Substituted heterocyclic carboxamides and uses thereof

Abstract

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

Description

[0001] This application relates to novel substituted heterocyclic formamides, methods of 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, particularly for the treatment and / or prevention of breathing difficulties, including sleep-induced breathing difficulties such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

[0002] Alpha-2-adrenergic receptors (α2-ARs) 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 (adrenaline, noradrenaline) released via synapses or reaching their sites of action via the bloodstream, they participate in mediating a variety of physiological effects in different tissues. α2-ARs play important physiological roles, primarily in the cardiovascular and central nervous systems. Biochemical, physiological, and pharmacological studies have shown that, in addition to various α1-AR subtypes, three α2-AR subtypes (α1-ARs) also exist in many cardiovascular-related target cells and tissues, as well as neuronal target cells and tissues. 2A α 2B and α 2C This makes them attractive targets for therapeutic interventions. However, due to the lack of highly selective ligands and / or antagonists for the corresponding α2-AR, the exact physiological tasks of the receptor subtypes have remained difficult to elucidate [Gyires et al., α 2 - Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The α 2 - 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 inhalation, the interaction between two opposing forces ensures the patency of the upper airway. The expansion of the upper airway muscles counteracts the negative pressure within the lumen, causing it to constrict. The active contraction of the diaphragm and other accessory respiratory muscles generates negative pressure in the airway, thus providing the driving force for respiration. The stability of the upper airway essentially depends on the coordination and contractile characteristics of the upper airway dilators.

[0005] It is believed that upper airway retraction in OSA occurs in early sleep because the activity of several upper airway dilators decreases, causing the physiologically sensitive airway to no longer remain open. However, some upper airway dilators, including the genioglossus muscle (which is the most important extensor muscle in the upper airway and is innervated by the hypoglossal nerve), can increase their activity during sleep in response to respiratory stimuli, potentially offsetting some of the changes observed in early sleep. It has been observed that OSA patients with non-apnea intervals show only a 25-40% increase in genioglossus muscle activity compared to sleep with frequent 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 hypolingual motor neuron activity [Horner RL]. Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008 , 164 (1-2): 179-196]. It is believed that reduced norepinephrine stimulation leads to decreased excitability of hypoglossal motor neurons induced by sleep, thereby reducing the activity of the upper airway dilators, especially the genioglossus muscle.

[0006] Studies have shown that increasing the concentration of norepinephrine in the brain by administering the selective norepinephrine reuptake inhibitor reboxetine can improve the severity of sleep apnea in patients with obstructive sleep apnea (Altree TJ, Aishah A, Loffler KA et al., The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial. J Clin SleepMed. 2023 Jan 1;19(1):85-96).

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

[0008] α 2C-Adrenergic receptors regulate norepinephrine released by central noradrenergic neurons. They are autoreceptors involved in the presynaptic feedback inhibition of norepinephrine. [Hein L. et al., Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999 , 402 (6758): 181-184]. Increased activity of motor neurons in the hypoglossal nerve, mediated by α2c adrenergic receptor antagonism, can stabilize the upper airway and protect it from collapse and obstruction. Furthermore, stabilizing the upper airway can also suppress snoring.

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

[0010] Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This leads to increased airway resistance and thus an increased 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, circulation, and sleep quality are comparable to those in obstructive sleep apnea. As in obstructive sleep apnea, the pathogenesis is thought to be the impairment of pharyngeal dilatational 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, leading to recurrent episodes of inadequate or absent breathing and impaired gas exchange. CSA presents in various forms. These include hyperotropic periodic breathing, idiopathic CSA (ICSA), central apnea induced by anesthetics, hypoventilation syndrome (OHS), and Cheyne-Stokes breathing (CSB). The exact mechanisms in different types of CSA can vary considerably; however, a key characteristic 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 can have various causes. The complex regulation of swallowing occurs in various structures of the brain. This involves bidirectional connections between the cerebral cortex, the corticobulbar tract, the brainstem, and the peripheral swallowing muscles. The regulation and execution of swallowing behavior essentially involves five pairs of cranial nerves (trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII)) and more than 25 muscle pairs [Arens C., Position paper of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German Society of Phoniatrics and Pediatric Audiology - current state of clinical and endoscopic diagnostics, evaluation, and therapy of swallowing disorders in children and adults. Laryngorhinootologie , 2015 Mar; 94 Suppl 1:306-54].

[0013] Dysphagia can have very different causes, such as structural disorders of the oral cavity and / or larynx, psychological causes, and neurological disorders (neurogenic dysphagia), including, for example, Parkinson's disease, myotonic dystrophy, amyotrophic lateral sclerosis, cerebral infarction, traumatic brain 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 breathing [Yamanishi T., Alpha2-adrenoceptors coordinate swallowing and respiration. J Dent Res 2010, 89 (3): 258-2639]. α2-AR also plays an important role in cardiovascular changes. For example, the regulation of cardiac contractility is primarily modulated through central modulation of the sympathetic efferent nerves. Furthermore, 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 in various vascular beds. This is also controlled by α2-AR, which is involved in the regulation of peripheral resistance. Thus, blood vessels are innervated by sympathetic nerve fibers located in the adventitia and terminally varicose veins that release norepinephrine. The released norepinephrine regulates local vascular tone in both endothelial cells and smooth muscle cells via α2-AR.

[0015] Besides its effects on sympathetic efferent nerves, peripheral cardiovascular function is also regulated by presynaptic and postsynaptic α2-AR. Smooth muscle cells and endothelial cells express different α2-AR isoforms. α2-AR on smooth muscle cells... 2A α 2B and α 2C Receptor activation leads to contraction and thus 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 vascular sizes. Therefore, α 2A -AR appears to be expressed almost exclusively in large arteries, while α 2B ARα contributes more to vascular tone in arterioles and veins. 2B It appears to play a role in salt-induced hypertension [Gyires et al., α 2 -Adrenoceptor subtypes- mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. ARα is not yet fully understood. 2C Effects on hemodynamics; however, ARα 2C Receptors appear to mediate venous vasoconstriction. They are also involved in the cryogenic enhancement of adrenergic receptor-induced vasoconstriction [Chotani et al., Silent α 2C adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol 278:H1075-H1083, 2000; Gyires et al., α 2 - Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, (2009)]. Cold and other factors (e.g., tissue proteins, estrogen) regulate ARα. 2C Functionally coupled to intracellular signaling pathways [Chotani et al., Distinct cAMP signaling pathways differentially regulate α 2C adrenenoxceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol 288: H69-H76, (2005)].

[0016] Under pathophysiological conditions, the adrenergic system can be activated, leading to conditions such as hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disturbances, stroke, and sexual dysfunction. Therefore, the pathophysiology of conditions like Raynaud's syndrome and scleroderma is largely unknown, but is associated with altered adrenergic activity. Consequently, patients with spastic Raynaud's syndrome show significantly elevated expression of, for example, ARα2 on their platelets. This may be related to the vasospasm episodes observed in these patients [Keenan and Porter, ...]. α 2 -Adrenergic receptors in platelets from patients with Raynaud's syndrome, Surgery , V94(2), (1983)).

[0017] Due to the anticipated high efficiency and low level of side effects, potential therapies targeting the regulation of the activated adrenergic system in the body are promising approaches for such conditions. Particularly in diabetic patients who frequently have elevated catecholamine levels, peripheral circulatory disturbances (microvascular complications) such as diabetic retinopathy, nephropathy, or significant wound healing impairment (diabetic foot ulcers) play a significant role. In peripheral occlusive diseases, diabetes is one of the most important comorbidities and also plays a decisive role in the progression of disease (microvascular and macrovascular complications). These pathophysiological processes in diabetic patients may involve adrenergic receptor α, which is associated with elevated catecholamine levels. 2C High expression of the receptor.

[0018] In 2011, there were 350 million people with diabetes worldwide (approximately 6.6% of the population), and this number is projected to double by 2028. Diabetic foot ulcers are the most common reason for hospitalization in diabetic patients. The lifetime risk of developing diabetic foot ulcers is 15-25% for people with diabetes, and 15% of all diabetic foot ulcers result in amputation. 40-70% of all non-traumatic amputations worldwide are performed on people with diabetes. Risk factors for diabetic foot ulcers include trauma, poor metabolic control, sensory, motor, and autonomic polyneuropathy, inappropriate footwear, infection, and peripheral artery disease. Treatment of diabetic foot ulcers requires an interdisciplinary team and a multifactorial approach: weight loss, revascularization (in cases of peripheral artery occlusive disease, PAOD), improved metabolic control, debridement, bandaging, dalteparin, Regrannex (PDGF), and amputation. The cost of treating each diabetic foot ulcer (without amputation) is USD 7,000-10,000. 33% of all diabetic foot ulcers fail to heal within 2 years, and the recurrence rate is high (34% in the first year and 61% in 3 years).

[0019] Arylpiperazine compounds as α2-adrenergic receptor C subtype (α-2C) antagonists, their preparation methods, and their uses as medicines are known from WO 03 / 082866 A1, in which such compounds are described as being used to treat conditions such as: stress disorders, Parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, Tourette syndrome, blepharospasm or other focal dystonia, temporal lobe epilepsy with psychosis, drug-induced psychosis, Huntington's disease, disorders caused by changes in sex hormone levels, panic disorder, Alzheimer's disease, or mild cognitive impairment. No information is known regarding the use of these compounds in treating sleep-related respiratory conditions (preferably obstructive and central sleep apnea and snoring).

[0020] The preparation of substituted heterocyclic formamides as effective inhibitors of α2-adrenergic receptor C subtype (α-2C) is disclosed in WO2021 / 089683 A1.

[0021] The compounds of this application are suitable for the prevention and treatment of diseases caused by activated or activated α-phospholipids. 2C - Diseases caused by adrenergic receptors, and those secondary to α 2C - Diseases related to adrenergic receptor damage.

[0022] Conditions that may be mentioned in this context include, in particular, dyspnea, sleep-induced dyspnea such as central and obstructive sleep apnea, mixed sleep apnea, Cheyne-Stokes respiration, snoring (primary and obstructive snoring), central respiratory drive disorders, sudden infant death syndrome, postoperative hypoxia and apnea, musculoskeletal disorders, respiratory disorders following prolonged ventilation, respiratory disorders during acclimatization at high altitudes, dysphagia, acute and chronic lung diseases with hypoxia and hypercapnia, and peripheral circulatory disorders (microvascular complications) such as diabetes mellitus. Retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers), peripheral and central nervous system disorders, especially dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without ADHD, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonia, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0023] The object of this invention is to provide a new substance that acts as an α 2C - An effective and selective antagonist of adrenergic receptors, and therefore suitable for the treatment and / or prevention of dyspnea, sleep-induced dyspnea such as obstructive and central sleep apnea, snoring, dysphagia, peripheral and central nervous system disorders and peripheral circulatory disorders (microvascular complications) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers).

[0024] This invention provides compounds of general formula (I), as well as their salts, solvates, and solvates of said salts. (I) in X is S, N, or O; Y is N, S, or O. Where X is S, Z is N; When X is 0, Z is N; Y is CR4, O, or NR4. When X is N and Z is N, Y is O; When X is S, Y is CR4 or NR4; R1 is a 5 to 10-membered heteroaryl, phenyl, (C4-C) group. 10 )-Heterocyclic alkyl or (C3-C 10 )-cycloalkyl, The 5 to 10 heteroaryl groups may be substituted by 1 to 3 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. The (C1-C4)-alkoxy group can be substituted by up to three halogens. The phenyl group may be substituted by one or two independent substituents selected from the following group: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. Among them (C3-C) 10 )-cycloalkyl and (C4-C 10 (C1-C4)-heterocyclic alkyl groups may be substituted by one or two independent substituents selected from the following group: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. Among them (C3-C) 10 )-cycloalkyl and (C4-C 10 )-Heterocyclic alkyl groups can fuse with 5 to 10 heteroaryl groups, The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; R2 is hydrogen, (C1-C4)-alkyl, or (C3-C5)-cycloalkyl; The (C1-C4)-alkyl group can be substituted by halogens up to three times. The (C1-C4)-alkyl group can be substituted with a cyano group or a (C1-C4)-alkoxy group. The (C3-C5)-cycloalkyl group can be substituted by halogens up to three times. or Together with the carbon atom bonded to R2, they form a (C3-C4)-cycloalkyl ring. or R1 and R2 together form a (C5-C8)-cycloalkyl group or (C5-C8)-cycloalkyl group. 10 )-Heterocyclic alkyl ring, (C5-C8)-cycloalkyl groups can fused with 5 to 10 heteroaryl groups. The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; Among them (C3-C) 10 )-Heterocyclic alkyl groups can fuse with 5 to 10 heteroaryl groups, The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; R3 is hydrogen or (C1-C4)-alkyl. The (C1-C4)-alkyl group can be substituted by halogens up to three times. R4 in CR4 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, or halogen; The (C1-C4)-alkyl groups can be substituted with halogens up to three times, and the phenyl groups can be substituted with halogens. NR4 is absent or contains hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, or phenyl. The (C1-C4)-alkyl groups can be substituted with halogens up to three times, and the phenyl groups can be substituted with halogens. R5 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen. R6 is a group of formula a), b), c), d), e), f), or g). Where *** indicates the connection with the adjacent piperidine ring. Where R7 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, or phenyl. The (C1-C4)-alkyl group can be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, or (C3-C4)-cycloalkoxy groups and can be trisubstituted by halogens up to three times. The (C1-C4)-alkoxy group can be substituted with (C3-C4)-cycloalkyl groups and can be trisubstituted with halogens. The (C3-C4)-cycloalkyl group can be substituted with monofluoromethyl, difluoromethyl or trifluoromethyl and can be disubstituted with halogens up to 100%. The (C1-C4)-alkoxy group can be substituted with (C3-C4)-cycloalkyl groups and can be trisubstituted with halogens. The (C3-C4)-cycloalkyl group can be mono- or di-substituted with halogens. The (C3-C4)-cycloalkoxy group can be disubstituted by halogens. R8 is either hydrogen or fluorine. R9 can be hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen. The (C1-C4)-alkyl group can be substituted with (C1-C4)-alkoxy groups. n represents 0 or 1, m represents 0, 1, or 2. p represents 0, 1, or 2, and q represents 0, 1, or 2.

[0025] The compounds of the present invention are compounds of formula (I) and their salts, solvates and solvates of the salts, compounds of formula (I) and having the formula mentioned below and their salts, solvates and solvates of the salts, and compounds of formula (I) and mentioned below as working examples, even if the compounds of formula (I) and mentioned below are not salts, solvates and solvates of the salts.

[0026] The compounds of this invention are also compounds of formula (I). N -Oxides and S -Oxides and their salts, solvates and solvates of the salts.

[0027] In the context of this invention, preferred Salt These are physiologically acceptable salts of the compounds of the present invention. This also includes salts that are not inherently suitable for pharmaceutical use but may be used, for example, for the isolation, purification, or storage of the compounds of the present invention.

[0028] Suitable pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of the compounds of the present invention having sufficient basic nitrogen atoms in the chain or ring, such as acid addition salts with inorganic or "mineral acids" or with organic acids, said inorganic acids being, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfonic acid, pyrosulfonic acid, phosphoric acid, or nitric acid; said organic acids being, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, and menthol. Cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthic acid, nicotinic acid, palmitic acid, pectic acid, 3-phenylpropionic acid, neopentanoic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecyl sulfuric 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, glucoheponic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanate.

[0029] In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention having sufficient acidity is an alkali metal salt, such as a sodium or potassium salt; an alkaline earth metal salt, such as a calcium, magnesium, or strontium salt; or an aluminum or zinc salt; or an ammonium salt derived from ammonia or from an organic primary, secondary, or tertiary amine having 1-20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyl diisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, etc. N 1,2-Methylmorpholine, arginine, lysine, 1,2-ethylenediamine N -Methylpiperidine, N β-methylglucosamine, N,N -Dimethylglucosamine, N -Ethylglucosamine, 1,6-hexanediamine, glucosamine, sarcosine, serine, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol; or with salts of quaternary ammonium ions having 1-20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl- N,N,N - Trimethylammonium, choline, or benzalkonium chloride.

[0030] 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.

[0031] This invention includes all possible salts of the compounds of this invention, as a single salt or any mixture of said salts in any proportion.

[0032] In this document, particularly in the experimental section, when referring to compounds as salts of the corresponding bases or acids obtained by their respective preparation and / or purification methods, the precise stoichiometric composition of the salt form is, in most cases, unknown for the synthesis of intermediates and embodiments of the present invention. Unless otherwise stated, suffixes in chemical names or structural formulas related to salts, such as "hydrochloride," "trifluoroacetate," "sodium salt," or "x HCl," "x CF3COOH," "x Na," etc., are used. + ", for example, means salt form where the stoichiometry of the salt form is not specified. This similarly applies to synthetic intermediates or instances of compounds or salts thereof that have been obtained by the described preparation and / or purification methods as solvates (such as hydrates).

[0033] solvatesIn the context of this invention, those forms of the compounds of the invention that are described as forming solid or liquid complexes by coordination with solvent molecules are described. Hydrates are a specific form of solvate in which coordination with water occurs. Hydrates are preferred solvates in the context of this invention.

[0034] According to the structure of the compounds of the invention, they can exist in different stereoisomeric forms, i.e., as configurational isomers or, if appropriate, as conformational isomers (enantiomers and / or diastereomers, including those in the case of transisomers). The invention therefore includes enantiomers and diastereomers and mixtures thereof. Stereoisomerically consistent components can be separated from such mixtures of enantiomers and / or diastereomers in known ways; for this purpose, chromatography, especially HPLC on achiral or chiral separating phases, is preferred. In the case of carboxylic acids as intermediates or final products, separation via diastereomeric salts using chiral amine bases is also possible.

[0035] In this invention, the term "enantiomer purity" is understood as follows: the compound in question is present in an enantiomer excess of greater than 95%, preferably greater than 98%, with respect to the absolute configuration of the chiral center. The enantiomer excess ee is calculated here by evaluating the HPLC chromatogram on the chiral phase using the following formula: .

[0036] If the compounds of the present invention can exist in tautomeric forms, then the present invention includes all tautomeric forms.

[0037] This invention also includes all suitable isotopic variants of the compounds of this invention. An isotopic variant of the compounds of this invention is understood herein to mean a compound in which at least one atom has been replaced by another atom having the same atomic number but a different atomic mass than that commonly or predominantly found in nature (“non-natural proportion”). The expression “non-natural proportion” should be understood to mean a proportion of such isotopes above their natural frequency. The natural frequencies of the isotopes used in this regard can be found in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998. Examples of isotopes that may be incorporated into the compounds of this 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、 32P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 129 I and 131 I. Certain isotopic variants of the compounds of the present invention, especially those incorporating one or more radioactive isotopes, may be beneficial, for example, in examining mechanisms of action or the distribution of active ingredients in vivo; due to their relative ease of preparation and detection, they can be used... 3 H or 14 Compounds labeled with C isotope are particularly suitable for this purpose. Furthermore, the incorporation of isotopes, such as deuterium, can provide specific therapeutic benefits due to greater metabolic stability of the compound, such as an extended half-life in vivo or a reduction in the required active dose; such modifications to the compounds of the present invention may therefore optionally constitute preferred embodiments of the invention. For the treatment and / or prevention of the obstacles specified herein, one or more isotopic variants of compounds of general formula (I) preferably contain deuterium (“compounds of general formula (I) containing deuterium”). Wherein one or more radioactive isotopes such as 3 H or 14 Isotopic variants of compounds of general formula (I) C are useful, for example, in studies of pharmaceutical and / or substrate tissue distribution. These isotopes are particularly preferred due to their ease of incorporation and detection. Positron-emitting isotopes, such as... 18 F or 11 Compounds incorporating C into general formula (I). These isotopic variants of compounds of general formula (I) are suitable for in vivo imaging applications. Deuterium-containing and deuterium-containing compounds of general formula (I) 13 Compounds of type C can be used in preclinical or clinical studies using mass spectrometry (HJ Leis et al., Curr. Org. Chem. (1998, 2, 131). Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as the procedures reported in the methods and examples described below, by using various reagents and / or corresponding isotopic modifications of the starting compounds.

[0038] Isotopic variants of compounds of general formula (I) are typically prepared by methods known to those skilled in the art, such as those described herein and / or in the examples, by using isotopic variants of the reagent, preferably deuterium-containing reagents instead. Depending on the desired deuteration site, in some cases, deuterium from D₂O may be directly incorporated into the compound or into a reagent that can be used to synthesize such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J. , 2007, 13, 4052). Photochemical deuteration and tritization methods are also 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 through alkene bonding (HJ Leis et al., 2007, 13, 4052). Curr. Org. Chem. , 1998, 2, 131; JR Morandi et al., J. Org. Chem. , 1969, 34 (6), 1889) and alkyne bond (NH Khan, J. Am. Chem. Soc. , 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron Catalytic deuteration (2011, 52, 3865). To directly replace hydrogen in functionalized hydrocarbons with deuterium, metal catalysts (i.e., Pd, Pt, and Rh) can also be used in the presence of deuterium (JGAtkinson et al., US Patent 3966781). Various deuterating reagents and synthetic apparatus are available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information relating to prior art regarding deuterium-hydrogen exchange has been 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.

[0039] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms have been replaced by one or more deuterium atoms and in which the deuterium frequency at each deuteration position in the compound of general formula (I) is higher than the natural frequency of deuterium (which is about 0.015%). Specifically, in the deuterium-containing compound of general formula (I), the deuterium frequency at each deuteration position in the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, preferably higher than 90%, 95%, 96%, or 97%, and more preferably higher than 98% or 99%. It is evident that the deuterium frequency at each deuteration position is independent of the deuterium frequencies at other deuteration positions.

[0040] The selective incorporation of one or more deuterium atoms into compounds of general formula (I) can alter 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 molecules, resulting in changes in the ratio of the parent compound to metabolites or the amount of metabolites formed. Such changes may provide specific therapeutic benefits and are therefore preferred in certain situations. Decreased metabolic rates and metabolic shifts, in which the ratio of metabolites changes, have been reported (DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure relative to the parent compound and metabolites have significant effects on the pharmacodynamics, tolerability, and potency of compounds containing deuterium of general formula (I). In some cases, deuteration reduces or eliminates the formation of unwanted or toxic metabolites and enhances the formation of desired metabolites (e.g., Nevirapine: AMSharma 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 primary effect of deuteration is to reduce the systemic clearance rate. Consequently, the biological half-life of the compound is increased. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak concentrations and increased trough concentrations. Depending on the pharmacokinetic / pharmacodynamic relationship of the respective compounds, this could result in lower side effects and enhanced potency.Examples of this deuterium effect include 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., WO2012 / 112363). Other cases have been reported where a reduced metabolic rate leads to increased drug exposure without altering systemic clearance rates (e.g., Rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs that exhibit this effect may have reduced dosage requirements (e.g., lower number of doses or lower doses to achieve the desired effect) and / or may produce a lower metabolite load.

[0041] Compounds of general formula (I) may possess multiple potential attack sites for metabolism. To optimize the aforementioned effects on physicochemical properties and metabolic status, deuterium-containing compounds of general formula (I) with one or more deuterium-hydrogen exchange sites can be selected. In particular, one or more deuterium atoms of the said (one or more) deuterium-containing compounds of general formula (I) are attached to a carbon atom and / or located at a position on a metabolic enzyme, such as cytochrome P. 450 The attack sites of compounds of general formula (I) at those positions.

[0042] This invention also includes prodrugs of the compounds of this invention. The term "prodrug" herein refers to a compound that may be biologically active or inactive on its own but is converted into the compounds of this invention when present in vivo (e.g., through metabolic or hydrolytic pathways).

[0043] In the context of this invention, unless otherwise specified, substituents have the following meanings: In the context of this invention, alkylIt is a straight-chain or branched alkyl group having a specified 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.

[0044] In the context of this invention, Alkoxy It is a straight-chain or branched alkoxy group with a specified number of carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0045] In the context of this invention, Cycloalkoxy It is a cyclic alkoxy group having 3 to 4 carbon atoms. Examples include cyclopropoxy or cyclobutoxy.

[0046] In the context of this invention, cycloalkyl or carbon ring The rings are monocyclic, polycyclic, or spirocyclic, each having a specified number of ring atoms; monocyclic or bicyclic saturated carbocyclic rings are preferred. Monocyclic saturated carbocyclic rings are synonymously referred to as cycloalkyl groups. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclic[1.1.1]pentyl, bicyclic[2.2.1]heptyl, bicyclic[4.1.0]heptyl, bicyclic[2.2.2]octyl, and tricyclic[3.3.1.13,7]decyl. Monocyclic cycloalkyl groups having 3 to 5 carbon atoms are preferred. Examples include: cyclopropyl, cyclobutyl, or cyclopentyl.

[0047] In the context of this invention, Heterocyclic or heterocyclic group A monocyclic or bicyclic saturated heterocycle having a specified number of ring atoms, containing one or two cyclic heteroatoms selected from N, O, S, SO and / or SO2, linked by a cyclic carbon atom or optionally a cyclic nitrogen atom. Examples include: azirrocyclobutane, oxacyclobutane, pyrrolithyl, pyrazolyl, tetrahydrofuranyl, thiocyclopentane, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, and hexahydro-1,4-diazepinyl. Preferred are azirrocyclobutane, oxacyclobutane, pyrrolithyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, and morpholinyl.

[0048] In the context of this invention, heteroaryl A heterocyclic or bicyclic aromatic compound (heteroaromatic compound) having a specified number of ring atoms, containing up to four identical or different cyclic heteroatoms selected from N, O and / or S, linked by a ring carbon atom or optionally by a ring nitrogen atom. Preferred examples include: furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, quinolinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, and triazinyl.

[0049] Generally, unless otherwise stated, heteroaryl includes all possible isomers, such as tautomers and positional isomers related to the connection points of the remaining part of the molecule. Thus, as a non-limiting example, the term pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, or the term thiophenyl includes 2-thiophenyl and 3-thiophenyl.

[0050] In the context of this invention, halogen Including fluorine, chlorine, bromine, and iodine. Chlorine or fluorine are preferred.

[0051] When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or poly-substituted. In the present invention, all groups appearing more than once are defined independently of each other. When a group in a compound of the present invention is substituted, unless otherwise specified, the group may be mono- or poly-substituted. Preferably, it is substituted by one substituent or two identical or different substituents.

[0052] In the context of this invention, the term "treatment" or "treating" includes the suppression, delay, prevention, relief, reduction, limitation, decrease, halt, repulsion, or cure of the development, process, or occurrence of a disease, condition, ailment, injury, or health problem, or such condition and / or symptoms of such condition. The term "therapeutic method" is hereby understood to be synonymous with the term "treatment".

[0053] The terms “prevention” and “prophylaxis” are used synonymously in this invention and refer to the avoidance or reduction of the risk of infection, occurrence, affliction or suffering from disease, condition, ailment, injury or health problem or such condition and / or the development or progression of symptoms of such condition.

[0054] Treatment or prevention of diseases, conditions, symptoms, injuries, or health problems can be achieved partially or completely.

[0055] In the context of this invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred. in X is either S or N; Y is N, S, or O. Where X is S, Z is N; When X is 0, Z is N; Y is CR4, N, or O. When X is N and Z is N, Y is O; When X is S, Y is N or CR4; R1 can be pyridyl, pyrazolyl, thiazolyl, thiophene, phenyl, heterocyclohexyl, or cyclohexyl. The pyridyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy. The pyrazolyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chloro, trifluoromethyl. The thiazolyl group can be substituted by one or two independent substituents selected from fluorine and chlorine. The thiophene group can be substituted by one or two independent substituents selected from fluorine and chlorine. The phenyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl. Heterocyclohexyl and cyclohexyl can fused with 5- to 6-membered heteroaryl groups. R2 is hydrogen, (C1-C2)-alkyl, or cyclopropyl; The (C1-C2)-alkyl group can be substituted with a cyano group or a (C1-C2)-alkoxy group. or Together with the carbon atom bonded to R2, they form a cyclopropyl ring. or R1 and R2 together form a cyclohexyl or (C6)-heterocyclic alkyl ring. The cyclohexyl group can fused with a 6-membered heteroaryl group. (C6)-heterocyclic alkyl groups can fused with 6-membered heteroaryl groups. R3 is hydrogen or (C1-C2)-alkyl. R4 is hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with a halogen. R5 can be hydrogen, (C1-C2)-alkyl, methoxy, or fluorine. R6 is a group of formula a), b), c), e), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 or R'7 is independently hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or phenyl. The (C1-C4)-alkyl group may be substituted with methoxy, n-butoxy, cyclopropyl, or cyclobutoxy and may be disubstituted with fluorine up to two times. The methoxy group can be replaced by cyclopropyl, cyclobutyl, or trifluoromethyl groups. The cyclopropyl group can be replaced by monofluoromethyl, difluoromethyl, or trifluoromethyl groups. The cyclopropyl group can be substituted with up to two fluorinated groups. The n-butoxy group can be fluorinated up to di-substituted. The (C1-C2)-alkoxy group can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, or trifluoromethyl groups, and The cyclopropyl and cyclobutyl groups can be fluorinated up to two-substituted. The (C3-C4)-cycloalkoxy group can be fluorinated up to polydisubstituted. Where R8 or R'8 is independently hydrogen or fluorine. R9 is 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.

[0056] In the context of this invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred. in Choose X, Y, and Z such that the five-membered ring of the Fang family has the structure h), i), j), k), r), or p). Where * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R1 can be pyridyl, pyrazolyl, thiazolyl, thiophene, phenyl, tetrahydropyranyl, or cyclohexyl. The pyridyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy. The pyrazolyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chloro, trifluoromethyl. The thiazolyl group can be replaced by chlorine. The thiophene group can be replaced by fluorine. The phenyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl. Cyclohexyl and tetrahydropyranyl can fuse with pyridyl groups. R2 is hydrogen or methyl. The methyl group can be replaced by a cyano group or a methoxy group. R3 is hydrogen or (C1-C2)-alkyl; R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine. R5 represents hydrogen and fluorine. R6 is a group of formula a), b''), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 or R'7 is independently hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or phenyl. The (C1-C4)-alkyl group may be substituted with methoxy, n-butoxy, cyclopropyl, or cyclobutoxy and may be disubstituted with fluorine up to two times. The methoxy group can be replaced by cyclopropyl, cyclobutyl, or trifluoromethyl groups. The cyclopropyl group can be replaced by monofluoromethyl, difluoromethyl, or trifluoromethyl groups. The cyclopropyl group can be substituted with up to two fluorinated groups. The n-butoxy group can be fluorinated up to di-substituted. The (C1-C2)-alkoxy group can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, or trifluoromethyl groups, and The cyclopropyl and cyclobutyl groups can be fluorinated up to two-substituted. The (C3-C4)-cycloalkoxy group can be fluorinated up to polydisubstituted. n represents 0 or 1, and m represents 1 or 2.

[0057] In the context of this invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred. Choose X, Y, and Z such that the five-membered ring of the Fang family has the structure h), i), j), k), r), or p). Where * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 represents hydrogen or methyl; R4 is hydrogen, ethyl, or trifluoromethyl; R5 is hydrogen, methyl, or fluorine; R6 is a group of formula a), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

[0058] In the context of this invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred. X, Y, and Z are 1,3-thiazolyl, 1,3-oxazolyl, and 1,2,4-oxadiazolyl; R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 represents hydrogen or methyl; R4 is hydrogen or methyl, ethyl, or trifluoromethyl; R5 is hydrogen, methyl, or fluorine; R6 is a group of formula a), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

[0059] In the context of this invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred. Choose X, Y, and Z such that the 5-member ring of the Fang family has the structure h'). R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 is either hydrogen or methyl; R5 represents hydrogen and fluorine. R6 is a group of formula a) or c'). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

[0060] One specific embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein Choose X, Y, and Z such that the five-membered ring of the Fang family has the structure h), i), j), k), or r). Where * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine.

[0061] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein X, Y, and Z are groups of formula (h) or (i); Where * indicates the connection with a carbonyl group and ** indicates the connection with the nitrogen atom of an adjacent amine group, and R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine.

[0062] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein Choose X, Y, and Z such that the five-membered ring of the Fang family has a structure h) or i). Where * indicates the connection with a carbonyl group and ** indicates the connection with the nitrogen atom of an adjacent amine group, and R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine.

[0063] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... X, Y, and Z are groups of formula h). Where * indicates the connection with a carbonyl group and ** indicates the connection with the nitrogen atom of an adjacent amine group, and R4 can be hydrogen, methyl, ethyl, or trifluoromethyl.

[0064] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... Choose X, Y, and Z such that the five-membered ring of the Fang family has a structure h). Where * indicates the connection with a carbonyl group and ** indicates the connection with the nitrogen atom of an adjacent amine group, and R4 is hydrogen.

[0065] One specific embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R1 can be pyridyl, pyrazolyl, thiazolyl, thiophenyl, or phenyl. The pyridyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy. The pyrazolyl group may be substituted by one or two substituents independently selected from the following group: methyl, chlorine, The thiazolyl group can be replaced by chlorine. The thiophene group can be replaced by fluorine. The phenyl group may be substituted by one or two substituents independently selected from the following group: (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl.

[0066] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R1 is pyridyl or phenyl. The pyridyl group may be substituted by one or two independent substituents selected from the following group: methyl, ethyl, fluorine, chloro, trifluoromethyl, trifluoromethoxy. The phenyl group may be substituted by one or two substituents independently selected from the following group: methyl, cyclopropyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl.

[0067] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R1 is a group of formula (f); (f) Where # indicates the adjacent -[CHR2] n Linkage of NR3- groups.

[0068] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R1 is a group of formula (f); (f) Where # indicates the adjacent -[CHR2] n Linkage of NR3- groups.

[0069] A particular embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R2 is hydrogen or (C1-C4)-alkyl; The (C1-C4)-alkyl group can be substituted by halogens up to three times. It may form a (C3-C4)-cycloalkyl ring together with the carbon atom bonded to R2.

[0070] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R2 is hydrogen, methyl, or a cyclopropyl ring formed together with the carbon atom bonded to R2.

[0071] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R2 is hydrogen.

[0072] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R2 is a methyl group.

[0073] A particular embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R3 is hydrogen or (C1-C4)-alkyl. The (C1-C4)-alkyl group can be substituted by up to three halogens.

[0074] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R3 represents hydrogen or methyl.

[0075] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R3 is hydrogen.

[0076] A particular embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine.

[0077] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R4 can be hydrogen, methyl, ethyl, or trifluoromethyl.

[0078] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R4 is hydrogen.

[0079] A particular embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R5 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen.

[0080] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R5 represents hydrogen and fluorine.

[0081] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R5 is hydrogen.

[0082] A particular embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R6 is a group of formula a), b'), b''), or c'), c''), or h). Where *** represents the connection with the adjacent piperidine ring, and R7 is either hydrogen or methyl. R'7 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, and fluorine.

[0083] A particularly preferred embodiment of the present invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R6 is a group of formula a), c'), or h. Where *** represents the connection with the adjacent piperidine ring, and R7 is hydrogen. R'7 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, and fluorine.

[0084] A particularly preferred embodiment of the present invention relates to compounds of formula (I), their salts, solvates, and solvates of the salts, wherein... R6 is a group of formula a). Where *** represents the connection with the adjacent piperidine ring, and R7 is hydrogen. R'7 represents methyl, ethyl, isopropyl, propyl, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3-difluorocyclobutylmethoxy, 2,2,2-trifluoroethoxymethyl, cyclopropylmethyl, 1-fluoromethylcyclopropylmethoxymethyl, 1-difluoromethylcyclopropylmethoxymethyl, 1-trifluoromethylcyclopropylmethoxymethyl, cyclobutylmethoxy, cyclopropylmethoxy, cyclobutoxymethyl, cyclopropylmethoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 3-fluorobutoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, 2-fluoroethyl, cyclopropyl, cyclobutyl, 2-methoxyethyl, and tert-butyl.

[0085] One specific embodiment of the present invention relates to a compound of formula (I), wherein n represents 0 or 1, And its salts, solvates and solvates of the salts.

[0086] A particularly preferred embodiment of the present invention relates to a compound of formula (I), wherein n represents 1, And its salts, solvates and solvates of the salts.

[0087] One specific embodiment of the present invention relates to a compound of formula (I), wherein m represents 1 or 2. And its salts, solvates and solvates of the salts.

[0088] A particularly preferred embodiment of the present invention relates to a compound of formula (I), wherein m represents 1, And its salts, solvates and solvates of the salts.

[0089] One specific embodiment of the present invention relates to a compound of formula (I), wherein p represents 0, 1, or 2. And its salts, solvates and solvates of the salts.

[0090] A particularly preferred embodiment of the present invention relates to a compound of formula (I), wherein p represents 1.

[0091] One specific embodiment of the present invention relates to a compound of formula (I), wherein q represents 0 or 2. And its salts, solvates and solvates of the salts.

[0092] A particularly preferred embodiment of the present invention relates to a compound of formula (I), wherein q represents 2. And its salts, solvates and solvates of the salts.

[0093] The definitions of the individual groups specified in the respective combinations or preferred combinations of groups are independent of the respective combinations of groups specified, and may be replaced by the definitions of groups in other combinations as needed.

[0094] A combination of two or more of the above-mentioned preferred ranges is highly preferred.

[0095] The present invention also provides a method for preparing a compound of formula (I), or a salt thereof, a solvate thereof, or a solvate of said salt, wherein... [A] Compound of formula (II) (II) in X, Y, Z, R5, R6, and m have the definitions given above. Hal is the leaving group, preferably chlorine, bromine, iodine, or methanesulfonyl. Reacts with the compound of formula (III) in the presence of a base. (III) in R1, R2, R3, and n have the definitions given above. Compounds of production formula (IA) (IA), or [B] Compounds of formula (IV) (IV) in X, Y, Z, R1, R2, R3, R4 and R5, as well as n and m, have the definitions given above. The compound of formula (V) reacts with a reducing agent and an optional acid (preferably an alkali metal borohydride and acetic acid) in the presence of a reducing agent. (V) in R6 has the definition given above. Compounds with production formula (IB) (IB), or [C] Compounds of formula (VI) (VI) in X, Y, Z, R1, R2, and R3, and n have the definitions given above. The compound of formula (VII) reacts with the compound in the presence of a condensing agent or activator (preferably a phosphorus compound). (VII) in R5, R6, and m have the definitions given above. Compounds of production formula (IC) (IC), Furthermore, the compounds of formula (IA), (IB), (IC) thus obtained are optionally isolated into their enantiomers and / or diastereomers and / or optionally converted into their solvates, salts and / or solvates of the salts using suitable (i) solvents and / or (ii) acids.

[0096] exist Method and 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 amine in compound (III), wherein the reaction depends on the reactivity of each case and can be carried out, for example, by heating in a solvent or dispersant.

[0097] Suitable bases for method step [A], particularly alkali metal carbonates such as sodium carbonate, potassium carbonate, or cesium carbonate, and tertiary amine bases such as triethylamine, N,N -Diisopropylethylamine, N -Methylmorpholine (NMM) N-Methylpiperidine (NMP), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,10-o-phenanthroline or 4- N,N -Dimethylaminopyridine (DMAP). The base used is preferably sodium carbonate, potassium carbonate, or cesium carbonate. The addition of an alkylation catalyst, such as lithium bromide, sodium iodide, potassium iodide, tetra-n-butylammonium bromide, copper iodide (I), or benzyltriethylammonium chloride, may be advantageous.

[0098] The alkali is preferably used in equimolar amounts or in excess, typically 1 to 5 times the molar amount, preferably 5 times.

[0099] In addition, the reaction can also be carried out by using Pd2(dba)3, cesium carbonate as an auxiliary base and palladium catalysis of the following ligand: 1,1'-[1,1'-binaphthyl]-2,2'-diylbis[1,1-diphenylphosphine] or 1,1'-(9,9-dimethyl-9H-xanthan-4,5-diyl)bis[1,1-diphenylphosphine] (see WO 2008052934 or WO 2015017305).

[0100] 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'-dimethylpropenylurea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of such solvents may also be used. Acetonitrile or dimethylformamide is preferred.

[0101] The reaction (II) + (III) → (IA) is generally carried out in the temperature range of 0°C to +150°C, preferably in the range of +20°C to +140°C.

[0102] exist Method and steps [B] In this reaction, 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 preferred. The addition of an acid, particularly acetic acid, and / or a dehydrating agent, such as a molecular sieve, trimethyl orthoformate, or triethyl orthoformate, can be advantageous in these reactions.

[0103] Suitable solvents for these reactions include, 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, dichloromethane; and polar aprotic solvents such as acetonitrile or... N,N - Dimethylformamide (DMF) or a mixture of such solvents; tetrahydrofuran is preferred. The reaction is generally carried out in a temperature range of 0°C to +50°C.

[0104] 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 (9). H -fluorene-9-ylmethoxy)carbonyl (Fmoc); preferably tert-butoxycarbonyl (BOC). The removal of the protecting group in the process steps is carried out by known methods. Therefore, tert-butoxycarbonyl is typically cleaved by treatment with a strong acid such as hydrochloric acid, hydrobromic acid, or trifluoroacetic acid in an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane, or acetic acid. In the case of benzyloxycarbonyl as the protecting group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst such as palladium on activated carbon. (9) H The -fluorene-9-ylmethoxy) carbonyl group is usually removed by means 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 , 3rd edition, Thieme, 2005.

[0105] Method and steps [B] (VI) + (VII) → (IC) [Amide Formation] is carried out by known methods using condensing agents or activators. Suitable reagents of this kind 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-oxazonium compounds such as 2-ethyl-5-phenyl-1,2-oxazonium Azoxazonium 3-sulfate or 2-tert-butyl-5-methylisoxazoonium perchlorate, amide 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, T3P) ®Diethyl cyanophosphonate, diphenyl azidophosphate (DPPA), bis-(2-oxo-3-oxazolyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), or ureon compounds such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureon tetrafluoroborate (TBTU), O-(1H-1-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TCTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU) or 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylureon tetrafluoroborate (TPTU), optionally combined with other auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and a suitable base is an alkali metal carbonate, such as sodium carbonate or potassium carbonate, or a tertiary amine base such as triethylamine, N-methylmorpholine (NMM), N-methylpiperidine (NMP), DIPEA, pyridine or 4-N,N-dimethylaminopyridine (DMAP). The preferred condensing agent or activator used is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU) combined with N,N-diisopropylethylamine as a base.

[0106] Suitable inert solvents for these amide formation reactions are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or bis(2-methoxyethyl) ether; hydrocarbons such as benzene, toluene, xylene, pentane, hexane, or cyclohexane; halogenated hydrocarbons such as dichloromethane, trichloromethane, 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'-dimethylpropenylurea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of such solvents may also be used. Dichloromethane, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, or mixtures of these solvents are preferred. The reaction is generally carried out in a temperature range of -20°C to +60°C, preferably in a range of 0°C to +40°C.

[0107] As for the compound of formula (II), it can be prepared by a method known in the literature [amide formation], which involves making an amine (VII) (VII) in R5 and R6 have the definitions given above. Reacts with compounds of formula (X) under the action of condensing agents or activators. (X) in X, Y, Z, R4, and Hal have the definitions given above. To produce compounds of formula (II) (II).

[0108] Compounds of formula (VII) can be prepared by a method known in the literature [reductive amination], which involves making the amine (V) (V) in R6 has the definition given above. Reaction with the protected piperidine derivative of formula (XI) (XI) in R5 and m have the definitions given above and PG is a suitable amine protecting group, preferably tert-butyloxycarbonyl, benzyloxycarbonyl, or (9 H -fluorene-9-ylmethoxy)carbonyl, Compounds of formula (VII') (VII') Among them, PG, R5, R6, and m have the definitions given above. Subsequently, the protecting group PG is removed to produce the compound of formula (VII). (VII)

[0109] Compounds of formula (IV) can be prepared by methods known in the literature [alkylation], which involves reacting compounds of formula (II) with the alkylation process. (II) Where X, Y, Z, and R5, as well as Hal and m, have the definitions given above. Reacts with the compound of formula (III) in the presence of a base. (III) Where R1, R2, R3, and n have the definitions given above. To produce compound (IV) (IV).

[0110] Compounds of formula (VI) can be prepared by alkylation, a method known from the literature, which involves reacting compounds of formula (XIII) with the alkylation process. (XIII) Where X, Y, Z, R4, and Hal have the definitions given above, and T1 is an -O-(C1-C4)-alkyl group. Reacts with the compound of formula (III) in the presence of a base. (III) Where R1, R2, R3, and n have the definitions given above. And hydrolyzes under conditions known in the literature to produce a compound of formula (VI). (VI).

[0111] The hydrolysis of ester group T1 is carried out by conventional methods, by treating the ester with acid or base in an inert solvent. In subsequent modifications, the initially formed salt is converted into a free carboxylic acid by acid treatment. In the case of tert-butyl esters, the hydrolysis of the ester is preferably carried out using acid.

[0112] Suitable inert solvents for these reactions are water or organic solvents commonly used for ester cracking. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane; or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide, or dimethyl sulfoxide. Mixtures of these solvents can also be used. In the case of basic ester hydrolysis, a mixture of water with dioxane, tetrahydrofuran, methanol, ethanol, and / or dimethylformamide is preferred. In the case of reaction with trifluoroacetic acid, dichloromethane is preferred, and in the case of reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water is preferred.

[0113] Suitable bases are common inorganic bases. These specifically include alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, or calcium carbonate. Lithium hydroxide, sodium hydroxide, or potassium hydroxide are preferred.

[0114] Suitable acids for ester hydrolysis are typically 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, with water optionally added. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0115] Ester hydrolysis is usually carried out in a temperature range from -20°C to +120°C, preferably from 0°C to +80°C.

[0116] The preparation of the compounds of the present invention can be illustrated, for example, by the following reaction scheme: Option 1 Option 2 Option 3 Option 4 The compounds of this invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0117] The compound according to the present invention is α 2C -Effective and selective antagonists of adrenergic receptors, and therefore suitable for the treatment and / or prevention of conditions and pathological processes, particularly those caused by activated or activated α-adrenergic receptors. 2C Those caused by adrenergic receptors, and those secondary to α 2C - Diseases related to adrenergic receptor damage.

[0118] The compounds of the present invention are used in methods for treating and / or preventing respiratory distress, dysphagia, peripheral and cardiovascular diseases, and peripheral and central nervous system diseases.

[0119] The compounds of the present invention are also used in methods of treating and / or preventing the following conditions: breathing difficulties, including sleep-induced breathing difficulties, such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

[0120] In the context of this invention, these include, in particular, the following conditions: dyspnea and sleep-induced dyspnea, such as, in particular, obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypoventilation syndrome), central sleep apnea, Cheyne-Stokes breathing, primary sleep apnea in infants, life-threatening events, central sleep apnea due to the use of drugs or other substances, obesity-related hypoventilation syndrome, interrupted central respiratory drive, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscle respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during high-altitude acclimatization, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and congenital central alveolar hypoventilation syndrome, and dysphagia.

[0121] The compounds of the present invention are preferably used in methods for treating and / or preventing breathing difficulties and swallowing difficulties, including sleep-induced breathing difficulties, including obstructive sleep apnea (in adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypoventilation syndrome), central sleep apnea, Cheyne-Stokes respiration, primary sleep apnea in infants, life-threatening events, central sleep apnea due to the use of drugs or other substances, obesity hypoventilation syndrome, interrupted central respiratory drive, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscle respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during high-altitude acclimatization, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation, and congenital central alveolar hypoventilation syndrome.

[0122] In the context of this invention, peripheral and cardiovascular conditions include diabetic microangiopathy, diabetic ulcers of the extremities, particularly wound healing for diabetic foot ulcers, diabetic heart failure, diabetic coronary microangiopathy, thromboembolic conditions and local ischemia, peripheral circulatory disturbances, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disorders, and intermittent claudication.

[0123] Also preferably, the compounds of the present invention are used in methods for treating and / or preventing peripheral and cardiovascular conditions, including diabetic microangiopathy, diabetic ulcers of the extremities, and particularly in methods for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microangiopathy, thromboembolic conditions and local ischemia, peripheral circulatory disturbances, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disorders and intermittent claudication.

[0124] Furthermore, the compounds of the present invention can be used in methods of treating and / or preventing the following conditions: peripheral and central nervous system disorders, such as dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonia, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, tau Protein lesions, frontotemporal dementia associated with chromosome 17 and Parkinson's syndrome, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedrich's ataxia, atrophy of the dentate nucleus, rubra, globus pallidus, and hypothalamus, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Kreutzfeldt-Jacob disease and its variants, infantile neural axonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal degeneration with ubiquitin-proteasome system, and familial encephalopathy with neurogenic serine protease inhibitor inclusion bodies.

[0125] The compounds of the present invention are preferably used in methods for treating and / or preventing the following conditions: conditions of the peripheral and central nervous systems, including dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonia, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0126] The compounds of the present invention are also used in methods of treating and / or preventing the following conditions: peripheral and central nervous system disorders, such as dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without hyperactivity, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonia, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, Pick's disease, Wilson's disease, progressive supranuclear palsy, corticobasal degeneration, and tau protein. Lesions, frontotemporal dementia associated with chromosome 17 with Parkinson's syndrome, multiple system atrophy, spinocerebellar ataxia, Kennedy-type spinobulbar muscular atrophy, Friedrich's ataxia, atrophy of the dentate nucleus, rubra, globus pallidus, and hypothalamus, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, Kreutzfeldt-Jacob disease and its variants, infantile neural axonal dystrophy, neurodegeneration with brain iron accumulation, frontotemporal degeneration with ubiquitin-proteasome system, and familial encephalopathy with neurogenic serine protease inhibitor inclusion bodies.

[0127] Furthermore, the compounds of this invention are also suitable for the treatment and / or prevention of cardiovascular conditions, such as arrhythmias, atrial and ventricular arrhythmias, and conduction impairments, such as first- to third-degree atrioventricular block, 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, AV nodal reentrant tachycardia, hypertension (excessive blood pressure), heart failure, coronary artery disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular conditions, and Wolff-Parkinson-White syndrome. Acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy), boxer's cardiomyopathy, aneurysm, shock such as cardiogenic shock, septic shock, and anaphylactic shock. It is also used to treat and / or prevent thromboembolic conditions and local ischemia, such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disease, coronary and peripheral artery spasm, and hydrocele. Edema formation, such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and large vessel injury (vasculitis), and prevention of restenosis, such as in thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery, pulmonary hypertension (PAH) and other forms of pulmonary hypertension (PH).

[0128] In the context of this invention, the term "heart failure" includes acute and chronic forms of heart failure, and specific or related disease types such as acute decompensated heart failure, right heart failure, left heart failure, biventricular heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart defects, heart failure associated with valvular heart defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, combined valvular heart defects, myocarditis (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and diastolic and systolic heart failure.

[0129] The compounds of this invention can also be used to treat and / or prevent asthma symptoms of varying severity with intermittent or persistent characteristics (refractory asthma, bronchial asthma, allergic asthma, endogenous 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, cough and cold (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, such as hay fever) and polyps.

[0130] Furthermore, the compounds of this invention are also suitable for the treatment and / or prevention of kidney diseases, particularly renal insufficiency and renal failure. In this invention, the terms "renal insufficiency" and "renal failure" include their acute and chronic clinical manifestations as well as underlying or related kidney diseases such as renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulonephritis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, and nephrotic diseases such as primary and congenital kidney diseases, nephritis, immune-mediated nephropathy such as kidney transplant rejection and immune complex-induced nephropathy, nephropathy induced by toxic substances, and contrast agent-induced nephropathy. Nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome are characterized, for example, by abnormally low creatinine and / or water excretion, abnormally high blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes such as gamma-glutamyl synthase, altered urine homotonicity or volume, elevated urine microalbuminuria, massive albuminuria, glomerular and arteriolar lesions, renal tubular dilatation, hyperphosphatemia, and / or the need for dialysis. This invention also includes the use of the compounds of this invention for the treatment and / or prevention of the following conditions: sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), and metabolic disorders of bone and carbohydrates.

[0131] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of conditions of the urogenital system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence, such as mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.

[0132] The compounds of this invention are also suitable for the treatment and / or prevention of inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory eye disease, sepsis (SIRS), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α-1 antitrypsin deficiency (AATD), emphysema (such as emphysema caused by cigarette smoke), cystic fibrosis (CF), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, and are also suitable for the treatment and / or prevention of fibrotic diseases of internal organs such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as fibrotic diseases of the skin and eyes. In the context of this invention, the term "fibrotic condition" specifically includes conditions such as liver fibrosis, cirrhosis, pulmonary fibrosis, endocardial myocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, diabetic fibrotic damage, myelofibrosis, peritoneal fibrosis and similar fibrotic conditions, scleroderma, morphine, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue conditions (such as sarcoidosis). The compounds of this invention can also be used to promote wound healing, control postoperative scar formation (e.g., after glaucoma surgery), and for cosmetic purposes on aging or keratotic skin.

[0133] Furthermore, the compounds of the present invention are suitable for treating and / or preventing neoplastic conditions such as skin cancer, breast cancer, lung cancer, colon cancer, and prostate cancer.

[0134] Furthermore, the compounds of this invention can be used to treat and / or prevent arteriosclerosis, impaired lipid metabolism and dyslipidemia (hypolipinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abeta-lipoproteinemia, sitosterolemia), xanthoma, Tangier's disease, hyperlipidemia, obesity, metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, gestational diabetes mellitus, hyperinsulinemia, insulin resistance, glucose intolerance and sequelae of diabetes, such as retinopathy, nephropathy and neuropathy), anemia such as hemolytic anemia, and hemoglobinopathies (such as sickle cell anemia). And thalassemia, megaloblastic anemia, iron deficiency anemia, anemia due to acute blood loss, myelopathy anemia, and aplastic anemia); gastrointestinal and abdominal diseases (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mast cell disease, Crohn's disease, colitis, proctitis, anal pruritus, diarrhea, celiac disease, hepatitis, liver fibrosis, cirrhosis, pancreatitis, and cholecystitis); central nervous system diseases and neurodegenerative disorders (stroke, epilepsy, depression); immune disorders; thyroid diseases (hyperthyroidism); skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis); Including 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), bone and joint and skeletal muscle disorders, and inflammatory changes in arteries (various forms of arteritis, such as endarteritis, mediastinitis, periarteritis). Peripheral inflammation, 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 Goran's arteritis), Muckle-Well syndrome, Kikuchi disease, polychondritis, scleroderma, and other diseases with inflammatory or immune components, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndromes, for rejection after organ transplantation and for wound healing and angiogenesis, especially in the case of chronic trauma.

[0135] Due to their properties, the compounds of the present invention are particularly suitable for treating and / or preventing breathing difficulties, including sleep-induced breathing difficulties such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

[0136] The diseases fully characterized above in humans may also occur in other mammals with comparable causes, and in which they can also be treated with the compounds of the present invention.

[0137] For the purposes of this invention, the term "treatment" includes the suppression, delay, prevention, relief, reduction, limitation, decrease, halt, repulsion, or cure of the development, process, or occurrence of a disease, symptom, condition, injury, or health problem, or such state and / or symptoms of such state. The term "therapeutic method" is hereby understood to be synonymous with the term "treatment".

[0138] The terms “prevention” and “prophylaxis” are used synonymously in this invention and refer to the avoidance or reduction of the risk of infection, occurrence, being afflicted with or suffering from disease, symptoms, ailments, injuries or health problems or such conditions and / or the development or progression of symptoms of such conditions.

[0139] Treatment or prevention of disease, symptoms, ailments, injuries, or health problems can be partial or complete.

[0140] The present invention therefore also provides the use of the compounds of the present invention for treating and / or preventing diseases, especially the aforementioned diseases.

[0141] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing diseases, especially the aforementioned diseases.

[0142] The present invention also provides a medicine comprising at least one compound of the present invention for treating and / or preventing conditions, especially the aforementioned conditions.

[0143] The present invention also provides the use of the compounds of the present invention in methods for treating and / or preventing diseases, especially the aforementioned diseases.

[0144] The present invention also provides a method for treating and / or preventing diseases, especially the aforementioned diseases, using an effective amount of at least one compound of the present invention.

[0145] The compounds of the present invention can be used alone or, if desired, in combination with one or more other pharmacologically active substances, provided that such combination does not cause unwanted and unacceptable side effects. Therefore, the present invention also provides medicaments comprising at least one compound of the present invention and one or more active ingredients, particularly for the treatment and / or prevention of the aforementioned diseases. Preferred examples of combinations of active ingredients suitable for this purpose include: •TASK1 and TASK3 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, and WO 2018 / 228909 A1; • P2X3 receptor antagonists, such as, and preferably, gefapixant; • Respiratory stimulants, such as, and preferably, theophylline, doxapram, nikethamide, and caffeine; • Psychotropic compounds, such as, and preferably, modafinil and armodafinil; • Amphetamines and amphetamine derivatives, such as and preferably amphetamine, methamphetamine, and methylphenidate; • Serotonin reuptake inhibitors, such as and preferably fluoxetine, paroxetine, citalopram, etapril, sertraline, fluvoxamine, and trazodone; • Serotonin precursor, such as, and preferably, L-tryptophan; • Selective serotonin-norepinephrine reuptake inhibitors, such as, and preferably, venlafaxine and duloxetine; • Norepinephrine and specific serotonergic antidepressants, such as, and preferably, mirtazapine; • Selective norepinephrine reuptake inhibitors, such as, and preferably, atomoxetine and reboxetine; • Muscarinic receptor antagonists, such as, and preferably, oxybutynin; • Tricyclic antidepressants, such as and preferably amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine, and desipramine; • GABA agonists, such as, and preferably, baclofen; • Alpha-like sensory nerve drugs, such as and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrahydrozoline, and tramazoline; • Glucocorticoids, such as and preferably fluticasone, budesonide, beclomethasone, mometasone, tecristosol, and triamcinolone; • Cannabinoid receptor agonists and antagonists; • Carbonic anhydrase inhibitors, such as, and preferably, acetazolamide, metronidazole and diclofenac; • Opioid and benzodiazepine receptor antagonists, such as, and preferably, flumazenil, naloxone, and naltrexone; • Cholinesterase inhibitors, such as and preferably neostigmine, pyridostigmine, physostigmine donepezil, galantamine, and rivastigmine; • N-methyl-D-aspartic acid and glutamate antagonists, such as and preferably amantadine, memantine, sabeluazole; • Nicotine receptor agonists; • Leukotriene receptor antagonists, such as, and preferably, montelukast and triprolist; • Dopamine receptor antagonists, such as and preferably domperidone, metoclopramide, benzamide, butyric acid phenoxyacetate, phenothiazine; • Appetite suppressants, such as and preferably sibutramine, topiramate, lipase inhibitors, cannabinoid receptor antagonists, and phentermine; • Proton pump inhibitors, such as and preferably pantoprazole, omeprazole, emeprazole, lansoprazole, and rabeprazole; • The antihypertensive active ingredient, for example and preferably selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, angiopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, and diuretics. • Active ingredients that 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-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists; • Inorganic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide nitrate, madolamine or SIN-1 and inhaled NO; • Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dassenafil, avanafil, mironafil or lodenafil; • NO- and heme-independent activators of soluble guanylate cyclase (sGC), particularly compounds described in, for example, WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510; • NO-independent but heme-dependent activators of soluble guanylate cyclase (sGC), particularly, for example, riociguat and compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; • Compounds that affect cardiac energy metabolism, such as, and preferably, etorolimus, dichloroacetate, ranolazine, or trimetazine; • Antithrombotic agents, such as, and preferably selected from, platelet aggregation inhibitors, anticoagulants and fibrinolytic substances; • Anti-obstructive agents, such as those used to treat chronic obstructive pulmonary disease (COPD) or bronchial asthma, such as and preferably selected from β-adrenergic receptor agonists (β-mimics) administered by inhalation or systemic administration and inhaled antimuscarinic substances; • Anti-inflammatory, immunomodulatory, immunosuppressive, and / or cytotoxic agents, such as and preferably selected from corticosteroids administered systemically or by inhalation, as well as dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferons, natezumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tepillulast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, IFN-γ, pirfenidone, or etanercept; • Compounds that inhibit signal transduction cascades, such as and preferably selected from kinase inhibitors, particularly tyrosine kinase and / or serine / threonine kinase inhibitors, such as and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, sidinib, axitinib, tellatinib, imatinib, brinib, pazopanib, vastarabine, gefitinib, erlotinib, lapatinib, cannatinib, letatinib, peritinib, cemanib or tandutinib; • Prostacyclin analogues and IP receptor agonists, such as and preferably iloprost, beraprost, troronil, eprostol or selepag; • Endothelin receptor antagonists, such as and preferably bosentan, darussentan, ambrisentan or sitassentan; • Compounds that inhibit human neutrophil elastase (HNE), such as and preferably cevelexat or DX-890 (Reltran); • Compounds that inhibit the degradation and alteration of the extracellular matrix, such as, and preferably, inhibitors of matrix metalloproteinases (MMPs), especially inhibitors of matrix lysins, collagenases, gelatinases and polyproteoglycans (in this context, particularly MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastase (MMP-12). • Compounds that block serotonin from binding to its receptor, such as, and preferably, 5-HT 2B Receptor antagonists, such as PRX-08066; • Antagonists of growth factors, cytokines and chemokines, such as and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; • Rho kinase inhibitory compounds, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; and / or • Antifibrotic agents, such as and preferably pirfenidone, lysophosphatidylcholine receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β inhibitors, etc. Antagonist.

[0146] In a particularly preferred embodiment of the invention, the compound of the invention is administered in combination with one or more other active compounds selected from respiratory stimulants, psychotropic compounds, serotonin reuptake inhibitors, norepinephrine-like agents, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants, and cytotoxic drugs.

[0147] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a β-adrenergic receptor agonist, such as and preferably salbutamol, isoproterenol, orsinol, terbutaline, fenoterol, formoterol, reproterol, salbutamol, or salmeterol.

[0148] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an antimuscarinic substance, such as and preferably ipratropium bromide, tiotropium bromide or oxorphine bromide.

[0149] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a corticosteroid, such as and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolone, budesonide, or fluticasone.

[0150] Antithrombotic agents are preferably understood to be compounds selected from platelet aggregation inhibitors, anticoagulants, and plasminogen substances.

[0151] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a platelet aggregation inhibitor, such as and preferably aspirin, clopidogrel, ticlopidine, or dipyridamole.

[0152] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thrombin inhibitor, such as and preferably tamethasone, melagatone, dabigatran, bivalirudin, or ketamine.

[0153] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a GPIIb / IIIa antagonist, such as and preferably tirofiban or abciximab.

[0154] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a factor Xa inhibitor, such as and preferably rivaroxaban, apixaban, fidexaban, razaxan, fondaparin, epoxetine, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

[0155] In a preferred embodiment of the invention, the compound of the invention is administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0156] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vitamin K antagonist, such as and preferably coumarin.

[0157] Antihypertensive agents are preferably understood to be compounds selected from calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and diuretics.

[0158] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil, or diltiazem.

[0159] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an α-1-receptor blocker, such as and preferably prazosin.

[0160] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a β-receptor blocker, such as and preferably propranolol, atenolol, timolol, indolol, alpraolol, oxenolol, pentbuprofenolol, blavolol, metenolol, naldolol, metinolol, caralolol, sotalolol, metoprolol, betalolol, celylolol, bisoprolol, carteolol, esmololol, labetalol, carvedilol, adalolol, lantiolol, nebiolol, epamolol, or buxinolol.

[0161] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an angiotensin AII antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan, or enbusartan.

[0162] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril, or trandopril.

[0163] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an endothelin antagonist, such as and preferably bosentan, darusentan, ambesentan, or sitasentan.

[0164] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a renin inhibitor, such as and preferably aliskiren, SPP-600 or SPP-800.

[0165] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a mineralocorticoid receptor antagonist, such as and preferably spironolactone, eplerenone, or feneformin.

[0166] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a diuretic, such as and preferably furosemide, bumetanide, torasemide, benzylfluorothiazide, chlorothiazide, hydrochlorothiazide, hydrofluorothiazide, methamphetamine, porithiazide, trichlorothiazide, chlorthalidone, indapamide, metoprazine, quinethazine, acetazolamide, dichlorosulfonamide, acetazolamide, glycerin, isosorbide, mannitol, amiloride, or triamterene.

[0167] Lipid metabolism regulators are preferably understood to be compounds selected from CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymerized bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0168] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CETP inhibitor, such as and preferably Tochepi (CP-529 414), JJT-705, or the CETP vaccine (Avant).

[0169] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thyroid receptor agonist, such as and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425, or axitiro (CGS 26214).

[0170] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an HMG-CoA reductase inhibitor selected from statins, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0171] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

[0172] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACAT inhibitor, such as and preferably avamidib, methyllinoleamide, partemidib, irubib, or SMP-797.

[0173] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an MTP inhibitor, such as and preferably impetatae, BMS-201038, R-103757 or JTT-130.

[0174] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-γ agonist, such as and preferably pioglitazone or rosiglitazone.

[0175] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-δ agonist, such as and preferably GW 501516 or BAY 68-5042.

[0176] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tequinone, or pamalogin.

[0177] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipase inhibitor, such as and preferably orlistat.

[0178] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a polymeric bile acid adsorbent, said polymeric bile acid adsorbent being, for example and preferably, cholestyramine, colestipol, colesolvam, cholestaGel, or colestimid.

[0179] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a bile acid reabsorption inhibitor, such as and preferably an ASBT (=IBAT) inhibitor, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0180] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipoprotein(a) antagonist, such as and preferably gemcabene calcium (CI-1027) or niacin.

[0181] Particularly preferred are the combinations of the compounds of the present invention with one or more other active compounds selected from respiratory stimulants, psychotropic compounds, serotonin reuptake inhibitors, norepinephrine-dependent agents, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, and / or anti-inflammatory drugs, immunomodulators, immunosuppressants, and / or cytotoxic drugs.

[0182] If desired, the compounds of the present invention can also be used in combination with one or more other medical interventions, provided that such combination does not produce unwanted and unacceptable side effects. Preferred examples of medical interventions suitable for this purpose include: • Devices for positive airway pressure ventilation, such as and preferably CPAP (continuous positive pressure ventilation) devices, BiPAP (bidirectional positive pressure ventilation) devices, and IPPV (intermittent positive pressure ventilation) devices; • A nerve stimulator for the hypoglossal nerve; • Intraoral assistive devices, such as, and preferably, protruding braces; • Disposable nasal valve; • Nasal support.

[0183] The present invention also provides a medicine comprising at least one compound of the present invention, typically with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the above purposes.

[0184] The compounds of the present invention can act systemically and / or locally. Therefore, they can be administered in suitable manner, for example by oral, parenteral, pulmonary, nasal, pharyngeal, sublingual, tongue, oral cavity, rectum, skin, transdermal, conjunctival, or ear, or as implants or scaffolds.

[0185] The compounds of the present invention can be administered in a form suitable for these routes of administration.

[0186] Suitable forms of administration for oral administration are those that work according to the prior art and release the compounds of the invention rapidly and / or in a controlled manner and contain the compounds of the invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, for example with an acid-resistant or delayed-dissolution or insoluble coating that controls the release of the compounds of the invention), tablets or films / rounds that disintegrate rapidly in the mouth, films / lyophilized products, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions.

[0187] Parenteral administration can bypass absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar administration) or involve absorption (e.g., inhalation, intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal administration). Suitable forms of administration for parenteral administration include, in particular, injectable and infusion formulations in the form of solutions, suspensions, emulsions, lyophilized products, or sterile powders.

[0188] 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 / tablets or capsules administered by the tongue, sublingually or orally, 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, powders, implants or stents.

[0189] Oral, parenteral, and topical administration are preferred, especially oral, intravenous, intranasal, and pharyngeal administration.

[0190] The compounds of the present invention can be converted into the aforementioned dosage forms. This can be achieved, in a manner known per se, by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, in particular, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, such as ascorbic acid), colorants (e.g., inorganic pigments, such as iron oxide), and flavor and / or odor modifiers.

[0191] It has generally been found advantageous to administer approximately 0.001 to 1 mg / kg body weight, preferably approximately 0.01 to 0.5 mg / kg body weight, to achieve effective results when administered parenterally. In the case of oral administration, the dose is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg body weight. In the case of intrapulmonary administration, the dose is typically approximately 0.1 to 50 mg per inhalation.

[0192] However, in some cases, deviations from the stated amounts may be necessary, especially depending on body weight, route of administration, individual response to the active ingredient, the nature of the formulation, and the time or time interval between administrations. For example, in some cases, less than the minimum amount mentioned above may be sufficient, while in others it may be necessary to exceed the mentioned upper limit. In cases where larger doses are administered, it may be recommended to divide them into several single doses throughout the day.

[0193] The following working examples illustrate the present invention. The present invention is not limited to these examples.

[0194] A. Example Abbreviations and acronyms: Absolute value Acetyl aq. containing water, aqueous solution Boc tert-butyloxycarbonyl br. width (in NMR signal) Example Bu Dingji c concentration ca. approximately, about cat. catalysis CI chemical ionization (in MS) d-bimodal (in NMR) d day Direct chemical ionization of DCI (in MS) dd doublet (in NMR) diamix diastereomer mixture DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) dq double quartet (in NMR) dt double triplet (in NMR) The Ot theory (in chemical yield) Electron collisional ionization (in MS) eq. equivalent ESI electrospray ionization (in MS) Et ethyl h hours HATU O -(7-azabenzotriazol-1-yl)- N,N,N',N' -Tetramethylurea hexafluorophosphate HOBt 1-hydroxy-1 H -Benztriazole hydrate HPLC (High-Performance Liquid Chromatography) iPr Isopropyl Concentrated (in the case of solution) LC liquid chromatography LC-MS (Liquid Chromatography-Mass Spectrometry) Lit. References m multiplets (in NMR) Memethyl min minutes MS mass spectrometry MTBE methyl tert-butyl ether NMR nuclear magnetic resonance spectroscopy Phphenyl Prpropyl q-quartet (in NMR) quant. (in chemical yield) Reversed-phase RP (in HPLC) RT room temperature / retention time R t Retention time (in HPLC, LC / MS) s singlet (in NMR) t triplet (in NMR) tBu tert-butyl TFA (trifluoroacetic acid) THF tetrahydrofuran UV spectroscopy v / v (the ratio of solution volume to volume) together LC-MS, GC-MS and HPLC methods Method 1 (LC-MS): MS instrument type: Thermo Scientific FT-MS; UHPLC+ instrument type: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; Mobile phase A: 1 L water + 0.01% formic acid; Mobile phase B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven: 50℃; Flow rate: 0.90 ml / min; UV detection: 210 nm / optimal integration path 210-300 nm.

[0195] Method 2 (LC-MS): Instruments: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 1 mm; Mobile phase: 1 L water + 0.25 ml 99% formic acid; Mobile phase B: 1 L acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50℃; Flow rate: 0.40 ml / min; UV detection: 210 nm.

[0196] Method 3 (LC-MS): MS instrument type: Thermo Scientific FT-MS; UHPLC+ instrument type: Thermo Scientific UltiMate 3000; Column: Waters, BEH C18 1.7 µ, 2.1 x 50 mm; Mobile phase A: 1 L water + 1.0 ml (25% ammonia); Mobile phase B: 1 L acetonitrile; Gradient: 0.0 min 5% 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.

[0197] Method 4 (LC-MS): MS instrument type: Thermo Scientific FT-MS; UHPLC+ instrument type: Thermo Scientific Vanquish; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; Mobile phase: 1 L water + 0.01% formic acid, Mobile phase B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven: 50℃; Flow rate: 0.90 ml / min; UV detection: 210 nm.

[0198] Method 5 (LC-MS): Instruments: Waters Single Quad MS System; Instruments: Waters UPLC Acquity; Column: Waters BEH C18 1.7 µ 50 x 2.1 mm; Mobile phase A: 1 L water + 1.0 ml (25% ammonia) / L, Mobile phase B: 1 L acetonitrile; Gradient: 0.0 min 92% A → 0.1 min 92% A → 1.8 min 5% A → 3.5 min 5% A; Oven: 50 °C; Flow rate: 0.45 ml / min; UV detection: 210 nm.

[0199] Method 6 (LC-MS): MS instrument: Waters SQD2; HPLC instrument: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 µm; Mobile phase A: Water + 0.025% formic acid, Mobile phase B: Acetonitrile (ULC) + 0.025% formic acid; Gradient: 0.0 min 98% A - 0.9 min 25% A - 1.0 min 5% A - 1.4 min 5% A - 1.41 min 98% A - 1.5 min 98% A; Oven: 40℃; Flow rate: 0.600 ml / min; UV detection: DAD; 210 nm.

[0200] Other details: The following text 1 The description of the coupling modes of H NMR signals is based on the visual appearance of the signals involved and does not necessarily correspond to a rigorous, physically correct interpretation. Generally, the chemical shift referred to is the center of the signal involved; in the case of wide multiplying, an interval is given.

[0201] In all 1 In H NMR spectral data, the chemical shift δ[ppm] is expressed in ppm.

[0202] The following paragraphs report 1 The multiplicity of the proton signal in a 1H NMR spectrum represents the signal form observed in each case, without considering any higher-order signal phenomena. Generally, the chemical shift refers to the center of the signal under discussion. In the case of broad multiplets, the interval is given. Signals masked by solvent or water are provisionally designated or not listed. Significantly broadened signals (e.g., due to rapid rotation of molecular moieties or proton exchange) are also provisionally designated (often referred to as broad multiplets or broad singlets) or not listed.

[0203] Selected synthetic intermediates and examples 1 H NMR data with 1 The peaks are listed in the form of an H-NMR peak list. For each signal peak, the δ[ppm] value is listed first, followed by the signal intensity in parentheses. The δ[ppm] value / signal intensity pairs of different signal peaks are listed separately with commas. Therefore, one embodiment of the peak list takes the following form: δ[ppm] = 1 (intensity 1), δ[ppm] = 2 (intensity 2), ..., δ[ppm] = i (strength i ), ... , δ[ppm] = n (strength n ).

[0204] The intensity of a sharp signal is correlated with the signal height (in cm) in the printed example of the NMR spectrum, and the true ratio of signal intensity to other signals is displayed. In the case of a broad signal, multiple peaks or the center of the signal and their relative intensity to the strongest signal in the spectrum can be displayed. 1 The list of H-NMR peaks is similar to that of conventional ones. 1 The H-NMR printouts, and therefore typically contain all the peaks listed in a conventional NMR interpretation. Furthermore, similar to conventional... 1 H-NMR printouts can display solvent signals, signals of stereoisomers of the target compound (which is also the subject of this invention), and / or impurity peaks. The peaks of the stereoisomers of the target compound and / or impurity peaks typically have lower average intensities than the peaks of the target compound (e.g., with >90% purity). Such stereoisomers and / or impurities may be typical for a particular preparation method. Therefore, their peaks help identify the reproducibility of our preparation method by referring to a “byproduct fingerprint.” A person skilled in the art who has calculated the peaks of the target compound using known methods (MestReC, ACD simulation, or using empirically evaluated expected values) can separate the peaks of the target compound as needed, optionally using additional intensity filters. This separation is similar to conventional methods. 1 Peak picking involved in H-NMR interpretation. A detailed description of NMR data presented 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 conventions described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be set between 1% and 4%. Depending on the type of chemical structure and / or the concentration of the compound being analyzed, it may be reasonable to set the parameter "MinimumHeight" to a value <1%.

[0205] Melting point and melting range (if noted) have not been corrected.

[0206] When the reaction products are obtained by grinding, stirring, or recrystallization, a greater quantity of product can often be separated from the respective mother liquors by chromatography. However, unless only the majority of the total yield can be separated in this step, a description of this chromatographic method will be omitted below.

[0207] For all reactants or reagents whose preparation is not explicitly described below, they were purchased from generally available sources. For all other reactants or reagents whose preparation is also not described below and which are not commercially available or are obtained from sources that are not generally available, refer to the published literature in which their preparation is described.

[0208] Starting materials and intermediates: Example 1A (5-bromo-1,3-thiazolyl-2-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 19.59 ml (112.48 mmol) N , N - Diisopropylethylamine was added to 7.8 g (37.49 mmol) of 2-bromo-1,3-thiazolyl-5-carboxylic acid and 9.57 g (37.49 mmol) of (3 R 3-Methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 312 ml of acetonitrile solution. Then, at room temperature, 29 ml (48.74 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 250 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was further purified by silica gel column chromatography (Isolera Biotage SNAP-Ultra 100 g column, mobile phase: dichloromethane → gradient 15 CV (CV = column volume) → dichloromethane / methanol 85:15). This yielded 9.5 g (25 mmol, 67% of the theoretical value) of the target compound as a yellow oil.

[0209] 1 H-NMR (600 MHz, DMSO- d6, δ / ppm): 0.74-0.89 (m, 4H, of which 0.83 (d, 3H)), 1.31-1.68 (m, 6H), 1.70-1.82 (m, 3H), 2.05 (td, 1H), 2.44-2.57 (m, 4H, partially masked by DMSO), 2.69-2.85 (m, 3H), 7.97 (s, 1H).

[0210] LC-MS (Method 1): R t = 0.69 min; m / z = 372 / 374 (M+H) + .

[0211] Example 2A (2-bromo-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidin]-1'-yl]methyl ketone hydrochloride (1:1) 15.22 ml (87.40 mmol) N , N - Diisopropylethylamine was added to 4 g (19.23 mmol) of 2-bromo-1,3-thiazolyl-5-carboxylic acid and 4.46 g (17.48 mmol) of (3 R 3-Methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 60 ml of acetonitrile solution. Then, 6.12 ml (20.98 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide was added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated under reduced pressure, and 30 ml of saturated sodium bicarbonate solution was added. The resulting mixture was repeatedly extracted with dichloromethane, the organic phase was removed, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was further purified by silica gel column chromatography (Isolera Biotage SNAP-Ultra 340 g column, mobile phase: dichloromethane → gradient 15 CV (CV = column volume) → dichloromethane / methanol 85:15). The fractions containing the product were combined and concentrated. The resulting residue was converted to hydrochloride, filtered, and dried under reduced pressure. This yielded 3.80 g (9.30 mmol, 100% purity, 53% of theoretical value) of the target product in solid form.

[0212] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.90 (d, 3H), 1.01-1.17 (m, 1H), 1.56-1.91 (m, 6H), 1.92-2.06 (m, 1H), 2.07-2.21 (, 2H), 2.42-2.63 (m, 2H, partially masked by DMSO), 2.74-2.94 (m, 2H), 3.22-3.55 (m, 2H, partially masked by H2O), 4.00-4.71 (m, 2H), 7.97-8.06 (m, 1H), 10.13 (br. s, 1H).

[0213] LC-MS (Method 2): R t = 0.53 min; m / z = 372 / 374 (M+H) + .

[0214] Example 3A 2-{[(1 S Methyl 1-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylate methyl 2-bromo-1,3-thiazolyl-5-carboxylate (1.30 g, 5.87 mmol), (1 S 1-(3-Fluoropyridin-2-yl)ethylamine dihydrochloride (1.50 g, 7.04 mmol) and N,N-diisopropylethylamine (6.0 ml, 34 mmol) were added to a microwave-safe container, which was then sealed, and the mixture was stirred at 110 °C. After 1 h, the reaction mixture was dissolved in water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was applied to an Isolute® column and purified using a Biotage column (50 g Sfähr HC; Cy / EA gradient: 12-100% EA; flow rate: 120 ml / min). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 497 mg (100% purity, 30% of theoretical value) of the target compound.

[0215] LC-MS (Method 1): R t = 1.43 min; MS (ESIpos): m / z = 282 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.476 (5.96), 1.490 (6.01), 3.706(16.00), 5.323 (0.45), 5.337 (0.66), 5.351 (0.45), 7.394 (0.66), 7.403(1.17), 7.412 (1.32), 7.420 (1.34), 7.429 (0.79), 7.691 (0.86), 7.693 (0.87), 7.710 (6.66), 7.714 (1.10), 7.728 (0.79), 7.731 (0.75), 8.404 (0.90), 8.407 (1.47), 8.410 (0.95), 8.414 (0.99), 8.416 (1.46), 8.419 (0.86), 9.042 (1.19), 9.057 (1.17).

[0216] Example 4A 2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid A lithium hydroxide solution (7.1 mL, 1.0 M, 7.1 mmol) was added to an initial feed of 2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylate (497 mg, 1.77 mmol) in 18 mL of THF, and the mixture was stirred at 60 °C. After 3 h, the reaction mixture was acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. This yielded 347 mg of the target compound (100% purity, 73% of the theoretical value).

[0217] LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 268 [M+H] + .

[0218] Example 5A (MBM12257-1) rac-3- Cyclopropyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (548 mg, 2.75 mmol), rac 3-Cyclopropylpiperidine hydrochloride (890 mg, 5.50 mmol) and N,N-diisopropylethylamine (960 µl, 5.5 mmol) were used to form the initial feed in 30 mL of dichloromethane. Subsequently, concentrated acetic acid (240 µl, 4.1 mmol) was added, and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added, and the mixture was stirred again at room temperature for 48 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 23 ml, mobile phase B 0–2 min 47 ml, mobile phase A 2–10 min from 23 ml to 0 ml and mobile phase B from 47 ml to 70 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 370 mg of the target compound (100% purity, 44% of the theoretical value).

[0219] LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 309 [M+H] + .

[0220] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.040 (0.69), 0.045 (0.55), 0.315(0.46), 0.326 (0.55), 0.331 (0.40), 0.335 (0.49), 0.344 (0.43), 1.380(16.00), 1.675(0.45), 1.966(0.48).

[0221] Example 6A rac 3-Cyclopropyl-1,4'-Bipiperidine Hydrochloride Add hydrochloric acid to 1,4-dioxane (1.5 ml, 4.0 M, 6.0 mmol) to... rac- 3-Cyclopropyl[1,4'-Bipiperidine]-1'-carboxylic acid tert-butyl ester (370 mg, 1.20 mmol) was dissolved in 12 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 269 mg (92% of the theoretical value) of the target compound.

[0222] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.007 (7.11), 0.107 (2.05), 0.129(8.51), 0.140 (13.48), 0.152 (8.25), 0.160 (4.71), 0.173 (2.21), 0.369(1.04), 0.382 (1.68), 0.401 (15.88), 0.421 (16.00), 0.441 (2.10), 0.492(1.16), 0.504 (2.34), 0.512 (2.98), 0.524 (4.52), 0.533 (3.66), 0.544 (3.85), 0.555 (2.17), 1.197 (0.84), 1.208 (0.81), 1.227 (2.58), 1.238 (2.52), 1.257(4.02), 1.268 (4.70), 1.285 (4.79), 1.296 (5.00), 1.324 (2.69), 1.394 (0.52), 1.773 (4.45), 1.801 (6.64), 1.829 (7.94), 1.880 (2.30), 1.932 (1.86), 1.954(4.46), 1.964 (4.20), 1.985 (6.58), 2.007 (4.29), 2.017 (4.74), 2.038 (1.68), 2.261 (4.98), 2.288 (7.77), 2.317 (3.98), 2.365 (0.52), 2.523 (0.96), 2.669 (0.45), 2.709 (0.53), 2.764 (1.68), 2.791 (4.85), 2.815 (6.49), 2.843 (6.08), 2.888 (6.34), 2.991 (0.41), 3.241 (5.33), 3.271 (5.29), 3.292 (5.19), 3.325 (5.22), 3.407 (10.60), 3.449 (4.30), 3.476 (2.20), 9.112 (1.96), 9.283 (2.33), 10.954 (2.68).

[0223] Example 7A rac- 3-Isopropyl[1,4'-Bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (940 mg, 4.72 mmol) and r ac 3-Isopropylpiperidine (1.20 g, 9.43 mmol) was used as the initial feed in 50 mL of dichloromethane. Subsequently, concentrated acetic acid (400 µl, 7.1 mmol) was added, and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (1.20 g, 5.66 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (1.20 g, 5.66 mmol) was added, and the mixture was stirred again at room temperature for 48 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v 20 v %), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, complete injection; gradient overview: mobile phase A 0–2 min 39 ml, mobile phase B 0–2 min 31 ml, mobile phase A 2–10 min 39 ml–15 ml and mobile phase B 31 ml–55 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 269 mg (100% purity, 18% of theoretical value) of the target compound.

[0224] LC-MS (Method 1): R t = 1.14 min; MS (ESIpos): m / z = 311 [M+H] + .

[0225] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.826 (2.33), 0.831 (2.37), 0.843(2.52), 0.848 (2.58), 1.363 (0.49), 1.379 (16.00), 1.396 (0.42), 1.640(0.47), 1.672(0.42), 1.854(0.44).

[0226] Example 8A rac -3-Isopropyl-1,4'-Bipiperidine Hydrochloride Hydrochloric acid was added to 1,4-dioxane (1.1 ml, 4.0 M, 4.3 mmol) to... rac- 3 - Cyclopropyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (269 mg, 866 µmol) was dissolved in 10 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 219 mg (102% of the theoretical value) of the target compound.

[0227] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (10.57), 0.870 (16.00), 0.888 (11.48), 1.101 (0.55), 1.127 (0.62), 1.140 (0.61), 1.155 (0.68), 1.170(0.71), 1.498 (0.84), 1.514 (1.24), 1.530 (1.22), 1.547 (0.77), 1.711 (1.13), 1.741 (0.99), 1.839 (2.12), 1.861 (2.62), 1.916 (0.50), 1.938 (1.06), 1.946 (1.09), 1.968 (1.54), 1.977 (1.55), 2.000 (1.14), 2.008 (1.10), 2.029 (0.41), 2.261 (1.10), 2.300 (1.48), 2.340 (0.92), 2.641 (0.43), 2.669 (1.15), 2.694 (0.99), 2.724 (0.46), 2.793 (0.64), 2.815 (0.80), 2.841 (0.94), 2.876 (1.42), 2.900 (1.37), 3.248 (1.20), 3.276 (1.19), 3.295 (0.46), 3.329 (1.88), 3.415 (3.01), 3.563 (0.51), 8.988 (0.51), 9.174 (0.61), 10.825 (0.69).

[0228] Example 9A rac- 3-tert-butyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (505 mg, 2.53 mmol), rac3-tert-butylpiperidine hydrochloride (900 mg, 5.06 mmol) and N,N-diisopropylethylamine (880 µl, 5.1 mmol) were used to form the initial feed in 25 mL of dichloromethane. Subsequently, concentrated acetic acid (220 µl, 3.8 mmol) was added, and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (644 mg, 3.04 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (644 mg, 3.04 mmol) was added, and the mixture was stirred again at room temperature for 48 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 23 ml, mobile phase B 0–2 min 47 ml, mobile phase A 2–10 min from 23 ml to 0 ml and mobile phase B from 47 ml to 70 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 318 mg of the target compound (100% purity, 39% of the theoretical value).

[0229] LC-MS (Method 1): R t = 1.20 min; MS (ESIpos): m / z = 325 [M+H] + .

[0230] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.828 (12.43), 1.379 (16.00), 1.643 (0.52), 1.674 (0.48), 1.838 (0.48), 3.325 (0.48), 3.394 (0.47).

[0231] Example 10A rac 3-tert-butyl-1,4'-piperidine hydrochloride Hydrochloric acid was added to 1,4-dioxane (1.2 ml, 4.0 M, 4.9 mmol) to... rac- 3-tert-butyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (318 mg, 980 µmol) was dissolved in 10 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 262 mg (102% of the theoretical value) of the target compound.

[0232] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.867 (16.00), 1.855 (0.79), 1.863 (0.79), 3.280 (0.47), 3.298 (0.49), 3.403 (0.64).

[0233] Example 11A rac- 3-Cyclobutyl[1,4'-Bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (622 mg, 3.12 mmol) and rac3-Isopropylpiperidine (870 mg, 6.25 mmol) was used as the initial feed in 30 mL of dichloromethane. Concentrated acetic acid (270 µl, 4.7 mmol) was then added, and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (795 mg, 3.75 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (795 mg, 3.75 mmol) was added, and the mixture was stirred again at room temperature for 48 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 23 ml, mobile phase B 0–2 min 47 ml, mobile phase A 2–10 min from 23 ml to 0 ml and mobile phase B from 47 ml to 70 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 285 mg of the target compound (100% purity, 28% of the theoretical value).

[0234] LC-MS (Method 1): R t = 1.21 min; MS (ESIpos): m / z = 323 [M+H] + .

[0235] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.376 (16.00), 1.588 (0.43), 1.615(0.69), 1.631 (0.54), 1.638 (0.62), 1.657 (0.54), 1.669 (0.44), 1.695 (0.51), 2.664 (0.40).

[0236] Example 12A rac 3-Cyclobutyl-1,4'-Bipiperidine hydrochloride Hydrochloric acid was added to 1,4-dioxane (1.1 ml, 4.0 M, 4.4 mmol) to... rac 3-Cyclobutyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (285 mg, 884 µmol) was dissolved in 10 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 239 mg (104% of the theoretical value) of the target compound.

[0237] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.007 (6.02), 0.870 (0.97), 0.924(1.22), 0.945 (3.13), 0.955 (3.18), 0.975 (3.52), 0.985 (3.20), 1.006 (1.58),1.016 (1.21), 1.100 (0.44), 1.622 (1.41), 1.644 (3.83), 1.664 (6.30), 1.684(11.25), 1.711 (15.25), 1.723 (13.76), 1.745 (6.18), 1.765 (2.62), 1.798 (5.25), 1.835 (12.60), 1.857 (6.07), 1.865 (5.13), 1.909 (6.81), 1.940 (14.55), 1.961 (16.00), 1.992 (11.77), 2.018 (7.93), 2.037 (4.66), 2.058 (1.74), 2.237 (5.21), 2.280 (5.86), 2.321 (4.20), 2.366 (0.71), 2.579 (2.03), 2.669 (0.44), 2.710 (0.71), 2.760 (1.61), 2.783 (3.71), 2.813 (3.96), 2.835 (4.04), 2.862 (6.36), 2.890 (6.50), 3.052 (0.80), 3.102 (5.60), 3.129 (4.84), 3.204 (0.58), 3.234 (0.65), 3.308 (6.16), 3.400 (12.79), 3.433 (4.77), 3.462 (2.40), 3.562 (13.01), 5.751 (5.23), 9.063 (2.45), 9.270 (3.09), 10.963 (3.35).

[0238] Example 13A rac 3-Ethyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (880 mg, 4.42 mmol) and rac3-Ethylpiperidine (1.00 g, 8.83 mmol) was used as the initial feed in 45 mL of dichloromethane. Concentrated acetic acid (380 µl, 6.6 mmol) was then added, and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (1.12 g, 5.30 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (1.12 g, 5.30 mmol) was added, and the mixture was stirred again at room temperature for 24 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v 20 v %), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, complete injection; gradient overview: mobile phase A 0–2 min 39 ml, mobile phase B 0–2 min 31 ml, mobile phase A 2–10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 413 mg (100% purity, 32% of theoretical value) of the target compound.

[0239] LC-MS (Method 1): R t = 1.02 min; MS (ESIpos): m / z = 297 [M+H] + .

[0240] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.824 (1.01), 0.842 (2.62), 0.861(1.26), 1.147 (0.42), 1.165 (0.44), 1.274 (0.47), 1.382 (16.00), 1.642(0.43), 1.670(0.54), 1.771(0.44), 2.731(0.48).

[0241] Example 14A rac3-Ethyl-1,4'-Bioperidine Hydrochloride Hydrochloric acid was added to 1,4-dioxane (1.7 ml, 4.0 M, 7.0 mmol) to... rac 3-Ethyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (413 mg, 1.39 mmol) was dissolved in 15 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 329 mg (101% of the theoretical value) of the target compound.

[0242] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.013 (0.73), 0.859 (6.26), 0.877(16.00), 0.896 (7.64), 1.033 (0.99), 1.045 (0.92), 1.064 (1.06), 1.076(0.99), 1.094 (0.47), 1.162 (0.68), 1.180 (1.11), 1.196 (1.51), 1.214 (1.77), 1.233 (1.16), 1.250 (0.66), 1.267 (1.17), 1.283 (1.51), 1.301 (1.62), 1.320 (0.90), 1.335 (0.57), 1.778 (1.45), 1.846 (2.85), 1.896 (1.77), 1.931 (2.06), 1.963 (1.96), 2.247 (1.45), 2.279 (2.41), 2.311 (1.15), 2.366 (0.42), 2.579 (1.36), 2.604 (1.18), 2.632 (0.52), 2.669 (0.41), 2.709 (0.40), 2.793 (0.93), 2.818 (0.98), 2.902 (1.75), 3.266 (1.53), 3.289 (1.51), 3.299 (1.34), 3.389(5.67), 3.421 (3.80), 3.464 (0.57), 8.902 (0.64), 9.081 (0.73), 10.735(0.76).

[0243] Example 15A rac 3-propyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (426 mg, 2.14 mmol), rac 3-Propylpiperidine hydrochloride (700 mg, 4.28 mmol) and N,N-diisopropylethylamine (740 µl, 4.3 mmol) were used to form the initial feed in 25 mL of dichloromethane. Subsequently, concentrated acetic acid (180 µl, 3.2 mmol) was added and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added, and the mixture was stirred again at room temperature for 24 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C185 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 23 ml, mobile phase B 0–2 min 47 ml, mobile phase A 2–10 min from 23 ml to 0 ml and mobile phase B from 47 ml to 70 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 262 mg (100% purity, 39% of the theoretical value) of the target compound.

[0244] LC-MS (Method 1): R t = 1.16 min; MS (ESIpos): m / z = 311 [M+H] + .

[0245] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.34), 0.820 (1.16), 0.838(2.67), 0.856 (1.34), 1.241 (0.67), 1.260 (0.99), 1.279 (0.61), 1.375(16.00), 1.633(0.59), 1.665(0.51), 1.764(0.42), 2.704(0.46).

[0246] Example 16A rac 3-Propyl-1,4'-Bipiperidine Hydrochloride Hydrochloric acid was added to 1,4-dioxane (1.1 ml, 4.0 M, 4.2 mmol) to... rac 3-propyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (262 mg, 844 µmol) was dissolved in 9 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 209 mg (100% of the theoretical value) of the target compound.

[0247] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.871 (16.00), 1.070 (2.56), 1.203(4.53), 1.313 (5.20), 1.757 (3.92), 1.844 (7.04), 1.956 (7.10), 2.272 (6.15), 2.903 (5.47), 8.881 (2.30), 9.035 (2.55), 10.678 (2.54).

[0248] Example 17A rac 3-(cyclobutoxy)[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester 4-O-piperidine-1-carboxylic acid tert-butyl ester (520 mg, 2.61 mmol), rac3-(cyclobutoxy)piperidine hydrochloride (1.00 g, 5.22 mmol) and N,N-diisopropylethylamine (910 µl, 5.2 mmol) were used to form the initial feed in 30 mL of dichloromethane. Subsequently, concentrated acetic acid (220 µl, 3.9 mmol) was added and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (663 mg, 3.13 mmol) was added, and the mixture was stirred overnight at room temperature. More sodium triacetoxyborohydride (663 mg, 3.13 mmol) was added, and the mixture was stirred again at room temperature for 24 h. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v 20 v %), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, complete injection; gradient overview: mobile phase A 0–2 min 39 ml, mobile phase B 0–2 min 31 ml, mobile phase A 2–10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 563 mg of the target compound (100% purity, 64% of the theoretical value).

[0249] LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 339 [M+H] + .

[0250] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.380 (16.00), 1.393 (0.57), 1.419(0.43), 1.582 (0.52), 1.624 (0.57), 1.657 (0.42), 1.788 (0.46), 1.811 (0.50), 1.922 (0.43), 2.104 (0.42), 2.639 (0.40), 3.966 (0.53), 3.984 (0.48).

[0251] Example 18A rac 3-(cyclobutoxy)-1,4'-bipiperidine hydrochloride Hydrochloric acid was added to 1,4-dioxane (2.1 ml, 4.0 M, 8.3 mmol) to... rac 3-(cyclobutoxy)[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (563 mg, 1.66 mmol) was dissolved in 9 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was stirred with MTBE. The solid was filtered off, washed with MTBE, and dried under high vacuum. This yielded 560 mg (123% of the theoretical value) of the target compound.

[0252] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.014 (1.61), 0.477 (0.73), 1.101(1.06), 1.295 (2.84), 1.318 (3.53), 1.341 (2.98), 1.370 (1.34), 1.380 (1.14),1.407 (3.70), 1.426 (7.05), 1.432 (6.36), 1.452 (9.04), 1.473 (4.46), 1.478(4.82), 1.498 (1.74), 1.596 (6.92), 1.621 (7.91), 1.716 (2.44), 1.752 (2.59), 1.801 (7.88), 1.827 (13.14), 1.851 (16.00), 1.918 (8.14), 1.952 (10.89), 1.983 (12.81), 2.141 (11.90), 2.156 (13.86), 2.249 (6.47), 2.277 (7.78), 2.684 (4.33), 2.709 (4.65), 2.734 (1.86), 2.862 (9.48), 2.892 (9.28), 3.008(2.10), 3.038 (2.19), 3.077 (1.92), 3.108 (3.04), 3.134 (2.28), 3.226 (3.32), 3.281 (8.20), 3.311 (12.64), 3.400 (14.00), 3.410 (15.15), 3.470 (4.85), 3.827 (8.21), 4.041 (6.97), 4.059 (9.25), 4.078 (6.14), 4.095 (1.76), 9.028(2.52), 9.176 (3.33), 9.256 (2.35), 9.325 (2.19), 11.297 (3.16).

[0253] Example 19A 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one 16.75 ml (96.14 mmol) N , NDiisopropylethylamine was added to a solution of 5 g (24.04 mmol) 2-bromo-1,3-thiazolyl-5-carboxylic acid and 3.26 g (24.04 mmol) piperidin-4-one hydrochloride (1:1) in 250 mL of acetonitrile. Then, at room temperature, 18.6 mL (19.88 mmol) of 50% T3P in ethyl acetate (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to this reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 250 mL of ethyl acetate. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was applied to Isolute® and purified using a Biotage column (50 g Sfähr HC; cyclohexane / ethyl acetate gradient: 12-100% ethyl acetate; flow rate: 120 ml / min). This yielded 4.89 g (16.91 mmol, 70% of the theoretical value) of the target compound as a white solid.

[0254] LC-MS (Method 1): R t = 0.96 min; m / z = 288 / 290 (M+H) + .

[0255] Example 20A (2-Bromo-1,3-thiazo-5-yl)[3-(methoxymethyl)[1,4'-bipiperidine]-1'-yl]methyl ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one (100 mg, 346 µmol) and 89 mg (692 µmol) of 3-(methoxymethyl)piperidine (racemic mixture) were dissolved in 3.5 mL of dichloromethane, and acetic acid (0.03 mL, 519 µmol) was added. Subsequently, sodium triacetoxyborohydride (88 mg, 415 µmol) was added to the reaction mixture, and the mixture was stirred at 37 °C for 2.5 h. Then, another 50 mg of sodium triacetoxyborohydride was added to the reaction mixture, and it was stirred at the same temperature for 2 days. After adding another 50 mg of sodium triacetoxyborohydride, the reaction mixture was heated to 50 °C and stirred at that temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and water. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; mobile phase A = water, B = acetonitrile; gradient: 0.0 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid; UV detection: DAD; 210 nm). Solvent removal yielded 51 mg (37% of the theoretical value) of the title compound.

[0256] LC-MS (Method 1): R t = 0.70 min; m / z = 402 / 404 (M+H) + .

[0257] 1 ¹H-NMR (400 MHz, DMSO-d⁶) δ [ppm]: 0.85–1.00 (m, 1H), 1.32–1.52 (m, 3H), 1.54–1.64 (m, 2H), 1.65–1.81 (m, 3H), 1.90 (t, 1H), 2.12 (t, 1H), 2.44–2.59 (m, 3H, masked by DMSO), 2.73 (br. d, 1H), 2.83 (br. d, 1H), 3.12–3.19 (m, 2H), 3.21 (s, 3H), 3.87–4.53 (m, 2H), 7.97 (s, 1H).

[0258] Example 21A (2-Bromo-1,3-thiazolyl-5-yl)[3-phenyl[1,4'-bipiperidin]-1'-yl]methyl ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one (500 mg, 1.73 mmol) and 558 mg (3.46 mmol) of 3-phenylpiperidine (racemic mixture) were dissolved in 17.5 mL of dichloromethane, and acetic acid (0.15 mL, 2.59 mmol) and a 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (440 mg, 2.08 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After filtration to remove the molecular sieve, a saturated sodium bicarbonate solution was added to the reaction mixture (caution: gas is violently released). The organic phase was then separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with a supersaturated sodium chloride solution and filtered through a hydrophobic filter (pleated filter, MN 616 WA1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; mobile phase A = water, B = acetonitrile; gradient: 0.0 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid; UV detection: DAD; 210 nm). Solvent removal yielded 188 mg (25% of the theoretical value) of the title compound.

[0259] LC-MS (Method 1): R t = 1.04 min; m / z = 434 / 436 (M+H) + .

[0260] Example 22A (2-Bromo-1,3-thiazo-5-yl)[3-isopropoxy[1,4'-bipiperidine]-1'-yl]methyl ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one (500 mg, 1.73 mmol) and 495 mg (3.46 mmol) of 3-isopropoxypiperidine (racemic mixture) were dissolved in 17.5 mL of dichloromethane, and acetic acid (0.15 mL, 2.59 mmol) and a 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (440 mg, 2.08 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. Then, another 400 mg of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After filtration to remove the molecular sieve, a saturated sodium bicarbonate solution was added to the reaction mixture (caution: gas is released violently). The organic phase was then separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with supersaturated sodium chloride solution and filtered through a hydrophobic filter (pleated filter, MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; mobile phase A = water, B = acetonitrile; gradient: 0.0 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid; UV detection: DAD; 210 nm). Solvent removal yielded 149 mg (21% of the theoretical value) of the title compound.

[0261] LC-MS (Method 1): R t = 0.81 min; m / z = 416 / 418 (M+H) + .

[0262] Example 23A (2-Bromo-1,3-thiazolyl-5-yl)[3-(cyclopropylmethoxy)[1,4'-bipiperidine]-1'-yl]methyl ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one (447 mg, 1.55 mmol) and 296 mg (1.55 mmol) 3-(cyclopropylmethoxy)piperidine hydrochloride (1:1) (racemic mixture) were dissolved in 17.5 mL of dichloromethane, and triethylamine (0.32 mL, 2.31 mmol) and a 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (393 mg, 1.85 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 45 °C. After filtration to remove the molecular sieve, a saturated sodium bicarbonate solution was added to the reaction mixture (caution: gas is released violently). The organic phase was then separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with supersaturated sodium chloride solution and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; mobile phase A = water, B = acetonitrile; gradient: 0.0 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid; UV detection: DAD; 210 nm). The solvent was removed, yielding 63 mg (9.5% of the theoretical value) of the title compound.

[0263] LC-MS (Method 1): R t = 0.85 min; m / z = 428 / 430 (M+H) + .

[0264] Example 24A (2-Bromo-1,3-thiazo-5-yl){3-[(cyclobutoxy)methyl][1,4'-bipiperidine]-1'-yl}methyl ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidin-4-one (300 mg, 1.04 mmol) and 213 mg (1.04 mmol) of 3-[(cyclobutoxy)methyl]piperidine hydrochloride (1:1) (racemic mixture) were dissolved in 3.5 mL of dichloromethane, and triethylamine (0.22 mL, 1.56 mmol) and a 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (264 mg, 1.25 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 45 °C. After filtration to remove the molecular sieve, a saturated sodium bicarbonate solution was added to the reaction mixture (caution: gas is released violently). The organic phase was then separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with supersaturated sodium chloride solution and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; mobile phase A = water, B = acetonitrile; gradient: 0.0 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid; UV detection: DAD; 210 nm). The solvent was removed, yielding 57 mg (12.5% ​​of the theoretical value) of the title compound.

[0265] LC-MS (Method 1): R t = 1.01 min; m / z = 442 / 444 (M+H) + .

[0266] Example 25A [2-Bromo-4-(trifluoromethyl)-1,3-thiazo-5-yl][(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 0.95 ml (5.43 mmol) N , N - Diisopropylethylamine was added to 0.5 g (1.81 mmol) of 2-bromo-4-(trifluoromethyl)-1,3-thiazolyl-5-carboxylic acid and 0.46 g (1.81 mmol) of (3 R1,4'-methyl-1,4'-piperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 15 ml of acetonitrile solution. Then, at room temperature, 1.4 ml (2.36 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 50 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was further purified by silica gel column chromatography (Isolera Biotage SNAP-Ultra 25 g column, mobile phase: dichloromethane → gradient 15 CV (CV = column volume) → dichloromethane / methanol 85:15). This yielded 270 mg (0.57 mmol, 32% of the theoretical value) of the target compound.

[0267] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74–0.89 (m, 4H, of which 0.82 (d, 3H)), 1.27–1.46 (m, 3H), 1.46–1.70 (m, 4H), 1.71–1.84 (m, 2H), 2.05 (br. t, 1H), 2.44–2.57 (m, 1H, partially masked by DMSO), 2.68–2.85 (m, 3H), 3.04 (br. t, 1H), 3.53 (br. d, 1H), 4.41 (br. d, 1H).

[0268] LC-MS (Method 1): R t = 0.98 min; m / z = 440 / 442 (M+H) + .

[0269] Example 26A (2-bromo-4-chloro-1,3-thiazo-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 1.1 ml (6.19 mmol)N , N - Diisopropylethylamine was added to 0.5 g (2.06 mmol) of 2-bromo-4-chloro-1,3-thiazolyl-5-carboxylic acid and 0.53 g (2.06 mmol) of (3 R 1,4'-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 17 ml of acetonitrile solution. Then, at room temperature, 1.6 ml (2.68 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 50 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This yielded 410 mg (1.01 mmol, 49% of the theoretical value) of the target compound.

[0270] LC-MS (Method 1): R t = 0.84 min; m / z = 406 / 408 (M+H) + .

[0271] Example 27A (2-Bromo-4-cyclopropyl-1,3-thiazo-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 10.5 ml (60.46 mmol) N , N - Diisopropylethylamine was added to 5 g (20.15 mmol) of 2-bromo-4-cyclopropyl-1,3-thiazolyl-5-carboxylic acid and 5.14 g (20.16 mmol) of (3 R1,4'-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 167 ml of acetonitrile solution. Then, at room temperature, 15.6 ml (26.20 mmol) of a solution of 50% T3P in ethyl acetate (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to this reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 50 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was further purified by silica gel column chromatography (Isolera Biotage Sfähr 25 g column, mobile phase: dichloromethane → gradient 15 CV (CV = column volume) → dichloromethane / methanol 85:15). This yielded 6.51 g (15.79 mmol, 78% of the theoretical value) of the target compound.

[0272] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74-0.84 (m, 4H, of which 0.82 (d, 3H)), 0.84-0.91 (m, 2H), 0.95-1.04 (m, 2H), 1.31-1.46 (m, 3H), 1.46-1.67 (m, 3H), 1.69-1.82 (m, 3H), 1.90-1.98 (m, 1H), 2.03 (br. t, 1H), 2.43-2.53 (m, 1H, partially masked by DMSO), 2.69-2.80 (m, 2H), 2.86-3.07 (m, 2H), 3.82-4.33 (m, 2H).

[0273] LC-MS (Method 1): R t = 0.94 min; m / z = 412 / 414 (M+H) + .

[0274] Example 28A (2-bromo-4-methyl-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 11.1 ml (63.50 mmol) N , N - Diisopropylethylamine was added to 4.7 g (21.17 mmol) of 2-bromo-4-methyl-1,3-thiazolyl-5-carboxylic acid and 5.4 g (21.17 mmol) of (3 R 1,4'-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 176 ml of acetonitrile solution. Then, at room temperature, 16.4 ml (27.52 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to this reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 50 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. The resulting residue was further purified by silica gel column chromatography (Isolera Biotage Sfähr 25 g column, mobile phase: dichloromethane → gradient 15 CV (CV = column volume) → dichloromethane / methanol 85:15). This yielded 6.48 g (16.77 mmol, 79% of the theoretical value) of the target compound.

[0275] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74-0.88 (m, 4H, of which 0.82 (d, 3H)), 1.28-1.46 (m, 3H), 1.46-1.67 (m, 3H), 1.67-1.82 (m, 3H), 1.97-2.07 (m, 1H), 2.31 (s, 3H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.68-2.79 (m, 2H), 2.82-3.08 (m, 2H), 3.65-4.51 (m, 2H).

[0276] LC-MS (Method 1): R t = 0.74 min; m / z = 386 / 388 (M+H) + .

[0277] Example 29A (2,4-bromo-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 0.91 ml (5.23 mmol) N , N - Diisopropylethylamine was added to 0.5 g (1.74 mmol) of 2,4-dibromo-1,3-thiazolyl-5-carboxylic acid and 0.45 g (1.74 mmol) of (3 R 1,4'-methyl-1,4'-piperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) was added dropwise to 14 ml of acetonitrile solution. Then, at room temperature, 1.35 ml (2.27 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, the solution was concentrated to dryness under reduced pressure and dissolved in approximately 50 ml of dichloromethane. The resulting organic solution was washed with saturated sodium bicarbonate solution, and the organic phase was separated and filtered through a hydrophobic filter (pleated filter, MN616 WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure. This yielded 0.52 g (1.12 mmol, 65% of the theoretical value) of the target compound.

[0278] LC-MS (Method 1): R t = 0.87 min; m / z = 449 (M+H) + .

[0279] Similar to Examples 20A to 24A, the compounds in Examples 30A to 33A were prepared from the specified starting materials: Example 34A (2-Bromo-1,3-thiazo-4-yl)(3,3-dimethyl[1,4'-bipiperidin]-1'-yl)methyl ketone 0.29 ml (1.67 mmol) N ,N Diisopropylethylamine was added to 116 mg (0.56 mmol) of 2-bromo-1,3-thiazolyl-4-carboxylic acid and 150 mg (0.56 mmol) of 3,3-dimethyl-1,4'-bipiperidine dihydrochloride (WO2021089683 Example 48A; CAS Registry No. 2642237-13-4) in 5 ml of acetonitrile solution. Then, at room temperature, 0.43 ml (0.72 mmol) of 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred overnight at room temperature. Subsequently, water was added to the solution, and the solution was extracted with ethyl acetate. After separating the organic phase, the resulting organic solution was washed with a saturated sodium chloride solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616WA 1 / 4, D = 12.5 cm), dried, and concentrated to dryness under reduced pressure.

[0280] The resulting residues were purified by preparative HPLC.

[0281] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 v / v / 20 v%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0-2 min 39 ml; Mobile phase B 0-2 min 31 ml; Mobile phase A 2-10 min 39 ml-15 ml and Mobile phase B 31 ml-55 ml; 10-12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, mobile phases C and D were maintained at a constant flow rate of 5 ml / min each.

[0282] In this manner, 73 mg (34% of the theoretical value, 0.19 mmol, 100% purity) of the title compound was obtained.

[0283] LC-MS (Method 1): R t = 0.79 min; m / z = 386 / 388 (M+H) + .

[0284] Example 35A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-4-carboxylic acid methyl ester methyl 2-bromo-1,3-thiazolyl-4-carboxylate (182 mg, 0.82 mmol) and N 1-Methyl-1-(pyridin-2-yl)methylamine (100 mg, 0.82 mmol) was dissolved in 2 mL of 1-methyl-2-pyrrolidone, and 0.42 mL of N,N-diisopropylethylamine was added. The reaction mixture (in a sealed container) was then stirred overnight at 140 °C. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength: 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 mL / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 109 mg (50% of the theoretical value, 0.41 mmol) of the target compound.

[0285] LC-MS (Method 1): R t = 1.05 min; MS (ESIpos): m / z = 264 [M+H] + .

[0286] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.14 (s, 3H), 3.75 (s, 3H), 4.79 (s, 2H), 7.24-7.33 (m, 2H), 7.64 (s, 1H), 7.77 (td, 1H), 8.51-8.56 (m, 1H).

[0287] Example 36A (HAHN 10982-2-1) 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-4-carboxylic acid Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-4-carboxylate (340 mg, 1.29 mmol) was dissolved in 12 ml of methanol, and 6.5 ml of 1N Sodium hydroxide solution (1.0 M, 6.5 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterward, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N The pH was adjusted to 3-4 with hydrochloric acid solution. The resulting solution was concentrated, stirred with methanol, filtered, and the filtrate was concentrated to dryness under reduced pressure. This yielded 134 mg (100% purity, 0.54 mmol, 42% of theoretical value) of the target compound.

[0288] LC-MS (Method 1): R t = 0.71 min; MS (ESIpos): m / z = 250 [M+H] + .

[0289] Example 37A 3-[(3,3-difluorocyclobutyl)methoxy]piperidine ( racemic ) 2.19 g (9.29 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy]pyridine (WO2021089683, Example 11A) was dissolved in 50 mL of ethanol, 0.5 mL (9.28 mmol) of sulfuric acid and 211 mg (0.93 mmol) of platinum oxide (IV) were added, and hydrogenation was carried out overnight under standard hydrogen pressure. After conversion, the reaction mixture was filtered through diatomaceous earth, and the filtrate was subsequently concentrated to dryness. The resulting residue was purified by preparative HPLC.

[0290] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 v / v / 20 v%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 70 ml; Mobile phase B 0 to 2 min 0 ml; Mobile phase A 2 to 10 min from 70 ml to 0 ml and Mobile phase B from 0 ml to 70 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, mobile phases C and D were maintained at a constant flow rate of 5 ml / min each.

[0291] The fractions containing the product were combined and lyophilized. 388 mg of the target compound was obtained. The target compound was further converted without analysis.

[0292] Example 38A 3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester ( racemic ) An initial feed was prepared in 10 mL of dichloromethane using tert-butyl 4-oxopiperidinium-1-carboxylate (340 mg, 1.71 mmol) and 3-[(3,3-difluorocyclobutyl)methoxy]piperidine (racemic mixture) (350 mg, 1.71 mmol). Concentrated acetic acid (146 µl, 2.56 mmol) was then added, and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (434 mg, 2.05 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was then separated, filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm), and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 39 ml, mobile phase B 0–2 min 31 ml, mobile phase A 2–10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 67 mg (0.17 mmol, 10% of the theoretical value) of the target compound.

[0293] 1¹H-NMR (400 MHz, DMSO-d⁶) δ [ppm]: 0.99–1.14 (m, 1H), 1.19–1.45 (m, 13H, of which 1.38 (s, 9H), 1.58–1.69 (m, 3H), 1.84–1.93 (m, 1H), 1.96 (t, 1H), 2.08 (t, 1H), 2.22–3.37 (m, 3H), 2.37–2.47 (m, 1H), 2.48–2.71 (m, 4H, partially masked by DMSO), 2.92 (br. d, 1H), 3.21–3.36 (m, 1H, partially masked by H₂O), 3.39–3.51 (m, 2H), 3.95 (br. d, 2H).

[0294] Example 39A 3-[(3,3-difluorocyclobutyl)methoxy]-1,4'-bipiperidine dihydrochloride ( racemic ) Hydrochloric acid was added to 1,4-dioxane (0.2 ml, 4.0 M, 0.84 mmol) to tert-butyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidine]-1'-carboxylate ( racemic (65 mg, 0.17 mmol) was added to a solution of dichloromethane in 5 mL, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. 60 mg of the target compound was obtained. The target compound was further converted without purification and analysis.

[0295] Example 40A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-5-carboxylic acid methyl ester methyl 2-bromothiazol-5-carboxylate (1.82 g, 8.19 mmol) and N 1-Methyl-1-(pyridin-2-yl)methylamine (1 g, 8.19 mmol) was dissolved in 50 ml of 1-methyl-2-pyrrolidone, and 3 ml of [unspecified solution] was added. N , N-Diisopropylethylamine. The reaction mixture (in a sealed container) was then stirred overnight at 140 °C. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with water and a saturated sodium chloride solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 879 mg (41% of the theoretical value, 0.33 mmol) of the target compound.

[0296] LC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 264 [M+H] + .

[0297] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.21 (s, 3H), 3.73 (s, 3H), 4.85 (s, 2H), 7.26-7.34 (m, 2H), 7.78 (td, 1H), 7.85 (s, 1H), 8.53 (d, 1H).

[0298] Example 41A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-4-carboxylic acid Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-5-carboxylate (870 mg, 3.30 mmol) was dissolved in 32 ml of methanol, and 16.5 ml of 1 N Sodium hydroxide solution (1.0 M, 6.5 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterward, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N Adjust the pH to 3-4 with hydrochloric acid solution. Concentrate the resulting solution to dryness under reduced pressure. Purify the residue by preparative HPLC.

[0299] method: Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% formic acid in water; Mobile phase D: acetonitrile / water (80 vol% / 20 vol%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 70 ml; Mobile phase B 0 to 2 min 0 ml; Mobile phase A 2 to 10 min 70 ml to 55 ml and Mobile phase B 0 ml to 15 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each.

[0300] The fractions containing the product were combined and lyophilized. This yielded 550 mg (2.21 mmol, 67% of the theoretical value) of the target compound.

[0301] LC-MS (Method 1): R t = 0.74 min; MS (ESIpos): m / z = 250 [M+H] + .

[0302] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.20 (s, 3H), 4.84 (s, 2H), 7.25-7.34 (m, 2H), 7.73-7.82 (m, 2H), 8.53 (d, 1H).

[0303] Example 42A 3-(2,2,2-trifluoroethoxy)[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester ( racemic ) 4-O-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.51 mmol) and 3-(2,2,2-trifluoroethoxy)piperidine ( racemicAn initial feed of sodium triacetoxyborohydride (460 mg, 2.51 mmol) was prepared in 15 mL of dichloromethane. Concentrated acetic acid (215 µl, 3.76 mmol) was then added, and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (658 mg, 3.01 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The residue was subjected to preparative HPLC (instrument: Waters Prep LC / MS system, LC-MS: R...). t = 2.03 min; MS (ESIpos): m / z = 366 [M] + Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 39 ml, mobile phase B 0–2 min 31 ml, mobile phase A 2–10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. (Constant flow rates of 5 ml / min for mobile phases C and D throughout the run) purification. Fractions containing product were combined and lyophilized. 450 mg (1.23 mmol, 49% of theoretical value) of the target compound was obtained, converted without further analysis.

[0304] Example 43A 3-(2,2,2-trifluoroethoxy)-1,4'-bipiperidine dihydrochloride ( racemic ) Hydrochloric acid was added to 1,4-dioxane (1.5 ml, 4.0 M, 6.09 mmol) to tert-butyl 3-(2,2,2-trifluoroethoxy)[1,4'-bipiperidine]-1'-carboxylate ( racemic (446 mg, 1.22 mmol) was added to a solution of dichloromethane in 20 mL, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. 399 mg of the target compound was obtained. The target compound was further converted without purification and analysis.

[0305] Example 44A 4-(6-azaspiro[3.5]non-6-yl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (a mixture of diastereomers) tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate ( racemic An initial feed of 6-azaspiro[3.5]nonane hydrochloride (1:1) (100 mg, 0.47 mmol) and 6-azaspiro[3.5]nonane hydrochloride (1:1) (83 mg, 0.52 mmol) was prepared in 2 mL of dichloromethane. Concentrated acetic acid (40 µl, 0.70 mmol) was then added, and the mixture was stirred overnight at room temperature. Subsequently, sodium triacetoxyborohydride (119 mg, 0.56 mmol) was added, and the mixture was stirred at room temperature for 96 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0306] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 vol% / 20 vol%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 23 ml; Mobile phase B 0 to 2 min 47 ml; Mobile phase A 2 to 10 min from 23 ml to 0 ml and Mobile phase B from 47 ml to 70 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each.

[0307] The fractions containing the product were combined and lyophilized. This yielded 54 mg (0.16 mmol, 35% of the theoretical value) of the target compound.

[0308] LC-MS (Method 3): diastereomer 1 : R t = 2.39 min (23.2%); MS (ESIpos): m / z= 323 [M+H] + ; diastereomer 2 : R t= 2.42 min (76.8%); MS (ESIpos): m / z = 323 [M+H] + .

[0309] Example 45A 6-(2-methylpiperidin-4-yl)-6-azaspiro[3.5]nonane dihydrochloride (a mixture of diastereomers) Hydrochloric acid in 1,4-dioxane (1 ml, 4.0 M, 4 mmol) was added to tert-butyl 4-(6-azaspiro[3.5]non-6-yl)-2-methylpiperidin-1-carboxylate ( diastereomer mixture (53 mg, 0.16 mmol) was added to a solution of dichloromethane in 2 mL, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. 61 mg of the target compound was obtained. The target compound was further converted without purification and analysis.

[0310] Example 46A 3-[methyl(pyridin-2-ylmethyl)amino]-1,2,4-oxadiazole-5-carboxylic acid ethyl ester Will N 276 mg (2.26 mmol) of methyl-1-(pyridin-2-yl)methylamine was dissolved in 10 ml of acetonitrile, followed by the addition of 0.79 ml of acetonitrile. N , N -Diisopropylethylamine and ethyl 3-bromo-1,2,4-oxadiazole-5-carboxylate (500 mg, 2.26 mmol). The reaction mixture was then stirred under reflux for three hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength: 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 181 mg (30% of theoretical value, 0.69 mmol) of the target compound.

[0311] LC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 263 [M+H] + .

[0312] Example 47A 3-[methyl(pyridin-2-ylmethyl)amino]-1,2,4-oxadiazole-5-carboxylic acid Ethyl 3-[methyl(pyridin-2-ylmethyl)amino]-1,2,4-oxadiazole-5-carboxylate (180 mg, 0.69 mmol) was dissolved in 7 ml of methanol, and 3.4 ml of 1 N Sodium hydroxide solution (1.0 M, 3.4 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterwards, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N Adjust the pH to 3-4 with hydrochloric acid solution. Concentrate the resulting solution to dryness under reduced pressure. Purify the residue by preparative HPLC.

[0313] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 v / v / 20 v%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0-2 min 70 ml; Mobile phase B 0-2 min 0 ml; Mobile phase A 2-10 min 70 ml-55 ml and Mobile phase B 15 ml-70 ml; 10-12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, mobile phases C and D were maintained at a constant flow rate of 5 ml / min each.

[0314] The fractions containing the product were combined and lyophilized. This yielded 116 mg (0.49 mmol, 72% of the theoretical value) of the target compound.

[0315] LC-MS (Method 3): R t = 0.33 min; MS (ESIpos): m / z = 235 [M+H] + .

[0316] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.96 (s, 3H), 4.64 (s, 2H), 7.22(d, 1H), 7.25-7.32 (m, 1H), 7.72-7.80 (m, 1H), 8.50-8.56 (m, 1H).

[0317] Example 48A ethyl 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-thiadiazole-2-carboxylate Will N 1-Methyl-1-(pyridin-2-yl)methylamine (258 mg, 2.11 mmol) was dissolved in 10 ml of acetonitrile, followed by the addition of 0.74 ml (4.22 mmol). N , N -Diisopropylethylamine and ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.11 mmol). The reaction mixture was then stirred under reflux for 4 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength: 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 539 mg (92% of theoretical value, 1.94 mmol) of the target compound.

[0318] LC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m / z = 279 [M+H] + .

[0319] Example 49A 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-thiadiazole-2-carboxylic acid Ethyl 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-thiadiazole-2-carboxylate (535 mg, 1.92 mmol) was dissolved in 20 ml of methanol, and 9.6 ml of 1... N Sodium hydroxide solution (1.0 M, 9.6 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterward, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N Adjust the pH to 3-4 with hydrochloric acid solution. Concentrate the resulting solution to dryness under reduced pressure. Purify the residue by preparative HPLC.

[0320] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 v / v / 20 v%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0-2 min 70 ml; Mobile phase B 0-2 min 0 ml; Mobile phase A 2-10 min 70 ml-55 ml and Mobile phase B 15 ml-70 ml; 10-12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, mobile phases C and D were maintained at a constant flow rate of 5 ml / min each.

[0321] The fractions containing the product were combined and lyophilized. This yielded 450 mg (1.80 mmol, 94% of the theoretical value) of the target compound.

[0322] LC-MS (Method 3): R t = 0.32 min; MS (ESIpos): m / z = 251 [M+H] + .

[0323] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.18 (s, 3H), 4.74 (s, 2H), 7.25-7.33 (m, 2H), 7.77 (td, 1H), 8.53 (d, 1H).

[0324] Example 50A 5-[methyl(pyridin-2-ylmethyl)amino]-1,2,4-thiadiazole-3-carboxylic acid methyl 5-bromo-1,2,4-thiadiazole-3-carboxylate (500 mg, 2.24 mmol) and N 1-Methyl-1-(pyridin-2-yl)methylamine (274 mg, 2.24 mmol) was dissolved in 15 ml of 1-methyl-2-pyrrolidone, and 1.2 ml of [amount missing] was added. N , N-Diisopropylethylamine. The reaction mixture (in a sealed container) was then stirred overnight at 140°C. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. The resulting residue was dissolved in 20 ml of methanol, and 9.6 ml of 1 N Sodium hydroxide solution (1.0 M, 9.6 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterward, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N The pH was adjusted to 3-4 with hydrochloric acid solution. The resulting solution was concentrated to dryness under reduced pressure. The residue was stirred repeatedly with methanol and filtered. The resulting filtrate was concentrated to dryness under reduced pressure. This yielded 490 mg (1.82 mmol, 81% of the theoretical value) of the target compound.

[0325] LC-MS (Method 1): R t = 0.45 min; MS (ESIpos): m / z = 251 [M+H] + .

[0326] Example 51A 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester Will N 1-Methyl-1-(pyridin-2-yl)methylamine (276 mg, 2.26 mmol) was dissolved in 10 ml of acetonitrile, followed by the addition of 1.18 ml (6.79 mmol). N , N-Diisopropylethylamine and ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (500 mg, 2.26 mmol). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength: 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 324 mg (55% of theoretical value, 1.24 mmol) of the target compound.

[0327] LC-MS (Method 4): R t = 1.09 min; MS (ESIpos): m / z = 263 [M+H] + .

[0328] Example 52A 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-thiadiazole-2-carboxylic acid Ethyl 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-oxadiazole-2-carboxylate (320 mg, 1.22 mmol) was dissolved in 20 ml of methanol, and 6.1 ml of 1... N Sodium hydroxide solution (1.0 M, 6.1 mmol) was prepared, and the mixture was stirred overnight at room temperature. Afterwards, the reaction mixture was concentrated to dryness, completely dissolved in water, and 1 N Adjust the hydrochloric acid solution to pH 3. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0329] method: (Column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid).

[0330] The fractions containing the product were combined and concentrated to dryness under reduced pressure. This yielded 412 mg (0.88 mmol, 72% of theoretical value, purity: 50%) of the target compound. The product was further converted without further purification.

[0331] LC-MS (Method 1): R t = 0.25 min; MS (ESIpos): m / z = 235 [M+H] + .

[0332] Example 53A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-oxazol-4-carboxylic acid methyl ester Will N 1-Methyl-1-(pyridin-2-yl)methylamine (297 mg, 2.43 mmol) was dissolved in 10 ml of acetonitrile, followed by the addition of 1.27 ml (7.28 mmol). N , N -Diisopropylethylamine and methyl 2-bromo-1,3-oxazol-4-carboxylate (500 mg, 2.43 mmol). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: Chromatorex C18 10 µm, 125 x 40 mm; wavelength: 210 nm; mobile phase A = water, B = acetonitrile; gradient: 5 min 10% B; 20 min 95% B; flow rate: 100 ml / min; 0.05% formic acid). The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 264 mg (43% of theoretical value, 1.05 mmol; purity: 98.8%) of the target compound.

[0333] LC-MS (Method 1): R t = 0.90 min; MS (ESIpos): m / z = 248 [M+H] + .

[0334] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.07 (s, 3H), 3.74 (s, 3H), 4.69 (s, 2H), 7.25-7.32 (m, 2H), 7.78 (td, 1H), 8.26 (s, 1H), 8.52 (d, 1H).

[0335] Example 54A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-oxazol-4-carboxylic acid Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-oxazol-4-carboxylate (260 mg, 1.05 mmol) was dissolved in 20 ml of methanol, and 6.3 ml of 1... N Sodium hydroxide solution (1.0 M, 5.3 mmol) was prepared, and the mixture was stirred at room temperature for 4 h. Afterwards, the reaction mixture was concentrated to dryness, completely dissolved in water, and then... N Adjust the pH to 3-4 with hydrochloric acid solution. Concentrate the resulting solution to dryness under reduced pressure. Purify the residue by preparative HPLC.

[0336] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 v / v / 20 v%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 70 ml; Mobile phase B 0 to 2 min 0 ml; Mobile phase A 2 to 10 min 70 ml to 55 ml and Mobile phase B 0 ml to 15 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the constant flow rates of Mobile phases C and D were 5 ml / min each.

[0337] The fractions containing the product were combined and concentrated to dryness under reduced pressure. This yielded 156 mg (0.67 mmol, 64% of the theoretical value) of the target compound.

[0338] LC-MS (Method 1): R t = 0.60 min; MS (ESIpos): m / z = 234 [M+H] + .

[0339] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.02 (s, 3H), 4.66 (s, 2H), 7.24-7.32 (m, 2H), 7.59 (s, 1H), 7.78 (td, 1H), 8.52 (d, 1H).

[0340] Example 55A 4-(6-azaspiro[3.5]non-6-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester (a mixture of diastereomers) tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate ( racemic (100 mg, 0.47 mmol), 6-azaspiro[3.5]nonane hydrochloride (1:1) (83 mg, 0.52 mmol), 4 Å molecular sieve and 90 µl (0.52 mmol) N , N -Diisopropylethylamine was initially fed with 2 mL of dichloromethane and stirred at room temperature for 10 min. Subsequently, concentrated acetic acid (40 µL, 0.70 mmol) was added and the mixture was stirred overnight at room temperature. Then, sodium triacetoxyborohydride (119 mg, 0.56 mmol) was added and the mixture was stirred at room temperature for 96 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was then separated and filtered through a hydrophobic filter (pleated filter, MN 616 WA 1 / 4, D = 12.5 cm) and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0341] method: Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5 µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% ammonia in water; Mobile phase D: acetonitrile / water (80 vol% / 20 vol%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 23 ml; Mobile phase B 0 to 2 min 47 ml; Mobile phase A 2 to 10 min from 23 ml to 0 ml and Mobile phase B from 47 ml to 70 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each.

[0342] The fractions containing the product were combined and lyophilized. This yielded 44 mg (0.14 mmol, 29% of the theoretical value) of the target compound.

[0343] LC-MS (Method 3): R t = 2.54 min; MS (ESIpos): m / z = 323 [M+H] + .

[0344] Example 56A 6-(2-methylpiperidin-4-yl)-6-azaspiro[3.5]nonane dihydrochloride (a mixture of diastereomers) Hydrochloric acid in 1,4-dioxane (1 ml, 4.0 M, 4 mmol) was added to a solution of 4-(6-azaspiro[3.5]non-6-yl)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (a mixture of diastereomers) (44 mg, 0.14 mmol) in 2 ml of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. 55 mg of the target compound was obtained. The target compound was further converted without purification and analysis.

[0345] Example 57A 4-(5-azaspiro[2.5]oct-5-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester ( racemic ) tert-butyl 3-fluoro-4-oxoperidin-1-carboxylate (racemic) (552 mg, 2.54 mmol), 5-azaspiro[2.5]octane hydrochloride (750 mg, 5.08 mmol) and N,NDiisopropylethylamine (880 µl, 5.1 mmol) was used as the initial feed in 25 mL of dichloromethane. Subsequently, concentrated acetic acid (220 µl, 3.8 mmol) was added and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (646 mg, 3.05 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% formic acid in water, mobile phase D: acetonitrile / water (80 v / v 20 v %), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 63 ml, mobile phase B 0–2 min 7 ml, mobile phase A 2–10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 477 mg of the target compound (100% purity, 60% of the theoretical value).

[0346] LC-MS (Method 1): R t = 0.89 min; MS (ESIpos): m / z = 313 [M+H] + .

[0347] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.245 (1.80), 0.027 (1.52), 0.999(0.70), 1.015 (0.67), 1.133 (16.00), 1.328 (0.73), 1.337 (1.03), 1.349(0.84), 2.086 (1.04), 2.104 (0.83), 2.249 (1.77), 2.254 (3.47), 2.258 (4.67), 2.263 (3.38), 2.267 (1.58), 2.298 (11.37), 2.358 (0.70), 2.371 (0.90), 2.384 (0.60), 2.925 (10.12), 5.507 (1.83), 7.917 (1.62).

[0348] Example 58A 5-(3-Fluoroperidin-4-yl)-5-azaspiro[2.5]octane hydrochloride (1:1) (racemate) Hydrochloric acid in 1,4-dioxane (1.9 ml, 4.0 M, 7.6 mmol) was added to tert-butyl 4-(5-azaspiro[2.5]oct-5-yl)-3-fluoropiperidine-1-carboxylate ( racemic (477 mg, 1.53 mmol) was added to a solution of dichloromethane in 15 mL, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was dried under high vacuum. This yielded 378 mg (100% of the theoretical value) of the target compound.

[0349] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.463 (8.13), 0.481 (3.22), 0.501(2.51), 0.525 (2.64), 0.539 (2.24), 0.550 (1.97), 0.627 (1.69), 0.654 (1.89),0.678 (1.55), 0.985 (1.58), 1.017 (1.40), 1.067 (1.12), 1.100 (1.21), 1.754(0.69), 1.784 (1.27), 1.820 (2.50), 1.852 (4.13), 1.883 (2.34), 1.983 (1.00), 2.019 (1.17), 2.046 (1.36), 2.077 (1.09), 2.124 (1.24), 2.159 (1.83), 2.191(1.51), 2.214 (0.64), 2.288 (1.61), 2.319 (2.18), 2.350 (0.96), 2.722 (1.84), 2.751 (3.27), 2.780 (1.63), 2.991 (1.88), 3.022 (1.87), 3.049 (1.30), 3.074(1.31), 3.103 (1.64), 3.128 (1.53), 3.166 (16.00), 3.219 (1.08), 3.345 (4.01), 3.385 (5.35), 3.501 (1.34), 3.568 (9.70), 3.622 (1.71), 3.655 (3.08), 3.681 (1.86), 3.700 (0.84), 3.714 (0.92), 3.725 (0.87), 3.754 (0.75), 3.806 (1.15), 3.866 (0.69), 3.897 (0.55), 5.613 (1.60), 5.644 (1.31), 5.732 (1.63), 5.760 (3.24), 9.099 (1.20), 10.127 (1.66), 10.747 (1.03), 10.939 (0.87).

[0350] Example 59A 4-(5-azaspiro[2.5]oct-5-yl)-3-ethylpiperidine-1-carboxylic acid tert-butyl ester ( racemic ) 3-Ethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester ( racemic (577 mg, 2.54 mmol), 5-azaspiro[2.5]octane hydrochloride (750 mg, 5.08 mmol) and N,N Diisopropylethylamine (880 µl, 5.1 mmol) was used as the initial feed in 25 mL of dichloromethane. Subsequently, concentrated acetic acid (220 µl, 3.8 mmol) was added and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (646 mg, 3.05 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% formic acid in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 63 ml, mobile phase B 0–2 min 7 ml, mobile phase A 2–10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 226 mg of the target compound (100% purity, 28% of the theoretical value).

[0351] LC-MS (Method 1): R t = 1.06 min; MS (ESIpos): m / z = 323 [M+H] + .

[0352] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.263 (1.70), 0.276 (0.48), 0.869(0.40), 0.887 (0.76), 0.905 (0.54), 1.380 (16.00), 1.587 (0.46), 1.601 (0.62), 1.615 (0.42), 2.151 (0.73), 2.177 (0.66), 3.169 (6.53), 5.753 (0.62), 8.165 (2.91).

[0353] Example 60A 5-(3-Ethylpiperidin-4-yl)-5-azaspiro[2.5]octane hydrochloride (1:1) (racemate) Hydrochloric acid in 1,4-dioxane (880 µl, 4.0 M, 3.5 mmol) was added to a solution of tert-butyl 4-(5-azaspiro[2.5]oct-5-yl)-3-ethylpiperidin-1-carboxylate (racemic mixture) (226 mg, 701 µmol) in 7 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dried under high vacuum. This yielded 202 mg (111% of the theoretical value) of the target compound.

[0354] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.475 (0.61), 0.486 (0.53), 0.495(0.65), 0.525 (0.43), 0.892 (0.66), 0.910 (1.50), 0.928 (1.01), 0.941 (1.21),0.959 (0.57), 1.800 (0.47), 1.879 (0.42), 2.183 (0.51), 2.838 (0.40), 2.867(0.47), 3.071 (0.57), 3.399 (0.67), 3.568 (16.00), 5.757 (2.20), 8.145 (0.86).

[0355] Example 61A 4-(5-azaspiro[2.5]oct-5-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester ( racemic ) tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate ( racemic (542 mg, 2.54 mmol), 5-azaspiro[2.5]octane hydrochloride (750 mg, 5.08 mmol) and N,N Diisopropylethylamine (880 µl, 5.1 mmol) was used as the initial feed in 25 mL of dichloromethane. Subsequently, concentrated acetic acid (220 µl, 3.8 mmol) was added and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (646 mg, 3.05 mmol) was added, and the mixture was stirred overnight at room temperature. The aqueous reaction mixture was then extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC / MS system, column: Phenomenex Kinetex C18 5 µm 100 x 30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% formic acid in water, mobile phase D: acetonitrile / water (80 v / v / 20 v%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, on-column injection (complete injection); gradient overview: mobile phase A 0–2 min 63 ml, mobile phase B 0–2 min 7 ml, mobile phase A 2–10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10–12 min 0 ml mobile phase A and 70 ml mobile phase B. Constant flow rates of 5 ml / min were maintained for mobile phases C and D throughout the run). The fractions containing the product were combined and lyophilized. This yielded 186 mg (100% purity, 24% of the theoretical value) of the target compound.

[0356] LC-MS (Method 1): R t = 0.93 min; MS (ESIpos): m / z = 309 [M+H] + .

[0357] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.268 (1.65), 0.281 (0.64), 0.290 (0.72), 0.305 (0.51), 0.759 (1.44), 0.777 (1.47), 1.380 (16.00), 1.592 (0.49), 1.607 (0.66), 1.620 (0.43), 2.203 (1.77), 3.169 (0.48), 5.754 (0.98), 8.174 (1.37).

[0358] Example 62A 5-(3-methylpiperidin-4-yl)-5-azaspiro[2.5]octane hydrochloride (1:1) racemic ) Hydrochloric acid was added to 1,4-dioxane (750 µl, 4.0 M, 3.0 mmol) to tert-butyl 4-(5-azaspiro[2.5]oct-5-yl)-3-methylpiperidine-1-carboxylate ( racemic (186 mg, 603 µmol) was added to a solution of dichloromethane in 6 ml, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was dried under high vacuum. This yielded 125 mg (85% of the theoretical value) of the target compound.

[0359] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.435 (1.48), 0.446 (1.99), 0.462(2.12), 0.471 (2.80), 0.508 (2.02), 0.520 (1.62), 0.528 (1.53), 0.541 (2.04),0.551 (1.95), 0.578 (1.29), 0.584 (1.46), 0.596 (1.30), 0.607 (0.80), 0.639(0.57), 0.651 (0.75), 0.663 (0.88), 0.674 (0.61), 1.029 (1.07), 1.062 (1.20),1.126 (8.26), 1.144 (8.50), 1.205 (5.77), 1.222 (6.06), 1.632 (0.61), 1.649(0.61), 1.665 (0.55), 1.768 (0.67), 1.800 (1.62), 1.823 (1.44), 1.858 (1.65),1.874 (1.70), 1.962 (0.76), 1.995 (1.27), 2.025 (0.98), 2.043 (1.05), 2.055(0.94), 2.077 (0.96), 2.087 (0.90), 2.133 (0.80), 2.178 (1.40), 2.212 (0.75),2.584 (0.72), 2.734 (1.31), 2.766 (1.50), 2.809 (1.29), 2.837 (1.88), 2.860(1.36), 2.955 (0.58), 2.988 (1.56), 3.006 (1.45), 3.021 (1.62), 3.037 (1.89),3.072 (1.23), 3.089 (1.36), 3.121 (0.53), 3.151 (1.18), 3.167 (16.00), 3.206(3.19), 3.239 (1.78), 3.287 (1.53), 3.319 (1.42), 3.380 (1.33), 3.490 (1.45),3.553 (0.73), 3.568 (1.75), 3.626 (1.05), 3.655 (1.64), 3.681 (0.47), 3.700(0.44), 8.742 (0.87), 9.669 (1.70), 9.956 (0.48).

[0360] Working Example: Example 1 [2-(benzylamino)-1,3-thiazolyl-5-yl][(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone In a Zinsser glass vial, 37 mg (0.10 mmol) of (2-bromo-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidin]-1'-yl] ketone and 21.3 mg (0.2 mmol) of benzylamine were dissolved in 0.8 mL of 1-methyl-2-pyrrolidone, and 50 µl of N,N-diisopropylethylamine was added. The vial was then placed in a Zinsser metal module, sealed with a gasket, and stirred overnight at 140 °C. After cooling to RT, the solution was filtered, and the filtrate was separated into fractions by preparative HPLC. HPLC instrument: Knauer / Labomatik (Chromatorex C18 column, 10 µm, 25*3 cm, mobile phase A: water + 0.1% TFA, mobile phase B: acetonitrile, gradient used; flow rate: 75 ml / min; UV detection: DAD; 210 nm.

[0361] The combined fractions were freeze-dried, then dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, followed by a saturated aqueous sodium chloride solution. The organic phase was separated, dried over Mg2SO4 and filtered, and the filtrate was concentrated on a rotary evaporator and dried under high vacuum.

[0362] In this manner, 20.9 mg (53% of the theoretical value, 100% purity) of the title compound was obtained.

[0363] LC-MS (Method 2): R t = 0.58 min; m / z = 399 (M+H) + .

[0364] 1H.NMR (500 MHz, (CD3)2SO): δ 8.57 (t, 1H), 7.40 (s, 1H), 7.33 (m,4H), 7.26 (m, 1H), 4.46 (d, 2H), 4.27 (d, 2H), 2.89 (t, 2H) 2.74 (t, 2H),2.47 (m, 1H), 2.05 (t, 1H), 1.74 (d, 3H), 1.65 – 1.55 (m, 2H), 1.51 (m, 1H),1.42 – 1.31 (m, 3H), 0.82 (d, 4H).

[0365] Example 2 {2-[(1H-benzimidazol-2-ylmethyl)amino]-1,3-thiazolyl-5-yl}[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone In a Zinsser glass vial, 37 mg (0.10 mmol) of (2-bromo-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidin]-1'-yl] methyl ketone and 29.4 mg (0.2 mmol) 1-(1H-benzimidazol-2-yl)methylamine were dissolved in 0.8 ml of 1-methyl-2-pyrrolidone, and 50 µl of [amount not specified] was added. N , N -Diisopropylethylamine. Next, place this vial in a Zinsser metal module, seal with a gasket, and stir overnight at 140°C. After cooling to RT, filter the solution and separate the filtrate into components by preparative LC-MS according to one of the following methods: Preparative LC-MS methods: MS instrument: Waters; HPLC instrument: Waters; Waters X-Bridge C18 column, 19 mm x 50 mm, 5 µm, mobile phase A: water + 0.375% ammonia, mobile phase B: acetonitrile (ULC) + 0.375% ammonia, gradient used; flow rate: 40 ml / min; UV detection: DAD; 210-400 nm.

[0366] or: MS instrument: Waters; HPLC instrument: Waters (column: Phenomenex Luna 5µ C18(2) 100A, AXIATech. 50 x 21.2 mm), mobile phase A: water + 0.0375% formic acid, mobile phase B: acetonitrile (ULC) + 0.0375% formic acid, gradient used; flow rate: 40 ml / min; UV detection: DAD; 210-400 nm.

[0367] In this manner, 15.1 mg (33% of the theoretical value, 96% purity) of the title compound was obtained.

[0368] LC-MS (Method 6): R t = 0.59 min; m / z = 437 (MH) - .

[0369] Through parallel synthesis similar to Example 1, from (2-bromo-1,3-thiazolyl)[(3 R The following compounds were prepared by reacting 3-methyl[1,4'-bipiperidin]-1'-yl] methyl ketone with its corresponding amine or salt: Example 25 (2-{[(3,5-difluoropyridin-2-yl)methyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-Methyl[1,4'-bipiperidin]-1'-yl]methyl ketone formate (1:1) In a 10 ml glass bottle, add 100 mg (0.25 mmol) (2-bromo-1,3-thiazolyl-5-yl)[(3 R3-Methyl[1,4'-bipiperidin]-1'-yl]methyl ketone hydrochloride and 88 mg (0.49 mmol) 1-(3,5-difluoropyridin-2-yl)methylamine hydrochloride (1:1) were suspended in 2 mL of DMF, and 0.3 mL of N,N-diisopropylethylamine was added. The reaction mixture was then reacted in a CEM microwave at 180 °C for 15 min. After cooling to room temperature, water was added to the solution, and the mixture was repeatedly extracted with ethyl acetate. The combined organic phases were washed once with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by preparative HPLC (column: Chromatorex C18 10µ 250x20mm, gradient: A = water + 0.5% HCOOH, B = CH3CN, 0 min = 5% B, 3 min = 5% B initial wash with no material, followed by injection, 5 min = 5% B, 25 min = 50% B, 38 min = 50% B, 38.1 min = 95% B, 43 min = 95% B, 43.01 min = 5% B, 48.0 min = 5% B, flow rate 20 ml / min, wavelength 210 nm). This yielded 12 mg (0.02 mmol, 10% of the theoretical value) of the target compound.

[0370] 1 H-NMR (600 MHz, DMSO- d 6, δ / ppm):, 0.90 (d, 3H), 1.01-1.16 (m, 1H), 1.54-1.90 (m, 6H), 2.04 (br. d, 2H), 2.44-2.57 (m, 4H, partially masked by DMSO), 2.80-3.02 (m, 3H), 3.27-3.51 (m, 1H, partially masked by H2O), 4.39 (br. d, 2H), 4.64 (br. d, 2H), 7.44 (s, 1H), 7.96 (ddd, 1H), 8.50 (d, 1H), 8.69 (t, 1H), 9.10 (br. s, 1H).

[0371] LC-MS (Method 2): R t = 0.57 min; m / z = 436 (M+H) + -(HCO2H).

[0372] Explorer Discorr SP (CEM) Overall dimensions: 14.5"W x 17.2"D x 8.7"H (36.2 cm x 43.7 cm x 22.1 cm); Weight: 30 lbs; Electrical requirements: 90 - 264 VAC 50 / 60 Hz, 10 Amp @ 120 VAC, 5 Amps @ 220 VAC; Magnetron frequency: 2450 MHz; Output power: 300 W; Pressure: Monitor 0 - 35 bar, control 0 - 20 bar; Temperature: -90℃ to 300℃ control range; Stirring: In-situ magnetic speed change; Microwave applicator: Circular, single-mode self-adjusting; Ethernet port: 10 base T, 10 MB / sec; Serial port: (2) RS-232, 9 pins IBM PC compatible.

[0373] Example 26 (2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 3 g (8.06 mmol) (5-bromo-1,3-thiazolyl-2-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 3.434 g (16.12 mmol) (1 S 1-(3-Fluoropyridin-2-yl)ethylamine dihydrochloride was dissolved in 60 mL of 1-methyl-2-pyrrolidone, and 7 mL of N,N-diisopropylethylamine was added. The reaction mixture (in a sealed container) was then stirred overnight at 140 °C. After cooling to room temperature, the solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was separated, and the solution was filtered through a hydrophobic filter and concentrated to dryness under reduced pressure. Partial epimerization was observed, and the resulting residue was purified by chiral preparative HPLC.

[0374] 1250 mg (0.89 mmol) (2-{[(1 S / R )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 RA mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IG, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + (0.2% diethylamine) / n-heptane 70:30; flow rate: 15 ml / min; UV detection: 220 nm; temperature: 50 °C].

[0375] This yielded 977 mg (28% of the theoretical value, purity > 99%) of the title compound (2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone and 138 mg of the diastereomer (2-{[(1 R )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone.

[0376] (2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R Analysis of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone: R t = 7.39 min; Chemical purity > 99%; > 99% de [Column: Chiralpak IG, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol (+0.2% diethylamine) 30:70; Flow rate: 1 ml / min; Temperature: 70 °C; UV detection: 235 nm].

[0377] LC-MS (Method 1): R t = 0.91 min; m / z = 432 (M+H) + .

[0378] 1 H-NMR (600 MHz, DMSO- d6, δ / ppm): 0.75-0.85 (m, 4H, of which 0.81 (d, 3H)), 1.29-1.43 (m, 3H), 1.47 (d, 3H), 1.48-1.54 (m, 1H), 1.54-1.59 (m, 1H), 1.54-1.65 (m, 1H), 1.69-1.76 (m, 3H), 2.00-2.08 (m, 1H), 2.43-2.51 (m, 1H, partially masked by DMSO), 2.69-2.76 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.26-5.32 (m, 1H), 7.33 (s, 1H), 7.39 (dt, 1H), 7.68 (td, 1H), 8.40 (d, 1H), 8.58(d, 1H).

[0379] [α] D 20 = -42.79° (c = 0.430, methanol).

[0380] Example 27 (2-{[(1 R )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yields after separation and purification (see Example 26): 138 mg (2-{[(1 R )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R Analysis of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone: R t = 6.15 min; Chemical purity > 99%; > 99% de [Column: Chiralpak IG, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol (+0.2% diethylamine) 30:70; Flow rate: 1 ml / min; Temperature: 70 °C; UV detection: 235 nm].

[0381] LC-MS (Method 1): R t= 0.91 min; m / z = 432 (M+H) + .

[0382] 1 H-NMR (600 MHz, DMSO- d 6, δ / ppm):, 0.75-0.85 (m, 4H, of which 0.81 (d, 3H)), 1.29-1.43 (m, 3H), 1.47 (d, 3H), 1.48-1.54 (m, 1H), 1.54-1.59 (m, 1H), 1.54-1.65 (m, 1H), 1.69-1.76 (m, 3H), 2.00-2.08 (m, 1H), 2.43-2.51 (m, 1H, partially masked by DMSO), 2.69-2.76 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.29 (br. s, 1H), 7.33 (s, 1H), 7.39 (dt, 1H), 7.68 (t, 1H), 8.40 (d, 1H), 8.57(br. d, 1H).

[0383] Preparation method 2: 120 mg (0.32 mmol) (5-bromo-1,3-thiazolyl-2-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 137 mg (0.64 mmol) (1 R 1-(3-fluoropyridin-2-yl)ethylamine dihydrochloride was dissolved in 2.4 ml of 1-methyl-2-pyrrolidone, and 0.28 ml of [amount not specified] was added. N , N -Diisopropylethylamine. The reaction mixture (in a sealed container) was then stirred overnight at 140°C. After cooling to room temperature, the solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After separating the organic phase, the solution was filtered through a hydrophobic filter and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC.

[0384] method: Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5µm 100 x 30 mm. Mobile phase A: water; Mobile phase B: acetonitrile; Mobile phase C: 2% formic acid in water; Mobile phase D: acetonitrile / water (80 vol% / 20 vol%); Total flow rate: 80 ml / min; Room temperature; Wavelength: 200-400 nm; On-column injection (complete injection); Gradient overview: Mobile phase A 0 to 2 min 70 ml; Mobile phase B 0 to 2 min 0 ml; Mobile phase A 2 to 10 min 70 ml to 55 ml and Mobile phase B 0 ml to 15 ml; 10 to 12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each.

[0385] 73 mg of the yellow foam was separated. The foam was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution, and the organic phase was separated. The solution was then filtered through a hydrophobic filter and concentrated to dryness under reduced pressure. This yielded 71 mg (51% of the theoretical value, 0.16 mmol, purity > 99%) of the title compound in the form of yellow foam.

[0386] LC-MS (Method 1): R t = 0.84 min; m / z = 432 (M+H) + .

[0387] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74-0.87 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.42 (m, 3H), 1.42-1.66 (m, 6H, of which 1.46 (d, 3H)), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.69-2.77 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.24-5.34 (m, 1H), 7.33 (s, 1H), 7.39 (dt, 1H), 7.69 (ddd, 1H). 8.40 (dt, 1H), 8.61 (d, 1H).

[0388] [α] D 20= +34.25° (c = 0.365, methanol).

[0389] Examples 28 and 29 [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 324 mg (0.78 mmol) [(3 R A mixture of diastereomers of 2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone (Example 13) was separated into enantiomers by preparative chiral HPLC [column: Daicel Chiralcel OZ-H, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 25 ml / min; UV detection: 220 nm; temperature: 30 °C]. Example 28 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 123 mg R t = 3.41 min; Chemical purity > 99%; > 99% de [Column: Chiraltek OZ-3, 3 µm, 100 mm x 4.6 mm; Mobile phase: isohexane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 25℃; UV detection: 220 nm].

[0390] LC-MS (Method 1): R t = 0.68 min; m / z = 412 (MH) - .

[0391] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74-0.91 (m, 4H, of which 0.81 (d, 3H)), 1.21-1.67 (m, 10H, of which 1.46 (d, 3H)), 1.68-1.83 (m, 3H), 2.06 (br. t, 1H), 2.69-2.80 (m, 2H), 2.88 (br. t, 2H), 4.24 (br. d, 2H), 4.83-4.93 (m, 1H), 7.26 (ddd, 1H), 7.35 (s, 1H), 7.37 (d, 1H), 7.75 (td, 1H), 8.52 (d, 1H), 8.61 (d, 1H).

[0392] [α] D 20 = -15.98° (c = 0.290, methanol).

[0393] Example 29 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 133 mg R t = 4.39 min; Chemical purity > 99%; > 94% de [Column: Chiraltek OZ-3, 3 µm, 100 mm x 4.6 mm; Mobile phase: isohexane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 25℃; UV detection: 220 nm].

[0394] LC-MS (Method 1): R t = 0.69 min; m / z = 412 (MH) - .

[0395] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.74-0.90 (m, 4H, of which 0.82 (d, 3H)), 1.21-1.67 (m, 10H, of which 1.46 (d, 3H)), 1.74 (br. d, 3H), 2.01-2.14 (m, 1H), 2.69-2.81 (m, 2H), 2.88 (br. t, 2H), 4.24 (br. d, 2H), 4.88 (quin., 1H), 7.26 (ddd, 1H), 7.35 (s, 1H), 7.37 (d, 1H), 7.76 (td, 1H), 8.52 (d, 1H), 8.61 (d, 1H).

[0396] [α] D 20 = +14.85° (c = 0.330, methanol).

[0397] Similar to Examples 1, 2 and 25 to 27, the compounds in Examples 30 to 56 below were prepared from the specified starting materials: Examples 57 and 58 {2-[6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazo-5-yl}[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomers 1 and 2 ) 195 mg (0.78 mmol) {2-[(6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazolyl-5-yl}[(3 RA mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 49) was separated into individual diastereomers by preparative chiral HPLC [column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 18 ml / min; UV detection: 220 nm; temperature: 40 °C]. Example 57 ( diastereomer 1 ): {2-[6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazo-5-yl}[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 64 mg R t = 7.405 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 220 nm].

[0398] LC-MS (Method 1): R t = 0.73 min; m / z = 424 (MH) - .

[0399] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.75-0.88 (m, 4H, of which 0.82 (d, 3H)), 1.31-1.46 (m, 3H), 1.47-1.68 (m, 3H), 1.71-1.81 (m, 3H), 1.85-1.97 (m, 1H), 2.01-2.10 (m, 1H), 2.44-2.55 (m, 1H, partially masked by DMSO), 2.55-2.64 (m, 1H), 2.71-2.79 (m, 2H), 2.80-3.01 (m, 4H), 4.29 (br. d, 2H), 5.15-5.24 (m, 1H), 7.24 (dd, 1H), 7.42 (s, 1H), 7.69 (d, 1H), 8.38 (d, 1H), 8.44 (d, 1H).

[0400] [α] D 20 = -15.41° (c = 0.305, methanol).

[0401] Example 58 ( diastereomer 2 ): {2-[6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazo-5-yl}[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 64 mg R t = 8.009 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 220 nm].

[0402] LC-MS (Method 1): R t = 0.73 min; m / z = 424 (MH) - .

[0403] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.75-0.88 (m, 4H, of which 0.82 (d, 3H)), 1.31-1.47 (m, 3H), 1.47-1.68 (m, 3H), 1.71-1.81 (m, 3H), 1.85-1.97 (m, 1H), 2.01-2.11 (m, 1H), 2.45-2.55 (m, 1H, partially masked by DMSO), 2.55-2.64 (m, 1H), 2.70-2.79 (m, 2H), 2.80-3.01 (m, 4H), 4.29 (br. d, 2H), 5.15-5.24 (m, 1H), 7.24 (dd, 1H), 7.42 (s, 1H), 7.69 (d, 1H), 8.38 (d, 1H), 8.44 (d, 1H).

[0404] [α] D 20= +8.12° (c = 0.275, methanol).

[0405] Examples 59 and 60 [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 167 mg (0.38 mmol) [(3 R A mixture of diastereomers of 2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl) ketone (Example 50) was separated into individual diastereomers by preparative chiral HPLC [column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 18 ml / min; UV detection: 220 nm; temperature: 40 °C]. Example 59 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 68 mg R t = 4.714 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 220 nm].

[0406] LC-MS (Method 1): R t = 0.90 min; m / z = 440 (MH) - .

[0407] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.74-0.84 (m, 4H, of which 0.81 (d, 3H)), 0.88 (t, 3H), 1.21-1.45 (m, 5H), 1.45-1.66 (m, 3H), 1.68-1.83 (m, 5H), 1.98-2.07 (m, 1H), 2.41-2.53 (m, 1H, partially masked by DMSO), 2.68-2.77 (m, 2H), 2.87 (br.t, 2H), 4.24 (br. d, 2H), 4.72-4.81 (m, 1H), 7.25 (ddd, 1H), 7.33 (s, 1H), 7.36 (d, 1H), 7.75 (td, 1H), 8.52 (dt, 1H), 8.60 (d, 1H).

[0408] [α] D 20 = +26.82° (c = 0.450, methanol).

[0409] Example 60 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 71 mg R t = 7.813 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 220 nm].

[0410] LC-MS (Method 1): R t = 0.90 min; m / z = 440 (MH) - .

[0411] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.73-0.85 (m, 4H, of which 0.81 (d, 3H)), 0.88 (t, 3H), 1.21-1.45 (m, 5H), 1.45-1.66 (m, 3H), 1.68-1.83 (m, 5H), 1.98-2.07 (m, 1H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br.t, 2H), 4.24 (br. d, 2H), 4.73-4.82 (m, 1H), 7.25 (ddd, 1H), 7.33 (s, 1H), 7.36 (d, 1H). 7.72-7.78 (m, 1H), 8.50-8.54 (m, 1H), 8.60 (d, 1H).

[0412] [α] D 20 = -37.69° (c = 0.260, methanol).

[0413] Examples 61 and 62 [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 66 mg (0.15 mmol) [(3 R A mixture of diastereomers of 2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone (Example 46) was separated into individual diastereomers by chiral preparative HPLC [column: Daicel Chiralpak ID, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 15 ml / min; UV detection: 210 nm; temperature: 40 °C]. Example 61 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 27 mg R t= 2.007 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0414] LC-MS (Method 1): R t = 0.70 min; m / z = 426 (MH) - .

[0415] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.72-0.90 (m, 4H, of which 0.81 (d, 3H)), 1.15-1.45 (m, 6H, of which 1.42 (d, 3H)), 1.45-1.66 (m, 3H), 1.67-1.79 (m, 3H), 1.99-2.10 (m, 1H), 2.39 (s, 3H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.67-2.78 (m, 2H), 2.87 (br. t, 2H), 4.24 (br. d, 2H), 5.21 (quin., 1H), 7.19 (dd, 1H), 7.34 (s, 1H), 7.56 (d, ...) 1H), 8.38 (d, 1H), 8.51 (d, 1H).

[0416] [α] D 20 = +19.60° (c = 0.250, methanol).

[0417] Example 62 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 29 mg R t = 2.958 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0418] LC-MS (Method 1): R t = 0.70 min; m / z = 426 (MH) - .

[0419] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.72-0.90 (m, 4H, of which 0.81 (d, 3H)), 1.14-1.46 (m, 6H, of which 1.42 (d, 3H)), 1.46-1.66 (m, 3H), 1.67-1.79 (m, 3H), 1.99-2.10 (m, 1H), 2.39 (s, 3H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.72 (br.d, 2H), 2.87 (br.t, 2H), 4.24 (br.d, 2H), 5.21 (quin., 1H), 7.19 (dd, 1H), 7.34 (s, 1H), 7.56 (d, 1H). 8.38 (d, 1H), 8.51 (d, 1H).

[0420] [α] D 20 = -25.33° (c = 0.250, methanol).

[0421] Examples 63 and 64 [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 195 mg (0.41 mmol) [(3 RA mixture of diastereomers of 1,4'-bipiperidin]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone formate (1:1) (Example 47) was separated into individual diastereomers by chiral preparative HPLC [column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 20 ml / min; UV detection: 300 nm; temperature: 40 °C]. Example 63 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 64 mg R t = 5.066 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40℃; UV detection: 300 nm].

[0422] LC-MS (Method 1): R t = 0.72 min; m / z = 426 (MH) - .

[0423] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.73-0.87 (m, 4H, of which 0.81 (d, 3H)), 1.26-1.47 (m, 6H, of which 1.44 (d, 3H)), 1.47-1.66 (m, 3H), 1.67-1.79 (m, 3H), 1.98-2.08 (m, 1H), 2.26 (s, 3H), 2.41-2.53 (m, 1H, partially masked by DMSO), 2.67-2.78 (m, 2H), 2.88 (br. t, 2H), 4.24 (br. d, 2H), 4.77-4.87 (m, 1H), 7.26 (d, 1H), 7.34 (s, 1H), 7.56 (dd, 1H), 8.35 (d, 1H), 8.58 (d, 1H).

[0424] [α] D 20 = +32.00° (c = 0.250, methanol).

[0425] Example 64 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 61 mg R t = 17.061 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 300 nm].

[0426] LC-MS (Method 1): R t = 0.72 min; m / z = 426 (MH) - .

[0427] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.26-1.47 (m, 6H, of which 1.44 (d, 3H)), 1.47-1.67 (m, 3H), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.26 (s, 3H), 2.41-2.53 (m, 1H, partially masked by DMSO), 2.69-2.77 (m, 2H), 2.87 (br. t, 2H), 4.24 (br. d, 2H), 4.78-4.88 (m, 1H), 7.27 (d, 1H), 7.34 (s, 1H), 7.56 (dd, 1H), 8.35 (d, 1H), 8.58 (d, 1H).

[0428] [α] D 20 = -42.57° (c = 0.350, methanol).

[0429] Examples 65 and 66 (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazo-5-yl)[(3R)-3-methyl[1,4'-piperidin]-1'-yl]methyl ketone diastereomers 1 and 2 ) 95 mg (0.21 mmol) (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R A mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone (Example 38) was separated into individual diastereomers by preparative chiral HPLC [column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 40:60; flow rate: 18 ml / min; UV detection: 300 nm; temperature: 30 °C]. Example 65 ( diastereomer 1 ): (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 39 mg R t= 5.53 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 60:40; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 300 nm].

[0430] LC-MS (Method 1): R t = 0.91 min; m / z = 448 (MH) - .

[0431] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.42 (m, 3H), 1.42-1.67 (m, 6H, of which 1.46 (d, 3H)), 1.68-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.68-2.77 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.20-5.30 (m, 1H), 7.33 (s, 1H), 7.86-7.95 (m, 1H), 8.48 (d, 1H). 8.62 (d, 1H).

[0432] [α] D 20 = +27.38° (c = 0.280, methanol).

[0433] Example 66 (diastereomer 2): (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 39 mg R t = 7.683 min; Chemical purity > 99%; > 99% de [Column: YMC Chiralart Amylose SA, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 60:40; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 300 nm].

[0434] LC-MS (Method 1): R t = 0.91 min; m / z = 448 (MH) - .

[0435] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.72-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.42 (m, 3H), 1.42-1.67 (m, 6H, of which 1.46 (d, 3H)), 1.68-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.42-2.53 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.20-5.30 (m, 1H), 7.33 (s, 1H), 7.86-7.95 (m, 1H), 8.48 (d, 1H). 8.62 (d, 1H).

[0436] [α] D 20 = -37.82° (c = 0.275, methanol). Examples 67 and 68 {2-[3,4-dihydro-2- H -pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazo-5-yl}[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomers 1 and 2 ) 111 mg (0.25 mmol) {2-[3,4-dihydro-2-] H -pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazo-5-yl}[(3 RA mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone (Example 51) was separated into individual diastereomers by preparative chiral HPLC [column: Daical Chiracel OX-H, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 40:60; flow rate: 16 ml / min; UV detection: 300 nm; temperature: 30 °C]. Example 67 ( diastereomer 1 ): {2-[3,4-dihydro-2- H -pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazo-5-yl}[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 45 mg R t = 15.14 min; Chemical purity > 99%; > 99% de [Column: Chiracel OX-H, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 60:40; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 300 nm].

[0437] LC-MS (Method 1): R t = 0.75 min; m / z = 440 (MH) - .

[0438] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.75-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.31-1.47 (m, 3H), 1.47-1.68 (m, 3H), 1.70-1.81 (m, 3H), 2.00-2.11 (m, 1H), 2.12-2.21 (m, 1H), 2.22-2.32 (m, 1H), 2.44-2.56 (m, 1H, partially masked by DMSO), 2.70-2.80 (m, 2H), 2.92 (br. t, 2H), 4.14-4.23 (m, 1H), 4.25-4.36 (m, 3H), 4.93-5.00 (m, 1H). 7.26 (d, 2H), 7.43 (s, 1H), 8.16 (t, 1H), 8.54 (d, 1H).

[0439] [α] D 20 = +20.25° (c = 0.260, methanol).

[0440] Example 68 ( diastereomer 2 ): {2-[3,4-dihydro-2- H -pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazo-5-yl}[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 44 mg R t = 16.11 min; Chemical purity > 99%; > 99% de [Column: Chiracel OX-H, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 60:40; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 300 nm].

[0441] LC-MS (Method 1): R t = 0.75 min; m / z = 440 (MH) - .

[0442] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.73-0.89 (m, 4H, of which 0.82 (d, 3H)), 1.31-1.46 (m, 3H), 1.46-1.69 (m, 3H), 1.70-1.81 (m, 3H), 2.01-2.11 (m, 1H), 2.12-2.21 (m, 1H), 2.22-2.32 (m, 1H), 2.44-2.56 (m, 1H, partially masked by DMSO), 2.70-2.80 (m, 2H), 2.92 (br. t, 2H), 4.13-4.23 (m, 1H), 4.25-4.36 (m, 3H), 4.93-5.00 (m, 1H). 7.26 (d, 2H), 7.43 (s, 1H), 8.16 (t, 1H), 8.54 (d, 1H).

[0443] [α] D 20 = -32.53° (c = 0.250, methanol).

[0444] Examples 69 and 70 3-[(5-{[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]carbonyl}-1,3-thiazolyl]amino]-3-(pyridin-2-yl)propionitrile( diastereomers 1 and 2 ) 65 mg (0.15 mmol) 3-[(5-{[(3 R A mixture of diastereomers of 3-methyl[1,4'-bipiperidin]-1'-yl]carbonyl}-1,3-thiazolyl]amino]-3-(pyridin-2-yl)propionitrile (Example 48) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 15 ml / min; UV detection: 210 nm; temperature: 40 °C]. Example 69 ( diastereomer 1 ): 3-[(5-{[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]carbonyl}-1,3-thiazolyl]amino]-3-(pyridin-2-yl)propionitrile Yield: 26 mg R t= 2.02 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiracel OX-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0445] LC-MS (Method 1): R t = 0.75 min; m / z = 437 (MH) - .

[0446] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.90 (m, 4H, of which 0.82 (d, 3H)), 1.28-1.46 (m, 3H), 1.46-1.67 (m, 3H), 1.68-1.80 (m, 3H), 1.98-2.10 (m, 1H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.69-2.79 (m, 2H), 2.91 (br. t, 2H), 3.10-3.27 (m, 2H), 4.26 (br. d, 2H), 5.26-5.36 (m, 1H), 7.34-7.40 (m, 1H), 7.42 (s, 1H), 7.50 (d, ...) 1H), 7.84 (td, 1H), 8.60 (d, 1H), 8.86 (br. d, 1H).

[0447] [α] D 20 = +19.74° (c = 0.260, methanol).

[0448] Example 70 ( diastereomer 2 ): 3-[(5-{[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]carbonyl}-1,3-thiazolyl]amino]-3-(pyridin-2-yl)propionitrile Yield: 27 mg R t = 2.43 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiracel OX-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0449] LC-MS (Method 1): R t = 0.76 min; m / z = 437 (MH) - .

[0450] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.74-0.89 (m, 4H, of which 0.81 (d, 3H)), 1.29-1.45 (m, 3H), 1.46-1.68 (m, 3H), 1.69-1.80 (m, 3H), 1.99-2.09 (m, 1H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.69-2.79 (m, 2H), 2.91 (br. t, 2H), 3.10-3.26 (m, 2H), 4.26 (br. d, 2H), 5.26-5.35 (m, 1H), 7.34-7.40 (m, 1H), 7.42 (s, 1H), 7.50 (d, ...) 1H), 7.84 (td, 1H), 8.60 (d, 1H), 8.86 (br. d, 1H).

[0451] [α] D 20 = -30.77° (c = 0.260, methanol).

[0452] Examples 71 and 72 [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 54 mg (0.13 mmol) [(3 RA mixture of diastereomers of 2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazo-5-yl) methyl ketone (Example 44) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IG, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 20 ml / min; UV detection: 210 nm; temperature: 50 °C]. Example 71 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 19 mg R t = 4.03 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IG-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0453] LC-MS (Method 1): R t = 0.78 min; m / z = 426 (MH) - .

[0454] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.71-0.93 (m, 7H, including 0.81 (d, 3H) and 0.88 (t, 3H)), 1.27-1.46 (m, 3H), 1.46-1.67 (m, 3H), 1.68-1.78 (m, 3H), 1.78-1.93 (m, 2H), 1.98-2.09 (m, 1H), 2.41-2.57 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.24 (br. d, 2H), 4.64-4.74 (m, 1H), 7.26 (ddd, 1H), 7.34 (s, 1H). 7.36 (d, 1H), 7.72-7.80 (m, 1H), 8.52 (d, 1H), 8.59 (d, 1H).

[0455] [α] D 20 = +31.70° (c = 0.265, methanol).

[0456] Example 72 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 19 mg R t = 7.25 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IG-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0457] LC-MS (Method 1): R t = 0.77 min; m / z = 426 (MH) - .

[0458] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.72-0.93 (m, 7H, of which 0.81 (d, 3H) and 0.88 (t, 3H)), 1.27-1.44 (m, 3H), 1.45-1.66 (m, 3H), 1.68-1.78 (m, 3H), 1.78-1.93 (m, 2H), 1.98-2.09 (m, 1H), 2.41-2.57 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.24 (br. d, 2H), 4.63-4.73 (m, 1H), 7.26 (ddd, 1H), 7.33 (s, 1H). 7.36 (d, 1H), 7.71-7.80 (m, 1H), 8.53 (d, 1H), 8.59 (d, 1H).

[0459] Examples 73 and 74 [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]{2-[5,6,7,8-tetrahydroquinoline-8-ylamino]-1,3-thiazolyl-5-yl} methyl ketone diastereomers 1 and 2 ) 66 mg (0.15 mmol) [(3 R A mixture of diastereomers of 2-[5,6,7,8-tetrahydroquinolino-8-ylamino]-1,3-thiazolyl-5-yl] methyl ketone (Example 43) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralcel OX-H, 5 µm, 250 mm x 20 mm; mobile phase: isopropanol + 0.2% diethylamine / n-heptane 40:60; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 50 °C]. Example 73 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]{2-[5,6,7,8-tetrahydroquinoline-8-ylamino]-1,3-thiazolyl-5-yl} methyl ketone Yield: 24 mg R t = 3.52 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / isopropanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0460] LC-MS (Method 1): R t = 0.74 min; m / z = 438 (MH) - .

[0461] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.75-0.89 (m, 4H, of which 0.82 (d, 3H)), 1.31-1.47 (m, 3H), 1.47-1.68 (m, 3H), 1.71-1.91 (m, 5H), 1.91-2.01 (m, 1H), 2.01-2.12 (m, 2H), 2.44-2.57 (m, 1H, partially masked by DMSO), 2.69-2.86 (m, 4H), 2.91 (br. t, 2H), 4.29 (br. d, 2H), 4.85-4.94 (m, 1H), 7.24 (dd, 1H), 7.41 (s, 1H), 7.55 (d, 1H). 8.34–8.44 (m, 2H).

[0462] [α] D 20 = +55.07° (c = 0.250, methanol).

[0463] Example 74 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]{2-[5,6,7,8-tetrahydroquinoline-8-ylamino]-1,3-thiazolyl-5-yl} methyl ketone Yield: 31 mg R t = 4.63 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak OX-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / isopropanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0464] LC-MS (Method 1): R t = 0.74 min; m / z = 438 (MH) - .

[0465] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.75-0.89 (m, 4H, of which 0.82 (d, 3H)), 1.31-1.46 (m, 3H), 1.46-1.68 (m, 3H), 1.70-1.91 (m, 5H), 1.92-2.01 (m, 1H), 2.01-2.12 (m, 2H), 2.45-2.56 (m, 1H, partially masked by DMSO), 2.69-2.86 (m, 4H), 2.91 (br. t, 2H), 4.29 (br. d, 2H), 4.86-4.94 (m, 1H), 7.24 (dd, 1H), 7.41 (s, 1H), 7.55 (d, 1H). 8.36–8.43 (m, 2H).

[0466] [α] D 20 = -68.36° (c = 0.275, methanol).

[0467] Examples 75 and 76 [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone diastereomers 1 and 2 ) 132 mg (0.31 mmol) [(3 R A mixture of diastereomers of 2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone (Example 41) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IE, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 18 ml / min; UV detection: 220 nm; temperature: 50 °C]. Example 75 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 53 mg R t = 3.99 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IE-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0468] LC-MS (Method 1): R t = 0.64 min; m / z = 426 (MH) - .

[0469] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.47 (m, 6H, of which 1.44 (d, 3H)), 1.47-1.67 (m, 3H), 1.68-1.79 (m, 3H), 1.98-2.10 (m, 1H), 2.30 (s, 3H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.69-2.78 (m, 3H), 2.88 (br. t, 2H), 4.24 (br. d, 2H), 4.78-4.89 (m, 1H), 7.09 (dd, 1H), 7.20 (s, 1H), 7.35 (s, 1H), 8.37 (d, 1H), 8.58 (d, 1H).

[0470] [α] D 20 = +36.06° (c = 0.305, methanol).

[0471] Example 76 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 53 mg R t = 5.60 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IE-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30℃; UV detection: 220 nm].

[0472] LC-MS (Method 1): R t = 0.63 min; m / z = 426 (MH) - .

[0473] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.28-1.46 (m, 6H, of which 1.44 (d, 3H)), 1.46-1.66 (m, 3H), 1.68-1.79 (m, 3H), 1.99-2.10 (m, 1H), 2.30 (s, 3H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.69-2.78 (m, 3H), 2.88 (br. t, 2H), 4.24 (br. d, 2H), 4.79-4.89 (m, 1H), 7.09 (dd, 1H), 7.20 (s, 1H), 7.35 (s, 1H), 8.37 (d, 1H), 8.57 (d, 1H).

[0474] [α] D 20 = -48.52° (c = 0.270, methanol).

[0475] Examples 77 and 78 (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomers 1 and 2 ) 68 mg (0.15 mmol) (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R A mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone (Example 55) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak I5, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 18 ml / min; UV detection: 210 nm; temperature: 40 °C]. Example 77 ( diastereomer 1 ): (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 15 mg R t = 1.17 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IB-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0476] LC-MS (Method 1): R t = 0.73 min; m / z = 442 (MH) - .

[0477] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.45 (m, 3H), 1.46-1.67 (m, 3H), 1.67-1.80 (m, 3H), 1.99-2.11 (m, 1H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.68-2.79 (m, 3H), 2.88 (br. t, 2H), 3.25 (s, 3H), 3.64-3.76 (m, 2H), 4.24 (br. d, 2H), 5.02-5.11 (m, 1H), 7.28 (ddd, 1H), 7.34 (s, 1H). 7.38 (d, 1H), 7.76 (td, 1H), 8.54 (d, 1H), 8.66 (d, 1H).

[0478] [α] D 20 = -34.69° (c = 0.270, methanol).

[0479] Example 78 ( diastereomer 2 ): (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 19 mg R t = 1.45 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IB-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0480] LC-MS (Method 1): R t = 0.72 min; m / z = 442 (MH) - .

[0481] 1 H-NMR (400 MHz, DMSO- d 6δ / ppm): 0.72-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.46 (m, 3H), 1.46-1.67 (m, 3H), 1.68-1.80 (m, 3H), 1.99-2.10 (m, 1H), 2.43-2.56 (m, 1H, partially masked by DMSO), 2.69-2.79 (m, 3H), 2.88 (br. t, 2H), 3.25 (s, 3H), 3.65-3.75 (m, 2H), 4.24 (br. d, 2H), 5.02-5.11 (m, 1H), 7.28 (ddd, 1H), 7.34 (s, 1H). 7.38 (d, 1H), 7.76 (td, 1H), 8.54 (d, 1H), 8.66 (d, 1H).

[0482] [α] D 20 = +18.98° (c = 0.260, methanol).

[0483] Examples 79 and 80 [(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone diastereomers 1 and 2 ) 103 mg (0.23 mmol) [(3 R A mixture of diastereomers of 2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl) ketone (Example 52) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IE, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 30:70; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 50 °C]. Example 79 ( diastereomer 1 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 41 mg Rt = 2.07 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 70:30; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0484] LC-MS (Method 1): R t = 1.00 min; m / z = 454 (MH) - .

[0485] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.74-0.86 (m, 4H, of which 0.81 (d, 3H)), 0.90 (d, 3H), 0.92 (d, 3H), 1.26-1.45 (m, 3H), 1.45-1.66 (m, 5H), 1.66-1.79 (m, 4H), 1.98-2.08 (m, 1H), 2.41-2.57 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 4.78-4.87 (m, 1H), 7.25 (ddd, 1H), 7.33 (s, 1H), 7.37 (d, 1H), 7.75 (td, 1H), 8.52 (d, 1H), 8.60 (d, 1H).

[0486] [α] D 20 = +27.58° (c = 0.255, methanol).

[0487] Example 80 ( diastereomer 2 ): [(3 R )-3-methyl[1,4'-bipiperidin]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 42 mg R t = 3.19 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 70:30; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0488] LC-MS (Method 1): R t = 1.01 min; m / z = 454 (MH) - .

[0489] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.86 (m, 4H, of which 0.81 (d, 3H)), 0.90 (d, 3H), 0.92 (d, 3H), 1.26-1.45 (m, 3H), 1.45-1.66 (m, 5H), 1.66-1.78 (m, 4H), 1.98-2.08 (m, 1H), 2.41-2.57 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 4.78-4.87 (m, 1H), 7.25 (ddd, 1H), 7.34 (s, 1H), 7.36 (d, 1H), 7.75 (td, 1H), 8.52 (d, 1H), 8.60 (d, 1H).

[0490] [α] D 20 = -32.30° (c = 0.290, methanol).

[0491] Examples 81 and 82 (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazo-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomers 1 and 2 ) 174 mg (0.36 mmol) (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazolyl-5-yl)[(3 RA mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone formate (Example 54) was separated into individual diastereomers by chiral preparative HPLC [column: Daicel Chiralpak ID, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 50:50; flow rate: 15 ml / min; UV detection: 220 nm; temperature: 40 °C]. Example 81 ( diastereomer 1 ): (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazo-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 61 mg R t = 1.91 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0492] LC-MS (Method 1): R t = 0.80 min; m / z = 438 (MH) - .

[0493] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.36-0.48 (m, 3H), 0.50-0.58 (m, 1H), 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.21-1.44 (m, 4H), 1.45-1.66 (m, 3H), 1.67-1.77 (m, 3H), 1.98-2.08 (m, 1H), 2.41-2.56 (m, 1H, partially masked by DMSO), 2.68-2.77 (m, 2H), 2.86 (br. t, 2H), 4.18-4.29 (m, 3H), 7.26 (ddd, 1H), 7.30 (s, 1H), 7.40 (d, 1H). 7.76 (td, 1H), 8.52 (d, 1H), 8.75 (d, 1H).

[0494] Example 82 ( diastereomer 2 ): (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazo-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 61 mg R t = 3.58 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak ID-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0495] LC-MS (Method 1): R t = 0.80 min; m / z = 438 (MH) - .

[0496] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.36-0.48 (m, 3H), 0.50-0.59 (m, 1H), 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.21-1.45 (m, 4H), 1.45-1.66 (m, 3H), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.41-2.56 (m, 1H, partially masked by DMSO), 2.68-2.77 (m, 2H), 2.87 (br. t, 2H), 4.18-4.30 (m, 3H), 7.26 (ddd, 1H), 7.30 (s, 1H), 7.40 (d, 1H). 7.76 (td, 1H), 8.52 (d, 1H), 8.75 (d, 1H).

[0497] [α] D 20 = -7.55° (c = 0.265, methanol).

[0498] Example 83 ( diastereomer 1 ) (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone 100 mg (0.27 mmol) (5-bromo-1,3-thiazolyl-2-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 103 mg (0.54 mmol) (1 S 1-(3-chloropyridin-2-yl)ethylamine hydrochloride (1:1) was dissolved in 1.2 mL of 1-methyl-2-pyrrolidone, and 0.14 mL of N,N-diisopropylethylamine was added. The reaction mixture (in a sealed container) was then stirred overnight at 140 °C. After cooling to room temperature, the solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was separated, the solution was filtered through a hydrophobic filter, and concentrated to dryness under reduced pressure. Partial epimerization was observed, therefore the resulting residue was purified by chiral preparative HPLC.

[0499] 57 mg (0.13 mmol) (2-{[(1 S / R )-1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3 R A mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak AZ-H, 5 µm, 250 mm x 20 mm; mobile phase: ethanol / n-heptane 50:50; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 50 °C]. This yields 32 mg of the title compound (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomer 1 ) and 5.4 mg diastereomer 2 (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone.

[0500] (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomer 1 Analysis of: R t= 3.16 min; Chemical purity > 99%; > 99% ee [Column: Chiralpak AZ-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0501] LC-MS (Method 1): R t = 1.00 min; m / z = 446 / 448 (MH) - .

[0502] 1 H-NMR (400 MHz, DMSO- d 6, δ / ppm): 0.73-0.87 (m, 4H, of which 0.81 (d, 3H)), 1.27-1.46 (m, 6H) darin 1.43 (d, 3H)), 1.46-1.66 (m, 3H), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.41-2.53 (m, 1H, partially masked by DMSO), 2.68-2.78 (m, 2H), 2.87 (br. t, 2H), 4.23 (br. d, 2H), 5.37-5.47 (m, 1H), 7.33 (s, 1H), 7.34 (dd, 1H), 7.91 (dd, 1H). 8.52 (dd, 1H), 8.63 (d, 1H).

[0503] [α] D 20 = +9.63° (c = 0.270, methanol).

[0504] Example 84 ( diastereomer 2 ) (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yields after separation and purification (see Example 83): 5.4 mg (2-{[1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomer 2 Analysis of: R t = 2.64 min; Chemical purity > 99%; > 99% ee [Column: Chiralpak AZ-3, 3 µm, 50 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 50:50; Flow rate: 1 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[0505] LC-MS (Method 1): R t = 0.99 min; m / z = 446 / 448 (MH) - .

[0506] [α] D 20 = -20.37° (c = 0.270, methanol).

[0507] Examples 85 and 86 (2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R )-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone diastereomers 1 and 2 ) 91 mg (0.20 mmol) (2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R A mixture of diastereomers of 3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 56) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IC, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + 0.2% diethylamine / n-heptane 30:70; flow rate: 20 ml / min; UV detection: 220 nm; temperature: 40 °C]. Example 85 ( diastereomer 1 ): (2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 28 mg R t = 14.64 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 70:30; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[0508] LC-MS (Method 1): R t = 0.96 min; m / z = 446 / 448 (MH) - .

[0509] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.73-0.88 (m, 4H, of which 0.81 (d, 3H)), 1.21-1.43 (m, 3H), 1.43-1.66 (m, 6H, of which 1.46 (d, 3H)), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.41-2.56 (m, 1H, partially masked by DMSO), 2.68-2.79 (m, 2H), 2.88 (br. t, 2H), 4.23 (br. d, 2H), 4.84-4.94 (m, 1H), 7.34 (s, 1H), 7.42 (d, 1H), 7.90 (dd, 1H), 8.57 (d, 1H), 8.64 (d, 1H).

[0510] [α] D 20 = -38.85° (c = 0.290, methanol).

[0511] Example 86 ( diastereomer 2 ): (2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3 R 3-Methyl[1,4'-bipiperidine]-1'-yl]methyl ketone Yield: 31 mg R t = 18.22 min; Chemical purity > 99%; > 99% de [Column: Daicel Chiralpak IC, 5 µm, 250 mm x 4.6 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 70:30; Flow rate: 1 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[0512] LC-MS (Method 1): R t = 0.94 min; m / z = 446 / 448 (MH) - .

[0513] 1 H-NMR (400 MHz, DMSO- d 6 δ / ppm): 0.72-0.89 (m, 4H, of which 0.81 (d, 3H)), 1.21-1.42 (m, 3H), 1.43-1.66 (m, 6H, of which 1.46 (d, 3H)), 1.67-1.78 (m, 3H), 1.98-2.08 (m, 1H), 2.41-2.56 (m, 1H, partially masked by DMSO), 2.69-2.78 (m, 2H), 2.88 (br. t, 2H), 4.23 (br. d, 2H), 4.84-4.94 (m, 1H), 7.34 (s, 1H), 7.42 (d, 1H), 7.89 (dd, 1H), 8.57 (d, 1H), 8.64 (d, 1H).

[0514] [α] D 20 = +32.24° (c = 0.305, methanol).

[0515] Example 87 (3-Cyclopropyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomer mixture ) To 2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac3-Cyclopropyl-1,4'-Bipiperidine hydrochloride (73.3 mg, 299 µmol) was added sequentially to a solution of 3 mL acetonitrile with N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. The residue was applied to Isolute® and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2-20% MeOH; flow rate: 25 ml / min). The fractions containing the product were combined and concentrated, and then dried under high vacuum. This yielded 59.0 mg (100% purity, 43% of theoretical value) of the target compound.

[0516] LC-MS (Method 1): R t = 0.98 min; MS (ESIneg): m / z = 456 [MH] - .

[0517] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.012 (1.04), 0.029 (2.43), 0.039(4.53), 0.045 (4.05), 0.305 (2.30), 0.312 (3.15), 0.323 (3.73), 0.332 (3.27),0.341 (2.98), 0.469 (0.94), 0.481 (1.45), 0.490 (1.29), 0.502 (1.40), 0.640(1.20), 0.666 (1.15), 0.940 (0.50), 0.960 (1.12), 0.970 (1.24), 0.991 (1.16),0.999 (1.17), 1.020 (0.52), 1.312 (2.04), 1.340 (2.67), 1.450 (14.17), 1.467(14.14), 1.572 (1.52), 1.604 (1.29), 1.706 (3.61), 1.736 (2.28), 1.938(1.55), 1.963 (2.85), 1.990 (1.58), 2.041 (1.02), 2.063 (1.81), 2.091 (1.12),2.327 (0.42), 2.366 (0.51), 2.459 (1.01), 2.669 (0.54), 2.694 (1.54), 2.710(1.43), 2.722 (1.45), 2.783 (1.58), 2.804 (1.64), 2.839 (1.28), 2.869 (2.05),2.899 (1.18), 3.258 (0.48), 3.269 (0.53), 3.275 (0.48), 3.289 (0.89), 3.306(1.05), 3.381 (1.77), 3.410 (0.42), 4.218 (2.74), 4.251 (2.61), 5.250 (0.48),5.267 (1.64), 5.285 (2.51), 5.302 (1.64), 5.319 (0.45), 5.749 (1.61), 7.331(16.00), 7.368 (1.80), 7.379 (3.04), 7.390 (3.52), 7.400 (3.60), 7.411(2.16), 7.661 (2.31), 7.664 (2.45), 7.681 (2.22), 7.686 (3.07), 7.690 (2.57), 7.707 (2.05), 7.710 (2.04), 7.969 (0.92), 7.982 (0.43), 8.387 (2.26), 8.390 (3.87), 8.394 (2.54), 8.399 (2.48), 8.402 (3.82), 8.598 (4.10), 8.617 (4.01).

[0518] Examples 88 and 89 (3-Cyclopropyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomers 1 and 2 ) 52 mg of (3-cyclopropyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S A mixture of diastereomers of 1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone (Example 87) was separated into individual diastereomers by preparative chiral HPLC [Daicel® Chiralpak ID column, 5 µm, 20 x 250 mm; mobile phase: 60% n-heptane & 40% ethanol + 0.2% diethylamine; flow rate: 20 ml / min; temperature: 50 °C; detection: 220 nm]: two diastereomers were collected and lyophilized separately.

[0519] Example 88 ( diastereomer 1 ): (3-Cyclopropyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 16 mg R t = 2,899 min; Chemical purity > 99%; > 99% de [Column: Chiralpak ID-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 50% n-heptane & 50% ethanol + 0.2% DEA].

[0520] LC-MS (Method 1): R t= 1.00 min; MS (ESIpos): m / z = 458 [M+H] + 。

[0521] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.010 (0.75), 0.006 (0.90), 0.031(2.56), 0.041 (4.79), 0.047 (4.00), 0.306 (2.44), 0.314 (3.16), 0.325 (3.84),0.334 (3.22), 0.343 (2.89), 0.472 (0.99), 0.483 (1.47), 0.492 (1.26), 0.503(1.38), 0.642 (1.23), 0.666 (1.18), 0.942 (0.48), 0.963 (1.23), 0.972 (1.22),0.994 (1.21), 1.022 (0.57), 1.315 (2.29), 1.345 (2.98), 1.364 (1.94), 1.373(1.89), 1.451 (14.85), 1.468 (14.85), 1.573 (1.59), 1.605 (1.28), 1.707(3.61), 1.942 (1.51), 1.968 (2.74), 1.994 (1.50), 2.046 (1.02), 2.067 (1.81),2.094 (1.04), 2.326 (0.47), 2.698 (1.56), 2.709 (1.42), 2.724 (1.45), 2.785(1.69), 2.809 (1.62), 2.838 (1.29), 2.870 (2.20), 3.380 (0.75), 4.220 (2.96),4.251 (2.85), 5.250 (0.48), 5.269 (1.78), 5.287 (2.70), 5.304 (1.76), 5.323(0.48), 7.333 (16.00), 7.369 (1.83), 7.380 (3.13), 7.391 (3.63), 7.401(3.78), 7.412 (2.23), 7.662 (2.35), 7.666 (2.56), 7.683 (2.29), 7.688 (3.23),7.691 (2.66), 7.709 (2.12), 7.712 (2.16), 8.392 (4.03), 8.395 (2.70), 8.403(3.98), 8.599 (4.35), 8.618 (4.twenty four)..

[0522] [α] D 20 = -20.82° (c = 0.255, methanol).

[0523] Example 89 ( diastereomer 2 ): (3-Cyclopropyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 15 mg R t = 3.525 min; Chemical purity > 99%; > 99% de [Column: Chiralpak ID-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 50% n-heptane & 50% ethanol + 0.2% DEA].

[0524] LC-MS (Method 1): R t = 1.01 min; MS (ESIpos): m / z = 458 [M+H] + .

[0525] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.043 (5.64), 0.316 (3.67), 0.326(4.56), 0.336 (3.72), 0.344 (3.18), 0.474 (1.18), 0.485 (1.72), 0.495 (1.51),0.506 (1.63), 0.516 (1.01), 0.619 (0.62), 0.643 (1.50), 0.668 (1.41), 0.944(0.64), 0.965 (1.41), 0.974 (1.46), 0.995 (1.46), 1.025 (0.64), 1.318 (2.56),1.347 (3.28), 1.361 (2.57), 1.454 (16.00), 1.471 (15.98), 1.575 (1.92), 1.607(1.52), 1.708 (4.84), 1.738 (2.97), 1.944 (1.75), 1.970 (3.28), 1.996 (1.73),2.048 (1.23), 2.071 (2.22), 2.099 (1.24), 2.465 (1.19), 2.699 (1.93), 2.725(1.75), 2.789 (2.06), 2.812 (1.99), 2.842 (1.60), 2.871 (2.77), 2.904 (1.54),4.222 (3.58), 4.255 (3.45), 5.255 (0.50), 5.272 (2.06), 5.290 (3.15), 5.307(2.07), 5.324 (0.51), 7.336 (15.92), 7.372 (1.90), 7.383 (3.33), 7.393(3.73), 7.404 (3.88), 7.415 (2.23), 7.665 (2.81), 7.668 (2.51), 7.686 (2.91),7.690 (3.75), 7.694 (2.72), 7.712 (2.47), 7.715 (2.14), 8.395 (4.52), 8.406 (4.37), 8.602 (4.77), 8.621 (4.67).

[0526] [a] D 20= -51.92° (c = 0.251, methanol).

[0527] Example 90 (2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl)methyl ketone diastereomer mixture ) To 2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac 3-Isopropyl-1,4'-Bipiperidine hydrochloride (73.9 mg, 299 µmol) was added sequentially to a solution of 3 mL acetonitrile with N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. The residue was applied to Isolute® and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2-20% MeOH; flow rate: 25 ml / min). The fractions containing the product were combined and concentrated, and then dried under high vacuum. This yielded 41.0 mg (100% purity, 30% of theoretical value) of the target compound.

[0528] LC-MS (Method 1): R t = 1.04 min; MS (ESIpos): m / z = 460 [M+H] + .

[0529] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.828 (14.65), 0.834 (15.31),0.844 (15.86), 0.851 (16.00), 0.883 (1.16), 0.891 (1.12), 0.913 (0.50), 0.923(0.44), 1.134 (0.47), 1.151 (0.84), 1.160 (1.02), 1.169 (0.92), 1.177 (1.01),1.316 (1.48), 1.337 (2.22), 1.347 (2.69), 1.366 (3.40), 1.376 (2.35), 1.383(2.80), 1.399 (2.47), 1.416 (1.16), 1.433 (0.49), 1.454 (13.04), 1.471(13.03), 1.585 (1.37), 1.626 (1.58), 1.665 (1.13), 1.705 (2.36), 1.737(2.02), 1.832 (1.41), 1.859 (2.64), 1.885 (1.36), 2.002 (0.94), 2.025 (1.67),2.052 (0.92), 2.461 (0.84), 2.470 (0.66), 2.715 (1.42), 2.752 (1.94), 2.781(1.36), 2.838 (1.02), 2.866 (1.78), 2.896 (1.01), 4.229 (2.43), 4.262 (2.32),5.272 (1.53), 5.290 (2.31), 5.307 (1.50), 7.334 (14.51), 7.371 (1.63), 7.382(2.78), 7.392 (3.22), 7.403 (3.30), 7.414 (1.99), 7.663 (2.12), 7.667 (2.20),7.684 (2.08), 7.689 (2.80), 7.692 (2.30), 7.710 (1.90), 7.713 (1.84), 8.390(2.11), 8.394 (3.57), 8.397 (2.25), 8.402 (2.23), 8.405 (3.48), 8.409 (2.01),8.602 (3.82), 8.621 (3.70)。

[0530] Examples 91 and 92 (2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl)methyl ketone diastereomers 1 and 2 ) 41 mg of (2-{[(1) S A mixture of diastereomers of 1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl)methyl ketone (Example 90) was separated into individual diastereomers by preparative chiral HPLC [Chiralpak AZ-H column, 250 x 20 mm; mobile phase: 70% n-heptane & 30% ethanol + 0.2% diethylamine; flow rate: 20 ml / min; temperature: 50 °C; detection: 220 nm]. Two diastereomers were collected separately and lyophilized.

[0531] Example 91 ( diastereomer 1 ): (2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl)methyl ketone Yield: 12 mg R t = 4.894 min; Chemical purity > 99%; > 99% de [Column: Chiralpak AZ-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30℃, mobile phase: 70% n-heptane & 30% ethanol + 0.2% DEA].

[0532] LC-MS (Method 1): R t = 1.03 min; MS (ESIneg): m / z = 458 [MH] - .

[0533] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.828 (14.82), 0.834 (15.57), 0.845 (16.00), 0.851 (15.94), 0.884 (1.18), 1.178 (1.18), 1.316 (1.58), 1.347(2.70), 1.367 (3.35), 1.384 (2.82), 1.401 (2.40), 1.417 (1.18), 1.452(13.14), 1.470 (13.05), 1.587 (1.37), 1.627 (1.73), 1.666 (1.18), 1.707(2.28), 1.738 (1.92), 1.836 (1.06), 1.863 (1.96), 1.889 (1.01), 2.001 (0.79), 2.031 (1.42), 2.056 (0.77), 2.368 (0.52), 2.712 (1.40), 2.754 (1.97), 2.783(1.33), 2.865 (1.63), 3.284 (0.52), 3.389 (0.65), 4.228 (2.39), 4.260 (2.28), 5.270 (1.52), 5.287 (2.32), 5.305 (1.56), 7.333 (14.79), 7.371 (1.65), 7.382(2.78), 7.392 (3.30), 7.403 (3.35), 7.414 (2.06), 7.664 (2.15), 7.667 (2.28), 7.684 (2.07), 7.689 (2.85), 7.693 (2.42), 7.710 (1.93), 7.714 (1.88), 8.390(2.08), 8.393 (3.57), 8.397 (2.33), 8.401 (2.22), 8.405 (3.49), 8.408 (2.09), 8.601 (3.78), 8.620 (3.67).

[0534] [α] D 20 = -32.40° (c = 0.250, methanol).

[0535] Example 92 ( diastereomer 2 ): (2-{[(1 S1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl)methyl ketone Yield: 12 mg R t = 5.972 min; Chemical purity > 99%; > 99% de [Column: Chiralpak AZ-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30℃, mobile phase: 70% n-heptane & 30% ethanol + 0.2% DEA].

[0536] LC-MS (Method 1): R t = 1.04 min; MS (ESIneg): m / z = 458 [MH] - .

[0537] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.828 (14.90), 0.834 (15.44), 0.845 (16.00), 0.851 (15.71), 0.885 (1.14), 0.894 (1.07), 0.916 (0.53), 1.179(1.21), 1.318 (1.45), 1.349 (2.60), 1.368 (3.32), 1.384 (2.75), 1.401 (2.44),1.418 (1.17), 1.453 (13.12), 1.470 (13.04), 1.588 (1.33), 1.629 (1.71), 1.666 (1.12), 1.709 (2.40), 1.737 (2.03), 1.838 (0.97), 1.863 (1.80), 1.890 (0.94), 2.006 (0.77), 2.032 (1.34), 2.059 (0.72), 2.720 (1.24), 2.756 (1.76), 2.785 (1.29), 2.835 (1.10), 2.866 (1.93), 2.896 (1.09), 4.229 (2.46), 4.261 (2.33), 5.270 (1.52), 5.288 (2.31), 5.305 (1.50), 5.323 (0.41), 7.334 (14.83), 7.371(1.71), 7.382 (2.80), 7.392 (3.27), 7.403 (3.37), 7.414 (2.04), 7.664 (2.18), 7.667 (2.24), 7.684 (2.11), 7.690 (2.80), 7.693 (2.34), 7.710 (1.96), 7.714(1.91), 8.390 (2.11), 8.393 (3.60), 8.397 (2.28), 8.402 (2.26), 8.405 (3.52), 8.409 (2.04), 8.602 (3.76), 8.621 (3.68).

[0538] [α] D 20 = -39.47° (c = 0.250, methanol).

[0539] Example 93 (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomer mixture ) To 2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac 3-tert-butyl-1,4'-bipiperidine hydrochloride (78.1 mg, 299 µmol) was added sequentially to a solution of 3 mL acetonitrile with N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. The residue was applied to Isolute® and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2-20% MeOH; flow rate: 25 ml / min). The fractions containing the product were combined and concentrated, and then dried under high vacuum. This yielded 39.0 mg (100% purity, 28% of theoretical value) of the target compound.

[0540] LC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m / z = 474 [M+H] + .

[0541] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.826 (16.00), 1.324 (0.46), 1.348(0.58), 1.369 (0.44), 1.449 (2.94), 1.466 (2.94), 1.705 (0.82), 1.735 (0.52),1.834 (0.67), 2.837 (0.57), 2.863 (0.74), 4.228 (0.56), 4.260 (0.53), 5.283(0.54), 5.749 (0.81), 7.331 (3.17), 7.378 (0.63), 7.388 (0.72), 7.399 (0.74), 7.409 (0.43), 7.659 (0.47), 7.662 (0.49), 7.679 (0.47), 7.684 (0.64), 7.687 (0.52), 7.705 (0.41), 7.708 (0.41), 8.389 (0.81), 8.393 (0.53), 8.397 (0.52), 8.401 (0.78), 8.596 (0.87), 8.616 (0.85).

[0542] Examples 94 and 95 (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomers 1 and 2 ) 32 mg of (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S A mixture of diastereomers of 1-(3-fluoropyridin-2-yl)ethyl[amino]-1,3-thiazolyl)methyl ketone (Example 93) was separated into individual diastereomers by preparative chiral HPLC [Chiralpak ID column, 250 x 20 mm; mobile phase: 80% n-heptane & 20% ethanol + 0.2% diethylamine; flow rate: 20 ml / min; temperature: 50 °C; detection: 220 nm]: two diastereomers were collected and lyophilized separately.

[0543] Example 94 ( diastereomer 1 ): (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 10 mg R t = 3.921 min; Chemical purity > 99%; > 99% de [Column: DAICEL Chiralpak ID-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 70% n-heptane & 30% ethanol + 0.2% DEA].

[0544] LC-MS (Method 1): R t = 1.12 min; MS (ESIneg): m / z = 472 [MH] - .

[0545] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.831 (16.00), 1.330 (0.44), 1.355(0.55), 1.452 (2.96), 1.469 (2.95), 1.709 (0.73), 1.740 (0.44), 1.844 (0.42),2.845 (0.52), 2.870 (0.62), 4.230 (0.51), 4.265 (0.49), 5.287 (0.53), 7.335(3.30), 7.382 (0.65), 7.392 (0.73), 7.403 (0.76), 7.413 (0.46), 7.663 (0.48),7.666 (0.51), 7.684 (0.48), 7.689 (0.63), 7.692 (0.54), 7.710 (0.45), 7.713(0.41), 8.393 (0.81), 8.397 (0.50), 8.401 (0.50), 8.404 (0.80), 8.600 (0.86),8.619 (0.82).

[0546] [α] D 20 = -30.13° (c = 0.250, methanol).

[0547] Example 95 diastereomer 2 ): (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 10 mg R t = 4.691 min; Chemical purity > 99%; > 96% de [Column: DAICEL Chiralpak ID-3 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 70% n-heptane & 30% ethanol + 0.2% DEA].

[0548] LC-MS (Method 1): R t = 1.12 min; MS (ESIneg): m / z = 472 [MH] - .

[0549] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.831 (16.00), 1.330 (0.49), 1.353(0.59), 1.373 (0.42), 1.453 (2.95), 1.470 (2.94), 1.708 (0.81), 1.740 (0.49),1.842 (0.52), 2.843 (0.52), 2.868 (0.74), 4.230 (0.57), 4.264 (0.56), 5.287(0.54), 7.335 (3.18), 7.382 (0.63), 7.392 (0.72), 7.402 (0.74), 7.413 (0.44),7.663 (0.48), 7.666 (0.49), 7.684 (0.47), 7.689 (0.64), 7.692 (0.52), 7.710(0.43), 7.713 (0.41), 8.393 (0.80), 8.397 (0.51), 8.401 (0.51), 8.404 (0.79), 8.600 (0.87), 8.620 (0.84).

[0550] [α] D 20 = -41.47° (c = 0.250, methanol).

[0551] Example 96 (3-Cyclobutyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomer mixture ) To 2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac 3-Cyclobutyl-1,4'-bipiperidine hydrochloride (77.5 mg, 299 µmol) was added sequentially to a solution of 3 mL acetonitrile with N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol), and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with acetonitrile, acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. The residue was applied to Isolute® and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2-20% MeOH; flow rate: 25 ml / min). The fractions containing the product were combined and concentrated, and then dried under high vacuum. This yielded 44.0 mg (100% purity, 31% of theoretical value) of the target compound.

[0552] LC-MS (Method 1): R t = 1.13 min; MS (ESIpos): m / z = 472 [M+H] + .

[0553] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.646 (0.52), 0.668 (1.25), 0.698(1.69), 0.724 (0.64), 0.825 (0.44), 1.048 (0.41), 1.064 (0.43), 1.317 (4.29),1.347 (4.03), 1.378 (1.55), 1.447 (15.89), 1.465 (16.00), 1.547 (1.82), 1.555(1.72), 1.584 (4.05), 1.612 (4.30), 1.634 (2.92), 1.653 (3.11), 1.678 (4.31),1.694 (6.70), 1.719 (4.76), 1.760 (2.03), 1.781 (1.75), 1.804 (1.08), 1.828(0.44), 1.876 (1.44), 1.894 (3.12), 1.916 (3.30), 1.935 (1.96), 1.960 (1.30),1.981 (2.02), 1.988 (1.74), 2.003 (2.04), 2.040 (2.31), 2.062 (1.22), 2.439(1.09), 2.467 (2.00), 2.644 (1.90), 2.674 (2.90), 2.709 (1.80), 2.857 (2.45),3.302 (0.85), 3.310 (1.37), 3.320 (1.35), 3.397 (1.68), 3.406 (1.26), 3.415(0.76), 3.574 (1.38), 4.213 (3.30), 4.245 (3.10), 5.245 (0.53), 5.263 (2.00),5.281 (2.98), 5.298 (1.99), 5.317 (0.51), 5.746 (0.88), 7.324 (15.64), 7.366(1.81), 7.377 (3.32), 7.387 (3.80), 7.398 (3.93), 7.409 (2.15), 7.657 (2.44),7.660 (2.46), 7.682 (3.60), 7.704 (2.15), 8.388 (4.36), 8.399 (4.17), 8.596(4.77), 8.615 (4.63).

[0554] Examples 97 and 98 (3-Cyclobutyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomers 1 and 2 ) 44 mg of (3-cyclobutyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S A mixture of diastereomers of 1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone (Example 96) was separated into individual diastereomers by preparative chiral HPLC [column: Daicel Chiralpak IG, 250 x 20 mm; mobile phase: 40% n-heptane & 60% ethanol + 0.2% diethylamine; flow rate: 15 ml / min; detection: 220 nm]: two diastereomers were collected and lyophilized separately.

[0555] Example 97 diastereomer 1 ): (3-Cyclobutyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 17 mg R t = 10.763 min; Chemical purity > 99%; > 99% de [Column: 250 x 4.6 mm packed with Daicel Chiralcel IG, 5 µm, flow rate: 1.0 ml / min, temperature: 60 °C, mobile phase: 50% n-heptane & 50% ethanol + 0.2% DEA].

[0556] LC-MS (Method 1): R t = 1.09 min; MS (ESIneg): m / z = 470 [MH] - .

[0557] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.671 (1.20), 0.700 (1.31), 0.728(0.63), 1.319 (4.25), 1.350 (4.05), 1.448 (15.31), 1.466 (15.32), 1.549(1.71), 1.587 (3.78), 1.614 (4.05), 1.637 (2.80), 1.656 (3.06), 1.674 (4.49), 1.699 (6.67), 1.723 (4.02), 1.762 (1.91), 1.784 (1.64), 1.806 (0.96), 1.831 (0.41), 1.879 (1.42), 1.897 (2.98), 1.919 (3.10), 1.938 (1.79), 1.963 (1.22), 1.984 (1.84), 2.006 (1.91), 2.038 (2.18), 2.066 (1.20), 2.327 (0.66), 2.366 (0.61), 2.441 (0.96), 2.469 (2.16), 2.645 (1.85), 2.674 (2.85), 2.709 (2.13), 2.858 (1.99), 3.279 (0.42), 3.386 (1.59), 3.437 (0.44), 4.212 (3.05), 4.246(2.89), 5.247 (0.51), 5.265 (1.94), 5.282 (2.85), 5.300 (1.84), 7.326(16.00), 7.368 (1.89), 7.379 (3.27), 7.389 (3.73), 7.400 (3.80), 7.411(2.21), 7.660 (2.56), 7.663 (2.56), 7.681 (2.62), 7.686 (3.37), 7.689 (2.61), 7.707 (2.21), 7.710 (2.05), 8.390 (4.22), 8.401 (4.06), 8.597 (4.55), 8.616 (4.37).

[0558] [α] D 20 = -24.37° (c = 0.290, methanol).

[0559] Example 98 ( diastereomer 2 ): (3-tert-butyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 17 mg R t = 13,475 min; Chemical purity > 99%; > 99% de [Column: 250 x 4.6 mm packed with Daicel Chiralcel IG, 5 µm, flow rate: 1.0 ml / min, temperature: 60 °C, mobile phase: 50% n-heptane & 50% ethanol + 0.2% DEA].

[0560] LC-MS (Method 1): R t = 1.09 min; MS (ESIneg): m / z = 470 [MH] - .

[0561] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.676 (1.20), 0.698 (1.35), 0.727(0.62), 1.319 (4.20), 1.349 (3.95), 1.448 (15.24), 1.466 (15.35), 1.550(1.75), 1.586 (3.76), 1.615 (4.01), 1.636 (2.71), 1.656 (2.93), 1.698 (6.17), 1.722 (4.28), 1.762 (1.98), 1.784 (1.63), 1.806 (1.01), 1.879 (1.43), 1.896 (2.94), 1.919 (3.09), 1.937 (1.81), 1.963 (1.25), 1.984 (1.86), 2.006 (1.90), 2.045 (2.16), 2.066 (1.17), 2.326 (0.70), 2.365 (0.88), 2.470 (2.09), 2.648 (1.80), 2.674 (2.96), 2.710 (2.32), 2.830 (1.39), 2.858 (2.52), 2.887 (1.37), 3.253 (0.47), 3.282 (1.24), 3.296 (1.60), 3.372 (2.02), 3.400 (1.20), 4.214(3.18), 4.246 (3.04), 5.265 (1.94), 5.283 (2.81), 5.300 (1.92), 7.326(16.00), 7.368 (1.86), 7.379 (3.25), 7.389 (3.78), 7.399 (3.81), 7.411(2.18), 7.660 (2.50), 7.663 (2.47), 7.685 (3.40), 7.707 (2.19), 7.710 (2.13), 8.389 (4.20), 8.401 (4.09), 8.597 (4.52), 8.617 (4.45).

[0562] [α] D 20 = -45.20° (c = 0.250, methanol).

[0563] Example 99 (3-Ethyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomer mixture ) To 2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac 3-Ethyl-1,4'-bipiperidine hydrochloride (69.7 mg, 299 µmol) was added sequentially to a solution of 3 mL acetonitrile with N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol), and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with acetonitrile, acidified with formic 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 15% B; 4.5 min 30% B; 11.5 min 50% B; 12 min 100% B; 18 min 100% B; flow rate: 50 mL / min; 0.1% formic acid). The fractions containing the product were combined and lyophilized. The residue was applied to Isolute® and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2-20% MeOH; flow rate: 25 ml / min). The fractions containing the product were combined and concentrated, and then dried under high vacuum. This yielded 84.0 mg (100% purity, 63% of theoretical value) of the target compound.

[0564] LC-MS (Method 1): R t = 0.98 min; MS (ESIpos): m / z = 446 [M+H] + .

[0565] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.740 (0.46), 0.770 (1.12), 0.799(1.31), 0.817 (6.42), 0.836 (16.00), 0.854 (7.79), 1.088 (0.61), 1.106(1.12), 1.122 (1.81), 1.140 (2.63), 1.158 (2.76), 1.176 (2.27), 1.194 (1.79),1.211 (0.96), 1.228 (0.79), 1.246 (0.65), 1.289 (1.80), 1.316 (2.68), 1.350(3.09), 1.380 (1.96), 1.411 (0.61), 1.448 (13.29), 1.466 (13.12), 1.558(1.55), 1.589 (1.19), 1.658 (1.33), 1.698 (3.78), 1.737 (3.59), 1.764 (2.73),1.789 (1.45), 2.028 (1.03), 2.050 (1.82), 2.055 (1.81), 2.077 (1.00), 2.447(0.92), 2.475 (1.89), 2.709 (1.85), 2.738 (2.83), 2.770 (1.53), 2.833 (1.20),2.864 (2.06), 2.894 (1.16), 3.281 (0.52), 3.292 (0.47), 3.310 (0.95), 3.410(0.93), 3.420 (1.03), 3.435 (0.48), 4.218 (2.79), 4.251 (2.65), 5.246 (0.43),5.264 (1.67), 5.282 (2.50), 5.300 (1.66), 5.317 (0.42), 5.746 (0.56), 7.327(12.85), 7.367 (1.51), 7.378 (2.74), 7.388 (3.11), 7.399 (3.20), 7.409(1.78), 7.661 (2.13), 7.683 (3.00), 7.707 (1.81), 8.389 (3.54), 8.400 (3.49),8.597 (3.87), 8.616 (3.79)。

[0566] Examples 100 and 101 (3-Ethyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S )-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone diastereomers 1 and 2 ) 70 mg of (3-ethyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S A mixture of diastereomers of 1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone (Example 99) was separated into individual diastereomers by preparative chiral HPLC [column: Chiralcel OD-H, 250 x 20 mm; mobile phase: 85% n-heptane & 15% ethanol + 0.2% diethylamine; flow rate: 20 ml / min; temperature: 30 °C; detection: 220 nm]: two diastereomers were collected and lyophilized separately.

[0567] Example 100 ( diastereomer 1 ): (3-Ethyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 28 mg R t = 1.716 min; Chemical purity > 99%; > 99% de [Column: DAIICEL Chiralcel OD-3, 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 80% n-heptane & 20% ethanol + 0.2% diethylamine].

[0568] LC-MS (Method 1): R t = 0.97 min; MS (ESIneg): m / z = 444 [MH] - .

[0569] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.64), 0.117 (0.62), 0.839(5.01), 0.854 (10.75), 0.869 (5.86), 1.159 (1.15), 1.173 (1.27), 1.212(1.16), 1.456 (16.00), 1.471 (15.84), 1.584 (0.54), 1.597 (0.57), 1.702(1.45), 1.722 (1.46), 2.889 (1.87), 4.276 (1.43), 5.263 (0.45), 5.277 (1.72), 5.291 (2.59), 5.306 (1.70), 5.320 (0.44), 7.356 (3.35), 7.379 (1.91), 7.387(3.13), 7.395 (3.54), 7.404 (3.57), 7.413 (2.07), 7.672 (2.22), 7.675 (2.28), 7.689 (2.27), 7.693 (3.11), 7.695 (2.43), 7.710 (2.04), 7.712 (1.97), 8.394(2.36), 8.396 (3.88), 8.399 (2.53), 8.403 (2.56), 8.406 (3.83), 8.409 (2.26), 8.636 (1.52), 8.650 (1.50).

[0570] [α] D 20 = -31.85° (c = 0.270, methanol).

[0571] Example 101 ( diastereomer 2 ): (3-Ethyl[1,4'-bipiperidine]-1'-yl)(2-{[(1 S 1-(3-Fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 28 mg R t = 2.04 min; Chemical purity > 99%; > 99% de [Column: DAIICEL Chiralcel OD-3, 3 µm 4.6 mm x 50 mm, flow rate: 1 ml / min, UV: 220 nm, temperature: 30 °C, mobile phase: 80% n-heptane & 20% ethanol + 0.2% diethylamine]. [0...

Claims

1. Compounds of general formula (I), and their salts, solvates, and solvates of said salts. (I) in X is S, N, or O; Y is N, S, or O. in, When X is S, Z is N; When X is 0, Z is N; Y is CR4, O, or NR4. When X is N and Z is N, Y is O; When X is S, Y is CR4 or NR4; R1 is a 5 to 10-membered heteroaryl, phenyl, (C4-C) group. 10 )-Heterocyclic alkyl or (C3-C 10 )-cycloalkyl, The 5 to 10 heteroaryl groups may be substituted by 1 to 3 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. The (C1-C4)-alkoxy group can be substituted by up to three halogens. The phenyl group may be substituted by one or two independent substituents selected from the following group: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. Among them (C3-C) 10 )-cycloalkyl and (C4-C 10 (C1-C4)-heterocyclic alkyl groups may be substituted by one or two independent substituents selected from the following group: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, halogen; The (C1-C4)-alkyl group can be substituted by halogens up to three times. Among them (C3-C) 10 )-cycloalkyl and (C4-C 10 )-Heterocyclic alkyl groups can fuse with 5 to 10 heteroaryl groups, The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; R2 is hydrogen, (C1-C4)-alkyl, or (C3-C5)-cycloalkyl; The (C1-C4)-alkyl group can be substituted by halogens up to three times. The (C1-C4)-alkyl group can be substituted with a cyano group or a (C1-C4)-alkoxy group. The (C3-C5)-cycloalkyl group can be substituted by halogens up to three times. or Together with the carbon atom bonded to R2, they form a (C3-C4)-cycloalkyl ring. or R1 and R2 together form a (C5-C8)-cycloalkyl group or (C5-C8)-cycloalkyl group. 10 )-Heterocyclic alkyl ring, (C5-C8)-cycloalkyl groups can fused with 5 to 10 heteroaryl groups. The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; Among them (C3-C) 10 )-Heterocyclic alkyl groups can fuse with 5 to 10 heteroaryl groups, The 5 to 10 heteroaryl groups may be substituted by 1 to 2 substituents independently selected from the following group: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; R3 is hydrogen or (C1-C4)-alkyl. The (C1-C4)-alkyl group can be substituted by halogens up to three times. R4 in CR4 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, or halogen; The (C1-C4)-alkyl groups can be substituted with halogens up to three times, and the phenyl groups can be substituted with halogens. NR4 is absent or contains hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, or phenyl. The (C1-C4)-alkyl groups can be substituted with halogens up to three times, and the phenyl groups can be substituted with halogens. R5 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen. R6 is a group of formula a), b), c), d), e), f), or g). Where *** indicates the connection with the adjacent piperidine ring. Where R7 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, or phenyl. The (C1-C4)-alkyl group can be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, or (C3-C4)-cycloalkoxy groups and can be trisubstituted by halogens up to three times. The (C1-C4)-alkoxy group can be substituted with (C3-C4)-cycloalkyl groups and can be trisubstituted with halogens. The (C3-C4)-cycloalkyl group can be substituted with monofluoromethyl, difluoromethyl or trifluoromethyl and can be disubstituted with halogens up to 100%. The (C1-C4)-alkoxy group can be substituted with (C3-C4)-cycloalkyl groups and can be trisubstituted with halogens. The (C3-C4)-cycloalkyl group can be mono- or di-substituted with halogens. The (C3-C4)-cycloalkoxy group can be disubstituted by halogens. R8 is either hydrogen or fluorine. R9 can be hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen. The (C1-C4)-alkyl group can be substituted with (C1-C4)-alkoxy groups. n represents 0 or 1, m represents 0, 1, or 2. p represents 0, 1, or 2, and q represents 0, 1, or 2.

2. The compound of formula (I) according to claim 1, and its salt, solvate, and solvate of said salt, wherein... Choose X, Y, and Z such that the five-membered ring of the Fang family has the structure h), i), j), k), r), or p). Where * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R1 can be pyridyl, pyrazolyl, thiazolyl, thiophene, phenyl, tetrahydropyranyl, or cyclohexyl. The pyridyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy. The pyrazolyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, fluorine, chloro, trifluoromethyl. The thiazolyl group can be replaced by chlorine. The thiophene group can be replaced by fluorine. The phenyl group may be substituted by one or two independent substituents selected from the following group: (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl. Cyclohexyl and tetrahydropyranyl can fuse with pyridyl groups. R2 is hydrogen or methyl. The methyl group can be replaced by a cyano group or a methoxy group. R3 is hydrogen or (C1-C2)-alkyl; R4 can be hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl. The phenyl group can be substituted with chlorine. R5 represents hydrogen and fluorine. R6 is a group of formula a), b''), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 or R'7 is independently hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or phenyl. The (C1-C4)-alkyl group may be substituted with methoxy, n-butoxy, cyclopropyl, or cyclobutoxy and may be disubstituted with fluorine up to two times. The methoxy group can be replaced by cyclopropyl, cyclobutyl, or trifluoromethyl groups. The cyclopropyl group can be replaced by monofluoromethyl, difluoromethyl, or trifluoromethyl groups. The cyclopropyl group can be substituted with up to two fluorinated groups. The n-butoxy group can be fluorinated up to di-substituted. The (C1-C2)-alkoxy group can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, or trifluoromethyl groups, and The cyclopropyl and cyclobutyl groups can be fluorinated up to two-substituted. The (C3-C4)-cycloalkoxy group can be fluorinated up to polydisubstituted. n represents 0 or 1, and m represents 1 or 2.

3. The compound of formula (I) according to claim 1, and its salt, solvate, and solvate of said salt, wherein... Choose X, Y, and Z such that the five-membered ring of the Fang family has the structure h), i), j), k), r), or p). Where * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 represents hydrogen or methyl; R4 is hydrogen, ethyl, or trifluoromethyl; R5 is hydrogen, methyl, or fluorine; R6 is a group of formula a), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

4. The compound of formula (I) according to claim 1, and its salt, solvate, and solvate of said salt, wherein... X, Y, and Z are 1,3-thiazolyl, 1,3-oxazolyl, and 1,2,4-oxadiazolyl; R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 represents hydrogen or methyl; R4 is hydrogen or methyl, ethyl, or trifluoromethyl; R5 is hydrogen, methyl, or fluorine; R6 is a group of formula a), c'), or h). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

5. The compound of formula (I) according to claim 1, and its salt, solvate, and solvate of said salt, wherein... Choose X, Y, and Z such that the 5-member ring of the Fang family has the structure h'). R1 is 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-thiophenyl; R2 is hydrogen or methyl; R3 is either hydrogen or methyl; R5 represents hydrogen and fluorine. R6 is a group of formula a) or c'). Where *** indicates the connection with the adjacent piperidine ring. Wherein R7 and R'7 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutoxymethyl, 3-fluorobutoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 1, and m represents 1.

6. A method for preparing a compound of formula (I) or a salt thereof, a solvate thereof, or a solvate of said salt thereof, wherein [A] Reacting the compound of formula (II) with the compound of formula (III) in the presence of a base to produce the compound of formula (IA). (II) in X, Y, Z, R5, R6, and m have the definitions given above. Hal is the leaving group, preferably chlorine, bromine, iodine, or methanesulfonyl. (III) in R1, R2, R3, and n have the definitions given above. (I-A), or [B] The compound of formula (IV) is reacted with the compound of formula (V) in the presence of a reducing agent and optionally an acid, preferably an alkali metal borohydride and acetic acid, to produce the compound of formula (IB). (IV) in X, Y, Z, R1, R2, R3, R4 and R5, as well as n and m, have the definitions given above. (V) in R6 has the definition given above. (I-B), or [C] The compound of formula (VI) is reacted with the compound of formula (VII) in the presence of a condensing agent or activator, preferably a phosphorus compound, to produce the compound of formula (IC). (WE) in X, Y, Z, R1, R2, and R3, and n have the definitions given above. (VII) in R5, R6, and m have the definitions given above. (I-C), Furthermore, the compounds of formula (IA), (IB), (IC) thus obtained are optionally isolated into their enantiomers and / or diastereomers and / or optionally converted into their solvates, salts and / or solvates of said salts using suitable (i) solvents and / or (ii) acids.

7. The compound as defined in any one of claims 1 to 5, for the treatment and / or prevention of disease.

8. The compound as defined in any one of claims 1 to 5, used in a method for treating and / or preventing respiratory distress, dysphagia, peripheral and cardiovascular diseases, and peripheral and central nervous system diseases.

9. The compound as defined in any one of claims 1 to 5, used in a method for treating and / or preventing the following conditions: breathing difficulties, including sleep-induced breathing difficulties such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); swallowing difficulties; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

10. The compound as defined in any one of claims 1 to 5, used in a method for treating and / or preventing breathing difficulties and swallowing difficulties, said breathing difficulties including sleep-induced breathing difficulties, such as, in particular, obstructive sleep apnea (adults and children), primary snoring, obstructive snoring (upper airway resistance syndrome, severe snoring, hypoventilation syndrome), central sleep apnea, Cheyne-Stokes respiration, primary sleep apnea in infants, life-threatening events, central sleep apnea caused by the use of drugs or other substances, obesity hypoventilation syndrome, central respiratory drive disorder, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, musculoskeletal respiratory disorders, respiratory disorders after prolonged ventilation, respiratory disorders during acclimatization at high altitudes, acute and chronic lung diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation, and congenital central alveolar hypoventilation syndrome.

11. The compound as defined in any one of claims 1 to 5, used in a method for treating and / or preventing peripheral and cardiovascular conditions including: diabetic microangiopathy; diabetic ulcers of the extremities, particularly for promoting wound healing of diabetic foot ulcers; diabetic heart failure; diabetic coronary microangiopathy; peripheral and cardiovascular conditions; thromboembolic conditions and local ischemia; peripheral circulatory disturbances, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disturbances, and intermittent claudication.

12. The compound as defined in any one of claims 1 to 5, used in methods for treating and / or preventing peripheral and central nervous system disorders including: dementia, depression, schizophrenia, attention deficit disorder (ADHS) with or without ADHD, Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonia, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

13. A medicament comprising a compound as defined in any one of claims 1 to 5, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

14. A medicament comprising a compound as defined in any one of claims 1 to 5 in combination with one or more other active compounds selected from the group consisting of: respiratory stimulants, psychotropic compounds, serotonin reuptake inhibitors, norepinephrine antidepressants, serotonergic antidepressants and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants and cytotoxic drugs.

15. The medicament according to claim 13 or 14, for the treatment and / or prevention of breathing difficulties, including sleep-induced breathing difficulties such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions.

16. A method for treating and / or preventing the following conditions in humans and animals: respiratory distress, including sleep-induced respiratory distress such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions, wherein the method is performed by administering an effective amount of at least one compound as defined in any one of claims 1 to 5 or a drug as defined in any one of claims 13 to 15.

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