INHIBITORS OF ADRENORECEPTOR ADRAC2

Abstract

The present application relates to novel substituted heterocyclic carboxamides, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases and to their use for producing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of breathing difficulties including sleep-induced breathing difficulties such as central and obstructive sleep apnoea, snoring (primary and obstructive snoring), dysphagia, peripheral and cardiac vascular disorders including diabetic microangiopathies and disorders of the peripheral and central nervous system including neurodegenerative and neuroinflammatory disorders.

Claims

1. A compound of formula (I) ##STR00309## in which X represents S, N or O; Y represents N, S or O, where, if X represents S, then Y represents N; where, if X represents O, then Y represents N; Z represents CR.sub.4, O or NR.sub.4, where, if X represents N and Y represents N, then Z represents O; where, if X represents S, then Z represents CR.sub.4 or NR.sub.4 R.sub.1 represents 5- or 6-membered heteroaryl, phenyl, where 5- to 6-membered heteroaryl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, halogen; where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen, where (C.sub.1-C.sub.4)-alkoxy may be up to trisubstituted by halogen, where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl, (C.sub.1-C.sub.4)-alkoxy, cyano, hydroxy, halogen; where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen, R.sub.2 represents hydrogen, (C.sub.1-C.sub.4)-alkyl; where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen, or together with the carbon atom to which R.sub.2 is attached forms a (C.sub.3-C.sub.4)-cycloalkyl ring, R.sub.3 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen, R.sub.4 in CR.sub.4 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, phenyl, halogen; where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen, in NR.sub.4 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, phenyl; where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by halogen and phenyl may be substituted by halogen, R.sub.5 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, halogen, R.sub.6 represents a group of formula a), b), c), d), e), f) or g) ##STR00310## where *** marks the attachment to the adjacent piperidine ring, where R.sub.7 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, (C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.4)-cycloalkoxy, phenyl, where (C.sub.1-C.sub.4)-alkyl may be substituted by (C.sub.3-C.sub.4)-cycloalkyl, (C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.4)-cycloalkoxy and up to trisubstituted by halogen, where (C.sub.1-C.sub.4)-alkoxy may be substituted by (C.sub.3-C.sub.4)-cycloalkyl and up to trisubstituted by halogen,  where (C.sub.3-C.sub.4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl or trifluoromethyl and up to disubstituted by halogen, where (C.sub.1-C.sub.4)-alkoxy may be substituted by (C.sub.3-C.sub.4)-cycloalkyl and up to trisubstituted by halogen, where (C.sub.3-C.sub.4)-cycloalkyl may be mono- or disubstituted by halogen, where (C.sub.3-C.sub.4)-cycloalkoxy may be up to disubstituted by halogen, where R.sub.8 represents hydrogen or fluorine, where R.sub.9 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, halogen; where (C.sub.1-C.sub.4)-alkyl may be substituted by (C.sub.1-C.sub.4)-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, or a salt, a solvate, or a solvate of a salt thereof.

2. The compound of claim 1, wherein X represents S or N; Y represents N, S or O, where, if X represents S, then Y represents N; Z represents CR.sub.4, N or O, where, if X represents N and Y represents N, then Z represents O; where, if X represents S, then Z represents N or CR.sub.4 R.sub.1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, phenyl, where pyridinyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, where pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, fluorine, chlorine, trifluoromethyl, where thiazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of fluorine, chlorine, where thienyl may be substituted by 1 to 2 substituents independently of one another selected from the group of fluorine, chlorine, where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R.sub.2 represents hydrogen, (C.sub.1-C.sub.2)-alkyl, or together with the carbon atom to which R.sub.2 is attached forms a cyclopropyl ring, R.sub.3 represents hydrogen, (C.sub.1-C.sub.2)-alkyl; R.sub.4 represents hydrogen, (C.sub.1-C.sub.2)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, trifluoromethyl, bromine, chlorine, phenyl; where phenyl may be substituted by halogen, R.sub.5 represents hydrogen, (C.sub.1-C.sub.2)-alkyl, methoxy, fluorine; R.sub.6 represents a group of the formula a), b), c) or e), ##STR00311## where *** marks the attachment to the adjacent piperidine ring, where R.sub.7 or R′.sub.7 independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, (C.sub.1-C.sub.2)-alkoxy, (C.sub.3-C.sub.4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, where (C.sub.1-C.sub.4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine,  where methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,  where cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,  where cyclobutyl may be up to disubstituted by fluorine, where n-butoxy may be up to disubstituted by fluorine, where (C.sub.1-C.sub.2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and  where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine, where (C.sub.3-C.sub.4)-cycloalkoxy may be up to disubstituted by fluorine, where R.sub.8 or R′.sub.8 independently of one another represent hydrogen or fluorine, where R.sub.9 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.2)-alkoxy, methoxyethyl, fluorine, chlorine; n represents 0 or 1 and m represents 1 or 2, q represents 0 or 2, or a salt, a solvate, or a solvate of a salt thereof.

3. The compound of claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h), i), j), k) or (r), ##STR00312## where * marks the attachment to the carbonyl group and ** marks the attachment to the nitrogen atom of the adjacent piperidine ring and R.sub.1 represents pyridinyl, pyrazolyl, thiazolyl, thienyl, phenyl, where pyridinyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, where pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, fluorine, chlorine, trifluoromethyl, where thiazolyl may be substituted by chlorine, where thienyl may be substituted by fluorine, where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group of (C.sub.1-C.sub.2)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, methoxy, cyano, hydroxy, fluorine, chlorine, trifluoromethyl; R.sub.2 represents hydrogen, methyl, or together with the carbon atom to which R.sub.2 is attached forms a cyclopropyl ring, R.sub.3 represents hydrogen, (C.sub.1-C.sub.2)-alkyl; R.sub.4 represents hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, bromine, chlorine, phenyl; where phenyl may be substituted by chlorine, R.sub.5 represents hydrogen, fluorine; R.sub.6 represents a group of the formula a), b′), b″), c′), c″) or e), ##STR00313## where *** marks the attachment to the adjacent piperidine ring, where R.sub.7 or R′.sub.7 independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, (C.sub.1-C.sub.2)-alkoxy, (C.sub.3-C.sub.4)-cycloalkoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, phenyl, where (C.sub.1-C.sub.4)-alkyl may be substituted by methoxy, n-butoxy, cyclopropyl, cyclobutoxy and up to disubstituted by fluorine,  where methoxy may be substituted by cyclopropyl, cyclobutyl, trifluoromethyl,  where cyclopropyl may be substituted by monofluoromethyl, difluoromethyl, trifluoromethyl,  where cyclobutyl may be up to disubstituted by fluorine, where n-butoxy may be up to disubstituted by fluorine, where (C.sub.1-C.sub.2)-alkoxy may be substituted by cyclopropyl, cyclobutyl, cyclobutoxy, trifluoromethyl and  where cyclopropyl and cyclobutyl may be up to disubstituted by fluorine, where (C.sub.3-C.sub.4)-cycloalkoxy may be up to disubstituted by fluorine, where R.sub.9 represents hydrogen, methyl, tert-butyl, methoxy, methoxymethyl, fluorine, chlorine; n represents 0 or 1 and m represents 1 or 2, or a salt, a solvate, or a solvate of a salt thereof.

4. The compound of claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h′), i′), j′) or k), ##STR00314## R.sub.1 represents pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R.sub.2 represents hydrogen or methyl; R.sub.3 represents hydrogen, methyl; R.sub.4 represents hydrogen, ethyl, trifluoromethyl; R.sub.5 represents hydrogen, fluorine; R.sub.6 represents a group of the formula a), c′) or c″) ##STR00315## where *** marks the attachment to the adjacent piperidine ring, where R.sub.7 and R′.sub.7 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 0 or 1 and m represents 1, or a salt, a solvate, or a solvate of a salt thereof.

5. The compound of claim 1, wherein X, Y and Z are selected such that the aromatic 5-membered ring has the structural formula h′) ##STR00316## R.sub.1 represents pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl, 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-hydroxyphenyl, 2,5-difluorophenyl, 5-chloro-2-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-cyclopropylphenyl, 4-chloro-1-methyl-1H-pyrazolyl, 5-chloro-1,3-thiazolyl, 5-fluoro-2-thienyl; R.sub.2 represents hydrogen or methyl; R.sub.3 represents hydrogen; R.sub.5 represents hydrogen, fluorine; R.sub.6 represents a group of the formula a), c′) or c″) ##STR00317## where *** marks the attachment to the adjacent piperidine ring, where R.sub.7 and R′.sub.7 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutylmethoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropylmethoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, fluorine; n represents 0 or 1 and m represents 1, or a salt, a solvate, or a solvate of a salt thereof.

6. A process for preparing a compound of formula (I) according to claim 1, or a salt, a solvate, or a solvate of a salt thereof, comprising [A] reacting a compound of formula (II) ##STR00318## in which X, Y, Z, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 and n are as defined in claim 1, and Hal represents a leaving group, in the presence of a base with a compound of formula (III) ##STR00319## in which R.sub.5 and R.sub.6 and m are as defined in claim 1, to give a compound of formula (I-A) ##STR00320## wherein the compound of formula (I-A) is the compound of formula (I); or [B] reacting a compound of formula (IV) ##STR00321## in which X, Y, Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 and n and m are as defined in claim 1, with a compound of formula (V)
H—R.sub.6  (V) in which R.sub.6 is as defined in claim 1, in the presence of a reducing agent to give a compound of formula (I-B) ##STR00322## wherein the compound of formula (I-B) is the compound of formula (I); or [C] reacting a compound of formula (VI) ##STR00323## in which X, Y, Z, R.sub.4, R.sub.5 and R.sub.6 and n and m are as defined in claim 1, with a compound of formula (VII) ##STR00324## in which R.sub.1, R.sub.2 and R.sub.3 and n are as defined in claim 1, in the presence of a condensating or activating agent to give a compound of formula (I-C) ##STR00325## wherein the compound of formula (I-C) is the compound of formula (I).

7. A method for treatment or prevention of a disease in a human or animal in need thereof, comprising administering an effective amount of a compound according to claim 1, or a solvate, a salt, or a solvate of the salt thereof.

8. A method for the treatment or prevention of breathing difficulties, dysphagia, peripheral and cardiac vascular disorders and disorders of the peripheral and central nervous system in a human or animal in need thereof, comprising administering an effective amount of a compound according to claim 1, or a solvate, a salt, or a solvate of the salt thereof.

9. The method of claim 8, wherein the breathing difficulties are sleep-induced breathing difficulties.

10. The method of claim 9, wherein the sleep-induced breathing difficulties are selected from the group consisting of obstructive sleep apnoea in adults, obstructive sleep apnoea in children, primary snoring, obstructive snoring, central sleep apnoea, Cheyne-Stokes respiration, primary sleep apnoea of infancy, apparent life-threatening event, central sleep apnoea as a result of the use of medicaments or the use of other substances, obesity hypoventilation syndrome, disrupted central respiratory drive, sudden infant death, primary alveolar hypoventilation syndrome, postoperative hypoxia and apnoea, muscular respiratory disorders, respiratory disorders following long-term ventilation, respiratory disorders during adaptation in high mountains, acute and chronic pulmonary diseases with hypoxia and hypercapnia, sleep-related non-obstructive alveolar hypoventilation and the congenital central alveolar hypoventilation syndrome.

11. The method of claim 8, wherein the peripheral and cardiac vascular disorders are selected from the group consisting of diabetic microangiopathies, diabetic ulcers at the extremities, diabetic heart failure, diabetic coronary microvascular cardiac disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disorders, Raynaud's phenomenon, systemic scleroderma, CREST syndrome, microcirculation disorders and intermittent claudication.

12. The method of claim 8, wherein the disorders of the peripheral and central nervous system are selected from the group consisting of dementia, depression, schizophrenia, attention deficit disorder with or without hyperaktivity (ADHS), Tourette syndrome, post-traumatic stress disorder, obsessive-compulsive disorder, blepharospasm or other focal dystonias, drug-induced psychosis, temporal lobe epilepsy with psychosis, panic disorder, disorders caused by changes in sexual hormones, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

13. A pharmaceutical composition, comprising a compound according to claim 1, or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

14. A pharmaceutical combination, comprising a compound according to claim 1, or a salt, a solvate, or a solvate of a salt thereof, in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, P2X3 antagonists, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.

15. A method for treatment or prevention of breathing difficulties dysphagia, peripheral and cardiac vascular disorders and disorders of the peripheral and central nervous system in a human or animal in need thereof, comprising administering to the human an effective amount of a pharmaceutical composition according to claim 13.

16. A method for treatment or prevention of breathing difficulties dysphagia, peripheral and cardiac vascular disorders and disorders of the peripheral and central nervous system in a human or animal in need thereof, comprising administering an effective amount of a pharmaceutical combination according to claim 14.

17. The process of claim 6, comprising reacting the compound of formula (IV) with the compound of formula (V) in the presence of a reducing agent and an acid.

18. The process of claim 6, further comprising: separating the compound of formula (I-A), the compound of formula (I-B), or the compound of formula (I-C) into its enantiomers and/or diastereomers; and/or converting the compound of formula (I-A), the compound of formula (I-B), or the compound of formula (I-C) with the appropriate (i) solvents and/or (ii) acids to give a solvate, a salt, or a solvate of the salt thereof.

Description

A. EXAMPLES

Abbreviations and Acronyms

[0554] abs. absolute [0555] Ac acetyl [0556] aq. aqueous, aqueous solution [0557] Boc tert-butoxycarbonyl [0558] br. broad (in NMR signal) [0559] Ex. Example [0560] Bu butyl [0561] c concentration [0562] cat. catalytic [0563] CI chemical ionization (in MS) [0564] d doublet (in NMR) [0565] d day(s) [0566] DCI direct chemical ionization (in MS) [0567] dd doublet of doublets (in NMR) [0568] diamix diastereomer mixture [0569] DMF N,N-dimethylformamide [0570] DMSO dimethyl sulfoxide [0571] dq doublet of quartets (in NMR) [0572] dt doublet of triplet (in NMR) [0573] o. t. of theory (in chemical yield) [0574] EI electron impact ionization (in MS) [0575] eq. equivalent(s) [0576] ESI electrospray ionization (in MS) [0577] Et ethyl [0578] h hour(s) [0579] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [0580] HOBt 1-hydroxy-1H-benzotriazole hydrate [0581] HPLC high-pressure, high-performance liquid chromatography [0582] iPr isopropyl [0583] conc. concentrated (in the case of a solution) [0584] LC liquid chromatography [0585] LC-MS liquid chromatography-coupled mass spectrometry [0586] lit. literature (reference) [0587] m multiplet (in NMR) [0588] Me methyl [0589] min minute(s) [0590] MS mass spectrometry [0591] NMR nuclear magnetic resonance spectrometry [0592] Ph phenyl [0593] Pr propyl [0594] q quartet (in NMR) [0595] quant. quantitative (in chemical yield) [0596] RP reverse phase (in HPLC) [0597] RT room temperature [0598] R.sub.t retention time (in HPLC, LC-MS) [0599] s singlet (in NMR) [0600] t triplet (in NMR) [0601] tBu tert-butyl [0602] TFA trifluoroacetic acid [0603] THF tetrahydrofuran [0604] UV ultraviolet spectrometry [0605] v/v volume to volume ratio (of a solution) [0606] tog. together

[0607] LC-MS, GC-MS and HPLC Methods

[0608] Method 1 (LC-MS):

[0609] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 um; mobile phase A: 1 l of water+0.01% formic acid; mobile phase B: 1 l of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

[0610] Method 2 (LC-MS):

[0611] MS instrument type: Waters TOF instrument; UPLC instrument type: Waters Acquity I-CLASS; column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; mobile phase A: 1 l of water+0.100 ml of 99% strength formic acid; mobile phase B: 1 l of acetonitrile+0.100 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210 nm.

[0612] Method 3 (GC-MS):

[0613] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m x 200 μm x 0.33 μm; constant flow rate with helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintain for 3.33 min).

[0614] Method 4 (LC-MS):

[0615] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210 nm.

[0616] Method 5 (LC-MS):

[0617] Instrument: Waters Single Quad MS System; instrument Waters UPLC Acquity; column: Waters BEH C18 1.7μ 50×2.1 mm; mobile phase A: 1 l of water+1.0 ml of (25% strength ammonia)/1, mobile phase B: 1l of acetonitrile; gradient: 0.0 min 92% A.fwdarw.0.1 min 92% A.fwdarw.1.8 min 5% A.fwdarw.3.5 min 5% A; oven: 50° C.; flow rate: 0.45 ml/min; UV detection: 210 nm.

[0618] Method 6 (LC-MS):

[0619] MS instrument: Waters SQD2 HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid; gradient: 0.0 min 98% A—0.9 min 25% A—1.0 min 5% A—1.4 min 5% A—1.41 min 98% A—1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UV detection: DAD; 210 nm.

[0620] Method 7 (Preparative HPLC):

[0621] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm.

[0622] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection).

[0623] Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0624] Method 8 (Preparative HPLC):

[0625] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm.

[0626] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection).

[0627] Gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0628] Method 9 (Preparative HPLC):

[0629] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm.

[0630] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection).

[0631] Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0632] Method 10 (Preparative HPLC):

[0633] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm.

[0634] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection).

[0635] Gradient profile: 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0636] Method 11 (Preparative HPLC):

[0637] Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B.fwdarw.95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B.fwdarw.10% B, 35.5-36.5 min 10% B; flow rate: 50 ml/min; room temperature; UV detection: 210 nm.

[0638] Method 12 (LC-MS):

[0639] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UV detection: 210 nm.

[0640] Further Details:

[0641] The descriptions of the coupling patterns of .sup.1H NMR signals which follow are guided by the visual appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. In general, the stated chemical shift refers to the center of the signal in question; in the case of broad multiplets, an interval is generally given.

[0642] All figures in .sup.1H NMR spectra indicate the chemical shifts δ [ppm]=in ppm.

[0643] The multiplicities of proton signals in .sup.1H NMR spectra that are given in the paragraphs that follow indicate the signal shape observed in each case and do not take account of higher-order signal phenomena. In general, the statement of the chemical shift relates to the centre of the signal in question. In the case of broad multiplets, an interval is given. Signals that are concealed by solvents or water were either assigned tentatively or are not listed. Significantly broadened signals—caused, for example, by rapid rotation of parts of molecules or owing to exchanging protons—were likewise assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not listed.

[0644] The .sup.1H NMR data of selected synthesis intermediates and working examples are stated in the form of .sup.1H NMR peak lists. For each signal peak, first the δ [ppm] value in ppm and then the signal intensity in round brackets are listed. The δ [ppm] value/signal intensity number pairs for different signal peaks are listed with separation from one another by commas. The peak list for an example therefore takes the following form: δ [ppm] (intensity.sub.1), δ [ppm]2 (intensity.sub.2), . . . , δ [ppm]i (intensity.sub.i), . . . , δ [ppm].sub.n (intensity.sub.n).

[0645] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities in comparison with other signals. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum. The lists of the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation. In addition, like conventional .sup.1H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities. The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of >90%). Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to “by-product fingerprints”. An expert calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, or using empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional .sup.1H NMR interpretation. A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (cf. Research Disclosure Database Number 605005, 2014, 1 Aug. 2014 or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine 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 depending on the concentration of the compound to be analysed, it may be advisable to set the parameter “MinimumHeight” to values of <1%.

[0646] Melting points and melting ranges, if stated, are uncorrected.

[0647] In cases where the reaction products were obtained by trituration, stirring or recrystallization, it was frequently possible to isolate further amounts of product from the respective mother liquor by chromatography. However, a description of this chromatography is dispensed with hereinbelow unless a large part of the total yield could only be isolated in this step.

[0648] All reactants or reagents whose preparation is not described explicitly hereinafter were purchased commercially from generally accessible sources. For all other reactants or reagents whose preparation is likewise not described hereinafter and which were not commercially obtainable or were obtained from sources which are not generally accessible, a reference is given to the published literature in which their preparation is described.

Starting Materials and Intermediates

Example 1A

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

[0649] ##STR00049##

[0650] 50.24 ml (288.41 mmol) of N,N-diisopropylethylamine were added to a solution of 20 g (96.14 mmol) of 2-bromo-1,3-thiazole-5-carboxylic acid and 29.21 g (134.59 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride in 450 ml of acetonitrile, the mixture was cooled to 0° C. using an ice bath and 74.4 ml (124.98 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate were then added dropwise to the reaction solution. After the addition had ended, the reaction solution was warmed to room temperature and stirred at this temperature for 4 h. About 250 ml of water were then added to the solution. The resulting aqueous phase was then extracted 3× with ethyl acetate. The combined organic phases were subsequently 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 obtained was triturated with diethyl ether and then air-dried. This gave 27.3 g (81.7 mmol, 85% of theory) of the target product as a light-beige solid. The recovered mother liquor was evaporated to dryness under reduced pressure and the resulting residue was purified further by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column; mobile phase: cyclohexane/ethyl acetate 9:1.fwdarw.gradient over 15 CV (CV=column volumes).fwdarw.cyclohexane/ethyl acetate 1:1). This gave a further 2.1 g (6.28 mmol, 6.5% of theory) of the target compound as a white solid.

[0651] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 4.59 (d, 2H), 7.90-7.95 (m, 1H), 8.27 (s, 1H), 8.48 (d, 1H), 9.32 (br. t, 1H).

[0652] LC-MS (method 1): R.sub.t=1.38 min; m/z=333/335 (M+H).sup.+.

[0653] Analogously to Example 1A, the following compounds Example 2A to 8A were prepared from the starting materials stated in each case:

TABLE-US-00001 Example Name/Structure/Starting materials Analytical data 2A [00050] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 2.48-2.56 (s, 3H, partially obscured by DMSO), 4.56 (d, 2H), 7.91-7.97 (m, 1H), 8.48 (d, 1H), 8.83 (br. t, 1H). LC-MS (method 1): R.sub.t = 1.55 min; m/z = 349/347 (M + H).sup.+. 3A [00051] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 2.48-2.56 (s, 3H, partially obscured by DMSO), 4.56 (d, 2H), 7.90-7.97 (m, 1H), 8.48 (d, 1H), 8.83 (br. t, 1H). LC-MS (method 1): R.sub.t = 1.51 min; m/z = 349/347 (M + H).sup.+. 4A [00052] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 4.60 (d, 2H), 7.89-7.96 (m, 1H), 8.31 (s, 1H), 8.47 (d, 1H), 8.89 (br. t, 1H). LC-MS (method 1): R.sub.t = 1.56 min; m/z = 333/335 (M + H).sup.+. 5A [00053] LC-MS (method 1): R.sub.t = 1.71 min; m/z = 401/403 (M + H).sup.+. 6A [00054] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.20 (t, 3H), 3.23 (q, 2H), 4.58 (d, 2H), 7.89-7.96 (m, 1H), 8.47 (d, 1H), 8.73 (br. t, 1H). LC-MS (method 1): R.sub.t = 2.06 min; m/z = 361/363 (M + H).sup.+. 7A [00055] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 4.57 (d, 2H), 7.89-7.95 (m, 1H), 8.46 (d, 1H), 8.77 (s, 1H), 8.81 (br. t, 1H). LC-MS (method 1): R.sub.t = 1.37 min; m/z = 317/319 (M + H).sup.+. 8A [00056] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 2.56 (s, 3H), 4.54 (d, 2H), 7.88-7.94 (m, 1H), 8.46 (d, 1H), 8.85 (br. t, 1H). LC-MS (method 1): R.sub.t = 1.64 min; m/z = 331/333 (M + H).sup.+.

Example 9A

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

[0654] ##STR00057##

[0655] 2 g (5.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were dissolved in 30 ml of THF, and 4.88 g (14.96 mmol) of caesium carbonate were added. 1.29 g (8.98 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane were then metered into the reaction solution which was subsequently stirred at reflux temperature overnight. After cooling, the reaction mixture was applied directly to silica gel and purified by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 50 g column; mobile phase: cyclohexane/ethyl acetate 85:15.fwdarw.gradient over 15 CV (CV=column volumes).fwdarw.ethyl acetate). The product fractions obtained were then combined, concentrated on a rotary evaporator and dried under reduced pressure. This gave 1.40 g (3.53 mmol, 99% of theory) of the target compound as a light-beige solid.

[0656] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.71 (t, 4H), 3.56 (t, 4H), 3.92 (s, 4H), 4.53 (br. d, 2H), 7.84 (s, 1H), 7.89-7.94 (m, 1H), 8.47 (d, 1H), 8.74 (t, 1H).

[0657] LC-MS (method 2): R.sub.t=0.73 min; m/z=397 (M+H).sup.+.

Example 10A

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

[0658] ##STR00058##

[0659] 2.3 g (5.80 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3-thiazole-5-carboxamide were dissolved in 15 ml of acetone, and 15 ml of semiconcentrated aqueous hydrochloric acid were added. The reaction solution was then stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and subsequently taken up in water. The aqueous solution was then adjusted to pH 7 using a saturated sodium bicarbonate solution. The resulting precipitate was filtered off with suction, repeatedly washed with water and dried under reduced pressure. This gave 1.96 g (5.49 mmol, 95% of theory) of the target compound as a white solid.

[0660] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 2.48-2.56 (t, 4H, partially obscured by DMSO), 3.82 (t, 4H), 4.54 (br. d, 2H), 7.89 (s, 1H), 7.90-7.94 (m, 1H), 8.48 (d, 1H), 8.78 (t, 1H).

[0661] LC-MS (method 1): R.sub.t=1.09 min; m/z=353 (M+H).sup.+.

Example 11A

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

[0662] ##STR00059##

[0663] 2 g (21.03 mmol) of pyridin-3-ol were dissolved in 40 ml of THF, and 7.17 g (27.34 mmol) of triphenylphosphine were added. The clear solution was then cooled to 0° C. A further 30 ml of THF were added to the resulting suspension. 5.53 g (27.34 mmol) of diisopropyl azodicarboxylate were added to this suspension and the mixture was stirred at this temperature for 5 min. 3.34 g (27.34 mmol) of (difluorocyclobutyl)methanol, dissolved in 10 ml of THF, were then added dropwise and after the end of the addition the ice bath was removed. After about one hour of stirring at room temperature a clear yellow solution had formed, which was stirred at this temperature overnight. Water was then added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, separated off 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 obtained was stirred with about 150 ml of cyclohexane. The precipitated triphenylphosphine oxide was then filtered off with suction and washed repeatedly with cyclohexane. The filtrates obtained were combined and concentrated to dryness under reduced pressure. This gave 3.69 g (18.52 mmol, 88% of theory) of the target compound as a yellow oil. The target compound obtained was reacted further without further purification.

[0664] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 2.42-2.55 (m, 2H, partially obscured by DMSO), 2.55-2.64 (m, 1H), 2.68-2.78 (m, 2H). 4.11 (d, 2H), 7.30-7.36 (m, 1H), 7.37-7.43 (m, 1H), 8.18 (dd, 1H), 8.30 (d, 1H).

[0665] LC-MS (method 1): R.sub.t=1.12 min; m/z=200 (M+H).sup.+.

Example 12A

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

[0666] ##STR00060##

[0667] 2.5 g (12.55 mmol) of 3-[(3,3-difluorocyclobutyl)methoxy]pyridine were dissolved in 20 ml of glacial acetic acid and hydrogenated using an H-Cube (ThalesNano H-Cube Pro™-1.7).

[0668] Reaction Conditions:

[0669] catalyst: Pd/C 10%; solvent: glacial acetic acid; cartridge pressure: 80 bar of hydrogen; flow rate: 1 ml/min; temperature: 80° C.

[0670] After the reaction had gone to completion, the reaction mixture was concentrated to dryness. The residue obtained was dried under reduced pressure at room temperature overnight. This gave 4.2 g of the target compound as a yellow oil. The target compound was reacted further without further purification.

[0671] GC-MS (method 3): R.sub.t=3.87 min; m/z=205 (M−C.sub.2H.sub.4O.sub.2).sup.+.

Example 13A

Benzyl 3-(difluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (Racemate)

[0672] ##STR00061##

[0673] 1 g (4.29 mmol) of benzyl 4-oxopiperidine-1-carboxylate, 883 mg (5.14 mmol) of 3-(difluoromethyl)piperidine hydrochloride (1:1) and 0.9 ml (5.14 mmol) of N,N-diisopropylethylamine in 15 ml of dichloromethane (a small amount of 4 Å molecular sieve was additionally added to the reaction solution) was stirred at room temperature for 1 h. 1.363 g (6.43 mmol) of sodium acetoxyborohydride were then added and stirring of the reaction mixture was then continued at room temperature overnight. The molecular sieve was then filtered off and washed with dichloromethane and the resulting filtrate was washed twice with sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. This gave 1.39 g (3.54 mmol, purity 89%, 83% of theory) of the target compound as a clear colourless oil. The target compound was reacted further without further purification.

[0674] LC-MS (method 1): R.sub.t=1.04 min; m/z=353 (M+H).sup.+.

[0675] Analogously to Example 13A, the following compounds of Examples 14A to 17A were prepared from the starting materials stated in each case:

TABLE-US-00002 Example Name/Structure/Starting materials Analytical data 14A Benzyl 3-(trifluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (racemate)   [00062] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.15-1.24 (m, 1H), 1.24- 1.38 (m, 2H), 1.38-1.48 (m, 1H), 1.69 (br. d, 3H), 1.84 (br. d, 1H), 2.06-2.17 (m, 2H), 2.31-2.42 (m, 1H), 2.48-2.58 (m, 1H, partially obscured by DMSO), 2.68-2.88 (m, 3H), 2.92 (br. d, 1H), 4.16 (br. d, 2H), 5.06 (s, 2H), 7.29-7.41 (m, 5H). LC-MS (method 4): R.sub.t = 0.62 min; m/z = 371 (M + H).sup.+. from benzyl 4-oxopiperidine-1-carboxylate and 3- (trifluoromethyl)piperidine 15A benzyl 3-(fluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (racemate)   [00063] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.96-1.04 (m, 1H), 1.25- 1.35 (m, 2H), 1.37-1.46 (m, 1H), 1.60 (br. d, 2H), 1.68 (br. d, 2H), 1.77-1.89 (m, 1H), 2.00 (t, 1H), 2.13 (t, 1H), 2.39-2.47 (m, 1H), 2.64-2.88 (m, 4H), 4.02 (br. d, 2H), 4.22-4.29 (m, 1H), 4.30-4.37 (m, 1H), 5.05 (s, 2H), 7.29-7.40 (m, 5H). LC-MS (method 1): R.sub.t = 1.02 min; m/z = 355(M + H).sup.+. from benzyl 4-oxopiperidine-1-carboxylate and 3- (fluoromethyl)piperidine hydrochloride (1:1) 16A benzyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidine]-1′- carboxylate (racemate)   [00064] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.00-1.12 (m, 1H), 1.25- 1.40 (m, 3H), 1.57-1.73 (m, 3H), 1.85-1.92 (m, 1H), 1.96 (t, 1H), 2.08 (t, 1H), 2.22-2.36 (m, 3H), 2.46 (t, 1H), 2.48-2.66 (m, 3H, partially obscured by DMSO), 2.66-2.87 (m, 2H), 2.92 (br. d, 1H), 3.21-3.29 (m, 1H), 3.40-3.50 (m, 2H), 4.03 (br. d, 2H), 5.06 (s, 2H), 7.28-7.40 (m, 5H). LC-MS (method 4): R.sub.t = 0.69 min; m/z = 423 (M + H).sup.+. from benzyl 4-oxopiperidine-1-carboxylate and 3-[(3,3- difluorocyclobutyl)methoxy]piperidine acetate (1:1) (racemate) 17A benzyl 3-(cyclopropylmethyl)[1,4′-bipiperidine]-1′-carboxylate (racemate)   [00065] LC-MS (method 4): R.sub.t = 0.68 min; m/z = 357 (M + H).sup.+. from benzyl 4-oxopiperidine-1-carboxylate and 3- (cyclopropylmethyl)piperidine (racemate)

Example 18A

rac-Benzyl 3-(hydroxymethyl)[1,4′-bipiperidine]-1′-carboxylate

[0676] ##STR00066##

[0677] Acetic acid (1.8 ml, 32 mmol) was added to a solution of rac-benzyl 4-oxopiperidine-1-carboxylate (5.00 g, 21.4 mmol) and piperidin-3-ylmethanol (4.94 g, 42.9 mmol) in 50 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (5.45 g, 25.7 mmol) was then added to the reaction and stirring was continued at room temperature. After 2 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off with suction, the filtrate was concentrated and the residue was applied to Isolute®. The mixture was then purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 100 g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 4.37 g (purity 100%, 61% of theory) of the target compound.

[0678] LC-MS (method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=333 [M+H].sup.+.

Example 19A

rac-Benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate

[0679] ##STR00067##

[0680] Under argon, rac-benzyl 3-(hydroxymethyl)[1,4′-bipiperidine]-1′-carboxylate (5.42 g, 16.3 mmol) was initially charged in 65 ml of dichloromethane, triethylamine (3.0 ml, 21 mmol) was added and the mixture was cooled to 0° C. At this temperature, methanesulfonyl chloride (1.5 ml, 20 mmol) was added dropwise. The mixture was then stirred at 0° C. for 15 min, after which the ice bath was removed and stirring was continued at room temperature. After 15 min, the reaction mixture was diluted with dichloromethane and washed successively with 1 N hydrochloric acid, sat. NaHCO.sub.3 solution and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried under high vacuum and reacted further without further purification. This gave 6.16 g (purity 100%, 92% of theory) of the target compound.

[0681] LC-MS (method 12): R.sub.t=1.39 min; MS (ESIpos): m/z=411 [M+H].sup.+.

Example 20A

rac-Benzyl 3-(methoxymethyl)[1,4′-bipiperidine]-1′-carboxylate

[0682] ##STR00068##

[0683] Sodium methoxide solution (840 μl, 25% in methanol, 3.7 mmol) was added to a solution of rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (500 mg, 1.22 mmol) in 10 ml of DMF, and the mixture was stirred at 50° C. overnight. The solvent was removed on a rotary evaporator and the residue was taken up in ethyl acetate and washed successively with water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 25 g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 75 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 146 mg (purity 100%, 35% of theory) of the target compound.

[0684] LC-MS (method 4): R.sub.t=0.59 min; MS (ESIpos): m/z=347 [M+H].sup.+.

Example 21A

diamix-Benzyl (3R)-3′-fluoro-3-methyl[1,4′-bipiperidine]-1′-carboxylate

[0685] ##STR00069##

[0686] Acetic acid (1.71 ml, 29.85 mmol) was added to a solution of rac-benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (5 g, 19.9 mmol) and (3R)-3-methylpiperidine (5.4 g, 39.8 mmol) in 200 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (5.06 g, 23.88 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator. The residue was applied to Isolute® and purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 100 g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 5.13 g (purity 55%, 42% of theory) of the target compound.

[0687] LC-MS (method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=335 [M+H].sup.+.

Example 22A

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

[0688] ##STR00070##

[0689] (3R)-3-Methylpiperidine hydrochloride (6.24 g, 46.0 mmol) was initially charged in 250 ml of 1,2-dichloroethane. N,N-Diisopropylethylamine (8.0 ml, 46 mmol) was added and the mixture was stirred at room temperature for 5 min. rac-tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate (5.00 g, 23.0 mmol) and acetic acid (2.0 ml, 35 mmol) were added and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (5.85 g, 27.6 mmol) was added and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 5.30 g (purity 100%, 77% of theory) of the target compound.

[0690] LC-MS (method 4): R.sub.t=0.52 min; MS (ESIpos): m/z=301 [M+H].sup.+.

Example 23A

rac-Benzyl 3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate

[0691] ##STR00071##

[0692] Under argon, 2,2,2-trifluoroethanol (66 μl, 910 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled in an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 h, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried under high vacuum. This gave 218 mg (purity 81%, 70% of theory) of the target compound.

[0693] LC-MS (method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=415 [M+H].sup.+.

Example 24A

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

[0694] ##STR00072##

[0695] Under argon, [1-(fluoromethyl)cyclopropyl]methanol (95.1 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. overnight. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried under high vacuum. This gave 204 mg (purity 40%, 32% of theory) of the target compound.

[0696] LC-MS (method 1): R.sub.t=1.36 min; MS (ESIpos): m/z=419 [M+H].sup.+.

Example 25A

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

[0697] ##STR00073##

[0698] Under argon, [1-(difluoromethyl)cyclopropyl]methanol (112 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled in an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 h, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried under high vacuum. This gave 197 mg (purity 51%, 37% of theory) of the target compound.

[0699] LC-MS (method 1): R.sub.t=1.41 min; MS (ESIpos): m/z=437 [M+H].sup.+.

Example 26A

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

[0700] ##STR00074##

[0701] Under argon, [1-(trifluoromethyl)cyclopropyl]methanol (128 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 h, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried under high vacuum. This gave 212 mg (purity 58%, 44% of theory) of the target compound.

[0702] LC-MS (method 1): R.sub.t=1.48 min; MS (ESIpos): m/z=455 [M+H].sup.+.

Example 27A

Benzyl 3,3-dimethyl[1,4′-bipiperidine]-1′-carboxylate

[0703] ##STR00075##

[0704] Acetic acid (74 μl, 1.3 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (200 mg, purity 58%, 857 μmol) and 3,3-dimethylpiperidine (240 μl, 1.7 mmol) in 7 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (218 mg, 1.03 mmol) was added to the reaction and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and sat. NaCl solution and dried over Na.sub.2SO.sub.4. The drying agent was filtered off, the filtrate was concentrated and the residue was dried under high vacuum. This gave 280 mg (purity 81%, 80% of theory) of the target compound.

[0705] LC-MS (method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=331 [M+H].sup.+.

Example 28A

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

[0706] ##STR00076##

[0707] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and 5-azaspiro[2.5]octane (286 mg, 2.57 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off, the filtrate was concentrated and the residue was dried under high vacuum. This gave 368 mg (purity 40%, 35% of theory) of the target compound.

[0708] LC-MS (method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=329 [M+H].sup.+.

Example 29A

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

[0709] ##STR00077##

[0710] Acetic acid (110 μl, 1.9 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (300 mg, 1.29 mmol) and rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (354 mg, 1.93 mmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (327 mg, 1.54 mmol) was added to the reaction and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off, the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 405 mg (purity 61%, 53% of theory) of the target compound.

[0711] LC-MS (method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=365 [M+H].sup.+.

Example 30A

rac-Benzyl 3-hydroxy[1,4′-bipiperidine]-1′-carboxylate

[0712] ##STR00078##

[0713] Triethylamine (1.8 ml, 13 mmol) and acetic acid (740 μl, 13 mmol) were added to a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g, 8.57 mmol) and piperidin-3-ol (1.73 g, 17.1 mmol) in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added to the reaction and the mixture was stirred at room temperature for 48 h. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 50 g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 1.87 g (purity 100%, 68% of theory) of the target compound.

[0714] LC-MS (method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=319 [M+H].sup.+.

Example 31A

rac-Benzyl 3-(cyclopropylmethoxy)[1,4′-bipiperidine]-1′-carboxylate

[0715] ##STR00079##

[0716] Under argon, rac-benzyl 3-hydroxy[1,4′-bipiperidine]-1′-carboxylate (250 mg, 785 μmol) was initially charged in 5 ml of THF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (47.1 mg, purity 60%, 1.18 mmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, (bromomethyl)cyclopropane (110 μl, 1.2 mmol) was added and the reaction mixture was stirred at 60° C. overnight. (Bromomethyl)cyclopropane (110 μl, 1.2 mmol) and sodium hydride (47.1 mg, purity 60%, 1.18 mmol) were added and the mixture was stirred at 60° C. for a further 24 h. Subsequently, the product was isolated by preparative HPLC (column: Chromatorex C18 10 μm, 250×30 mm, mobile phase A=water, B=acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml/min; 0.1% formic acid). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 68.0 mg (purity 68%, 16% of theory) of the target compound.

[0717] LC-MS (method 1): R.sub.t=1.25 min; MS (ESIpos): m/z=373 [M+H].sup.+.

Example 32A

rac-Benzyl 3-[(cyclobutyloxy)methyl][1,4′-bipiperidine]-1′-carboxylate

[0718] ##STR00080##

[0719] Under argon, cyclobutanol (72 μl, 910 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. overnight. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 290 mg (purity 46%, 57% of theory) of the target compound.

[0720] LC-MS (method 4): R.sub.t=0.73 min; MS (ESIpos): m/z=387 [M+H].sup.+.

Example 33A

rac-Benzyl 3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate

[0721] ##STR00081##

[0722] Under argon, sodium hydride (268 mg, purity 60%, 6.70 mmol) was initially charged in 25 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, cyclopropylmethanol (540 μl, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (2.50 g, 6.09 mmol) was added and the reaction mixture was stirred at 55° C. overnight. Cyclopropylmethanol (540 μl, 6.7 mmol) and sodium hydride (268 mg, purity 60%, 6.70 mmol) were added and the mixture was stirred at 55° C. for a further 24 h. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature, wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 241 mg (purity 78%, 8% of theory) of the target compound.

[0723] LC-MS (method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=387 [M+H].sup.+.

Example 34A

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

[0724] ##STR00082##

[0725] Acetic acid (72 μl, 1.3 mmol) was added to a solution of tert-butyl 4-oxoazepane-1-carboxylate (179 mg, 840 μmol) and (3R)-3-methylpiperidine (167 mg, 1.68 mmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature. After 5 h, sodium triacetoxyborohydride (214 mg, 1.01 mmol) was added to the reaction and the mixture was stirred at room temperature overnight. Subsequently, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off with suction, the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 215 mg of a mixture which was reacted further without further purification and analysis.

Example 35A

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

[0726] ##STR00083##

[0727] Under argon, rac-(2,2-difluorocyclopropyl)methanol (98.7 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 343 mg (purity 56%, 74% of theory) of the target compound.

[0728] LC-MS (method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=423 [M+H].sup.+.

Example 36A

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

[0729] ##STR00084##

[0730] Under argon, (3,3-difluorocyclobutyl)methanol (112 mg, 913 μmol) was initially charged in 5 ml of DMF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (36.5 mg, purity 60%, 913 μmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, rac-benzyl 3-[(methyl sulfonyl)oxy]methyl[1,4′-bipiperidine]-1′-carboxylate (250 mg, 609 μmol) was added and the reaction mixture was stirred at 60° C. After 6 h, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 287 mg (purity 33%, 36% of theory) of the target compound.

[0731] LC-MS (method 1): R.sub.t=1.44 min; MS (ESIpos): m/z=437 [M+H].sup.+.

Example 37A

3-(Difluoromethyl)-1,4′-bipiperidine dihydrochloride (Racemate)

[0732] ##STR00085##

[0733] 1.35 g (3.83 mmol) of benzyl 3-(difluoromethyl)[1,4′-bipiperidine]-1′-carboxylate (racemate) were dissolved in 100 ml of ethanol and hydrogenated using an H-Cube (ThalesNano H-Cube Pro™-1.7).

[0734] Reaction Conditions:

[0735] catalyst: Pd/C 10%; solvent: ethanol; cartridge pressure: 1 bar of hydrogen; flow rate: 1 ml/min; temperature: 50° C.

[0736] After complete conversion, 4 N HCl (in dioxane) was added and the reaction mixture was concentrated to dryness. The residue obtained was dried under reduced pressure at room temperature overnight. This gave 1,107 g (3.80 mmol, 99% of theory) of the target compound as a white solid. The target compound was reacted further without further purification.

[0737] GC-MS (method 3): R.sub.t=4.87 min; m/z=218 (M−2HCl).sup.+.

Example 38A

3-[(3,3-Difluorocyclobutyl)methoxy]-1,4′-bipiperidine (Racemate)

[0738] ##STR00086##

[0739] 2.7 g (6.39 mmol) of benzyl 3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidine]-1′-carboxylate (racemate) were dissolved in 90 ml of ethanol and hydrogenated using an H-Cube (ThalesNano H-Cube Pro™-1.7).

[0740] Reaction Conditions:

[0741] catalyst: Pd/C 10%; solvent: ethanol; cartridge pressure: 50 bar of hydrogen; flow rate: 1 ml/min; temperature: 50° C.

[0742] After the reaction had gone to completion, the reaction mixture was concentrated to dryness. The residue obtained was dried under reduced pressure at room temperature overnight. This gave 1.27 g (4.40 mmol, 69% of theory) of the target compound as a yellow oil. The target compound was reacted further without further purification.

[0743] GC-MS (method 3): R.sub.t=6.42 min; m/z=288 (M)±.

[0744] Analogously to Examples 37A and 38A, the following compounds of Examples 39A to 41A were prepared from the starting materials stated in each case:

TABLE-US-00003 Example Name/Structure/Starting materials Analytical data 39A 3-(trifluoromethyl)-1,4′-bipiperidine dihydrochloride (racemate)   [00087] GC-MS (method 3): R.sub.t = 4.33 min; m/z = 236 (M − 2HCl).sup.+. from benzyl 3-(trifluoromethyl)[1,4′- bipiperidine]-1′-carboxylate (racemate) 40A 3-(trifluoromethyl)-1,4′-bipiperidine dihydrochloride (racemate)   [00088] GC-MS (method 3): R.sub.t = 5.07 min; m/z = 200 (M − 2HCl).sup.+. from benzyl 3-(fluoromethyl)[1,4′- bipiperidine-]-1′-carboxylate (racemate) 41A 3-(cyclopropylmethyl)-1,4′-bipiperidine (racemate)   [00089] GC-MS (method 3): R.sub.t = 5.81 min; m/z = 222 (M).sup.+. from benzyl 3-(cyclopropylmethyl)[1,4′- bipiperidine-]-1′-carboxylate (racemate)

Example 42A

rac-3-(Methoxymethyl)-1,4′-bipiperidine dihydrochloride

[0745] ##STR00090##

[0746] rac-Benzyl 3-(methoxymethyl)[1,4′-bipiperidine]-1′-carboxylate (145 mg, 419 μmol) was initially charged in 5 ml of THF, and palladium (50.0 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (310 μl, 2.0 M, 630 μmol) was added to the filtrate, and the precipitated solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 92.0 mg (purity 76%, 59% of theory) of the target compound.

[0747] GC-MS (method 3): R.sub.t=5.45 min; MS (ESIpos): m/z=212 [M−HCl].sup.+.

Example 43A

diamix-(3R)-3′-Fluoro-3-methyl-1,4′-bipiperidine dihydrochloride

[0748] ##STR00091##

[0749] Synthesis Method 1:

[0750] diamix-Benzyl (3R)-3′-fluoro-3-methyl[1,4′-bipiperidine]-1′-carboxylate (5.13 g, purity 55%, 8.40 mmol) was initially charged in 250 ml of THF, and palladium (382 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (6.3 ml, 2.0 M, 13 mmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, and the solid was filtered off with suction, washed with dichloromethane and dried under high vacuum. This gave 2.31 g (100% of theory) of the target compound.

[0751] LC-MS (method 4): MS (ESIpos): m/z=200 [M−2HCl].sup.+.

[0752] Synthesis Method 2:

[0753] 4 M Hydrochloric acid in 1,4-dioxane (22 ml, 4.0 M, 88 mmol) was added to a solution of diamix-tert-butyl (3R)-3′-fluoro-3-methyl[1,4′-bipiperidine]-1′-carboxylate (5.30 g, 17.6 mmol) in 250 ml of dichloromethane, and the mixture was stirred at room temperature for 48 h. The precipitated solid was filtered off with suction, washed with dichloromethane and dried in a vacuum drying cabinet at 40° C. overnight. This gave 3.47 g (purity 100%, 72% of theory) of the target compound.

[0754] GC-MS (method 3): MS (ESIpos): m/z=200 [M−2HCl].sup.+.

Example 44A

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

[0755] ##STR00092##

[0756] rac-Benzyl 3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate (218 mg, purity 81%, 526 μmol) was initially charged in 12 ml of THF, and palladium (63 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 3.5 h the catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (390 μl, 2.0 M, 790 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 164 mg (purity 74%, 66% of theory) of the target compound.

[0757] GC-MS (method 3): R.sub.t=5.26 min; MS (full ms): m/z=280 [M−2HCl].sup.+.

Example 45A

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

[0758] ##STR00093##

[0759] rac-Benzyl 3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (204 mg, purity 40%, 487 μmol) was initially charged in 10 ml of THF, and palladium (58 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 2 h the catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (370 μl, 2.0 M, 740 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 133 mg of a mixture which was reacted without further purification and analysis.

Example 46A

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

[0760] ##STR00094##

[0761] rac-Benzyl 3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (197 mg, purity 51%, 451 μmol) was initially charged in 10 ml of THF, and palladium (54 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 h the catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (374 μl, 2.0 M, 680 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 112 mg of a mixture which was reacted without further purification and analysis.

Example 47A

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

[0762] ##STR00095##

[0763] rac-Benzyl 3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (212 mg, purity 58%, 466 μmol) was initially charged in 10 ml of THF, and palladium (56 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere. After 1.5 h the catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (350 μl, 2.0 M, 700 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 129 mg of a mixture which was reacted further without further purification and analysis.

Example 48A

3,3-Dimethyl-1,4′-bipiperidine dihydrochloride

[0764] ##STR00096##

[0765] Benzyl 3,3-dimethyl[1,4′-bipiperidine]-1′-carboxylate (260 mg, purity 81%, 637 μmol) was initially charged in 18 ml of THF, and palladium (27 mg; 10% on activated carbon, 255 μmol) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (478 μL 2.0 M, 956 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 180 mg of a mixture which was reacted further without further purification and analysis.

Example 49A

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

[0766] ##STR00097##

[0767] Benzyl 4-(5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (368 mg, purity 40%, 1.12 mmol) was initially charged in 32 ml of THF, and palladium (51 mg, 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (840 μL 2.0 M, 1.7 mmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane. The precipitated solid was filtered off with suction, washed with dichloromethane and dried under high vacuum. This gave 185 mg of a mixture which was reacted further without further purification and analysis.

Example 50A

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

[0768] ##STR00098##

[0769] rac-Benzyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidine-1-carboxylate (405 mg, purity 61%, 1.11 mmol) was initially charged in 32 ml of THF, and palladium (51 mg, 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (840 μl, 2.0 M, 1.7 mmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated on a rotary evaporator and dried under high vacuum. This gave 280 mg of a mixture which was reacted further without further purification and analysis.

Example 51A

rac-3-(Cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride

[0770] ##STR00099##

[0771] rac-Benzyl 3-(cyclopropylmethoxy)[1,4′-bipiperidine]-1′-carboxylate (68.0 mg, purity 68%, 124 μmol) was initially charged in 5 ml of THF, and palladium (22 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (93 μl, 2.0 M, 186 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 51 mg of a mixture which was reacted further without further purification and analysis.

Example 52A

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

[0772] ##STR00100##

[0773] rac-Benzyl 3-[(cyclobutyloxy)methyl][1,4′-bipiperidine]-1′-carboxylate (290 mg, purity 46%, 386 μmol) was initially charged in 15 ml of THF, and palladium (41 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (259 μl, 2.0 M, 518 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 225 mg of a mixture which was reacted further without further purification and analysis.

Example 53A

[0774] rac-3-[(Cyclopropylmethoxy)methyl]-1,4′-bipiperidine dihydrochloride

##STR00101##

[0775] rac-Benzyl 3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidine]-1′-carboxylate (241 mg, purity 78%, 486 μmol) was initially charged in 20 ml of THF, and palladium (58 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (360 μl, 2.0 M, 730 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 155 mg of a mixture which was reacted further without further purification and analysis.

Example 54A

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

[0776] ##STR00102##

[0777] 4 M Hydrochloric acid in 1,4-dioxane (2.2 ml, 4.0 M, 8.6 mmol) was added to a solution of tert-butyl 4-[(3R)-3-methylpiperidin-1-yl]azepane-1-carboxylate (215 mg) in 5.4 ml of dichloromethane, and the mixture was stirred at room temperature. After 2 h, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 237 mg of a mixture which was reacted further without further purification and analysis.

Example 55A

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

[0778] ##STR00103##

[0779] diamix-Benzyl 3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4′-bipiperidine]-1′-carboxylate (343 mg, purity 56%, 446 μmol) was initially charged in 25 ml of THF, and palladium (53 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (330 μl, 2.0 M, 670 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 218 mg of a mixture which was reacted further without further purification and analysis.

Example 56A

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

[0780] ##STR00104##

[0781] rac-Benzyl 3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4′-bipiperidine]-1′-carboxylate (287 mg, purity 33%, 217 μmol) was initially charged in 15 ml of THF, and palladium (26 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (163 μl, 2.0 M, 325 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. This gave 286 mg of a mixture which was reacted further without further purification and analysis.

Example 57A

Methyl 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylate

[0782] ##STR00105##

[0783] 5 g (22.52 mmol) of methyl 2-bromo-1,3-thiazole-5-carboxylate, 4.926 g (22.52 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride and 9.4 ml (67.55 mmol) of triethylamine in 30 ml of 2-propanol were heated to boiling point (oil bath temperature ˜100° C.) and stirred at this temperature overnight. After cooling of the reaction mixture, the solution was concentrated to dryness using a rotary evaporator. This gave 14.29 g (crude product, purity ˜34%) of the target product and the triethylamine salts. The mixture was reacted further without further purification.

[0784] LC-MS (method 4): R.sub.t=0.51 min; m/z=324 (M+H).sup.+.

Example 58A

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

[0785] ##STR00106##

[0786] 14.29 g of the mixture of methyl 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylate and triethylamine salts were dissolved in water, and 221 ml of a 1 N NaOH solution were added. A brown oil separated off, which was dissolved by addition of 50 ml of THF. The reaction mixture was then heated to 60° C. and stirred at this temperature for one hour. After cooling of the reaction mixture to room temperature, the solution was concentrated to dryness on a rotary evaporator, taken up in water and acidified with concentrated hydrochloric acid. The solution was then once more concentrated to dryness. This gave 20.54 g of a beige solid which was purified by column chromatography.

[0787] Conditions: The separation was carried out using 1 g portions. RP column Chromatorex C18, 10 μm; 125×30 mm, acetonitrile/water (+0.05% formic acid) 5/95.fwdarw.gradient over 20 min.fwdarw.acetonitrile/water (+0.05% formic acid) 95/5, flow rate 75 ml/min.

[0788] Finally, product-containing fractions were combined and concentrated to dryness under reduced pressure and dried. This gave 4.75 g (12.42 mmol, 83% of theory) of the target compound as a light-beige solid.

[0789] LC-MS (method 1): R.sub.t=0.54 min; m/z=310 (M+H−2HCl).sup.+.

Example 59A

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

[0790] ##STR00107##

[0791] Ethyl 3-bromo-1,2,4-oxadiazole-5-carboxylate (100 mg, 452 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (173 mg, 679 μmol) were stirred in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4.0 mmol) at 120° C. After 30 min, the reaction mixture was acidified with 2 N hydrochloric acid and purified by preparative HPLC (column: Chromatorex C18 10 μm, 250×30 mm, mobile phase A=water, B=acetonitrile; gradient: 0.0 min 5% B; 3 min 5% B; 20 min 50% B; 23 min 100% B; 26 min 5% B; flow rate: 50 ml/min; 0.1% formic acid). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 25 mg (purity 60%, 11% of theory) of the target compound.

[0792] LC-MS (method 1): R.sub.t=0.47 min; MS (ESIpos): m/z=295 [M+H].sup.+.

Example 60A

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

[0793] ##STR00108##

[0794] Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in 25 ml of THF and the mixture was cooled in an ice bath to 0° C. At this temperature, diisopropyl azodicarboxylate (1.3 ml, 9.3 mmol) was added and the mixture was stirred at 0° C. for 5 min. Subsequently, a solution of rac-2,2-difluorocyclopropanemethanol (1.00 g, 9.25 mmol) in 5 ml of THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The oily residue was stirred with 75 ml of cyclohexane for 30 min. The precipitated solid was filtered off and the filtrate was concentrated to afford a residue. The residue was dissolved in 50 ml of MTBE, and 5 ml of hydrochloric acid (4N in 1,4-dioxane) were added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 698 mg (purity 93%, 41% of theory) of the target compound.

[0795] LC-MS (method 4): R.sub.t=0.40 min; MS (ESIpos): m/z=186 [M−HCl].sup.+.

Example 61A

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

[0796] ##STR00109##

[0797] Under argon, rac-3-[(2,2-difluorocyclopropyl)methoxy]pyridine hydrochloride (698 mg, purity 93%, 2.93 mmol) was dissolved in 35 ml of ethanol. Sulfuric acid (168 μL 3.15 mmol) and platinum(IV) oxide (179 mg, 0.79 mmol) were added and the mixture was hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through Celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gave 761 mg (74% of theory) of the target compound.

[0798] LC-MS (method 5): MS (ESIpos): m/z=192 [M−HCl−H.sub.2SO.sub.4].sup.+.

Example 62A

3-(Cyclobutyloxy)pyridine hydrochloride

[0799] ##STR00110##

[0800] Triphenylphosphine (7.17 g, 27.3 mmol) was added to a solution of pyridin-3-ol (2.00 g, 21.0 mmol) in 70 ml of THF and the mixture was cooled in an ice bath to 0° C. At this temperature, diisopropyl azodicarboxylate (3.9 ml, 27 mmol) was added and the mixture was stirred at 0° C. for 5 min. Subsequently, a solution of cyclobutanol (2.1 ml, 27 mmol) in 10 ml of THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature over the weekend. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The oily residue was stirred with 150 ml of cyclohexane for 30 min. The solid was filtered off and the filtrate was concentrated to afford a residue. The residue was dissolved in 100 ml of MTBE, and 5 ml of hydrochloric acid (4N in 1,4-dioxane) were added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 2.02 g (purity 51%, 26% of theory) of the target compound.

[0801] LC-MS (method 5): R.sub.t=1.34 min; MS (ESIpos): m/z=150 [M−HCl].sup.+.

Example 63A

rac-3-(Cyclobutyloxy)piperidine sulfate hydrochloride

[0802] ##STR00111##

[0803] Under argon, 3-(cyclobutyloxy)pyridine hydrochloride (2.0 g, purity 51%, 5.51 mmol) was dissolved in 95 ml of ethanol. Sulfuric acid (550 μl, 10 mmol) and platinum(IV) oxide (612 mg, 2.6 mmol) were added and the mixture was hydrogenated under a hydrogen atmosphere overnight. The catalyst was filtered off through Celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gave 2.52 g (157% of theory) of the target compound.

[0804] LC/MS (method 4): MS (ESIpos): m/z=156 [M−HCl−H.sub.2SO.sub.4].sup.+.

Example 64A

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

[0805] ##STR00112##

[0806] Triphenylphosphine (2.43 g, 9.25 mmol) was added to a solution of pyridin-3-ol (677 mg, 7.12 mmol) in 25 ml of THF and the mixture was cooled in an ice bath to 0° C. At this temperature, diisopropyl azodicarboxylate (1.3 ml, 9.3 mmol) was added and the mixture was stirred at 0° C. for 5 min. Subsequently, a solution of 3,3-difluorocyclobutanol (1.00 g, 9.25 mmol) in 5 ml of THF was added dropwise to the mixture. The ice bath was then removed and the mixture was stirred at room temperature overnight. The reaction mixture was stirred at 80° C. for 5 h and then extracted between water and ethyl acetate. The organic phase was washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The oily residue was stirred with 150 ml of cyclohexane for 30 min. The precipitated solid was filtered off and the filtrate was concentrated to afford a residue. The residue was dissolved in 100 ml of MTBE, and 5 ml of hydrochloric acid (4N in 1,4-dioxane) were added. The precipitated solid was filtered off with suction, washed with MTBE and dried under high vacuum. This gave 289 mg (purity 94%, 17% of theory) of the target compound.

[0807] LC-MS (method 4): R.sub.t=1.01 min; MS (ESIpos): m/z=186 [M−HCl].sup.+.

Example 65A

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

[0808] ##STR00113##

[0809] Under argon, 3-[(3,3-difluorocyclobutyl)oxy]pyridine hydrochloride (298 mg, 1.34 mmol) was dissolved in 12 ml of ethanol. Sulfuric acid (72 μl, 1.3 mmol) and platinum(IV) oxide (76.3 mg, 336 μmol) were added and the mixture was hydrogenated under a hydrogen atmosphere for 3 h. The catalyst was filtered off through Celite and washed with ethanol. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gave 297 mg (68% of theory) of the target compound.

[0810] LC/MS (method 4): MS (ESIpos): m/z=192 [M−HCl−H.sub.2SO.sub.4].sup.+.

Example 66A

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

[0811] ##STR00114##

[0812] N,N-Diisopropylethylamine (680 μl, 3.9 mmol) and propylphosphonic anhydride (1.0 ml, 50% in ethyl acetate, 1.7 mmol) were added to a solution of 2-bromo-1,3-oxazole-4-carboxylic acid (250 mg, 1.30 mmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (283 mg, 1.30 mmol) in 10 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 193 mg (46% of theory, purity 84%) of the target compound, which was reacted further without further purification.

[0813] LC-MS (method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=274 [M+H].sup.+.

Example 67A

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

[0814] ##STR00115##

[0815] N,N-Diisopropylethylamine (630 μl, 3.6 mmol) and propylphosphonic anhydride (930 μl, 50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and 1-(5-chloro-2-fluorophenyl)methanamine (192 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 106 mg (purity 96%, 24% of theory) of the target compound.

[0816] LC-MS (method 1): R.sub.t=1.85 min; MS (ESIpos): m/z=348 [M+H].sup.+.

Example 68A

Benzyl (3R)-3-hydroxy[1,4′-bipiperidine]-1′-carboxylate

[0817] ##STR00116##

[0818] Triethylamine (3.0 ml, 21 mmol) and acetic acid (740 μl, 13 mmol) were added to a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g, 8.57 mmol) and (3R)-piperidin-3-ol hydrochloride (2.36 g, 17.1 mmol) in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 h. Subsequently, sodium triacetoxyborohydride (2.18 g, 10.3 mmol) was added to the mixture and the mixture was stirred at room temperature for 48 h. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 50 g; DCM/MeOH gradient: 2% MeOH-20% MeOH; flow rate 100 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 1.79 g (purity 100%, 66% of theory) of the target compound.

[0819] LC-MS (method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=319 [M+H].sup.+.

Example 69A

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

[0820] ##STR00117##

[0821] Under argon, benzyl (3R)-3-hydroxy[1,4′-bipiperidine]-1′-carboxylate (1.79 g, 5.62 mmol) was initially charged in 40 ml of THF, and the mixture was cooled with an ice bath to 0° C. At this temperature, sodium hydride (337 mg, purity 60%, 8.43 mmol) was added and the mixture was stirred at room temperature for 30 min. Subsequently, (bromomethyl)cyclopropane (820 μl, 8.4 mmol) was added and the reaction mixture was stirred at 60° C. overnight. (Bromomethyl)cyclopropane (820 μl, 8.4 mmol) and sodium hydride (337 mg, purity 60%, 8.43 mmol) were added and the mixture was stirred at 60° C. for a further 24 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The product was purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm. mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 100.0 mg (purity 100%, 4.8% of theory) of the target compound.

[0822] LC-MS (method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=373 [M+H].sup.+.

Example 70A

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

[0823] ##STR00118##

[0824] Benzyl (3R)-3-(cyclopropylmethoxy)[1,4′-bipiperidine]-1′-carboxylate (100 mg, 268 μmol) was initially charged in 7.5 ml of THF, and palladium (32.1 mg; 10% on activated carbon) was added under argon. The mixture was then hydrogenated under a hydrogen atmosphere for 2 h. The catalyst was filtered off through kieselguhr and washed with THF. Hydrochloric acid in diethyl ether (200 μl, 2.0 M, 400 μmol) was added to the filtrate and the mixture was concentrated on a rotary evaporator. The residue was stirred with dichloromethane, concentrated and dried under high vacuum. This gave 66 mg of a mixture which was reacted further without further purification and analysis.

Example 71A

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

[0825] ##STR00119##

[0826] N,N-Diisopropylethylamine (630 μL 3.6 mmol) and propylphosphonic anhydride (930 μL 50% in ethyl acetate, 1.6 mmol) were added to a solution of 2-bromo-1,3-thiazole-5-carboxylic acid (250 mg, 1.20 mmol) and rac-1-(2,5-difluorophenyl)ethanamine (189 mg, 1.20 mmol) in 10 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was applied to Isolute® and the mixture was purified by column chromatography (Biotage® Isolera One; column: Snap Ultra 10 g; Cy/EA gradient: 8% EA-66% EA; flow rate 36 ml/min). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 148 mg (purity 100%, 35% of theory) of the target compound.

[0827] LC-MS (method 1): R.sub.t=1.81 min; MS (ESIpos): m/z=346 [M+H].sup.+.

Example 72A

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

[0828] ##STR00120##

[0829] Ethyl 2-bromo-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate (150 mg, 433 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (166 mg, 649 μmol) were combined and stirred at 120° C. in sodium carbonate solution (870 μl, 2.0 M, 1.7 mmol) for 30 min. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 199 mg (purity 95%, 98% of theory) of the target compound.

[0830] LC-MS (method 1): R.sub.t=1.34 min; MS (ESIpos): m/z=449 [M+H].sup.+.

Example 82A

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

[0831] ##STR00121##

[0832] 4 M hydrochloric acid in 1,4-dioxane (720 μl, 4.0 M, 2.9 mmol) was added to a solution of diamix-tert-butyl 4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate (179 mg, 573 μmol) in 8 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 162 mg of a mixture which was reacted further without further purification and analysis.

Example 73A

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

[0833] ##STR00122##

[0834] Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylate (199 mg, 444 μmol) was dissolved in 10 ml of THF. Aqueous sodium hydroxide solution (4 ml, 2.0 M, 8 mmol) was added to the solution and the mixture was stirred at room temperature for 5 days. The THF was removed on a rotary evaporator and the residue was acidified with hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gave 160 mg (purity 98%, 84% of theory) of the target compound.

[0835] LC-MS (method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=420 [M+H].sup.+.

Example 74A

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

[0836] ##STR00123##

[0837] 2,4-Dibromo-1,3-thiazole-5-carboxylic acid (150 mg, 523 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (133 mg, 523 μmol) were combined and stirred at 120° C. in sodium carbonate solution (1.0 ml, 2.0 M, 2.1 mmol) for 1 h. Subsequently, the reaction mixture was concentrated to dryness and stirred with DCM/MeOH 5:1. The insoluble salts were filtered off with suction. The filtrate was concentrated by evaporation and the residue was dried in high vacuum. This gave 240 mg (purity 100%, 118% of theory) of the target compound.

[0838] LC-MS (method 1): R.sub.t=0.70 min; MS (ESIpos): m/z=388 [M+H].sup.+.

Example 75A

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

[0839] ##STR00124##

[0840] N,N-Diisopropylethylamine (720 μL 4.1 mmol) and propylphosphonic anhydride (800 μL 50% in ethyl acetate, 1.3 mmol) were added to a solution of 2-bromo-4-chloro-1,3-thiazole-5-carboxylic acid (250 mg, 1.03 mmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (291 mg, 1.34 mmol) in 14 ml of acetonitrile, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dried under high vacuum. This gave 250 mg (purity 95%, 62% of theory) of the target compound.

[0841] LC-MS (method 1): R.sub.t=1.79 min; MS (ESIpos): m/z=367 [M+H].sup.+.

Example 76A

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

[0842] ##STR00125##

[0843] N,N-Diisopropylethylamine (560 μL 3.2 mmol) and propylphosphonic anhydride (620 μL 50% in ethyl acetate, 1.0 mmol) were added to a solution of 2-bromo-4-cyclopropyl-1,3-thiazole-5-carboxylic acid (200 mg, 806 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (227 mg, 1.05 mmol) in 11 ml of acetonitrile, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dried under high vacuum. This gave 239 mg (purity 78%, 62% of theory) of the target compound.

[0844] LC-MS (method 1): R.sub.t=1.87 min; MS (ESIpos): m/z=373 [M+H].sup.+.

Example 77A

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

[0845] ##STR00126##

[0846] Methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate (150 mg, 600 μmol) was dissolved in 3 ml of THF. Aqueous sodium hydroxide solution (3 ml, 2.0 M, 6 mmol) was added to the solution and the mixture was stirred at room temperature overnight. The THF was removed on a rotary evaporator and the residue was acidified with 2 N hydrochloric acid. The precipitated solid was filtered off and dried under high vacuum. This gave 100 mg (purity 98%, 69% of theory) of the target compound.

[0847] LC-MS (method 1): R.sub.t=1.30 min; MS (ESIpos): m/z=235 [M+H].sup.+.

Example 78A

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

[0848] ##STR00127##

[0849] N,N-Diisopropylethylamine (300 μl, 1.7 mmol) and propylphosphonic anhydride (330 μl, 50% in ethyl acetate, 550 μmol) were added to a solution of 2-bromo-4-ethyl-1,3-thiazole-5-carboxylic acid (100 mg, 424 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (120 mg, 550 μmol) in 5.7 ml of acetonitrile, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with sat. NaHCO.sub.3 solution, water and sat. NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dried under high vacuum. This gave 150 mg (purity 95%, 93% of theory) of the target compound.

[0850] LC-MS (method 4): R.sub.t=0.86 min; MS (ESIpos): m/z=364 [M+H].sup.+.

Example 79A

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

[0851] ##STR00128##

[0852] N,N-Diisopropylethylamine (570 μl, 3.3 mmol) was added to a solution of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (600 mg, 3.27 mmol) in 15 ml of 1,2-dichloroethane, and the mixture was stirred for 5 min, after which rac-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (355 mg, 1.63 mmol) and acetic acid (140 μl, 2.5 mmol) were added to the mixture. The mixture was then stirred at room temperature. After 5 h, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 264 mg (purity 100%, 46% of theory) of the target compound.

[0853] LC-MS (method 4): R.sub.t=0.56 min; MS (ESIpos): m/z=349 [M+H].sup.+.

Example 80A

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

[0854] ##STR00129##

[0855] 4 M hydrochloric acid in 1,4-dioxane (950 μl, 4.0 M, 3.8 mmol) was added to a solution of diamix-tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidine-1-carboxylate (264 mg, 760 μmol) in 10 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 246 mg of a mixture which was reacted further without further purification and analysis.

Example 81A

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

[0856] ##STR00130##

[0857] N,N-Diisopropylethylamine (410 μl, 2.4 mmol) was added to a solution of 5-azaspiro[2.5]octane hydrochloride (350 mg, 2.37 mmol) in 10 ml of 1,2-dichloroethane, and the mixture was stirred for 5 min, after which rac-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (257 mg, 1.19 mmol) and acetic acid (100 μl, 1.8 mmol) were added to the mixture. The mixture was then stirred at room temperature. After 5 h, sodium triacetoxyborohydride (416 mg, 1.96 mmol) was added to the mixture and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm. mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 179 mg (purity 100%, 48% of theory) of the target compound.

[0858] LC-MS (method 4): R.sub.t=0.53 min; MS (ESIpos): m/z=313 [M+H].sup.+.

Example 82A

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

[0859] ##STR00131##

[0860] 3.67 ml (21.09 mmol) of N,N-diisopropylethylamine were added to 1 g (4.22 mmol) of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate and 1.077 g (4.22 mmol) of 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride in 25 ml of acetonitrile, and the mixture was heated to 80° C. and stirred at this temperature overnight. After cooling of the reaction mixture, the solution was diluted with ethyl acetate and washed with water. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. This gave 1.29 g (3.81 mmol, 90% of theory) of the target compound as a red solid.

[0861] NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.77-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.30 (t, 3H), 1.34-1.46 (m, 1H), 1.48-1.67 (m, 5H), 1.72-1.85 (m, 3H), 2.06 (br. t, 1H), 2.48-2.58 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.24 (td, 2H), 3.98 (br. d, 2H), 4.34 (q, 2H).

[0862] LC-MS (method 1): R.sub.t=0.82 min; m/z=339 (M+H).sup.+.

Example 83A

5-[(3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-1,3,4-thiadiazole-2-carboxylic acid

[0863] ##STR00132##

[0864] 1.52 g (4.49 mmol) of ethyl 5-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3,4-thiadiazole-2-carboxylate were dissolved in 8 ml of THF, 538 mg (22.45 mmol) of lithium hydroxide were added and 5 ml of water were then added to the reaction solution. The reaction solution was then stirred at room temperature for several hours. After complete conversion, the reaction solution was adjusted to pH 7 with 1 N HCl and concentrated to dryness on a rotary evaporator. This gave 2.95 g of an amber oil which was purified by column chromatography.

[0865] Conditions: The separation was carried out using portions of about 1 g. RP column Chromatorex C18, 10 μm; 125×30 mm, acetonitrile/water 10/90.fwdarw.gradient over 38 min 4 acetonitrile/water 90/10, flow rate 75 ml/min.

[0866] Finally, product-containing fractions were combined and concentrated to dryness under reduced pressure and dried. This gave 487 mg (1.57 mmol, 35% of theory) of the target compound as a white solid.

[0867] LC-MS (method 1): R.sub.t=0.39 min; m/z=311 (M+H).sup.+.

Example 84A

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

[0868] ##STR00133##

[0869] To an initial charge of 5-azaspiro[2.5]octane hydrochloride (346 mg, 2.34 mmol) in 7 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (410 μl, 2.3 mmol) and the mixture was stirred for 5 min, before tert-butyl 4-oxoazepane-1-carboxylate (250 mg, 1.17 mmol) and acetic acid (100 μl, 1.8 mmol) were added. This was followed by stirring at room temperature for 5 h. After this time, sodium triacetoxyborohydride (298 mg, 1.41 mmol) was added to the mixture, which was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution and water. The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by means of preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile/water (80% by vol./20% by vol.) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, on-column injection (complete injection). gradient profile: eluent A 0 to 2 min 70 ml, eluent B 0 to 2 min 0 ml, eluent A 2 to 10 min from 70 ml to 0 ml and eluent B from 0 ml to 70 ml, 10 to 12 min 0 ml eluent A and 70 ml eluent B. Eluent C and eluent D at constant flow rate of 5 ml/min in each case over the entire run time). After the solvents had been removed, 140 mg (39% of theory) of the title compound was obtained.

[0870] LC-MS (method 4): MS (ESIpos): m/z=309 [M+H].sup.+.

Example 85A

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

[0871] ##STR00134##

[0872] rac-tert-Butyl 4-(5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (140 mg, 454 μmol) was dissolved in 4 ml of dichloromethane, HCl in dioxane (570 μL 4.0 M, 2.3 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. 139 mg (125% of theory) of the target compound was obtained.

[0873] LC-MS (method 4): MS (ESIpos): m/z=208 [M−HCl].sup.+.

Example 86A

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

[0874] ##STR00135##

[0875] To an initial charge of rac-1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (500 mg, 2.72 mmol) in 10 ml 1,2-dichloroethane was added N,N-diisopropylethylamine (470 μL 2.7 mmol), and the mixture was stirred at room temperature for 5 min before tert-butyl 4-oxoazepane-1-carboxylate (290 mg, 1.36 mmol) and acetic acid (120 μl, 2.0 mmol) were added. The mixture was stirred at room temperature for 5 h. After this time, sodium triacetoxyborohydride (346 mg, 1.63 mmol) was added to the mixture, which was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution and water. The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by means of preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile/water (80% by vol./20% by vol.) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection. gradient profile: eluent A 0 to 2 min 70 ml, eluent B 0 to 2 min 0 ml, eluent A 2 to 10 min from 70 ml to 0 ml and eluent B from 0 ml to 70 ml, 10 to 12 min 0 ml eluent A and 70 ml eluent B. Eluent C and eluent D constant flow rate of 5 ml/min in each case over the entire run time). The product-containing fractions were combined and lyophilized. 292 mg (62% of theory) of the target compound was obtained.

[0876] LC-MS (method 4): MS (ESIpos): m/z=345 [M+H].sup.+.

Example 87A

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

[0877] ##STR00136##

[0878] To a solution of diamix-tert-butyl 4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azepane-1-carboxylate (292 mg, 848 μmol) in 8 ml of dichloromethane was added HCl in dioxane (1.1 ml, 4.0 M, 4.2 mmol), and the mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. 194 mg (72% of theory) of the target compound was obtained.

[0879] LC-MS (method 4): MS (ESIpos): m/z=245 [M−2HCl].sup.+.

Example 88A

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

[0880] ##STR00137##

[0881] To (3R)-3-methylpiperidine hydrochloride (318 mg, 2.34 mmol) in 5.8 ml of 1,2-dichloroethane was added N,N-diisopropylethylamine (410 μl, 2.3 mmol), and the mixture was stirred at room temperature for 5 min, before rac-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (250 mg, 1.17 mmol) and acetic acid (100 μl, 1.8 mmol) were added. Subsequently, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (298 mg, 1.41 mmol) was added to the mixture, which was stirred at room temperature for a further 5 h. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution and water. The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was filtered off and the filtrate was concentrated. The residue (340 mg) was converted further without analysis.

Example 89A

diamix-(3R)-2′,3-Dimethyl-1,4′-bipiperidine dihydrochloride

[0882] ##STR00138##

[0883] diamix-tert-Butyl (3R)-2′,3-dimethyl[1,4′-bipiperidine]-1′-carboxylate (340 mg, 1.15 mmol) was dissolved in 16 ml of dichloromethane, HCl in dioxane (1.4 ml, 4.0 M, 5.7 mmol) was added, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated and the residue was dried under high vacuum. The residue (290 mg) was converted further without analysis.

Example 90A

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

[0884] ##STR00139##

[0885] 1 g (2.99 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide was added to 40 ml of water and admixed with 1.9 g (17.96 mmol) of sodium carbonate. 538 mg (3.29 mmol) of 3-ethylpiperidin-4-one hydrochloride was then metered into the reaction solution, which was subsequently stirred at reflux temperature overnight. After cooling, the reaction mixture was extracted with dichloromethane. The resulting organic phase was washed by means of sodium hydrogencarbonate solution, separated off and filtered through a water-repellent filter (MN 616 WA 1/4 fluted filter, D=12.5 cm). The resultant filtrate was then concentrated on a rotary evaporator and dried under reduced pressure. 1.1 g (2.89 mmol, 97% of theory) of the target compound was obtained as an amorphous solid, which, without further purification, was separated into the enantiomers by means of chiral preparative HPLC.

[0886] LC-MS (method 1): R.sub.t=1.42 min; m/z=381 (M+H).sup.+.

Example 91A and Example 92A

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

[0887] ##STR00140##

[0888] 1.1 g (2.89 mmol) of racemic N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm (SFC); eluent: CO.sub.2/2-propanol 55:45; pressure: 90 bar; flow rate: 95 g/min; UV detection: 210 nm; temperature: 40° C.]:

Example 91A (Enantiomer 1)

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

[0889] Yield: 487 mg

[0890] R.sub.t=4.02 min; chemical purity >99%; >97% ee

[0891] [column: Chiraltek AY-3, 3 μm, 100 mm×4.6 mm; eluent: CO.sub.2/ethanol) 90:10; flow rate: 3 ml/min;

[0892] pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0893] LC-MS (method 1): R.sub.t=1.41 min; m/z=381 (M+H).sup.+.

[0894] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.89 (t, 3H), 1.25-1.33 (m, 1H), 1.65-1.75 (m, 1H), 2.41-2.48 (1, 2H), 2.48-2.56 (m, 1H, partly concealed by DMSO), 2.56-2.63 (m, 1H), 3.36 (dd, 1H), 3.60-3.67 (m, 1H), 3.96-4.04 (m, 1H), 4.05-4.11 (m, 1H), 4.55 (br. d, 2H), 7.87-7.94 (m, 2H), 7.93-8.47 (d, 1H), 8.76 (t, 1H).

[0895] [α].sub.D.sup.20=−14.69° (c=0.440, methanol).

Example 92A (Enantiomer 2)

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

[0896] Yield: 476 mg

[0897] R.sub.t=5.98 min; chemical purity >99%; >97% ee

[0898] [column: Chiraltek AY-3, 3 μm, 100 mm×4.6 mm; eluent: CO.sub.2/Ethanol) 90:10; flow rate: 3 ml/min; pressure: 130 bar; temperature: 40° C.; UV detection: 210 nm].

[0899] LC-MS (method 1): R.sub.t=1.41 min; m/z=381 (M+H).sup.+.

[0900] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.89 (t, 3H), 1.25-1.33 (m, 1H), 1.65-1.75 (m, 1H), 2.42-2.48 (1, 2H), 2.48-2.56 (m, 1H, partly concealed by DMSO), 2.55-2.63 (m, 1H), 3.36 (dd, 1H), 3.60-3.67 (m, 1H), 3.96-4.03 (m, 1H), 4.04-4.11 (m, 1H), 4.55 (br. d, 2H), 7.87-7.94 (m, 2H), 7.93-8.47 (d, 1H), 8.76 (t, 1H).

[0901] [α].sub.D.sup.20=+11.64° (c=0.435, methanol).

Example 93A

Diamix-cis-Benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidin]-1′-carboxylate

[0902] ##STR00141##

[0903] To an initial charge of (3R)-3-methylpiperidine hydrochloride (1000 mg, 4.04 mmol) in 25 ml of dichloromethane was added N,N-diisopropylethylamine (1.41 ml, 8.1 mmol), and the mixture was stirred at room temperature for 5 min before rac-benzyl 3-methyl-4-oxopiperidine-1-carboxylate (1.1 g, 8.1 mmol) and acetic acid (0.35 ml, 6.1 mmol) were added. Then sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added to the mixture, which was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed successively with sat. NaHCO.sub.3 solution and water. The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was filtered off and the filtrate was concentrated. The residue obtained was dissolved in a mixture of 18 ml of acetonitrile+MeOH and purified by means of preparative HPLC.

[0904] Method: instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm.

[0905] eluent A: water, eluent B: acetonitrile, eluent C: 1% ammonia in water; total flow rate: 80 ml/min, 40° C., wavelength 210 nm.

[0906] Gradient profile: eluent A 0 to 4 min 25%, eluent B 0 to 4 min 70%, eluent C 0 to 4 min 5%. Eluent A 4 to 4.71 min 0%, eluent B 4 to 4.71 min 95%, eluent C 4 to 4.71 min 5%. Eluent A 4.71 to 4.78 min 25%, eluent B 4.71 to 4.78 min 70%, eluent C 4.71 to 4.78 min 5%.

[0907] After the solvents had been removed, 716 mg (2.13 mmol, 98% purity, 53% of theory) of the title compound was obtained.

[0908] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, including at 0.82 (d, 3H)), 1.22-1.33 (m, 1H), 1.33-1.44 (m, 1H), 1.44-1.55 (m, 2H), 1.55-1.66 (m, 2H), 1.66-1.78 (m, 2H), 1.98-2.16 (m, 2H), 2.60-2.96 (m, 4H), 3.88 (br. d, 1H), 4.07 (br. d, 1H), 5.06 (s, 2H), 7.27-7.41 (m, 5H).

Example 94A and Example 95A

cis-Benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate (Diastereomer 1 and 2)

[0909] ##STR00142##

[0910] 716 mg (2.17 mmol) of the cis diastereomer mixture diamix-cis-benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate was separated into the cis diastereomers 1 and 2 by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; eluent: n-heptane/(ethanol+0.2% diethylamine) 95:5; flow rate: 15 ml/min; UV detection: 220 nm; temperature: 30° C.]:

Example 94A (Cis Diastereomer 1)

cis-Benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate

[0911] Yield: 287 mg

[0912] R.sub.t=7.44 min; chemical purity >99%; >99% de

[0913] [column: Chiralpak AY-H, 5 μm, 250 mm×4.6 mm; eluent: n-heptane/(ethanol+0.2% diethylamine) 95:5; flow rate: 1 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0914] LC-MS (method 1): R.sub.t=1.02 min; m/z=331 (M+H).sup.+.

[0915] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76 (d, 3H), 0.79-0.90 (m, 4H, including at 0.82 (d, 3H)), 1.22-1.33 (m, 1H), 1.33-1.44 (m, 1H), 1.44-1.55 (m, 2H), 1.55-1.66 (m, 2H), 1.66-1.78 (m, 2H), 1.98-2.16 (m, 2H), 2.60-2.96 (m, 4H), 3.88 (br. d, 1H), 4.07 (br. d, 1H), 5.06 (s, 2H), 7.27-7.41 (m, 5H).

Example 95A (Cis Diastereomer 2)

cis-Benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate

[0916] Yield: 135 mg

[0917] R.sub.t=8.06 min; chemical purity >99%; >99% de

[0918] [column: Chiralpak AY-H, 5 μm, 250 mm×4.6 mm; eluent: n-heptane/(ethanol+0.2% diethylamine) 95:5; flow rate: 1 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0919] LC-MS (method 1): R.sub.t=1.02 min; m/z=331 (M+H).sup.+.

[0920] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76 (d, 3H), 0.79-0.89 (m, 4H, including at 0.83 (d, 3H)), 1.22-1.32 (m, 1H), 1.33-1.43 (m, 1H), 1.46-1.55 (m, 2H), 1.55-1.67 (m, 2H), 1.67-1.76 (m, 2H), 2.00-2.15 (m, 2H), 2.62-2.99 (m, 4H), 3.88 (br. d, 1H), 4.07 (br. d, 1H), 5.06 (s, 2H), 7.27-7.40 (m, 5H).

Example 96A

Cis-(3R)-3,3′-Dimethyl-1,4′-bipiperidine dihydrobromide (Diastereomer 1)

[0921] ##STR00143##

[0922] 280 mg (0.85 mmol) of cis-benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate (diastereomer 1; Example 94A) was dissolved in 5 ml of an HBr/glacial acetic acid mixture while cooling with ice and stirred at 0° C. for 15 min. Subsequently, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was admixed with diethyl ether, and the precipitate formed was filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum. 260 mg (0.73 mmol, 86% of theory) of the title compound was obtained, which has been converted further without further analysis.

Example 97A

Cis-(3R)-3,3′-Dimethyl-1,4′-bipiperidine dihydrobromide (Diastereomer 2)

[0923] ##STR00144##

[0924] 130 mg (0.39 mmol) of cis-benzyl (3R)-3,3′-dimethyl[1,4′-bipiperidine]-1′-carboxylate (diastereomer 2; Example 95A) was dissolved in 3 ml of an HBr/glacial acetic acid mixture while cooling with ice and stirred at 0° C. for 15 min. Subsequently, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was admixed with diethyl ether, and the precipitate formed was filtered off with suction, washed repeatedly with diethyl ether and dried under high vacuum. 124 mg (0.35 mmol, 88% of theory) of the title compound was obtained, which has been converted further without further analysis.

WORKING EXAMPLES

Example 1

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[0925] ##STR00145##

[0926] 13 g (38.91 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 8.51 g (38.91 mmol) of (3R)-3-methyl-1,4′-bipiperidine hydrochloride (1:1) (WO2015091420 Example 1A; CAS Registry Number 1799475-27-6) and 20.62 g (194.53 mmol) of sodium carbonate in 200 ml of water were heated to 120° C. and stirred at this temperature overnight. After cooling of the reaction mixture, the solution was extracted with ethyl acetate. The separated organic phase was subsequently filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The residue obtained was taken up in acetonitrile, heated to 80° C. and, with stirring, slowly cooled back to room temperature. The precipitated solid was filtered off with suction and washed with acetonitrile. The residue was then once more taken up in acetonitrile and recrystallized again. This gave 10.75 g (24.68 mmol, 63% of theory) of the target compound as a light-beige solid. The two mother liquors were combined and concentrated to dryness on a rotary evaporator. The residue obtained was purified further by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 100 g column, mobile phase: dichloromethane.fwdarw.gradient over 20 CV (CV=column volumes).fwdarw.dichloromethane/methanol 9:1). The product fractions obtained were then combined, concentrated on a rotary evaporator and recrystallized from acetonitrile. This gave a further 3.28 g (7.48 mmol, 19% of theory) of the target compound as a light-beige solid.

[0927] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.66 (m, 6H), 1.71-1.81 (m, 3H), 2.01-2.09 (m, 1H), 2.44-2.56 (m, 1H, partially obscured by DMSO), 2.69-2.77 (m, 2H), 3.04 (td, 2H), 3.93 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.88-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[0928] LC-MS (method 4): R.sub.t=0.50 min; m/z=436 (M+H).sup.+.

[0929] [α].sub.D.sup.20=−8.06° (c=0.430, methanol).

Example 2

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[0930] ##STR00146##

[0931] 60 mg (0.18 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 51 mg (0.18 mmol) of 2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride and 95 mg (0.9 mmol) of sodium carbonate in 1 ml of water in a closed vessel were heated to 160° C. and stirred at this temperature for 30 min. After cooling of the reaction mixture, water was added and the solution was extracted with dichloromethane. The separated organic phase was subsequently filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The residue obtained was purified further by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column, mobile phase: ethyl acetate.fwdarw.gradient over 5 CV (CV=column volumes).fwdarw.ethyl acetate/methanol 95:5). The product fractions obtained were then combined and concentrated to dryness on a rotary evaporator. This gave 62.7 mg (0.13 mmol, 74% of theory) of the target compound as a yellow solid.

[0932] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.55-1.65 (m, 2H), 1.86-1.94 (m, 2H), 2.67-2.73 (m, 1H), 2.73-2.81 (m, 4H), 3.12 (br. t, 2H), 3.70 (s, 2H), 3.97 (br. d, 2H), 4.53 (br. d, 2H), 7.01-7.12 (m, 4H), 7.85 (s, 1H), 7.93 (td, 1H), 8.48 (d, 1H), 8.76 (t, 1H).

[0933] LC-MS (method 1): R.sub.t=0.97 min; m/z=470 (M+H).sup.+.

Example 3

2-[3-(Cyclopropylmethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Racemate)

[0934] ##STR00147##

[0935] 32 mg (0.10 mmol) of 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, 22 mg (0.10 mmol) of 3-(cyclopropylmethyl)-1,4′-bipiperidine (racemate) and 31 mg (0.29 mmol) of sodium carbonate in 1 ml of water in a closed vessel were heated to 120° C. and stirred at this temperature for 30 min. After cooling of the reaction mixture the solution was extracted with dichloromethane. The separated organic phase was subsequently filtered through a hydrophobic filter (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The residue obtained was purified using the following method.

[0936] Method 7: instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0937] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0938] Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0939] This gave 40.8 mg (0.09 mmol, 88% of theory) of the target compound as a white lyophylisate.

[0940] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): −0.07-0.03 (m, 2H), 0.34-0.43 (m, 2H), 0.60-0.73 (m, 1H), 0.80-0.94 (m, 1H), 0.99-1.14 (m, 2H), 1.32-1.65 (m, 5H), 1.68-1.91 (m, 4H), 2.02-2.14 (m, 1H), 2.44-2.59 (m, 1H, partially obscured by DMSO), 2.73 (br. d, 1H), 2.83 (br. d, 1H), 3.04 (br. t, 2H), 3.94 (br. d, 2H), 4.52 (br. d, 2H), 7.83 (s, 1H), 7.87-7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[0941] LC-MS (method 1): R.sub.t=1.13 min; m/z=476 (M+H).sup.+.

[0942] Analogously to Examples 1 to 3, the following compounds of Examples 4 to 14 were prepared from the starting materials stated in each case:

TABLE-US-00004 Example Name/Structure/Starting materials Analytical data 4 2-[3-(difluoromethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]- 1,3-thiazole-5-carboxamide (racemate)   [00148]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide and .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.11-1.21 (m, 1H), 1.37- 1.53 (m, 3H), 1.62-1.72 (m, 2H), 1.73-1.81 (m, 2H), 1.88-1.98 (m, 1H), 2.10-2.21 (m, 2H), 2.46-2.60 (m, 1H, partially obscured by DMSO), 2.72 (br. d, 1H), 2.79 (br. d, 1H), 3.05 (td, 2H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 5.82-6.06 (m, 1H), 7.84 (s, 1H), 7.93 (td, 1H), 8.47 (d, 1H), 8.75 (t, 1H). LC-MS (method 5): R.sub.t = 1.51 min; m/z = 472 (M + H).sup.+. 3-(difluoromethyl)-1,4′-bipiperidine dihydrochloride (racemate) 5 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-5-carboxamide (racemate)   [00149]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide and 1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 1.15-1.27 (m, 1H), 1.38- 1.56 (m, 3H), 1.65-1.73 (m, 1H), 1.74-1.82 (m, 2H), 1.82-1.88 (m, 1H), 2.06-2.20 (m, 2H), 2.32-2.44 (m, 1H), 2.57-2.66 (m, 1H), 2.81 (br. d, 1H), 2.96 (br. d, 1H), 3.00- 3.10 (m, 2H), 3.95 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.88-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H). LC-MS (method 5): R.sub.t = 1.63 min; m/z = 490 (M + H).sup.+. 3-(trifluoromethyl)-1,4′-bipiperidine dihydrochloride (racemate) 6 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-5-carboxamide (racemate)   [00150]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide .sup.1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 0.95-1.07 (m, 1H), 1.37- 1.54 (m, 3H), 1.61 (br. d, 2H), 1.73-1.91 (m, 3H), 2.02 (t, 1H), 2.15 (t, 1H), 2.47-2.57 (m, 1H, partially obscured by DMSO), 2.68-2.75 (m, 1H), 2.80 (br. d, 1H), 3.01-3.10 (m, 2H). 3.94 (br. d, 2H), 4.21-4.29 (m, 1H),4.31- 4.39 (m, 1H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.88-7.94 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H). and 3-(difluoromethyl)-1,4′-bipiperidine dihydrochloride (racemate) LC-MS (method 5): R.sub.t = 1.48 min; m/z = 454 (M + H).sup.+. 7 2-{3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5- difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (racemate)   [00151]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide .sup.1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 1.02-1.12 (m, 1H), 1.30- 1.40 (m, 1H), 1.44-1.54 (m, 2H), 1.60-1.67 (m, 1H), 1.73-1.80 (m, 2H), 1.87-1.93 (m. 1H), 1.98 (br. t, 1H), 2.06-2.14 (m, 1H); 2.24-2.35 (m, 3H), 2.48-2.62 (m, 3H, partially obscured by DMSO), 2.62-2.68 (m, 1H), 2.95 (br. d, 1H), 3.04 (br. t, 2H), 3.24-3.30 (m, 1H), 3.41-3.50 (m, 2H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.88-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H). LC-MS (method 1): R.sub.t = 1.11 min; m/z = 542 (M + H).sup.+. and 3-[(3,3-difluorocyclobutyl)methoxy]-1,4′-bipiperidine (racemate) 8 N-[(3,5-difluoropyridin-2-yl)methyl]-4-methyl-2-[(3R)-3-methyl[1,4′-bipiperidin]- 1′-yl]-1,3-thiazole-5-carboxamide   [00152]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazole-5- .sup.1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.34- 1.67 (m, 6H), 1.71-1.82 (m, 3H), 2.05 (br. t, 1H), 2.38 (s, 3H), 2.44- 2.56 (m, 1H, partially obscured by DMSO), 2.70-2.78 (m, 2H), 3.02 (br. t, 2H), 3.90 (br. d, 2H), 4.50 (br. d, 2H), 7.86-7.93 (m, 1H), 8.01 (t, 1H), 8.46 (d, 1H). LC-MS (method 1): R.sub.t = 0.98 min; m/z = 450 (M + H).sup.+. carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride 9 N-[(3,5-difluoropyridin-2-yl)methyl]-5-methyl-2-[(3R)-3-methyl[1,4′-bipiperidin]- 1′-yl]-1,3-thiazole-4-carboxamide   [00153]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.73-0.92 (m, 4H, including at 0.82 (d, 3H)), 1.32- 1.68 (m, 6H), 1.70-1.86 (m, 3H), 1.97-2.14 (m. 1H), 2.38 (s, 3H), 2.44-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.82 (m, 2H), 3.03 (br. t, 2H), 3.90 (br. d, 2H), 4.50 (br. d, 2H), 7.86-7.95 (m, 1H), 8.02 (br. t, 1H), 8.46 (d, 1H). LC-MS (method 1): R.sub.t = 0.92 min; m/z = 450 (M + H).sup.+. 10 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-4-carboxamide   [00154]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.36- 1.45 (m, 1H), 1.46-1.55 (m, 3H), 1.56-1.67 (m, 2H), 1.73-1.84 (m, 3H), 2.06 (br. t, 1H). 2.44-2.56 (m, 1H, partially obscured by DMSO), 2.71-2.80 (m, 2H), 3.02 (td, 2H), 3.97 (br. d, 2H), 4.58 (d, 2H), 7.38 (s, 1H), 7.89-7.95 (m, 1H), 8.46 (d, 1H), 8.48 (t, 1H). LC-MS (method 4): R.sub.t = 0.56 min; m/z = 436 (M + H).sup.+. 11 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1-yl]- 4-(trifluoromethyl)-1,3-thiazole-5-carboxamide   [00155]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-(trifluoromethyl)-1,3- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.34- 1.45 (m, 1H), 1.45-1.55 (m, 3H), 1.55-1.66 (m, 2H), 1.75 (t, 1H), 1.80 (br. d, 2H), 2.05 (td, 1H), 2.45-2.56 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.09 (td, 2H), 3.88 (br. d, 2H), 4.52 (br. d, 2H), 7.89-7.97 (m, 1H), 8.47 (d, 1H), 8.90 (t, 1H). LC-MS (method 1): R.sub.t = 1.24 min; m/z = 504 (M + H).sup.+. thiazole-5-carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride 12 N-[(3,5-difluoropyridin-2-yl)methyl]-5-ethyl-2-[(3R)-3-methyl[1,4′-bipiperidin]- 1′-yl]-1,3-thiazole-4-carboxamide   [00156]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-5-ethyl-1,3-thiazole-4- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.13 (t, 3H), 1.35-1.45 (m. 1H), 1.45-1.56 (m, 3H), 1.56-1.67 (m, 2H), 1.71- 1.80 (m, 3H), 2.06 (br. t, 1H). 2.42-2.52 (m, 1H, partially obscured by DMSO), 2.75 (br. t, 2H), 2.96 (td, 2H), 3.10 (q, 2H), 3.91 (br. d, 2H), 4.56 (d, 2H), 7.88-7.95 (m, 1H), 8.44 (t, 1H), 8.46 (d, 1H). LC-MS (method 4): R.sub.t = 0.68 min; m/z = 464 (M + H).sup.+. carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride 13 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3-oxazole-4-carboxamide   [00157]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.33- 1.67 (m, 6H), 1.71-1.82 (m, 3H), 2.01-2.10 (m, 1H), 2.40-2.56 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 2.97 (br. t, 2H), 3.99 (br. d, 2H), 4.56 (d, 2H), 7.89-7.95 (m, 1H), 8.02 (s, 1H), 8.24 (t, 1H), 8.47 (d, 1H). LC-MS (method 4): R.sub.t = 0.52 min; m/z = 420 (M + H).sup.+. 14 N-[(3,5-difluoropyridin-2-yl)methyl]-5-methyl-2-[(3R)-3-methyl[1,4′-bipiperidin]- 1′-yl]-1,3-oxazole-4-carboxamide   [00158]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-5-methyl-1,3-oxazole-4- carboxamide and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride 1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35- 1.67 (m, 6H), 1.76 (br. d, 3H), 2.05 (br. t, 1H), 2.36-2.58 (m, 4H, partially obscured by DMSO, including at 2.50 (br. s, 3H)), 2.70- 2.80 (m, 2H), 2.92 (br. t, 2H), 3.94 (br. d, 2H), 4.54 (br. d, 2H), 7.91 (br. t, 1H), 8.09 (br. t, 1H), 8.47 (br. s, 1H). LC-MS (method 4): R.sub.t = 0.57 min; m/z = 434 (M + H).sup.+.

Example 15

N-[ (3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methoxy[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[0943] ##STR00159##

[0944] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were dissolved in 5 ml of dichloromethane, and 65 mg (0.57 mmol) of (3R)-3-methoxypiperidine and 24 μl (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride were then metered in and stirring of the reaction solution was then continued at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium hydrogencarbonate solution. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0945] Method 8:

[0946] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0947] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0948] Gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0949] This gave 62 mg (0.14 mmol, 48% of theory) of the target compound as a white lyophylisate.

[0950] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.00-1.11 (m, 1H), 1.30-1.40 (m, 1H), 1.43-1.54 (m, 2H), 1.59-1.66 (m, 1H), 1.77 (br. d, 2H), 1.86-1.93 (m, 1H), 1.98 (t, 1H), 2.11 (t, 1H), 2.47-2.58 (m, 1H, partially obscured by DMSO), 2.64 (br. d, 1H), 2.94 (br. d, 1H), 3.04 (br. t, 2H), 3.12-3.19 (m, 1H), 3.23 (s, 3H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.91 (td, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

[0951] LC-MS (method 1): R.sub.t=0.83 min; m/z=452 (M+H).sup.+.

Example 16

2-[3-(Difluoromethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Racemate)

[0952] ##STR00160##

[0953] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were dissolved in 5 ml of dichloromethane, and 86 mg (0.57 mmol) of 3-(difluoromethoxy)piperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride were then metered in and stirring of the reaction solution was then continued at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium hydrogencarbonate solution. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0954] Method 9:

[0955] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0956] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0957] Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0958] This gave 60 mg (0.12 mmol, 44% of theory) of the target compound as a white lyophylisate.

[0959] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.27-1.36 (m, 1H), 1.36-1.53 (m, 3H), 1.62-1.69 (m, 1H), 1.73-1.81 (m, 2H), 1.85-1.93 (m, 1H), 2.13-2.25 (m, 2H), 2.54-2.67 (m, 2H), 2.90 (br. d, 1H), 3.05 (br. t, 2H), 3.94 (br. d, 2H), 4.01-4.08 (m, 1H), 4.53 (d, 2H), 6.57-6.88 (m, 1H), 7.83 (s, 1H), 7.91 (t, 1H), 8.47 (d, 1H), 8.72 (t, 1H).

[0960] LC-MS (method 1): R.sub.t=0.91 min; m/z=488 (M+H).sup.+.

Example 17

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-ethyl[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide (Racemate)

[0961] ##STR00161##

[0962] 100 mg (0.28 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide were dissolved in 5 ml of dichloromethane, and 64 mg (0.57 mmol) of 3-ethylpiperidine (racemate) and 24 μl (0.43 mmol) of glacial acetic acid were added. 72 mg (0.34 mmol) of sodium acetoxyborohydride were then metered in and stirring of the reaction solution was then continued at room temperature overnight. Subsequently, the reaction mixture was diluted with dichloromethane and washed with sodium hydrogencarbonate solution. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0963] Method 7:

[0964] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0965] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0966] Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0967] This gave 46 mg (0.10 mmol, 36% of theory) of the target compound as a white lyophylisate.

[0968] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.85 (t, 3H)), 1.09-1.25 (m, 2H), 1.26-1.34 (m, 1H), 1.34-1.43 (m, 1H), 1.44-1.53 (m, 2H), 1.55-1.62 (m, 1H), 1.65-1.71 (m, 1H), 1.73-1.83 (m, 3H), 2.08 (br. t 1H), 2.46-2.56 (m, 1H, partially obscured by DMSO), 2.70-2.79 (m, 2H), 3.04 (br. t, 2H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 7.82 (s, 1H), 7.89 (br. t, 1H), 8.46 (d, 1H), 8.67 (t, 1H).

[0969] LC-MS (method 1): R.sub.t=0.99 min; m/z=450 (M+H).sup.+.

Example 18

2-[(3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-5-carboxamide

[0970] ##STR00162##

[0971] 0.46 ml (2.62 mmol) of N,N-diisopropylethylamine was added to 200 mg (0.52 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 122 mg (0.58 mmol) of 1-[4-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (1:1) in 20 ml of acetonitrile, and 0.34 ml (0.58 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was then added dropwise to the reaction solution at room temperature. After the addition had ended, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0972] Method 7:

[0973] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0974] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0975] Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0976] This gave 55 mg (0.12 mmol, 23% of theory) of the target compound as a white lyophylisate.

[0977] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.74-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.68 (m, 6H), 1.70-1.84 (m, 3H), 1.99-2.11 (m, 1H), 2.44-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.80 (m, 2H), 3.06 (td, 2H), 3.95 (br. d, 2H), 4.59 (d, 2H), 7.62 (s, 1H), 7.67 (d, 1H), 7.87 (s, 1H), 8.81 (d, 1H), 8.89 (t, 1H).

[0978] LC-MS (method 1): R.sub.t=1.05 min; m/z=469 (M+H).sup.+.

Example 19

2-[(3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[0979] ##STR00163##

[0980] 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride were dissolved in 10 ml of dichloromethane, 56 mg (0.42 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added and the mixture was stirred at room temperature for 30 min. Subsequently, 60 μl of pyridine and then 46 mg (0.26 mmol) of 1-[3-(trifluoromethyl)phenyl]methanamine were metered into the reaction solution and the mixture was stirred at room temperature overnight. After addition of water, the resulting precipitate was filtered off with suction. The biphasic filtrate obtained was separated off and the resulting organic phase was filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0981] Method 11:

[0982] Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0-3 min 10% B, 3-27 min 10% B.fwdarw.95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B.fwdarw.10% B, 35.5-36.5 min 10% B; flow rate: 50 ml/min; room temperature; UV detection: 210 nm.

[0983] This gave 45 mg (0.10 mmol, 37% of theory) of the target compound.

[0984] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.78-0.91 (m, 4H, including at 0.83 (d, 3H)), 1.37-1.69 (m, 6H), 1.73-1.94 (m, 3H), 2.05-2.23 (m, 1H), 2.56-2.67 (m, 1H), 2.73-2.90 (m, 2H), 3.06 (br. t, 2H), 3.96 (br. d, 2H), 4.48 (d, 2H), 7.54-7.65 (m, 4H), 7.84 (s, 1H), 8.84 (t, 1H).

[0985] LC-MS (method 1): R.sub.t=1.31 min; m/z=467 (M+H).sup.+.

Example 20

N-[(3-Fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[0986] ##STR00164##

[0987] 0.18 ml (1.05 mmol) of N,N-diisopropylethylamine was added to 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 47 mg (0.29 mmol) of 1-(3-fluoropyridin-2-yl)methanamine hydrochloride (1:1) in 10 ml of acetonitrile, and 0.17 ml (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition had ended, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0988] Method 9:

[0989] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0990] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[0991] Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[0992] This gave 5.4 mg (0.01 mmol, 5% of theory) of the target compound as a white lyophylisate.

[0993] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.33-1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.05 (br. t, 1H), 2.44-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.80 (m, 2H), 3.05 (td, 2H), 3.94 (br. d, 2H), 4.56 (dd, 2H), 7.36-7.43 (m, 1H), 7.64-7.72 (m, 1H), 7.84 (s, 1H), 8.38 (dt, 1H), 8.69 (t, 1H).

[0994] LC-MS (method 4): R.sub.t=0.48 min; m/z=418 (M+H).sup.+.

Example 21

N-(5-Chloro-2-fluorobenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[0995] ##STR00165##

[0996] 0.18 ml (1.05 mmol) of N,N-diisopropylethylamine was added to 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 46 mg (0.29 mmol) of 1-(5-chloro-2-fluorophenyl)methanamine in 10 ml of acetonitrile, and 0.17 ml (0.29 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition had ended, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0997] Method 7:

[0998] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[0999] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[1000] Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[1001] This gave 45 mg of a mixture which was purified further by column chromatography on silica gel (Isolera Biotage SNAP-Ultra 10 g column; mobile phase: cyclohexane/ethyl acetate 8:2.fwdarw.gradient over 15 CV (CV=column volumes).fwdarw.cyclohexane/ethyl acetate 2:8). This gave 16 mg (0.04 mmol, 14% of theory) of the target compound as a beige solid.

[1002] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35-1.67 (m, 6H), 1.72-1.82 (m, 3H), 2.05 (br. t, 1H), 2.45-2.57 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.05 (td, 2H), 3.94 (br. d, 2H), 4.41 (d, 2H), 7.26 (t, 1H), 7.33-7.40 (m, 2H), 7.85 (s, 1H), 8.76 (t, 1H).

[1003] LC-MS (method 4): R.sub.t=0.68 min; m/z=451/453 (M+H).sup.+.

Example 22

2-[(3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-N-[4-(trifluoromethyl)benzyl]-1,3-thiazole-5-carboxamide

[1004] ##STR00166##

[1005] 0.22 ml (1.23 mmol) of N,N-diisopropylethylamine was added to 200 mg (0.31 mmol, purity 59%) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 59 mg (0.34 mmol) of 1-[4-(trifluoromethyl)phenyl]methanamine in 10 ml of acetonitrile, and 0.2 ml (0.34 mmol) of a 50% strength solution of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide) in ethyl acetate was then metered into the reaction solution at room temperature. After the addition had ended, the reaction solution was stirred at room temperature overnight. The reaction mixture was then extracted with water and with dichloromethane. The organic phase was finally separated off and the organic solution obtained was then filtered through hydrophobic filters (pleated filter MN 616 WA 1/4, D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[1006] Method 10:

[1007] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm

[1008] Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, At-Column Injection (complete injection)

[1009] Gradient profile: 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time.

[1010] This gave 25 mg (0.05 mmol, 17% of theory) of the target compound as a white lyophylisate.

[1011] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.74-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.33-1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.00-2.10 (m, 1H), 2.45-2.57 (m, 1H, partially obscured by DMSO), 2.70-2.79 (m, 2H), 3.06 (td, 2H), 3.94 (br. d, 2H), 4.47 (d, 2H), 7.50 (d, 2H), 7.70 (d, 2H), 7.84 (s, 1H), 8.83 (t, 1H).

[1012] LC-MS (method 1): R.sub.t=1.27 min; m/z=467 (M+H).sup.+.

[1013] Analogously to Examples 18 to 22, the following compounds of Examples 23 to 37 were prepared from the starting materials stated in each case:

TABLE-US-00005 Example Name/Structure/Starting material Analytical data 23 N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′- yl]-1,3-thiazole-5-carboxamide   [00167]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(5-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.74-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.32- 1.67 (m, 6H), 1.71-1.82 (m, 3H), 2.00-2.10 (m, 1H), 2.44-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.04 (td, 2H), 3.93 (br. d, 2H), 4.53 (dd, 2H), 7.83 (s, 1H), 8.06 (dd, 1H), 8.48 (d, 1H), 8.73 (t, 1H). LC-MS (method 1): R.sub.t = 1.04 min; m/z = 452/454 (M + H).sup.+. (1:1) 24 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N-[(3-methylpyridin-2-yl)methyl]- 1,3-thiazole-5-carboxamide   [00168]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(3-methylpyridin-2-yl)methanamine .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.33- 1.68 (m, 6H), 1.70-1.83 (m, 3H), 2.00-2.11 (m, 1H), 2.31 (s, 3H), 2.43-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.80 (m, 2H), 3.04 (td, 2H), 3.94 (br. d, 2H), 4.50 (d, 2H), 7.21 (dd, 1H), 7.57 (dd, 1H), 7.86 (s, 1H), 8.35 (dd, 1H), 8.54 (t, 1H). LC-MS (method 1): R.sub.t = 0.66 min; m/z = 414 (M + H).sup.+. 25 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N-[(4-methylpyridin-2-yl)methyl]- 1,3-thiazole-5-carboxamide   [00169]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(4-methylpyridin-2-yl)methanamine .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.35- 1.67 (m, 6H), 1.71-1.81 (m, 3H), 2.05 (br. t, 1H), 2.29 (s, 3H), 2.46- 2.53 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.05 (td, 2H), 3.95 (br. d, 2H), 4.44 (d, 2H), 7.09 (d, 1H), 7.11 (s, 1H), 7.86 (s, 1H), 8.35 (d, 1H), 8.78 (t, 1H). LC-MS (method 1): R.sub.t = 0.63 min; m/z = 414 (M + H).sup.+. 26 N-[(3-chloropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-5-carboxamide   [00170]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(3-chloropyridin-2-yl)methanamine hydrochloride (1:1) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.33- 1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.05 (br. t, 1H), 2.44-2.57 (m, 1H, partially obscured by DMSO), 2.69-2.80 (m, 2H), 3.05 (br. t, 2H), 3.94 (br. d, 2H), 4.60 (d, 2H), 7.36 (dd, 1H), 7.86 (s, 1H), 7.92 (dd, 1H), 8.50 (dd, 1H), 8.64 (t, 1H). LC-MS (method 1): R.sub.t = 0.93 min; m/z = 434/436 (M + H).sup.+. 27 N-[(3-fluoropyridin-2-yl)methyl]-N-methyl-2-[(3R)-3-methyl[1,4′- bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide   [00171]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and (3-fluoropyridin-2-yl)-N-methylmethanamine .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.74-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.32- 1.67 (m, 6H), 1.70-1.83 (m, 3H), 2.05 (br. t, 1H), 2.43-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.04 (td, 2H), 3.16 (br. s, 3H), 3.94 (br. d, 2H), 4.86 (s, 2H), 7.38-7.46 (m, 1H), 7.59 (s, 1H), 7.68-7.77 (m, 1H), 8.37-8.45 (m, 1H). LC-MS (method 1): R.sub.t = 0.91 min; m/z = 432 (M + H).sup.+. 28 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N-{[6-(trifluoromethyl)pyridin-2- yl]methyl}-1,3-thiazole-5-carboxamide   [00172] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.33- 1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.05 (br. t, 1H), 2.45-2.58 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.06 (td, 2H), 3.95 (br. d, 2H), 4.54 (d, 2H), 7.61 (d, 1H), 7.79 (d, 1H), 7.87 (s, 1H), 8.07 (t, 1H), 8.95 (t, 1H). LC-MS (method 1): R.sub.t = 1.09 min; m/z = 468 (M + H).sup.+. from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-[6-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (1:1) 29 N-[(5-chloropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- LC-MS (method 1): 1,3-thiazole-5-carboxamide R.sub.t = 0.91 min; m/z = 434/436 from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic (M + H).sup.+. acid dihydrochloride and 1-(5-chloropyridin-2-yl)methanamine 30 N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxamide (diastereomer mixture)   [00173]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.32- 1.66 (m, 9H, including at 1.42 (d, 3H)), 1.71-1.81 (m, 3H), 2.05 (td, 1H), 2.46-2.56 (m, 1H, partially obscured by DMSO), 2.73 (br. t, 2H), 3.01-3.09 (m, 2H), 3.90-3.99 (m, 2H), 5.22-5.29 (m, 1H), 7.09- 7.16 (m, 1H), 7.19-7.26 (m, 2H), 7.92 (s, 1H), 8.55 (d, 1H). LC-MS (method 1): R.sub.t = 1.22 min; m/z = 449 (M + H).sup.+. acid dihydrochloride and 1-(2,5-difluorophenyl)ethanamine (racemate) 31 N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 1′-yl]-1,3-thiazole-5-carboxamide δ/ppm): 0.75-0.88 (m, 4H, from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic including at 0.82 (d, 3H)), 1.33- acid dihydrochloride and 1-(3-chloro-5-fluoropyridin-2-yl)methanamine 1.68 (m, 6H), 1.71-1.83 (m, 3H), hydrochloride (1:1) 2.06 (br. t, 1H), 2.44-2.57 (m, 1H, partially obscured by DMSO), 2.69-2.80 (m, 2H), 3.05 (br. t, 2H), 3.94 (br. d, 2H), 4.57 (d, 2H), 7.85 (s, 1H), 8.09 (dd, 1H), 8.57 (d, 1H), 8.66 (t, 1H). LC-MS (method 1): R.sub.t = 1.02 min; m/z = 452/454 (M + H).sup.+. 32 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N-{[6-(trifluoromethyl)pyridin-2- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, yl]methyl}-1,3-thiazole-5-carboxamide δ/ppm): 0.75-0.89 (m, 4H, from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid including at 0.82 (d, 3H)), 1.33- dihydrochloride and 1-[6-(trifluoromethoxy)pyridin-2-yl]methanamine 1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.05 (br. t, 1H), 2.43-2.57 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.06 (br. t, 2H), 3.95 (br. d, 2H), 4.44 (d, 2H), 7.16 (d, 1H), 7.33 (d, 1H), 7.86 (s, 1H), 7.99 (t, 1H), 8.87 (t, 1H). LC-MS (method 4): R.sub.t = 0.65 min; m/z = 484 (M + H).sup.+. 33 N-(4-chlorobenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide   [00174]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(4-chlorophenyl)methanamine .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75-0.88 (m, 4H, including at 0.82 (d, 3H)), 1.33- 1.68 (m, 6H), 1.71-1.83 (m, 3H), 2.00-2.10 (m, 1H), 2.44-2.57 (m, 1H, partially obscured by DMSO), 2.69-2.79 (m, 2H), 3.05 (br. td, 2H), 3.94 (br. d, 2H), 4.37 (d, 2H), 7.27-7.33 (m, 2H), 7.35-7.42 (m, 2H), 7.82 (s, 1H), 8.75 (t, 1H). LC-MS (method 1): R.sub.t = 1.18 min; m/z = 433/435 (M + H).sup.+. 34 N-(2-chloro-5-fluorobenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, 5-carboxamide δ/ppm): 0.76-0.87 (m, 4H, from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid including at 0.82 (d, 3H)), 1.35- dihydrochloride and 1-(2-chloro-5-fluorophenyl)methanamine 1.67 (m, 6H), 1.72-1.83 (m, 3H), 2.05 (td, 1H), 2.46-2.57 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.06 (td, 2H), 3.96 (br. d, 2H), 4.44 (d, 2H), 7.13 (dd, 1H), 7.18 (td, 1H), 7.51 (dd, 1H), 7.88 (s, 1H), 8.77 (t, 1H). LC-MS (method 1): R.sub.t = 1.23 min; m/z = 451/453 (M + H).sup.+. 35 N-(4-methylbenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide   [00175]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.34- 1.66 (m, 6H), 1.71-1.81 (m, 3H), 2.05 (br. t, 1H), 2.27 (s, 3H), 2.45- 2.56 (m, 1H. partially obscured by DMSO), 2.73 (br. t, 2H), 3.04 (td, 2H), 3.94 (br. d, 2H), 4.34 (d, 2H), 7.15 (q, 4H), 7.81 (s, 1H), 8.68 (t, 1H). LC-MS (method 1): R.sub.t = 1.19 min; m/z = 413 (M + H).sup.+. dihydrochloride and 1-(4-methylphenyl)methanamine 36 N-(3-methylbenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide   [00176]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(3-methylphenyl)methanamine .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35- 1.67 (m, 6H), 1.71-1.81 (m, 3H), 2.05 (br. t, 1H), 3.02 (s, 3H), 2.45- 2.56 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.04 (td, 2H), 3.94 (br. d, 2H), 4.35 (d, 2H), 7.03-7.11 (m, 3H), 7.20 (t, 1H), 7.82 (s, 1H), 8.69 (t, 1H). LC-MS (method 1): R.sub.t = 1.19 min; m/z = 413 (M + H).sup.+. 37 N-(2-methylbenzyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide   [00177]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(2-methylphenyl)methanamine .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.86 (m, 4H, including at 0.82 (d, 3H)), 1.35- 1.66 (m, 6H), 1.72-1.81 (m, 3H), 2.05 (br. t, 1H), 3.05 (s, 3H), 2.46- 2.55 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.04 (td, 2H), 3.94 (br. d, 2H), 4.37 (d, 2H), 7.13-7.18 (m, 3H), 7.19-7.24 (m, 1H), 7.85 (s, 1H), 8.58 (t, 1H). LC-MS (method 1): R.sub.t = 1.16 min; m/z = 413 (M + H).sup.+.

Example 38 and Example 39

2-[3-(Difluoromethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1014] ##STR00178##

[1015] 203 mg (0.43 mmol) of the racemic 2-[3-(difluoromethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 4) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; mobile phase: 2-propanol+0.2% diethylamine/n-heptane 50:50; flow rate: 20 ml/min; UV detection: 220 nm; temperature: 40° C.]:

Example 38 (Enantiomer 1)

2-[(3S)-3-(Difluoromethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1016] ##STR00179##

[1017] yield: 97 mg

[1018] R.sub.t=4.93 min; chemical purity >99%; >99% ee

[1019] [column: Chiraltek AY-3, 3 μm, 100 mm×4.6 mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1020] LC-MS (method 5): R.sub.t=1.52 min; m/z=472 (M+H).sup.+.

Example 39 (Enantiomer 2)

2-[(3R)-3-(Difluoromethyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1021] ##STR00180##

[1022] yield: 101 mg

[1023] R.sub.t=6.03 min; chemical purity >96%; >94% ee

[1024] [column: Chiraltek AY-3, 3 μm, 100 mm×4.6 mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1025] LC-MS (method 5): R.sub.t=1.52 min; m/z=472 (M+H).sup.+.

[1026] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.11-1.22 (m, 1H), 1.37-1.54 (m, 3H), 1.62-1.72 (m, 2H), 1.73-1.81 (m, 2H), 1.88-1.99 (m, 1H), 2.10-2.21 (m, 2H), 2.47-2.60 (m, 1H, partially obscured by DMSO), 2.72 (br. d, 1H), 2.79 (br. d, 1H), 3.05 (br. t, 2H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 5.82-6.06 (m, 1H), 7.84 (s, 1H), 7.93 (td, 1H), 8.47 (d, 1H), 8.75 (t, 1H).

Example 40 and Example 41

N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1027] ##STR00181##

[1028] 144 mg (0.32 mmol) of the racemic N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Example 6) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IG, 5 μm, 250 mm×20 mm; mobile phase: ethanol; flow rate: 15 ml/min; UV detection: 220 nm; temperature: 70° C.]:

Example 40 (Enantiomer 1)

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3S)-3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1029] ##STR00182##

[1030] yield: 71 mg R.sub.t=10.94 min; chemical purity 99%; 99% ee

[1031] [column: Daicel Chiralcel IG, 5 μm, 250 mm×4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 235 nm].

[1032] LC-MS (method 1): R.sub.t=0.85 min; m/z=454 (M+H).sup.+.

Example 41 (Enantiomer 2)

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-(fluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1033] ##STR00183##

[1034] yield: 70 mg

[1035] R.sub.t=12.21 min; chemical purity 99%; 99% ee

[1036] [column: Daicel Chiralcel IG, 5 μm, 250 mm×4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 235 nm].

[1037] LC-MS (method 1): R.sub.t=0.84 min; m/z=454 (M+H).sup.+.

[1038] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.94-1.10 (m, 1H), 1.35-1.55 (m, 3H), 1.61 (br. d, 2H), 1.72-1.92 (m, 3H), 2.03 (t, 1H), 2.16 (br. t, 1H), 2.47-2.57 (m, 1H, partially obscured by DMSO), 2.65-2.76 (m, 1H), 2.80 (br. d, 1H), 3.05 (br. t, 2H), 3.94 (br. d, 2H), 4.19-4.29 (m, 1H), 4.31-4.41 (m, 1H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.87-7.96 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

Example 42 and Example 43

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1039] ##STR00184##

[1040] 143 mg (0.29 mmol) of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Example 5) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak IG, 5 μm, 250 mm×20 mm; mobile phase: ethanol; flow rate: 15 ml/min; UV detection: 220 nm; temperature: 40° C.]:

Example 42 (Enantiomer 1)

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(35)-3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1041] ##STR00185##

[1042] yield: 67 mg

[1043] R.sub.t=11.22 min; chemical purity 99%; 99% ee

[1044] [column: Daicel Chiralcel IG, 5 μm, 250 mm×4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

[1045] LC-MS (method 1): R.sub.t=0.97 min; m/z=490 (M+H).sup.+.

Example 43 (Enantiomer 2)

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1046] ##STR00186##

[1047] yield: 67 mg

[1048] R.sub.t=11.87 min; chemical purity 99%; >96% ee

[1049] [column: Daicel Chiralcel IG, 5 μm, 250 mm×4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50° C.; UV detection: 235 nm].

[1050] LC-MS (method 1): R.sub.t=0.96 min; m/z=490 (M+H).sup.+.

[1051] .sup.1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 1.14-1.27 (m, 1H), 1.39-1.57 (m, 3H), 1.65-1.73 (m, 1H), 1.74-1.82 (m, 2H), 1.82-1.88 (m, 1H), 2.06-2.20 (m, 2H), 2.32-2.44 (m, 1H), 2.61 (br. t, 1H), 2.81 (br. d, 1H), 2.96 (br. d, 1H), 3.05 (td, 2H), 3.95 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.88-7.94 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

Example 44 and Example 45

2-{3-[(3,3-Difluorocyclobutyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomers 1 and 2)

[1052] ##STR00187##

[1053] 251 mg (0.46 mmol) of 2-{3-[(3,3-difluorocyclobutyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Example 7) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OD-H, 5 μm, 250 mm×20 mm; mobile phase: n-heptane/2-propanol+0.2% diethylamine 50:50; flow rate: 20 ml/min; UV detection: 220 nm; temperature: 30° C.]:

Example 44 (Enantiomer 1)

2-{(3R)-3-[(3,3-Difluorocyclobutyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1054] ##STR00188##

[1055] yield: 93 mg

[1056] R.sub.t=1.50 min; chemical purity >99%; 99% ee

[1057] [column: Phenomenex Cellulose-1, 3 μm, 50 mm×4.6 mm; mobile phase: n-heptane/2-propanol+0.2% diethylamine); flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1058] LC-MS (method 4): R.sub.t=0.63 min; m/z=542 (M+H).sup.+.

Example 45 (Enantiomer 2)

2-{(35)-3-[(3,3-Difluorocyclobutyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1059] ##STR00189##

[1060] yield: 86 mg

[1061] R.sub.t=2.21 min; chemical purity >99%; 99% ee

[1062] [column: Phenomenex Cellulose-1, 3 μm, 50 mm×4.6 mm; mobile phase: n-heptane/2-propanol+0.2% diethylamine); flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1063] LC-MS (method 4): R.sub.t=0.62 min; m/z=542 (M+H).sup.+.

[1064] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.02-1.12 (m, 1H), 1.30-1.42 (m, 1H), 1.42-1.56 (m, 2H), 1.58-1.68 (m, 1H), 1.72-1.83 (m, 2H), 1.85-1.94 (m, 1H), 1.99 (br. t, 1H), 2.10 (br. t, 1H), 2.21-2.38 (m, 3H), 2.48-2.62 (m, 3H, partially obscured by DMSO), 2.62-2.70 (m, 1H), 2.95 (br. d, 1H), 3.04 (br. t, 2H), 3.22-3.34 (m, 1H, partially obscured by H.sub.2O), 3.40-3.51 (m, 2H), 3.95 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.87-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H).

Example 46 and Example 47

N-[1-(2,5-Difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole carboxamide (Diastereomers 1 and 2)

[1065] ##STR00190##

[1066] 51 mg (0.11 mmol) of the diastereomer mixture N-[1-(2,5-difluorophenyl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Example 30) were separated into the diastereomers by preparative HPLC on a chiral phase [column: Daicel Chiralcel OX-H 5 μm, 250 mm×20 mm; mobile phase: n-heptane/ethanol 50:50; flow rate: 20 ml/min; UV detection: 220 nm; temperature: 40° C.]:

Example 46 (Diastereomer 1)

[1067] yield: 20 mg

[1068] R.sub.t=1.32 min; chemical purity >99%; 99% ee

[1069] [column: Daicel Chiralpak OX-3, 3 μm, 50 mm×4.6 mm; mobile phase: n-heptane/ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1070] LC-MS (method 1): R.sub.t=1.22 min; m/z=449 (M+H).sup.+.

[1071] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.66 (m, 9H, including at 1.42 (d, 3H)), 1.70-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.56 (m, 1H, partially obscured by DMSO), 2.68-2.80 (m, 2H), 3.00-3.09 (m, 2H), 3.95 (br. t, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.19-7.25 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).

Example 47 (Diastereomer 2)

[1072] yield: 19 mg

[1073] R.sub.t=1.78 min; chemical purity >99%; 99% ee

[1074] [column: Daicel Chiralpak OX-3, 3 μm, 50 mm×4.6 mm; mobile phase: n-heptane/ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 25° C.; UV detection: 220 nm].

[1075] LC-MS (method 1): R.sub.t=1.19 min; m/z=449 (M+H).sup.+.

[1076] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.89 (m, 4H, including at 0.82 (d, 3H)), 1.34-1.67 (m, 9H, including at 1.42 (d, 3H)), 1.72-1.84 (m, 3H), 2.00-2.12 (m, 1H), 2.44-2.60 (m, 1H, partially obscured by DMSO), 2.69-2.81 (m, 2H), 3.05 (br. t, 2H), 3.89-4.00 (m, 2H), 5.21-5.29 (m, 1H), 7.09-7.16 (m, 1H), 7.18-7.26 (m, 2H), 7.92 (s, 1H), 8.56 (d, 1H).

Example 48

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1077] ##STR00191##

[1078] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (124 mg, 370 μmol) and rac-3-(methoxymethyl)-1,4′-bipiperidine dihydrochloride (123 mg, purity 75%, 285 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4.0 mmol) for 1 h. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 60.0 mg (purity 100%, 35% of theory) of the target compound.

[1079] LC-MS (method 4): R.sub.t=0.51 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1080] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.903 (0.47), 0.918 (0.53), 1.389 (0.42), 1.409 (0.44), 1.432 (0.44), 1.445 (0.53), 1.452 (0.88), 1.460 (0.62), 1.465 (0.64), 1.472 (0.94), 1.480 (0.56), 1.578 (1.12), 1.596 (1.00), 1.716 (0.49), 1.755 (1.11), 1.774 (0.96), 1.878 (0.66), 1.895 (1.06), 1.912 (0.56), 2.091 (0.43), 2.106 (0.78), 2.109 (0.78), 2.124 (0.42), 2.483 (0.43), 2.520 (0.42), 2.706 (0.61), 2.724 (0.57), 2.795 (0.63), 2.809 (0.61), 3.018 (0.74), 3.023 (0.88), 3.040 (1.54), 3.043 (1.52), 3.060 (0.87), 3.064 (0.76), 3.129 (0.51), 3.144 (1.48), 3.157 (1.78), 3.159 (1.83), 3.169 (1.56), 3.175 (0.63), 3.184 (0.52), 3.200 (16.00), 3.920 (1.12), 3.941 (1.06), 4.521 (2.22), 4.530 (2.22), 7.828 (5.37), 7.893 (0.59), 7.897 (0.63), 7.910 (0.90), 7.913 (0.94), 7.925 (0.60), 7.929 (0.62), 8.465 (2.32), 8.468 (2.28), 8.701 (0.73), 8.710 (1.47), 8.720 (0.71).

Example 49

N-[(3,5-Difluoropyridin-2-yl)methyl]-3-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,2,4-oxadiazole carboxamide

[1081] ##STR00192##

[1082] N,N-Diisopropylethylamine (44 μl, 250 mmol) and propylphosphonic anhydride (66 μl, 50% in ethyl acetate, 110 μmol) were added to a solution of 3-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,2,4-oxadiazole-5-carboxylic acid (25.0 mg, 84.9 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (24.0 mg, 110 μmol) in 1 ml of acetonitrile, and the mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 7.00 mg (purity 100%, 20% of theory) of the target compound.

[1083] LC-MS (method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=421 [M+H].sup.+.

[1084] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.780 (0.59), 0.786 (0.66), 0.813 (14.94), 0.824 (16.00), 0.841 (0.69), 0.847 (0.57), 1.370 (0.56), 1.377 (0.45), 1.391 (1.47), 1.411 (1.58), 1.431 (1.38), 1.437 (1.22), 1.457 (2.49), 1.472 (2.70), 1.493 (1.64), 1.498 (1.66), 1.510 (1.34), 1.516 (1.25), 1.522 (1.29), 1.527 (1.13), 1.567 (1.91), 1.583 (1.19), 1.588 (1.52), 1.618 (1.61), 1.639 (1.55), 1.744 (2.47), 1.760 (5.97), 1.778 (4.64), 2.040 (1.21), 2.055 (2.23), 2.074 (1.19), 2.449 (1.19), 2.467 (2.20), 2.487 (1.30), 2.732 (2.07), 2.746 (3.74), 2.763 (1.77), 2.931 (2.53), 2.949 (4.76), 2.969 (2.54), 3.905 (3.81), 3.927 (3.64), 4.586 (6.49), 4.596 (6.41), 7.930 (1.47), 7.934 (1.53), 7.949 (2.60), 7.962 (1.51), 7.966 (1.50), 8.476 (5.87), 8.479 (5.69), 9.631 (1.76), 9.641 (3.44), 9.651 (1.75).

Example 50

diamix-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1085] ##STR00193##

[1086] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (142 mg, 519 μmol) were combined and stirred at 120° C. in 1.2 ml of sodium carbonate solution (1.2 ml, 2.0 M, 2.4 mmol) for 30 min. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 192 mg (purity 100%, 70% of theory) of the target compound.

[1087] LC-MS (method 4): R.sub.t=0.54 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1088] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.807 (8.04), 0.818 (8.54), 0.823 (9.19), 0.833 (9.26), 0.845 (1.26), 0.851 (1.27), 0.865 (0.57), 0.872 (0.48), 1.375 (0.72), 1.396 (0.88), 1.425 (0.72), 1.513 (0.76), 1.524 (0.78), 1.550 (1.22), 1.572 (1.24), 1.578 (1.30), 1.600 (1.01), 1.624 (1.99), 1.639 (1.94), 1.647 (1.92), 1.795 (1.24), 1.817 (0.99), 1.923 (0.96), 1.932 (0.79), 1.940 (1.73), 1.948 (1.32), 1.958 (1.00), 1.964 (0.66), 2.226 (1.04), 2.245 (1.98), 2.264 (1.01), 2.424 (0.59), 2.653 (0.51), 2.730 (2.22), 2.744 (2.48), 2.801 (1.20), 2.813 (1.28), 3.129 (1.00), 3.134 (1.13), 3.154 (1.85), 3.169 (1.17), 3.214 (0.84), 3.226 (1.61), 3.235 (1.14), 3.247 (1.52), 3.261 (0.83), 3.286 (0.43), 3.705 (1.26), 3.726 (1.18), 4.117 (0.76), 4.123 (0.88), 4.136 (1.42), 4.144 (1.43), 4.156 (0.80), 4.162 (0.74), 4.527 (5.54), 4.536 (5.52), 4.691 (0.60), 4.698 (0.88), 4.705 (1.12), 4.713 (0.79), 4.719 (0.57), 4.773 (0.59), 4.779 (0.81), 4.787 (1.13), 4.794 (0.85), 4.801 (0.57), 7.844 (16.00), 7.899 (1.65), 7.903 (1.77), 7.916 (2.25), 7.918 (2.38), 7.931 (1.68), 7.935 (1.72), 8.468 (6.33), 8.472 (6.30), 8.754 (1.79), 8.764 (3.76), 8.773 (1.86).

Example 51

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1089] ##STR00194##

[1090] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide were separated into the stereoisomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IA, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 20 ml/min; temperature 60° C., detection: 220 nm). The stereoisomer having a retention time of 7.873 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 88 mg (99% ee) of the title compound.

[1091] LC-MS (method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1092] .sup.1H.NMR (500 MHz, DMSO-d.sub.6) δ [ppm]: δ 8.72 (t, 1H), 8.47 (d, 1H), 7.94-7.89 (m, 1H), 7.82 (s, 1H), 5.10 (d, 1H), 4.53 (d, 2H), 4.18 (m, 1H), 4.00 (m, 1H), 3.32 (dd, 1H), 3.18-3.11 (m, 1H), 2.82 (m, 2H), 2.70-2.57 (m, 1H), 2.20-2.14 (m, 1H), 1.94-1.83 (m, 2H), 1.70-1.51 (m, 4H), 1.43-1.33 (m, 1H), 0.88-0.78 (m, 1H), 0.82 (d, 3H).

Example 52

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1093] ##STR00195##

[1094] 190 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide were separated into the stereoisomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IA, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 20 ml/min; temperature 60° C., detection: 220 nm). The stereoisomer having a retention time of 10.179 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 91 mg (99% ee) of the title compound.

[1095] LC-MS (method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1096] .sup.1H.NMR (500 MHz, DMSO-d.sub.6) δ [ppm]: δ 8.72 (t, 1H), 8.47 (d, 1H), 7.94-7.89 (m, 1H), 7.82 (s, 1H), 5.10 (d, 1H), 4.53 (d, 2H), 4.18 (m, 1H), 4.00 (m, 1H), 3.32 (dd, 1H), 3.19-3.12 (m, 1H), 2.82 (d br, 2H), 2.70-2.57 (m, 1H), 2.21-2.15 (m, 1H), 1.94-1.84 (m, 2H), 1.70-1.56 (m, 3H), 1.53-1.38 (m, 2H), 0.88-0.78 (m, 1H), 0.81 (d, 3H).

Example 53

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1097] ##STR00196##

[1098] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-4-methylazepane (32.1 mg, 284 μmol) in 2.5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and stirring of the mixture at room temperature was continued. After 2 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 43.0 mg (100% purity, 67% of theory) of the title compound.

[1099] LC-MS (method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1100] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.874 (16.00), 0.886 (15.94), 1.166 (1.35), 1.173 (2.14), 1.180 (1.44), 1.189 (2.16), 1.195 (1.69), 1.206 (1.49), 1.223 (2.09), 1.240 (2.28), 1.257 (1.07), 1.262 (0.94), 1.417 (1.40), 1.431 (3.73), 1.438 (3.97), 1.451 (4.78), 1.457 (4.63), 1.471 (3.48), 1.478 (2.98), 1.491 (1.13), 1.499 (0.91), 1.566 (1.97), 1.572 (1.71), 1.590 (2.05), 1.609 (1.83), 1.632 (4.40), 1.642 (4.13), 1.649 (3.78), 1.727 (2.59), 1.747 (4.36), 1.766 (2.28), 2.519 (3.82), 2.525 (2.88), 2.567 (1.76), 2.574 (1.84), 2.588 (3.16), 2.594 (2.42), 2.603 (2.38), 2.610 (2.22), 2.636 (3.23), 2.645 (6.11), 2.653 (6.12), 2.664 (4.76), 2.675 (3.65), 2.684 (1.53), 3.020 (3.04), 3.038 (5.45), 3.059 (3.16), 3.327 (0.99), 3.921 (4.02), 3.941 (3.84), 4.523 (7.77), 4.532 (7.71), 7.819 (13.98), 7.877 (1.85), 7.881 (1.92), 7.895 (3.21), 7.897 (3.22), 7.909 (1.86), 7.913 (1.83), 8.458 (6.41), 8.462 (6.13), 8.662 (2.36), 8.671 (4.40), 8.680 (2.29).

Example 54

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(3-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide

[1101] ##STR00197##

[1102] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-methylazepane hydrochloride (42.5 mg, 284 μmol) in 2.5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and stirring of the mixture at room temperature was continued. After 2 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 40.0 mg (purity 100%, 63% of theory) of the target compound.

[1103] LC-MS (method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=450 [M+H].sup.+

[1104] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.813 (15.55), 0.823 (16.00), 1.127 (0.63), 1.144 (1.47), 1.151 (1.29), 1.168 (1.44), 1.409 (0.90), 1.422 (3.44), 1.428 (3.08), 1.440 (5.99), 1.449 (4.90), 1.461 (3.41), 1.468 (2.80), 1.481 (1.05), 1.561 (1.44), 1.573 (1.70), 1.589 (0.97), 1.610 (3.22), 1.629 (4.80), 1.637 (3.85), 1.648 (2.15), 1.738 (3.86), 1.757 (3.39), 2.188 (2.20), 2.202 (2.24), 2.210 (2.45), 2.224 (2.31), 2.569 (0.93), 2.578 (1.13), 2.591 (2.08), 2.600 (2.09), 2.609 (1.71), 2.630 (1.60), 2.639 (4.89), 2.644 (4.73), 2.660 (4.71), 2.664 (4.78), 2.683 (1.26), 3.018 (2.77), 3.035 (5.01), 3.039 (4.91), 3.056 (2.76), 3.256 (0.45), 3.933 (3.56), 3.953 (3.40), 4.524 (7.13), 4.533 (7.07), 7.819 (13.92), 7.880 (1.63), 7.883 (1.71), 7.896 (2.87), 7.899 (2.96), 7.911 (1.68), 7.915 (1.70), 8.460 (6.36), 8.463 (6.29), 8.662 (2.12), 8.672 (4.27), 8.681 (2.16).

Example 55

diamix-N-[1-(3,5-Difluoropyridin-2-yl)ethyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1105] ##STR00198##

[1106] N,N-Diisopropylethylamine (182 μl, 105 μmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and rac-1-(3,5-difluoropyridin-2-yl)ethanamine (45.5 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 12.0 mg (purity 100%, 10% of theory) of the target compound.

[1107] LC-MS (method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1108] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.788 (0.72), 0.811 (14.96), 0.822 (16.00), 0.843 (0.68), 1.389 (1.55), 1.409 (1.64), 1.440 (14.70), 1.452 (14.49), 1.480 (2.90), 1.502 (2.05), 1.564 (1.99), 1.586 (1.51), 1.615 (1.65), 1.636 (1.56), 1.735 (1.85), 1.753 (4.97), 1.779 (3.32), 2.032 (1.18), 2.049 (2.19), 2.069 (1.17), 2.423 (0.65), 2.466 (1.28), 2.653 (0.49), 2.716 (2.04), 2.731 (3.74), 2.748 (1.88), 3.015 (2.36), 3.036 (4.36), 3.057 (2.38), 3.224 (0.42), 3.249 (0.65), 3.316 (0.89), 3.913 (2.65), 5.317 (0.57), 5.329 (2.00), 5.341 (3.01), 5.353 (1.96), 7.861 (1.44), 7.876 (2.73), 7.893 (1.49), 7.912 (11.30), 8.468 (5.59), 8.531 (3.80), 8.543 (3.75).

Example 56

N-[(5-Chloro-1,3-thiazol-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1109] ##STR00199##

[1110] N,N-Diisopropylethylamine (230 μl, 1.3 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-chloro-1,3-thiazol-2-yl)methanamine hydrochloride (53.2 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 14.0 mg (purity 100%, 12% of theory) of the target compound.

[1111] LC-MS (method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=440 [M+H].sup.+.

[1112] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: −0.149 (0.78), 0.146 (0.87), 0.811 (14.60), 0.827 (16.00), 1.475 (2.13), 1.498 (2.88), 1.605 (1.71), 1.729 (1.52), 1.756 (3.69), 1.802 (2.53), 2.051 (1.90), 2.366 (1.52), 2.710 (2.65), 3.041 (2.14), 3.067 (3.51), 3.098 (1.95), 3.937 (2.72), 3.966 (2.56), 4.573 (8.03), 4.588 (7.85), 7.731 (15.89), 7.837 (15.31), 9.094 (1.71), 9.108 (3.31), 9.122 (1.68).

Example 57

N-[(5-Fluoro-2-thienyl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1113] ##STR00200##

[1114] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(5-fluoro-2-thienyl)methanamine (37.7 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 12.0 mg (purity 100%, 11% of theory) of the target compound.

[1115] LC-MS (method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=423 [M+H].sup.+.

[1116] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.783 (0.52), 0.790 (0.59), 0.813 (15.03), 0.824 (16.00), 0.843 (0.57), 0.850 (0.47), 1.370 (0.50), 1.391 (1.25), 1.411 (1.35), 1.431 (0.57), 1.454 (0.72), 1.474 (1.98), 1.494 (2.47), 1.511 (1.80), 1.529 (0.96), 1.540 (0.58), 1.565 (1.59), 1.571 (1.23), 1.582 (0.96), 1.587 (1.28), 1.616 (1.32), 1.637 (1.24), 1.737 (1.79), 1.754 (3.23), 1.771 (4.08), 1.788 (2.51), 2.036 (1.05), 2.050 (1.91), 2.054 (1.88), 2.069 (1.04), 2.471 (1.13), 2.477 (0.78), 2.722 (1.66), 2.734 (3.05), 2.752 (1.45), 3.031 (1.84), 3.035 (2.16), 3.052 (3.73), 3.055 (3.70), 3.072 (2.12), 3.077 (1.85), 3.257 (0.59), 3.278 (0.99), 3.927 (2.78), 3.948 (2.65), 4.394 (4.22), 4.398 (4.54), 4.404 (4.54), 4.408 (4.29), 6.512 (3.08), 6.516 (3.37), 6.518 (3.69), 6.522 (3.52), 6.660 (2.25), 6.666 (4.14), 6.672 (2.16), 7.780 (13.01), 8.786 (1.58), 8.796 (3.27), 8.806 (1.66).

Example 58

2-[(3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide

[1117] ##STR00201##

[1118] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(pyridin-4-yl)methanamine (31.1 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 7.00 mg (purity 100%, 7% of theory) of the target compound.

[1119] LC-MS (method 1): R.sub.t=0.48 min; MS (ESIneg): m/z=398 [M−H].sup.−.

[1120] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: 0.776 (0.54), 0.796 (1.55), 0.812 (14.81), 0.828 (16.00), 0.855 (0.65), 0.865 (0.55), 0.950 (1.20), 0.966 (1.16), 1.356 (0.44), 1.387 (1.16), 1.417 (1.35), 1.446 (1.24), 1.474 (2.25), 1.499 (2.83), 1.525 (1.95), 1.534 (1.73), 1.563 (1.86), 1.604 (1.82), 1.645 (1.30), 1.731 (1.87), 1.758 (4.55), 1.783 (2.68), 1.796 (2.56), 2.030 (1.05), 2.052 (1.88), 2.058 (1.85), 2.080 (1.06), 2.366 (0.57), 2.473 (1.30), 2.725 (2.30), 2.741 (2.70), 3.031 (2.07), 3.057 (3.71), 3.088 (2.13), 3.932 (2.97), 3.965 (2.79), 4.401 (6.43), 4.416 (6.43), 7.269 (4.34), 7.280 (4.58), 7.849 (13.88), 8.505 (1.83), 8.800 (1.58), 8.815 (3.27), 8.830 (1.59).

Example 59

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidin]-1′-yl}-1,3-thiazole-5-carboxamide

[1121] ##STR00202##

[1122] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (118 mg, 353 μmol) and rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4′-bipiperidine dihydrochloride (164 mg, purity 75%, 348 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 56.0 mg (purity 100%, 30% of theory) of the target compound.

[1123] LC-MS (method 5): R.sub.t=1.64 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1124] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.937 (0.65), 0.955 (1.56), 0.970 (1.59), 0.988 (0.67), 1.381 (0.58), 1.402 (1.31), 1.420 (1.45), 1.431 (1.19), 1.439 (1.22), 1.452 (2.08), 1.458 (1.80), 1.465 (1.92), 1.471 (3.02), 1.478 (1.98), 1.485 (1.91), 1.492 (2.15), 1.505 (0.81), 1.512 (0.59), 1.589 (3.51), 1.605 (3.09), 1.767 (4.45), 1.952 (1.98), 1.969 (3.12), 1.986 (1.74), 2.133 (1.36), 2.148 (2.51), 2.166 (1.33), 2.513 (2.55), 2.689 (1.93), 2.707 (1.83), 2.776 (2.08), 2.791 (2.00), 3.029 (2.57), 3.049 (4.90), 3.070 (2.56), 3.425 (0.45), 3.443 (7.66), 3.454 (8.96), 3.925 (3.82), 3.947 (3.63), 3.976 (3.33), 3.992 (9.56), 4.008 (9.29), 4.023 (3.00), 4.525 (7.17), 4.534 (7.14), 7.824 (16.00), 7.877 (1.74), 7.881 (1.86), 7.897 (2.97), 7.909 (1.76), 7.913 (1.81), 8.458 (6.85), 8.462 (6.81), 8.666 (2.27), 8.676 (4.58), 8.685 (2.26).

Example 60

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1125] ##STR00203##

[1126] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (75.5 mg, 226 μmol) and rac-3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride (133 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 10.5 mg (purity 100%, 9% of theory) of the target compound.

[1127] LC-MS (method 5): R.sub.t=1.65 min; MS (ESIpos): m/z=538 [M+H].sup.+.

[1128] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.500 (0.62), 0.507 (0.85), 0.526 (0.86), 0.531 (1.03), 1.601 (0.40), 3.051 (0.52), 3.242 (1.08), 3.253 (1.11), 3.279 (2.71), 3.289 (16.00), 3.923 (0.41), 3.943 (0.40), 4.219 (0.96), 4.301 (0.97), 4.524 (0.77), 4.533 (0.76), 7.824 (1.56), 8.459 (0.67), 8.463 (0.68), 8.675 (0.48).

Example 61

rac-2-[3-({[1-(Difluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1129] ##STR00204##

[1130] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 300 μmol) and rac-3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride (112 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 49.8 mg (purity 100%, 30% of theory) of the target compound.

[1131] LC-MS (method 5): R.sub.t=1.71 min; MS (ESIpos): m/z=556 [M+H].sup.+.

[1132] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.608 (6.75), 0.611 (6.72), 0.725 (3.50), 0.733 (9.17), 0.735 (8.79), 0.743 (2.54), 0.904 (0.57), 0.921 (1.21), 0.936 (1.35), 0.955 (0.59), 1.372 (0.53), 1.391 (1.17), 1.411 (1.22), 1.437 (0.65), 1.444 (0.72), 1.456 (1.67), 1.466 (1.85), 1.476 (2.47), 1.485 (1.95), 1.496 (1.74), 1.515 (0.52), 1.587 (2.51), 1.592 (2.61), 1.599 (2.32), 1.722 (1.44), 1.739 (1.01), 1.759 (2.61), 1.781 (2.25), 1.909 (1.70), 1.926 (2.76), 1.943 (1.48), 2.109 (1.17), 2.125 (2.16), 2.142 (1.16), 2.486 (1.43), 2.522 (1.19), 2.699 (1.73), 2.718 (1.60), 2.791 (1.81), 2.806 (1.75), 3.029 (2.22), 3.050 (4.07), 3.071 (2.19), 3.237 (7.84), 3.248 (8.49), 3.384 (0.66), 3.403 (16.00), 3.422 (0.65), 3.922 (3.21), 3.943 (3.05), 4.524 (6.21), 4.533 (6.24), 5.805 (2.61), 5.901 (5.22), 5.996 (2.47), 7.824 (12.56), 7.878 (1.45), 7.882 (1.55), 7.897 (2.60), 7.910 (1.53), 7.914 (1.57), 8.458 (5.72), 8.462 (5.73), 8.666 (1.94), 8.675 (3.99), 8.684 (2.01).

Example 62

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1133] ##STR00205##

[1134] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (110 mg, 329 μmol) and rac-3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)-1,4′-bipiperidine dihydrochloride (129 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 56.0 mg (purity 100%, 30% of theory) of the target compound.

[1135] LC-MS (method 5): R.sub.t=1.78 min; MS (ESIpos): m/z=574 [M+H].sup.+.

[1136] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.808 (7.29), 0.908 (0.91), 0.926 (1.41), 0.934 (3.81), 0.942 (9.64), 0.953 (2.74), 1.393 (1.17), 1.411 (1.23), 1.432 (0.90), 1.440 (0.99), 1.452 (1.48), 1.460 (2.20), 1.470 (2.07), 1.480 (2.36), 1.500 (0.99), 1.584 (2.93), 1.600 (2.53), 1.721 (1.36), 1.757 (2.85), 1.779 (2.43), 1.907 (1.65), 1.925 (2.68), 1.941 (1.46), 2.110 (1.18), 2.125 (2.13), 2.144 (1.12), 2.482 (1.29), 2.519 (1.31), 2.699 (1.69), 2.717 (1.59), 2.788 (1.78), 2.804 (1.71), 3.031 (2.12), 3.052 (3.86), 3.073 (2.08), 3.233 (0.60), 3.252 (5.22), 3.262 (7.02), 3.456 (0.42), 3.475 (16.00), 3.495 (0.43), 3.920 (3.15), 3.942 (3.00), 4.524 (6.08), 4.533 (6.04), 7.824 (11.55), 7.879 (1.35), 7.883 (1.50), 7.897 (2.52), 7.911 (1.45), 7.914 (1.45), 8.459 (5.46), 8.462 (5.45), 8.666 (1.84), 8.675 (3.81), 8.685 (1.89).

Example 63

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3,3-dimethyl[1,4′-bipiperidin]-1′-yl)-1,3-thiazole carboxamide

[1137] ##STR00206##

[1138] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (50.0 mg, 150 μmol) and 3,3-dimethyl-1,4′-bipiperidine dihydrochloride (52.3 mg) were initially charged in 1 ml of water. Sodium carbonate (63.4 mg, 599 μmol) was added and the mixture was stirred at 120° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 37.0 mg (purity 100%, 55% of theory) of the target compound.

[1139] LC-MS (method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1140] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.882 (16.00), 1.150 (0.79), 1.160 (1.14), 1.170 (0.89), 1.468 (1.40), 1.479 (1.32), 1.488 (1.33), 1.729 (0.86), 1.747 (0.73), 2.097 (2.01), 2.392 (0.76), 2.473 (0.61), 3.034 (0.54), 3.038 (0.63), 3.056 (1.10), 3.076 (0.63), 3.080 (0.54), 3.902 (0.87), 3.923 (0.82), 4.520 (1.58), 4.529 (1.56), 7.826 (3.86), 7.894 (0.42), 7.898 (0.44), 7.911 (0.63), 7.913 (0.67), 7.926 (0.43), 7.930 (0.43), 8.464 (1.64), 8.468 (1.59), 8.699 (0.51), 8.709 (1.03), 8.719 (0.50).

Example 64

2-[4-(5-Azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1141] ##STR00207##

[1142] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 μmol) and 5-(piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (180 mg) were initially charged in 2 ml of water. Sodium carbonate (254 mg, 2.39 mmol) was added and the mixture was stirred at 120° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 108 mg (purity 100%, 40% of theory) of the target compound.

[1143] LC-MS (method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=448 [M+H].sup.+.

[1144] .sup.1H.NMR (500 MHz, DMSO-d.sub.6) δ [ppm]: δ 8.70 (t, 1H), 8.46 (d, 1H), 7.94-7.89 (m, 1H), 7.82 (s, 1H), 4.52 (d, 2H), 3.90 (d br, 2H), 3.08-3.02 (m, 2H), 2.47-2.40 (m, 3H), 2.19 (s, 2H) 1.77 (d br, 2H), 1.57 (m, 2H), 1.50-1.40 (m, 2H), 1.24 (t, 2H), 0.28-0.21 (m, 4H).

Example 65

rac-2-[4-(1,1-Difluoro-5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1145] ##STR00208##

[1146] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and rac-1,1-difluoro-5-(piperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (104 mg) were initially charged in 1 ml of water. Sodium carbonate (127 mg, 1.20 mmol) was added and the mixture was stirred at 120° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 62.0 mg (purity 100%, 43% of theory) of the target compound.

[1147] LC-MS (method 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1148] .sup.1H.NMR (500 MHz, DMSO-d.sub.6) δ [ppm]: δ 8.71 (t, 1H), 8.46 (d, 1H), 7.94-7.89 (m, 1H), 7.83 (s, 1H), 4.52 (d, 2H), 3.92 (d br, 2H), 3.10-3.02 (m, 2H), 2.67-2.57 (m, 3H), 2.44-2.37 (m, 2H), 1.78 (t br, 2H), 1.60 (m, 1H), 1.53-1.42 (m, 5H), 1.26-1.14 (m, 2H).

Example 66

rac-2-[3-(Cyclobutylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1149] ##STR00209##

[1150] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (12 μl, 210 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-(cyclobutylmethoxy)piperidine hydrochloride (58.4 mg, 284 μmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 μmol) was added and stirring of the mixture at room temperature was continued. After 1.5 h, more sodium triacetoxyborohydride (36.1 mg, 170 μmol) was added and stirring of the mixture at room temperature was continued. After 2 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 5.00 mg (purity 100%, 7% of theory) of the target compound.

[1151] LC-MS (method 1): R.sub.t=1.22 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1152] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.009 (0.53), 1.016 (0.59), 1.029 (1.45), 1.036 (1.37), 1.053 (1.53), 1.066 (0.71), 1.074 (0.56), 1.316 (0.60), 1.337 (1.44), 1.357 (1.50), 1.376 (0.65), 1.453 (0.95), 1.472 (2.73), 1.492 (2.83), 1.511 (1.08), 1.610 (1.84), 1.632 (1.99), 1.643 (3.00), 1.657 (3.90), 1.672 (3.26), 1.685 (1.32), 1.759 (3.93), 1.781 (4.11), 1.796 (2.12), 1.808 (3.21), 1.822 (4.29), 1.836 (2.48), 1.840 (1.45), 1.849 (0.87), 1.854 (0.98), 1.867 (0.44), 1.890 (1.64), 1.904 (1.62), 1.919 (1.99), 1.931 (3.81), 1.945 (6.23), 1.953 (3.44), 1.961 (4.23), 1.974 (1.09), 2.059 (1.35), 2.073 (2.48), 2.092 (1.33), 2.403 (1.00), 2.415 (2.19), 2.427 (2.80), 2.440 (2.11), 2.452 (0.94), 2.564 (1.15), 2.652 (2.37), 2.669 (1.88), 2.942 (1.96), 2.954 (1.82), 3.018 (2.55), 3.038 (4.84), 3.058 (2.54), 3.205 (1.36), 3.214 (1.73), 3.221 (2.34), 3.229 (1.64), 3.237 (1.32), 3.244 (0.74), 3.293 (0.74), 3.354 (1.90), 3.365 (2.08), 3.370 (5.42), 3.382 (7.32), 3.394 (5.38), 3.399 (2.01), 3.410 (1.64), 3.929 (3.33), 3.949 (3.21), 4.520 (6.95), 4.530 (6.93), 7.828 (16.00), 7.894 (1.82), 7.898 (1.94), 7.913 (2.92), 7.926 (1.83), 7.930 (1.88), 8.465 (7.15), 8.468 (7.02), 8.701 (2.24), 8.711 (4.57), 8.721 (2.24).

Example 67

rac-2-[3-(Cyclopropylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1153] ##STR00210##

[1154] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (60.8 mg, 182 μmol) and rac-3-(cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride (50.0 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 20.0 mg (purity 100%, 22% of theory) of the target compound.

[1155] LC-MS (method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1156] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.114 (2.20), 0.122 (7.19), 0.129 (7.41), 0.137 (2.33), 0.410 (2.11), 0.416 (6.34), 0.419 (6.12), 0.430 (6.52), 0.433 (6.08), 0.439 (1.85), 0.923 (1.53), 0.935 (2.28), 0.947 (1.44), 1.024 (0.64), 1.038 (1.55), 1.060 (1.59), 1.075 (0.78), 1.316 (0.66), 1.336 (1.50), 1.357 (1.60), 1.376 (0.70), 1.451 (1.00), 1.471 (2.74), 1.482 (2.39), 1.491 (2.85), 1.499 (1.88), 1.511 (1.16), 1.610 (1.97), 1.633 (1.67), 1.758 (3.91), 1.777 (3.38), 1.886 (1.71), 1.900 (1.62), 1.926 (2.05), 1.942 (3.48), 1.959 (2.11), 2.062 (1.42), 2.077 (2.57), 2.095 (1.40), 2.423 (0.62), 2.520 (1.90), 2.558 (1.22), 2.652 (2.62), 2.669 (2.02), 2.943 (2.00), 2.956 (1.92), 3.018 (2.70), 3.037 (5.11), 3.057 (2.70), 3.240 (13.81), 3.251 (14.04), 3.264 (2.67), 3.271 (1.87), 3.280 (1.60), 3.288 (1.56), 3.344 (0.84), 3.927 (3.48), 3.946 (3.30), 4.520 (7.38), 4.529 (7.39), 7.827 (16.00), 7.895 (1.83), 7.899 (1.91), 7.915 (3.15), 7.927 (1.89), 7.931 (1.94), 8.465 (7.46), 8.469 (7.11), 8.702 (2.42), 8.711 (4.84), 8.721 (2.39).

Example 68

rac-2-{3-[(Cyclobutyloxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1157] ##STR00211##

[1158] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and rac-3-[(cyclobutyloxy)methyl]-1,4′-bipiperidine dihydrochloride (144 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength: 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 38.0 mg (purity 100%, 25% of theory) of the target compound.

[1159] LC-MS (method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1160] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.880 (0.72), 0.897 (1.70), 0.913 (1.85), 0.932 (0.78), 1.361 (0.72), 1.381 (1.75), 1.387 (1.75), 1.404 (2.77), 1.418 (3.45), 1.435 (3.99), 1.443 (2.72), 1.450 (3.84), 1.463 (3.80), 1.483 (2.61), 1.574 (4.23), 1.588 (6.01), 1.604 (4.37), 1.622 (1.30), 1.659 (1.93), 1.753 (6.08), 1.761 (6.58), 1.768 (6.61), 1.774 (6.32), 1.804 (0.59), 1.883 (2.18), 1.900 (3.68), 1.917 (1.93), 2.099 (5.66), 2.113 (7.26), 2.131 (2.89), 2.522 (1.55), 2.691 (2.43), 2.709 (2.25), 2.788 (2.57), 2.802 (2.45), 3.022 (3.24), 3.041 (6.13), 3.061 (3.30), 3.084 (4.70), 3.098 (4.88), 3.101 (5.01), 3.111 (4.67), 3.117 (2.12), 3.127 (1.53), 3.294 (0.66), 3.357 (0.67), 3.793 (0.85), 3.805 (3.00), 3.818 (4.35), 3.829 (2.93), 3.842 (0.82), 3.924 (4.69), 3.945 (4.39), 4.520 (8.81), 4.529 (8.73), 7.827 (16.00), 7.896 (1.92), 7.911 (3.69), 7.926 (1.86), 8.464 (7.34), 8.467 (7.27), 8.700 (2.70), 8.709 (5.37), 8.719 (2.66).

Example 69

rac-2-{3-[(Cyclopropylmethoxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1161] ##STR00212##

[1162] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (50.9 mg, 152 μmol) and rac-3-[(cyclopropylmethoxy)methyl]-1,4′-bipiperidine dihydrochloride (44.0 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 15.0 mg (purity 100%, 19% of theory) of the target compound.

[1163] LC-MS (method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1164] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.118 (2.25), 0.126 (9.10), 0.134 (9.17), 0.142 (2.22), 0.419 (2.38), 0.426 (7.33), 0.427 (7.44), 0.439 (7.57), 0.441 (7.33), 0.448 (1.98), 0.889 (0.73), 0.904 (1.72), 0.922 (2.00), 0.947 (2.51), 0.958 (2.65), 0.969 (1.73), 0.978 (0.81), 1.369 (0.75), 1.388 (1.75), 1.409 (1.76), 1.428 (1.26), 1.435 (1.20), 1.447 (2.46), 1.467 (3.67), 1.487 (2.56), 1.507 (0.71), 1.573 (2.43), 1.579 (2.59), 1.593 (4.27), 1.609 (2.19), 1.705 (1.94), 1.766 (3.63), 1.894 (2.27), 1.911 (3.77), 1.928 (1.94), 2.099 (1.66), 2.114 (3.06), 2.132 (1.60), 2.526 (1.44), 2.701 (2.49), 2.719 (2.26), 2.802 (2.62), 2.817 (2.51), 3.026 (3.23), 3.045 (6.22), 3.064 (3.23), 3.147 (0.41), 3.165 (13.68), 3.176 (13.45), 3.191 (1.65), 3.206 (5.08), 3.219 (9.08), 3.228 (5.08), 3.234 (1.95), 3.244 (1.30), 3.296 (0.60), 3.923 (4.82), 3.944 (4.45), 4.521 (8.96), 4.530 (8.75), 7.827 (16.00), 7.893 (2.03), 7.896 (2.11), 7.911 (3.75), 7.924 (2.05), 7.928 (2.02), 8.464 (8.06), 8.467 (7.70), 8.700 (2.76), 8.710 (5.37), 8.719 (2.62).

Example 70

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-ethoxy[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1165] ##STR00213##

[1166] Acetic acid (12 μl, 210 μmol) was added to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-ethoxypiperidine (36.7 mg, 284 μmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 μmol) was added and stirring of the mixture at room temperature was continued. After 4 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 15.0 mg (purity 100%, 23% of theory) of the target compound.

[1167] LC-MS (method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1168] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.021 (0.44), 1.035 (0.92), 1.042 (0.86), 1.057 (8.38), 1.068 (16.00), 1.080 (8.12), 1.320 (0.40), 1.342 (0.87), 1.360 (0.89), 1.472 (1.63), 1.492 (1.70), 1.511 (0.65), 1.611 (1.11), 1.617 (0.92), 1.627 (0.80), 1.634 (1.00), 1.759 (2.28), 1.778 (1.99), 1.887 (0.97), 1.901 (0.93), 1.935 (1.27), 1.951 (2.00), 1.967 (1.30), 2.062 (0.81), 2.076 (1.56), 2.080 (1.49), 2.095 (0.84), 2.523 (1.00), 2.561 (0.76), 2.652 (1.54), 2.670 (1.13), 2.938 (1.14), 2.949 (1.07), 3.019 (1.52), 3.038 (2.87), 3.058 (1.56), 3.221 (0.46), 3.228 (0.88), 3.235 (1.05), 3.244 (1.46), 3.251 (1.03), 3.259 (0.83), 3.266 (0.45), 3.346 (0.70), 3.351 (0.76), 3.423 (0.98), 3.427 (1.06), 3.434 (1.21), 3.438 (4.04), 3.450 (6.06), 3.461 (4.04), 3.465 (1.20), 3.473 (1.09), 3.477 (0.96), 3.927 (1.96), 3.948 (1.87), 4.521 (4.14), 4.530 (4.13), 7.828 (11.05), 7.895 (1.16), 7.899 (1.24), 7.912 (1.70), 7.914 (1.80), 7.927 (1.19), 7.931 (1.24), 8.465 (4.56), 8.469 (4.52), 8.702 (1.37), 8.712 (2.80), 8.721 (1.38).

Example 71

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-{4-[(3R)-3-methylpiperidin-1-yl]azepan-1-yl}-1,3-thiazole-5-carboxamide

[1169] ##STR00214##

[1170] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (70.0 mg, 209 μmol) and 4-[(3R)-3-methylpiperidin-1-yl]azepane dihydrochloride (48.8 mg) were initially charged in 1 ml of water. Sodium carbonate (88.8 mg, 838 μmol) was added and the mixture was stirred at 120° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 38.0 mg (purity 100%, 40% of theory) of the target compound.

[1171] LC-MS (method 5): R.sub.t=1.80 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1172] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.763 (0.66), 0.790 (11.01), 0.794 (11.81), 0.800 (12.77), 0.805 (11.44), 1.354 (1.54), 1.368 (3.05), 1.373 (2.83), 1.387 (2.70), 1.409 (1.20), 1.488 (1.52), 1.534 (2.35), 1.556 (2.32), 1.593 (2.70), 1.614 (2.01), 1.688 (1.57), 1.705 (1.69), 1.722 (0.79), 1.740 (1.27), 1.757 (4.10), 1.773 (4.04), 1.790 (2.51), 1.894 (3.01), 2.065 (1.69), 2.383 (1.59), 2.399 (2.60), 2.417 (1.27), 2.599 (4.31), 2.615 (3.21), 3.354 (1.52), 3.378 (2.77), 3.397 (2.73), 3.655 (1.75), 4.519 (7.77), 4.528 (7.74), 7.825 (16.00), 7.893 (1.86), 7.897 (1.91), 7.909 (3.18), 7.924 (1.95), 7.928 (1.92), 8.463 (7.52), 8.467 (7.26), 8.646 (2.37), 8.656 (4.74), 8.665 (2.33).

Example 72

2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N-[(6-methylpyridin-3-yl)methyl]-1,3-thiazole-5-carboxamide

[1173] ##STR00215##

[1174] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (100 mg, 262 μmol) and 1-(6-methylpyridin yl)methanamine (35.1 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 19.0 mg (purity 100%, 18% of theory) of the target compound.

[1175] LC-MS (method 1): R.sub.t=0.55 min; MS (ESIneg): m/z=412 [M−H].sup.−.

[1176] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.799 (0.74), 0.811 (7.56), 0.822 (8.04), 1.388 (0.65), 1.408 (0.66), 1.466 (1.03), 1.490 (1.23), 1.508 (0.93), 1.519 (0.60), 1.525 (0.54), 1.564 (0.83), 1.580 (0.51), 1.586 (0.67), 1.615 (0.70), 1.636 (0.67), 1.732 (0.88), 1.750 (1.63), 1.767 (2.09), 1.783 (1.34), 2.032 (0.52), 2.046 (0.96), 2.050 (0.94), 2.065 (0.52), 2.431 (16.00), 2.470 (0.64), 2.720 (0.87), 2.734 (1.57), 2.751 (0.74), 3.026 (1.11), 3.044 (1.97), 3.064 (1.13), 3.924 (1.42), 3.945 (1.35), 4.349 (3.74), 4.359 (3.72), 7.196 (2.33), 7.210 (2.52), 7.556 (1.53), 7.560 (1.54), 7.570 (1.45), 7.573 (1.43), 7.795 (6.86), 8.366 (2.40), 8.370 (2.40), 8.711 (0.92), 8.721 (1.84), 8.731 (0.92).

Example 73

N-Benzyl-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1177] ##STR00216##

[1178] N,N-Diisopropylethylamine (100 μl, 580 μmol) and propylphosphonic anhydride (47 μl, 50% in ethyl acetate, 160 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid hydrochloride (50.0 mg, 145 μmol) and 1-phenylmethanamine (17 μl, 160 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature. After 30 min, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 25.0 mg (purity 100%, 43% of theory) of the target compound.

[1179] LC-MS (method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=399 [M+H].sup.+.

[1180] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.785 (0.53), 0.791 (0.62), 0.815 (14.94), 0.826 (16.00), 0.844 (0.63), 0.851 (0.53), 1.372 (0.52), 1.393 (1.35), 1.407 (0.92), 1.413 (1.45), 1.433 (0.62), 1.458 (0.78), 1.477 (2.21), 1.496 (2.75), 1.513 (2.00), 1.531 (1.04), 1.542 (0.63), 1.567 (1.74), 1.572 (1.34), 1.583 (1.05), 1.589 (1.39), 1.617 (1.47), 1.638 (1.39), 1.739 (1.91), 1.757 (3.65), 1.773 (4.17), 1.788 (2.83), 2.038 (1.12), 2.053 (2.08), 2.056 (2.04), 2.071 (1.14), 2.471 (1.17), 2.477 (0.82), 2.724 (1.87), 2.736 (3.43), 2.754 (1.63), 3.030 (2.28), 3.048 (4.18), 3.068 (2.31), 3.929 (3.15), 3.951 (2.98), 4.387 (7.95), 4.397 (7.93), 7.225 (1.22), 7.237 (3.31), 7.248 (2.13), 7.277 (4.54), 7.289 (8.70), 7.310 (6.60), 7.322 (7.31), 7.336 (2.52), 7.822 (11.60), 8.684 (1.68), 8.694 (3.35), 8.704 (1.70).

Example 74

diamix-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-({[3-fluorobutyl]oxy}methyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1181] ##STR00217##

[1182] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and diamix-3-[(3-fluorobutoxy)methyl]-1,4′-bipiperidine dihydrochloride (92.4 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 45.0 mg (purity 100%, 29% of theory) of the target compound.

[1183] LC-MS (method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=526 [M+H].sup.+.

[1184] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.894 (0.51), 0.910 (1.21), 0.927 (1.31), 0.946 (0.55), 1.231 (1.01), 1.249 (9.88), 1.259 (9.97), 1.289 (9.92), 1.300 (9.69), 1.367 (0.53), 1.387 (1.24), 1.407 (1.28), 1.426 (0.92), 1.434 (0.92), 1.445 (1.68), 1.455 (1.93), 1.465 (2.52), 1.476 (2.04), 1.485 (1.80), 1.493 (0.81), 1.504 (0.53), 1.574 (1.89), 1.589 (2.71), 1.595 (2.68), 1.698 (1.15), 1.710 (1.65), 1.721 (1.89), 1.729 (1.76), 1.734 (1.74), 1.742 (2.56), 1.752 (3.56), 1.758 (3.71), 1.768 (3.79), 1.771 (3.66), 1.777 (3.74), 1.780 (3.74), 1.787 (2.97), 1.799 (1.97), 1.808 (0.76), 1.900 (1.21), 1.915 (2.14), 1.931 (1.08), 2.101 (1.15), 2.115 (2.11), 2.133 (1.13), 2.485 (1.36), 2.522 (1.14), 2.698 (1.78), 2.716 (1.64), 2.788 (1.77), 2.804 (1.72), 3.023 (2.35), 3.043 (4.47), 3.064 (2.31), 3.181 (0.85), 3.197 (1.94), 3.209 (5.46), 3.221 (4.27), 3.231 (1.98), 3.237 (1.28), 3.247 (0.88), 3.368 (0.58), 3.378 (1.01), 3.384 (1.18), 3.387 (0.79), 3.394 (1.92), 3.401 (3.11), 3.411 (4.27), 3.421 (2.19), 3.428 (1.41), 3.431 (1.34), 3.441 (1.12), 3.444 (0.79), 3.457 (0.56), 3.921 (3.36), 3.943 (3.18), 4.521 (6.49), 4.530 (6.43), 4.687 (0.71), 4.698 (0.98), 4.708 (0.96), 4.718 (0.66), 4.769 (0.74), 4.780 (1.12), 4.790 (1.10), 4.800 (0.71), 7.828 (16.00), 7.892 (1.77), 7.896 (1.83), 7.909 (2.66), 7.911 (2.78), 7.924 (1.78), 7.928 (1.78), 8.463 (7.00), 8.467 (6.72), 8.701 (2.17), 8.710 (4.39), 8.720 (2.11).

Example 75

rac-2-(3-{[(3,3-Difluorocyclobutyl)methoxy]methyl}[1,4′-bipiperidin]-1′-yl)-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1185] ##STR00218##

[1186] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and rac-3-{[(3,3-difluorocyclobutyl)methoxy]methyl}-1,4′-bipiperidine dihydrochloride (286 mg) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 42.0 mg (purity 100%, 25% of theory) of the target compound.

[1187] LC-MS (method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=556 [M+H].sup.+.

[1188] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.911 (0.78), 0.928 (1.72), 0.945 (1.85), 0.963 (0.81), 1.374 (0.78), 1.394 (1.76), 1.414 (1.76), 1.434 (1.28), 1.441 (1.17), 1.454 (2.40), 1.466 (2.42), 1.473 (3.58), 1.486 (2.51), 1.493 (2.58), 1.596 (3.83), 1.731 (2.04), 1.759 (4.07), 1.917 (2.39), 1.935 (3.91), 1.952 (2.04), 2.110 (1.73), 2.126 (3.13), 2.144 (1.58), 2.261 (0.89), 2.274 (1.32), 2.295 (3.70), 2.317 (5.95), 2.336 (3.61), 2.485 (2.03), 2.521 (1.62), 2.564 (2.23), 2.574 (2.41), 2.578 (2.59), 2.587 (3.86), 2.601 (2.66), 2.611 (2.16), 2.701 (2.47), 2.719 (2.29), 2.789 (2.63), 2.804 (2.46), 3.029 (3.08), 3.050 (5.72), 3.070 (3.05), 3.231 (0.68), 3.247 (9.82), 3.258 (11.25), 3.358 (0.88), 3.381 (7.63), 3.389 (5.10), 3.405 (0.86), 3.921 (4.65), 3.943 (4.34), 4.524 (8.79), 4.534 (8.71), 7.823 (16.00), 7.878 (1.95), 7.882 (2.02), 7.897 (3.64), 7.910 (1.95), 7.914 (2.00), 8.458 (7.56), 8.462 (7.46), 8.665 (2.65), 8.674 (5.27), 8.684 (2.62).

Example 76

N-[(3-Fluoropyridin-4-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1189] ##STR00219##

[1190] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid hydrochloride (100 mg, 262 μmol) and 1-(3-fluoropyridin yl)methanamine (36.3 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 21.0 mg (purity 100%, 19% of theory) of the target compound.

[1191] LC-MS (method 1): R.sub.t=0.82 min; MS (ESIneg): m/z=416 [M−H].sup.−.

[1192] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.788 (0.58), 0.814 (15.04), 0.825 (16.00), 0.842 (0.70), 1.371 (0.56), 1.392 (1.36), 1.412 (1.46), 1.432 (0.62), 1.473 (2.29), 1.493 (2.88), 1.511 (2.09), 1.568 (1.79), 1.589 (1.42), 1.618 (1.54), 1.640 (1.49), 1.738 (1.72), 1.756 (3.14), 1.773 (4.60), 1.792 (2.86), 2.037 (1.07), 2.056 (2.00), 2.071 (1.12), 2.425 (0.56), 2.520 (1.70), 2.653 (0.50), 2.726 (1.87), 2.738 (3.35), 2.757 (1.60), 3.042 (2.38), 3.059 (4.22), 3.080 (2.39), 3.287 (0.93), 3.937 (3.04), 3.959 (2.92), 4.466 (7.56), 4.476 (7.60), 7.336 (2.33), 7.345 (3.35), 7.355 (2.45), 7.859 (12.63), 8.383 (4.52), 8.391 (4.59), 8.511 (6.60), 8.513 (6.51), 8.819 (1.88), 8.829 (3.81), 8.839 (1.85).

Example 77

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(2,2,2-trifluoroethoxy)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1193] ##STR00220##

[1194] Acetic acid (12 μl, 210 μmol) was added to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-(2,2,2-trifluoroethoxy)piperidine (52.0 mg, 284 μmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 μmol) was added and stirring of the mixture at room temperature was continued. After 1.5 h, more sodium triacetoxyborohydride (36.1 mg, 170 μmol) was added and stirring of the mixture at room temperature was continued. After 2 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 7.00 mg (purity 100%, 9% of theory) of the target compound.

[1195] LC-MS (method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=520 [M+H].sup.+.

[1196] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.124 (1.34), 1.147 (1.39), 1.160 (0.64), 1.343 (1.36), 1.365 (1.39), 1.475 (1.80), 1.496 (2.67), 1.516 (1.84), 1.637 (1.77), 1.658 (1.46), 1.758 (3.69), 1.777 (3.15), 1.916 (1.56), 2.015 (1.74), 2.032 (2.94), 2.048 (1.77), 2.106 (1.29), 2.120 (2.39), 2.138 (1.28), 2.423 (0.93), 2.565 (2.35), 2.584 (0.93), 2.640 (1.95), 2.652 (2.04), 2.658 (1.76), 2.969 (1.90), 2.981 (1.80), 3.025 (2.41), 3.045 (4.81), 3.065 (2.50), 3.282 (1.41), 3.289 (0.62), 3.345 (1.02), 3.350 (0.92), 3.447 (1.28), 3.455 (1.66), 3.462 (2.19), 3.470 (1.56), 3.478 (1.17), 3.934 (3.16), 3.953 (3.03), 4.042 (1.46), 4.049 (1.60), 4.058 (4.17), 4.065 (4.12), 4.073 (4.05), 4.081 (3.91), 4.096 (1.27), 4.520 (6.74), 4.529 (6.68), 7.828 (16.00), 7.895 (1.76), 7.900 (1.83), 7.915 (2.87), 7.927 (1.78), 7.931 (1.82), 8.465 (6.78), 8.469 (6.85), 8.703 (2.10), 8.712 (4.35), 8.722 (2.21).

Example 78

N-[(4,6-Dimethylpyridin-3-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1197] ##STR00221##

[1198] N,N-Diisopropylethylamine (180 μl, 1.0 mmol) and propylphosphonic anhydride (86 μl, 50% in ethyl acetate, 290 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid hydrochloride (100 mg, 262 μmol) and 1-(4,6-dimethylpyridin yl)methanamine (39.2 mg, 288 μmol) in 5 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm; mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume); total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 8.00 mg (purity 100%, 7% of theory) of the target compound.

[1199] LC-MS (method 1): R.sub.t=0.53 min; MS (ESIneg): m/z=426 [M−H].sup.−.

[1200] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: −0.149 (0.57), 0.146 (0.57), 0.808 (8.12), 0.825 (8.74), 1.382 (0.62), 1.413 (0.76), 1.422 (0.69), 1.465 (1.17), 1.486 (1.46), 1.494 (1.54), 1.513 (0.97), 1.559 (0.97), 1.601 (0.93), 1.640 (0.67), 1.724 (1.01), 1.751 (2.71), 1.776 (1.44), 1.786 (1.36), 2.023 (0.58), 2.045 (0.99), 2.073 (0.56), 2.263 (16.00), 2.327 (0.71), 2.366 (1.24), 2.386 (15.84), 2.459 (0.67), 2.669 (0.76), 2.674 (0.57), 2.710 (2.03), 2.736 (1.41), 3.013 (1.10), 3.039 (1.91), 3.070 (1.13), 3.294 (2.40), 3.916 (1.56), 3.949 (1.50), 4.352 (3.75), 4.366 (3.82), 7.051 (3.86), 7.802 (8.23), 8.243 (4.42), 8.518 (0.89), 8.532 (1.87), 8.546 (0.89).

Example 79

N-[(4-Chloro-1-methyl-1H-pyrazol-5-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1201] ##STR00222##

[1202] 30.9 mg (0.10 mmol) of 2-[(3R)-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-thiazole-5-carboxylic acid, 53.2 mg (0.14 mmol) of HATU and 50 μl of 4-methylmorpholine were dissolved in 0.7 ml of DMF and stirred at RT for 30 min. The solution was then added to 29.2 mg (0.20 mmol) of 1-(4-chloro-1-methyl-1H-pyrazol-5-yl)methanamine, which had been initially charged into a well of a 96-well multititre plate, and the multititre plate was sealed and shaken at RT overnight. 0.2 ml of water were then added, the mixture was filtered and the filtrate was separated into its components by preparative LC-MS using one of the following methods:

[1203] Prep. LC-MS Methods:

[1204] MS instrument: Waters, HPLC instrument: Waters (column Waters X-Bridge C18, 19 mm×50 mm, 5 μm, mobile phase A: water+0.375% ammonia, mobile phase B: acetonitrile (ULC)+0.375% ammonia with gradient; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

[1205] or alternatively:

[1206] MS instrument: Waters, HPLC instrument: Waters (column Phenomenex Luna 5μ C18(2) 100A, AXIA Tech. 50×21.2 mm, mobile phase A: water+0.0375% formic acid, mobile phase B: acetonitrile (ULC)+0.0375% formic acid with gradient; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

[1207] In this way, 27.7 mg (63% of theory, 96% purity) of the title compound were obtained.

[1208] LC-MS (method 6, ESIpos): R.sub.t=0.69 min; m/z=437 (M+H).sup.+.

[1209] .sup.1H-NMR (500 MHz, DMSO-d.sub.6, δ/ppm): 0.90 (d, 3H), 1.03-1.15 (m, 1H), 1.60-1.90 (m, 6H), 2.05-2.14 (m, 2H), 2.56-2.65 (m, 1H), 2.80-2.91 (m, 1H), 3.12 (br. t, 2H), 3.33 (br. d, 1H), 3.36-3.51 (m, 1H, partially obscured by H.sub.2O), 3.82 (s, 3H), 4.08 (br. d, 2H), 4.45 (d, 2H), 7.49 (s, 1H), 7.85 (s, 1H), 8.68 (t, 1H), 8.96-9.04 (m, 1H).

[1210] In a parallel-synthetic manner analogously to Example 79, the following compounds of Examples 80 to 98 were prepared from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid and the appropriate amine or its salt:

TABLE-US-00006 IUPAC name/structure Example (yield; purity) LC-MS (Method 6) 80 N-(3-methoxybenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.73 min; m/z = 429 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00223] 81 N-(2,5-difluorobenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.75 min; m/z = 435 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00224] 82 N-(3-hydroxybenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.66 min; m/z = 415 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00225] 83 rel-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N- R.sub.t = 0.76 min; m/z = 427 (M + H).sup.+ [(2R)-2-phenylpropyl]-1,3-thiazole-5- carboxamide (2 diastereomers) [00226] 84 N-(4-fluorobenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.73 min; m/z = 417 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00227] 85 2-[3R)-3-Methyl[1,4′-bipiperidin]-1′-yl]-N- R.sub.t = 0.63 min; m/z = 400 (M + H).sup.+ (pyridin-3-ylmethyl)-1,3-thiazole-5-carboxamide [00228] 86 N-(3-fluorobenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.72 min; m/z = 417 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00229] 87 N-(2-fluorobenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.73 min; m/z = 417 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00230] 88 N-(2-chloro-4-fluorophenyl)-2-[(3R)-3- R.sub.t = 0.76 min; m/z = 437 (M + H).sup.+ methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide [00231] 89 N-(3-cyano-4-fluorophenyl)-2-[(3R)-3- R.sub.t = 0.77 min; m/z = 428 (M + H).sup.+ methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide [00232] 90 N-methyl-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′- R.sub.t = 0.60 min; m/z = 414 (M + H).sup.+ yl]-N-(pyridin-3-ylmethyl)-1,3-thiazole-5- carboxamide [00233] 91 N-methyl-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′- R.sub.t = 0.57 min; m/z = 414 (M + H).sup.+ yl]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5- carboxamide [00234] 92 N-benzyl-N-methyl-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.75 min; m/z = 413 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00235] 93 N-(2-cyclopropylphenyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.87 min; m/z = 425 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00236] 94 N-(3-chlorobenzyl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.85 min; m/z = 433 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00237] 95 rel-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-N- R.sub.t = 0.87 min; m/z = 427 (M + H).sup.+ [(1R)-1-(4-methylphenyl)ethyl]-1,3-thiazole-5- carboxamide (2 diastereomers) [00238] 96 N-(5-chloro-2-hydroxyphenyl)-2-[(3R)-3- R.sub.t = 0.85 min; m/z = 435 (M + H).sup.+ methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide [00239] 97 N-(5-fluoro-2-methoxyphenyl)-2-[(3R)-3- R.sub.t = 0.87 min; m/z = 433 (M + H).sup.+ methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5- carboxamide [00240] 98 N-(2-ethylpyridin-4-yl)-2-[(3R)-3-methyl[1,4′- R.sub.t = 0.65 min; m/z = 414 (M + H).sup.+ bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide [00241]

Example 99

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1211] ##STR00242##

[1212] 45 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IG, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 15 ml/min; temperature 55° C., detection: 220 nm). The enantiomer having a retention time of 10.838 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 23 mg (99% ee) of the title compound.

[1213] LC-MS (method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1214] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.911 (0.66), 0.927 (0.72), 1.392 (0.58), 1.410 (0.63), 1.436 (0.52), 1.457 (1.21), 1.477 (1.28), 1.497 (0.51), 1.582 (1.53), 1.598 (1.39), 1.719 (0.66), 1.758 (1.52), 1.778 (1.33), 1.887 (0.89), 1.904 (1.48), 1.921 (0.77), 2.097 (0.59), 2.114 (1.12), 2.132 (0.59), 2.707 (0.80), 2.726 (0.79), 2.796 (0.89), 2.809 (0.83), 3.026 (1.13), 3.044 (2.13), 3.065 (1.14), 3.136 (0.55), 3.151 (1.82), 3.164 (3.39), 3.173 (1.89), 3.189 (0.57), 3.203 (16.00), 3.919 (1.63), 3.941 (1.53), 4.522 (2.97), 4.531 (2.96), 7.822 (5.28), 7.879 (0.69), 7.897 (1.23), 7.910 (0.69), 8.459 (2.58), 8.462 (2.46), 8.663 (0.90), 8.673 (1.76), 8.682 (0.91).

Example 100

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1215] ##STR00243##

[1216] 45 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IG, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 15 ml/min; temperature 55° C., detection: 220 nm). The enantiomer having a retention time of 11.879 min (HPLC: column Daicel® Chiralpak IE 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 19 mg (99% ee) of the title compound.

[1217] LC-MS (method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1218] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.912 (0.54), 0.927 (0.59), 1.393 (0.47), 1.411 (0.49), 1.437 (0.45), 1.458 (0.99), 1.469 (0.70), 1.478 (1.03), 1.497 (0.43), 1.582 (1.26), 1.599 (1.14), 1.720 (0.53), 1.759 (1.25), 1.778 (1.08), 1.887 (0.77), 1.904 (1.24), 1.921 (0.65), 2.098 (0.48), 2.113 (0.90), 2.132 (0.48), 2.521 (0.54), 2.708 (0.69), 2.725 (0.65), 2.795 (0.72), 2.809 (0.70), 3.027 (0.95), 3.044 (1.74), 3.065 (0.96), 3.136 (0.52), 3.151 (1.62), 3.164 (3.04), 3.173 (1.73), 3.179 (0.62), 3.189 (0.51), 3.203 (16.00), 3.920 (1.30), 3.942 (1.23), 4.523 (2.44), 4.532 (2.44), 7.822 (5.22), 7.878 (0.60), 7.882 (0.63), 7.897 (1.01), 7.910 (0.61), 7.914 (0.60), 8.459 (2.33), 8.462 (2.25), 8.664 (0.75), 8.673 (1.50), 8.683 (0.73).

Example 101

ent-2-{3-[(Cyclobutyloxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1219] ##STR00244##

[1220] 28 mg of rac-2-{3-[(cyclobutyloxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IG, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 15 ml/min; temperature 35° C., detection: 220 nm). The enantiomer having a retention time of 13.192 min (HPLC: column Daicel® Chiralpak IG 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 40° C.; detection: 220 nm) was collected. Removal of the solvents gave 11 mg (99% ee) of the title compound.

[1221] LC-MS (method 4): R.sub.t=0.61 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1222] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.890 (0.70), 0.905 (1.48), 0.923 (1.66), 0.941 (0.75), 1.236 (0.70), 1.365 (0.68), 1.384 (1.52), 1.391 (1.55), 1.405 (2.41), 1.409 (2.43), 1.422 (3.30), 1.426 (2.37), 1.436 (2.51), 1.439 (3.65), 1.453 (3.11), 1.457 (3.28), 1.469 (3.44), 1.477 (2.22), 1.488 (2.22), 1.576 (3.79), 1.592 (5.01), 1.608 (3.25), 1.626 (1.13), 1.661 (1.66), 1.736 (0.87), 1.757 (5.34), 1.765 (5.46), 1.772 (5.55), 1.779 (5.30), 1.809 (0.51), 1.892 (2.15), 1.909 (3.40), 1.926 (1.85), 2.088 (1.66), 2.092 (2.09), 2.105 (5.13), 2.120 (5.86), 2.132 (1.97), 2.136 (2.23), 2.421 (0.40), 2.523 (1.40), 2.693 (2.11), 2.711 (1.92), 2.788 (2.15), 2.803 (2.11), 3.027 (2.76), 3.045 (5.15), 3.065 (2.86), 3.077 (1.68), 3.093 (4.48), 3.106 (7.14), 3.117 (4.69), 3.123 (1.81), 3.132 (1.31), 3.260 (0.75), 3.797 (0.82), 3.810 (2.77), 3.822 (3.96), 3.834 (2.63), 3.846 (0.73), 3.924 (4.03), 3.945 (3.80), 4.523 (7.43), 4.532 (7.38), 7.822 (16.00), 7.878 (1.81), 7.882 (1.92), 7.897 (3.16), 7.910 (1.88), 7.913 (1.87), 8.458 (7.01), 8.462 (6.89), 8.664 (2.34), 8.673 (4.66), 8.683 (2.34).

Example 102

ent-2-{3-[(Cyclobutyloxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1223] ##STR00245##

[1224] 28 mg of rac-2-{3-[(cyclobutyloxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IG, 5 μm, 250×20 mm; mobile phase: 100% ethanol+0.2% diethylamine; flow rate 15 ml/min; temperature 35° C., detection: 220 nm). The enantiomer having a retention time of 15.649 min (HPLC: column Daicel® Chiralpak IG 5 μm, flow rate 1 ml/min; mobile phase: 100% ethanol+0.2% diethylamine; temperature 40° C.; detection: 220 nm) was collected. Removal of the solvents gave 15 mg (99% ee) of the title compound.

[1225] LC-MS (method 4): R.sub.t=0.61 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1226] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.892 (0.70), 0.911 (1.47), 0.925 (1.61), 0.944 (0.75), 1.181 (0.58), 1.236 (0.75), 1.393 (1.83), 1.406 (2.67), 1.410 (2.79), 1.423 (3.49), 1.427 (2.71), 1.437 (2.88), 1.441 (3.93), 1.454 (3.44), 1.458 (3.62), 1.471 (3.83), 1.479 (2.52), 1.490 (2.38), 1.578 (4.21), 1.593 (5.37), 1.609 (3.64), 1.627 (1.42), 1.664 (1.80), 1.737 (1.27), 1.758 (5.60), 1.766 (5.97), 1.773 (5.87), 1.781 (5.68), 1.810 (0.82), 1.898 (1.60), 1.915 (2.56), 1.931 (1.34), 2.089 (2.00), 2.093 (2.40), 2.107 (5.04), 2.111 (4.26), 2.117 (4.59), 2.122 (4.87), 2.136 (2.03), 2.423 (0.43), 2.572 (0.60), 2.697 (1.87), 2.716 (1.71), 2.793 (2.04), 2.808 (1.91), 3.028 (2.85), 3.046 (5.10), 3.066 (3.05), 3.078 (2.04), 3.094 (4.70), 3.108 (6.61), 3.118 (4.75), 3.124 (2.06), 3.134 (1.53), 3.798 (0.78), 3.811 (2.64), 3.822 (3.74), 3.835 (2.51), 3.847 (0.68), 3.926 (3.99), 3.947 (3.69), 4.524 (7.26), 4.533 (7.00), 7.824 (16.00), 7.878 (2.01), 7.882 (2.03), 7.895 (2.96), 7.898 (2.98), 7.910 (1.94), 7.914 (1.86), 8.459 (7.08), 8.463 (6.55), 8.665 (2.41), 8.675 (4.52), 8.684 (2.21).

Example 103

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-isopropyl[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide

[1227] ##STR00246##

[1228] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50.0 mg, 142 μmol) and rac-3-isopropylpiperidine (36.1 mg, 284 μmol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and stirring of the mixture at room temperature was continued. After 15 h, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 23.0 mg (100% purity, 35% of theory) of the title compound.

[1229] LC-MS (method 5): R.sub.t=1.85 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1230] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.837 (14.82), 0.843 (15.99), 0.848 (16.00), 0.854 (15.31), 0.877 (1.10), 0.883 (1.12), 0.897 (1.16), 0.903 (1.14), 0.917 (0.49), 0.923 (0.43), 1.160 (0.54), 1.171 (0.93), 1.177 (1.09), 1.183 (0.97), 1.188 (1.09), 1.195 (0.85), 1.206 (0.49), 1.334 (0.44), 1.354 (1.17), 1.375 (1.58), 1.387 (1.58), 1.398 (2.24), 1.409 (1.94), 1.420 (1.12), 1.441 (0.42), 1.448 (0.49), 1.461 (1.12), 1.467 (1.32), 1.486 (1.96), 1.506 (1.42), 1.525 (0.55), 1.533 (0.43), 1.600 (1.43), 1.606 (1.16), 1.616 (0.92), 1.622 (1.22), 1.627 (0.94), 1.647 (1.19), 1.668 (1.14), 1.765 (1.59), 1.778 (2.27), 1.792 (1.35), 1.866 (1.66), 1.883 (3.02), 1.901 (1.55), 2.024 (1.02), 2.038 (1.80), 2.042 (1.78), 2.057 (1.01), 2.524 (1.03), 2.733 (1.42), 2.751 (1.37), 2.770 (1.47), 2.786 (1.40), 3.020 (1.59), 3.026 (1.23), 3.041 (2.88), 3.057 (1.18), 3.063 (1.59), 3.931 (2.24), 3.948 (2.14), 4.523 (4.92), 4.532 (4.94), 7.821 (13.40), 7.879 (1.40), 7.883 (1.52), 7.895 (2.03), 7.898 (2.11), 7.910 (1.43), 7.914 (1.50), 8.459 (5.28), 8.462 (5.28), 8.662 (1.61), 8.672 (3.25), 8.681 (1.63).

Example 104

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1231] ##STR00247##

[1232] 33 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase: 70% n-heptane, mobile phase B: 30% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 60° C., detection: 220 nm). The enantiomer having a retention time of 10.241 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 70% n-heptane, mobile phase B: 30% ethanol+0.2% diethylamine in B; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 15 mg (99% ee) of the title compound.

[1233] LC-MS (method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1234] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.876 (16.00), 0.887 (15.94), 1.181 (1.40), 1.200 (1.81), 1.223 (2.27), 1.240 (2.37), 1.257 (1.01), 1.446 (2.85), 1.460 (3.55), 1.479 (2.38), 1.572 (1.57), 1.595 (1.81), 1.613 (1.45), 1.619 (1.81), 1.642 (3.31), 1.648 (3.08), 1.655 (2.78), 1.756 (2.90), 2.422 (0.41), 2.611 (1.54), 2.668 (2.96), 3.023 (2.75), 3.040 (5.00), 3.061 (2.82), 3.926 (3.42), 3.946 (3.24), 4.523 (7.45), 4.532 (7.44), 7.820 (14.18), 7.879 (1.77), 7.882 (1.83), 7.895 (3.04), 7.910 (1.83), 7.914 (1.85), 8.458 (6.84), 8.462 (6.66), 8.663 (2.10), 8.672 (4.24), 8.682 (2.21).

Example 105

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1235] ##STR00248##

[1236] 33 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(4-methylazepan-1-yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase: 70% n-heptane, mobile phase B: 30% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 60° C., detection: 220 nm). The enantiomer having a retention time of 10.783 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 70% n-heptane, mobile phase B: 30% ethanol+0.2% diethylamine in B; temperature 60° C.; detection: 220 nm) was collected. Removal of the solvents gave 16 mg (99% ee) of the title compound.

[1237] LC-MS (method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1238] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.876 (15.76), 0.887 (16.00), 1.181 (1.39), 1.201 (1.73), 1.223 (2.16), 1.240 (2.40), 1.257 (1.05), 1.444 (2.79), 1.458 (3.56), 1.477 (2.43), 1.572 (1.52), 1.596 (1.76), 1.641 (3.34), 1.647 (3.12), 1.655 (2.79), 1.754 (3.00), 2.610 (1.55), 2.664 (3.12), 3.023 (2.70), 3.040 (4.97), 3.060 (2.82), 3.258 (0.86), 3.324 (0.78), 3.924 (3.44), 3.944 (3.25), 4.522 (7.39), 4.531 (7.46), 7.819 (14.10), 7.879 (1.72), 7.882 (1.79), 7.895 (3.01), 7.910 (1.67), 7.914 (1.76), 8.458 (6.66), 8.462 (6.47), 8.663 (2.16), 8.672 (4.25), 8.682 (2.15).

Example 106

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidin]-1′-yl}-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1239] ##STR00249##

[1240] 53 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidin]-1′-yl}-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase A: 55% n-heptane, mobile phase B: 45% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 60° C., detection: 220 nm). The enantiomer having a retention time of 5.622 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; temperature 70° C.; detection: 220 nm) was collected. Removal of the solvents gave 27 mg (99% ee) of the title compound.

[1241] LC-MS (method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1242] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.957 (1.60), 0.972 (1.65), 0.991 (0.73), 1.405 (1.42), 1.422 (1.56), 1.433 (1.26), 1.453 (2.17), 1.474 (3.10), 1.493 (2.23), 1.591 (3.88), 1.609 (3.56), 1.771 (4.73), 1.974 (1.76), 2.155 (1.88), 2.697 (1.60), 2.780 (1.80), 2.796 (1.72), 3.030 (2.88), 3.051 (5.58), 3.071 (2.93), 3.322 (0.44), 3.426 (0.55), 3.443 (8.06), 3.454 (9.47), 3.926 (4.21), 3.948 (4.04), 3.977 (3.49), 3.993 (10.05), 4.008 (9.84), 4.024 (3.21), 4.524 (8.20), 4.533 (8.19), 7.823 (16.00), 7.879 (1.88), 7.882 (2.06), 7.898 (3.42), 7.910 (1.91), 7.914 (2.03), 8.458 (7.35), 8.462 (7.51), 8.667 (2.44), 8.676 (4.94), 8.685 (2.45).

Example 107

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidin]-1′-yl}-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1243] ##STR00250##

[1244] 53 mg of rac-N-[ (3,5-difluoropyridin-2-yl)methyl]-2-{3-[(2,2,2-trifluoroethoxy)methyl][1,4′-bipiperidin]-1′-yl}-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase A: 55% n-heptane, mobile phase B: 45% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 60° C., detection: 220 nm). The enantiomer having a retention time of 6.301 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; temperature 70° C.; detection: 220 nm) was collected. Removal of the solvents gave 25 mg (99% ee) of the title compound.

[1245] LC-MS (method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1246] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.956 (1.27), 0.972 (1.33), 1.403 (1.14), 1.422 (1.29), 1.433 (1.11), 1.453 (1.79), 1.473 (2.52), 1.493 (1.88), 1.592 (3.06), 1.608 (2.89), 1.770 (3.84), 1.973 (1.45), 2.154 (1.54), 2.693 (1.28), 2.780 (1.42), 2.794 (1.42), 3.030 (2.30), 3.050 (4.43), 3.071 (2.43), 3.426 (0.52), 3.443 (6.29), 3.454 (7.83), 3.926 (3.34), 3.947 (3.28), 3.977 (3.35), 3.992 (9.35), 4.008 (9.05), 4.024 (3.07), 4.524 (6.38), 4.532 (6.45), 7.823 (16.00), 7.878 (1.79), 7.882 (1.93), 7.895 (2.60), 7.897 (2.76), 7.910 (1.89), 7.914 (1.90), 8.458 (6.68), 8.462 (6.64), 8.666 (2.02), 8.676 (4.13), 8.685 (2.11).

Example 108

diamix-2-{3-[(2,2-Difluorocyclopropyl)methoxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1247] ##STR00251##

[1248] N,N-Diisopropylethylamine (200 μl, 1.1 mmol) was added to a solution of diamix-3-[(2,2-difluorocyclopropyl)methoxy]piperidine sulfate hydrochloride (185 mg, 568 μmol) in 5 ml of dichloromethane, and the mixture was stirred for 5 min, after which N-[(3,5-difluoropyridin yl)methyl-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (100 mg, 284 μmol) and acetic acid (19 μl, 340 μmol) were added to the mixture. The mixture was then stirred at room temperature. After 3 h, sodium triacetoxyborohydride (90.2 mg, 426 μmol) was added to the mixture and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 10.0 mg (purity 100%, 7% of theory) of the target compound.

[1249] LC-MS (method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=528 [M+H].sup.+.

[1250] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.074 (1.61), 1.091 (1.50), 1.237 (1.72), 1.251 (1.61), 1.348 (1.50), 1.367 (1.61), 1.488 (2.47), 1.548 (1.93), 1.556 (1.40), 1.568 (1.83), 1.623 (1.83), 1.764 (3.97), 1.783 (3.54), 1.907 (2.58), 1.963 (1.61), 1.982 (2.79), 1.997 (1.61), 2.098 (1.83), 2.383 (0.97), 2.422 (1.29), 2.566 (1.40), 2.611 (0.86), 2.651 (2.79), 2.942 (2.04), 2.956 (1.93), 3.023 (2.79), 3.043 (5.26), 3.063 (2.79), 3.254 (1.40), 3.260 (0.64), 3.315 (3.76), 3.322 (3.97), 3.375 (1.07), 3.391 (2.58), 3.406 (2.79), 3.423 (1.40), 3.570 (2.04), 3.581 (1.93), 3.928 (3.65), 3.950 (3.44), 4.524 (7.73), 4.532 (7.84), 7.822 (16.00), 7.879 (1.93), 7.883 (2.15), 7.897 (3.22), 7.910 (2.04), 7.914 (2.04), 8.459 (7.30), 8.462 (7.41), 8.666 (2.36), 8.675 (4.83), 8.685 (2.36).

Example 109

rac-2-[3-(Cyclobutyloxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1251] ##STR00252##

[1252] N,N-Diisopropylethylamine (200 μl, 1.1 mmol) and acetic acid (19 μl, 340 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (100 mg, 284 μmol) and rac-3-(cyclobutyloxy)piperidine sulfate hydrochloride (164 mg, 568 μmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 μmol) was added and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 10.0 mg (purity 100%, 7% of theory) of the target compound.

[1253] LC-MS (method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1254] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.034 (0.72), 1.046 (1.63), 1.069 (1.63), 1.083 (0.81), 1.091 (0.68), 1.311 (0.68), 1.333 (1.54), 1.352 (1.72), 1.372 (1.08), 1.385 (1.04), 1.390 (1.58), 1.403 (2.76), 1.407 (1.72), 1.416 (1.72), 1.420 (3.07), 1.433 (1.99), 1.438 (2.26), 1.445 (1.31), 1.458 (2.98), 1.464 (3.12), 1.478 (3.30), 1.485 (3.12), 1.498 (1.45), 1.505 (1.27), 1.550 (0.90), 1.567 (2.53), 1.585 (2.71), 1.600 (2.85), 1.623 (1.76), 1.757 (4.84), 1.777 (6.37), 1.790 (4.07), 1.810 (3.30), 1.823 (2.53), 1.838 (1.76), 1.937 (2.21), 1.953 (3.66), 1.969 (2.26), 2.046 (1.49), 2.064 (2.71), 2.079 (1.54), 2.112 (3.44), 2.120 (3.39), 2.383 (0.45), 2.422 (0.59), 2.465 (0.50), 2.611 (0.54), 2.641 (2.26), 2.651 (1.94), 2.659 (2.12), 2.864 (2.08), 2.882 (1.94), 3.019 (2.89), 3.037 (5.24), 3.057 (2.94), 3.234 (1.63), 3.243 (2.12), 3.250 (2.85), 3.257 (3.12), 3.924 (3.98), 3.946 (3.84), 3.968 (0.90), 3.980 (2.71), 3.993 (3.80), 4.005 (2.62), 4.017 (0.77), 4.523 (7.73), 4.532 (7.73), 7.823 (16.00), 7.879 (1.90), 7.882 (2.08), 7.897 (3.30), 7.910 (1.99), 7.914 (2.03), 8.459 (7.28), 8.462 (7.37), 8.666 (2.44), 8.676 (4.79), 8.685 (2.44).

Example 110

rac-2-{3-[(3,3-Difluorocyclobutyl)oxy][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin yl)methyl]-1,3-thiazole-5-carboxamide

[1255] ##STR00253##

[1256] N,N-Diisopropylethylamine (200 μl, 1.1 mmol) and acetic acid (19 μl, 340 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (100 mg, 284 μmol) and rac-3-[(3,3-difluorocyclobutyl)oxy]piperidine sulfate hydrochloride (185 mg, 568 μmol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 μmol) was added and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 30.0 mg (purity 100%, 20% of theory) of the target compound.

[1257] LC-MS (method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=528 [M+H].sup.+.

[1258] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.083 (0.83), 1.097 (2.04), 1.119 (2.12), 1.134 (0.94), 1.324 (0.86), 1.344 (1.99), 1.364 (2.10), 1.384 (0.88), 1.478 (3.86), 1.498 (4.08), 1.518 (1.52), 1.621 (2.46), 1.643 (2.15), 1.757 (5.57), 1.777 (4.80), 1.853 (2.32), 1.867 (2.21), 2.003 (2.54), 2.019 (4.36), 2.035 (2.65), 2.084 (1.85), 2.100 (3.42), 2.117 (1.88), 2.422 (2.26), 2.431 (2.76), 2.441 (2.59), 2.446 (2.68), 2.451 (2.73), 2.459 (2.87), 2.468 (2.12), 2.524 (2.07), 2.561 (1.68), 2.636 (2.87), 2.654 (2.79), 2.874 (4.00), 2.884 (5.49), 2.901 (3.70), 3.019 (3.59), 3.040 (6.90), 3.061 (3.56), 3.257 (0.66), 3.265 (0.69), 3.308 (2.37), 3.317 (2.76), 3.325 (3.06), 3.331 (2.48), 3.340 (1.74), 3.929 (5.08), 3.951 (4.86), 4.101 (2.37), 4.524 (9.90), 4.533 (9.74), 7.824 (16.00), 7.882 (2.21), 7.897 (4.14), 7.914 (2.18), 8.459 (7.92), 8.462 (8.17), 8.667 (2.84), 8.677 (5.71), 8.686 (2.92).

Example 111

diamix-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-4-carboxamide

[1259] ##STR00254##

[1260] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (70.9 mg, 259 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm, mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 78.0 mg (purity 100%, 57% of theory) of the target compound.

[1261] LC-MS (method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1262] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.816 (10.43), 0.823 (12.35), 0.826 (12.52), 0.834 (10.93), 0.849 (1.65), 0.869 (0.67), 1.386 (0.84), 1.406 (1.13), 1.428 (1.10), 1.448 (0.90), 1.469 (0.43), 1.497 (0.61), 1.503 (0.75), 1.514 (0.75), 1.552 (0.84), 1.572 (2.20), 1.588 (1.25), 1.594 (1.45), 1.629 (1.77), 1.649 (1.68), 1.689 (1.68), 1.706 (1.97), 1.887 (1.48), 1.896 (1.86), 1.904 (2.87), 1.917 (2.26), 1.923 (2.52), 1.938 (1.57), 1.946 (1.48), 1.958 (0.55), 1.965 (0.43), 2.175 (1.28), 2.193 (2.38), 2.210 (1.19), 2.591 (1.04), 2.596 (1.01), 2.611 (1.25), 2.650 (1.25), 2.672 (1.01), 2.838 (3.19), 2.846 (3.16), 3.105 (1.42), 3.122 (2.61), 3.126 (2.52), 3.143 (1.42), 3.213 (2.09), 3.236 (2.17), 3.262 (0.78), 3.279 (3.51), 3.302 (2.87), 4.028 (1.68), 4.049 (1.59), 4.189 (1.10), 4.210 (2.03), 4.229 (1.01), 4.578 (7.30), 4.588 (7.30), 5.065 (2.26), 5.149 (2.29), 7.373 (16.00), 7.883 (1.88), 7.887 (2.00), 7.902 (2.96), 7.915 (1.88), 7.919 (1.94), 8.452 (7.65), 8.456 (8.70), 8.467 (4.12), 8.477 (2.09).

Example 112

diamix-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-oxazole-4-carboxamide

[1263] ##STR00255##

[1264] 2-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide (100 mg, 314 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (86.5 mg, 317 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm, mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 81.0 mg (purity 100%, 51% of theory) of the target compound.

[1265] LC-MS (method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=438 [M+H].sup.+.

[1266] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.809 (11.35), 0.817 (14.02), 0.820 (14.57), 0.827 (12.10), 0.841 (2.08), 0.862 (0.75), 1.379 (1.01), 1.398 (1.40), 1.419 (1.40), 1.440 (1.11), 1.460 (0.55), 1.505 (0.91), 1.564 (2.73), 1.586 (1.85), 1.623 (2.24), 1.644 (4.13), 1.665 (2.50), 1.864 (1.53), 1.880 (3.45), 1.889 (3.32), 1.900 (2.57), 1.906 (2.57), 2.068 (5.46), 2.160 (1.56), 2.178 (3.09), 2.197 (1.63), 2.578 (1.40), 2.615 (1.46), 2.636 (1.33), 2.824 (4.33), 3.057 (1.72), 3.075 (3.28), 3.096 (1.76), 3.181 (2.67), 3.205 (2.83), 3.246 (2.83), 3.259 (1.01), 3.271 (3.77), 3.317 (0.52), 4.085 (2.37), 4.106 (2.28), 4.130 (1.63), 4.150 (2.67), 4.173 (1.46), 4.561 (9.04), 4.570 (9.01), 5.028 (2.86), 5.111 (2.89), 7.883 (2.02), 7.887 (2.05), 7.901 (3.64), 7.915 (2.05), 7.919 (2.02), 8.004 (16.00), 8.207 (2.47), 8.217 (4.81), 8.226 (2.37), 8.459 (7.93), 8.463 (7.61).

Example 113

diamix-N-(5-Chloro-2-fluorobenzyl)-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1267] ##STR00256##

[1268] 2-Bromo-N-(5-chloro-2-fluorobenzyl)-1,3-thiazole-5-carboxamide (100 mg, 286 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (67.7 mg, 248 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm, mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 25.0 mg (purity 97%, 18% of theory) of the target compound.

[1269] LC-MS (method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=469 [M+H].sup.+.

[1270] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.809 (11.21), 0.818 (13.98), 0.820 (14.09), 0.828 (11.39), 0.843 (2.02), 0.863 (0.72), 1.122 (0.47), 1.381 (0.94), 1.401 (1.30), 1.423 (1.26), 1.443 (1.08), 1.464 (0.58), 1.496 (0.90), 1.565 (2.85), 1.587 (1.84), 1.623 (2.16), 1.645 (2.09), 1.681 (1.98), 1.699 (2.38), 1.884 (3.14), 1.892 (3.71), 1.909 (2.56), 1.927 (0.58), 2.162 (1.41), 2.180 (2.70), 2.199 (1.41), 2.384 (0.43), 2.422 (0.47), 2.607 (1.37), 2.622 (1.15), 2.665 (1.15), 2.682 (1.15), 2.823 (4.07), 3.143 (1.62), 3.160 (3.03), 3.181 (1.69), 3.241 (2.59), 3.265 (3.96), 3.307 (3.14), 3.332 (2.49), 3.411 (0.86), 4.001 (2.09), 4.024 (1.98), 4.174 (1.37), 4.195 (2.34), 4.217 (1.23), 4.405 (10.20), 4.414 (10.13), 5.058 (2.77), 5.140 (2.74), 7.231 (3.17), 7.247 (6.09), 7.262 (3.96), 7.352 (4.36), 7.362 (6.56), 7.375 (2.56), 7.382 (2.45), 7.822 (16.00), 8.713 (2.52), 8.722 (5.01), 8.732 (2.56).

Example 114

2-[(3R)-3-(Cyclopropylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1271] ##STR00257##

[1272] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (80.2 mg, 240 μmol) and (3R)-3-(cyclopropylmethoxy)-1,4′-bipiperidine dihydrochloride (66.0 mg, 212 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 hour. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm, mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature, wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 46.0 mg (purity 100%, 39% of theory) of the target compound.

[1273] LC-MS (method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1274] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.116 (2.25), 0.124 (7.52), 0.131 (7.71), 0.140 (2.25), 0.411 (2.21), 0.417 (6.60), 0.420 (6.38), 0.431 (6.78), 0.433 (6.27), 0.440 (1.84), 0.915 (0.77), 0.926 (1.59), 0.937 (2.32), 0.948 (1.55), 1.023 (0.59), 1.030 (0.66), 1.044 (1.59), 1.067 (1.66), 1.080 (0.77), 1.088 (0.66), 1.320 (0.70), 1.339 (1.59), 1.359 (1.62), 1.380 (0.70), 1.455 (1.11), 1.474 (2.95), 1.486 (2.40), 1.494 (3.13), 1.514 (1.25), 1.613 (2.06), 1.636 (1.73), 1.762 (4.17), 1.781 (3.65), 1.885 (1.81), 1.900 (1.73), 1.933 (2.21), 1.949 (3.69), 1.965 (2.25), 2.067 (1.51), 2.081 (2.73), 2.099 (1.47), 2.422 (0.44), 2.521 (1.73), 2.557 (1.33), 2.652 (2.54), 2.671 (2.14), 2.943 (2.18), 2.955 (2.03), 3.021 (2.80), 3.040 (5.46), 3.060 (2.88), 3.243 (14.49), 3.255 (14.56), 3.268 (3.61), 3.320 (0.81), 3.927 (3.80), 3.946 (3.61), 4.523 (7.74), 4.532 (7.71), 7.822 (16.00), 7.878 (1.92), 7.882 (1.99), 7.895 (3.17), 7.910 (1.95), 7.914 (1.92), 8.459 (7.37), 8.462 (7.12), 8.665 (2.43), 8.675 (4.83), 8.684 (2.40).

Example 115

ent-2-{3-[(Cyclopropylmethoxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1275] ##STR00258##

[1276] 67 mg of rac-2-{3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase A: 60% n-heptane, mobile phase B: 40% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 55° C., detection: 220 nm). The enantiomer having a retention time of 8.062 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; temperature 55° C.; detection: 220 nm) was collected. Removal of the solvents gave 30 mg (99% ee) of the title compound.

[1277] LC-MS (method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1278] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: −0.146 (2.10), −0.024 (1.44), −0.017 (5.45), −0.009 (5.51), 0.275 (1.55), 0.282 (4.53), 0.285 (4.49), 0.288 (2.09), 0.295 (4.69), 0.298 (4.42), 0.305 (1.34), 0.755 (0.46), 0.773 (1.01), 0.791 (1.41), 0.794 (1.44), 0.804 (1.40), 0.807 (1.47), 0.815 (1.92), 0.823 (1.00), 0.826 (1.08), 0.835 (0.50), 1.230 (0.43), 1.249 (1.00), 1.269 (1.02), 1.290 (0.76), 1.298 (0.72), 1.310 (1.42), 1.322 (1.47), 1.330 (2.10), 1.338 (1.53), 1.350 (1.51), 1.369 (0.44), 1.433 (1.41), 1.439 (1.58), 1.451 (2.33), 1.467 (1.38), 1.566 (1.12), 1.617 (2.07), 1.623 (2.07), 1.764 (0.92), 1.781 (1.55), 1.798 (0.81), 1.965 (0.79), 1.983 (1.44), 2.000 (0.76), 2.352 (9.20), 2.355 (11.79), 2.357 (8.79), 2.369 (1.29), 2.394 (16.00), 2.580 (1.15), 2.662 (1.37), 2.678 (1.31), 2.885 (1.91), 2.904 (3.60), 2.923 (1.91), 3.026 (9.38), 3.037 (9.30), 3.053 (1.05), 3.069 (3.29), 3.080 (5.47), 3.089 (3.47), 3.095 (1.22), 3.105 (0.91), 3.143 (10.67), 3.780 (2.83), 3.801 (2.66), 4.379 (5.25), 4.388 (5.22), 7.679 (11.00), 7.732 (1.28), 7.735 (1.33), 7.748 (2.15), 7.750 (2.18), 7.763 (1.30), 7.767 (1.30), 8.313 (4.95), 8.316 (4.80), 8.520 (1.64), 8.529 (3.26), 8.538 (1.62).

Example 116

ent-2-{3-[(Cyclopropylmethoxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1279] ##STR00259##

[1280] 67 mg of rac-2-{3-[(cyclopropylmethoxy)methyl][1,4′-bipiperidin]-1′-yl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak AY-H, 5 μm, 250×20 mm; mobile phase A: 60% n-heptane, mobile phase B: 40% ethanol+0.2% diethylamine in B; flow rate 15 ml/min; temperature 55° C., detection: 220 nm). The enantiomer having a retention time of 8.740 min (HPLC: column Daicel® Chiralpak AY-H 5 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; temperature 55° C.; detection: 220 nm) was collected. Removal of the solvents gave 28 mg (99% ee) of the title compound.

[1281] LC-MS (method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1282] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: −0.146 (2.11), −0.024 (0.87), −0.017 (3.12), −0.015 (3.03), −0.009 (3.17), −0.007 (3.10), 0.275 (0.95), 0.282 (2.68), 0.285 (2.76), 0.288 (1.22), 0.292 (1.19), 0.295 (2.78), 0.298 (2.72), 0.305 (0.83), 0.774 (0.55), 0.791 (0.83), 0.793 (0.81), 0.804 (0.78), 0.807 (0.82), 0.815 (1.19), 0.823 (0.58), 0.826 (0.62), 1.250 (0.55), 1.270 (0.56), 1.291 (0.42), 1.298 (0.41), 1.310 (0.79), 1.322 (0.82), 1.330 (1.17), 1.338 (0.85), 1.350 (0.84), 1.452 (1.28), 1.467 (0.79), 1.567 (0.60), 1.623 (1.14), 1.766 (0.43), 1.783 (0.69), 1.984 (0.68), 2.351 (8.08), 2.354 (10.97), 2.357 (8.10), 2.369 (0.63), 2.393 (16.00), 2.581 (0.58), 2.662 (0.72), 2.679 (0.68), 2.886 (1.09), 2.904 (2.03), 2.924 (1.09), 3.026 (5.94), 3.037 (5.84), 3.054 (0.64), 3.069 (1.97), 3.081 (3.29), 3.089 (2.05), 3.095 (0.72), 3.105 (0.53), 3.141 (15.73), 3.779 (1.60), 3.801 (1.51), 4.378 (3.00), 4.387 (2.96), 7.678 (7.07), 7.732 (0.80), 7.736 (0.84), 7.749 (1.21), 7.751 (1.24), 7.764 (0.81), 7.768 (0.81), 8.312 (3.04), 8.316 (2.99), 8.519 (0.96), 8.529 (1.94), 8.538 (0.95).

Example 117

diamix-N-[1-(2,5-Difluorophenyl)ethyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1283] ##STR00260##

[1284] rac-2-Bromo-N-[1-(2,5-difluorophenyl)ethyl]-1,3-thiazole-5-carboxamide (145 mg, 418 μmol) and diamix-(3R)-3′-fluoro-3-methyl-1,4′-bipiperidine dihydrochloride (98.9 mg, 362 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 117 mg (purity 100%, 60% of theory) of the target compound.

[1285] LC-MS (method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=467 [M+H].sup.+.

[1286] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.808 (6.23), 0.816 (13.24), 0.826 (12.53), 0.841 (1.66), 0.861 (0.65), 1.378 (1.12), 1.398 (1.48), 1.417 (16.00), 1.429 (15.57), 1.544 (1.06), 1.563 (2.56), 1.580 (1.42), 1.585 (1.64), 1.622 (1.79), 1.643 (1.71), 1.675 (1.64), 1.693 (1.97), 1.863 (1.00), 1.872 (2.46), 1.888 (3.25), 1.905 (2.33), 2.157 (1.20), 2.176 (2.36), 2.194 (1.22), 2.617 (1.14), 2.655 (1.04), 2.676 (1.00), 2.805 (1.54), 2.820 (3.23), 3.131 (1.10), 3.153 (2.11), 3.175 (1.10), 3.232 (1.60), 3.257 (2.09), 3.322 (1.73), 3.998 (1.42), 4.018 (1.34), 4.194 (1.34), 5.053 (2.25), 5.135 (2.27), 5.228 (0.55), 5.240 (2.19), 5.251 (3.23), 5.263 (2.17), 5.276 (0.51), 7.099 (1.22), 7.113 (2.42), 7.120 (1.81), 7.127 (1.62), 7.133 (0.85), 7.195 (1.64), 7.203 (2.01), 7.211 (4.14), 7.218 (4.04), 7.226 (2.84), 7.233 (2.40), 7.902 (11.61), 7.914 (0.51), 8.535 (3.76), 8.547 (3.57).

Example 118

4-(2-Chlorophenyl)-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1287] ##STR00261##

[1288] N,N-Diisopropylethylamine (250 μl, 1.4 mmol) and propylphosphonic anhydride (280 μl, 50% in ethyl acetate, 460 μmol) were added to a solution of 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid (150 mg, 357 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (101 mg, 464 μmol) in 4.8 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature, wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 19.0 mg (purity 100%, 10% of theory) of the target compound.

[1289] LC-MS (method 5): R.sub.t=2.13 min; MS (ESIpos): m/z=546 [M+H].sup.+.

[1290] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.796 (0.63), 0.819 (15.20), 0.830 (16.00), 0.850 (0.61), 0.857 (0.57), 1.377 (0.51), 1.397 (1.27), 1.418 (1.39), 1.438 (0.57), 1.485 (0.85), 1.492 (1.06), 1.505 (2.64), 1.512 (3.04), 1.525 (3.40), 1.531 (3.30), 1.544 (1.54), 1.573 (1.65), 1.595 (1.35), 1.621 (1.37), 1.642 (1.31), 1.746 (1.78), 1.763 (3.06), 1.782 (3.83), 1.806 (2.62), 2.040 (1.06), 2.055 (1.90), 2.073 (1.06), 2.423 (0.40), 2.474 (1.12), 2.740 (1.75), 2.753 (3.19), 2.770 (1.50), 3.061 (2.13), 3.078 (3.80), 3.098 (2.16), 3.258 (0.53), 3.314 (0.63), 3.319 (0.53), 3.917 (2.75), 3.939 (2.62), 4.384 (5.88), 4.392 (5.81), 7.141 (1.88), 7.149 (3.80), 7.157 (1.86), 7.393 (1.10), 7.404 (3.34), 7.417 (3.30), 7.427 (4.23), 7.430 (5.09), 7.440 (2.18), 7.443 (1.73), 7.480 (1.46), 7.484 (1.25), 7.494 (3.15), 7.497 (2.71), 7.506 (2.41), 7.508 (2.30), 7.522 (5.28), 7.535 (2.37), 7.857 (1.42), 7.861 (1.52), 7.873 (2.37), 7.877 (2.47), 7.889 (1.48), 7.893 (1.52), 8.248 (5.85), 8.252 (5.81).

Example 119

4-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1291] ##STR00262##

[1292] N,N-Diisopropylethylamine (180 μL 1.0 mmol) and propylphosphonic anhydride (200 μL 50% in ethyl acetate, 330 μmol) were added to a solution of 4-bromo-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid (100 mg, 258 μmol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (72.7 mg, 335 μmol) in 4.0 ml of acetonitrile, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in DMSO, filtered and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature, wavelength 200-400 nm, complete injection; gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 24.0 mg (purity 100%, 18% of theory) of the target compound.

[1293] LC-MS (method 5): R.sub.t=2.00 min; MS (ESIneg): m/z=513 [M−H].sup.−.

[1294] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.785 (0.48), 0.791 (0.54), 0.805 (1.48), 0.815 (15.08), 0.826 (16.00), 0.845 (0.61), 0.851 (0.50), 1.371 (0.48), 1.391 (1.23), 1.411 (1.30), 1.425 (0.40), 1.432 (0.56), 1.458 (0.71), 1.479 (1.90), 1.495 (2.41), 1.500 (2.41), 1.512 (1.82), 1.518 (1.65), 1.529 (0.94), 1.541 (0.59), 1.567 (1.57), 1.573 (1.21), 1.583 (0.96), 1.589 (1.26), 1.617 (1.28), 1.638 (1.25), 1.737 (1.80), 1.754 (3.05), 1.772 (3.93), 1.795 (2.40), 2.035 (1.03), 2.050 (1.90), 2.054 (1.86), 2.069 (1.69), 2.482 (1.21), 2.519 (1.17), 2.722 (1.72), 2.734 (2.95), 2.751 (1.42), 3.063 (1.74), 3.068 (2.05), 3.085 (3.51), 3.088 (3.41), 3.105 (2.05), 3.110 (1.76), 3.318 (0.48), 3.876 (2.18), 3.898 (2.07), 4.591 (5.46), 4.600 (5.48), 7.911 (1.44), 7.915 (1.53), 7.928 (2.03), 7.930 (2.15), 7.943 (1.48), 7.947 (1.55), 8.178 (1.69), 8.187 (3.45), 8.196 (1.71), 8.478 (5.56), 8.482 (5.54).

Example 120

4-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1295] ##STR00263##

[1296] 2-Bromo-4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 271 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (69.2 mg, 271 μmol) were combined and stirred at 120° C. in sodium carbonate solution (540 μl, 2.0 M, 1.1 mmol) for 1 h. The solid obtained was then filtered off with suction, washed with MTBE and dried under high vacuum. This gave 111 mg (purity 100%, 87% of theory) of the target compound.

[1297] LC-MS (method 5): R.sub.t=1.96 min; MS (ESIpos): m/z=470 [M+H].sup.+.

[1298] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: −0.149 (0.48), 0.146 (0.50), 0.773 (0.60), 0.810 (14.86), 0.826 (16.00), 0.852 (0.70), 0.862 (0.57), 1.352 (0.47), 1.383 (1.15), 1.413 (1.36), 1.443 (1.27), 1.472 (2.29), 1.495 (2.91), 1.504 (2.92), 1.522 (2.00), 1.531 (1.75), 1.560 (1.89), 1.602 (1.85), 1.641 (1.32), 1.725 (1.91), 1.751 (3.63), 1.775 (3.60), 1.797 (2.47), 2.023 (1.08), 2.046 (1.94), 2.052 (1.91), 2.074 (1.10), 2.328 (0.60), 2.367 (0.85), 2.670 (0.64), 2.674 (0.49), 2.710 (2.59), 2.719 (2.45), 2.736 (2.63), 3.055 (2.04), 3.080 (3.62), 3.111 (2.12), 3.868 (2.52), 3.900 (2.37), 4.580 (5.48), 4.593 (5.48), 7.910 (1.38), 7.916 (1.50), 7.935 (2.01), 7.938 (2.12), 7.941 (1.91), 7.957 (1.46), 7.963 (1.55), 8.146 (1.68), 8.159 (3.47), 8.173 (1.63), 8.483 (4.79), 8.489 (4.63).

Example 121

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-propyl[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide

[1299] ##STR00264##

[1300] N,N-Diisopropylethylamine (49 μl, 280 μmol) and acetic acid (9.7 μl, 170 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50 mg, 142 μmol) and rac-3-propylpiperidine (36.1 mg, 284 μmol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and concentrated and the residue was dried under high vacuum. This gave 9.00 mg (purity 100%, 14% of theory) of the target compound.

[1301] LC-MS (method 5): R.sub.t=1.89 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1302] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.782 (0.42), 0.796 (0.99), 0.802 (1.00), 0.815 (1.07), 0.822 (1.05), 0.834 (7.50), 0.847 (16.00), 0.859 (8.04), 1.080 (0.68), 1.091 (0.99), 1.094 (0.85), 1.103 (1.64), 1.116 (1.70), 1.128 (1.13), 1.137 (1.31), 1.152 (1.62), 1.163 (1.21), 1.174 (0.77), 1.185 (0.44), 1.249 (0.74), 1.261 (2.17), 1.274 (3.33), 1.286 (2.73), 1.298 (1.24), 1.354 (0.40), 1.374 (1.15), 1.380 (0.89), 1.393 (1.72), 1.409 (1.32), 1.414 (1.31), 1.420 (1.00), 1.426 (0.70), 1.440 (0.48), 1.448 (0.57), 1.461 (1.18), 1.470 (1.54), 1.480 (1.76), 1.490 (1.64), 1.499 (1.26), 1.509 (0.64), 1.570 (1.35), 1.575 (1.08), 1.586 (0.84), 1.591 (1.10), 1.654 (1.11), 1.659 (1.08), 1.667 (0.72), 1.675 (1.11), 1.762 (2.32), 1.778 (3.07), 1.795 (2.67), 1.813 (1.30), 2.057 (0.93), 2.072 (1.64), 2.075 (1.62), 2.090 (0.89), 2.473 (0.92), 2.479 (0.63), 2.727 (1.42), 2.743 (2.48), 2.753 (1.62), 3.021 (1.72), 3.041 (3.32), 3.062 (1.72), 3.923 (2.55), 3.944 (2.45), 4.524 (4.71), 4.533 (4.70), 7.822 (12.11), 7.878 (1.31), 7.882 (1.39), 7.894 (1.90), 7.897 (1.97), 7.909 (1.32), 7.913 (1.36), 8.458 (5.03), 8.462 (4.90), 8.663 (1.52), 8.673 (3.08), 8.683 (1.51).

Example 122

4-Cyclopropyl-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1303] ##STR00265##

[1304] 2-Bromo-4-cyclopropyl-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 267 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (68.2 mg, 267 μmol) were combined and stirred at 120° C. in sodium carbonate solution (530 μl, 2.0 M, 1.1 mmol) for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume), total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 80.0 mg (purity 98%, 62% of theory) of the target compound.

[1305] LC-MS (method 5): R.sub.t=2.11 min; MS (ESIpos): m/z=476 [M+H].sup.+.

[1306] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.787 (0.64), 0.801 (1.39), 0.812 (15.16), 0.823 (16.00), 0.834 (1.40), 0.841 (3.13), 0.846 (4.94), 0.850 (3.91), 0.855 (2.63), 0.860 (5.16), 0.868 (3.30), 0.872 (4.59), 0.876 (4.88), 0.880 (5.43), 0.884 (3.26), 0.892 (0.83), 1.366 (0.47), 1.387 (1.21), 1.407 (1.28), 1.431 (1.04), 1.444 (2.03), 1.451 (2.08), 1.464 (2.21), 1.471 (2.10), 1.485 (1.20), 1.491 (1.33), 1.502 (0.89), 1.508 (1.05), 1.519 (1.03), 1.526 (0.92), 1.564 (1.52), 1.580 (0.92), 1.585 (1.23), 1.615 (1.25), 1.636 (1.21), 1.733 (1.89), 1.750 (5.64), 1.768 (3.44), 2.029 (1.03), 2.044 (1.84), 2.048 (1.84), 2.063 (1.02), 2.423 (0.47), 2.442 (1.04), 2.461 (1.92), 2.479 (1.09), 2.652 (0.41), 2.715 (1.59), 2.728 (2.95), 2.746 (1.40), 2.772 (0.74), 2.781 (1.42), 2.786 (1.50), 2.794 (2.41), 2.802 (1.38), 2.807 (1.33), 2.816 (0.65), 2.974 (1.92), 2.991 (3.49), 3.012 (1.96), 3.264 (0.81), 3.321 (0.75), 3.826 (2.55), 3.847 (2.41), 4.507 (5.32), 4.516 (5.29), 7.868 (1.47), 7.872 (1.67), 7.885 (2.09), 7.887 (2.23), 7.888 (2.12), 7.900 (1.60), 7.903 (1.61), 7.955 (1.67), 7.964 (3.49), 7.973 (1.71), 8.452 (5.76), 8.455 (5.74).

Example 123

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-ethoxy[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1307] ##STR00266##

[1308] 97 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethoxy[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 μm, 250×20 mm; mobile phase A: 40% n-heptane, mobile phase B: 60% ethanol+0.2% diethylamine in B; flow rate 20 ml/min; temperature 50° C., detection: 220 nm). The enantiomer having a retention time of 2.336 min (HPLC: column Daicel® Chiralpak ID-3 3 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; detection: 220 nm) was collected. Removal of the solvents gave 38 mg (99% ee) of the title compound.

[1309] LC-MS (method 2): R.sub.t=0.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1310] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.060 (8.60), 1.071 (16.00), 1.083 (8.26), 1.235 (0.59), 1.346 (1.07), 1.365 (1.08), 1.478 (2.05), 1.497 (2.16), 1.615 (1.29), 1.638 (1.12), 1.765 (2.83), 1.784 (2.51), 1.886 (1.30), 1.901 (1.26), 1.943 (0.94), 1.959 (1.62), 1.975 (0.96), 2.066 (0.82), 2.084 (1.44), 2.100 (0.79), 2.422 (0.44), 2.651 (1.43), 2.936 (1.37), 2.952 (1.34), 3.024 (2.23), 3.043 (4.12), 3.061 (2.16), 3.248 (1.59), 3.263 (1.29), 3.312 (0.54), 3.431 (1.22), 3.442 (3.89), 3.453 (5.34), 3.464 (4.14), 3.476 (1.31), 3.479 (1.09), 3.929 (2.79), 3.948 (2.67), 4.524 (6.31), 4.533 (6.25), 7.824 (13.37), 7.879 (1.72), 7.882 (1.81), 7.898 (2.60), 7.910 (1.70), 7.914 (1.78), 8.459 (6.60), 8.462 (6.49), 8.666 (1.78), 8.676 (3.41), 8.685 (1.73).

Example 124

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-ethoxy[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1311] ##STR00267##

[1312] 97 mg of rac-N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3-ethoxy[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 μm, 250×20 mm; mobile phase A: 40% n-heptane, mobile phase B: 60% ethanol+0.2% diethylamine in B; flow rate 20 ml/min; temperature 50° C., detection: 220 nm). The enantiomer having a retention time of 4.263 min (HPLC: column Daicel® Chiralpak ID-3 3 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; detection: 220 nm) was collected. Removal of the solvents gave 37 mg (99% ee) of the title compound.

[1313] LC-MS (method 2): R.sub.t=0.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1314] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.858 (0.50), 1.060 (8.69), 1.072 (16.00), 1.083 (8.44), 1.236 (1.50), 1.355 (1.34), 1.366 (1.33), 1.479 (2.47), 1.498 (2.65), 1.616 (1.60), 1.767 (3.37), 1.785 (3.03), 1.888 (1.68), 1.904 (1.66), 1.960 (1.76), 2.084 (1.62), 2.611 (0.50), 2.652 (1.56), 2.939 (1.58), 3.024 (2.76), 3.044 (5.20), 3.064 (2.72), 3.251 (2.20), 3.431 (1.40), 3.443 (4.13), 3.454 (5.81), 3.465 (4.31), 3.477 (1.43), 3.930 (3.48), 3.951 (3.36), 4.524 (8.10), 4.533 (8.05), 7.824 (12.08), 7.879 (1.78), 7.882 (1.96), 7.897 (3.40), 7.910 (1.75), 7.914 (1.92), 8.459 (7.08), 8.462 (7.27), 8.667 (2.01), 8.676 (3.85), 8.685 (1.99).

Example 125

ent-2-[3-(Cyclobutylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1315] ##STR00268##

[1316] 60 mg of rac-2-[3-(cyclobutylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IF, 5 μm, 250×20 mm; mobile phase A: 100% ethanol+0.2% diethylamine; flow rate 18 ml/min; temperature 70° C., detection: 220 nm). The enantiomer having a retention time of 9.999 min (HPLC: column Daicel® Chiralpak IF 5 μm, flow rate 1 ml/min; mobile phase A: 100% ethanol+0.2% diethylamine; temperature 70° C.; detection: 220 nm) was collected. Removal of the solvents gave 28 mg (99% ee) of the title compound.

[1317] LC-MS (method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1318] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.040 (2.07), 1.059 (2.23), 1.146 (0.91), 1.158 (1.69), 1.171 (1.07), 1.234 (0.93), 1.341 (2.06), 1.360 (2.22), 1.478 (3.96), 1.497 (4.40), 1.615 (2.66), 1.645 (5.09), 1.661 (6.44), 1.675 (5.50), 1.690 (2.56), 1.765 (5.75), 1.784 (6.56), 1.809 (6.11), 1.824 (6.18), 1.837 (3.88), 1.856 (1.91), 1.888 (2.92), 1.904 (2.89), 1.922 (3.01), 1.936 (6.49), 1.950 (8.09), 2.081 (3.01), 2.405 (1.46), 2.418 (3.03), 2.430 (3.84), 2.442 (3.00), 2.455 (1.53), 2.654 (3.03), 2.941 (2.94), 2.954 (2.67), 3.022 (4.06), 3.041 (7.67), 3.061 (4.38), 3.225 (3.06), 3.357 (3.40), 3.373 (7.35), 3.384 (12.29), 3.396 (7.41), 3.411 (2.89), 3.929 (5.35), 3.950 (5.23), 4.523 (11.02), 4.532 (11.02), 7.823 (16.00), 7.878 (2.73), 7.895 (4.72), 7.910 (2.65), 8.458 (9.67), 8.664 (3.17), 8.674 (5.69), 8.683 (3.01).

Example 126

ent-2-[3-(Cyclobutylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1319] ##STR00269##

[1320] 60 mg of rac-2-[3-(cyclobutylmethoxy)[1,4′-bipiperidin]-1′-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IF, 5 μm, 250×20 mm; mobile phase A: 100% ethanol+0.2% diethylamine; flow rate 18 ml/min; temperature 70° C., detection: 220 nm). The enantiomer having a retention time of 13.165 min (HPLC: column Daicel® Chiralpak IF 5 μm, flow rate 1 ml/min; mobile phase A: 100% ethanol+0.2% diethylamine; temperature 70° C.; detection: 220 nm) was collected. Removal of the solvents gave 28 mg (99% ee) of the title compound.

[1321] LC-MS (method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1322] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.023 (0.51), 1.037 (1.19), 1.060 (1.31), 1.078 (0.73), 1.143 (1.12), 1.155 (2.25), 1.167 (1.19), 1.235 (0.77), 1.321 (0.52), 1.341 (1.20), 1.361 (1.25), 1.381 (0.56), 1.477 (2.28), 1.497 (2.44), 1.516 (0.97), 1.614 (1.60), 1.635 (1.78), 1.647 (2.81), 1.662 (3.59), 1.677 (2.98), 1.690 (1.31), 1.766 (3.39), 1.775 (2.10), 1.785 (3.78), 1.793 (2.73), 1.800 (2.08), 1.810 (3.38), 1.815 (1.70), 1.824 (4.53), 1.829 (1.22), 1.838 (2.43), 1.842 (1.48), 1.852 (0.85), 1.857 (0.97), 1.870 (0.53), 1.889 (1.42), 1.903 (1.41), 1.923 (1.61), 1.927 (1.22), 1.932 (1.92), 1.936 (3.89), 1.945 (3.31), 1.953 (4.52), 1.956 (4.37), 1.964 (2.83), 1.970 (2.58), 1.978 (1.21), 2.065 (1.01), 2.082 (1.80), 2.099 (0.98), 2.406 (0.92), 2.418 (1.98), 2.431 (2.54), 2.443 (1.88), 2.456 (0.85), 2.564 (0.87), 2.655 (1.60), 2.672 (1.48), 2.908 (0.92), 2.921 (0.98), 2.942 (1.72), 2.955 (1.58), 3.023 (2.34), 3.042 (4.41), 3.061 (2.35), 3.210 (1.08), 3.218 (1.46), 3.225 (1.90), 3.233 (1.43), 3.242 (1.19), 3.317 (0.46), 3.357 (1.62), 3.369 (1.91), 3.373 (5.39), 3.385 (10.05), 3.396 (5.32), 3.401 (1.89), 3.412 (1.57), 3.930 (3.09), 3.950 (2.94), 4.524 (6.50), 4.533 (6.41), 7.813 (0.48), 7.824 (16.00), 7.878 (1.87), 7.882 (1.93), 7.894 (2.71), 7.897 (2.72), 7.910 (1.85), 7.913 (1.87), 8.458 (7.25), 8.462 (6.95), 8.665 (2.10), 8.675 (4.20), 8.684 (2.03).

Example 127

rac-Formic acid N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(2-fluoroethyl)[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1323] ##STR00270##

[1324] N,N-Diisopropylethylamine (49 μL 280 μmol) and acetic acid (9.7 μL 170 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (50 mg, 142 μmol) and rac-3-(2-fluoroethyl)piperidine (37.2 mg, 284 μmol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 μmol) was added and the mixture was stirred at room temperature overnight. Sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% strength formic acid in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 63 ml, mobile phase B 0 to 2 min 7 ml, mobile phase A 2 to 10 min from 63 ml to 39 ml and mobile phase B from 7 ml to 31 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 8.3 mg (purity 90%, 62% of theory) of the target compound.

[1325] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.891 (0.41), 0.908 (0.96), 0.929 (1.03), 0.943 (0.48), 1.380 (0.46), 1.401 (1.07), 1.421 (1.24), 1.440 (0.58), 1.471 (1.05), 1.485 (2.38), 1.491 (3.31), 1.504 (2.79), 1.511 (2.62), 1.524 (1.89), 1.532 (1.25), 1.542 (0.86), 1.552 (1.29), 1.562 (1.40), 1.586 (2.60), 1.592 (3.22), 1.598 (2.82), 1.609 (2.29), 1.613 (2.28), 1.620 (2.03), 1.630 (0.77), 1.681 (1.29), 1.702 (1.25), 1.774 (3.02), 1.794 (2.62), 1.901 (1.30), 1.917 (2.00), 1.934 (1.18), 2.135 (1.06), 2.150 (1.91), 2.154 (1.87), 2.168 (1.12), 2.520 (0.99), 2.564 (1.18), 2.652 (0.44), 2.735 (1.56), 2.754 (1.54), 2.781 (1.79), 2.799 (1.71), 3.028 (2.21), 3.048 (4.09), 3.068 (2.26), 3.102 (0.54), 3.480 (1.58), 3.563 (1.40), 3.934 (3.17), 3.955 (3.05), 4.430 (1.61), 4.438 (3.14), 4.448 (1.87), 4.509 (1.96), 4.519 (4.42), 4.525 (6.57), 4.533 (5.92), 7.824 (16.00), 7.865 (0.74), 7.879 (1.67), 7.883 (1.74), 7.895 (2.30), 7.898 (2.39), 7.910 (1.74), 7.914 (1.69), 8.171 (3.02), 8.459 (6.28), 8.463 (6.04), 8.668 (1.79), 8.678 (3.62), 8.687 (1.72).

Example 128

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

[1326] ##STR00271##

[1327] Acetic acid (9.7 μl, 170 μmol) was added to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (100.0 mg, 284 μmol) and piperidine (56 μl, 570 μmol) in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 μmol) was added and the mixture was stirred at room temperature overnight. Subsequently, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was concentrated on a rotary evaporator and the residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume). Total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 22.0 mg (100% purity, 18% of theory) of the title compound.

[1328] LC-MS (method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=422 [M+H].sup.+.

[1329] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.366 (3.44), 1.375 (2.92), 1.444 (1.06), 1.453 (3.16), 1.463 (7.91), 1.471 (9.96), 1.482 (6.13), 1.490 (4.09), 1.504 (1.17), 1.512 (1.00), 1.769 (3.09), 1.790 (2.71), 2.430 (5.90), 2.439 (8.35), 2.447 (6.39), 2.466 (1.66), 2.471 (2.35), 2.517 (0.56), 2.651 (0.41), 3.021 (2.01), 3.025 (2.37), 3.042 (4.07), 3.045 (4.08), 3.062 (2.33), 3.067 (2.09), 3.259 (0.66), 3.920 (3.18), 3.942 (3.09), 4.523 (5.69), 4.532 (5.70), 7.821 (16.00), 7.879 (1.63), 7.882 (1.78), 7.895 (2.33), 7.897 (2.41), 7.910 (1.70), 7.914 (1.76), 8.458 (6.16), 8.462 (6.16), 8.664 (1.76), 8.673 (3.62), 8.683 (1.83).

Example 129

N-[1-(3,5-Difluoropyridin-2-yl)cyclopropyl]-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1330] ##STR00272##

[1331] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32.6 mg, 170 μmol), 1-hydroxy-1H-benzotriazole hydrate (26.0 mg, 170 μmol) and N,N-diisopropylethylamine (110 μl, 650 μmol) were added to a solution of 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride (50.0 mg, 131 μmol) in 2 ml of DMF and the mixture was stirred for 5 min, after which 1-(3,5-difluoropyridin-2-yl)cyclopropanamine hydrochloride (1:1) (29.7 mg, 144 μmol) was added. The mixture was then stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC [instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 47 ml, mobile phase B 0 to 2 min 23 ml, mobile phase A 2 to 10 min from 47 ml to 23 ml and mobile phase B from 23 ml to 47 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 37.0 mg (100% purity, 61% of theory) of the title compound.

[1332] LC-MS (method 2): R.sub.t=0.56 min; MS (ESIpos): m/z=462 [M+H].sup.+.

[1333] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.782 (0.51), 0.788 (0.60), 0.812 (15.17), 0.823 (16.00), 0.842 (0.59), 0.848 (0.53), 0.955 (0.47), 1.174 (2.26), 1.182 (6.55), 1.187 (6.16), 1.194 (2.43), 1.369 (0.51), 1.389 (1.31), 1.409 (1.42), 1.429 (0.62), 1.449 (0.85), 1.464 (2.23), 1.477 (4.28), 1.484 (9.56), 1.488 (8.40), 1.496 (3.72), 1.521 (1.41), 1.527 (1.17), 1.565 (1.73), 1.581 (1.06), 1.586 (1.39), 1.615 (1.46), 1.636 (1.39), 1.737 (1.83), 1.755 (5.18), 1.772 (2.86), 1.779 (2.96), 2.036 (1.15), 2.051 (2.05), 2.070 (1.12), 2.470 (1.22), 2.720 (1.75), 2.732 (3.29), 2.748 (1.72), 2.956 (0.44), 3.020 (2.17), 3.037 (3.83), 3.058 (2.15), 3.915 (2.81), 3.936 (2.67), 6.779 (0.67), 6.785 (0.65), 7.120 (0.64), 7.125 (0.60), 7.740 (1.36), 7.744 (1.44), 7.755 (1.57), 7.759 (2.67), 7.763 (1.55), 7.774 (1.38), 7.778 (1.38), 7.835 (11.84), 8.360 (5.23), 8.364 (4.87), 8.928 (5.546).

Example 130

N-[(3,5-Difluoropyridin-2-yl)methyl]-4-ethyl-2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide

[1334] ##STR00273##

[1335] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-ethyl-1,3-thiazole-5-carboxamide (150 mg, 414 μmol) and (3R)-3-methyl-1,4′-bipiperidine dihydrochloride (106 mg, 414 μmol) were combined and stirred at 120° C. in sodium carbonate solution (830 μl, 2.0 M, 1.7 mmol) for 1 h. The reaction mixture was then purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 74.0 mg (purity 100%, 39% of theory) of the target compound.

[1336] LC-MS (method 2): R.sub.t=0.60 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1337] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ [ppm]: 0.799 (1.09), 0.813 (11.56), 0.827 (12.24), 0.847 (0.47), 1.091 (7.29), 1.106 (16.00), 1.121 (7.29), 1.388 (0.88), 1.395 (0.58), 1.412 (0.97), 1.438 (0.80), 1.447 (0.69), 1.464 (1.55), 1.472 (1.65), 1.488 (2.07), 1.495 (2.07), 1.510 (1.47), 1.521 (1.26), 1.530 (0.74), 1.544 (0.47), 1.565 (1.25), 1.571 (0.94), 1.584 (0.71), 1.591 (0.92), 1.598 (0.74), 1.615 (0.99), 1.641 (0.96), 1.733 (1.37), 1.754 (2.49), 1.774 (2.92), 1.793 (1.87), 2.029 (0.79), 2.047 (1.42), 2.052 (1.39), 2.069 (0.80), 2.453 (0.77), 2.459 (0.54), 2.469 (0.96), 2.475 (1.59), 2.482 (1.28), 2.523 (0.42), 2.727 (1.39), 2.740 (2.26), 2.760 (1.12), 2.789 (1.99), 2.804 (6.09), 2.819 (5.92), 2.834 (1.81), 2.998 (1.35), 3.003 (1.59), 3.024 (2.79), 3.028 (2.70), 3.048 (1.59), 3.891 (2.15), 3.917 (2.01), 4.488 (4.13), 4.499 (4.03), 7.879 (1.35), 7.883 (1.42), 7.897 (1.69), 7.899 (1.75), 7.901 (1.82), 7.903 (1.63), 7.917 (1.34), 7.921 (1.38), 7.989 (1.38), 8.000 (2.84), 8.011 (1.31), 8.452 (4.92), 8.456 (4.69).

Example 131

ent-2-[4-(1,1-Difluoro-5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1338] ##STR00274##

[1339] 60 mg of rac-2-[4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 μm, 250×20 mm; mobile phase A: 30% n-heptane, mobile phase B: 70% ethanol+0.2% diethylamine in B; flow rate 20 ml/min; temperature 40° C., detection: 220 nm). The enantiomer having a retention time of 1.927 min (HPLC: column Daicel® Chiralpak ID-3 3 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; detection: 220 nm) was collected. Removal of the solvents gave 23 mg (98% ee) of the title compound.

[1340] LC-MS (method 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1341] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.146 (0.84), 1.158 (2.52), 1.170 (2.50), 1.186 (1.37), 1.198 (1.48), 1.215 (2.36), 1.226 (2.39), 1.436 (0.92), 1.456 (3.88), 1.476 (8.04), 1.494 (7.15), 1.603 (2.19), 1.755 (2.31), 1.776 (4.13), 1.799 (1.99), 2.377 (2.43), 2.396 (3.21), 2.422 (2.44), 2.514 (4.21), 2.568 (1.52), 2.620 (1.95), 3.046 (3.16), 3.063 (5.74), 3.083 (3.23), 3.907 (3.91), 3.926 (3.72), 4.523 (8.18), 4.532 (8.18), 7.822 (16.00), 7.878 (1.98), 7.882 (2.00), 7.897 (3.37), 7.910 (2.00), 7.913 (1.97), 8.458 (7.68), 8.461 (7.29), 8.666 (2.49), 8.676 (4.92), 8.685 (2.41).

Example 132

ent-2-[4-(1,1-Difluoro-5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1342] ##STR00275##

[1343] 60 mg of rac-2-[4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the enantiomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 μm, 250×20 mm; mobile phase A: 30% n-heptane, mobile phase B: 70% ethanol+0.2% diethylamine in B; flow rate 20 ml/min; temperature 40° C., detection: 220 nm). The enantiomer having a retention time of 3.317 min (HPLC: column Daicel® Chiralpak ID-3 3 μm, flow rate 1 ml/min; mobile phase A: 50% n-heptane, mobile phase B: 50% ethanol+0.2% diethylamine in B; detection: 220 nm) was collected. Removal of the solvents gave 23 mg (99% ee) of the title compound.

[1344] LC-MS (Method 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1345] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.146 (0.75), 1.158 (1.98), 1.171 (1.91), 1.186 (1.08), 1.198 (1.15), 1.215 (1.81), 1.227 (1.85), 1.239 (0.96), 1.436 (0.80), 1.456 (2.96), 1.477 (5.97), 1.495 (5.35), 1.522 (1.38), 1.603 (1.63), 1.613 (1.24), 1.756 (1.75), 1.780 (3.00), 1.800 (1.48), 2.377 (1.82), 2.396 (2.41), 2.422 (1.92), 2.514 (3.06), 2.568 (1.08), 2.620 (1.43), 2.651 (0.41), 3.042 (2.15), 3.046 (2.46), 3.063 (4.28), 3.083 (2.49), 3.088 (2.11), 3.906 (2.87), 3.926 (2.70), 4.523 (6.11), 4.532 (6.07), 7.822 (16.00), 7.878 (1.73), 7.882 (1.81), 7.895 (2.55), 7.897 (2.67), 7.910 (1.78), 7.914 (1.86), 8.458 (6.46), 8.461 (6.36), 8.667 (1.89), 8.676 (3.89), 8.686 (1.94).

Example 133

rac-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3-phenyl[1,4′-bipiperidin]-1′-yl)-1,3-thiazole-5-carboxamide

[1346] ##STR00276##

[1347] N,N-Diisopropylethylamine (69 μl, 400 μmol) and acetic acid (14 μl, 240 μmol) were added in succession to a solution of N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (70.0 mg, 199 μmol) and rac-3-phenylpiperidine (64.1 mg, 397 μmol) in 4.2 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (63.2 mg, 298 μmol) was added and the mixture was stirred at room temperature for 5 h. Subsequently, sat. NaHCO.sub.3 solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water and dried over Na.sub.2SO.sub.4. The drying agent was filtered off and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 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 of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 17.0 mg (purity 100%, 17% of theory) of the target compound.

[1348] LC-MS (method 5): R.sub.t=1.74 min; MS (ESIpos): m/z=498 [M+H].sup.+.

[1349] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: −0.149 (0.91), 0.146 (0.77), 1.378 (0.42), 1.400 (1.08), 1.408 (1.16), 1.430 (1.35), 1.439 (1.38), 1.461 (1.11), 1.496 (1.85), 1.510 (2.16), 1.528 (2.44), 1.560 (1.50), 1.704 (1.58), 1.736 (1.16), 1.796 (3.14), 1.819 (2.95), 2.073 (2.48), 2.157 (1.25), 2.185 (1.75), 2.201 (1.77), 2.228 (3.01), 2.255 (1.62), 2.328 (1.28), 2.367 (1.69), 2.524 (3.95), 2.574 (2.01), 2.601 (0.88), 2.666 (1.83), 2.670 (1.83), 2.693 (1.57), 2.711 (2.19), 2.856 (2.82), 2.883 (2.55), 3.015 (1.85), 3.045 (3.45), 3.075 (1.89), 3.921 (2.88), 3.954 (2.64), 4.514 (4.86), 4.527 (4.95), 7.166 (1.21), 7.172 (0.84), 7.182 (3.04), 7.193 (1.08), 7.199 (1.96), 7.204 (1.62), 7.241 (2.91), 7.257 (12.12), 7.263 (16.00), 7.280 (6.40), 7.299 (1.70), 7.820 (15.56), 7.881 (1.54), 7.887 (1.58), 7.906 (2.02), 7.910 (2.10), 7.929 (1.58), 7.935 (1.60), 8.173 (0.95), 8.460 (4.70), 8.465 (4.61), 8.685 (1.67), 8.699 (3.57), 8.713 (1.70).

Example 134

diamix-2-[4-(1,1-Difluoro-5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1350] ##STR00277##

[1351] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and diamix-1,1-difluoro-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (96.1 mg, 299 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 30 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 46.0 mg (purity 100%, 31% of theory) of the target compound.

[1352] LC-MS (method 5): R.sub.t=1.52 min; MS (ESIpos): m/z=502 [M+H].sup.+.

[1353] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: −0.149 (0.40), 1.174 (2.35), 1.195 (4.08), 1.216 (2.33), 1.232 (0.76), 1.462 (1.17), 1.481 (2.78), 1.501 (4.70), 1.523 (1.86), 1.608 (1.52), 1.623 (1.37), 1.668 (1.19), 1.703 (1.07), 1.846 (0.95), 1.858 (1.09), 1.879 (1.18), 1.890 (1.21), 1.911 (0.72), 1.923 (0.63), 2.328 (0.44), 2.367 (0.65), 2.524 (3.86), 2.604 (2.69), 2.633 (1.49), 2.670 (1.14), 2.699 (2.14), 2.710 (2.28), 2.769 (0.60), 2.788 (0.77), 3.126 (1.00), 3.158 (1.99), 3.190 (1.15), 3.214 (1.44), 3.250 (1.52), 3.987 (1.42), 4.019 (1.34), 4.153 (0.87), 4.187 (1.56), 4.217 (0.79), 4.521 (5.39), 4.534 (5.43), 5.026 (1.17), 5.056 (0.66), 5.149 (1.18), 5.177 (0.67), 7.812 (16.00), 7.885 (1.58), 7.891 (1.73), 7.908 (2.00), 7.910 (2.18), 7.913 (2.27), 7.916 (2.13), 7.933 (1.66), 7.938 (1.74), 8.464 (5.05), 8.470 (5.00), 8.709 (1.84), 8.724 (3.89), 8.738 (1.87).

Example 135

diamix-2-[4-(5-Azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1354] ##STR00278##

[1355] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 μmol) and diamix-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (85.4 mg, 299 μmol) were combined and stirred at 120° C. in 2 ml of sodium carbonate solution (2 ml, 2.0 M, 4 mmol) for 30 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and filtered and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Mobile phase A: water, mobile phase B: acetonitrile, mobile phase C: 2% ammonia in water, mobile phase D: acetonitrile/water (80% by volume/20% by volume) total flow rate: 80 ml/min; room temperature; wavelength 200-400 nm, complete injection. Gradient profile: mobile phase A 0 to 2 min 55 ml, mobile phase B 0 to 2 min 15 ml, mobile phase A 2 to 10 min from 55 ml to 31 ml and mobile phase B from 15 ml to 39 ml, 10 to 12 min 0 ml of mobile phase A and 70 ml of mobile phase B. Mobile phase C and mobile phase D constant flow rate of 5 ml/min each over the entire running time). The product-containing fractions were combined and lyophilized. This gave 18.0 mg (purity 100%, 13% of theory) of the target compound.

[1356] LC-MS (method 5): R.sub.t=1.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1357] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: 0.236 (9.32), 0.259 (7.85), 0.278 (1.43), 0.294 (0.46), 1.209 (0.58), 1.227 (1.61), 1.242 (3.77), 1.257 (3.72), 1.271 (1.81), 1.290 (0.55), 1.561 (2.71), 1.571 (3.44), 1.585 (2.57), 1.669 (1.21), 1.694 (1.73), 1.787 (0.48), 1.797 (0.60), 1.818 (1.34), 1.828 (1.46), 1.849 (1.31), 1.860 (1.24), 1.880 (0.46), 2.073 (1.21), 2.269 (1.36), 2.297 (5.25), 2.313 (4.36), 2.328 (0.76), 2.339 (1.10), 2.367 (0.61), 2.577 (4.23), 2.589 (5.56), 2.602 (3.30), 2.635 (0.93), 2.644 (0.90), 2.666 (1.15), 2.710 (0.57), 3.110 (1.17), 3.136 (2.08), 3.142 (2.03), 3.167 (1.24), 3.199 (1.78), 3.235 (2.02), 3.968 (1.52), 4.001 (1.41), 4.142 (0.95), 4.172 (1.62), 4.206 (0.88), 4.520 (5.56), 4.533 (5.59), 5.026 (1.83), 5.148 (1.86), 7.810 (16.00), 7.884 (1.64), 7.890 (1.76), 7.909 (2.28), 7.913 (2.39), 7.915 (2.23), 7.932 (1.72), 7.938 (1.80), 8.164 (0.74), 8.463 (5.37), 8.469 (5.31), 8.706 (1.86), 8.720 (3.88), 8.734 (1.86).

[1358] Analogously to Examples 15 to 17, the following compounds of Examples 136 to 149 were prepared from the starting materials stated in each case:

TABLE-US-00007 Example Name/Structure/Starting materials Analytical data 136 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(2- oxa-6-azaspiro[3.5]nonan-6-yl)piperidin-1-yl]- 1,3-thiazole-5-carboxamide   [00279] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.37-1.44 (m, 2H), 1.46- 1.56 (m, 2H), 1.57-1.65 (m, 2H), 1.78 (br. d, 2H), 2.37 (br. s, 2H), 2.52-2.63 (m, 3H, partially obscured by DMSO), 3.07 (td, 2H), 3.94 (br. d, 2H), 4.19 (s, 4H), 4.53 (d, 2H), 7.83 (s, 1H), 7.90 (td, 1H), 8.46 (d, 1H), 8.68 (t, 1H). LC-MS (method 1): R.sub.t = 0.76 min; m/z = 464 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 2-oxa-6-azaspiro[3.5]nonane oxalic acid (2:1) 137 2-(3-cyclopropyl[1,4′-bipiperidin]-1′-yl)-N-[(3,5- difluoropyridin-2-yl)methyl]-1,3-thiazole-5- carboxamide (racemic)   [00280]   from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 3-cyclopropylpiperidine hydrochloride (1:1) (racemic) .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.01-0.08 (m, 2H), 0.29- 0.37 (m, 2H), 0.47-0.54 (m, 1H), 0.63-0.72 (m, 1H), 0.99 (qd, 1H), 1.28-1.38 (m, 1H), 1.42-1.54 (m, 2H), 1.56-1.63 (m, 1H), 1.66-1.72 (m, 1H), 1.74-1.81 (m, 2H), 1.99 (t, 1H), 2.05-2.12 (m, 1H), 2.47- 2.55 (m, 1H, partially obscured by DMSO), 2.71 (br. d, 1H), 2.80 (br. d, 1H), 3.04 (td, 2H), 3.93 (br. d, 2H), 4.52 (d, 2H), 7.82 (s, 1H), 7.89 (td, 1H), 8.46 (d, 1H), 8.67 (t, 1H). LC-MS (method 1): R.sub.t = 1.02 min; m/z = 462 (M + H).sup.+. 138 2-(3-cyclobutyl[1,4′-bipiperidin]-1′-yl)-N-[(3,5- difluoropyridin-2-yl)methyl]-1,3-thiazole-5- carboxamide (racemic)   [00281] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.67-0.75 (m, 1H), 1.30- 1.40 (m, 2H), 1.41-1.52 (m, 2H), 1.54-1.83 (m, 9H), 1.88-1.95 (m, 2H), 1.97-2.10 (m, 2H), 2.44-2.52 (m, 1H, partially obscured by DMSO), 2.67 (br. d, 1H), 2.71 (br. d, 1H), 2.99-3.08 (m, 2H), 3.93 (br. d, 2H), 4.53 (d, 2H), 7.82 (s, 1H), 7.89 (td, 1H), 8.46 (d, 1H), 8.67 (t, 1H). LC-MS (method 1): R.sub.t = 1.13 min; m/z = 476 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 3-cyclobutylpiperidine (racemic) The product obtained was purified using Method 10 (preparative HPLC). 139 2-[4-(7-chloro-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-5-carboxamide   [00282] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.51-1.66 (m,2H), 1.89 (br. d, 2H), 2.65-2.80 (m, 5H), 3.12 (br. t, 2H), 3.70 (s, 2H), 3.96 (br. d, 2H), 4.53 (br. d, 2H), 7.07- 7.18 (m, 3H), 7.84 (s, 1H), 7.88- 7.95 (m, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R = 1.10 min; m/z = 504/506 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 7-chloro-1,2,3,4-tetrahydroisoquinoline 140 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(8- methoxy-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00283] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.51-1.66 (m, 2H), 1.90 (br. d, 2H), 2.65-2.79 (m, 5H), 3.12 (br. t, 2H), 3.58 (s, 2H), 3.75 (s, 3H), 3.97 (br. d, 2H), 4.53 (br. d, 2H), 6.68 (d, 1H), 6.74 (d, 1H), 7.08 (t, 1H), 7.85 (s, 1H), 7.91 (ddd, 1H), 8.48 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.01 min; m/z = 500 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 8-methoxy-1,2,3,4-tetrahydroisoquinoline 141 2-[4-(8-chloro-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-5-carboxamide   [00284] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.53-1.67 (m, 2H), 1.92 (br. d, 2H), 2.70-2.85 (m, 5H), 3.13 (br. t, 2H), 3.70 (s, 2H), 3.99 (br. d, 2H), 4.53 (br. d, 2H), 7.10 (d, 1H), 7.16 (t, 1H), 7.24 (d, 1H), 7.85 (s, 1H), 7.91 (ddd, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.07 min; m/z = 504/506 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 8-chloro-1,2,3,4-tetrahydroisoquinoline 142 2-[4-(5-chloro-3,4-dihydroisoquinolin-2(1H)- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2- δ/ppm): 1.52-1.66 (m, 2H), 1.90 yl)methyl]-1,3-thiazole-5-carboxamide (br. d, 2H), 2.67-2.77 (m, 3H), [00285]   from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 5-chloro-1,2,3,4-tetrahydroisoquinoline 2.78-2.85 (m, 2H), 3.12 (br. t, 2H), 3.72 (s, 2H), 3.97 (br. d, 2H), 4.53 (br. d, 2H), 7.06 (d, 1H), 7.15 (t, 1H), 7.25 (d, 1H), 7.85 (s, 1H), 7.91 (ddd, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.07 min; m/z = 504/506 (M + H).sup.+. 143 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(7- methyl-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00286] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.52-1.66 (m, 2H), 1.90 (br. d, 2H), 2.22 (s, 3H), 2.61-2.78 (m, 5H), 3.12 (br. t, 2H), 3.65 (s, 2H), 3.96 (br. d, 2H), 4.53 (br. d, 2H), 6.85 (s, 1H), 6.90 (d, 1H), 6.95 (d, 1H), 7.85 (s, 1H), 7.91 (ddd, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.06 min; m/z = 484 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 7-methyl-1,2,3,4-tetrahydroisoquinoline 144 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(8- fluoro-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00287] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.53-1.67 (m, 2H), 1.91 (br. d, 2H), 2.72-2.84 (m, 5H), 3.12 (br. t, 2H), 3.70 (s, 2H), 3.98 (br. d, 2H), 4.53 (br. d, 2H), 6.91- 6.98 (m, 2H), 7.11-7.19 (m, 1H), 7.85 (s, 1H), 7.91 (ddd, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.00 min; m/z = 488 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 8-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (1:1) 145 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(6- methoxy-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00288] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.53-1.64 (m, 2H), 1.89 (br. d, 2H), 2.65-2.71 (m, 1H), 2.71-2.78 (m, 4H), 3.12 (br. t, 2H), 3.63 (s, 2H), 3.69 (s, 3H), 3.95 (br. d, 2H), 4.53 (br. d, 2H), 6.64 (d, 1H), 6.67 (dd, 1H), 6.95 (d, 1H), 7.84 (s, 1H), 7.90 (ddd, 1H), 8.46 (d, 1H), 8.69 (t, 1H). LC-MS (method 1): R.sub.t = 1.00 min; m/z = 500 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 6-methoxy-1,2,3,4-tetrahydroisoquinoline 146 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(6- methyl-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00289] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 1.51-1.66 (m, 2H), 1.90 (br. d, 2H), 2.22 (s, 3H), 2.64-2.78 (m, 5H), 3.11 (br. t, 2H), 3.65 (s, 2H), 3.96 (br. d, 2H), 4.53 (br. d, 2H), 6.85-6.95 (m, 3H), 7.84 (s, 1H), 7.91 (ddd, 1H), 8.47 (d, 1H), 8.72 (t, 1H). LC-MS (method 1): R.sub.t = 1.06 min; m/z = 484 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1:1) 147 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[4-(5- fluoro-3,4-dihydroisoquinolin-2(1H)- yl)piperidin-1-yl]-1,3-thiazole-5-carboxamide   [00290] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 1.55-1.65 (m, 2H), 1.90 (br. d, 2H), 2.68-2.76 (m, 3H), 2.76-2.82 (m, 2H), 3.12 (br. t, 2H), 3.72 (s, 2H), 3.97 (br. d, 2H), 4.53 (d, 2H), 6.89-6.97 (m, 2H), 7.11- 7.16 (m, 1H), 7.84 (s, 1H), 7.90 (td, 1H), 8.46 (d, 1H), 8.69 (t, 1H). LC-MS (method 1): R.sub.t = 1.00 min; m/z = 488 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 5-fluoro-1,2,3,4-tetrahydroisoquinoline 148 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[3-(2- methoxyethyl)[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide (racemic)   [00291] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.92 (m, 1H), 1.25- 1.89 (m, 13H), 2.03-2.15 (m, 1H), 2.38-2.58 (m, 1H, partially obscured by DMSO), 2.64-2.78 (m, 2H), 3.04 (br. t, 2H), 3.20 (s, 3H), 3.94 (br. d, 2H), 4.53 (br. d, 2H), 7.83 (s, 1H), 7.87-7.95 (m, 1H), 8.47 (d, 1H), 8.71 (t, 1H). LC-MS (method 1): R.sub.t = 0.90 min; m/z = 480 (M + H).sup.+. from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 3-(2-methoxyethyl)piperidine hydrochloride (1:1) (racemic) The product obtained was purified using Method 9 (preparative HPLC). 149 2-(3-tert-butyl[1,4′-bipiperidin]-1′-yl)-N-[(3,5- difluoropyridin-2-yl)methyl]-1,3-thiazole-5- carboxamide (racemic)   [00292]   from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(4- oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide and 3-tert-butylpiperidine hydrochloride (1:1) (racemic) The product obtained was purified using Method 10 (preparative HPLC). .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.78-0.96 (m, 10H, including at 0.84 (s, 9H)), 1.18 (br. t, 1H), 1.30-1.40 (m, 1H), 1.43- 1.56 (m, 2H), 1.64 (br. d, 1H), 1.70 (br. d, 1H), 1.75-1.82 (m, 2H), 1.86 (t, 1H), 1.98 (br. t, 1H), 2.48-2.55 (m, 1H, partially obscured by DMSO), 2.78 (br. d, 1H), 2.87 (br. d, 1H), 3.00-3.09 (m, 2H), 4.53 (br. d, 2H), 7.82 (s, 1H), 7.88 (td, 1H), 8.46 (d, 1H), 8.67 (t, 1H). LC-MS (method 1): R.sub.t = 1.14 min; m/z = 478 (M + H).sup.+.

[1359] Analogously to Examples 18 to 22, the following compounds of Examples 150 to 152 were prepared from the starting materials stated in each case:

TABLE-US-00008 Example Name/Structure/Starting material Analytical data 150 N-[(3,5-difluoropyridin-2-yl)methyl]-N-methyl- 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide   [00293]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(3,5-difluoropyridin-2-yl)-N- methylmethanamine hydrochloride (1:1) .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.76-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.35- 1.67 (m, 6H), 1.71-1.82 (m, 3H), 2.05 (br. t, 1H), 2.45-2.56 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.05 (t, 2H), 3.16 (br. s, 3H), 3.94 (br. d, 2H), 4.83 (br. s, 2H), 7.59 (s, 1H), 7.93 (t, 1H), 8.48 (d, 1H). LC-MS (method 1): R.sub.t = 0.99 min; m/z = 450 (M + H).sup.+. 151 N-(2-chlorobenzyl)-2-[(3R)-3-methyl[1,4′- bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide   [00294]   from 2-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(2-chlorophenyl)methanamine .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.77-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.34- 1.67 (m, 6H), 1.72-1.82 (m, 3H), 2.01-2.10 (m, 1H), 2.45-2.56 (m, 1H, partially obscured by DMSO), 2.74 (br. t, 2H), 3.06 (td, 2H), 3.95 (br. d, 2H), 4.46 (d, 2H), 7.26-7.37 (m, 3H), 7.41-7.49 (m, 1H), 7.87 (s, 1H), 7.87 (t, 1H). LC-MS (method 1): R.sub.t = 1.17 min; m/z = 433/435 (M + H).sup.+. 152 N-[(3,5-difluoropyridin-2-yl)methyl]-5-[(3R)-3- methyl[1,4′-bipiperidin]-1′-yl]-1,3,4-thiadiazole- 2-carboxamide   [00295]   from 5-[(3R)-3-methyl[1,4′-bipiperidin]-1′-yl]- 1,3,4-thiadiazole-2-carboxylic acid and 1-(3,5- difluoropyridin-2-yl)methanamine dihydrochloride .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.78-0.87 (m, 4H, including at 0.82 (d, 3H)), 1.36- 1.45 (m, 1H), 1.48-1.67 (m, 5H), 1.73-1.84 (m, 3H), 2.02-2.10 (m, 1H), 2.45-2.57 (m, 1H, partially obscured by DMSO), 2.70-2.78 (m, 2H), 3.20 (td, 2H), 3.94 (br. d, 2H), 4.59 (d, 2H), 7.91 (td, 1H), 8.46 (d, 1H), 9.11 (t, 1H). LC-MS (method 1): R.sub.t = 0.94 min; m/z = 437 (M + H).sup.+.

Example 153

rac-2-[4-(5-Azaspiro[2.5]octan-5-yl)azepan-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1360] ##STR00296##

[1361] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (190 mg, 568 μmol) and rac-5-(azepan-4-yl)-5-azaspiro[2.5]octane hydrochloride (139 mg, 568 μmol) was stirred at 120° C. in 5 ml of sodium carbonate solution (5.0 ml, 2.0 M, 10 mmol). After 30 min, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the desiccant was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by means of preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Eluent A: water, eluent B: acetonitrile, eluent C: 2% ammonia in water, eluent D: acetonitrile/water (80% by vol./20% by vol.) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection, gradient profile: eluent A 0 to 2 min 47 ml, eluent B 0 to 2 min 23 ml, eluent A 2 to 10 min from 47 ml to 23 ml and eluent B from 23 ml to 47 ml, 10 to 12 min 0 ml eluent A and 70 ml eluent B. Eluent C and eluent D constant flow rate of 5 ml/min in each case over the entire run time). The product-containing fractions were combined and lyophilized. 65.0 mg (100% purity, 25% of theory) of the target compound was obtained.

[1362] LC-MS (method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=462 [M+H].sup.+.

[1363] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: −0.198 (5.60), −0.018 (0.69), 0.010 (2.52), 0.016 (1.67), 0.027 (1.99), 0.043 (6.17), 0.048 (4.92), 0.054 (2.80), 0.067 (0.96), 1.018 (3.68), 1.147 (0.51), 1.152 (0.58), 1.169 (1.67), 1.187 (1.84), 1.205 (0.77), 1.209 (0.68), 1.340 (3.14), 1.348 (4.28), 1.356 (3.45), 1.366 (1.72), 1.379 (1.32), 1.390 (1.15), 1.397 (1.21), 1.413 (0.50), 1.455 (0.48), 1.462 (0.56), 1.471 (0.99), 1.478 (1.45), 1.486 (1.01), 1.495 (1.57), 1.501 (1.15), 1.511 (0.68), 1.518 (0.59), 1.554 (1.38), 1.576 (1.21), 1.662 (1.28), 1.672 (1.28), 1.691 (2.34), 1.714 (1.18), 1.945 (10.99), 2.175 (1.22), 2.192 (2.33), 2.209 (1.29), 2.241 (4.34), 2.301 (9.23), 2.303 (11.81), 2.306 (8.61), 2.342 (16.00), 3.113 (4.59), 3.166 (1.35), 3.172 (1.41), 3.189 (2.63), 3.195 (2.20), 3.206 (2.26), 3.212 (2.58), 3.229 (1.15), 4.325 (6.54), 4.334 (6.54), 7.620 (13.19), 7.677 (1.57), 7.681 (1.61), 7.694 (2.63), 7.696 (2.64), 7.709 (1.63), 7.713 (1.61), 8.258 (6.08), 8.262 (5.84), 8.410 (2.03), 8.420 (3.98), 8.429 (2.01).

Example 154

ent-2-[4-(5-Azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 1)

[1364] ##STR00297##

[1365] 30 mg of diamix-2-[4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide were separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralpak AY-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 17 ml/min; temperature 60° C., detection: 300 nm). The stereoisomer having a retention time of 7.369 min (HPLC: Daicel® Chiralpak AY-H column, 5 μm 250×4.6 mm, flow rate 1 ml/min; eluent A: 50% n-heptane, eluent B: 50% ethanol; temperature 40° C.; detection: 300 nm) was collected. After the solvents had been removed, 13.8 mg (95% purity, 44% of theory) of the title compound was obtained.

[1366] LC-MS (method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=466 [M*1].sup.+.

[1367] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: 0.236 (10.79), 0.258 (8.99), 1.090 (0.54), 1.108 (1.06), 1.125 (0.51), 1.209 (0.73), 1.227 (2.07), 1.241 (4.56), 1.256 (4.39), 1.270 (2.23), 1.288 (0.77), 1.560 (3.15), 1.572 (4.03), 1.585 (3.05), 1.668 (1.38), 1.693 (2.00), 1.787 (0.54), 1.797 (0.68), 1.818 (1.54), 1.828 (1.68), 1.849 (1.49), 1.860 (1.48), 1.880 (0.52), 1.892 (0.43), 2.154 (0.91), 2.267 (1.33), 2.296 (5.50), 2.311 (4.85), 2.338 (1.24), 2.366 (1.57), 2.575 (5.38), 2.588 (6.31), 2.601 (3.87), 2.641 (1.14), 2.665 (1.32), 2.670 (1.33), 2.710 (1.63), 3.110 (1.26), 3.135 (2.36), 3.141 (2.29), 3.167 (1.39), 3.199 (1.92), 3.234 (1.99), 3.332 (3.95), 3.968 (1.80), 4.000 (1.68), 4.142 (1.13), 4.171 (1.92), 4.206 (1.06), 4.520 (6.58), 4.533 (6.75), 5.025 (2.13), 5.148 (2.16), 7.811 (16.00), 7.885 (1.66), 7.891 (1.75), 7.909 (2.58), 7.915 (2.63), 7.933 (1.75), 7.939 (1.80), 8.464 (5.71), 8.469 (5.60), 8.705 (2.14), 8.719 (4.42), 8.734 (2.16).

Example 155

ent-2-[4-(5-Azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (Enantiomer 2)

[1368] ##STR00298##

[1369] 30 mg of diamix-2-[4-(5-azaspiro[2.5]octan-5-yl)-3-fluoropiperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide was separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralpak AY-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 17 ml/min; temperature 60° C., detection: 300 nm). The stereoisomer having a retention time of 10.529 min (HPLC: Daicel® Chiralpak AY-H column, 5 μm, flow rate 1 ml/min; eluent A: 50% n-heptane, eluent B: 50% ethanol; temperature 40° C.; detection: 300 nm) was collected. After the solvents had been removed, 14 mg (94% purity, 99% ee) of the title compound was obtained.

[1370] LC-MS (method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1371] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: 0.236 (11.06), 0.258 (9.20), 1.090 (0.62), 1.107 (1.28), 1.125 (0.64), 1.209 (0.81), 1.241 (4.81), 1.256 (4.57), 1.270 (2.32), 1.288 (0.85), 1.560 (3.23), 1.570 (4.14), 1.584 (3.10), 1.667 (1.44), 1.693 (2.05), 1.786 (0.58), 1.797 (0.71), 1.817 (1.60), 1.828 (1.73), 1.848 (1.56), 1.859 (1.52), 1.879 (0.55), 1.891 (0.45), 2.153 (1.06), 2.267 (1.39), 2.296 (5.60), 2.311 (4.94), 2.337 (1.29), 2.366 (0.85), 2.575 (5.05), 2.587 (6.35), 2.600 (3.87), 2.640 (1.11), 2.670 (1.33), 2.710 (0.84), 3.109 (1.29), 3.134 (2.45), 3.141 (2.38), 3.166 (1.37), 3.198 (1.98), 3.234 (2.01), 3.332 (4.25), 3.967 (1.85), 4.000 (1.74), 4.141 (1.18), 4.171 (1.95), 4.206 (1.08), 4.519 (6.81), 4.533 (6.87), 5.025 (2.18), 5.147 (2.20), 7.810 (16.00), 7.885 (1.65), 7.891 (1.70), 7.909 (2.59), 7.914 (2.63), 7.933 (1.70), 7.938 (1.74), 8.463 (5.57), 8.469 (5.44), 8.705 (2.16), 8.719 (4.49), 8.733 (2.19).

Example 156

diamix-2-[4-(1,1-Difluoro-5-azaspiro[2.5]octan-5-yl)azepan-1-yl]-N-[(3,5-difluoropyridin-2-yl)-methyl]-1,3-thiazole-5-carboxamide

[1372] ##STR00299##

[1373] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (204 mg, 612 μmol) and diamix-5-(azepan-4-yl)-1,1-difluoro-5-azaspiro[2.5]octane dihydrochloride (194 mg, 612 μmol) were stirred at 120° C. in 5 ml of sodium carbonate solution (5.0 ml, 2.0 M, 10 mmol). After 30 min, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the desiccant was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by means of preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Eluent A: water, eluent B: acetonitrile, eluent C: 2% ammonia in water, eluent D: acetonitrile/water (80% by vol./20% by vol.) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection, gradient profile: eluent A 0 to 2 min 47 ml, eluent B 0 to 2 min 23 ml, eluent A 2 to 10 min from 47 ml to 23 ml and eluent B from 23 ml to 47 ml, 10 to 12 min 0 ml eluent A and 70 ml eluent B. Eluent C and eluent D constant flow rate of 5 ml/min in each case over the entire run time). The product-containing fractions were combined and lyophilized. 189 mg (100% purity, 62% of theory) of the title compound was obtained.

[1374] LC-MS (method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=498 [M+H].sup.+

[1375] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 1.133 (2.06), 1.142 (1.83), 1.164 (0.97), 1.178 (0.90), 1.186 (1.69), 1.197 (1.47), 1.206 (1.48), 1.215 (0.88), 1.227 (0.45), 1.351 (1.08), 1.369 (1.22), 1.374 (0.96), 1.381 (0.58), 1.387 (0.62), 1.395 (0.96), 1.399 (1.20), 1.417 (1.58), 1.422 (1.32), 1.436 (1.96), 1.458 (3.65), 1.476 (4.32), 1.490 (2.59), 1.503 (1.49), 1.579 (2.76), 1.587 (2.68), 1.593 (2.48), 1.597 (2.45), 1.602 (2.32), 1.620 (1.16), 1.644 (0.54), 1.660 (0.68), 1.666 (1.01), 1.683 (1.31), 1.689 (1.08), 1.699 (1.04), 1.705 (1.28), 1.722 (1.03), 1.729 (0.74), 1.739 (0.47), 1.786 (1.62), 1.808 (0.81), 1.885 (1.92), 1.902 (2.88), 1.908 (2.66), 2.338 (1.81), 2.357 (2.71), 2.384 (1.25), 2.397 (1.98), 2.402 (1.93), 2.420 (3.53), 2.435 (3.12), 2.453 (2.78), 2.466 (2.20), 2.482 (1.24), 3.315 (0.82), 3.374 (1.71), 3.379 (1.45), 3.391 (2.82), 3.396 (3.31), 3.413 (2.79), 3.432 (0.78), 3.634 (1.33), 3.668 (1.30), 4.523 (8.18), 4.531 (8.26), 7.820 (16.00), 7.876 (2.24), 7.880 (2.38), 7.892 (3.31), 7.895 (3.49), 7.907 (2.32), 7.911 (2.36), 8.455 (7.27), 8.459 (7.23), 8.612 (2.58), 8.621 (5.17), 8.631 (2.61).

Example 157

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-4-carboxamide (Diastereomer 1)

[1376] ##STR00300##

[1377] 65 mg of diamix-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-thiazole-4-carboxamide was separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralcel OZ-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 18 ml/min; temperature 50° C., detection:

[1378] 210 nm). The stereoisomer having a retention time of 4.883 min (HPLC: Chiraltec OZ-3 column, 3 μm, flow rate 1 ml/min; eluent A: 50% i-hexane, eluent B: 50% ethanol+0.2% diethylamine; detection: 220 nm) was collected. After the solvents had been removed, 21 mg (100% purity, 99% ee) of the title compound was obtained.

[1379] LC-MS (method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1380] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.823 (14.86), 0.835 (16.00), 0.849 (1.42), 0.869 (0.63), 1.236 (0.85), 1.387 (1.14), 1.407 (1.22), 1.573 (2.13), 1.596 (1.28), 1.630 (1.35), 1.650 (1.31), 1.689 (1.24), 1.707 (1.39), 1.889 (1.27), 1.906 (2.38), 1.916 (1.76), 1.923 (2.52), 1.937 (1.47), 1.945 (1.32), 1.957 (0.51), 2.068 (0.62), 2.175 (0.82), 2.194 (1.52), 2.212 (0.85), 2.383 (0.49), 2.422 (0.58), 2.596 (0.68), 2.611 (1.03), 2.651 (1.20), 2.672 (0.67), 2.827 (1.46), 2.845 (2.46), 2.865 (1.33), 3.106 (1.10), 3.123 (2.00), 3.127 (1.96), 3.144 (1.09), 3.213 (1.63), 3.237 (1.65), 3.256 (0.81), 3.300 (5.24), 3.319 (0.75), 4.026 (1.36), 4.047 (1.35), 4.190 (0.88), 4.213 (1.55), 4.233 (0.86), 4.577 (5.51), 4.587 (5.59), 5.068 (1.55), 5.149 (1.56), 7.373 (13.52), 7.883 (1.47), 7.887 (1.57), 7.900 (2.20), 7.902 (2.27), 7.915 (1.59), 7.919 (1.70), 8.452 (6.07), 8.456 (7.08), 8.467 (3.22), 8.476 (1.57).

Example 158

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-4-carboxamide (Diastereomer 2)

[1381] ##STR00301##

[1382] 65 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-thiazole-4-carboxamide was separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralcel OZ-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 18 ml/min; temperature 50° C., detection: 210 nm). The stereoisomer having a retention time of 6.565 min (HPLC: Chiraltec OZ-3 column, 3 μm, flow rate 1 ml/min; eluent A: 50% i-hexane, eluent B: 50% ethanol+0.2% diethylamine; detection: 220 nm) was collected. After the solvents had been removed, 22 mg (100% purity, 99% ee) of the title compound was obtained.

[1383] LC-MS (method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=454 [M+H].sup.+

[1384] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.816 (14.95), 0.827 (16.00), 0.844 (1.56), 0.850 (1.48), 0.865 (0.73), 1.235 (0.95), 1.259 (0.49), 1.429 (1.23), 1.449 (1.33), 1.469 (0.69), 1.505 (1.15), 1.577 (1.72), 1.598 (1.31), 1.629 (1.49), 1.651 (1.43), 1.690 (1.29), 1.708 (1.52), 1.883 (0.96), 1.897 (2.04), 1.918 (2.19), 1.925 (1.68), 1.939 (1.52), 1.947 (1.43), 1.960 (0.55), 2.068 (1.18), 2.177 (0.94), 2.194 (1.68), 2.212 (0.97), 2.422 (0.40), 2.595 (0.72), 2.614 (0.91), 2.651 (1.01), 2.675 (0.67), 2.837 (2.71), 2.855 (2.60), 3.105 (1.16), 3.122 (2.09), 3.126 (2.06), 3.143 (1.18), 3.214 (1.69), 3.237 (1.76), 3.255 (0.67), 3.302 (3.65), 4.031 (1.52), 4.052 (1.43), 4.186 (0.95), 4.209 (1.64), 4.229 (0.90), 4.578 (5.83), 4.587 (5.87), 5.066 (1.70), 5.149 (1.74), 7.373 (12.51), 7.883 (1.46), 7.887 (1.60), 7.902 (2.37), 7.915 (1.61), 7.919 (1.65), 8.452 (6.19), 8.456 (7.23), 8.466 (3.38), 8.476 (1.74).

Example 159

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-oxazole-4-carboxamide (Diastereomer 1)

[1385] ##STR00302##

[1386] 69 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-oxazole-4-carboxamide was separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralcel OZ-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 17 ml/min; temperature 50° C., detection: 210 nm). The stereoisomer having a retention time of 4.187 min (HPLC: Chiraltec OZ-3 column, 3 μm, flow rate 1 ml/min; eluent A: 50% i-hexane, eluent B: 50% ethanol+0.2% diethylamine; detection: 220 nm) was collected. After the solvents had been removed, 24 mg (100% purity, 99% ee) of the title compound was obtained.

[1387] LC-MS (method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=438 [M+H].sup.+.

[1388] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.817 (14.98), 0.828 (16.00), 0.842 (1.57), 0.848 (1.55), 0.862 (0.71), 1.183 (1.16), 1.236 (0.78), 1.259 (0.42), 1.360 (0.49), 1.380 (1.19), 1.400 (1.28), 1.420 (0.55), 1.545 (1.16), 1.566 (2.24), 1.582 (1.25), 1.587 (1.43), 1.623 (1.47), 1.650 (2.35), 1.670 (1.45), 1.853 (0.52), 1.861 (0.65), 1.874 (2.32), 1.882 (1.97), 1.895 (2.84), 1.903 (1.88), 1.924 (0.60), 2.163 (0.76), 2.182 (1.38), 2.200 (0.80), 2.560 (0.76), 2.581 (0.60), 2.624 (0.62), 2.643 (0.58), 2.813 (1.42), 2.832 (2.40), 2.853 (1.29), 3.057 (1.11), 3.074 (2.04), 3.078 (2.01), 3.096 (1.15), 3.182 (1.64), 3.206 (1.68), 3.247 (1.77), 3.272 (2.52), 4.084 (1.52), 4.102 (1.38), 4.106 (1.50), 4.132 (1.01), 4.150 (1.66), 4.154 (1.57), 4.174 (0.92), 4.560 (5.67), 4.570 (5.70), 5.030 (1.59), 5.112 (1.58), 7.883 (1.46), 7.887 (1.54), 7.900 (2.18), 7.903 (2.27), 7.915 (1.53), 7.919 (1.60), 8.005 (12.95), 8.206 (1.59), 8.216 (3.17), 8.226 (1.64), 8.459 (5.78), 8.463 (5.70).

Example 160

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3-oxazole-4-carboxamide (Diastereomer 2)

[1389] ##STR00303##

[1390] 69 mg of diamix-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3′-fluoro-3-methyl[1,4′-bipiperidin]-F-yl]-1,3-oxazole-4-carboxamide was separated into the stereoisomers by means of chiral HPLC (preparative HPLC: Daicel® Chiralcel OZ-H column, 5 μm, 250×20 mm; eluent A: 50% n-heptane, eluent B: 50% ethanol+0.2% diethylamine; flow rate 17 ml/min; temperature 50° C., detection: 210 nm). The stereoisomer having a retention time of 5.588 min (HPLC: Chiraltec OZ-3 column, 3 μm, flow rate 1 ml/min; eluent A: 50% i-hexane, eluent B: 50% ethanol+0.2% diethylamine; detection: 220 nm) was collected. After the solvents had been removed, 25 mg (100% purity, 99% ee) of the title compound was obtained.

[1391] LC-MS (method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=438 [M+H].sup.+.

[1392] .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ [ppm]: 0.809 (14.88), 0.821 (16.00), 0.837 (1.47), 0.843 (1.50), 0.859 (1.88), 0.870 (0.67), 1.181 (1.27), 1.237 (1.02), 1.401 (0.50), 1.421 (1.11), 1.441 (1.23), 1.462 (0.67), 1.495 (1.05), 1.569 (1.52), 1.591 (1.21), 1.624 (1.48), 1.645 (2.41), 1.665 (1.40), 1.865 (1.31), 1.879 (2.59), 1.886 (2.46), 1.900 (2.08), 1.907 (1.57), 1.921 (0.62), 1.928 (0.53), 2.068 (1.85), 2.166 (0.82), 2.182 (1.46), 2.200 (0.85), 2.560 (0.89), 2.580 (0.67), 2.617 (0.67), 2.640 (0.60), 2.651 (0.55), 2.824 (2.58), 2.841 (2.48), 3.058 (1.09), 3.075 (1.99), 3.079 (1.97), 3.097 (1.09), 3.167 (0.69), 3.175 (0.78), 3.182 (1.67), 3.206 (1.64), 3.248 (1.85), 3.257 (0.98), 3.260 (0.94), 3.272 (2.79), 3.320 (0.82), 4.085 (1.49), 4.107 (1.48), 4.131 (0.98), 4.150 (1.59), 4.173 (0.90), 4.560 (5.51), 4.570 (5.53), 5.031 (1.47), 5.112 (1.47), 7.884 (1.53), 7.888 (1.65), 7.900 (2.13), 7.903 (2.27), 7.915 (1.60), 7.920 (1.63), 8.005 (13.82), 8.206 (1.60), 8.216 (3.12), 8.226 (1.56), 8.459 (5.88), 8.463 (5.86).

Example 161

ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-2′,3-dimethyl[1,4′-bipiperidin]-1′-yl]-1,3-thiazole-5-carboxamide (Diastereomer 1)

[1393] ##STR00304##

[1394] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (190 mg, 568 μmol) and diamix-(3R)-2′,3-dimethyl-1,4′-bipiperidine dihydrochloride (80.6 mg, 299 μmol) was stirred at 120° C. in 2 ml of sodium carbonate solution (2.0 ml, 2.0 M, 4 mmol). After 1 h, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, the desiccant was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in DMSO and purified by means of preparative HPLC (instrument: Waters Prep LC/MS System, column: XBridge C18 5 μm 100×30 mm. Eluent A: water, eluent B: acetonitrile, eluent C: 2% ammonia in water, eluent D: acetonitrile/water (80% by vol./20% by vol.) total flow rate: 80 ml/min, room temperature, wavelength 200-400 nm, complete injection, gradient profile: eluent A 0 to 2 min 47 ml, eluent B 0 to 2 min 23 ml, eluent A 2 to 10 min from 47 ml to 23 ml and eluent B from 23 ml to 47 ml, 10 to 12 min 0 ml eluent A and 70 ml eluent B. Eluent C and eluent D constant flow rate of 5 ml/min in each case over the entire run time). The product-containing fractions were combined and lyophilized. 8.00 mg (82% purity, 5% of theory) of the target compound was obtained.

[1395] LC-MS (method 5): R.sub.t=1.72 min; MS (ESIpos): m/z=450 [M+H].sup.+

[1396] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]: 0.146 (0.43), 0.771 (0.56), 0.809 (13.00), 0.826 (15.28), 0.844 (2.58), 0.851 (2.10), 1.166 (14.79), 1.183 (15.12), 1.235 (0.44), 1.296 (1.97), 1.301 (1.60), 1.312 (2.07), 1.317 (1.56), 1.373 (1.37), 1.383 (1.84), 1.393 (2.21), 1.404 (2.07), 1.413 (2.10), 1.423 (2.05), 1.434 (1.41), 1.454 (0.86), 1.512 (1.28), 1.560 (2.23), 1.592 (2.05), 1.618 (2.40), 1.637 (2.72), 1.652 (3.46), 1.665 (4.32), 1.676 (3.70), 1.728 (1.19), 1.754 (2.06), 1.764 (1.63), 1.790 (3.56), 1.817 (2.90), 2.012 (0.60), 2.041 (1.19), 2.074 (1.20), 2.102 (0.58), 2.328 (0.62), 2.366 (0.89), 2.670 (0.69), 2.710 (3.13), 2.725 (3.59), 2.732 (3.58), 3.123 (1.06), 3.149 (1.93), 3.155 (1.93), 3.182 (1.13), 3.820 (1.15), 3.852 (1.08), 4.364 (1.34), 4.517 (6.60), 4.530 (6.70), 7.811 (3.31), 7.822 (16.00), 7.885 (1.94), 7.891 (2.06), 7.910 (2.71), 7.913 (2.88), 7.932 (1.99), 7.938 (2.02), 8.462 (6.46), 8.468 (6.34), 8.644 (0.43), 8.659 (0.91), 8.673 (2.24), 8.687 (3.93), 8.701 (1.91).

[1397] Analogously to Examples 15 to 17, the following compounds of Examples 162 to 163 were prepared from the reactants specified in each case:

TABLE-US-00009 Example Name/Structure/Reactants Analytical data 162 N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′- ethyl-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide (cis diastereomer 1)   [00305]   from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3- ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5- carboxamide (Example 91A (Enantiomer 1)), and (3R)-3-methylpiperidine hydrochloride .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.79-0.88 (m, 4H, including at 0.84 (d, 3H)), 0.88- 0.94 (m, 3H), 1.02-1.12 (m, 1H), 1.33-1.56 (m, 5H), 1.57-1.67 (m, 2H), 1.74-1.81 (m, 1H), 1.81-1.91 (m, 2H), 2.12-2.20 (m, 1H), 2.82- 2.90 (m, 1H), 2.91-3.05 (m, 3H), 3.92-4.04 (m, 2H), 4.52 (br. d, 2H), 7.79 (s, 1H), 7.87-7.93 (m, 1H), 8.46 (d, 1H), 8.66 (t, 1H). LC-MS (method 4): R.sub.t = 0.56 min; m/z = 464 (M + H).sup.+. [α].sub.D.sup.20 = −20.21° (c = 0.310, methanol). 163 N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)-3′- ethyl-3-methyl[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide (cis diastereomer 2)   [00306]   from N-[(3,5-difluoropyridin-2-yl)methyl]-2-(3- ethyl-4-oxopiperidin-1-yl)-1,3-thiazole-5- carboxamide (Example 92A (Enantiomer 2)), and (3R)-3-methylpiperidine hydrochloride .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.80-0.88 (m, 4H, including at 0.84 (d, 3H)), 0.88- 0.94 (m, 3H), 1.02-1.12 (m, 1H), 1.33-1.57 (m, 5H), 1.57-1.67 (m, 2H), 1.74-1.80 (m, 1H), 1.81-1.90 (m, 2H), 2.12-2.19 (m, 1H), 2.82- 3.05 (m, 4H), 3.93-4.03 (m, 2H), 4.52 (br. d, 2H), 7.79 (s, 1H), 7.87-7.93 (m, 1H), 8.46 (d, 1H), 8.66 (t, 1H). LC-MS (method 4): R.sub.t = 0.56 min; m/z = 464 (M + H).sup.+. [α].sub.D.sup.20 = −17.69° (c = 0.360, methanol).

[1398] Analogously to Examples 1 to 3, the following compounds of Examples 164 to 165 were prepared from the reactants specified in each case:

TABLE-US-00010 Example Name/Structure/Reactants Analytical data 164 N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)- 3,3′-dimethyl[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide (cis-Diastereomer 1)   [00307]   from 2-bromo-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-5-carboxamide and (3R)- 3,3′-dimethyl-1,4′-bipiperidine dihydrobromide (cis-Diastereomer 1, Example 96A) .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.79-0.88 (m, 7H), 1.37- 1.55 (m, 4H), 1.57-1.67 (m, 2H), 1.75-1.85 (m, 2H), 2.13-2.18 (m, 1H), 2.21-2.28 (m, 1H), 2.86-3.00 (m, 3H), 3.14 (dd, 1H), 3.80 (br. d, 1H), 3.99 (br. d, 1H), 4.53 (d, 2H), 7.79 (s, 1H), 7.89 (td, 1H), 8.46 (d, 1H), 8.65 (t, 1H). LC-MS (method 1): R.sub.t = 0.88 min; m/z = 450 (M + H).sup.+. [α].sub.D.sup.20 = −12.17° (c = 0.345, methanol). 165 N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[(3R)- 3,3′-dimethyl[1,4′-bipiperidin]-1′-yl]-1,3- thiazole-5-carboxamide (cis-Diastereomer 2)   [00308]   from 2-bromo-N-[(3,5-difluoropyridin-2-yl)- methyl]-1,3-thiazole-5-carboxamide and (3R)- 3,3′-dimethyl-1,4′-bipiperidine dihydrobromide (cis-Diastereomer 2, Example 97A) .sup.1H-NMR (600 MHz, DMSO-d.sub.6, δ/ppm): 0.79-0.90 (m, 7H), 1.35- 1.49 (m, 2H), 1.50-1.57 (m, 2H), 1.57-1.66 (m, 2H), 1.73-1.80 (m, 1H), 1.81-1.87 (m, 1H), 2.12-2.18 (m, 1H), 2.20-2.26 (m, 1H), 2.84- 2.91 (m, 2H), 2.93-3.00 (m, 1H), 3.15 (dd, 1H), 3.78 (br. d, 1H), 4.00 (br. d, 1H), 4.52 (d, 2H), 7.79 (s, 1H), 7.87-7.92 (m, 1H), 8.46 (d, 1H), 8.65 (t, 1H). LC-MS (method 1): R.sub.t = 0.88 min; m/z = 450 (M + H).sup.+. [α].sub.D.sup.20 = −25.14° (c = 0.350, methanol).

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

[1399] The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples. Binding studies (B-1.) and activity studies (B-2.) were carried out for in vitro characterization of receptor/substance interaction and determination of biological activity, respectively.

[1400] B-1 In Vitro Radioligand Binding Studies for Determination of the Dissociation Constants K, at the Human Adrenoreceptor ADRA2C (Eurojins Panlabs Discovery Services, Taiwan, Ltd)

[1401] A competition assay based on [.sup.3H] rauwolscine as radioliganden was used to determine the binding affinity of the test substances at the human ADRA2C receptor.

[1402] To configure the competition assay, the equilibrium dissociation constant K.sub.d of the radioligand [.sup.3H] rauwolscine was determined in a saturation experiment. To this end, homogenates of CHO-K1 cells recombinantly expressing the human ADRA2C receptor were incubated with increasing concentrations of the radiotracers for 1 h at 4° C. in binding buffer (50 mM Tris-HCl, 1 mM EDTA, pH 7.4). Unspecific binding was determined by addition of an excess of the not radioactively labelled ligand prazosin (10 μM). The radioactivity was determined in a scintiation counter.

[1403] The competition experiments were carried out in the presence of 0.5 nM [.sup.3H] rauwolscine and increasing concentrations of the test substances to be characterized under the conditions described above. The substance concentration which displaces 50% of the radiolabelled ligand is referred to as IC.sub.50 value.

[1404] From the IC.sub.50 value measured in the competition experiment and the K.sub.d value from the saturation experiment, the equilibrium constant Ki of the inhibitor, which describes the affinity of the test substances to the receptor, was calculated using the Cheng Prusoff equation [Cheng Y, Prusoff W H. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (ISO) of an enzymatic reaction. Biochem Pharmacol. 22 (23): 3099-108. doi:10.1016/0006-2952(73)90196-2. PMID 4202581 PMID: 4202581].

[00002]$\begin{array}{cc}\mathrm{Ki}=\frac{\mathrm{IC}50}{\left(1+\frac{L}{\mathrm{Kd}}\right)}& \mathrm{Formula}1\end{array}$

[1405] Cheng Prusoff equation. K.sub.i=equilibrium constant of the inhibitor, IC.sub.50=concentration which displaces 50% of the ligand, K.sub.d=equilibrium constant of the ligand, L=concentration of the ligand

[1406] Table 1 below shows the binding affinity to the human ADRA2C receptor (Ki [nM]) and the half-maximal inhibition of the human ADRA2C receptor (IC50 [nM]) of representative embodiments of the invention:

TABLE-US-00011 TABLE 1 Example hARα.sub.2C hARα.sub.2C No. IC.sub.50 [nM] K.sub.i [nM] 1 54 24 41 130 56 64 6.2 2.8 124 5.1 2.3

[1407] The data in Table 1 show that the test substances listed both bind to the human ADRA2C receptor and block the biological activity of the human ADRA2C receptor. Accordingly, the results in Table 1 confirm the mechanism of action of the compounds according to the invention as ADRA2C inhibitors.

[1408] B-2. In Vitro Activity Assay to Determine the Inhibition of Recombinant ADRA2C

[1409] The human ADRA2C receptor belongs to the G protein (guanine-dependent protein)-coupled receptors, the main function of which is the transduction of signals into the interior of the cell.

[1410] The investigations of the inhibition of the recombinant human ADRA2C receptors were carried out with stably transfected CHO-K1 cells coexpressing the G.sub.αq protein and the calcium-sensitive photoprotein aequorin. In this recombinant system, binding of the agonists noradrenaline to the ADRA2C receptor leads, after activation of a signal cascade, to calcium release from intracellular stores, which is detected by the intracellular calcium sensor aequorin as a bioluminescent signal. The method is described in detail in the reference below. [Wunder F., Kalthof B., Muller T., Hueser J. Functional Cell-Based Assays in Microliter Volumes for Ultra-High Throughput Screening. Combinatorial Chemistry & High Throughput Screening, Volume 11, Number 7, 2008, pp. 495-504(10). doi.org/10.2174/138620708785204054]

[1411] The activity of the test substances was determined via their ability to inhibit the agonist-induced increase of the bioluminescence signal. The concentration which can block half of this signal increase is referred to as IC.sub.50. The IC.sub.50 value is calculated using the 4 parameter logistic function (Hill function):

[00003]$\begin{array}{cc}Y\left(x\right)=\mathrm{Bottom}+\frac{\mathrm{Top}-\mathrm{Bottom}}{1+{10}^{\left(\mathrm{logIC}50+x\right)-\mathrm{HillSlope}}}& \mathrm{Formula}2:\mathrm{Hill}\mathrm{function}\end{array}$

[1412] Top=upper threshold, Bottom=lower threshold, Slope=slope, IC.sub.50=turning point

[1413] Table 2 below lists the IC.sub.50 values from this assay determined for individual working examples of the invention (some as mean values from multiple independent individual determinations):

TABLE-US-00012 TABLE 2 Example ARα.sub.2C No. IC.sub.50 [nM] 1 121 2 5.2 3 2.9 4 169 5 335 6 335 7 49.6 8 591 9 170 10 21.4 11 140 12 107 13 209 14 211 15 1850 16 2000 17 26.5 18 6800 19 690 20 110 21 7.2 22 640 23 17 24 1060 25 2400 26 280 27 310 28 890 29 96 31 89 32 640 33 15 34 640 35 1000 36 190 37 200 38 2340 39 135 41 243 43 261 44 41.2 46 8.3 47 25 48 17 49 56 50 73.5 51 150 52 6.7 53 110 54 230 55 150 56 240 57 830 58 870 59 11 60 74 61 87 62 130 63 570 64 1.4 65 4.5 66 1.5 67 2.2 68 4.3 69 5.5 70 22 71 100 72 180 73 219 74 285 75 345 76 400 77 640 78 755 79 50.3 80 90.5 81 22.2 82 102 83 98.1 84 65 85 600 86 28 87 25.5 88 489 89 230 90 971 91 284 92 85 93 630 94 150 95 800 96 1000 97 1300 98 1600 99 590 100 2.9 101 2.3 102 0.085 103 0.83 104 10 105 4.3 106 0.5 107 37 108 0.37 109 0.85 110 1.5 111 0.49 112 1.2 113 0.61 114 1.3 115 0.61 116 11 117 0.65 118 7.7 119 30 120 41 121 0.65 122 13 123 260 124 2.9 125 0.49 126 2.3 127 8.4 128 550 129 10 130 0.54 131 1.9 132 0.71 133 0.95 134 0.74 135 0.26 136 320 137 19 138 6.5 139 0.65 140 0.32 141 8.7 142 6.7 143 0.42 144 1.8 145 1.0 146 1.72 148 1.3 149 35 150 200 151 170 152 660 153 23 154 31 155 2.5 156 36 157 2.7 158 98 159 25 160 435 161 233 162 810 163 480 164 24 165 410

[1414] The data in Table 2 show that the test substances listed block the biological activity of the human ADRA2C receptor. Accordingly, the results in Table 1 confirm the mechanism of action of the compounds according to the invention as ADRA2C inhibitors.

[1415] B-3 Animal Model of Obstructive Sleep Apnoea in the Pig

[1416] Using negative pressure, it is possible to induce collapse and thus obstruction of the upper respiratory tract in anesthetized, spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

[1417] German Landrace pigs are used for the model. The pigs are anesthetized and tracheotomized. One cannula each is inserted into the rostral and the caudal part of the trachea. Using a T connector, the rostral cannula is connected on the one hand to a device generating negative pressures and on the other hand to the caudal cannula. Using a T connector, the caudal cannula is connected to the rostral cannula and to a tube which allows spontaneous breathing circumventing the upper respiratory tract. By appropriate closing and opening of the tubes it is thus possible for the pig to change from normal nasal breathing to breathing via the caudal cannula during the time when the upper respiratory tract is isolated and connected to the device for generating negative pressures. The muscle activity of the musculus genioglossus is recorded by electromyogram (EMG).

[1418] At certain points in time, the collapsibility of the upper respiratory tract is tested by having the pig breathe via the caudal cannula and applying negative pressures of −50, −100 and −150 cm water head (cmH.sub.2O) to the upper respiratory tract. This causes the upper respiratory tract to collapse, which manifests itself in an interruption of the airflow and a pressure drop in the tube system. This test is conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. An appropriately effective test substance can prevent this collapse of the respiratory tract in the inspiratory phase.

[1419] Administration of the test substance can be intranasal, intravenous, subcutaneous, intraperitoneal, intraduodenal or intragastral.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

[1420] The compounds of the invention can be converted to pharmaceutical preparations as follows:

[1421] Tablet:

[1422] Composition:

[1423] 100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

[1424] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

[1425] Production:

[1426] The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

[1427] Suspension for Oral Administration:

[1428] Composition:

[1429] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

[1430] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

[1431] Production:

[1432] The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

[1433] Solution for Oral Administration:

[1434] Composition:

[1435] 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400.

[1436] 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

[1437] Production:

[1438] The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound of the invention is complete.

[1439] i.v. Solution:

[1440] The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.

[1441] Solution for Nasal Administration:

[1442] The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. purified water, phosphate buffer, citrate buffer). The solution may contain further additives for isotonization, for preservation, for adjusting the pH, for improvement in the solubility and/or for stabilization.