

[0649] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, for example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or clexapro.

[0650] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, for example and preferably tirofiban or abciximab.

[0651] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, fidexaban, razoxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0652] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0653] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin.

[0654] Antihypertensive agents are preferably understood as meaning compounds selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics.

[0655] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as for example and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0656] 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.

[0657] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-blocker, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adalol, lantiolol, nebivolol, epanolol or bucindolol.

[0658] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as for example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.

[0659] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandolapril.

[0660] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.

[0661] 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.

[0662] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably spironolactone, eplerenone or finerenon.

[0663] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, for example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorsulfamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0664] Fat metabolism regulators are preferably understood as meaning compounds selected from the group consisting of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bileacid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0665] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, for example and preferably torcetuximab (CP-529414), JJT-705 or CETP vaccine (Avant).

[0666] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as for example and preferably D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS23425 or acitreol (CGS26214).

[0667] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor selected from the group consisting of statins, such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0668] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.

[0669] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as for example and preferably avasimibe, melinamide, patiimibe, eflumimibe or SMP-797.

[0670] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as for example and preferably implitapide, BMS-201038, R-103757 or JTT-130.

[0671] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone or rosiglitazone.

[0672] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, for example and preferably GW 501516 or BAY 68-5042.

[0673] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as for example and preferably ezetimibe, tiqueside or pamaside.

[0674] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, for example and preferably orlistat.

[0675] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, for example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimid.

[0676] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, for example and preferably an ASBT (=IBAT) inhibitor, such as, for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0677] 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.

[0678] Particularly preferred are combinations of the compounds of the invention with one or more further active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

[0679] If necessary, the compounds of the present invention may be used in combination with one or more other medical means, provided that the combination does not produce undesirable and unacceptable side effects. Preferred examples of medical means suitable for this purpose include:

[0680] Devices for positive airway pressure ventilation, for example and preferably CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Bidirectional Positive Airway Pressure) devices and IPPV (Intermittent Positive Airway Pressure) devices;

[0681] A neurostimulator for the hypoglossal nerve;

[0682] Intraoral auxiliary devices, such as and preferably protruding braces;

[0683] Disposable nasal valve;

[0684] Nasal stent.

[0685] The invention also provides medicaments comprising at least one compound according to the invention, usually in association with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

[0686] The compounds of the present invention can act systemically and / or locally. For this reason, they can be administered in a suitable manner, for example, orally, parenterally, pulmonary, nasal, pharyngeal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, through the ear or as an implant or stent.

[0687] The compounds of the invention can be administered in administration forms suitable for these administration routes.

[0688] Suitable dosage forms for oral administration are those which work according to the prior art and release the compound according to the invention rapidly and / or in a controlled manner and contain the compound according to the invention in crystalline and / or amorphous and / or dissolved form, for example tablets (uncoated or coated tablets, for example with a gastric-resistant or delayed-dissolution or insoluble coating which controls the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the mouth, films / lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

[0689] Parenteral administration can bypass the reabsorption step (e.g. intravenous, intraarterial, intracardial, intraspinal or intralumbar) or include reabsorption (e.g. inhalation, intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Suitable administration forms for parenteral administration include, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

[0690] For other routes of administration, suitable examples are inhalable dosage forms (including powder inhalers, sprays, metered aerosols), nasal drops, nasal solutions or sprays, throat sprays, tablets, films / wafers or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents.

[0691] Oral, parenteral and topical administration are preferred, in particular oral, intravenous, intranasal and pharyngeal administration.

[0692] The compounds of the invention can be converted into the aforementioned administration forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, in particular, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinyl pyrrolidone), 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 taste and / or odor correctives.

[0693] It is generally found to be advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight in the case of parenteral administration to achieve effective results. In the case of oral administration, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, most preferably 0.1 to 10 mg / kg body weight. In the case of intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.

[0694] However, in some cases, it may be necessary to deviate from the stated amounts, in particular depending on body weight, route of administration, individual response to the active ingredient, properties of the formulation and the time or interval at which administration is carried out. Thus, in some cases less than the above-mentioned minimum amount may be sufficient, while in other cases the upper limit mentioned must be exceeded. In the case of administering larger amounts, it may be advisable to divide them into several single doses over the day.

[0695] The following working examples illustrate the invention. The invention is not limited to these examples.

[0696] A. Example

[0697] Abbreviations and acronyms:

[0698] abs.Absolute value

[0699] Ac acetyl

[0700] aq. containing water, aqueous solution

[0701] Boc tert-butyloxycarbonyl

[0702] br. width (in NMR signal)

[0703] Bsp. Example

[0704] Butyl

[0705] c concentration

[0706] cat.catalysis

[0707] CI Chemical Ionization (in MS)

[0708] d Doublet (in NMR)

[0709] d day

[0710] DCI Direct Chemical Ionization (in MS)

[0711] dd doublet (in NMR)

[0712] diamix diastereoisomer mixture

[0713] DMF N,N-dimethylformamide

[0714] DMSO dimethyl sulfoxide

[0715] dq doublet quartet (in NMR)

[0716] dt doublet triplet (in NMR)

[0717] ot theoretical (in chemical yield)

[0718] EI Electron Impact Ionization (in MS)

[0719] eq. equivalent

[0720] ESI Electrospray ionization (in MS)

[0721] Et ethyl

[0722] h hour

[0723] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0724] HOBt1-Hydroxy-1H-benzotriazole hydrate

[0725] HPLC High-pressure liquid chromatography

[0726] iPr Isopropyl

[0727] konz concentrated (in the case of a solution)

[0728] LC liquid chromatography

[0729] LC-MS liquid chromatography-mass spectrometry

[0730] Lit. Literature (reference)

[0731] m multiplet (in NMR)

[0732] Me methyl

[0733] min

[0734] MS

[0735] NMR nuclear magnetic resonance spectroscopy

[0736] Ph Phenyl

[0737] Pr Propyl

[0738] q quartet (in NMR)

[0739] quant. quantitative (in chemical yield)

[0740] RP Reversed Phase (in HPLC)

[0741] RT Room temperature

[0742] R t Retention time (in HPLC, LC / MS)

[0743] s Singlet (in NMR)

[0744] t triplet (in NMR)

[0745] tBu tert-butyl

[0746] TFA trifluoroacetic acid

[0747] THF Tetrahydrofuran

[0748] UV spectroscopy

[0749] v / v (solution) volume / volume ratio

[0750] tog.tog

[0751] LC-MS, GC-MS, and HPLC methods

[0752] Method 1 (LC-MS):

[0753] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1x75 mm, C181.8 μm; mobile phase: 1 liter water + 0.01% formic acid; mobile phase B: 1 liter 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.

[0754] Method 2 (LC-MS):

[0755] MS instrument type: Waters Tinstrument; UPLC instrument type: Waters Acquity I-CLASS; column: Waters Acquity UPLC HSS T3 1.8 μm 50x1 mm; mobile phase: 1 liter water + 0.100 ml 99% strength formic acid; mobile phase B: 1 liter acetonitrile + 0.100 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.

[0756] Method 3 (GC-MS):

[0757] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; Column: Restek RTX-35MS, 15 m x 200 μm x 0.33 μm; Constant helium flow rate: 1.20 ml / min; Oven: 60°C; Inlet: 220°C; Gradient: 60°C, 30°C / min→300°C (hold for 3.33 min).

[0758] Method 4 (LC-MS):

[0759] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 x 1 mm; Mobile phase: 1 liter water + 0.25 ml 99% strength formic acid, Mobile phase B: 1 liter 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.

[0760] Method 5 (LC-MS):

[0761] Instrument: Waters Single Quad MS system; instrument Waters UPLC Acquity; column: Waters BEH C18 1.7μ 50x2.1mm; mobile phase: 1 liter of water + 1.0 ml (25% strength ammonia) / l, mobile phase B: 1 liter of acetonitrile; gradient: 0.0 min 92% A→0.1 min 92% A→1.8 min 5% A→3.5 min 5% A; oven: 50°C; flow rate: 0.45 ml / min; UV detection: 210 nm.

[0762] Method 6 (LC-MS):

[0763] MS instrument: Waters SQD2 HPLC instrument: Waters UPLC; column: Z or bax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 μm; mobile phase: 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.

[0764] Method 7 (preparative HPLC):

[0765] Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm.

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

[0767] Gradient overview: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[0768] Method 8 (preparative HPLC):

[0769] Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm.

[0770] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection).

[0771] Gradient overview: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[0772] Method 9 (preparative HPLC):

[0773] Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm.

[0774] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection).

[0775] Gradient overview: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[0776] Method 10 (preparative HPLC):

[0777] Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm.

[0778] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection).

[0779] Gradient overview: mobile phase A 0 to 2 min 39 ml, mobile phase B 0 to 2 min 31 ml, mobile phase A 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[0780] Method 11 (preparative HPLC):

[0781] Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm x 30 mm; mobile phase: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B→95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B→10% B, 35.5-36.5 min 10% B; flow rate: 50 ml / min; room temperature; UV detection: 210 nm.

[0782] Method 12 (LC-MS):

[0783] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 x 1 mm; Mobile phase: 1 liter water + 0.25 ml 99% strength formic acid, Mobile phase B: 1 liter 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.

[0784] Other details:

[0785] The description of the coupling patterns of 1H NMR signals below is based on the visual appearance of the signals in question and does not necessarily correspond to a strict, physically correct interpretation. In general, the chemical shifts mentioned refer to the center of the signal in question; in the case of broad multiplets, intervals are given.

[0786] All numbers in the 1H NMR spectra indicate chemical shifts δ [ppm] = in ppm.

[0787] The multiplicity of the proton signals in the H NMR spectrum provided in the following paragraphs indicates the signal shape observed in each case, and does not take into account higher order signal phenomena. Generally speaking, the explanation of chemical shift is relevant to the center of the relevant signal. In the case of wide multiplets, intervals are provided. Signals masked by solvent or water are either temporarily assigned or not listed. For example, the signal broadened by the rapid rotation of the molecular part or due to the significant broadening caused by proton exchange is also temporarily assigned (commonly referred to as wide multiplets or wide singlets) or not listed.

[0788] 1H NMR data for selected synthetic intermediates and examples are listed in the form of 1H-NMR peak lists. For each signal peak, the δ[ppm] value in ppm is listed first, followed by the signal intensity in parentheses. The δ[ppm] value / signal intensity pairs for different signal peaks are listed separated by commas. Thus, the peak list for one example takes the following form: δ[ppm]1 (intensity 1), δ[ppm]2 (intensity 2), ..., δ[ppm] i (strength i ),...,,,,δ[ppm] n (strength n ).

[0789] The intensity of sharp signals is correlated to the signal height (in cm) in the printed NMR spectrum and displays the true ratio of signal intensity compared to other signals. In the case of broad signals, multiple peaks or signal centers may be displayed, along with their relative intensities compared to the strongest signal in the spectrum. 1H-NMR peak lists are similar to conventional 1H-NMR printouts and therefore typically contain all peaks listed in conventional NMR interpretations. Furthermore, similar to conventional 1H-NMR printouts, they may display solvent signals, signals of stereoisomers of the target compound, which is also the subject of the present invention, and / or peaks of impurities. Peaks of stereoisomers of the target compound and / or peaks of impurities typically have, on average, lower intensities than peaks of the target compound (e.g., with a purity greater than 90%). Such stereoisomers and / or impurities may be typical for a particular preparation method. Therefore, their peaks here help identify reproducible versions of our preparation method by reference to "byproduct fingerprints." A person skilled in the art who calculates the peaks of the target compound using known methods (MestReC, ACD simulation, or using empirically determined expectation values) can, if desired, separate the peaks of the target compound, optionally using additional intensity filters. This separation is similar to the peak picking involved in conventional 1H-NMR interpretation. A detailed description of the display of NMR data in peak list format can be found in the publication "Citation NMR Peaklist Data within Patent Applications" (see Research Disclosure Database Number 605005, 2014, August 1, 2014 or http: / / www.researchdisclosure.com / searching-disclosures). In the peak picking convention described in Research Disclosure Database Number 605005, the parameter "Minimum Height" can be set between 1% and 4%. Depending on the type of chemical structure and / or on the concentration of the compound to be analyzed, it may be reasonable to set the parameter "Minimum Height" to a value of <1%.

[0790] Melting points and melting ranges, if given, are uncorrected.

[0791] In the case where the reaction product is obtained by grinding, stirring or recrystallization, it is often possible to separate a larger amount of product from each mother liquor by chromatographic separation. However, unless a major part of the total yield can only be separated in this step, a description of this chromatography will be omitted below.

[0792] For all reactants or reagents whose preparation is not explicitly described below, they were purchased from commonly available sources. For all other reactants or reagents whose preparation is also not described below and which are not commercially available or obtained from sources that are not commonly available, reference is made to the published literature where their preparation is described.

[0793] Starting materials and intermediates:

[0794] Example 1A

[0795] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[0796]

[0797] 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. 74.4 ml (124.98 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide) in ethyl acetate was then added dropwise to the reaction solution. After the addition was complete, the reaction solution was warmed to room temperature and stirred at this temperature for 4 hours. Approximately 250 ml of water was then added to the solution. The resulting aqueous phase was then extracted three times with ethyl acetate. The combined organic phases were then filtered through a hydrophobic filter (folded filter MN616WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was triturated with diethyl ether and then air-dried. This gave 27.3 g (81.7 mmol, 85% of theory) of the target product as a light beige solid. The recovered mother liquor was evaporated to dryness under reduced pressure, and the resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column; mobile phase: cyclohexane / ethyl acetate 9:1 → gradient 15 CV (CV = column volume) → cyclohexane / ethyl acetate 1:1). This gave a further 2.1 g (6.28 mmol, 6.5% of theory) of the target compound as a white solid.

[0798] 1 H-NMR (600MHz, 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).

[0799] LC-MS (Method 1): R t =1.38min; m / z=333 / 335(M+H) + .

[0800] Analogously to Example 1A, the following compound Examples 2A to 8A were prepared from the starting materials described in each case:

[0801]

[0802]

[0803] Example 9A

[0804] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxamide

[0805]

[0806] 2 g (5.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were dissolved in 30 ml of THF, and 4.88 g (14.96 mmol) of cesium carbonate were added. 1.29 g (8.98 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane were then metered into the reaction solution, which was subsequently stirred at reflux overnight. After cooling, the reaction mixture was applied directly to silica gel and purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 50 g column; mobile phase: cyclohexane / ethyl acetate 85:15 → gradient 15 CV (CV = column volume) → ethyl acetate). The resulting product fractions were then combined, concentrated on a rotary evaporator, and dried under reduced pressure. This gave 1.40 g (3.53 mmol, 99% of theory) of the target compound as a light beige solid.

[0807] 1 H-NMR (600MHz, 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).

[0808] LC-MS (Method 2): Rt=0.73 min; m / z=397 (M+H) + .

[0809] Example 10A

[0810] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[0811]

[0812] 2.3 g (5.80 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-thiazole-5-carboxamide were dissolved in 15 ml of acetone and 15 ml of semi-concentrated aqueous hydrochloric acid were added. The reaction solution was then stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and subsequently placed in water. The aqueous solution was then 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.

[0813] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 2.48-2.56 (t, 4H, partially masked by DMSO), 3.82 (t, 4H), 4.54 (br.d, 2H), 7.89 (s, 1H), 7.90-7.94 (m, 1H), 8.48 (d, 1H), 8.78 (t, 1H).

[0814] LC-MS (Method 1): Rt=1.09 min; m / z=353 (M+H) + .

[0815] Example 11A

[0816] 3-[(3,3-difluorocyclobutyl)methoxy]pyridine

[0817]

[0818] 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 then cooled to 0°C. 30 ml of THF was added to the resulting suspension. 5.53 g (27.34 mmol) of diisopropyl azodicarboxylate was added to this 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 then added dropwise, and the ice bath was removed after the addition was complete. After stirring at room temperature for approximately one hour, a clear yellow solution was formed, which was stirred at this temperature overnight.

[0819] Water was then added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, separated, and filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was stirred with approximately 150 ml of cyclohexane. The precipitated triphenylphosphine was then filtered off with suction and washed repeatedly with cyclohexane. The resulting filtrates were combined and concentrated to dryness under reduced pressure. This yielded 3.69 g (18.52 mmol, 88% of theory) of the title compound as a yellow oil. The resulting title compound was reacted further without further purification.

[0820] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 2.42-2.55 (m, 2H, partially masked by DMSO), 2.55-2.64 (m, 1H), 2.68-2.78 (m, 2H), 4.11 (d, 2H), 7.30-7.36 (m, 1H), 7.37-7.43 (m, 1H), 8.18 (dd, 1H), 8.30 (d, 1H).

[0821] LC-MS (Method 1): R t =1.12min; m / z=200(M+H) + .

[0822] Example 12A

[0823] 3-[(3,3-Difluorocyclobutyl)methoxy]piperidine acetate (1:1) (racemate)

[0824]

[0825] 2.5 g (12.55 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy]pyridine were dissolved in 20 ml of glacial acetic acid and hydrogenated using an H-Cube (Thales Nano H-Cube Pro™-1.7).

[0826] Reaction conditions:

[0827] Catalyst: Pd / C 10%; solvent: glacial acetic acid; cylinder pressure: 80 bar hydrogen; flow rate: 1 ml / min; temperature: 80°C.

[0828] After the reaction was complete, the reaction mixture was concentrated to dryness. The resulting residue was dried under reduced pressure at room temperature overnight. This yielded 4.2 g of the title compound as a yellow oil. The title compound was reacted further without further purification.

[0829] GC-MS (Method 3): R t=3.87min; m / z=205(M-C2H4O2).

[0830] Example 13A

[0831] Benzyl 3-(difluoromethyl)[1,4′-bipiperidinyl]-1′-carboxylate (racemic)

[0832]

[0833] 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 were dissolved in 15 ml of dichloromethane (a small amount of The mixture was stirred at room temperature for 1 hour (100 μg / min, 0.5 ...

[0834] LC-MS (Method 1): R t =1.04min; m / z=353 (M+H) + .

[0835] Analogously to Example 13A, the following compounds of Examples 14A to 17A were prepared from the starting materials stated in each case:

[0836]

[0837]

[0838]

[0839] Example 18A

[0840] rac-3-(hydroxymethyl)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0841]

[0842] Acetic acid (1.8 ml, 32 mmol) was added to a solution of rac-4-oxopiperidine-1-carboxylic acid benzyl ester (5.00 g, 21.4 mmol) and piperidin-3-ylmethanol (4.94 g, 42.9 mmol) in 50 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (5.45 g, 25.7 mmol) was then added to the reaction and continued to stir at room temperature. After 2 hours, 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 desiccant was filtered off with suction, and the filtrate was concentrated and the residue was applied to Then column chromatography ( The mixture was purified using Isolera One; column: Snap Ultra 100g; DCM / MeOH gradient: 2% MeOH to 20% MeOH; flow rate: 100 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 4.37 g (100% purity, 61% of theory) of the target compound.

[0843] LC-MS (Method 1): R t =0.92min; MS (ESIpos): m / z=333[M+H] + .

[0844] Example 19A

[0845] rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidinyl]-1'-carboxylic acid benzyl ester

[0846]

[0847] Under argon, benzyl rac-3-(hydroxymethyl)[1,4′-bipiperidinyl]-1′-carboxylate (5.42 g, 16.3 mmol) was initially charged in 65 ml of dichloromethane, triethylamine (3.0 ml, 21 mmol) was added, and the mixture was cooled to 0° C. At this temperature, methanesulfonyl chloride (1.5 ml, 20 mmol) was added dropwise. The mixture was then stirred at 0° C. for 15 minutes, after which the ice bath was removed and stirring was continued at room temperature. After 15 minutes, the reaction mixture was diluted with dichloromethane and washed successively with 1N hydrochloric acid, saturated NaHCO 3 solution, and saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered, and concentrated. The residue was dried under high vacuum and reacted further without further purification. This gave 6.16 g (100% purity, 92% of theory) of the target compound.

[0848] LC-MS (Method 12): R t=1.39min; MS (ESIpos): m / z=411[M+H] + .

[0849] Example 20A

[0850] rac-3-(methoxymethyl)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0851]

[0852] Sodium methoxide solution (840 μl, 25% in methanol, 3.7 mmol) was added to a solution of rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-carboxylic acid benzyl ester (500 mg, 1.22 mmol) in 10 ml of DMF, and the mixture was stirred at 50° C. overnight. The solvent was removed on a rotary evaporator, and the residue was taken up in ethyl acetate and washed successively with water and saturated NaCl solution. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was applied to The mixture was purified by column chromatography ( The product was purified using an Isolera One (Isolera One; column: Snap Ultra 25g; DCM / MeOH gradient: 2% MeOH to 20% MeOH; flow rate: 75 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 146 mg (100% purity, 35% of theory) of the target compound.

[0853] LC-MS (Method 4): Rt=0.59 min; MS (ESIpos): m / z=347 [M+H] + .

[0854] Example 21A

[0855] diamix-(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0856]

[0857] Acetic acid (1.71 ml, 29.85 mmol) was added to a solution of rac-3-fluoro-4-oxopiperidine-1-carboxylic acid benzyl ester (5 g, 19.9 mmol) and (3R)-3-methylpiperidine (5.4 g, 39.8 mmol) in 200 ml of dichloromethane, and the mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (5.06 g, 23.88 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO solution, water and saturated NaCl solution in sequence. The organic phase was dried over NaSO, filtered and concentrated on a rotary evaporator. The residue was applied to and by column chromatography ( The product was purified using an Isolera One column (Isolera One; column: Snap Ultra 100g; DCM / MeOH gradient: 2% MeOH to 20% MeOH; flow rate: 100 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 5.13 g (55% purity, 42% of theory) of the target compound.

[0858] LC-MS (Method 1): R t =1.05min; MS (ESIpos): m / z=335[M+H].

[0859] Example 22A

[0860] tert-Butyl diamix-(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-carboxylate

[0861]

[0862] (3R)-3-methylpiperidine hydrochloride (6.24g, 46.0mmol) is initially loaded in 250ml1,2-dichloroethane.Add N, N-diisopropylethylamine (8.0ml, 46mmol), and the mixture is stirred at room temperature for 5 minutes.Add the fluoro-4-oxopiperidine-1-t-butyl formates of rac-3- (5.00g, 23.0mmol) and acetic acid (2.0ml, 35mmol) and the mixture is stirred at room temperature for 4h.Subsequently, add sodium triacetoxyborohydride (5.85g, 27.6mmol), then the reaction mixture is stirred at room temperature and spend the night.The reaction mixture is diluted with dichloromethane, and used saturated NaHCO solution, water and saturated NaCl solution washing successively.With organic phase through Na SO drying, filter and concentrate. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100x30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 minutes 47 ml, mobile phase B 0 to 2 minutes 23 ml, mobile phase A 2 to 10 minutes from 47 ml to 23 ml, mobile phase B from 23 ml to 47 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 5.30 g (100% purity, 77% of theory) of the target compound.

[0863] LC-MS (Method 4): R t =0.52min; MS (ESIpos): m / z=301[M+H] + .

[0864] Example 23A

[0865] rac-3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0866]

[0867] Under argon, 2,2,2-trifluoroethanol (66 μl, 910 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0° C. in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The residue was dried under high vacuum. This produced 218 mg (81% purity, 70% of theoretical value) of the target compound.

[0868] LC-MS (method 1): Rt = 1.33 min; MS (ESIpos): m / z = 415 [M+H] + .

[0869] Example 24A

[0870] rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0871]

[0872] Under argon, [1-(fluoromethyl)cyclopropyl]methanol (95.1 mg, 913 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0° C. with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl 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. The residue was dried under high vacuum. This produced 204 mg (40% purity, 32% of theoretical value) of the target compound.

[0873] LC-MS (method 1): Rt = 1.36 min; MS (ESIpos): m / z = 419 [M+H] + .

[0874] Example 25A

[0875] rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0876]

[0877] Under argon, [1-(difluoromethyl)cyclopropyl]methanol (112 mg, 913 μmol) was initially charged in 5 ml of DMF and the mixture was cooled to 0° C. in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzylcarboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The residue was dried under high vacuum. This produced 197 mg (51% purity, 37% of theory) of the target compound.

[0878] LC-MS (Method 1): R t =1.41min; MS (ESIpos): m / z=437[M+H] + .

[0879] Example 26A

[0880] rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0881]

[0882] Under argon, [1-(trifluoromethyl)cyclopropyl]methanol (128 mg, 913 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0° C. with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzylcarboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The residue was dried under high vacuum. This produced 212 mg (58% purity, 44% of theory) of the target compound.

[0883] LC-MS (Method 1): R t=1.48min; MS (ESlpos): m / z=455[M+H] + .

[0884] Example 27A

[0885] 3,3-Dimethyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0886]

[0887] Acetic acid (74 μl, 1.3 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (200 mg, 58% purity, 857 μmol) and 3,3-dimethylpiperidine (240 μl, 1.7 mmol) in 7 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (218 mg, 1.03 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Saturated NaHCO 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 Na2SO4. The desiccant was filtered off, the filtrate was concentrated, and the residue was dried under high vacuum. This produced 280 mg (81% purity, 80% of theoretical value) of the target compound.

[0888] LC-MS (method 1): Rt = 1.18 min; MS (ESIpos): m / z = 331 [M+H] + .

[0889] Example 28A

[0890] Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate

[0891]

[0892] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and 5-azaspiro[2.5]octane (286 mg, 2.57 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. Saturated NaHCO solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The desiccant was filtered off, the filtrate was concentrated, and the residue was dried under high vacuum. This produced 368 mg (purity 40%, 35% of theoretical value) of the target compound.

[0893] LC-MS (method 1): Rt = 1.12 min; MS (ESIpos): m / z = 329 [M+H] + .

[0894] Example 29A

[0895] rac-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylic acid benzyl ester

[0896]

[0897] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (300 mg, 1.29 mmol) and rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (354 mg, 1.93 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction, 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 desiccant was filtered off, the filtrate was concentrated on a rotary evaporator, and the residue was dried under high vacuum. This produced 405 mg (purity 61%, 53% of theoretical value) of the target compound.

[0898] LC-MS (method 1): Rt = 1.14 min; MS (ESIpos): m / z = 365 [M+H] + .

[0899] Example 30A

[0900] rac-3-hydroxy[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0901]

[0902] Triethylamine (1.8ml, 13mmol) and acetic acid (740μl, 13mmol) are added to a solution of 4-oxopiperidine-1-carboxylic acid benzyl ester (2.00g, 8.57mmol) and piperidine-3-ol (1.73g, 17.1mmol) in 100ml dichloromethane, and the mixture is stirred at room temperature for 4 hours. Subsequently, sodium triacetoxyborohydride (2.18g, 10.3mmol) is added to the reaction, and the mixture is stirred at room temperature for 48 hours. Saturated NaHCO3 solution is added, and the reaction mixture is extracted with dichloromethane. The organic phase is washed with water and dried over Na2SO4. The desiccant is filtered out, and the filtrate is concentrated. The residue is applied to The mixture was purified by column chromatography ( The product was purified using an Isolera One column (Isolera One; column: Snap Ultra 50g; DCM / MeOH gradient: 2% MeOH to 20% MeOH; flow rate: 100 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 1.87 g (100% purity, 68% of theory) of the target compound.

[0903] LC-MS (method 1): Rt = 0.88 min; MS (ESIpos): m / z = 319 [M+H] + .

[0904] Example 31A

[0905] rac-3-(cyclopropylmethoxy)[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0906]

[0907] Under argon, 3-hydroxy [1,4 '-bipiperidinyl] -1 '-carboxylic acid benzyl ester (250mg, 785μmol) was initially loaded in 5ml THF and the mixture was cooled to 0 ℃ with an ice bath. At this temperature, sodium hydride (47.1mg, 60% purity, 1.18mmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl) cyclopropane (110μl, 1.2mmol) was added and the mixture was stirred at 60 ℃ overnight. (Bromomethyl) cyclopropane (110μl, 1.2mmol) and sodium hydride (47.1mg, 60% purity, 1.18mmol) were added and the mixture was stirred at 60 ℃ for another 24 hours. The product was subsequently isolated by preparative HPLC (column: Chromatorex C18 10 μm, 250 x 30 mm, mobile phase A = water, B = acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml / min; 0.1% formic acid). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This yielded 68.0 mg (68% purity, 16% of theory) of the target compound.

[0908] LC-MS (method 1): Rt = 1.25 min; MS (ESIpos): m / z = 373 [M+H] + .

[0909] Example 32A

[0910] rac-3-[(cyclobutyloxy)methyl][1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0911]

[0912] Under argon, cyclobutanol (72 μl, 910 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0° C. with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl 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 a saturated NaCl solution and dried over Na2SO4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This produced 290 mg (46% purity, 57% of theoretical value) of the target compound.

[0913] LC-MS (Method 4): Rt =0.73min; MS (ESIpos): m / z=387[M+H] + .

[0914] Example 33A

[0915] rac-3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0916]

[0917] Under argon, sodium hydride (268 mg, purity 60%, 6.70 mmol) was initially loaded in 25 ml DMF, and the mixture was cooled to 0 ° C with an ice bath. At this temperature, cyclopropylmethanol (540 μ l, 6.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl carboxylate (2.50 g, 6.09 mmol) was added, and the reaction mixture was stirred at 55 ° C overnight. Cyclopropylmethanol (540 μ l, 6.7 mmol) and sodium hydride (268 mg, purity 60%, 6.70 mmol) were added, and the mixture was stirred for another 24 hours at 55 ° C. 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 purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, 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: mobile phase A 0 to 2 minutes 63 ml, mobile phase B 0 to 2 minutes 7 ml, mobile phase A 2 to 10 minutes from 63 ml to 39 ml, mobile phase B from 7 ml to 31 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The product-containing fractions were combined and lyophilized. This yielded 241 mg (78% purity, 8% of theory) of the target compound.

[0918] LC-MS (method 1): Rt = 1.27 min; MS (ESIpos): m / z = 387 [M+H] + .

[0919] Example 34A

[0920] tert-Butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate

[0921]

[0922] Acetic acid (72 μ l, 1.3 mmol) is added to a solution of tert-butyl 4-oxoazepane-1-formate (179 mg, 840 μ mol) and (3R)-3-methylpiperidine (167 mg, 1.68 mmol) in 5 ml of dichloromethane, and the mixture is stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (214 mg, 1.01 mmol) is added to the reaction, and the mixture is stirred at room temperature overnight. Subsequently, saturated NaHCO solution is added, and the reaction mixture is extracted with dichloromethane. The organic phase is washed with water, and through Na SO drying. Suction is filtered off to remove desiccant, the filtrate is concentrated on a rotary evaporator, and the residue is dried under high vacuum. This generates a mixture of 215 mg, which is further reacted without further purification and analysis.

[0923] Example 35A

[0924] Benzyl diamix-3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-carboxylate

[0925]

[0926] Under argon, rac-(2,2-difluorocyclopropyl)methanol (98.7 mg, 913 μmol) was initially charged in 5 ml of DMF and the mixture was cooled to 0° C. in an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl 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 gave 343 mg (56% purity, 74% of theory) of the target compound.

[0927] LC-MS (method 1): Rt = 1.32 min; MS (ESIpos): m / z = 423 [M+H] + .

[0928] Example 36A

[0929] rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[0930]

[0931] Under argon, (3,3-difluorocyclobutyl)methanol (112 mg, 913 μmol) was initially loaded in 5 ml of DMF and the mixture was cooled to 0° C. with an ice bath. At this temperature, sodium hydride (36.5 mg, 60% purity, 913 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, rac-3-{[(methylsulfonyl)oxy]methyl}[1,4'-bipiperidine]-1'-benzyl carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 hours, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This produced 287 mg (33% purity, 36% of theoretical value) of the target compound.

[0932] LC-MS (method 1): Rt = 1.44 min; MS (ESIpos): m / z = 437 [M+H] + .

[0933] Example 37A

[0934] 3-(Difluoromethyl)-1,4′-bipiperidine dihydrochloride (racemic)

[0935]

[0936] 1.35 g (3.83 mmol) of benzyl 3-(difluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (racemate) was dissolved in 100 ml of ethanol and hydrogenated using an H-Cube (Thales Nano H-Cube Pro™-1.7).

[0937] Reaction conditions:

[0938] Catalyst: Pd / C 10%; Solvent: Ethanol; Cartridge pressure: 1 bar hydrogen; Flow rate: 1 ml / min; Temperature: 50°C

[0939] After complete conversion, 4N HCl (in dioxane) was added and the reaction mixture was concentrated to dryness. The resulting residue was dried overnight at room temperature under reduced pressure. This gave 1,107 g (3.80 mmol, 99% of theory) of the target compound as a white solid. This target compound was reacted further without further purification.

[0940] GC-MS (Method 3): R t =4.87min; m / z=218(M-2HCl) + .

[0941] Example 38A

[0942] 3-[(3,3-difluorocyclobutyl)methoxy]-1,4′-bipiperidine (racemic)

[0943]

[0944] 2.7 g (6.39 mmol) of benzyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidine]-1′-carboxylate (racemate) was dissolved in 90 ml of ethanol and hydrogenated using an H-Cube (Thales Nano H-Cube Pro™-1.7).

[0945] Reaction conditions:

[0946] Catalyst: Pd / C 10%; Solvent: Ethanol; Cartridge pressure: 50 bar hydrogen; Flow rate: 1 ml / min; Temperature: 50°C

[0947] After the reaction is complete, the reaction mixture is concentrated to dryness. The resulting residue is dried overnight at room temperature under reduced pressure. This yields 1.27 g (4.40 mmol, 69% of theory) of the target compound as a yellow oil. The target compound is reacted further without further purification.

[0948] GC-MS (Method 3): R t =6.42min; m / z=288(M) + .

[0949] Analogously to Examples 37A and 38A, the following compounds of Examples 39A to 41A were prepared from the starting materials stated in each case.

[0950]

[0951] Example 42A

[0952] rac-3-(methoxymethyl)-1,4′-bipiperidine dihydrochloride

[0953]

[0954] Benzyl rac-3-(methoxymethyl)[1,4′-bipiperidinyl]-1′-carboxylate (145 mg, 419 μmol) was initially loaded in 5 ml of THF and palladium (50.0 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (310 μl, 2.0 M, 630 μmol) was added to the filtrate, and the precipitated solid was filtered off with suction, washed with ether and dried under high vacuum. This gave 92.0 mg (76% purity, 59% of theory) of the target compound.

[0955] GC-MS (Method 3): Rt = 5.45 min; MS (ESIpos): m / z = 212 [M-HCl] + .

[0956] Example 43A

[0957] diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride

[0958]

[0959] Synthesis method 1:

[0960] Benzyl diamix-(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-carboxylate (5.13 g, 55% purity, 8.40 mmol) was initially charged in 250 ml of THF and palladium (382 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in 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.

[0961] LC-MS (Method 4): MS (ESIpos): m / z=200 [M-2HCl] + .

[0962] Synthesis method 2:

[0963] 4M hydrochloric acid in 1,4-dioxane (22 ml, 4.0 M, 88 mmol) was added to a solution of tert-butyl diamix-(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-carboxylate (5.30 g, 17.6 mmol) in dichloromethane, and the mixture was stirred at room temperature for 48 hours. The precipitated solid was filtered off with suction, washed with dichloromethane, and dried in a vacuum drying cabinet at 40° C. overnight. This gave 3.47 g (100% purity, 72% of theory) of the target compound.

[0964] GC-MS (Method 3): MS (ESIpos): m / z = 200 [M-2HCl] + .

[0965] Example 44A

[0966] rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4′-bipiperidine dihydrochloride

[0967]

[0968] Benzyl rac-3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidinyl]-1′-carboxylate (218 mg, 81% purity, 526 μmol) was initially charged in 12 ml of THF, and palladium (63 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 3.5 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid in 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 (74% purity, 66% of theory) of the target compound.

[0969] GC-MS (Method 3): R t =5.26min; MS (full ms): m / z=280[M-2HCl] + .

[0970] Example 45A

[0971] rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride

[0972]

[0973] Benzyl rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (204 mg, 40% purity, 487 μmol) was initially loaded in 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 celite and washed with THF. Hydrochloric acid in ether (370 μl, 2.0 M, 740 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This produced 133 mg of a mixture that was reacted without further purification or analysis.

[0974] Example 46A

[0975] rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride

[0976]

[0977] Benzyl rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (197 mg, 51% purity, 451 μmol) was initially loaded in 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 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (374 μl, 2.0 M, 680 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This produced 112 mg of a mixture that was reacted without further purification or analysis.

[0978] Example 47A

[0979] rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride

[0980]

[0981] Benzyl rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (212 mg, 58% purity, 466 μmol) was initially loaded in 10 ml of THF, and palladium (56 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 hours, the catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (350 μl, 2.0 M, 700 μmol) was added to the filtrate, and the mixture was concentrated on a rotary evaporator. This produced 129 mg of a mixture that was reacted further without further purification or analysis.

[0982] Example 48A

[0983] 3,3-Dimethyl-1,4′-bipiperidine dihydrochloride

[0984]

[0985] 3,3-dimethyl[1,4'-bipiperidine]-1'-benzyl carboxylate (260 mg, purity 81%, 6371 μmol) was initially loaded in 18 ml of THF and palladium (27 mg; 10% on activated carbon, 255 μmol) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in 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 generated 180 mg of a mixture that was further reacted without further purification and analysis.

[0986] Example 49A

[0987] 5-(Piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[0988]

[0989] 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylic acid benzyl ester (368mg, purity 40%, 1.12mmol) is initially loaded in 32mlTHF, and palladium (51mg, 10% on activated carbon) is added under argon. Then the mixture is hydrogenated overnight under a hydrogen atmosphere. The catalyst is filtered out through diatomaceous earth and washed with THF. Hydrochloric acid (840μl, 2.0M, 1.7mmol) in ether is added to the filtrate, and the mixture is concentrated on a rotary evaporator. The residue is stirred with dichloromethane. The precipitated solid is filtered off with suction, washed with dichloromethane, and dried under high vacuum. This generates a mixture of 185mg, which is further reacted without further purification and analysis.

[0990] Example 50A

[0991] rac-1,1-difluoro-5-(piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[0992]

[0993] By rac-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylic acid benzyl ester (405mg, purity 61%, 1.11mmol) initially loaded in 32mlTHF, and under argon, add palladium (51mg, 10% on activated carbon).Then under hydrogen atmosphere, the mixture is hydrogenated overnight.The catalyst is filtered out by diatomaceous earth and washed with THF.Hydrochloric acid (840μl, 2.0M, 1.7mmol) in ether is added to the filtrate, and the mixture is concentrated on a rotary evaporator.The residue is stirred together with dichloromethane, concentrated on a rotary evaporator and dried under high vacuum.This generates a mixture of 280mg, which is further reacted without further purification and analysis.

[0994] Example 51A

[0995] rac-3-(cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride

[0996]

[0997] Benzyl rac-3-(cyclopropylmethoxy)[1,4′-bipiperidine]-1′-formate (68.0 mg, 68% purity, 124 μmol) was initially loaded in 5 ml of THF and palladium (22 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in 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 generated 51 mg of a mixture that was further reacted without further purification and analysis.

[0998] Example 52A

[0999] rac-3-[(cyclobutyloxy)methyl]-1,4′-bipiperidine dihydrochloride

[1000]

[1001] Benzyl rac-3-[(cyclobutyloxy)methyl][1,4′-bipiperidine]-1′-carboxylate (290 mg, 46% purity, 3861 μmol) was initially loaded in 15 ml of THF and palladium (41 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (259 μl, 2.0 M, 518 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This produced 225 mg of a mixture that was reacted further without further purification or analysis.

[1002] Example 53A

[1003] rac-3-[(cyclopropylmethoxy)methyl]-1,4′-bipiperidine dihydrochloride

[1004]

[1005] Benzyl rac-3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate (241 mg, 78% purity, 486 μmol) was initially loaded in 20 ml of THF and palladium (58 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (360 μl, 2.0 M, 730 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This produced 155 mg of a mixture that was reacted further without further purification or analysis.

[1006] Example 54A

[1007] 4-[(3R)-3-Methylpiperidin-1-yl]azepane dihydrochloride

[1008]

[1009] 4M hydrochloric acid in 1,4-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 5.4 ml of dichloromethane, and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 237 mg of a mixture that was reacted further without further purification and analysis.

[1010] Example 55A

[1011] diamix-3-[(3-fluorobutoxy)methyl]-1,4′-bipiperidine dihydrochloride

[1012]

[1013] Benzyl diamix-3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (343 mg, 56% purity, 446 μmol) was initially loaded in 25 ml of THF and palladium (53 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (330 μl, 2.0 M, 670 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This generated 218 mg of a mixture that was reacted further without further purification and analysis.

[1014] Example 56A

[1015] rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}-1,4′-bipiperidine dihydrochloride

[1016]

[1017] Benzyl rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4′-bipiperidine]-1′-formate (287 mg, 33% purity, 217 μmol) was initially loaded in 15 ml of THF and palladium (26 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in ether (163 μl, 2.0 M, 325 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This generated 286 mg of a mixture that was reacted further without further purification and analysis.

[1018] Example 57A

[1019] 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid methyl ester

[1020]

[1021] 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 overnight at this temperature. After the reaction mixture had cooled, the solution was concentrated to dryness using a rotary evaporator. This yielded 14.29 g (crude product, approximately 34% purity) of the target product and the triethylamine salt. The mixture was reacted further without further purification.

[1022] LC-MS (Method 4): R t =0.51min; m / z=324 (M+H) + .

[1023] Example 58A

[1024] 2-[(3R)-3-Methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride

[1025]

[1026] A mixture of 14.29 g of methyl 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylate and triethylamine salt was dissolved in water, and 221 ml of 1N NaOH solution was added. A brown oil was separated and dissolved in 50 ml of THF. The reaction mixture was then heated to 60° C. and stirred at this temperature for 1 hour. After the reaction mixture had cooled to room temperature, the solution was concentrated to dryness on a rotary evaporator, placed in water and acidified with concentrated hydrochloric acid. The solution was then concentrated to dryness once more. This gave 20.54 g of a beige solid, which was purified by column chromatography.

[1027] Conditions: Separation using 1 g aliquots: RP column Chromatorex C18, 10 μm; 125 x 30 mm, gradient: acetonitrile / water (+0.05% formic acid) 5 / 95 → 20 min → acetonitrile / water (+0.05% formic acid) 95 / 5, flow rate: 75 ml / min.

[1028] Finally, the product-containing fractions were combined, concentrated to dryness under reduced pressure and dried. This gave 4.75 g (12.42 mmol, 83% of theory) of the target compound as a light beige solid.

[1029] LC-MS (Method 1): R t =0.54min; m / z=310(M+H-2HCl) + .

[1030] Example 59A

[1031] 3-[(3R)-3-Methyl[1,4′-bipiperidinyl]-1′-yl]-1,2,4-oxadiazole-5-carboxylic acid

[1032]

[1033] Ethyl 3-bromo-1,2,4-oxadiazole-5-carboxylate (100 mg, 452 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (173 mg, 679 μmol) were stirred in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4.0 mmol) at 120° C. After 30 minutes, the reaction mixture was acidified with 2N hydrochloric acid and purified by preparative HPLC (column: Chromatorex C18 10 μm, 250 x 30 mm, mobile phase A = water, B = acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml / min; 0.1% formic acid). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 25 mg (60% purity, 11% of theory) of the target compound.

[1034] LC-MS (Method 1): R t =0.47min; MS (ESlpos): m / z=295[M+H] + .

[1035] Example 60A

[1036] rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride

[1037]

[1038] Triphenylphosphine (2.43g, 9.25mmol) is added to a solution of pyridine-3-ol (677mg, 7.12mmol) in 25mlTHF, and the mixture is cooled to 0°C in an ice bath. At this temperature, diisopropyl azodicarboxylate (1.3ml, 9.3mmol) is added, and the mixture is stirred at 0°C for 5 minutes. Subsequently, a solution of rac-2,2-difluorocyclopropylmethanol (1.00g, 9.25mmol) in 5mlTHF is added dropwise to the mixture. The ice bath is then removed, and the mixture is stirred at room temperature overnight. Water is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The oily residue is stirred with 75ml cyclohexane for 30 minutes. The precipitated solid is filtered out and the filtrate is concentrated to obtain a residue. The residue is dissolved in 50mlMTBE, and 5ml hydrochloric acid (4N in 1,4-dioxane) is added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 698 mg (93% purity, 41% of theory) of the target compound.

[1039] LC-MS (Method 4): R t=0.40min; MS (ESIpos): m / z=186[M-HCl] + .

[1040] Example 61A

[1041] diamix-3-[(2,2-difluorocyclopropyl)methoxy]piperidine sulfate hydrochloride

[1042]

[1043] 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 overnight under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried under high vacuum. This gave 761 mg (74% of theory) of the target compound.

[1044] LC-MS (Method 5): MS (ESIpos): m / z=192 [M-HCl-H2SO4] + .

[1045] Example 62A

[1046] 3-(Cyclobutyloxy)pyridine hydrochloride

[1047]

[1048] Triphenylphosphine (7.17g, 27.3mmol) is added to a solution of pyridine-3-ol (2.00g, 21.0mmol) in 70mlTHF, and the mixture is cooled to 0°C in an ice bath. At this temperature, diisopropyl azodicarboxylate (3.9ml, 27mmol) is added, and the mixture is stirred at 0°C for 5 minutes. Subsequently, a solution of cyclobutanol (2.1ml, 27mmol) in 10mlTHF is added dropwise to the mixture. The ice bath is then removed, and the mixture is stirred at room temperature over the weekend. Water is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The oily residue is stirred with 150ml cyclohexane for 30 minutes. Filter out the solid and concentrate the filtrate to obtain a residue. The residue is dissolved in 100mlMTBE, and 5ml hydrochloric acid (4N in 1,4-dioxane) is added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 2.02 g (51% purity, 26% of theory) of the target compound.

[1049] LC-MS (Method 5): R t =1.34min; MS (ESIpos): m / z=150[M-HCl].

[1050] Example 63A

[1051] rac-3-(cyclobutyloxy)piperidine sulfate hydrochloride

[1052]

[1053] 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 overnight under a hydrogen atmosphere. The catalyst was filtered off 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 (157% of theory) of the target compound.

[1054] LC / MS (Method 4): MS (ESIpos): m / z=156 [M-HCl-H2SO4] + .

[1055] Example 64A

[1056] 3-[(3,3-difluorocyclobutyl)oxy]pyridine hydrochloride

[1057]

[1058] Triphenylphosphine (2.43g, 9.25mmol) is added to a solution of pyridine-3-alcohol (677mg, 7.12mmol) in 25mlTHF, and the mixture is cooled to 0 ℃ in an ice bath. At this temperature, diisopropyl azodicarboxylate (1.3ml, 9.3mmol) is added, and the mixture is stirred at 0 ℃ for 5 minutes. Subsequently, a solution of 3,3-difluorocyclobutanol (1.00g, 9.25mmol) in 5mlTHF is added dropwise to the mixture. The ice bath is then removed, and the mixture is stirred at room temperature overnight. The reaction mixture is stirred at 80 ℃ for 5 hours, then extracted between water and ethyl acetate. The organic phase is washed with saturated NaCl solution, through Na SO Drying, filtered and concentrated. The oily residue was stirred 30 minutes with 150ml hexamethylene. Filter out the precipitated solid, concentrated filtrate, and obtain residue. The residue was dissolved in 100 ml of MTBE and 5 ml of hydrochloric acid (4N in 1,4-dioxane) were added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 289 mg (94% purity, 17% of theory) of the target compound.

[1059] LC-MS (Method 4): R t =1.01min; MS (ESIpos): m / z=186[M-HCl] + °

[1060] Example 65A

[1061] rac-3-[(3,3-difluorocyclobutyl)oxy]piperidine sulfate hydrochloride

[1062]

[1063] 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 for 3 hours under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried under high vacuum. This produced 297 mg (68% of theory) of the target compound.

[1064] LC / MS (method 4): MS (ES1pos): m / z=192 [M-HCl-H2SO4] + .

[1065] Example 66A

[1066] 2-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide

[1067]

[1068] N, N-diisopropylethylamine (680 μl, 3.9 mmol) and propylphosphonic anhydride (1.0 ml, 50% in ethyl acetate, 1.7 mmol) are 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)methylamine dihydrochloride (283 mg, 1.30 mmol) in 10 ml of acetonitrile, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na2SO4. The drying agent is filtered off and the filtrate is concentrated. The residue is applied to The mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 10g; Cy / EA gradient: 8% EA to 66% EA; flow rate 36 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 193 mg (46% of theory, 84% purity) of the target compound, which was reacted further without further purification.

[1069] LC-MS (Method 1): R t =1.32min; MS (ESIpos): m / z=274[M+H] + .

[1070] Example 67A

[1071] 2-Bromo-N-(5-chloro-2-fluorobenzyl)-1,3-thiazole-5-carboxamide

[1072]

[1073] N, N-diisopropylethylamine (630 μl, 3.6 mmol) and propylphosphonic anhydride (930 μl, 50% in ethyl acetate, 1.6 mmol) are added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and 1-(5-chloro-2-fluorophenyl)methylamine (192 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na2SO4. The drying agent is filtered off and the filtrate is concentrated. The residue is applied to The mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 10g; Cy / EA gradient: 8% EA to 66% EA; flow rate 36 ml / min. Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 106 mg (96% purity, 24% of theory) of the target compound.

[1074] LC-MS (Method 1): R t =1.85min; MS (ESIpos): m / z=348[M+H] + .

[1075] Example 68A

[1076] (3R)-3-Hydroxy[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[1077]

[1078] Triethylamine (3.0 ml, 21 mmol) and acetic acid (740 μl, 13 mmol) were added to a solution of 4-oxopiperidine-1-carboxylic acid benzyl ester (2.00 g, 8.57 mmol) and (3R)-piperidin-3-ol hydrochloride (2.36 g, 17.1 mmol) in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 48 hours. Saturated NaHCO solution was added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na2SO4. The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to The mixture was purified by column chromatography ( The product was purified using an Isolera One column (Isolera One; Snap Ultra 50g column; DCM / MeOH gradient: 2% MeOH to 20% MeOH; flow rate 100 ml / min). Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 1.79 g (100% purity, 66% of theory) of the target compound.

[1079] LC-MS (Method 1): R t =0.87min; MS (ESIpos): m / z=319[M+H] + .

[1080] Example 69A

[1081] Benzyl (3R)-3-(cyclopropylmethoxy)[1,4′-bipiperidinyl]-1′-carboxylate

[1082]

[1083] Under argon, (3R)-3-hydroxy [1,4 '-bipiperidine] -1 '-benzyl formate (1.79g, 5.62mmol) was initially loaded in 40mlTHF, and the mixture was cooled to 0 ℃ with an ice bath. At this temperature, sodium hydride (337mg, purity 60%, 8.43mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, (bromomethyl) cyclopropane (820 μl, 8.4mmol) was added, and the reaction mixture was stirred at 60 ℃ overnight. (bromomethyl) cyclopropane (820 μl, 8.4mmol) and sodium hydride (337mg, purity 60%, 8.43mmol) were added, and the mixture was stirred at 60 ℃ for another 24 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, and dried over Na2SO4. Desiccant was filtered out, and the filtrate was concentrated. The product was purified by preparative HPLC (instrument: 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 formic acid in water, 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: mobile phase A 0 to 2 minutes 63 ml, mobile phase B 0 to 2 minutes 7 ml, mobile phase A 2 to 10 minutes from 63 ml to 39 ml, mobile phase B from 7 ml to 31 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 100.0 mg (100% purity, 4.8% of theory) of the target compound.

[1084] LC-MS (Method 1): R t =1.19min; MS (ESIpos): m / z=373[M+H] + .

[1085] Example 70A

[1086] (3R)-3-(Cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride

[1087]

[1088] (3R)-3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-benzyl carboxylate (100 mg, 268 μmol) was initially loaded in 7.5 ml of THF and palladium (32.1 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated for 2 hours under a hydrogen atmosphere. The catalyst was filtered off through celite and washed with THF. Hydrochloric acid in 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 generated 66 mg of a mixture that was reacted further without further purification and analysis.

[1089] Example 71A

[1090] rac-2-bromo-N-[1-(2,5-difluorophenyl)ethyl]-1,3-thiazole-5-carboxamide

[1091]

[1092] N, N-diisopropylethylamine (630 μl, 3.6 mmol) and propylphosphonic anhydride (930 μl, 50% in ethyl acetate, 1.6 mmol) are added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and rac-1-(2,5-difluorophenyl)ethylamine (189 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na2SO4. The drying agent is filtered off and the filtrate is concentrated. The residue is applied to The mixture was purified by column chromatography ( Isolera One; column: Snap Ultra 10g; Cy / EA gradient: 8% EA to 66% EA; flow rate 36 ml / min. Product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This yielded 148 mg (100% purity, 35% of theory) of the target compound.

[1093] LC-MS (Method 1): R t =1.81min; MS (ESIpos): m / z=346[M+H] + .

[1094] Example 72A

[1095] 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid ethyl ester

[1096]

[1097] 2-Bromo-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylic acid ethyl ester (150 mg, 433 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (166 mg, 649 μmol) were combined and stirred at 120° C. in a sodium carbonate solution (870 μl, 2.0 M, 1.7 mmol) for 30 minutes. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na SO and filtered, and the filtrate was concentrated on a rotary evaporator. The residue was dried under high vacuum. This produced 199 mg (95% purity, 98% of theoretical value) of the target compound.

[1098] LC-MS (Method 1): R t =1.34min; MS (ESIpos): m / z=449[M+H] + .

[1099] Example 82A

[1100] diamix-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[1101]

[1102] 4M hydrochloric acid (720 μ l, 4.0 M, 2.9 mmol) in 1,4-dioxane is added to a solution of tert-butyl diamix-4-(5-azaspiro [2.5] octane-5-yl)-3-fluoropiperidine-1-carboxylate (179 mg, 573 μ mol) in 8 ml of dichloromethane, and the mixture is stirred at room temperature overnight. Subsequently, the reaction mixture is concentrated on a rotary evaporator, and the residue is dried under high vacuum. This generates a mixture of 162 mg, which is further reacted without further purification and analysis.

[1103] Example 73A

[1104] 4-(2-Chlorophenyl)-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid

[1105]

[1106] Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylate (199 mg, 444 μmol) was dissolved in 10 ml of THF. Aqueous sodium hydroxide solution (4 ml, 2.0 M, 8 mmol) was added to the solution and the mixture was stirred at room temperature for 5 days. 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 (98% purity, 84% of theory) of the target compound.

[1107] LC-MS (Method 1): R t =0.97min; MS (ESIpos): m / z=420[M+H] + .

[1108] Example 74A

[1109] 4-Bromo-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid

[1110]

[1111] 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 at 120° C. in sodium carbonate solution (1.0 ml, 2.0 M, 2.1 mmol) for 1 hour. The reaction mixture was subsequently 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 (100% purity, 118% of theory) of the target compound.

[1112] LC-MS (Method 1): R t =0.70min; MS (ESIpos): m / z=388[M+H] + .

[1113] Example 75A

[1114] 2-Bromo-4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1115]

[1116] N, N-diisopropylethylamine (720 μ l, 4.1 mmol) and propylphosphonic anhydride (800 μ l, 50% in ethyl acetate, 1.3 mmol) are 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)methylamine dihydrochloride (291 mg, 1.34 mmol) in 14 ml of acetonitrile, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na SO. Filter out the desiccant and concentrate the filtrate. The residue is dried under high vacuum. This generates 250 mg (purity 95%, 62% of theoretical value) of the target compound.

[1117] LC-MS (Method 1): R t =1.79min; MS (ESIpos): m / z=367[M+H] + .

[1118] Example 76A

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

[1120]

[1121] N, N-diisopropylethylamine (560 μ l, 3.2 mmol) and propylphosphonic anhydride (620 μ l, 50% in ethyl acetate, 1.0 mmol) are added to a solution of 2-bromo-4-cyclopropyl-1,3-thiazole-5-carboxylic acid (200 mg, 806 μ mol) and 1-(3,5-difluoropyridin-2-yl)methylamine dihydrochloride (227 mg, 1.05 mmol) in 11 ml of acetonitrile, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na SO. The desiccant is filtered off and the filtrate is concentrated. The residue is dried under high vacuum. This generates 239 mg (purity 78%, 62% of theoretical value) of the target compound.

[1122] LC-MS (Method 1): R t =1.87min; MS (ESIpos): m / z=373[M+H] + .

[1123] Example 77A

[1124] 2-Bromo-4-ethyl-1,3-thiazole-5-carboxylic acid

[1125]

[1126] 2-Bromo-4-ethyl-1,3-thiazole-5-methylformate (150mg, 600μmol) is dissolved in 3mlTHF. Into the solution, add aqueous sodium hydroxide solution (3ml, 2.0M, 6mmol), and the mixture is stirred at room temperature overnight. On a rotary evaporator, remove THF and acidify the residue with 2N hydrochloric acid. Filter out the precipitated solid and dry under high vacuum. This generates 100mg (purity 98%, 69% of theoretical value) of the target compound.

[1127] LC-MS (Method 1): R t =1.30min; MS (ESIpos): m / z=235[M+H] + .

[1128] Example 78A

[1129] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-ethyl-1,3-thiazole-5-carboxamide

[1130]

[1131] N, N-diisopropylethylamine (300 μ l, 1.7 mmol) and propylphosphonic anhydride (330 μ l, 50% in ethyl acetate, 550 μ mol) are added to a solution of 2-bromo-4-ethyl-1,3-thiazole-5-carboxylic acid (100 mg, 424 μ mol) and 1-(3,5-difluoropyridin-2-yl)methylamine dihydrochloride (120 mg, 550 μ mol) in 5.7 ml of acetonitrile, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated, and the residue is placed in ethyl acetate and washed with saturated NaHCO solution, water and saturated NaCl solution. The organic phase is dried over Na SO. The desiccant is filtered off and the filtrate is concentrated. The residue is dried under high vacuum. This generates 150 mg (purity 95%, 93% of theoretical value) of the target compound.

[1132] LC-MS (Method 4): R t =0.86min; MS (ESIpos): m / z=364[M+H] + .

[1133] Example 79A

[1134] tert-Butyl diamix-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate

[1135]

[1136] N, N-diisopropylethylamine (570 μl, 3.3 mmol) is added to a solution of rac-1,1-difluoro-5-azaspiro [2.5] octane hydrochloride (600 mg, 3.27 mmol) in 15 ml of 1,2-dichloroethane, and the mixture is stirred for 5 minutes. Subsequently, rac-3-fluoro-4-oxopiperidine-1-tert-butyl carboxylate (355 mg, 1.63 mmol) and acetic acid (140 μl, 2.5 mmol) are added to the mixture. The mixture is then stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg, 1.96 mmol) is added to the mixture, and the mixture is stirred at room temperature overnight. Saturated NaHCO solution is added, and the reaction mixture is extracted with dichloromethane. The organic phase is washed with water and dried over Na SO. Desiccant is filtered out, and the filtrate is concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile / water (80% by volume / 20% by volume). Total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, complete injection. Gradient overview: mobile phase A 0 to 2 minutes 70 ml, mobile phase B 0 to 2 minutes 0 ml, mobile phase A 2 to 10 minutes from 70 ml to 55 ml, mobile phase B from 0 ml to 15 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This gave 264 mg (100% purity, 46% of theory) of the target compound.

[1137] LC-MS (Method 4): R t =0.56min; MS (ESIpos): m / z=349[M+H] + .

[1138] Example 80A

[1139] diamix-1,1-difluoro-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride

[1140]

[1141] By 1,4-dioxane 4M hydrochloric acid (950 μ l, 4.0 M, 3.8 mmol) is added to diamix-4-(1,1-difluoro-5-azaspiro [2.5] octane-5-yl)-3-fluoropiperidine-1-t-butyl carboxylate (264 mg, 760 μ mol) in a solution of tert-butyl carboxylate in 10 ml of dichloromethane, and the mixture is stirred at room temperature overnight. Subsequently, the reaction mixture is concentrated on a rotary evaporator, and the residue is dried under high vacuum. This generates a mixture of 246 mg, which is further reacted without further purification and analysis.

[1142] Example 81A

[1143] tert-Butyl diamix-4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate

[1144]

[1145] N, N-diisopropylethylamine (410 μ l, 2.4 mmol) is added to a solution of 5-azaspiro [2.5] octane hydrochloride (350 mg, 2.37 mmol) in 10 ml of dichloroethane, and the mixture is stirred for 5 minutes. Afterwards, rac-3-fluoro-4-oxopiperidine-1-tert-butyl formate (257 mg, 1.19 mmol) and acetic acid (100 μ l, 1.8 mmol) are added to the mixture. The mixture is then stirred at room temperature. After 5 hours, sodium triacetoxyborohydride (416 mg, 1.96 mmol) is added to the mixture, and the mixture is stirred at room temperature overnight. Saturated NaHCO solution is added, and the reaction mixture is extracted with dichloromethane. The organic phase is washed with water, and through Na SO drying. Filter out desiccant, and concentrate the filtrate. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: 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 formic acid in water, 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 overview: mobile phase A 0 to 2 minutes 70 ml, mobile phase B 0 to 2 minutes 0 ml, mobile phase A 2 to 10 minutes from 70 ml to 55 ml, mobile phase B from 0 ml to 15 ml, 10 to 12 minutes 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The product-containing fractions were combined and concentrated, and the residue was dried under high vacuum. This gave 179 mg (100% purity, 48% of theory) of the target compound.

[1146] LC-MS (Method 4): R t =0.53min; MS (ESIpos): m / z=313[M+H] + .

[1147] Example 82A

[1148] 5-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3,4-thiadiazole-2-carboxylic acid ethyl ester

[1149]

[1150] 3.67 ml (21.09 mmol) of N,N-diisopropylethylamine were added to 1 g (4.22 mmol) of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate and 1.077 g (4.22 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride in 25 ml of acetonitrile. The mixture was heated to 80° C. and stirred at this temperature overnight. After the reaction mixture had cooled, the solution was diluted with ethyl acetate and washed with water. Finally, the organic phase was separated off, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This gave 1.29 g (3.81 mmol, 90% of theory) of the target compound as a red solid.

[1151] 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 masked by DMSO), 2.74 (br. t, 2H), 3.24 (td, 2H), 3.98 (br. d, 2H), 4.34 (q, 2H).

[1152] LC-MS (Method 1): R t =0.82min; m / z=339 (M+H) + .

[1153] Example 83A

[1154] 5-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3,4-thiadiazole-2-carboxylic acid

[1155]

[1156] 1.52 g (4.49 mmol) of ethyl 5-[(3R)-3-methyl[1,4′-bipiperidinyl]-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 were then added to the reaction solution. The reaction solution was then stirred at room temperature for several hours. After complete conversion, the reaction solution was adjusted to pH 7 with 1N hydrochloric acid and concentrated to dryness on a rotary evaporator. This produced 2.95 g of an amber oil, which was purified by column chromatography.

[1157] Conditions: Separation was performed using approximately 1 g fractions. RP column Chromatorex C18, 10 μm; 125 x 30 mm, gradient from acetonitrile / water 10 / 90 over 38 minutes to acetonitrile / water 90 / 10 over 38 minutes, flow rate 75 ml / min.

[1158] Finally, the product-containing fractions were combined, concentrated to dryness under reduced pressure, and dried. This resulted in 487 mg (1.57 mmol, 35% of theory) of the target compound as a white solid.

[1159] LC-MS (Method 1): R t =0.39min; m / z=311 (M+H) + .

[1160] Example 84A

[1161] tert-Butyl rac-4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate

[1162]

[1163] To 7ml1,5-azaspiro [2.5] octane hydrochloride (346mg, 2.34mmol) in the initial loading of 2-dichloroethane, add N, N-diisopropylethylamine (410 μ l, 2.3mmol), and the mixture was stirred for 5 minutes, then 4-oxoazacycloheptane-1-tert-butyl formates (250mg, 1.17mmol) and acetic acid (100 μ l, 1.8mmol) were added. Then stirred at room temperature for 5 hours. Afterwards, sodium triacetoxyborohydride (298mg, 1.41mmol) was added to the mixture, it was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and washed with saturated NaHCO solution and water successively. The organic phase was passed through Na SO drying. Filter out desiccant, and concentrate the filtrate. The residue was dissolved in DMSO and purified by preparative HPLC (Instrument: Waters Prep LC / MS system, column. Phenomenex Kinetex C18 5μm 100x30mm eluent A: water eluent B: acetonitrile eluent C: 2% formic acid in water eluent D: acetonitrile / water (80% volume / 20% volume). Total flow rate: 80ml / min, room temperature, wavelength 200-400nm, on-column injection (complete injection). Gradient overview: eluent A 0-2 minutes 70ml, eluent B 0-2 minutes 0ml, eluent A 2-10 minutes from 70ml to 0ml, eluent B from 0ml to 70ml, 10-12 minutes 0ml, eluent A and 70ml, eluent B eluent C and eluent D each at a constant flow rate of 5ml / min during the entire run time). After removal of the solvent, 140 mg (39% of theory) of the title compound were obtained.

[1164] LC-MS (method 4): MS (ESIpos): m / z=309 [M+H] + .

[1165] Example 85A

[1166] rac-5-(azepan-4-yl)-5-azaspiro[2.5]octane hydrochloride

[1167]

[1168] Tert-butyl rac-4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (140 mg, 454 μmol) was dissolved in 4 ml of dichloromethane, hydrochloric acid in dioxane (570 μl, 4.0 M, 2.3 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dried under high vacuum. 139 mg (125% of theory) of the target compound were obtained.

[1169] LC-MS (Method 4): MS (ESIpos): m / z=208 [M-HCl] + .

[1170] Example 86A

[1171] tert-Butyl diamix-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate

[1172]

[1173] To 10ml1, the fluoro-5-azaspiro [2.5] octane hydrochloride (500mg, 2.72mmol) of rac-1 in 2-dichloroethane is initially loaded with N, N-diisopropylethylamine (470 μ l, 2.7mmol), and the mixture is stirred at room temperature for 5 minutes, then 4-oxoazacycloheptane-1-tert-butyl formates (290mg, 1.36mmol) and acetic acid (120 μ l, 2.0mmol) are added. The mixture is stirred at room temperature for 5 hours. After this, sodium triacetoxyborohydride (346mg, 1.63mmol) is added to the mixture, it is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane, and successively washed with saturated NaHCO solution and water. By the organic phase through Na SO drying. Filter out desiccant, and concentrated filtrate. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm. Eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile / water (80% volume / 20% volume) total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, complete injection. Gradient overview: eluent A 0-2 minutes 70 ml, eluent B 0-2 minutes 0 ml, eluent A 2-10 minutes from 70 ml to 0 ml, eluent B from 0 ml to 70 ml, 10-12 minutes 0 ml eluent A and 70 ml eluent B, eluent C and eluent D each at a constant flow rate of 5 ml / min over the entire run time). The fractions containing the product were combined and lyophilized. This gave 292 mg (62% of theory) of the target compound.

[1174] LC-MS (method 4): MS (ESIpos): m / z=345 [M+H] + .

[1175] Example 87A

[1176] diamix-5-(azepan-4-yl)-1,1-difluoro-5-azaspiro[2.5]octane dihydrochloride

[1177]

[1178] To a solution of tert-butyl diamix-4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (292 mg, 848 μmol) in 8 ml of dichloromethane was added hydrochloric acid in dioxane (1.1 ml, 4.0 M, 4.2 mmol), and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum to obtain 194 mg (72% of theory) of the target compound.

[1179] LC-MS (Method 4): MS (ESIpos): m / z=245 [M-2HCl] + .

[1180] Example 88A

[1181] tert-Butyl diamix-(3R)-2′,3-dimethyl[1,4′-bipiperidinyl]-1′-carboxylate

[1182]

[1183] To 5.8ml1, (3R)-3-methylpiperidine hydrochloride (318mg, 2.34mmol) in 2-dichloroethane, add N, N-diisopropylethylamine (410 μ l, 2.3mmol), and the mixture was stirred at room temperature for 5 minutes, then added rac-2-methyl-4-oxopiperidine-1-tert-butyl formate (250mg, 1.17mmol) and acetic acid (100 μ l, 1.8mmol). Subsequently, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (298mg, 1.41mmol) was added to the mixture, which was stirred at room temperature for another 5 hours. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO solution and water successively. The organic phase was dried over Na SO drying. Filter out desiccant, and concentrate the filtrate. Residue (340mg) was further converted without analysis.

[1184] Example 89A

[1185] diamix-(3R)-2′,3-dimethyl-1,4′-bipiperidine dihydrochloride

[1186]

[1187] Tert-butyl diamix-(3R)-2′,3-dimethyl[1,4′-bipiperidinyl]-1′-carboxylate (340 mg, 1.15 mmol) was dissolved in 16 ml of dichloromethane, hydrochloric acid in dioxane (1.4 ml, 4.0 M, 5.7 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was dried under high vacuum. The residue (290 mg) was not further converted without analysis.

[1188] Example 90A

[1189] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1190]

[1191] 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 then metered into the reaction solution, which was then stirred at reflux overnight. 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 (MN 616WA 1 / 4 fluted filter, D = 12.5 cm). The resulting filtrate was then 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 were separated into the enantiomers by chiral preparative HPLC without further purification.

[1192] LC-MS (Method 1): R t =1.42min; m / z=381(M+H) + .

[1193] Example 91A and Example 92A

[1194] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1195]

[1196] 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 the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm (SFC); eluent: CO 2 / 2-propanol 55:45; pressure: 90 bar; flow rate: 95 g / min; UV detection: 210 nm; temperature: 40° C.]:

[1197] Example 91A (Enantiomer 1):

[1198] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1199] Yield: 487 mg

[1200] R t =4.02min; chemical purity>99%;>97%ee

[1201] [Column: Chiraltek AY-3, 3 μm, 100 mm×4.6 mm; eluent: CO 2 / ethanol) 90:10; flow rate: 3 ml / min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[1202] LC-MS (Method 1): Rt=1.41 min; m / z=381 (M+H) + .

[1203] 1 H-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 masked by DMSO), 2.56-2.63 (m, 1H), 3.36 (dd, 1H), 3.60-3.67 (m, 1H), 3.96-4.04 (m, 1H), 4.05-4.11 (m, 1H), 4.55 (br.d, 2H), 7.87-7.94 (m, 2H), 7.938.47 (d, 1H), 8.76 (t, 1H).

[1204] [α]D 20 =-14.69° (c=0.440, methanol).

[1205] Example 92A (Enantiomer 2):

[1206] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide

[1207] Yield: 476 mg

[1208] R t =5.98min; chemical purity>99%;>97%ee

[1209] [Column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; eluent: CO₂ / ethanol 90:10; flow rate: 3 ml / min; pressure: 130 bar; temperature: 40°C; UV detection: 210 nm].

[1210] LC-MS (Method 1): R t =1.41min; m / z=381(M+H) + .

[1211] 1 H-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 masked by DMSO), 2.55-2.63 (m, 1H), 3.36 (dd, 1H), 3.60-3.67 (m, 1H), 3.96-4.03 (m, 1H), 4.04-4.11 (m, 1H), 4.55 (br.d, 2H), 7.87-7.94 (m, 2H), 7.938.47 (d, 1H), 8.76 (t, 1H).

[1212] [α]D 20 =+11.64° (c=0.435, methanol).

[1213] Example 93A

[1214] Diamix-cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[1215]

[1216] (3R)-3-methylpiperidine hydrochloride (1000mg, 4.04mmol) in 25ml dichloromethane is initially loaded with N, N-diisopropylethylamine (1.41ml, 8.1mmol), and the mixture is stirred at room temperature for 5 minutes, then add rac-3-methyl-4-oxopiperidine-1-benzyl formate (1.1g, 8.1mmol) and acetic acid (0.35ml, 6.1mmol).Then sodium triacetoxyborohydride (1.03g, 4.85mmol) is added to the mixture, and it is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane, and successively used saturated NaHCO solution and water washing. With the organic phase through Na SO drying. Filter out desiccant, and concentrated filtrate. The gained residue is dissolved in the mixture of 18ml acetonitrile+MeOH, and with preparation HPLC purifying.

[1217] Method: Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm.

[1218] Eluent A: water, eluent B: acetonitrile, eluent C: 1% ammonia in water; total flow rate: 80 ml / min, 40°C, wavelength 210 nm.

[1219] Gradient overview: Eluent A 0 to 4 min 25%, Eluent B 0 to 4 min 70%, Eluent C 0 to 4 min 5%. Eluent A 4 to 4.71 min 0%, Eluent B 4 to 4.71 min 95%, Eluent C 4 to 4.71 min 5%. Eluent A 4.71 to 4.78 min 25%, Eluent B 4.71 to 4.78 min 70%, Eluent C 4.71 to 4.78 min 5%.

[1220] After removal of the solvent, 716 mg (2.13 mmol, 98% purity, 53% of theory) of the title compound were obtained.

[1221] 1 H-NMR (600MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, included in 0.82 (d, 3H)), 1.22-1.33 (m, 1H), 1.33-1.44 (m, 1H), 1.44-1.55 (m, 2H), 1 .55-1.66(m, 2H), 1.66-1.78(m, 2H), 1.98-2.16(m, 2H), 2.60-2.96(m, 4H), 3.88(br.d, 1H), 4.07(br.d, 1H), 5.06(S, 2H), 7.27-7.41(m, 5H).

[1222] Example 94A and Example 95A

[1223] cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester (diastereomers 1 and 2)

[1224]

[1225] 716 mg (2.17 mmol) of the cis-diastereoisomer mixture diamix-cis-benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylate were separated into 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.]:

[1226] Example 94A (cis diastereomer 1):

[1227] cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[1228] Yield: 287 mg

[1229] R t =7.44min; chemical purity>99%;>99%de

[1230] [Column: Chiralpak AY-H, 5 μm, 250 mm x 4.6 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 1 ml / min; temperature: 30°C; UV detection: 220 nm].

[1231] LC-MS (Method 1): R t =1.02min; m / z=331(M+H) + .

[1232] 1H-NMR (600MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, included in 0.82 (d, 3H)), 1.22-1.33 (m, 1H), 1.33-1.44 (m, 1H), 1.44-1.55 (m, 2H), 1 .55-1.66(m, 2H), 1.66-1.78(m, 2H), 1.98-2.16(m, 2H), 2.60-2.96(m, 4H), 3.88(br.d, 1H), 4.07(br.d, 1H), 5.06(S, 2H), 7.27-7.41(m, 5H).

[1233] Example 95A (cis diastereomer 2):

[1234] cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylic acid benzyl ester

[1235] Yield: 135 mg

[1236] R t =8.06min; chemical purity>99%;>99%de

[1237] [Column: Chiralpak AY-H, 5 μm, 250 mm x 4.6 mm; eluent: n-heptane / (ethanol + 0.2% diethylamine) 95:5; flow rate: 1 ml / min; temperature: 30°C; UV detection: 220 nm].

[1238] LC-MS (Method 1): R t =1.02min; m / z=331(M+H) + .

[1239] 1 H-NMR (600MHz, DMSO-d6, δ / ppm): 0.76 (d, 3H), 0.79-0.89 (m, 4H, included in 0.83 (d, 3H)), 1.22-1.32 (m, 1H), 1.33-1.43 (m, 1H), 1.46-1.55 (m, 2H), 1 .55-1.67(m, 2H), 1.67-1.76(m, 2H), 2.00-2.15(m, 2H), 2.62-2.99(m, 4H), 3.88(br.d, 1H), 4.07(br.d, 1H), 5.06(S, 2H), 7.27-7.40(m, 5H).

[1240] Example 96A

[1241] cis-(3R)-3,3′-dimethyl-1,4′-bipiperidine dihydrobromide (diastereomer 1)

[1242]

[1243] 280 mg (0.85 mmol) of benzyl cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylate (diastereomer 1; Example 94A) were dissolved in 5 ml of an HBr / glacial acetic acid mixture while cooling with ice and stirred at 0° C. for 15 minutes. The ice bath was then removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with diethyl ether, and the precipitate formed was filtered off with suction, washed repeatedly with diethyl ether, and dried under high vacuum. This gave 260 mg (0.73 mmol, 86% of theory) of the title compound, which was converted further without further analysis.

[1244] Example 97A

[1245] cis-(3R)-3,3′-dimethyl-1,4′-bipiperidine dihydrobromide (diastereomer 2)

[1246]

[1247] 130 mg (0.39 mmol) of benzyl cis-(3R)-3,3′-dimethyl[1,4′-bipiperidinyl]-1′-carboxylate (diastereomer 2; Example 95A) were dissolved in 3 ml of an HBr / glacial acetic acid mixture while cooling with ice and stirred at 0° C. for 15 minutes. The ice bath was then removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with diethyl ether, and the precipitate formed was filtered off with suction, washed repeatedly with diethyl ether, and dried under high vacuum. This gave 124 mg (0.35 mmol, 88% of theory) of the title compound, which was converted further without further analysis.

[1248] Working Example:

[1249] Example 1

[1250] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1251]

[1252] 13 g (38.91 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 8.51 g (38.91 mmol) of (3R)-3-methyl-1,4′-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Reg. No. 1799475-27-6), and 20.62 g (194.53 mmol) of sodium carbonate were heated to 120°C in 200 ml of water and stirred at this temperature overnight. After the reaction mixture cooled, the solution was extracted with ethyl acetate. The separated organic phase was then filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The resulting residue was taken up in acetonitrile, heated to 80°C, and slowly cooled back to room temperature with stirring. The precipitated solid is filtered off with suction and washed with acetonitrile. The residue is then taken up in acetonitrile and recrystallized again. This produces 10.75 g (24.68 mmol, 63% of theoretical value) of the target compound as a light beige solid. The two mother liquors are combined and concentrated to dryness on a rotary evaporator. The resulting residue is further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column mobile phase: dichloromethane → gradient 20 CV (CV = column volume) → dichloromethane / methanol 9: 1). The resulting product fractions are then combined, concentrated on a rotary evaporator and recrystallized from acetonitrile. This produces another 3.28 g (7.48 mmol, 19% of theoretical value) of the target compound as a light beige solid.

[1253] 1 H-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 masked by DMSO), 2.69-2.77 (m, 2H), 3.04 (td, 2H), 3.93 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (s, 1H), 7.88-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1254] LC-MS (Method 4): R t =0.50min; m / z=436 (M+H) + .

[1255] [α] D 20 =-8.06° (c=0.430, methanol).

[1256] Example 2

[1257] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1258]

[1259] 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 a sealed container in 1 ml of water and stirred at this temperature for 30 minutes. After the reaction mixture cooled, water was added, and the solution was extracted with dichloromethane. The separated organic phase was then filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The resulting residue was further purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column, mobile phase: ethyl acetate → gradient 5 CV (CV = column volume) → ethyl acetate / methanol 95:5). The resulting product fractions were then combined and concentrated to dryness on a rotary evaporator. This resulted in 62.7 mg (0.13 mmol, 74% of theory) of the target compound as a yellow solid.

[1260] 1 H-NMR (600MHz, 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, 2 H), 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).

[1261] LC-MS (Method 1): R t =0.97min; m / z=470 (M+H) + .

[1262] Example 3

[1263] 2-[3-(Cyclopropylmethyl)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemic)

[1264]

[1265] 32 mg (0.10 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 22 mg (0.10 mmol) of 3-(cyclopropylmethyl)-1,4′-bipiperidine (racemate), and 31 mg (0.29 mmol) of sodium carbonate were heated to 120° C. in a sealed container in 1 ml of water and stirred at this temperature for 30 minutes. After the reaction mixture had cooled, the solution was extracted with dichloromethane. The separated organic phase was subsequently filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D=12.5 cm), dried, and concentrated to dryness on a rotary evaporator. The resulting residue was purified by the following method.

[1266] Method 7: Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1267] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1268] Gradient overview: Mobile phase A 0 to 2 min 47 ml, Mobile phase B 0 to 2 min 23 ml, Mobile phase A 2 to 10 min from 47 ml to 23 ml and Mobile phase B from 23 ml to 47 ml. 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1269] This gave 40.8 mg (0.09 mmol, 88% of theory) of the target compound in the form of a white lyophilisate.

[1270] 1H-NMR (400MHz, 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 masked by DMSO), 2.73 (br.d, 1H), 2.83 (br.d, 1H), 3.04 (br.t, 2H), 3.94 (br.d, 2H), 4.52 (br.d, 2H), 7.83 (s, 1H), 7.87-7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1271] LC-MS (Method 1): R t =1.13min; m / z=476 (M+H) + .

[1272] Prepared analogously to Examples 1 to 3 from the starting materials described in each case Examples 4 to 14 The following compounds:

[1273]

[1274]

[1275]

[1276]

[1277] Example 15

[1278] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methoxy[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1279]

[1280] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were 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 were then metered in, and the reaction solution was stirred at room temperature overnight. The reaction mixture was subsequently diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase was separated off, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1281] Method 8:

[1282] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1283] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1284] Gradient overview: Mobile phase A 0 to 2 min 63 ml, Mobile phase B 0 to 2 min 7 ml, Mobile phase A 2 to 10 min from 63 ml to 39 ml and Mobile phase B from 7 ml to 31 ml. 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1285] This gave 62 mg (0.14 mmol, 48% of theory) of the target compound as a white lyophilisate.

[1286] 1H-NMR (600MHz, 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, IH), 1.77(br.d, 2H), 1.86-1.93(m, 1H), 1.98(t, 1H), 2.11(t, 1H), 2.47-2.58(m, 1H, partially masked by DMSO), 2.64 (br.d, 1H), 2.94 (br.d, 1H), 3.04 (br.t, 2H), 3.12-3.19 (m, 1H), 3.23 (s, 3H), 3.94 (br.d, 2H), 4.53 (br.d, 2H), 7.83 (s, 1H), 7.91 (td, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1287] LC-MS (Method 1): R t =0.83min; m / z=452 (M+H) + .

[1288] Example 16

[1289] 2-[3-(Difluoromethoxy)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemic)

[1290]

[1291] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were dissolved in 5 ml of dichloromethane, and 86 mg (0.57 mmol) of 3-(difluoromethoxy)piperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride were then metered in, and the reaction solution was stirred at room temperature overnight. The reaction mixture was subsequently diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase was separated off, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN616 WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1292] Method 9:

[1293] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1294] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1295] Gradient overview: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1296] This gave 60 mg (0.12 mmol, 44% of theory) of the target compound as a white lyophilisate.

[1297] 1 H-NMR (600MHz, 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), 4.5 3(d, 2H), 6.57-6.88(m, 1H), 7.83(S, 1H), 7.91(t, 1H), 8.47(d, 1H), 8.72(t, 1H).

[1298] LC-MS (Method 1): R t =0.91min; m / z=488 (M+H) + .

[1299] Example 17

[1300] N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl[1,4′-bipiperidinyl]-1′-yl)-1,3-thiazole-5-carboxamide (racemic)

[1301]

[1302] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were dissolved in 5 ml of dichloromethane, and 64 mg (0.57 mmol) of 3-ethylpiperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride were then metered in, and the reaction solution was stirred at room temperature overnight. The reaction mixture was subsequently diluted with dichloromethane and washed with sodium bicarbonate solution. Finally, the organic phase was separated off, and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D = 12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1303] Method 7:

[1304] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1305] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1306] Gradient overview: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1307] This gave 46 mg (0.10 mmol, 36% of theory) of the target compound as a white lyophilisate.

[1308] 1H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.87 (m, 4H, including 0.85 (t, 3H)), 1.09-1.25 (m, 2H), 1.26-1.34 (m, 1H), 1.34-1.43 (m, 1H), 1.44-1.53 ​​(m, 2H), 1.55-1.62 (m, 1H), 1.65-1.71 (m, 1H), 1.73-1.83 (m, 3H), 2.08 (br.t 1H), 2.46-2.56 (m, 1H, partially masked by DMSO), 2.70-2.79 (m, 2H), 3.04 (br. t, 2H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 7.82 (s, 1H), 7.89 (br. t, 1H), 8.46 (d, 1H), 8.67 (t, 1H).

[1309] LC-MS (Method 1): R t =0.99min; m / z=450 (M+H) + .

[1310] Example 18

[1311] 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-5-carboxamide

[1312]

[1313] 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′-bipiperidinyl]-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. 0.34 ml (0.58 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide) in ethyl acetate was then 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 then extracted with water and dichloromethane. Finally, the organic phase was separated and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1314] Method 7:

[1315] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1316] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1317] Gradient overview: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1318] This gave 55 mg (0.12 mmol, 23% of theory) of the target compound as a white lyophilisate.

[1319] 1 H-NMR (400 MHz, DMSO-d6, δ / ppm): 0.74-0.89 (m, 4H, included in 0.82 (d, 3H)), 1.34-1.68 (m, 6H), 1.70-1.84 (m, 3H), 1.99-2.11 (m, 1H), 2.44-2.58 (m, 1H, partially masked by DMSO), 2.69-2.80 (m, 2H), 3.06 (td, 2H), 3.95 (br.d, 2H), 4.59 (d, 2H), 7.62 (s, 1H), 7.67 (d, 1H), 7.87 (s, 1H), 8.81 (d, 1H), 8.89 (t, 1H).

[1320] LC-MS (Method 1): R t =1.05min; m / z=469 (M+H) + .

[1321] Example 19

[1322] 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[1323]

[1324] 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride were dissolved in 10 ml of dichloromethane, 56 mg (0.42 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-amine were added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 60 μl of pyridine and then 46 mg (0.26 mmol) of 1-[3-(trifluoromethyl)phenyl]methanamine were metered into the reaction solution, and the mixture was stirred at room temperature overnight. After adding water, the resulting precipitate was filtered off with suction. The resulting biphasic filtrate was separated, and the resulting organic phase was filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1325] Method 11:

[1326] Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm x 30 mm; mobile phase: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B→95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B→10% B, 35.5-36.5 min 10% B; flow rate: 50 ml / min; room temperature; UV detection: 210 nm.

[1327] This gave 45 mg (0.10 mmol, 37% of theory) of the target compound.

[1328] 1 H-NMR (600MHz, DMSO-d6, δ / ppm): 0.78-0.91 (m, 4H, included in 0.83 (d, 3H)), 1.37-1.69 (m, 6H), 1.73-1.94 (m, 3H), 2.05-2.23 (m, 1H), 2 .56-2.67 (m, 1H), 2.73-2.90 (m, 2H), 3.06 (br.t, 2H), 3.96 (br.d, 2H), 4.48 (d, 2H), 7.54-7.65 (m, 4H), 7.84 (S, 1H), 8.84 (t, 1H).

[1329] LC-MS (Method 1): Rt=1.31 min; m / z=467 (M+H) + .

[1330] Example 20

[1331] N-[(3-fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1332]

[1333] 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′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 47 mg (0.29 mmol) of 1-(3-fluoropyridin-2-yl)methanamine hydrochloride (1:1) in 10 ml of acetonitrile. 0.17 ml (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and dichloromethane. Finally, the organic phase was separated and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN616 WA 1 / 4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1334] Method 9:

[1335] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1336] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1337] Gradient overview: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1338] This gave 5.4 mg (0.01 mmol, 5% of theory) of the target compound as a white lyophilisate.

[1339] 1H-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 masked by DMSO), 2.69-2.80 (m, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.56 (dd, 2H), 7.36-7.43 (m, 1H), 7.64-7.72 (m, 1H), 7.84 (s, 1H), 8.38 (dt, 1H), 8.69 (t, 1H).

[1340] LC-MS (Method 4): Rt=0.48 min; m / z=418 (M+H) + .

[1341] Example 21

[1342] N-(5-chloro-2-fluorobenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1343]

[1344] 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′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 46 mg (0.29 mmol) of 1-(5-chloro-2-fluorophenyl)methanamine in 10 ml of acetonitrile. 0.17 ml (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and dichloromethane. Finally, the organic phase was separated and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616 WA 1 / 4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1345] Method 7:

[1346] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1347] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1348] Gradient overview: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1349] This resulted in 45 mg of the 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 15 CV (CV = column volume)→ cyclohexane / ethyl acetate 2:8). This resulted in 16 mg (0.04 mmol, 14% of theory) of the target compound as a beige solid.

[1350] 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 masked by DMSO), 2.74 (br.t, 2H), 3.05 (td, 2H), 3.94 (br.d, 2H), 4.41 (d, 2H), 7.26 (t, 1H), 7.33-7.40 (m, 2H), 7.85 (s, 1H), 8.76 (t, 1H).

[1351] LC-MS (Method 4): R t =0.68min; m / z=451 / 453(M+H) + .

[1352] Example 22

[1353] 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[1354]

[1355] 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′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 59 mg (0.34 mmol) of 1-[4-(trifluoromethyl)phenyl]methanamine in 10 ml of acetonitrile. 0.2 ml (0.34 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and dichloromethane. Finally, the organic phase was separated and the resulting organic solution was filtered through a hydrophobic filter (folded filter MN 616 WA1 / 4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The resulting residue was purified by the following method.

[1356] Method 10:

[1357] Instrument: Waters Prep LC / MS system, column: XBridge C18 5μm 100x30mm

[1358] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength 200-400 nm, on-column injection (complete injection)

[1359] Gradient overview: mobile phase A 0 to 2 min 39 ml, mobile phase B 0 to 2 min 31 ml, mobile phase A 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time.

[1360] This gave 25 mg (0.05 mmol, 17% of theory) of the target compound as a white lyophilisate.

[1361] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 0.74-0.89 (m, 4H, included in 0.82 (d, 3H)), 1.33-1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.00-2.10 (m, 1H), 2.45-2.57 (m, 1H, partially masked by DMSO), 2.70-2.79 (m, 2H), 3.06 (td, 2H), 3.94 (br.d, 2H), 4.47 (d, 2H), 7.50 (d, 2H), 7.70 (d, 2H), 7.84 (s, 1H), 8.83 (t, 1H).

[1362] LC-MS (Method 1): R t =1.27min; m / z=467 (M+H) + .

[1363] Prepared analogously to Examples 18 to 22 from the starting materials described in each case Examples 23 to 37 The following compounds:

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370] Example 38 and Example 39

[1371] 2-[3-(Difluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1372]

[1373] 203 mg (0.43 mmol) of racemic 2-[3-(difluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 4) were separated into the 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.]:

[1374] Example 38 (Enantiomer 1):

[1375] 2-[(3S)-3-(Difluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1376]

[1377] Yield: 97 mg

[1378] Rt = 4.93 min; chemical purity > 99%; > 99% ee

[1379] [Column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; mobile phase: isohexane / 2-propanol + 0.2% diethylamine 20:80; flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1380] LC-MS (Method 5): Rt=1.52 min; m / z=472 (M+H) + .

[1381] Example 39 (Enantiomer 2):

[1382] 2-I(3R)-3-(difluoromethyl)I1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1383]

[1384] Yield: 101 mg

[1385] R t =6.03min; chemical purity>96%;>94%ee

[1386] [Column: Chiraltek AY-3, 3 μm, 100 mm x 4.6 mm; mobile phase: isohexane / 2-propanol + 0.2% diethylamine 20:80; flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1387] LC-MS (Method 5): R t =1.52min; m / z=472 (M+H) + .

[1388] 1 H-NMR (600MHz, 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, part d, 1H), 7.84 (s, 1H), 7.93 (td, 1H), 8.47 (d, 1H), 8.75 (t, 1H).

[1389] Example 40 and Example 41

[1390] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1391]

[1392] 144 mg (0.32 mmol) of racemic N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Example 6) were separated into the 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.]:

[1393] Example 40 (Enantiomer 1):

[1394] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3S)-3-(fluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1395]

[1396] Yield: 71 mg

[1397] R t =10.94min; chemical purity 99%; 99% ee

[1398] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 40°C; UV detection: 235 nm].

[1399] LC-MS (Method 1): R t =0.85min; m / z=454 (M+H) + .

[1400] Example 41 (Enantiomer 2):

[1401] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-(fluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1402]

[1403] Yield: 70 mg

[1404] R t =12.21min; chemical purity 99%; 99% ee

[1405] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 40°C; UV detection: 235 nm].

[1406] LC-MS (Method 1): R t =0.84min; m / z=454 (M+H) + .

[1407] 1H-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 masked by DMSO), 2.65-2 .76(m, 1H), 2.80(br.d, 1H), 3.05(br.t, 2H), 3.94(br.d, 2H), 4.19-4.29(m, 1H), 4.31- 4.41 (m, 1H), 4.53 (br.d, 2H), 7.83 (S, 1H), 7.87-7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[1408] Example 42 and Example 43

[1409] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1410]

[1411] 143 mg (0.29 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Example 5) were separated into the 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.]:

[1412] Example 42 (Enantiomer 1):

[1413] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3S)-3-(trifluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1414]

[1415] Yield: 67 mg

[1416] Rt = 11.22 min; chemical purity 99%; 99% ee

[1417] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 50°C; UV detection: 235 nm].

[1418] LC-MS (Method 1): R t =0.97min; m / z=490 (M+H) + .

[1419] Example 43 (Enantiomer 2):

[1420] N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-(trifluoromethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1421]

[1422] Yield: 67 mg

[1423] R t =11.87min; chemical purity 99%; >96%ee

[1424] [Column: Daicel Chiralcel IG, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 50°C; UV detection: 235 nm].

[1425] LC-MS (Method 1): R t =0.96min; m / z=490 (M+H) + .

[1426] 1 H-NMR (500MHz, 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).

[1427] Example 44 and Example 45

[1428] 2-{3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidinyl]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1429]

[1430] 251 mg (0.46 mmol) of 2-{3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidinyl]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 7) were separated into the 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.]:

[1431] Example 44 (Enantiomer 1):

[1432] 2-{(3R)-3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidinyl]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1433]

[1434] Yield: 93 mg

[1435] R t =1.50min; chemical purity>99%; 99%ee

[1436] [Column: Phenomenex Cellulose-1, 3 μm, 50 mm x 4.6 mm; mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1437] LC-MS (Method 4): R t =0.63min; m / z=542 (M+H) + .

[1438] Example 45 (Enantiomer 2):

[1439] 2-{(3S)-3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidinyl]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1440]

[1441] Yield: 86 mg

[1442] R t =2.21min; chemical purity>99%; 99%ee

[1443] [Column: Phenomenex Cellulose-1, 3 μm, 50 mm x 4.6 mm; mobile phase: n-heptane / 2-propanol + 0.2% diethylamine); flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1444] LC-MS (Method 4): Rt=0.62 min; m / z=542 (M+H) + .

[1445] 1H-NMR (400MHz, 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).

[1446] Example 46 and Example 47

[1447] N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (diastereomers 1 and 2)

[1448]

[1449] 51 mg (0.11 mmol) of the diastereomeric mixture N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Example 30) were separated into the 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.]:

[1450] Example 46 (Diastereomer 1):

[1451] Yield: 20 mg

[1452] R t =1.32min; chemical purity>99%; 99%ee

[1453] [Column: Daicel Chiralpak OX-3, 3 μm, 50 mm x 4.6 mm; mobile phase: n-heptane / ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1454] LC-MS (Method 1): R t =1.22min; m / z=449 (M+H) + .

[1455] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.87 (m, 4H, included in 0.82 (d, 3H)), 1.34-1.66 (m, 9H, included in 1.42 (d, 3H)), 1.70-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.56 (m, 1H, partially masked by DMSO), 2.68-2.80 (m, 2H), 3.00-3.09 (m, 2H), 3.95 (br.t, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.19-7.25 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).

[1456] Example 47 (Diastereomer 2):

[1457] Yield: 19 mg

[1458] R t =1.78min; chemical purity>99%; 99%ee

[1459] [Column: Daicel Chiralpak OX-3, 3 μm, 50 mm x 4.6 mm; mobile phase: n-heptane / ethanol + 0.2% diethylamine; flow rate: 1 ml / min; temperature: 25°C; UV detection: 220 nm].

[1460] LC-MS (Method 1): R t =1.19min; m / z=449 (M+H) + .

[1461] 1 H-NMR (600 MHz, DMSO-d6, δ / ppm): 0.76-0.89 (m, 4H, included in 0.82 (d, 3H)), 1.34-1.67 (m, 9H, included in 1.42 (d, 3H)), 1.72-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.60 (m, 1H, partially masked by DMSO), 2.69-2.81 (m, 2H), 3.05 (br.t, 2H), 3.89-4.00 (m, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.18-7.26 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).

[1462] Example 48

[1463] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1464]

[1465] 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 then concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min over the entire run time). The fractions containing the product were combined and lyophilized. This gave 60.0 mg (100% purity, 35% of theory) of the target compound.

[1466] LC-MS (Method 4): Rt=0.51 min; MS (ESIpos): m / z=466 [M+H] + .

[1467] 1H-NMR (600MHz, DMSO-d6) δ [ppm]: 0.903 (0.47), 0.918 (0.53), 1.389 (0.42), 1.409 (0.44), 1.432 (0.44), 1.44 5(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), 2.80 9(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).

[1468] Example 49

[1469] N-[(3,5-difluoropyridin-2-yl)methyl]-3-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,2,4-oxadiazole-5-carboxamide

[1470]

[1471] N,N-Diisopropylethylamine (44 μl, 250 mmol) and propylphosphonic anhydride (66 μl, 50% in ethyl acetate, 110 μmol) were added to a solution of 3-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,2,4-oxadiazole-5-carboxylic acid (25.0 mg, 84.9 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (24.0 mg, 110 μmol) in 1 ml of acetonitrile, and the mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 7.00 mg (100% purity, 20% of theory) of the target compound.

[1472] LC-MS (Method 1): R t =0.96min; MS (ESIpos): m / z=421[M+H] + .

[1473] 1H-NMR (600MHz, 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(2.4 7), 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).

[1474] Example 50

[1475] diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1476]

[1477] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (142 mg, 519 μmol) were combined and stirred in 1.2 ml of sodium carbonate solution (1.2 ml, 2.0 M, 2.4 mmol) at 120° C. for 30 minutes. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min over the entire run time). The product-containing fractions were combined and lyophilized. This gave 192 mg (100% purity, 70% of theory) of the target compound.

[1478] LC-MS (Method 4): R t =0.54min; MS (ESIpos): m / z=454[M+H] + .

[1479] 1H-NMR(600MHz,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)。

[1480] Example 51

[1481] ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1482]

[1483] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide were separated into stereoisomers by chiral HPLC (preparative HPLC: column Chiralpak IA, 5 μm, 250x20 mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 20 ml / min; temperature 60°C, detection: 220 nm). The stereoisomer with a retention time of 7.873 minutes was collected (HPLC column Chiralpak IE 5 μm (flow rate 1 ml / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60° C.; detection: 220 nm). The solvent was removed to yield 88 mg (99% ee) of the title compound.

[1484] LC-MS (Method 1): R t =0.93min; MS (ESIpos): m / z=454[M+H] + .

[1485] 1 H.NMR (500MHz, DMSO-d6) δ [ppm]: δ8.72 (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), 1.94-1.8 3(m, 2H), 1.70-1.51(m, 4H), 1.43-1.33(m, 1H), 0.88-0.78(m, 1H), 0.82(d, 3H).

[1486] Example 52

[1487] ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1488]

[1489] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide were separated into stereoisomers by chiral HPLC (preparative HPLC: column Chiralpak IA, 5 μm, 250x20 mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 20 ml / min; temperature 60°C, detection: 220 nm). The stereoisomer with a retention time of 10.179 minutes was collected (HPLC column Chiralpak IE 5 μm (flow rate 1 ml / min; mobile phase: 100% ethanol + 0.2% diethylamine; temperature 60° C.; detection: 220 nm). The solvent was removed to yield 91 mg (99% ee) of the title compound.

[1490] LC-MS (Method 1): R t =0.93min; MS (ESIpos): m / z=454[M+H] + .

[1491] 1 H.NMR (500MHz, DMSO-d6) δ [ppm]: δ8.72 (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).

[1492] Example 53

[1493] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1494]

[1495] N, N-diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) are added successively to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-4-methylazepane (32.1 mg, 284 μmol) in 2.5 ml of dichloromethane, and the mixture is stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) is added, and the mixture is continued to stir at room temperature. After 2 hours, saturated NaHCO solution is added, and the reaction mixture is extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator, and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 43.0 mg (100% purity, 67% of theory) of the title compound.

[1496] LC-MS (method 1): Rt = 0.98 min; MS (ESIpos): m / z = 450 [M+H] + .

[1497] 1H-NMR (600MHz, 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), 1.43 8(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), 2.5 19(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).

[1498] Example 54

[1499] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(3-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1500]

[1501] 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 2.5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and the mixture was continued to stir at room temperature. After 2 hours, 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 (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min over the entire run time). The product-containing fractions were combined and lyophilized. This gave 40.0 mg (100% purity, 63% of theory) of the target compound.

[1502] LC-MS (Method 1): R t =0.97min; MS (ESIpos): m / z=450[M+H] +

[1503] H-NMR (600MHz, 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), 2.5 78(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).

[1504] Example 55

[1505] diamix-N-[1-(3,5-difluoropyridin-2-yl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1506]

[1507] N,N-Diisopropylethylamine (182 μl, 105 μmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-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 5 ml of acetonitrile, 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 (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 12.0 mg (100% purity, 10% of theory) of the target compound.

[1508] LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m / z = 450 [M+H] + .

[1509] H-NMR (600MHz, DMSO-d6) δ [ppm]: 0.788 (0.72), 0.811 (14.96), 0.822 (16.00), 0.84 3(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), 3.91 3(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).

[1510] Example 56

[1511] N-[(5-chloro-1,3-thiazol-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1512]

[1513] N,N-Diisopropylethylamine (230 μl, 1.3 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-chloro-1,3-thiazol-2-yl)methanamine hydrochloride (53.2 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred 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 (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min over the entire run time). The fractions containing the product were combined and lyophilized. This gave 14.0 mg (100% purity, 12% of theory) of the target compound.

[1514] LC-MS (Method 1): R t =1.00min; MS (ESlpos): m / z=440[M+H] + .

[1515] 1H-NMR (400MHz, DMSO-d6) δ [ppm]: -0.149 (0.78), 0.146 (0.87), 0.811 (14.60), 0.827 (16.00), 1.47 5(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), 2.3 66(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).

[1516] Example 57

[1517] N-[(5-Fluoro-2-thienyl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1518]

[1519] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-fluoro-2-thienyl)methanamine (37.7 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred 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 (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min over the entire run time). The fractions containing the product were combined and lyophilized. This gave 12.0 mg (100% purity, 11% of theory) of the target compound.

[1520] LC-MS (method 1): Rt = 1.09 min; MS (ESIpos): m / z = 423 [M+H] + .

[1521] 1H-NMR (600MHz, DMSO-d6) δ [ppm]: 0.783 (0.52), 0.790 (0.59), 0.813 (15.03), 0.824 (16.00), 0.843 (0.57), 0.8 50(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(1.8 8), 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).

[1522] Example 58

[1523] 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide

[1524]

[1525] N, N-diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(pyridin-4-yl)methylamine (31.1 mg, 288 μmol) in 5 ml of acetonitrile, 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. (Instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The product-containing fractions were combined and lyophilized. This yielded 7.00 mg (100% purity, 7% of theory) of the target compound.

[1526] LC-MS (Method 1): R t =0.48min; MS(ESIneg): m / z=398[MH]-.

[1527] 1H-NMR (400MHz, 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), 1.38 7(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), 1.7 83(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).

[1528] Example 59

[1529] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidinyl]-1′-yl}-1,3-thiazole-5-carboxamide

[1530]

[1531] 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 at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 56.0 mg (100% purity, 30% of theory) of the target compound.

[1532] LC-MS (Method 5): Rt=1.64 min; MS (ESIpos): m / z=534 [M+H] + .

[1533] 1H-NMR (600MHz, 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), 2.51 3(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).

[1534] Example 60

[1535] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1536]

[1537] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (75.5 mg, 226 μmol) and rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride (133 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 10.5 mg (100% purity, 9% of theory) of the target compound.

[1538] LC-MS (Method 5): Rt=1.65 min; MS (ESIpos): m / z=538 [M+H] + .

[1539] 1 H-NMR (600MHz, DMSO-d6) δ [ppm]: 0.500 (0.62), 0.507 (0.85), 0.526 (0.86), 0.5 31(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).

[1540] Example 61

[1541] rac-2-[3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1542]

[1543] 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 at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 μm 100×30 mm; mobile phase: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, 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: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Mobile phase C and mobile phase D were each at a constant flow rate of 5 ml / min throughout the run time). The fractions containing the product were combined and lyophilized. This gave 49.8 mg (100% purity, 30% of theory) of the target compound.

[1544] LC-MS (Method 5): R t =1.71min; MS(ESIpos): m / z=556[M+H] + .

[1545] 1H-NMR (600MHz, 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(0.7 2), 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).

[1546] Example 62

[1547] rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidinyl]-1′-yl]-1,3-thiazole-5-carboxamide

[1548]

[1549] 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 at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na2SO4, the drying agent was filtered off, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC / MS system, co...

Claims

1. Compounds of formula (I) in X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h'), i'), j') or k), where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine, wherein the thienyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine, wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R2 represents hydrogen, (C1-C4)-alkyl; Wherein the (C1-C4)-alkyl radical may be substituted up to three times by halogen, or Together with the carbon atom to which R2 is attached, it forms a (C3-C4)-cycloalkyl ring, R3 represents hydrogen, (C1-C4)-alkyl, Wherein the (C1-C4)-alkyl radical may be substituted up to three times by halogen, R4 in CR4 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, halogen; wherein the (C1-C4)-alkyl radical may be up to three times substituted by halogen and the phenyl radical may be substituted by halogen, R5 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, and R6 represents a radical of the formula a), b), c), d), e), f) or g) where *** indicates the connection to the adjacent piperidine ring, wherein R7 represents hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkyloxy, phenyl, Wherein (C1-C4)-alkyl may be (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy substituted and up to trisubstituted by halogen, wherein the (C1-C4)-alkoxy radical may be substituted by a (C3-C4)-cycloalkyl radical and may be substituted up to three times by halogen, where (C3-C4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen, where (C1-C4)-alkoxy may be substituted by (C3-C4)-cycloalkyl and up to trisubstituted by halogen, Wherein (C3-C4)-cycloalkyl may be mono- or di-substituted by halogen, Wherein the (C3-C4)-cycloalkoxy group may be up to disubstituted by halogen, wherein R8 represents hydrogen or fluorine, wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; Wherein the (C1-C4)-alkyl group may be substituted by a (C1-C4)-alkoxy group, n represents 0 or 1, m represents 0, 1 or 2, p represents 0, 1 or 2 and q represents 0, 1 or 2, and its salts.

2. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h'), i'), j') or k), where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine, wherein the thienyl group may be substituted by 1 to 2 substituents independently selected from fluorine and chlorine, wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (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 group may be substituted by halogen. R5 represents hydrogen, (C1-C2)-alkyl, methoxy, fluorine; R6 represents a group of formula a), b), c) or e), where *** indicates the connection to the adjacent piperidine ring, wherein R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, Wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and may be substituted up to two times by fluorine, The methoxy group can be substituted by cyclopropyl, cyclobutyl or trifluoromethyl. The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl. The cyclobutyl group may be substituted with fluorine up to two times. The n-butoxy group may be substituted with fluorine up to two times. Wherein (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times, Wherein the (C3-C4)-cycloalkoxy group may be up to disubstituted by fluorine, wherein R8 or R'8 independently represent hydrogen or fluorine, wherein R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine or chlorine; n represents 0 or 1 and m represents 1 or 2, q represents 0 or 2, and its salts.

3. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h'), i'), j') or k), where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and R1 represents pyridyl, pyrazolyl, thiazolyl, thienyl, phenyl, wherein the pyridyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by 1 to 2 substituents independently selected from (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, The thiazolyl group may be substituted with chlorine. The thienyl group may be substituted with fluorine. wherein the phenyl group may be substituted by 1 to 2 substituents independently selected from (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 group may be substituted by chlorine. R5 represents hydrogen or fluorine; R6 represents a group in formula a), b'), b"), c'), c") or e), where *** indicates the connection to the adjacent piperidine ring, wherein R7 or R'7 independently of one another represent hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, Wherein (C1-C4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutyloxy and may be substituted up to two times by fluorine, The methoxy group can be substituted by cyclopropyl, cyclobutyl or trifluoromethyl. The cyclopropyl group may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl. The cyclobutyl group may be substituted with fluorine up to two times. The n-butoxy group may be substituted with fluorine up to two times. Wherein (C1-C2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutyloxy, trifluoromethyl and Among them, cyclopropyl and cyclobutyl may be substituted with fluorine up to two times, Wherein the (C3-C4)-cycloalkoxy group may be up to disubstituted by fluorine, wherein R9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, or chlorine; n represents 0 or 1 and m means 1 or 2, and its salts.

4. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h'), i'), j') or k), where * marks the connection to the carbonyl group and ** marks the connection to the nitrogen atom of the adjacent piperidine ring and R1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R2 represents hydrogen or methyl; R3 represents hydrogen or methyl; R4 represents hydrogen, ethyl, trifluoromethyl; R5 represents hydrogen or fluorine; R6 represents a group in formula a), c') or c") where *** indicates the connection to the adjacent piperidine ring, wherein R7 and R'7 independently represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutoxymethyl, 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 and m represents 1, and its salts.

5. The compound of formula (I) according to claim 1, wherein X, Y and Z are selected so that the aromatic 5-membered ring has the structural formula h') R1 represents pyridyl, 2-ethylpyridyl, 4,6-dimethylpyridyl, 3,5-difluoropyridyl, 3-fluoropyridyl, 4-trifluoromethylpyridyl, 6-trifluoromethylpyridyl, 5-chloro-3-fluoropyridyl, 3-chloro-5-fluoropyridyl, 3-methylpyridyl, 4-methylpyridyl, 6-methylpyridyl, 3-chloropyridyl, 5-chloropyridyl, 6-trifluoromethoxypyridyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4- trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R2 represents hydrogen or methyl; R3 represents hydrogen; R5 represents hydrogen or fluorine; R6 represents a group in formula a), c') or c") where *** indicates the connection to the adjacent piperidine ring, wherein R7 and R'7 independently represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutoxymethyl, 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 and m represents 1, and its salts.

6. N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidinyl]-1'-yl]-1,3-thiazole-5-carboxamide 7. 2-[4-(5-Azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide 8.ent-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4'-bipiperidinyl]-1'-yl]-1,3-thiazole-5-carboxamide 9. 4-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4'-bipiperidinyl]-1'-yl]-1,3-thiazole-5-carboxamide 10. N-[1-(3,5-difluoropyridin-2-yl)cyclopropyl]-2-[(3R)-3-methyl[1,4'-bipiperidinyl]-1'-yl]-1,3-thiazole-5-carboxamide 11. A method for preparing a compound of formula (I) or a salt thereof, wherein X, Y, Z, R1, R2, R3, R5, R6, m and n have the meanings given in any one of claims 1 to 5, in [A] Compound of formula (II) in X, Y, Z, R1, R2, R3n have the meanings given in any one of claims 1 to 5, Hal represents a leaving group, In the presence of a base, react with a compound of formula (III) in R5 and R6 and m have the meanings given in any one of claims 1 to 5, To generate the compound of formula (IA) in X, Y, Z, R2, R3, R5, R6, n and m have the meanings given in any one of claims 1 to 5, or [B] Compound of formula (IV) in X, Y, Z, R1, R2, R3 and R5 and n and m have the meanings given in any one of claims 1 to 5, reacting with a compound of formula (V) in the presence of a reducing agent and optionally an acid H-R6(V), in R6 has the meaning given in any one of claims 1 to 5, To generate a compound of formula (IB) in X, Y, Z, R1, R2, R3, R5, R6, n and m have the meanings given in any one of claims 1 to 5, or [C] Compound of formula (VI) in X, Y, Z, R5 and R6 and m have the meanings given in any one of claims 1 to 5, In the presence of a condensing agent or an activating agent, react with a compound of formula (VII) in R1, R2 and R3 and n have the meanings given in any one of claims 1 to 5, To generate compound (IC) in X, Y, Z, R1, R2, R3, R5, R6, n and m have the meanings given in any one of claims 1 to 5, And the compound of formula (IA), (IB), (IC) thus obtained is optionally converted into a salt thereof with a suitable acid (ii).

12. Use of a compound as defined in any one of claims 1 to 10 as an ADRA2C inhibitor.

13. A medicament comprising a compound as defined in any one of claims 1 to 10 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

14. A medicament comprising a compound as defined in any one of claims 1 to 10 in combination with one or more other active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

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