Substituted heterocyclic carboxamindes and use 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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480062566.9 (22) Application Date 2024.09.27 (30) Priority Data 23200306.1 2023.09.28 EP (85) PCT International Application Entering National Phase Date 2026.03.27 (86) PCT International Application Application Data PCT / EP2024 / 077295 2024.09.27 (87) PCT International Application Publication Data WO2025 / 068514 EN 2025.04.03 (71) Applicant: Bayer AG Address: Leverkusen, Germany (72) Inventors: M. Delbeck, M. Hahn, T. Muller, L. Dietz, F. Wand, D. Maibom, P. Buchgraber, N. Lindner, E. M. Becker-Perst, C. Schmaker, D. Lang, H. Schimmel (74) Patent Agency: Beijing Beixiang Intellectual Property Agency Co., Ltd. 11285 Patent Attorneys: Xie Xiaohan, Zhou Zhiming (51) Int.Cl. C07D 417 / 14 (2006.01) A61K 31 / 4545 (2006.01) A61K 31 / 4709 (2006.01) A61K 31 / 55 (2006.01) A61P 9 / 00 (2006.01) A61P 11 / 00 (2006.01) A61P 25 / 28 (2006.01) A61P 29 / 00 (2006.01) A61P 43 / 00 (2006.01) C07D 413 / 14 (2006.01) (54) Invention Title Substituted Heterocyclic Formamide and Its Use (57) Abstract This application relates to novel substituted heterocyclic formamides, their preparation methods, 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 respiratory distress, including sleep-induced respiratory distress such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular diseases, including diabetic microangiopathy; and peripheral and central nervous system diseases, including neurodegenerative and neuroinflammatory diseases. Claims 9 pages, Description 178 pages, Claims amended according to Article 19 of the Treaty 9 pages CN 121986100 A 2026.05.05 CN 1 21 98 61 00 A 1. A compound of general formula (I), and its salt, solvate and solvate of said salt (I) wherein X is S, N or O; Y is N, S or O, wherein when X is S, Z is N; wherein when X is O, Z is N;Y is CR4, O, or NR4, wherein Y is O when X is N and Z is N; wherein Y is CR4 or NR4 when X is S; R1 is a 5- to 10-membered heteroaryl, phenyl, (C4-C10)-heterocyclic alkyl, or (C3-C10)-cycloalkyl, wherein the 5- to 10-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; wherein the (C1-C4)-alkyl may be substituted by up to three halogens; wherein the (C1-C4)-alkoxy may be substituted by up to three halogens; wherein the phenyl may be substituted by 1 to 2 substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxyl, halogen; wherein the (C1-C4)-alkyl may be substituted by up to three halogens. The (C3-C10)-cycloalkyl and (C4-C10)-heterocycloalkyl groups may be substituted by one or two substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, and halogen; the (C1-C4)-alkyl group may be substituted by up to three halogens; the (C3-C10)-cycloalkyl and (C4-C10)-heterocycloalkyl groups may be fused with 5 to 10 heteroaryl groups, the 5 to 10 heteroaryl groups may be substituted by one or two substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; R2 is hydrogen, (C1-C4)-alkyl, or (C3-C5)-cycloalkyl; the (C1-C4)-alkyl group may be substituted by up to three halogens. The (C1-C4)-alkyl group may be substituted with a cyano or (C1-C4)-alkoxy group; the (C3-C5)-cycloalkyl group may be substituted with a halogen up to three times; or may form a (C3-C4)-cycloalkyl ring together with the carbon atom bonded to R2; or R1 and R2 may form a (C5-C8)-cycloalkyl or (C5-C10)-heteroalkyl ring; the (C5-C8)-cycloalkyl group may be fused with 5 to 10 heteroaryl groups; (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; the (C3-C10)-heteroalkyl group may be fused with 5 to 10 heteroaryl groups. (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen groups may be substituted with 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen groups; the (C3-C10)-heteroalkyl group may be 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; R3 is hydrogen, (C1-C4)-alkyl, wherein the (C1-C4)-alkyl may be trisubstituted by halogen, and R4 in CR4 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, or halogen;In NR4, the (C1-C4)-alkyl group may be up to trisubstituted with a halogen and the phenyl group may be substituted with a halogen. NR4 is absent or may be hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, or phenyl. 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 a connection to an adjacent piperidine ring. R7 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, or phenyl. The (C1-C4)-alkyl group may be substituted with (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, or (C3-C4)-cycloalkoxy and may be up to trisubstituted with a halogen. Wherein (C1-C4)-alkoxy can be substituted by (C3-C4)-cycloalkyl and at most trisubstituted by halogen; where (C3-C4)-cycloalkyl can be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and at most disubstituted by halogen; where (C1-C4)-alkoxy can be substituted by (C3-C4)-cycloalkyl and at most trisubstituted by halogen; where (C3-C4)-cycloalkyl can be monosubstituted or disubstituted by halogen; where (C3-C4)-cycloalkoxy can be at most disubstituted by halogen; where R8 is hydrogen or fluorine; where R9 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen; where (C1-C4)-alkyl can be substituted by (C1-C4)-alkoxy; 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 X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k), r) or p), wherein * indicates a connection with a carbonyl group and ** indicates a connection with the nitrogen atom of an adjacent amine group, and R1 is pyridyl, pyrazolyl, thiazolyl, thiophene, phenyl, tetrahydropyranyl or cyclohexyl, wherein the pyridyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by chlorine, wherein the thiophene group may be substituted 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, wherein the cyclohexyl and tetrahydropyranyl groups may be fused with the pyridyl group, and R2 is hydrogen or methyl.Wherein, methyl can be substituted with cyano or methoxy; R3 is hydrogen, (C1-C2)-alkyl; R4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl; wherein the phenyl can be substituted with chlorine; R5 is hydrogen, fluorine; R6 is a group of formula a), b''), c'), or h), wherein *** indicates a connection with an adjacent piperidine ring; claims 3 / 9, page 4, CN 121986100 A, wherein R7 or R'7 is independently hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl; wherein the (C1-C4)-alkyl can be substituted with methoxy, n-butoxy, cyclopropyl, cyclobutoxy and at most disubstituted with fluorine; wherein the methoxy can be substituted with cyclopropyl, cyclobutyl, or trifluoromethyl. The cyclopropyl group may be substituted with monofluoromethyl, difluoromethyl, or trifluoromethyl; the cyclopropyl group may be fluorinated up to a certain extent disubstituted; the n-butoxy group may be fluorinated up to a certain extent disubstituted; the (C1-C2)-alkoxy group may be substituted with cyclopropyl, cyclobutyl, cyclobutoxy, or trifluoromethyl; and the cyclopropyl and cyclobutyl groups may be fluorinated up to a certain extent disubstituted; the (C3-C4)-cycloalkoxy group may be fluorinated up to a certain extent disubstituted; 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 X, Y, and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k), r), or p). Where * indicates a connection to a carbonyl group and ** indicates a connection to 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-thiophene; R2 is hydrogen or methyl; R3 is 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). Claims 4 / 9, 5 CN121986100 A Where *** indicates the connection with the adjacent piperidine ring, and 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, 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-thiophene; R2 is hydrogen or methyl; R3 is hydrogen, methyl; R4 is hydrogen or methyl, ethyl, trifluoromethyl; R5 is hydrogen, methyl or fluorine; R6 is a group of formula a), or c') or h), wherein *** indicates a connection with an 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 (Claims 5 / 9, page 6, CN)121986100 A group, 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 X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula 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-thiophene; R2 is hydrogen or methyl; R3 is hydrogen or methyl; R5 is hydrogen or fluorine; R6 is a group of formula a) or c'), where *** indicates a connection to an 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 thereof, wherein claims 6 / 9 pages 7 CN 121986100 A [A] reacting a compound of formula (II) with a compound of formula (III) in the presence of a base to produce a compound (II) of formula (I-A) wherein X, Y, Z, R5, R6, and m have the definitions given above,Hal is a leaving group, preferably chlorine, bromine, iodine or methanesulfonyl, (III) wherein R1, R2 and R3 and n have the definitions given above, (I-A), or [B] reacting a compound of formula (IV) with a 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 a compound of formula (I-B) (IV) wherein X, Y, Z, R1, R2, R3, R4 and R5 and n and m have the definitions given above, (V) wherein R6 has the definition given above, Claims 7 / 9 pages 8 CN 121986100 A (I-B), or [C] reacting a compound of formula (VI) with a compound of formula (VII) in the presence of a condensing agent or activator, preferably a phosphorus compound, to produce a compound of formula (I-C) (VI) wherein X, Y, Z, R1, R2 and R3 and n have the definitions given above, (VII) Wherein R5 and R6 and m have the definitions given above, (I-C), and the compounds of formula (I-A), (I-B), (I-C) thus obtained are optionally isolated into their enantiomers and / or diastereomers and / or optionally converted with suitable (i) solvents and / or (ii) acids into their solvates, salts and / or solvates of said salts. 7. A compound as defined in any one of claims 1 to 5, used for treating and / or preventing diseases. 8. A compound as defined in any one of claims 1 to 5, used in methods 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. Claims 8 / 9, page 9, CN 121986100 A 10. A 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 driveMotor disorders, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, musculoskeletal 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 methods for treating and / or preventing peripheral and cardiovascular diseases 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 diseases; thromboembolic diseases and local ischemia; peripheral circulatory disorders, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculatory disturbances, and intermittent claudication. 12. A 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-mediated antidepressants, serotonergic antidepressants and tricyclic antidepressants, P2X3 antagonists, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory drugs, immunomodulators, immunosuppressants, and cytotoxic drugs. 15. The medicament of claim 13 or 14, for the treatment and / or prevention of dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea, snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and peripheral and central nervous system conditions, including neurodegenerative and neuroinflammatory conditions. 16. Methods for treating and / or preventing the following conditions in humans and animals: 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 neurological disorders.In cases of inflammatory conditions, the method involves administering an effective amount of at least one compound as defined in any one of claims 1 to 5 or a medicament as defined in any one of claims 13 to 15. Claims 9 / 9 pages 10 CN 121986100 A Substituted Heterocyclic Formamides and Their Uses

[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 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.

[0002] α2-adrenergic receptors (α2-AR) belong to the G protein-coupled receptor family. They bind to pertussis toxin-sensitive inhibitory G proteins G1 and G0 and reduce adenylate cyclase activity. When stimulated by endogenous catecholamines (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 (α2A, α2B, and α2C) exist in many cardiovascular-related target cells and tissues, as well as neuronal target cells and tissues, making them attractive targets for therapeutic interventions. However, due to the lack of corresponding highly selective ligands and / or antagonists for α2-AR, the exact physiological tasks of receptor subtypes remain difficult to explain [Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The α2-Adrenergic Receptors: Adrenergic Receptors in the 21st Century / Receptors, 2005, 241-265].

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

[0004] During inspiration, the interaction between two opposing forces ensures the patency of the upper airway. The expansion of the upper airway muscles...The diaphragm acts to counteract the negative pressure within the airway, causing it to contract. 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 properties of the upper airway dilators.

[0005] It is believed that upper airway collapse 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 counteracting some of the changes that occur in early sleep. It has been observed that in OSA patients with non-apnea intervals, the activity of the genioglossus muscle during these periods is only 25-40% higher than in 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 hypoglossal 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, particularly 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, randomizedCrossover trial. J Clin Sleep Med. 2023 Jan 1;19(1):85-96).

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

[0008] α2C-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 through alpha2c adrenergic receptor antagonism can stabilize the upper airway and protect it from collapse and obstruction. Furthermore, snoring can be suppressed by stabilizing the upper airway.

[0009] In primary snoring, there is no obstruction of the upper airway. 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 subsequently produces the typical snoring noise.

[0010] Obstructive snoring (upper airway resistance syndrome, severe snoring, hypoventilation 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, blood circulation, and sleep quality are comparable to those in obstructive sleep apnea. As in obstructive sleep apnea, the pathogenesis is thought to be the 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, resulting in recurrent episodes of inadequate or absent breathing and impaired gas exchange. CSA has various manifestations. These include high-altitude periodic breathing, idiopathic CSA (ICSA), central apnea induced by anesthetics,Hypopnea syndrome (OHS) and Cheyne-Stokes breathing (CSB). The exact mechanisms in different types of CSA can vary greatly; however, a key feature is unstable respiratory stimulation during sleep [Eckert DJ et al., Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607].

[0012] Dysphagia is a difficulty in swallowing that can have a variety of causes. The complex regulation of swallowing occurs in various structures of the brain. This is a bidirectional connection between the cerebral cortex, the corticobulbar tract, the brainstem, and the peripheral swallowing muscle tissue. The regulation and execution of swallowing behavior essentially involve five pairs of cranial nerves (trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII)) and more than 25 muscle pairs [Arens C., Position paper of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German 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] Norepinephrine neurons and α2-AR play a role in the coordination of swallowing and breathing [Yamanishi T., Alpha2-adrenoceptors coordinate swallowing and

[0015] In addition to 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 subtypes. For example, the regulation of cardiac contractility is primarily regulated by central modulation of the sympathetic efferent nerves. Furthermore, the sympathetic efferent system also regulates direct effects on smooth muscle cells and vascular endothelial cells. Thus, 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 whose distal ends have varicose veins for the release of norepinephrine. The released norepinephrine regulates local vascular tone in endothelial cells and smooth muscle cells via α2-AR. Activation of α2A, α2B, and α2C receptors on smooth muscle cells 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 vessel sizes. Thus, α2A-AR appears to be expressed almost exclusively in large arteries, while α2B-AR contributes more to vascular tone in arterioles and veins. AR α2B appears to play a role in salt-induced hypertension [Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447–453, (2009)]. The role of ARα2C in hemodynamics is not fully understood; however, ARα2C receptors appear to mediate venous vasoconstriction. They also participate in the cold-induced enhancement of adrenergic receptor-induced vasoconstriction [Chotani et al., Silent α2C adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol 278:H1075-H1083, 2000; Gyires et al., α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions, neurochemistry].International 55, 447-453, (2009)]. Cold and other factors (e.g., tissue proteins, estrogen) regulate ARα2C function coupled to intracellular signaling pathways [Chotani et al., Distinct cAMP signaling pathways differentially regulate α2C adrenenoxceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol 288: H69-H76, (2005)].

[0016] Under pathophysiological conditions, the adrenergic system can be activated, which can lead to, for example, hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disorders, stroke, and sexual dysfunction. Thus, for example, the pathophysiology of Raynaud's syndrome and scleroderma is largely unknown, but is associated with altered adrenergic activity. Therefore, patients with spastic Raynaud's syndrome show significantly elevated expression of, for example, ARα2 on their platelets. This may be associated with the vasospasm episodes observed in these patients [Keenan and Porter, α2-Adrenergic receptors in platelets from patients with Raynaud's syndrome, Surgery, V94(2), (1983)].

[0017] Potential therapies for such conditions targeting the regulation of the activated adrenergic system in the organism are promising approaches due to the expected high efficacy and low level of side effects. In particular, peripheral circulatory disturbances (microvascular complications) such as diabetic retinopathy, nephropathy, or significant wound healing disorders (diabetic foot ulcers) play a significant role in diabetic patients who often have elevated catecholamine levels. Diabetes is one of the most important comorbidities in peripheral occlusive diseases, and also plays a decisive role in the progression of the disease (microvascular and macrovascular complications). These pathophysiological processes in diabetic patients may involve higher expression of adrenergic receptor α2C receptors associated with elevated catecholamine levels.

[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 cause of hospitalization in diabetic patients.The risk of developing diabetic foot ulcers in a lifetime is 15-25%, and 15% of all diabetic foot ulcers result in amputation. 40-70% of all non-traumatic amputations worldwide are performed on diabetic patients. 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 use as pharmaceuticals 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 such compounds in treating sleep-related respiratory conditions (preferably obstructive and central sleep apnea and snoring).

[0020] Substituted heterocyclic formamides as effective inhibitors of α2-adrenergic receptor C subtype (α-2C) and their preparation are disclosed in WO2021 / 089683 A1.

[0021] The compounds of this application are suitable for the prevention and treatment of diseases caused by activated or reactivated α2C-adrenergic receptors, as well as diseases secondary to α2C-adrenergic receptor-related 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 after prolonged ventilation, respiratory disorders during acclimatization at high altitudes, dysphagia, acute and chronic lung diseases with hypoxia and hypercapnia, peripheral circulatory disorders (microvascular complications) such as diabetic retinopathy, diabetic nephropathy and impaired wound healing (diabetic foot ulcers), peripheral and central nervous system disorders, especially dementia, depression, schizophrenia, and those accompanied by...Attention deficit hyperactivity 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, conditions caused by sex hormone changes, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease.

[0023] The object of the present invention is to provide a novel substance that acts as an effective and selective antagonist of α2C-adrenergic receptors and is therefore suitable for the treatment and / or prevention of dyspnea, sleep-induced dyspnea such as obstructive and central sleep apnea, snoring, dysphagia, conditions of the peripheral and central nervous systems and peripheral circulatory disorders (microvascular diseases) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers).

[0024] The present invention provides compounds of general formula (I), as well as their salts, solvates and solvates of said salts. Specification 4 / 178 pages 14 CN 121986100 A (I) wherein X is S, N or O; Y is N, S or O, wherein when X is S, Z is N; wherein when X is O, Z is N; Y is CR4, O or NR4, wherein when X is N and Z is N, Y is O; wherein when X is S, Y is CR4 or NR4; R1 is 5 to 10 heteroaryl, phenyl, (C4-C10)-heterocyclic alkyl or (C3-C10)-cycloalkyl, wherein the 5 to 10 heteroaryl can be substituted by 1 to 3 substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen; wherein the (C1-C4)-alkyl can be substituted by up to three halogens. The (C1-C4)-alkoxy group may be halogenated up to trisubstituted, and the phenyl group may be substituted by one or two substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, and halogen; the (C1-C4)-alkyl group may be halogenated up to trisubstituted, and the (C3-C10)-cycloalkyl and (C4-C10)-heterocyclic alkyl groups may be substituted by one or two substituents independently selected from the group consisting of: (C1-C4)-alkyl, (C3-C5)-cycloalkyl, (C1-C4)-alkoxy, cyano, hydroxy, and halogen; the (C1-C4)-alkyl group may be halogenated up to trisubstituted, and the (C3-C10)-cycloalkyl and (C4-C10)-heterocyclic alkyl groups may be 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; R2 is hydrogen, (C1-C4)-alkyl, or (C3-C5)-cycloalkyl; wherein the (C1-C4)-alkyl group may be substituted by up to three halogens.The (C1-C4)-alkyl group may be substituted with a cyano or (C1-C4)-alkoxy group; the (C3-C5)-cycloalkyl group may be substituted with a halogen up to three times; or may form a (C3-C4)-cycloalkyl ring together with the carbon atom bonded to R2; or R1 and R2 may form a (C5-C8)-cycloalkyl or (C5-C10)-heteroalkyl ring; the (C5-C8)-cycloalkyl group may be fused with 5 to 10 heteroaryl groups; the 5 to 10 heteroaryl groups may be substituted with 1 to 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, and halogen; the (C3-C10)-heteroalkyl group may be fused with 5 to 10 heteroaryl groups. (See specification 5 / 178 pages, 15 CN 121986100 A) 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, (C1-C4)-alkyl, wherein the (C1-C4)-alkyl may be substituted by up to three halogens; R4 in CR4 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, phenyl, or halogen; wherein the (C1-C4)-alkyl may be substituted by up to three halogens and the phenyl may be substituted by a halogen; in NR4, it is absent or is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, or phenyl; wherein the (C1-C4)-alkyl may be substituted by up to three halogens and the phenyl may be substituted by a halogen; 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 a connection to an adjacent piperidine ring; R7 is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, (C3-C4)-cycloalkoxy, or phenyl; wherein the (C1-C4)-alkyl can be substituted by (C3-C4)-cycloalkyl, (C1-C4)-alkoxy, or (C3-C4)-cycloalkoxy and is at most trisubstituted by a halogen; wherein the (C1-C4)-alkoxy can be substituted by (C3-C4)-cycloalkyl and is at most trisubstituted by a halogen; wherein the (C3-C4)-cycloalkyl can be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl and is at most disubstituted by a halogen; and wherein the (C1-C4)-alkoxy can be substituted by (C3-C4)-cycloalkyl and is at most trisubstituted by a halogen. Wherein (C3-C4)-cycloalkyl can be mono- or di-substituted with halogen, where (C3-C4)-cycloalkoxy can be di-substituted with halogen, where R8 is hydrogen or fluorine, where R9 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen; where (C1-C4)-alkyl can be substituted with (C1-C4)-alkoxy, 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, i.e., the compounds of formula (I) and mentioned below are not salts, solvates and solvates of the salts.

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

[0027] In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the present invention. Salts that are not suitable for pharmaceutical use but can be used, for example, for the isolation, purification or storage of the compounds of the present invention are also included.

[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 acids 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, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy- 2-Naphthyl 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-naphthylsulfonic 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, tri(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-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 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 number of known methods.

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

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

[0033] In the context of this invention, solvates are described as those forms of the compounds of the invention that form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination with water occurs. In the context of this invention, the preferred solvate is a hydrate. Specification 7 / 178 pages 17 CN 121986100 A

[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 a known manner; 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 can also be used.

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

[0036] If the compounds of this invention can exist in tautomeric forms, then this invention encompasses 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 as a compound in which at least one atom of the compound of this invention 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 as referring to the 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 can be incorporated into the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I, and 131I. Certain isotopic variants of the compounds of the present invention, particularly those incorporating one or more radioisotopes, may be beneficial, for example, in examining mechanisms of action or the distribution of active ingredients in vivo; compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose due to their relatively easy preparation and detection. Furthermore, the incorporation of isotopes, such as deuterium, can provide specific therapeutic benefits due to the greater metabolic stability of the compound, such as an extended half-life in vivo or a reduction in the required active dose; such modifications of 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, isotopic variants of compounds of formula (I) preferably contain deuterium (“compounds of formula (I) containing deuterium”). Isotopic variants of compounds of formula (I) incorporating one or more radioisotopes such as 3H or 14C are beneficial, 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 18F or 11C can be incorporated into compounds of 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)Compounds of 13C can be used in preclinical or clinical studies for mass spectrometry analysis (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 generally prepared by methods known to those skilled in the art, as described herein and / or in the examples, by using isotopic variants of the reagents, preferably deuterium-containing reagents instead of the reagents. Depending on the desired deuteration site, in some cases, deuterium from D2O can be directly incorporated into the compound or into reagents that can be used to synthesize such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Specification 8 / 178 pages 18 CN 121986100 A Chem. Eur. J., 2007, 13, 4052). Photochemical deuteration and tritation methods are also described (Y. Y. Loh et al., Science 10.1126 / science.aap9674 (2017). Another useful reagent for incorporating deuterium into molecules is deuterium gas. Rapid pathways for incorporating deuterium include alkene bonds (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34(6), 1889) and alkyne bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74(12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, ). Catalytic deuteration of hydrocarbons containing functional groups (3865). To directly replace hydrogen with deuterium in functionalized hydrocarbons, 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, for example, C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ.Companies like those in the United States. Further information relating to existing techniques for deuterium-hydrogen exchange has been found in, for example, 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%). In particular, 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% at this position or at these positions, preferably higher than 90%, 95%, 96% or 97%, and more preferably higher than 98% or 99%. It is obvious that the deuterium frequency at each deuteration position is independent of the deuterium frequency 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; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], hydrophilicity, etc.).The metabolic status of lipids (B. Testa et al., Int. J. Pharm., 1984, 19(3), 271) and / or molecules, and causes changes in the ratio of 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 is altered, 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 (page 9 / 178, CN 121986100 A, 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…Drug exposure is increased 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 exhibiting this effect may have reduced dose requirements (e.g., lower dose number or lower dose to achieve the desired effect) and / or may produce lower metabolite loads.

[0041] Compounds of general formula (I) may have multiple potential attack sites for metabolism. To optimize the above-described 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. Specifically, one or more deuterium atoms of the deuterium-containing compound of general formula (I) are attached to carbon atoms and / or located at those positions of the compound of general formula (I) that serve as attack sites for metabolic enzymes, such as cytochrome P450.

[0042] The present invention further includes prodrugs of the compounds of the present 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 the present invention when present in vivo (e.g., through metabolic or hydrolytic pathways).

[0043] In the context of the present invention, unless otherwise specified, substituents have the following meanings: In the context of the present invention, alkyl is a straight-chain or branched alkyl group having a specified specific number of carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4,4-dimethylpentyl, and 1,4,4-trimethylpentyl.

[0044] In the context of this invention, an alkoxy group is a straight-chain or branched alkoxy group having 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, a cycloalkoxy group 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 carbocyclic refers to a monocyclic, polycyclic, or spirocyclic ring having a specified number of ring atoms, preferably a monocyclic or bicyclic saturated carbocyclic ring. A monocyclic saturated carbocyclic ring is synonymously referred to as cycloalkyl. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, spirocyclic...[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, tricyclic[3.3.1.13,7]decyl. Preferably, it is a monocyclic cycloalkyl group having 3 to 5 carbon atoms. Examples include: cyclopropyl, cyclobutyl, or cyclopentyl.

[0047] In the context of this invention, a heterocycle or heterocyclic group is a monocyclic or bicyclic saturated heterocycle having a specified specific number of ring atoms, containing one or two cyclic heteroatoms selected from N, O, S, SO and / or SO2, and linked by a cyclic carbon atom or optionally a cyclic nitrogen atom. Examples include: azircyclic butyl, oxacyclic butyl, pyrrolyl, pyrazolyl, tetrahydrofuranyl, thiocyclic pentyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, and hexahydro-1,4-diazepinyl. Preferred are azircyclic butyl, oxacyclic butyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, and morpholinyl. (See specification 10 / 178 pages 20 CN 121986100 A for tetrahydropyranyl and morpholinyl.)

[0048] In the context of this invention, a heteroaryl group is a monocyclic or bicyclic aromatic heterocycle (heteroaromatic compound) having a specified specific number of ring atoms, containing up to four identical or different cyclic heteroatoms selected from N, O and / or S, linked by a cyclic carbon atom or optionally by a cyclic 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 groups include all possible isomers, such as tautomers and positional isomers related to the connection points of the remaining part of the molecule. Therefore, as a non-limiting example, the term pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, or the term thiophene includes 2-thiophene and 3-thiophene.

[0050] In the context of this invention, halogens include fluorine, chlorine, bromine, and iodine. Chlorine or fluorine is 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 this invention, all groups that appear 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 inhibition, delay, and other related terms.The development, progression, or occurrence of a disease, condition, symptom, injury, or health problem, or such condition and / or symptoms of such a condition, is delayed, prevented, alleviated, weakened, limited, reduced, suppressed, repelled, or cured. The term “therapeutic” is understood herein to be synonymous with the term “treatment.”

[0053] The terms “prevention” and “prophylaxis” are used synonymously in this invention and refer to avoiding or reducing the risk of infection, occurrence, entrapment, or development or progression of a disease, condition, symptom, injury, or health problem, or such condition and / or symptoms of such a condition.

[0054] Treatment or prevention of a disease, condition, symptom, injury, or health problem 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, wherein X is S or N; Y is N, S, or O, wherein when X is S, Z is N; wherein when X is O, Z is N; Y is CR4, N, or O, wherein when X is N and Z is N, Y is O; wherein when X is S, Y is N or CR4; R1 is pyridinyl, pyrazolyl, thiazolyl, thiophene, phenyl, heterocyclohexyl, or cyclohexyl, wherein the pyridinyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by one or two substituents independently selected from the group consisting of fluorine and chlorine. The thiophene group may be substituted by one or two independent substituents selected from fluorine and chlorine. (See specification 11 / 178, page 21, CN 121986100 A). The phenyl group may be substituted by one or two independent substituents selected from the following groups: (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl. The heterocyclohexyl and cyclohexyl groups may be fused with a 5- or 6-membered heteroaryl group. R2 is hydrogen, (C1-C2)-alkyl, or cyclopropyl. The (C1-C2)-alkyl group may be substituted by a cyano or (C1-C2)-alkoxy group, or together with the carbon atom bonded to R2, form a cyclopropyl ring, or R1 and R2 together form a cyclohexyl or (C6)-heterocycloalkyl ring. The cyclohexyl group may be fused with a 6-membered heteroaryl group. The (C6)-heterocycloalkyl group may be fused with a 6-membered heteroaryl group. R3 is hydrogen, (C1-C2)-alkyl; R4 is hydrogen, (C1-C2)-alkyl, (C3-C4)-cycloalkyl, trifluoromethyl, bromine, chlorine, or phenyl; wherein the phenyl group may be substituted with a halogen; R5 is hydrogen, (C1-C2)-alkyl, methoxy, or fluorine; R6 is a group of formula a), b), c), e), or h), wherein *** indicates a connection to an adjacent piperidine ring; wherein R7 or RR7 is independently hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C1-C2)-alkoxy, (C3-C4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or phenyl, wherein the (C1-C4)-alkyl may be substituted with methoxy, n-butoxy, cyclopropyl, or cyclobutoxy and may be fluorinated up to a maximum of two-substituted alkyl groups; wherein the methoxy group may be substituted with cyclopropyl, cyclobutyl, or trifluoromethyl; wherein the cyclopropyl group may be substituted with monofluoromethyl, difluoromethyl, or trifluoromethyl; wherein the cyclopropyl group may be fluorinated up to a maximum of two-substituted alkyl groups; wherein the n-butoxy group may be fluorinated up to a maximum of two-substituted alkyl groups; wherein the (C1-C2)-alkoxy group may be substituted with cyclopropyl, cyclobutyl, cyclobutoxy, or trifluoromethyl, and wherein the cyclopropyl and cyclobutyl groups may be fluorinated up to a maximum of two-substituted alkyl groups; wherein the (C3-C4)-cycloalkoxy group may be fluorinated up to a maximum of two-substituted alkyl groups; wherein R8 or R'8 is independently hydrogen or fluorine. Where R9 represents hydrogen, (C1-C4)-alkyl, (C1-C2)-alkoxy, methoxyethyl, fluorine, or chlorine; Specification 12 / 178 pages 22 CN 121986100 A 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 salt, are preferred, wherein X, Y, and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k), r), or p), wherein * indicates a connection to a carbonyl group and ** indicates a connection to a nitrogen atom of an adjacent amino group, and R1 is pyridinyl, pyrazolyl, thiazolyl, thiophene, phenyl, tetrahydropyranyl, or cyclohexyl, wherein the pyridinyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, wherein the pyrazolyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, wherein the thiazolyl group may be substituted by chlorine, wherein the thiophene group may be substituted by fluorine, wherein the phenyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)- Cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl, wherein cyclohexyl and tetrahydropyranyl can be fused with pyridinyl, R2 is hydrogen, methyl, wherein methyl can be substituted with cyano or methoxy, R3 is hydrogen, (C1-C2)-alkyl; R4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl; wherein phenyl can be substituted with chlorine, R5 is hydrogen, fluorine; R6 is a group of formula a), b''), c') or h), specification 13 / 178 pages 23 CN 121986100 A wherein *** 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, phenyl, wherein (C1-C4)-alkyl can be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and fluorinated up to two-substituted compounds, wherein methoxy can be substituted by cyclopropyl, cyclobutyl, trifluoromethyl, wherein cyclopropyl can be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl, wherein cyclopropyl can be fluorinated up to two-substituted compounds, wherein n-butoxy can be fluorinated up to two-substituted compounds, wherein (C1-C2)-alkoxy can be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl, and wherein cyclopropyl and cyclobutyl can be fluorinated up to two-substituted compounds, wherein (C3-C4)-cycloalkoxy can be fluorinated up to two-substituted compounds, n represents 0 or 1, and m represents 1 or 2.

[0057] In the context of the present invention, compounds of formula (I), as well as their salts, solvates, and solvates of the salts, are preferred, wherein X, Y, and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k), r), or p), wherein * indicates a connection to a carbonyl group and ** indicates a connection to a 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-Methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 2-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-thiophene; R2 is hydrogen or methyl; R3 is 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 a connection to an adjacent piperidine ring, and 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, wherein X, Y, and Z are 1,3-thiazolyl, 1,3-oxazolyl, 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-thiophene; R2 is hydrogen or methyl; R3 is hydrogen, methyl; R4 is hydrogen or methyl, ethyl, trifluoromethyl; R5 is hydrogen, methyl or fluorine; R6 is a group of formula a), or c') or h). (Specification 15 / 178 pages 25 CN 121986100 A) Where *** indicates the connection with the adjacent piperidine ring. Where 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, whereinX, Y, and Z are chosen such that the aromatic 5-membered ring has the structural formula h'), 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-thiophene; R2 is hydrogen or methyl; R3 is hydrogen or methyl; R5 is hydrogen or fluorine; R6 is a group of formula a) or c'), where *** indicates the connection with the adjacent piperidine ring, and 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, difluoromethyl. (Instruction manual 16 / 178 pages 26 CN 121986100 A) Oxygen, 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] A specific embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, wherein X, Y, and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k), or r), wherein * indicates a connection to a carbonyl group and ** indicates a connection to a nitrogen atom of an adjacent amine group, and R4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl, wherein the phenyl group may be substituted with chlorine.

[0061] A particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, wherein X, Y, and Z are groups of formula (h) or (i); wherein * indicates a connection to a carbonyl group and ** indicates a connection to a nitrogen atom of an adjacent amine group, andR4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl, wherein the phenyl group may be substituted with chlorine.

[0062] A particularly preferred embodiment of the invention relates to a compound of formula (I), its salt, solvate, and solvate of the salt, wherein X, Y, and Z are selected such that the aromatic 5-membered ring has the structural formula h) or i), wherein * indicates a connection with a carbonyl group and ** indicates a connection with a nitrogen atom of an adjacent amine group, and R4 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl, wherein the phenyl group may be substituted with chlorine.

[0063] A very particularly preferred embodiment of the invention relates to a compound of formula (I), its salt, solvate, and solvate of the salt, wherein X, Y, and Z are groups of formula h), wherein * indicates a connection with a carbonyl group and ** indicates a connection with a nitrogen atom of an adjacent amine group, and R4 is hydrogen, methyl, ethyl, or trifluoromethyl.

[0064] A very 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 selected such that the aromatic 5-membered ring has the structural formula h), wherein * indicates the connection with the carbonyl group and ** indicates the connection with the nitrogen atom of the adjacent amine group, and R4 is hydrogen.

[0065] A specific 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, pyrazolyl, thiazolyl, thiophene, or phenyl; wherein the pyridyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, fluorine, chlorine, trifluoromethyl, or trifluoromethoxy; wherein the pyrazolyl group may be substituted by one or two substituents independently selected from the group consisting of methyl or chlorine; wherein the thiazolyl group may be substituted by chlorine; wherein the thiophene group may be substituted by fluorine; wherein the phenyl group may be substituted by one or two substituents independently selected from the group consisting of (C1-C2)-alkyl, (C3-C4)-cycloalkyl, methoxy, cyano, hydroxyl, fluorine, chlorine, or 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, wherein the pyridyl group may be substituted by one or two substituents independently selected from the group consisting of: methyl, ethyl, fluorine, chloro, trifluoromethyl, trifluoromethoxy, wherein the phenyl group may be substituted by one or two substituents independently selected from the group consisting of: methyl, cyclopropyl, methoxy, cyano, hydroxy, fluorine, chloro, trifluoromethyl. Specification 18 / 178 pages 28 CN 121986100 A

[0067] A very 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 a group of formula (f); (f)Wherein # indicates a connection with an adjacent -[CHR2]nNR3- group.

[0068] A very particularly preferred embodiment of the invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R1 is a group of formula (f); (f) wherein # indicates a connection with an adjacent -[CHR2]nNR3- group.

[0069] A particular embodiment of the invention relates to a compound of formula (I), and its salt, solvate, and solvate of the salt, wherein R2 is hydrogen, (C1-C4)-alkyl; wherein the (C1-C4)-alkyl may be halogenated up to trisubstituted, or together with the carbon atom bonded to R2 to form a (C3-C4)-cycloalkyl ring.

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

[0071] A particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, wherein R2 is hydrogen.

[0072] A particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, wherein R2 is methyl.

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

[0074] A particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, wherein R3 is hydrogen, methyl. Specification 19 / 178 pages 29 CN 121986100 A

[0075] A particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, 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 is hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, or phenyl; wherein the phenyl group may 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 is hydrogen, methyl, ethyl, or trifluoromethyl.

[0078] A very 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 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), a salt thereof, a solvate thereof, and a solvate thereof, wherein R5 is hydrogen or fluorine.

[0081] A very particularly preferred embodiment of the present invention relates to a compound of formula (I), a salt thereof, a solvate thereof, and a solvate thereof, 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), wherein *** indicates a connection with an adjacent piperidine ring, and R7 is hydrogen or methyl, R'7 is 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-fluorobutoxy... (Specification 20 / 178 pages 30 CN 121986100 A) Methyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine.

[0083] A particularly preferred embodiment of the invention relates to compounds of formula (I), and their salts, solvates and solvates of the salt, wherein R6 is a group of formula a), c') or h, wherein *** indicates a connection to an 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 very 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), wherein *** indicates a connection to an adjacent piperidine ring, and R7 is hydrogen.R'7 is methyl, ethyl, isopropyl, propyl, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3-difluorocyclobutylmethoxy, 2,2,2-trifluoroethoxymethyl, cyclopropylmethyl, 1-fluoromethylcyclopropylmethoxymethyl, 1-difluoromethylcyclopropylmethoxymethyl, 1-trifluoromethylcyclopropylmethoxymethyl, cyclobutylmethoxy, cyclopropylmethoxy, cyclobutoxymethyl, cyclopropylmethoxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 3-fluorobutoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutoxy, 3,3-difluorocyclobutoxy, 2-fluoroethyl, cyclopropyl, cyclobutyl, 2-methoxyethyl, tert-butyl.

[0085] A specific embodiment of the present invention relates to compounds of formula (I), wherein n represents 0 or 1, and salts, solvates and solvates of the salts thereof.

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

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

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

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

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

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

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

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

[0094] Combinations of two or more of the above preferred ranges are very particularly preferred.

[0095] The invention also provides a method for preparing a compound of formula (I), or its salt, its solvate, or a solvate of said salt, wherein [A] a compound of formula (II) wherein X, Y, Z, R5, R6, and m have the definitions given above, Hal is a leaving group, preferably chlorine, bromine, iodine, or methanesulfonyl, is reacted with a compound of formula (III) in the presence of a base. (Page 22 / 178, 32 CN)121986100 A (III) wherein R1, R2, and R3 and n have the definitions given above, to produce a compound of formula (I-A), or [B] reacting a compound of formula (IV) wherein X, Y, Z, R1, R2, R3, R4, and R5, and n and m have the definitions given above, with a compound of formula (V) in the presence of a reducing agent and optionally an acid (preferably an alkali metal borohydride and acetic acid). wherein R6 has the definition given above, to produce a compound of formula (I-B), or [C] reacting a compound of formula (VI) in the presence of a condensing agent or activating agent (preferably a phosphorus compound). (VII) Wherein R5 and R6 and m have the definitions given above, to produce compound (I-C) of formula (I-C), and, the compounds of formula (I-A), (I-B), (I-C) 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 by suitable (i) solvents and / or (ii) acids.

[0096] In method step [A], the reaction of compound (II) with compound (III) to produce compound (I-A) is the substitution of the Hal group in compound (II) with the nitrogen atom of the amine in compound (III), wherein the reaction, depending on the reactivity in each case, can be carried out, for example, by heating in a solvent or dispersant.

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

[0098] The base 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 with the following ligand: 1,1'-[1,1'-binaphthyl]-2,2'-diylbis[1,1-diphenylphosphine] or 1,1'-(9,9-dimethyl-9H-xanthon-4,5-diyl)bis[1,1-diphenylphosphine] (see WO for reference).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'-dimethylpropenyl urea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of such solvents may also be used. Acetonitrile or dimethylformamide is preferred.

[0101] Reaction (II) + (III) → (I-A) is generally carried out in a temperature range of 0°C to +150°C, preferably between +20°C and +140°C.

[0102] In method step [B], the reaction of compound (IV) with (V) to form compound (I-B) 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, such as, in particular, 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 are, in particular, alcohols, such as methanol, ethanol, n-propanol or isopropanol; ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, dichloromethane; polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of such solvents; tetrahydrofuran is preferred. The reactions are 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 (9H-fluorene-9-ylmethoxy)carbonyl (Fmoc); tert-butoxycarbonyl (BOC) is preferred. The removal of the protecting group in the method steps is carried out by known methods. Therefore, the tert-butoxycarbonyl group 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 a benzyloxycarbonyl group as the protecting group, this is preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst such as palladium on activated carbon. The (9H-fluorene-9-ylmethoxy)carbonyl group is typically 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; P.J. Kocienski, Protecting Groups, 3rd edition, Thieme, 2005.

[0105] Method steps [B] (VI) + (VII) → (I-C) [amide formation] are carried out by known methods with the aid of 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 3-sulfate or 2-tert-butyl-5-methylisooxazonium perchlorate; amide compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; and α-chloroenamines such as 1-chloro-N,N,2-trimethylpropyl-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 condensing agent or activator used is preferably combined with N,N-diisopropylethylamine as a base.O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HATU). Specification 25 / 178 pages 35 CN 121986100 A

[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 preferably used. The reaction is generally carried out in a temperature range of -20°C to +60°C, preferably in a temperature range of 0°C to +40°C.

[0107] With regard to the compound of formula (II), it can be prepared by a method known in the literature [amide formation], which involves reacting an amine (VII) where R5 and R6 have the definitions given above with a compound of formula (X) in the presence of a condensing agent or activator to produce compound (II) of formula (II).

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

[0109] The compound of formula (IV) can be prepared by a method known in the literature [alkylation], which involves reacting a compound of formula (II) wherein X, Y, Z, and R5, and Hal and m have the definitions given above, with a compound of formula (III) wherein R1, R2, R3, and n have the definitions given above, in the presence of a base, to produce compound (IV). (Specification 27 / 178)Page 37 CN 121986100 A (IV).

[0110] The compound of formula (VI) can be prepared by a method known from the literature [alkylation], which involves reacting the compound of formula (XIII) (XIII) where X, Y, Z, R4 and Hal have the definitions given above, and T1 is -O-(C1-C4)-alkyl, with the compound of formula (III) (III) where R1, R2, R3 and n have the definitions given above, and hydrolyzing it under conditions known from the literature to produce the compound of formula (VI).

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

[0112] Suitable inert solvents for these reactions are water or organic solvents common for ester cleavage. These preferred solvents 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 may 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. Specification 28 / 178 pages 38 CN 121986100 A

[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, optionally with the addition of water. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0115] Ester hydrolysis is generally 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 schemes: Scheme 1 Scheme 2 Specification 29 / 178 pages 39 CN 121986100 A Scheme 3 Specification 30 / 178 pages 40 CN 121986100 A Scheme 4 Specification 31 / 178 pages 41CN 121986100 A The compounds of the present invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0117] The compounds according to the present invention are effective and selective antagonists of α2C-adrenergic receptors and are therefore suitable for the treatment and / or prevention of conditions and pathological processes, particularly those caused by activated or induced α2C-adrenergic receptors, and diseases secondary to α2C-adrenergic receptor-related damage.

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

[0119] The compounds of the present invention are also used in methods of treating and / or preventing: dyspnea, including sleep-induced dyspnea, such as central and obstructive sleep apnea; snoring (primary and obstructive snoring); dysphagia; peripheral and cardiovascular conditions, including diabetic microangiopathy; and 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: for example, 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 hypoventilation syndrome, interrupted central respiratory drive, sudden infant death syndrome, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnea, muscle respiratory disorders, respiratory disorders after long-term 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, said breathing 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, muscular respiratory disorders, and respiratory disorders after prolonged ventilation.

[0122] In the context of this invention, peripheral and cardiovascular conditions include diabetic microangiopathy, diabetic ulcers of the extremities, particularly wound healing for promoting 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 disturbances 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: conditions of the peripheral and central nervous systems, 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 spinal-bulbar muscular atrophy, Friedrich's ataxia, dentate nucleus, rubra pallidus, hypothalamic nucleus atrophy, 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 lobe 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 of 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 this invention are also used in methods of treating and / or preventing the following conditions: conditions of the peripheral and central nervous systems, 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 the product specification, page 33 / 178, CN 121986100 A. 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, dentate nucleus, rubra pallidus, hypothalamic nucleus atrophy, 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 the present 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, atrioventricular junctional premature contractions, sick sinus syndrome, syncope, atrioventricular 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 ischemic attacks, preeclampsia, inflammatory cardiovascular disease, coronary and peripheral artery spasm, edema formation such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, etc.Microvascular and large vessel damage (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 the present 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 the present invention are also suitable for treating and / or preventing kidney disease, 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 insufficiency, hypotension during dialysis, obstructive urinary tract disease, 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 nephropathy induced by contrast agents. (Instructions for use 34 / 178 pages, 44 CN 121986100 A) Nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome are characterized by features such as abnormally low creatinine and / or water excretion, abnormally high blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme activity (e.g., gamma-glutamyl synthase), altered urine homotonicity or volume, and abnormal urine microbiota.Elevated albumin levels, 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 this invention are suitable for the treatment and / or prevention of conditions of the genitourinary system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), neurogenic overactive bladder (OAB), incontinence, such as mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence, or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, and erectile dysfunction and female sexual dysfunction.

[0132] The compounds of the present 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 dysfunction syndrome (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 skin fibrosis and eye fibrosis. 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, fibrotic damage caused by diabetes, myelofibrosis, peritoneal fibrosis and similar fibrotic conditions, scleroderma, lentigines, 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 this 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, aβ-lipoproteinemia).Diabetes mellitus (including hypersitosterolemia), xanthomas, 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, impaired glucose tolerance, and sequelae of diabetes, such as retinopathy, nephropathy, and neuropathy), anemia such as hemolytic anemia, hemoglobinopathies (such as sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, and anemia attributable to acute blood loss), and other conditions. Myelodysplastic anemia and aplastic anemia), gastrointestinal and abdominal diseases (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, 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), and skin diseases (psoriasis). Acne, eczema, neurodermatitis, various forms of dermatitis, as well as keratitis, bullous disease, 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 virus, adenovirus, etc.). (Instructions 35 / 178) Page 45 CN 121986100 A Viruses and coronaviruses, such as HPV, HCMV, HIV, SARS), diseases of bones and joints and skeletal muscles, inflammatory changes in arteries (various forms of arteritis, such as endarteritis, medial arteritis, periarteritis, 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 performance characteristics, 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 diseases, including diabetic microangiopathy; and peripheral and central nervous system diseases, including neurodegenerative and neuroinflammatory diseases.

[0136] The diseases fully characterized above in humans can also occur in other mammals with comparable etiologies and in theirThe compounds of the present invention can also be used for treatment.

[0137] For the purposes of the present invention, the term “treatment” includes the suppression, delay, prevention, relief, weakening, restriction, reduction, inhibition, repulsion, or cure of a disease, symptom, condition, injury, or health problem, or such condition and / or the development, process, or progression of symptoms of such a condition. The term “therapeutic method” is hereby understood to be synonymous with the term “treatment”.

[0138] The terms “prevention” and “prophylaxis” are used synonymously in the present invention and refer to avoiding or reducing the risk of infection, occurrence, affliction, or health problem, or such condition and / or the development or progression of symptoms of such a condition.

[0139] Treatment or prevention of a disease, symptom, condition, injury, or health problem may be partial or complete.

[0140] The present invention therefore also provides the use of the compounds of the present invention for the treatment and / or prevention of conditions, especially the aforementioned conditions.

[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 conditions, especially the aforementioned conditions.

[0142] The present invention also provides medicaments 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 conditions, especially the aforementioned conditions.

[0144] The present invention also provides methods for treating and / or preventing conditions, especially the aforementioned conditions, 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 treating and / or preventing the aforementioned diseases. Preferred examples of conjugated active ingredients suitable for this purpose include: • TASK1 and TASK3 channel blockers, such as and preferably those disclosed in WO 2017 / 097792 A1, WO 2017 / 097671 A1, WO 2018 / 015196 A1, WO 2018 / 228907 A1, and WO 2018 / 228909 A1; • P2X3 receptor antagonists, such as and preferably gefapixant; • Respiratory stimulants, such as and preferably theophylline, doxapram, nikethamide, and caffeine; • Psychostimulant compounds, such as and preferably modafinil and armodafinil; (Specification 36 / 178 pages, 46 CN 121986100 A)• Amphetamines and amphetamine derivatives, such as and preferably amphetamine, methamphetamine, methylphenidate; • Serotonin reuptake inhibitors, such as and preferably fluoxetine, paroxetine, citalopram, entapril, sertraline, fluvoxamine, trazodone; • Serotonin precursors, such as and preferably L-tryptophan; • Selective serotonin-norepinephrine reuptake inhibitors, such as and preferably venlafaxine, duloxetine; • Noradrenergic 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, desipramine; • GABA agonists, such as and preferably baclofen; • Alpha-mimicking sensory neurotransmitters, such as and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrahydrozoline, tramazoline; • Glucocorticoids, such as and preferably fluticasone, budesonide, beclomethasone, mometasone, tecrisoxol valerate, 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, naltrexone; • Cholinesterase inhibitors, such as and preferably neostigmine, pyridostigmine, physostigmine donepezil, galantamine, rivastigmine; • N-methyl-D-aspartate and glutamate antagonists, such as and preferably amantadine, memantine, sabeluzole; • Nicotine receptor agonists; • Leukotriene receptor antagonists, such as and preferably montelukast and tripolilast; • Dopamine receptor antagonists, such as and preferably domperidone, metoclopramide, benzamide, butyrate, and 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; • Antihypertensive active ingredients, such as and preferably selected from calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, angiopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and diuretics; • Active ingredients regulating lipid metabolism, such as and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, such as and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, and 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 nitrate 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 phosphoric acid esterases (PDEs) 1, 2, 3, 4 and / or 5, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dassenafil, avanafil, mirtenafil, or lodenafil; • NO- and heme-independent activators of soluble guanylate cyclase (sGC), particularly such as WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO Compounds described in 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, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; • Compounds affecting cardiac energy metabolism, for example and preferably etorolimus, dichloroacetate, ranolazine or trimetazidine; • Antithrombotic agents, for example 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 by systemic or inhalation, as well as dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferons, natamizumab, 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, tillatinib, imatinib, brinib, and pazopatib.Nitroglycerin, vatalanib, gefitinib, erlotinib, lapatinib, canenatinib, letatinib, peritinib, cemannib, or tandutinib; • prostacyclin analogs and IP receptor agonists, such as and preferably iloprost, beraprost, trolonil, eprostol, or selexipag; • endothelin receptor antagonists, such as and preferably bosentan, darusentan, ambrisentan, or sitassentan; • compounds that inhibit human neutrophil elastase (HNE), such as and preferably cevelex 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 matrix lysins, collagenases, gelatinases, and polyproteoglycans (particularly MMP-1, ... 3. Inhibitors of MMP-8, MMP-9, MMP-10, MMP-11, and MMP-13, and inhibitors of metalloelastase (MMP-12); • Compounds that block serotonin binding to its receptor, such as, and preferably, antagonists of the 5-HT2B receptor, like 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 antagonists.

[0146] In a particularly preferred embodiment of the invention, the compounds of the invention are administered in combination with one or more other active compounds selected from respiratory stimulants, psychostimulant compounds, serotonin reuptake inhibitors, norepinephrine, 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 oxaprium 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] The antithrombotic agent is preferably understood to be a compound selected from platelet aggregation inhibitors, anticoagulants, and plasminogen activators.

[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, melagatine, 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, raszaxaban, fondaparin, epoxetine, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, 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, said vitamin K antagonist being, for example and preferably, coumarin.

[0157] The antihypertensive agent is preferably understood to be a compound selected from calcium channel blockers, angiotensin II antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-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 channel blocker, said calcium channel blocker being, for example 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, said α-1-receptor blocker being, for example 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, said β-receptor blocker being, for example and preferably, prazosin.The β-receptor blockers mentioned are, for example and preferably, propranolol, atenolol, timolol, indolol, alpraolol, oxenolol, pentbuprofen, blavolol, metenolol, naldolol, metinolol, caralolol, sotalol, metoprolol, betalolol, celylolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adalolol, lanteolol, nebiolol, epamolol, or buxinolol. Specification 39 / 178 pages 49 CN 121986100 A

[0161] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist, said angiotensin AII antagonist being, for example and preferably, losartan, candesartan, valsartan, telmisartan, or enbosartan.

[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, darushentan, ambesentan, or sitassentan.

[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 fenelrenone.

[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, porbithiazine, trichlorothiazide, chlorothiazide, indapamide, metoprazine, quinethazine, acetazolamide, dichlorosulfonamide, acetazolamide, glycerol, 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 present invention, the compound of the present invention is administered in combination with a CETP inhibitor, wherein...CETP inhibitors, for example 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), CGS 23425, 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 avamid, methyllinoleamide, partemid, 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 impetavir, 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, as described on pages 40 / 178 of the specification (CN 121986100 A), said cholesterol absorption inhibitor being, for example and preferably, ezetimibe, tequinan, or pamalogidine.

[0177] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipase inhibitor, said lipase inhibitor being, for example 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 is the combination of the compound of the invention with one or more other active compounds selected from respiratory stimulants, psychotropic compounds, serotonin reuptake inhibitors, norepinephrine, 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 may also be used in combination with one or more other medical means, provided that such combination does not produce unwanted and unacceptable side effects. Preferred examples of medical means suitable for this purpose include: • devices for positive airway pressure ventilation, such as and preferably CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Bidirectional Positive Airway Pressure) devices, and IPPV (Intermittent Positive Airway Pressure) devices; • nerve stimulators for the hypoglossal nerve; • intraoral assistive devices, such as and preferably protruding braces; • disposable nasal valves; • nasal stents.

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

[0184] The compounds of the present invention can act systemically and / or locally. For this purpose, they can be administered in suitable manner, such as by oral, parenteral, pulmonary, nasal, pharyngeal, sublingual, tongue, oral cavity, rectum, skin, transdermal, conjunctival, or transauricular route, or as implants or stents.

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

[0186] Forms suitable for oral administration are those that work according to the prior art and release the compounds of the present invention rapidly and / or in a controlled manner and contain the compounds of the present invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, e.g., with an acid-resistant or delayed-dissolution or insoluble coating that controls the release of the compounds of the present invention), tablets or films / tablets 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] Suitable examples of other routes of administration are inhalable dosage forms (including powder inhalers, sprays, metered aerosols), nasal drops, nasal solutions or sprays, throat sprays, tablets, films / tablets or capsules, 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, particularly oral, intravenous, intranasal, and pharyngeal administration.

[0190] The compounds of the present invention can be converted into the aforementioned administration forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, in particular, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium 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 about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight, in the case of parenteral administration to achieve effective results. In the case of oral administration, the dose is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg body weight. In the case of intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.

[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 stated above may be sufficient, while in others it may be necessary to exceed the stated upper limit. In cases where larger amounts are administered, it may be recommended that they be divided into several single doses within a day.

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

[0194] A. Examples and abbreviations: abs. absolute value Ac acetyl aq. aqueous solution Boc tert-butyloxycarbonyl br. broad (in NMR signal) Ex. example Bu butyl c concentration ca. about, approximately cat. catalytic CI chemical ionization (in MS) d doublet (in NMR) d day DCI direct chemical ionization (in MS) dd doublet (in NMR) diamix diastereomer mixture DMF N,N-dimethylformamide DMSO dimethyl sulfoxide specification 42 / 178 pages 52 CN 121986100 A dq double quartet (in NMR) dt double tritet (in NMR) ot theoretical (in chemical yield) EI electron collision ionization (in MS) eq. equivalent ESI electrospray ionization (in MS) Et ethyl h hour HATU O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate HOBt 1-hydroxy-1H-benzotriazole hydrate HPLC high-performance liquid chromatography iPr isopropyl concentrated (in solution) LC liquid chromatography LC-MS liquid chromatography-mass spectrometry Lit. Literature (reference) m multiplet (in NMR) Me methyl min min MS mass spectrometry MTBE methyl tert-butyl ether NMR nuclear magnetic resonance spectroscopy Ph phenyl Pr propyl q quartet (in NMR) quant. quantification (in chemical yield) RP reversed phase (HPLC) RT room temperature / retention time Rt retention time (in HPLC, LC / MS) s singlet (in NMR) t triplet (in NMR) tBu tert-butyl TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet spectroscopy v / v (volume to volume ratio of solution) tog. LC-MS, GC-MS and HPLC methods Method 1 (LC-MS): Instruction manual 43 / 178 pages 53 CN 121986100 A 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): Instrument: 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 °C; Flow rate: 0.90 ml / min; UV detection: 210 nm.

[0198] Method 5 (LC-MS): Instrument: Waters Single Quad MS System; Instrument: 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 °C; Flow rate: 0.600 ml / min; UV detection: DAD; 210 nm.

[0200] Other details: The following description of the coupling modes of the 1H 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 in question; in the case of broad multiplets, the interval is given.

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

[0202] The proton signal multiplicity in the 1H NMR spectra reported in the following paragraphs 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 in question. In the case of broad multiplets, the interval is given. Signals masked by solvent or water are temporarily designated or not listed. Significantly broadened signals (e.g., due to rapid rotation of molecular moieties or due to proton exchange) are also temporarily designated (often referred to as broad multiplets or broad singlets) or not listed. Specification 44 / 178 pages 54 CN 121986100 A

[0203] The 1H NMR data of the selected synthetic intermediates and examples are listed in the form of a 1H-NMR peak list. For each signal peak, the δ[ppm] value in ppm is listed first, followed by the signal intensity in parentheses. The δ [ppm] values / signal intensity values ​​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 (intensity i), ..., δ [ppm] = n (intensity 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 wide signal, the center of multiple peaks or signals and their relative intensity compared to the strongest signal in the spectrum can be displayed. The list of 1H-NMR peaks is similar to that of a conventional 1H-NMR printout, and because...This typically contains all the peaks listed in a conventional NMR interpretation. Furthermore, similar to conventional 1H-NMR printouts, they may display solvent signals, signals from stereoisomers of the target compound (also the subject of this invention), and / or impurity peaks. The peaks of the stereoisomers of the target compound and / or impurity peaks generally have lower intensities on average than those 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 calculates 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 the peak picking involved in a conventional 1H-NMR interpretation. A detailed description of the 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 points and melting ranges (if noted) are uncorrected.

[0206] In cases where the reaction products are obtained by grinding, stirring, or recrystallization, a greater quantity of product can often be separated from the respective mother liquor by chromatographic separation. However, unless only a large portion of the total yield can be separated in this step, a description of such chromatographic methods 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 not described below and which are not commercially available or are obtained from sources 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)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone Specification 45 / 178 pages 55 CN 121986100 A 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 (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) in 312 ml of acetonitrile solution. Then, at room temperature, 29 ml (48.74 mmol) of a solution of 50% T3P in ethyl acetate (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, 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 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 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] 1H-NMR (600 MHz, DMSO-d 6, 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): Rt = 0.69 min; m / z = 372 / 374 (M+H)+.

[0211] Example 2A (2-bromo-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone hydrochloride (1:1) 15.22 ml (87.40 mmol) of 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 (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1).(WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) In a 60 mL solution of acetonitrile, 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] ¹H-NMR (400 MHz, DMSO-d₆, 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 (d, 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): Rt = 0.53 min; m / z = 372 / 374 (M+H)+. Specification 46 / 178 pages 56 CN 121986100 A

[0214] Example 3A 2-{[(1S)-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), (1S)-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. 1After 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 Isolute® 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): Rt = 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-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid Lithium hydroxide solution (7.1 ml, 1.0 M, 7.1 mmol) was added to the initial feed of methyl 2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (497 mg, 1.77 mmol) in 18 ml THF, and the mixture was stirred at 60 °C. After 3 h, the reaction mixture was acidified with formic acid and passed through 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 50% B).Purification was performed using 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 (100% purity, 73% of theoretical value) of the target compound.

[0217] LC-MS (Method 1): Rt = 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 specification 47 / 178 pages 57 CN 121986100 A 4-oxopiperidinyl-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 prepared as an 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. Add more sodium triacetoxyborohydride (700 mg, 3.30 mmol) and stir the mixture at room temperature for another 48 h. Add water to the reaction mixture and extract it with dichloromethane. Wash the organic phase with saturated sodium bicarbonate solution and dry it with sodium sulfate. Filter off the drying agent and concentrate the filtrate. 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): Rt = 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 Hydrochloric acid in 1,4-dioxane (1.5 ml, 4.0 M, 6.0 mmol) was added to a solution of rac-3-cyclopropyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (370 mg, 1.20 mmol) 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] H-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), Specification 48 / 178 pages 58 CN 121986100 A 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 tert-butyl rac-3-isopropyl[1,4'-bipiperidine]-1'-carboxylate A tert-butyl 4-oxopiperidinium-1-carboxylate (940 mg, 4.72 mmol) and rac-3-isopropylpiperidine (1.20 g, 9.43 mmol) were prepared as an 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 subjected to 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 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm, complete injection; gradient overview: mobile phase A 0 to 2 min 39 ml, mobile phase B 0 to 2 min 31 ml).Mobile phase A was 39 ml to 15 ml for 2 to 10 min and mobile phase B was 31 ml to 55 ml for 10 to 12 min. Mobile phase A was 0 ml and mobile phase B was 70 ml. Mobile phases C and D were purified at a constant flow rate of 5 ml / min 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): Rt = 1.14 min; MS (ESIpos): m / z = 311 [M+H]+.

[0225] 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 in 1,4-dioxane (1.1 ml, 4.0 M, 4.3 mmol) was added to a solution of rac-3-cyclopropyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (269 mg, 866 µmol) 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] H-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 tert-butyl rac-3-tert-butyl[1,4'-bipiperidine]-1'-carboxylate A tert-butyl 4-oxopiperidinium-1-carboxylate (505 mg, 2.53 mmol), rac-3-tert-butylpiperidine hydrochloride (900 mg, 5.06 mmol), and N,N-diisopropylethylamine (880 µl, 5.1 mmol) were prepared as an 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. Further 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 saturated sodium bicarbonate solution and dried with sodium sulfate. The desiccant was filtered off and the filtrate was concentrated. The residue was subjected to 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 / 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 23 ml, mobile phase B 0 to 2 min 47 ml, mobile phase A 2 to 10 min from 23 ml to 0 ml).The mobile phase A was increased from 47 ml to 70 ml, and the mobile phase B was increased from 0 ml to 70 ml over 10 to 12 min. The mobile phases C and D were purified at constant flow rates of 5 ml / min throughout the run. The fractions containing the product were combined and lyophilized. This yielded 318 mg (100% purity, 39% of theoretical value) of the target compound.

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

[0230] 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'-bipiperidine hydrochloride, specification 50 / 178 pages, 60 CN 121986100 A. Hydrochloric acid in 1,4-dioxane (1.2 ml, 4.0 M, 4.9 mmol) was added to a solution of rac-3-tert-butyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (318 mg, 980 µmol) 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] 1H-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 4-oxopiperidine-1-carboxylic acid tert-butyl ester (622 mg, 3.12 mmol) and rac-3-isopropylpiperidine (870 mg, 6.25 mmol) were initially fed in 30 ml of dichloromethane. Subsequently, concentrated acetic acid (270 µl, 4.7 mmol) was added, and the mixture was stirred overnight at room temperature. Add sodium triacetoxyborohydride (795 mg, 3.75 mmol) and continue stirring the mixture overnight at room temperature. Add more sodium triacetoxyborohydride (795 mg, 3.75 mmol) and continue stirring the mixture overnight at room temperature.The mixture was stirred at room temperature for another 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 (100% purity, 28% of theoretical value) of the target compound.

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

[0235] 1H-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, specification 51 / 178 pages, 61 CN 121986100 A. Hydrochloric acid in 1,4-dioxane (1.1 ml, 4.0 M, 4.4 mmol) was added to a solution of rac-3-cyclobutyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (285 mg, 884 µmol) 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'-piperidine]-1'-carboxylic acid tert-butyl ester 4-oxopiperidinyl-1-carboxylic acid tert-butyl ester (880 mg, 4.42 mmol) and rac-3-ethylpiperidine (1.00 g, 8.83 mmol) were heated at 45°C.The initial feed was formed in 1 ml of dichloromethane. Subsequently, concentrated acetic acid (380 µl, 6.6 mmol) was 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. Throughout the run, mobile phases C and D were kept at constant flow rates of 5 ml / min each). 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): Rt = 1.02 min; MS (ESIpos): m / z = 297 [M+H]+.

[0240] 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 rac-3-ethyl-1,4'-bipiperidine hydrochloride Hydrochloric acid was added to rac-3-ethyl[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (413) in 1,4-dioxane (1.7 ml, 4.0 M, 7.0 mmol).The target compound (1.39 mmol) was dissolved in 15 mL of dichloromethane and 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] 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-oxopiperidinium-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.An initial feed of 3.2 mmol (180 µl, 3.2 mmol) was formed 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 again overnight at room temperature. More sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added, and the mixture was stirred for another 24 h at room temperature. Water was added to the reaction mixture, and the mixture was 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 262 mg (100% purity, 39% of theoretical value) of the target compound.

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

[0245] H-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 rac-3-propyl[1]pyridine in 1,4-dioxane (1.1 ml, 4.0 M, 4.2 mmol).262 mg (844 µmol) of tert-butyl 4'-[bipiperidine]-1'-carboxylate was added to a solution of 9 mL 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] 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 tert-butyl rac-3-(cyclobutoxy)[1,4'-bipiperidine]-1'-carboxylate A tert-butyl 4-oxopiperidinium-1-carboxylate (520 mg, 2.61 mmol), rac-3-(cyclobutoxy)piperidine hydrochloride (1.00 g, 5.22 mmol), and N,N-diisopropylethylamine (910 µl, 5.2 mmol) were prepared as an 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. Further 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 saturated sodium bicarbonate solution and dried with sodium sulfate. The desiccant was filtered off and the filtrate was concentrated. The residue was passed through a preparative HPLC system (instrument: Waters Prep LC / MS system, column: XBridge, manual page 54 / 178, 64 CN 121986100 A 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, complete injection; gradient overview: mobile phase A 0 to 2 min 39 ml, mobile phase B 0 to 2 min 31 ml, mobile phase A 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min from 39 ml to 15 ml).0 ml of mobile phase A and 70 ml of mobile phase B were used. Mobile phases C and D were kept at a constant flow rate of 5 ml / min throughout the run. The fractions containing the product were combined and lyophilized. This yielded 563 mg (100% purity, 64% of theoretical value) of the target compound.

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

[0250] 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 in 1,4-dioxane (2.1 ml, 4.0 M, 8.3 mmol) was added to a solution of rac-3-(cyclobutoxy)[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (563 mg, 1.66 mmol) 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] H-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,N-diisopropylethylamine was added to 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 solution. (See specification 55 / 178, page 65, CN 121986100 A). Then, at room temperature, 18.6 ml (19.88 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, 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 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 applied to…Isolute® and purification was performed 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): Rt = 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] ketone (racemic mixture) 1-[(2-bromo-1,3-thiazo-5-yl)carbonyl]piperidine-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. Afterward, 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). The solvent was removed, yielding 51 mg (37% of the theoretical value) of the title compound. LC-MS (Method 1): Rt = 0.70 min; m / z = 402 / 404 (M+H)+.

[0257] 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'-bipiperidine]-1'-yl] methyl ketone (racemic mixture) Specification 56 / 178 pages 66 CN 121986100 A 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidine-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 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 filtering 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 phase was 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 188 mg (25% of the theoretical value) of the title compound.

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

[0260] Example 22A (2-bromo-1,3-thiazo-5-yl)[3-isopropoxy[1,4'-piperidine]-1'-yl] ketone (racemic mixture) 1-[(2-bromo-1,3-thiazo-5-yl)carbonyl]piperidine-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 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (440 mg, 2 Å) was added to the reaction.The mixture was stirred at room temperature for 1 h. Then, 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). Subsequently, the organic phase was 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 149 mg (21% of the theoretical value) of the title compound.

[0261] LC-MS (Method 1): Rt = 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] ketone (racemic mixture) 1-[(2-bromo-1,3-thiazolyl-5-yl)carbonyl]piperidine-4-one (447 mg, 1.55 mmol) and 296 mg of 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 4 Å molecular sieve were added. Subsequently, sodium triacetoxyborohydride (393 mg, 1.85 mmol) was added to the reaction, 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 a 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 subjected to 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 rpm).Purification was performed using a solvent at a concentration of 0.05% formic acid (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): Rt = 0.85 min; m / z = 428 / 430 (M+H)+.

[0264] Example 24A (2-bromo-1,3-thiazo-5-yl){3-[(cyclobutoxy)methyl][1,4'-piperidine]-1'-yl} ketone (racemic mixture) 1-[(2-bromo-1,3-thiazo-5-yl)carbonyl]piperidine-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 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 filtering 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 phase was 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): Rt = 1.01 min; m / z = 442 / 444 (M+H)+.

[0266] Example 25A [2-bromo-4-(trifluoromethyl)-1,3-thiazolyl][(3R)-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) 2-bromo-4-(trifluoromethyl)-1,3-thiazolyl-5-carboxylic acid and 0.46 g (1.81 mmol) (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) at 15In a solution of acetonitrile, 1.4 ml (2.36 mmol) of a solution of 50% T3P in ethyl acetate (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane 2,4,6-trioxide) was added dropwise to the reaction solution at room temperature, according to the instructions on page 58 / 178, 68 CN 121986100 A. 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 about 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] 1H-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): Rt = 0.98 min; m / z = 440 / 442 (M+H)+.

[0269] Example 26A (2-bromo-4-chloro-1,3-thiazolyl)[(3R)-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) 2-bromo-4-chloro-1,3-thiazolyl-5-carboxylic acid and 0.53 g (2.06 mmol) (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) in a solution of acetonitrile, and then at room temperature,1.6 ml (2.68 mmol) of a solution of 50% T3P in ethyl acetate (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane 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 about 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. This yielded 410 mg (1.01 mmol, 49% of the theoretical value) of the target compound.

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

[0271] Example 27A (2-bromo-4-cyclopropyl-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone 10.5 ml (60.46 mmol) N,N-diisopropylethylamine was added to 5 g (20.15 mmol) 2-bromo-4-cyclopropyl-1,3-thiazolyl-5-carboxylic acid and 5.14 g (20.16 mmol) (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1: [Instructions for Use] 59 / 178 pages 69 CN 121986100 A 1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) in 167 ml of acetonitrile solution, and then 15.6 ml was added dropwise to the reaction solution at room temperature. (26.20 mmol) 50% T3P in ethyl acetate solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphacyclohexane 2,4,6-trioxide). 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 about 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. 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): Rt = 0.94 min; m / z = 412 / 414 (M+H)+.

[0274] Example 28A (2-bromo-4-methyl-1,3-thiazolyl)[(3R)-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) 2-bromo-4-methyl-1,3-thiazolyl-5-carboxylic acid and 5.4 g (21.17 mmol) (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) in 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-) was added dropwise to the reaction solution. Tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane 2,4,6-trioxide). 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 about 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. 1H-NMR (400 MHz, DMSO-d 6, δ / ppm): 0.74-0.88 (m, 4H,Among them, 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): Rt = 0.74 min; m / z = 386 / 388 (M+H)+.

[0277] Example 29A (2,4-bromo-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone Specification 60 / 178 pages 70 CN 121986100 A 0.91 ml (5.23 mmol) N,N-diisopropylethylamine was added to 0.5 g (1.74 mmol) 2,4-dibromo-1,3-thiazolyl-5-carboxylic acid and 0.45 g (1.74 mmol) (3R)-3-methyl-1,4'-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry No. 1799475-27-6) in 14 ml of acetonitrile solution. Then, at room temperature, 1.35 ml (2.27 mmol) was added dropwise to the reaction solution. A solution of 50% T3P in ethyl acetate (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane 2,4,6-trioxide). 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 about 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. This yielded 0.52 g (1.12 mmol, 65% of the theoretical value) of the target compound.

[0278] LC-MS (Method 1): Rt = 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: Specification 61 / 178 pages 71 CN 121986100 A Example 34A (2-bromo-1,3-thiazo-4-yl)(3,3-dimethyl[1,4'-bipiperidine]-1'-yl) methyl ketone SpecificationPage 62 / 178, 72 CN 121986100 A: 0.29 ml (1.67 mmol) of 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 a solution of 50% T3P in ethyl acetate (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. Water was then added to the solution, and it was extracted with ethyl acetate. After separating the organic phase, the resulting organic solution was washed with saturated sodium chloride solution, and then 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.

[0280] The obtained residue was purified by preparative HPLC.

[0281] Method: 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 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 39 ml, mobile phase B 0 to 2 min 31 ml, mobile phase A 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Throughout the run, the constant flow rates of mobile phase C and mobile phase D were each 5 ml / min.

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

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

[0284] Example 35A Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-4-carboxylate Methyl 2-bromo-1,3-thiazolyl-4-carboxylate (182 mg, 0.82 mmol) and N-methyl-1-(pyridin-2-yl)methylamine (100 mg, 0.82 mmol) were dissolved in 20.42 ml of N,N-diisopropylethylamine was added to 1-methyl-2-pyrrolidone. 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 product specification page 63 / 178, 73 CN 121986100 A were combined and concentrated, and the residues were 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): Rt = 1.05 min; MS (ESIpos): m / z = 264 [M+H]+. 1H-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-carboxylic acid (340 mg, 1.29 mmol) was dissolved in 12 ml of methanol, 6.5 ml of 1N sodium hydroxide solution (1.0 M, 6.5 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3-4 with 1N hydrochloric acid solution. The resulting solution was concentrated, stirred with methanol, and filtered. 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): Rt = 0.71 min; MS (ESIpos): m / z = 250 [M+H]+.

[0289] Example 37A3-[(3,3-difluorocyclobutyl)methoxy]piperidine (racemic mixture) 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] Methods: Instruments: 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 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, the constant flow rates of Mobile phase C and Mobile phase D were each 5 ml / min.

[0291] The fractions containing the product were combined and lyophilized. 388 mg of the target compound was obtained. The target compound was further described in the specification 64 / 178 pages 74 CN 121986100 A and converted without analysis.

[0292] Example 38A 3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (racemate) 4-oxopiperidinidine-1-carboxylic acid tert-butyl ester (340 mg, 1.71 mmol) and 3-[(3,3-difluorocyclobutyl)methoxy]piperidine (racemate) (350 mg, 1.71 mmol) were prepared as an initial feed in 10 ml of dichloromethane. Subsequently, concentrated acetic acid (146 µl, 2.56 mmol) was 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 at room temperature overnight. Water was added to the reaction mixture, and it was extracted with dichloromethane. 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 then subjected to preparative HPLC (instrument: Waters Prep LC / MS system, column: XBridge C18 5 µm 100 x 100 μm).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 0–2 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] ¹H-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 (racemate) Hydrochloric acid in 1,4-dioxane (0.2 ml, 4.0 M, 0.84 mmol) was added to a solution of tert-butyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4'-bipiperidine]-1'-carboxylate (racemate) (65 mg, 0.17 mmol) in 5 ml of dichloromethane, 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. (Instructions for Use 65 / 178, page 75) CN 121986100 A

[0295] Example 40A 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-thiazolyl-5-carboxylate methyl 2-bromothiazolyl-5-carboxylate (1.82 g, 8.19 g)1 g (8.19 mmol) and N-methyl-1-(pyridin-2-yl)methylamine (1 g, 8.19 mmol) were dissolved in 50 mL of 1-methyl-2-pyrrolidone, and 3 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 879 mg (41% of the theoretical value, 0.33 mmol) of the target compound.

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

[0297] 1H-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-carboxylic acid (870 mg, 3.30 mmol) was dissolved in 32 ml of methanol, 16.5 ml of 1N sodium hydroxide solution (1.0 M, 6.5 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3-4 with 1N hydrochloric acid solution. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0299] Methods: Instruments: 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: 80ml / 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 55 ml and mobile phase B from 0 ml to 15 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.

[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. Specification 66 / 178 pages 76 CN 121986100 A

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

[0302] 1H-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 (racemate) 4-oxopiperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.51 mmol) and 3-(2,2,2-trifluoroethoxy)piperidine (racemate) (460 mg, 2.51 mmol) were used as the initial feed in 15 ml of dichloromethane. Subsequently, concentrated acetic acid (215 µl, 3.76 mmol) was 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 at room temperature overnight. 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 passed through a preparative HPLC system (instrument: Waters Prep LC / MS system, LC-MS: Rt = 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 vol% / 20 vol%), total flow rate: 80 ml / min, room temperature, wavelength: 200–400 nm).nm, on-column injection (complete injection); gradient overview: mobile phase A 0 to 2 min 39 ml, mobile phase B 0 to 2 min 31 ml, mobile phase A 2 to 10 min from 39 ml to 15 ml and mobile phase B from 31 ml to 55 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. 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. 450 mg (1.23 mmol, 49% of theoretical value) of the target compound was obtained, which was converted without further analysis.

[0304] Example 43A 3-(2,2,2-trifluoroethoxy)-1,4'-bipiperidine dihydrochloride (racemate) Hydrochloric acid was added to a solution of tert-butyl 3-(2,2,2-trifluoroethoxy)[1,4'-bipiperidine]-1'-carboxylate (racemate) (446 mg, 1.22 mmol) in 20 ml of dichloromethane, 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 (diastereomeric mixture) Specification 67 / 178 pages 77 CN 121986100 A 2-methyl-4-oxopiperidinidine-1-carboxylic acid tert-butyl ester (racemic) (100 mg, 0.47 mmol) and 6-azaspiro[3.5]nonane hydrochloride (1:1) (83 mg, 0.52 mmol) were prepared as an initial feed in 2 ml of dichloromethane. Subsequently, concentrated acetic acid (40 µl, 0.70 mmol) was 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] Methods: Instruments: 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.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, mobile phases C and D were maintained at a constant flow rate of 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: Rt = 2.39 min (23.2%); MS (ESIpos): m / z = 323 [M+H]+; Diastereomer 2: Rt = 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 (diastereomeric mixture) Hydrochloric acid in 1,4-dioxane (1 ml, 4.0 M, 4 mmol) was added to a solution of tert-butyl 4-(6-azaspiro[3.5]non-6-yl)-2-methylpiperidin-1-carboxylate (diastereomeric mixture) (53 mg, 0.16 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. 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 Specification 68 / 178 pages 78 CN 121986100 A N-methyl-1-(pyridin-2-yl)methylamine (276 mg, 2.26 mmol) was dissolved in 10 ml acetonitrile, followed by the addition of 0.79 ml N,N-diisopropylethylamine and 3-bromo-1,2,4-oxadiazole-5-carboxylic acid ethyl ester (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 subjected to 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).Purification. The fractions containing the product were combined and concentrated, and the residue was dried under high vacuum. This yielded 181 mg (30% of the theoretical value, 0.69 mmol) of the target compound.

[0311] LC-MS (Method 1): Rt = 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-carboxylic acid (180 mg, 0.69 mmol) was dissolved in 7 ml of methanol, 3.4 ml of 1N sodium hydroxide solution (1.0 M, 3.4 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3-4 with 1N hydrochloric acid solution. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0313] Method: 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 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 from 70 ml to 55 ml and mobile phase B from 15 ml to 70 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Throughout the run, the flow rates of mobile phase C and mobile phase D were kept constant at 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): Rt = 0.33 min; MS (ESIpos): m / z = 235 [M+H]+.

[0316] 1H-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 Specification 69 / 178 pages 79 CN 121986100 AEthyl 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-thiadiazole-2-carboxylate: N-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) of 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 the theoretical value, 1.94 mmol) of the target compound.

[0318] LC-MS (Method 1): Rt = 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-carboxylic acid (535 mg, 1.92 mmol) was dissolved in 20 ml of methanol, 9.6 ml of 1N sodium hydroxide solution (1.0 M, 9.6 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3-4 with 1N hydrochloric acid solution. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0320] Methods: Instruments: 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 0–2 min 70 ml, Mobile phase B 0–2 min 0 ml, Mobile phase A 2–10 min from 70 ml to 55 ml and Mobile phase B from 15 ml to 70 ml, 10–12 min 0 ml Mobile phase A and 70 ml Mobile phase B. Throughout the run, the flow rates of mobile phases C and D were constant.The flow rate was kept constant at 5 ml / min.

[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): Rt = 0.32 min; MS (ESIpos): m / z = 251 [M+H]+.

[0323] 1H-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 Specification 70 / 178 pages 80 CN 121986100 A Methyl 5-bromo-1,2,4-thiadiazole-3-carboxylic acid (500 mg, 2.24 mmol) and N-methyl-1-(pyridin-2-yl)methylamine (274 mg, 2.24 mmol) were dissolved in 15 ml of 1-methyl-2-pyrrolidone, and 1.2 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 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. The resulting residue was dissolved in 20 ml of methanol, and 9.6 ml of 1N sodium hydroxide solution (1.0 M, 9.6 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3–4 with 1N 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): Rt = 0.45 min; MS (ESIpos): m / z =251 [M+H]+.

[0326] Example 51A 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-oxadiazole-2-carboxylate ethyl 5-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) of N,N-diisopropylethylamine and 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 the theoretical value, 1.24 mmol) of the target compound.

[0327] LC-MS (Method 4): Rt = 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 Specification 71 / 178 pages 81 CN 121986100 A Ethyl 5-[methyl(pyridin-2-ylmethyl)amino]-1,3,4-oxadiazole-2-carboxylic acid (320 mg, 1.22 mmol) was dissolved in 20 ml of methanol, 6.1 ml of 1N sodium hydroxide solution (1.0 M, 6.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3 with 1N hydrochloric acid solution. 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): Rt = 0.25min; MS (ESIpos): m / z = 235 [M+H]+.

[0332] Example 53A Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-oxazol-4-carboxylate N-methyl-1-(pyridin-2-yl)methylamine (297 mg, 2.43 mmol) was dissolved in 10 ml 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): Rt = 0.90 min; MS (ESIpos): m / z = 248 [M+H]+.

[0334] 1H-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 Specification 72 / 178 pages 82 CN 121986100 A Methyl 2-[methyl(pyridin-2-ylmethyl)amino]-1,3-oxazol-4-carboxylic acid (260 mg, 1.05 mmol) was dissolved in 20 ml of methanol, 6.3 ml of 1N sodium hydroxide solution (1.0 M, 5.3 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated to dryness, completely dissolved in water, and adjusted to pH 3-4 with 1N hydrochloric acid solution. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC.

[0336] Method: Instruments: 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 70 ml, mobile phase B 0 to 2 min 0 ml, mobile phase A 2 to 10 min from 70 ml to 55 ml and mobile phase B from 0 ml to 15 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.

[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. LC-MS (Method 1): Rt = 0.60 min; MS (ESIpos): m / z = 234 [M+H]+. 1H-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-methylpiperidin-1-carboxylic acid tert-butyl ester (diastereomeric mixture) 3-methyl-4-oxopipedin-1-carboxylic acid tert-butyl ester (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) of N,N-diisopropylethylamine were added to an initial feed of 2 ml 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 at room temperature overnight. 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.

[0341] Methods: Instruments: 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, mobile phases C and D were maintained at a constant flow rate of 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. Instructions for Use, 73 / 178 pages, 83 CN 121986100 A

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

[0344] Example 56A 6-(2-methylpiperidin-4-yl)-6-azaspiro[3.5]nonane dihydrochloride (diastereomeric mixture) 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 (diastereomeric mixture) (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-carboxylate tert-butyl ester (racemate) tert-butyl ester (3-fluoro-4-oxopiperidinidine-1-carboxylate) (552 mg, 2.54 mmol), 5-azaspiro[2.5]octane hydrochloride (750 mg, 5.08 mmol), and N,N-diisopropylethylamine (880 µl, 5.1 mmol) were prepared as an 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, and it was extracted with dichloromethane. The organic phase was washed with a saturated sodium bicarbonate solution and dried over sodium sulfate. Filter out the desiccant and concentrate the filtrate. Pass the residue through a preparative HPLC system (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 (100% purity, 60% of theoretical value) of the target compound.

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

[0347] H-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). Instructions for Use, pages 74 / 178, CN 121986100 A

[0348] Example 58A 5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane hydrochloride (1:1) (racemic mixture) Hydrochloric acid in 1,4-dioxane (1.9 ml, 4.0 M, 7.6 mmol) was added to a solution of 4-(5-azaspiro[2.5]oct-5-yl)-3-fluoropiperidin-1-carboxylic acid tert-butyl ester (racemic mixture) (477 mg, 1.53 mmol) in 15 ml of dichloromethane.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] H-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-carboxylate tert-butyl ester (racemate) 3-ethyl-4-oxopiperidinidine-1-carboxylate tert-butyl ester (racemate) (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) were used to form an 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. Add sodium triacetoxyborohydride (646 mg, 3.05 mmol) and continue stirring the mixture overnight at room temperature. Add water to the reaction mixture and extract it with dichloromethane. Wash the organic phase with a saturated sodium bicarbonate solution and dry it with sodium sulfate. Filter off the drying agent and concentrate the filtrate. The residue was passed through a preparative HPLC system (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 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 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml mobile phase A and 70 ml mobile phase B. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each. Purification. The fractions containing the product were combined and lyophilized. This yielded 226 mg (100% purity, 28% of theoretical value) of the target compound.

[0351] LC-MS (Method 1): Rt = 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 (racemate) (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] 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-methylpiperidin-1-carboxylic acid tert-butyl ester (racemate) 3-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (racemate) (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) were prepared as an 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. Add sodium triacetoxyborohydride (646 mg, 3.05 mmol) and continue stirring the mixture overnight at room temperature. Add the solution to the aqueous reaction mixture and extract with dichloromethane. Wash the organic phase with a saturated sodium bicarbonate solution and then with sulfur.Dry with sodium sulfate. Filter out the desiccant and concentrate the filtrate. The residue was passed through a preparative HPLC system (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 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 0–2 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. Throughout the run, the constant flow rates of mobile phases C and D were 5 ml / min each. Purification. The fractions containing the product were combined and lyophilized. This yielded 186 mg (100% purity, 24% of theoretical value) of the target compound.

[0356] LC-MS (Method 1): Rt = 0.93 min; MS (ESIpos): m / z = 309 [M+H]+. H-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 mixture) Hydrochloric acid in 1,4-dioxane (750 µl, 4.0 M, 3.0 mmol) was added to a solution of tert-butyl 4-(5-azaspiro[2.5]oct-5-yl)-3-methylpiperidin-1-carboxylate (racemic mixture) (186 mg, 603 µmol) in 6 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 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-(Benzoamino)-1,3-thiazolyl-5-yl][(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone Instruction manual 77 / 178 pages 87 CN 121986100 A In a Zinsser glass vial, 37 mg (0.10 mmol) of (2-bromo-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl 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 components 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 saturated sodium bicarbonate aqueous solution, followed by washing with saturated sodium chloride aqueous 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 theoretical value, 100% purity) of the title compound was obtained.

[0363] LC-MS (Method 2): Rt = 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-thiazol-5-yl}[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone In a Zinsser glass bottle, 37 mg (0.10 mmol) of (2-bromo-1,3-thiazol-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 29.4 mg (0.2 mmol) of 1-(1H-benzimidazol-2-yl)methylamine were dissolved in 0.8 ml of 1-methyl-2-pyrrolidone, and 50 µl of N,N-diisopropylethylamine was added. Next, the vial was 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 LC-MS according to one of the following methods: Preparative LC-MS method: 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. Instructions for use, pages 78 / 178, CN 121986100 A

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

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

[0368] LC-MS (Method 6): Rt = 0.59 min; m / z = 437 (M-H)-.

[0369] The following compounds were prepared from (2-bromo-1,3-thiazo-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and their corresponding amines or salts by parallel synthesis similar to that in Example 1: (Specification 79 / 178 pages 89 CN 121986100 A Specification 80 / 178 pages 90 CN 121986100 A Specification 81 / 178 pages)91 CN 121986100 A Instruction Manual 82 / 178 pages 92 CN 121986100 A Instruction Manual 83 / 178 pages 93 CN 121986100 A Instruction Manual 84 / 178 pages 94 CN 121986100 A Example 25 (2-{[(3,5-difluoropyridin-2-yl)methyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone formate (1:1) Instruction Manual 85 / 178 pages 95 CN 121986100 A In a 10 ml glass bottle, 100 mg (0.25 mmol) (2-Bromo-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-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 DMF, and 0.3 ml 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] ¹H-NMR (600 MHz, DMSO-d₆, 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). LC-MS (Method 2): Rt = 0.57 min; m / z = 436 (M+H)+-(HCO2H).

[0372] Explorer Discorer 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°C to 300°C control range; Stirring: In-situ magnetic speed control; Microwave applicator: Circular, single-mode self-adjusting; Ethernet port: 10 baseT, 10 MB / sec; Serial port: (2) RS-232, 9-pin IBM PC compatible.

[0373] Example 26 (2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone Instruction manual 86 / 178 pages 96 CN 121986100 A Dissolve 3 g (8.06 mmol) of (5-bromo-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 3.434 g (16.12 mmol) of (1S)-1-(3-fluoropyridin-2-yl)ethylamine dihydrochloride in 60 ml of 1-methyl-2-pyrrolidone, and add 7 ml N,N-Diisopropylethylamine. The reaction mixture (closed 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. Partial epimerization was found, therefore the resulting residue was purified by chiral preparative HPLC.

[0374] 1250 mg (0.89 mmol) of a mixture of diastereomers of 2-{[(1S / R)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] ketone was purified by chiral preparative 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] separated into diastereomers.

[0375] This yielded 977 mg (28% of the theoretical value, purity > 99%) of the title compound (2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone and 138 mg of the diastereomer (2-{[(1R)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone).

[0376] Analysis of (2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] methyl ketone: Rt = 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): Rt = 0.91 min; m / z = 432 (M+H)+.

[0378] ¹H-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). [α]D20 = -42.79° (c = 0.430, methanol).

[0380] Example 27 (2-{[(1R)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone, specification 87 / 178 pages 97 CN 121986100 A. Yield after separation and purification (see Example 26): 138 mg. Analysis of (2-{[(1R)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone: Rt = 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℃; UV detection: 235 nm].

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

[0382] ¹H-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), 5.29 (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) of (5-bromo-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone and 137 mg (0.64 mmol) of (1R)-1-(3-fluoropyridin-2-yl)ethylamine dihydrochloride were dissolved in 2.4 ml0.28 ml of N,N-diisopropylethylamine was added to 1-methyl-2-pyrrolidone. 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: Instrument: 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 from 70 ml to 55 ml and mobile phase B from 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 phase C and mobile phase D were each 5 ml / min.

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

[0386] LC-MS (Method 1): Rt = 0.84 min; m / z = 432 (M+H)+. Instruction manual, pages 88 / 178, CN 121986100 A

[0387] 1H-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 [(3R)-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 13) was subjected to a chiral preparative 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℃] Separated into enantiomers: Example 28 (diastereomer 1): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 123 mg Rt = 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): Rt = 0.68 min; m / z = 412 (M-H)-.

[0391] ¹H-NMR (400 MHz, DMSO-d⁶, 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): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 133 mg Rt = 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): Rt = 0.69 min; m / z = 412 (M-H)-.

[0395] ¹H-NMR (400 MHz, DMSO-d⁶, 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 of Examples 30 to 56 below were prepared from the specified starting materials: Specification 90 / 178 pages 100 CN 121986100 A Specification 91 / 178 pages 101 CN 121986100 A Specification 92 / 178 pages 102 CN 121986100 A Specification 93 / 178 pages 103 CN 121986100 A Specification 94 / 178 pages 104 CN121986100 A Instruction manual 95 / 178 pages 105 CN 121986100 A Instruction manual 96 / 178 pages 106 CN 121986100 A Examples 57 and 58 {2-[6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazo-5-yl}[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone (diastereomers 1 and 2) 195 mg (0.78 mmol) A mixture of diastereomers of {2-[(6,7-dihydro-5H-cyclopentane[b]pyridin-7-ylamino]-1,3-thiazo-5-yl}[(3R)-3-methyl[1,4'-piperidine]-1'-yl] ketone (Example 49) 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: 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}[(3R)-3-methyl[1,4'-piperidine]-1'-yl] ketone 4'-Bipiperidine]-1'-yl]methyl ketone yield: 64 mg Rt = 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℃; UV detection: 220 nm].

[0398] LC-MS (Method 1): Rt = 0.73 min; m / z = 424 (M-H)-.

[0399] 1H-NMR (400 MHz, DMSO-d6, 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). [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-thiazolyl-5-yl}[(3R)-3-methyl[1,4'-piperidine]-1'-yl]methyl ketone yield: 64 mg Rt = 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): Rt = 0.73 min; m / z = 424 (M-H)-.

[0403] ¹H-NMR (400 MHz, DMSO-d⁶, 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). Specification 98 / 178 pages 108 CN 121986100 A

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

[0405] Examples 59 and 60 [(3R)-3-methyl[1,4'-bipiperidine]-1[(3R)-3-methyl[1,4'-piperidin]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (diastereomers 1 and 2)] A mixture of 167 mg (0.38 mmol) of diastereomers of [(3R)-3-methyl[1,4'-piperidin]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 50) 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: 18 ml / min; UV detection: 220 nm; temperature: 40 °C]: Example 59 (diastereomer 1): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl)methyl ketone yield: 68 mg Rt = 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℃; UV detection: 220 nm].

[0406] LC-MS (Method 1): Rt = 0.90 min; m / z = 440 (M-H)-.

[0407] ¹H-NMR (400 MHz, DMSO-d⁶, δ / 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): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 71 mg Rt = 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): Rt = 0.90 min; m / z = 440 (M-H)-.

[0411] ¹H-NMR (400 MHz, DMSO-d⁶, δ / 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). [α] D 20 = -37.69° (c = 0.260, methanol).

[0413] Examples 61 and 62 [(3R)-3-methyl[1,4'-bipiperidine]-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 46) was subjected to preparative chiral 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] Separated into diastereomers: Example 61 (diastereomer 1): [(3R)-3-methyl[1,4'-piperidin]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 27 mg Rt = 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: 15 ml / min; UV detection: 210 nm; temperature: 40 °C] ml / min; temperature: 30℃; UV detection: 220 nm].

[0414] LC-MS (Method 1): Rt = 0.70 min; m / z = 426 (M-H)-.

[0415] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [α] D 20 = +19.60° (c = 0.250, methanol).

[0417] Example 62 (diastereomer 2): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(3-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone. Yield: 29 mg. Rt = 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℃; UV detection: 220 nm]. Instructions for use 100 / 178 pages 110 CN 121986100 A

[0418] LC-MS (Method 1): Rt = 0.70 min; m / z = 426 (M-H)-.

[0419] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [α] D 20 = -25.33° (c = 0.250, methanol).

[0421] Examples 63 and 64 [(3R)-3-methyl[1,4'-bipiperidine]-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone formate (1:1) (Example 47) was subjected to a 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℃] Separated into diastereomers: Example 63 (diastereomer 1): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl)methyl ketone Yield: 64 mg Rt = 5.066min; 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): Rt = 0.72 min; m / z = 426 (M-H)-.

[0423] ¹H-NMR (400 MHz, DMSO-d⁶, δ / 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). [α] D 20 = +32.00° (c = 0.250, methanol).

[0425] Example 64 (diastereomer 2): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(5-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 61 mg. [Instructions for Use 101 / 178 pages 111 CN 121986100 A Rt= 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℃; UV detection: 300 nm]. LC-MS (Method 1): Rt = 0.72 min; m / z = 426 (M-H)-. H-NMR (400 MHz, DMSO-d6, δ / 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 95 mg (0.21 mmol) of a mixture of diastereomers of (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 38) was subjected to a 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℃] Separated into diastereomers: Example 65 (diastereomer 1): (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] methyl ketone Yield: 39 mg Rt = 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): Rt = 0.91 min; m / z = 448 (M-H)⁻.

[0431] ¹H-NMR (400 MHz, DMSO-d⁶, 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): Specification 102 / 178 pages 112 CN 121986100 A (2-{[1-(3,5-difluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone Yield: 39 mg Rt = 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°C; UV detection: 300 nm].

[0434] LC-MS (Method 1): Rt = 0.91 min; m / z = 448 (M-H)-.

[0435] ¹H-NMR (400 MHz, DMSO-d⁶, 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-2H-pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazolyl}[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (diastereomers 1 and 2) 111 mg (0.25 mmol) of a mixture of diastereomers of {2-[3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazolyl}[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 51) was subjected to preparative chiral HPLC [column: Daical Chiracel]. [Column: 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] Separated into diastereomers: Example 67 (diastereomer 1): {2-[3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazolyl}[(3R)-3-methyl[1,4'-piperidine]-1'-yl] methyl ketone Yield: 45 mg Rt = 15.14 min; Chemical purity > 99%; > 99% de [Column: Chiracel OX-H, 5 µm, 250 mm x 20 mm; Mobile phase: n-heptane / ethanol + 0.2% diethylamine 60:40; Flow rate: 16 ml / min; UV detection: 300 nm; Temperature: 30 °C] ml / min; temperature: 30℃; UV detection: 300 nm].

[0437] LC-MS (Method 1): Rt = 0.75 min; m / z = 440 (M-H)-.

[0438] ¹H-NMR (400 MHz, DMSO-d⁶, δ / 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), Specification 103 / 178 pages 113 CN 121986100 A 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-2H-pyrano[3,2-b]pyridin-4-ylamino]-1,3-thiazolyl-5-yl}[(3R)-3-methyl[1,4'-piperidine]-1'-yl]methyl ketone yield: 44 mg Rt = 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): Rt = 0.75 min; m / z = 440 (M-H)-.

[0442] ¹H-NMR (400 MHz, DMSO-d⁶, δ / 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 2O = -32.53° (c = 0.250, methanol).

[0444] Examples 69 and 70 3-[(5-{[(3R)-3-methyl[1,4][5-{[(3R)-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) of a mixture of diastereomers of 3-[(5-{[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]carbonyl}-1,3-thiazolyl)amino]-3-(pyridin-2-yl)propionitrile (Example 48)] was separated into individual diastereomers by chiral preparative 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-{[(3R)-3-methyl[1,4'-piperidine]-1'-yl]carbonyl}-1,3-thiazolyl-2-yl)amino]-3-(pyridin-2-yl)propionitrile Yield: 26 mg Rt = 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 °C; UV detection: 220 nm].

[0445] LC-MS (Method 1): Rt = 0.75 min; m / z = 437 (M-H)-.

[0446] ¹H-NMR (400 MHz, DMSO-d⁶, 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-{[(3R)-3-methyl[1,4'-piperidine]-1'-yl]carbonyl}-1,3-thiazolyl-2-yl)amino]-3-(pyridin-2-yl)propionitrile Yield: 27 mg Rt = 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 °C; UV detection: 220 nm].

[0449] LC-MS (Method 1): Rt = 0.76 min; m / z = 437 (M-H)-.

[0450] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [α] D 20 = -30.77° (c = 0.260, methanol).

[0452] Examples 71 and 72 [(3R)-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 44) was subjected to 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] separated into diastereomers: Example 71 (diastereomer 1): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 19 mg Rt = 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): Rt = 0.78 min; m / z = 426 (M-H)-. Instruction manual, pages 105 / 178, CN 121986100 A

[0454] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 0.71–0.93 (m, 7H, of which 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). [α] D 20 = +31.70° (c = 0.265, methanol).

[0456] Example 72 (diastereomer 2): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(pyridin-2-yl)propyl]amino}-1,3-thiazolyl-5-yl)methyl ketone. Yield: 19 mg Rt =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): Rt = 0.77 min; m / z = 426 (M-H)-.

[0458] ¹H-NMR (400 MHz, DMSO-d⁶, δ / ppm): 0.72–0.93 (m, 7H, including 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 [(3R)-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]{2-[5,6,7,8-tetrahydroquinoline-8-ylamino]-1,3-thiazolyl-5-yl} methyl ketone (Example 43) was subjected to a chiral preparative 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℃] Separated into individual diastereomers: Example 73 (diastereomer 1):[(3R)-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 Rt = 3.52 min; chemical purity > 99%; > 99% de Product manual 106 / 178 pages 116 CN 121986100 A [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): Rt = 0.74 min; m / z = 438 (M-H)-.

[0461] ¹H-NMR (400 MHz, DMSO-d⁶, 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 0.85–4.94 (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): [(3R)-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 Rt = 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 °C; UV detection: 220 nm].

[0464] LC-MS (Method 1): Rt = 0.74 min; m / z = 438 (M-H)-.

[0465] ¹H-NMR (400 MHz, DMSO-d⁶, 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 0.86–4.94 (m, 1H), 7.24 (dd, 1H), 7.41 (s, 1H), 7.55 (d, 1H), 8.36–8.43 (m, 2H).

[0466] [α]D 2O = -68.36° (c = 0.275, methanol).

[0467] Examples 75 and 76 [(3R)-3-methyl[1,4'-bipiperidine]-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 41) was subjected to a chiral preparative 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℃] Separated into diastereomers: Example 75 (diastereomer 1): [(3R)-3-methyl[1,4'-piperidin]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1, 3-thiazolyl-5-yl) methyl ketone yield: 53 mg Rt = 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): Rt = 0.64 min; m / z = 426 (M-H)-.

[0469] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [α] D 20 = +36.06° (c = 0.305, methanol).

[0471] Example 76 (diastereomer 2): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[1-(4-methylpyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)methyl ketone yield: 53 mg Rt = 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 °C; UV detection: 220 nm].

[0472] LC-MS (Method 1): Rt = 0.63 min; m / z = 426 (M-H)-.

[0473] ¹H-NMR (400 MHz, DMSO-d⁶, 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 2O = -48.52° (c = 0.270, methanol).

[0475] Examples 77 and 78 68 mg (0.15 mmol) of a mixture of diastereomers of (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 55) was subjected to 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℃] Separated into diastereomers: Instructions for use 108 / 178 pages 118 CN 121986100 A Example 77 (diastereomer 1): (2-{[2-methoxy-1-(pyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] ketone Yield: 15 mg Rt = 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℃; UV detection: 220 nm].

[0476] LC-MS (Method 1): Rt = 0.73 min; m / z = 442 (M-H)⁻.

[0477] ¹H-NMR (400 MHz, DMSO-d⁻⁶, δ / 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)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] ketone yield: 19 mg Rt = 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): Rt = 0.72 min; m / z = 442 (M-H)-.

[0481] ¹H-NMR (400 MHz, DMSO-d₆, δ / 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. d₆, δ / ppm). , 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 [(3R)-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) of a mixture of diastereomers of [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (Example 52) was prepared by chiral phase preparative HPLC [column: Daicel Chiralpak IE, 5 µm, 250 mm x 20 mm; mobile phase: ethanol + ... (See specification 109 / 178 pages 119 CN 121986100 A […](…) ... Separation into diastereomers: Example 79 (diastereomer 1): [(3R)-3-methyl[1,4'-piperidin]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl) 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): Rt = 1.00 min; m / z = 454 (M-H)-.

[0485] ¹H-NMR (400 MHz, DMSO-d⁶, 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): [(3R)-3-methyl[1,4'-bipiperidine]-1'-yl](2-{[3-methyl-1-(pyridin-2-yl)butyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 42 mg Rt = 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): Rt = 1.01 min; m / z = 454 (M-H)-.

[0489] ¹H-NMR (400 MHz, DMSO-d⁶, 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 2O = -32.30° (c = 0.290, methanol).

[0491] Examples 81 and 82 (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketone (diastereomers 1 and 2) Specification 110 / 178 pages 120 CN 121986100 AA mixture of diastereomers of 174 mg (0.36 mmol) of (2-{[cyclopropyl(pyridin-2-yl)methyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-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-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl]methyl ketone yield: 61 mg Rt = 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℃; UV detection: 220 nm].

[0492] LC-MS (Method 1): Rt = 0.80 min; m / z = 438 (M-H)-.

[0493] 1H-NMR (400 MHz, DMSO-d6, 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-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] methyl ketoneYield: 61 mg Rt = 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℃; UV detection: 220 nm].

[0495] LC-MS (Method 1): Rt = 0.80 min; m / z = 438 (M-H)-.

[0496] ¹H-NMR (400 MHz, DMSO-d⁶, 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). Instructions for Use, Pages 111 / 178, 121 CN 121986100 A

[0498] Example 83 (Diastereomeric 1) (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone 100 mg (0.27 mmol) (5-bromo-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone and 103 mg (0.54 mmol) (1S)-1-(3-chloropyridin-2-yl)ethylamine hydrochloride (1:1) were 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 then mixed with a saturated sodium bicarbonate solution.Washing. After separating the organic phase, the solution was filtered through a hydrophobic filter and concentrated to dryness under reduced pressure. Partial epimerization was found, so the resulting residue was purified by chiral preparative HPLC.

[0499] A mixture of 57 mg (0.13 mmol) of diastereomers of 2-{[(1S / R)-1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidin]-1'-yl] ketone was separated into individual diastereomers by chiral preparative 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 yielded 32 mg of the title compound (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidin]-1'-yl] ketone. 2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (diastereomer 1) and 5.4 mg of diastereomer 2 (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone).

[0500] Analysis of (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl]methyl ketone (diastereomer 1): Rt = 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): Rt = 1.00 min; m / z = 446 / 448 (M-H)-.

[0502] ¹H-NMR (400 MHz, DMSO-d₆, δ / ppm): 0.73–0.87 (m, 4H, of which 0.81 (d, 3H)), 1.27–1.46 (m, 6H), 1.43 (d, 3H) darin, 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). [α] D 20 = +9.63° (c = 0.270, methanol).

[0504] Example 84 (Diarrhetinic 2) (2-{[1-(3-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone Specification 112 / 178 pages 122 CN 121986100 A Yield after separation and purification (see Example 83): 5.4 mg Analysis of (2-{[1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (diarrhetinic 2): Rt = 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℃; UV detection: 220 nm].

[0505] LC-MS (Method 1): Rt = 0.99 min; m / z = 446 / 448 (M-H)-.

[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)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (diastereomers 1 and 2) 91 mg (0.20 mmol) of a mixture of diastereomers of 2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl)[(3R)-3-methyl[1,4'-bipiperidine]-1'-yl] ketone (Example 56) was analyzed by chiral preparative 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℃] Separated into individual diastereomers: Example 85 (diastereomer 1):(2-{[1-(5-chloropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)[(3R)-3-methyl[1,4'-piperidine]-1'-yl]methyl ketone yield: 28 mg Rt = 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℃; UV detection: 235 nm].

[0508] LC-MS (Method 1): Rt = 0.96 min; m / z = 446 / 448 (M-H)-.

[0509] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [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)[(3R)-3-methyl[1,4'-piperidine]-1'-yl] methyl ketone, specification 113 / 178 pages, 123 CN 121986100 A. Yield: 31 mg, Rt = 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): Rt = 0.94 min; m / z =446 / 448 (M-H)-.

[0513] ¹H-NMR (400 MHz, DMSO-d⁶, 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). [α] D 20 = +32.24° (c = 0.305, methanol).

[0515] Example 87 (3-Cyclopropyl[1,4'-Bipiperidine]-1'-yl)(2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (a mixture of diastereomers) To a solution of 2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-carboxylic acid (80.0 mg, 299 µmol) and rac-3-cyclopropyl-1,4'-bipiperidine hydrochloride (73.3 mg, 299 µmol) in 3 ml of acetonitrile, N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride in ethyl acetate (230 µl, 50% purity, 390 µmol) were added sequentially, 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 an Isolute® column and purified using a Biotage column (28 g Sfähr NH; DCM / MeOH gradient: 2–20% MeOH; flow rate: 25 ml / min).The fractions of the compound were combined and concentrated, and dried under high vacuum. This yielded 59.0 mg (100% purity, 43% of theoretical value) of the target compound.

[0516] LC-MS (Method 1): Rt = 0.98 min; MS (ESIneg): m / z = 456 [M-H]-.

[0517] H-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), Instruction manual 114 / 178 pages 124 CN 121986100 A 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'-Bipiperidin]-1'-yl)(2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone (diastereomers 1 and 2) 52 mg of a mixture of diastereomers of (3-cyclopropyl[1,4'-Bipiperidin]-1'-yl)(2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl) methyl ketone (Example 87) was subjected to a chiral preparative 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℃, detection: 220 nm] Separation into diastereomers: Collect two diastereomers and freeze-dry them separately.

[0519] Example 88 (diastereomer 1): (3-cyclopropyl[1,4'-piperidin]-1'-yl)(2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone Yield: 16 mg Rt = 2,899 min; chemical purity > 99%; > 99% de [Column: Chiralpak ID-3 3 µm 4.6 mm x 50 mm, flow rate: 1ml / min, UV: 220 nm, temperature: 30℃, mobile phase: 50% n-heptane & 50% ethanol + 0.2% DEA.

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

[0521] H-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), Instruction manual 115 / 178 pages 125 CN 121986100 A 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 (4.24).

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

[0523] Example 89 (diastereomer 2): (3-cyclopropyl[1,4'-piperidin]-1'-yl)(2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl) methyl ketone yield: 15 mg Rt = 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): Rt = 1.01 min; MS (ESIpos): m / z = 458 [M+H]+.

[0525] H-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] [α]D 20 = -51.92° (c = 0.251, methanol).

[0527] Example 90 (2-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]amino}-1,3-thiazolyl-5-yl)(3-isopropyl[1,4'-bipiperidine]-1'-yl) methyl ketone (a mixture of diastereomers) Specification 116 / 178 pages 126 CN 121986100 A To a solution of 2-{[(1S)-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) in 3 ml of acetonitrile, N,N-diisopropylethylamine (210 µl, 1.2 mmol) and propylphosphonic anhydride (230 µl) in ethyl acetate were added sequentially. µl, 50% purity, 390The mixture was stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile, acidified with form...

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.