COMBINATION OF AN ALPHA2-ADRENOCEPTOR SUBTYPE C (ALPHA-2C) ANTAGONIST WITH A TASK1/3 CHANNEL BLOCKER FOR THE TREATMENT OF SLEEP APNEA

Abstract

The present invention relates to a combination of selective blockers of TASK-1 and TASK-3 channels, in particular substituted imidazo [1,2-a]pyrimidine and substituted imidazo [1,2-a]pyridine derivatives of formula (II) and 2-Adrenoceptor subtype C (alpha-2C) antagonists, in particular substituted heterocyclic carboxamides of formula (I) for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

Claims

1. A combination of compounds of formula (I) ##STR00268## wherein X is S, N, or O; Y is N, S, or O, wherein if X is S, then Y is N; Z is C, O, or N, wherein if X is N and Y is N, then Z is O; R.sub.1 is 5- or 6-membered heteroaryl or phenyl, wherein 5- or 6-membered heteroaryl may be substituted by 1 or 2 substituents independently selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, and halogen, wherein (C.sub.1-C.sub.4)-alkyl may be substituted up to trisubstituted by halogen, wherein (C.sub.1-C.sub.4)-alkoxy may be substituted up to trisubstituted by halogen, wherein phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl, (C.sub.1-C.sub.4)-alkoxy, cyano, hydroxy, and halogen, wherein (C.sub.1-C.sub.4)-alkyl may be substituted up to trisubstituted by halogen; R.sub.2 is hydrogen or (C.sub.1-C.sub.4)-alkyl, wherein (C.sub.1-C.sub.4)-alkyl may be substituted up to trisubstituted by halogen, or together with the carbon atom to which R.sub.2 is attached, form a (C.sub.3-C.sub.4)-cycloalkyl ring; R.sub.3 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, wherein (C.sub.1-C.sub.4)-alkyl may be substituted up to trisubstituted by halogen; R.sub.4 is absent when Z represents N or O, or is hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, phenyl or halogen when Z represents C, wherein (C.sub.1-C.sub.4)-alkyl may be substituted up to trisubstituted by halogen, and phenyl may be substituted by halogen; R.sub.5 is hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, or halogen; R.sub.6 is a group selected from the group consisting of the formula a), b), c), d), e), f), or g) ##STR00269## wherein *** marks the bond to the adjacent piperidine ring, wherein R.sub.7 is 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, or phenyl, wherein (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, or (C.sub.3-C.sub.4)-cycloalkoxy and may be up to trisubstituted by halogen, wherein (C.sub.1-C.sub.4)-alkoxy in turn may be substituted by (C.sub.3-C.sub.4)-cycloalkyl and may be up to trisubstituted by halogen, wherein (C.sub.3-C.sub.4)-cycloalkyl may be substituted by monofluoromethyl, difluoromethyl, or trifluoromethyl and may be up to disubstituted by halogen, wherein (C.sub.1-C.sub.4)-alkoxy may be substituted by (C.sub.3-C.sub.4)-cycloalkyl and may be up to trisubstituted by halogen, in which (C.sub.3-C.sub.4)-cycloalkyl may be monosubstituted or disubstituted by halogen, wherein (C.sub.3-C.sub.4)-cycloalkoxy may be up to disubstituted by halogen, wherein R.sup.8 is hydrogen or fluoro, wherein R.sub.9 is hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, or halogen, wherein (C.sub.1-C.sub.4)-alkyl in turn may be substituted by (C.sub.1-C.sub.4)-alkoxy; n is 0 or 1; m is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1, or 2, with compounds of the formula (II) ##STR00270## wherein the ring Q is a piperazine or a diazaheterobicyclic system of the formula ##STR00271## wherein * denotes the bond to the adjacent CHR.sup.2 group and ** denotes the bond to the carbonyl group; W.sup.1, W.sup.2, and W.sup.3 are each independently CH or N; R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, or cyclobutyl where (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; R.sup.2 is (C.sub.4-C.sub.6)-cycloalkyl in which a ring CH.sub.2 group may be replaced by O, or R.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c), or an azole group of the formula (d), (e), (f), or (g), ##STR00272## wherein *** marks the bond to the adjacent carbonyl group; R.sup.3 is hydrogen, fluorine, chlorine, bromine, or methyl, R.sup.4 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may each be up to trisubstituted by fluorine; R.sup.5 is hydrogen, fluorine, chlorine, bromine, or methyl; R.sup.6 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine, R.sup.7 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, or (C.sub.1-C.sub.3)-alkoxy; R.sup.8A and R.sup.8B are each independently hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl, or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may each be up to trisubstituted by fluorine; R.sup.9 is hydrogen, (C.sub.1-C.sub.3)-alkyl, or amino; and in subformula (d), Y is O, S, or N(CH.sub.3), in subformula (e) and (f), Y is O or S, or R.sup.2 is OR.sup.10 or NR.sup.11R.sup.12, wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl, or [(C.sub.3-C.sub.6)-cycloalkyl]methyl; R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl, benzyl, 1-phenylethyl, or 2-phenylethyl, wherein (C.sub.1-C.sub.6)-alkyl may be up to trisubstituted by fluorine, and wherein phenyl and the phenyl group in benzyl, 1-phenylethyl, and 2-phenylethyl may be up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, and (trifluoromethyl)sulfanyl, or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine, or thiomorpholine ring, or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a tetrahydroquinoline ring of the formula (c) or a tetrahydroisoquinoline ring of the formula (d), ##STR00273## wherein ** marks the bond to the carbonyl group, or a salt, solvate, or solvate of a salt thereof.

2. The combination of claim 1, wherein X, Y, and Z are selected from the group consisting of S, N, O, and C to form 1,3-thiazolyl, 1,3-oxazolyl, or 1,2,4-oxadiazolyl; R.sub.1 is pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 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, or 5-fluoro-2-thienyl; R.sub.2 is hydrogen or methyl; R.sub.3 is hydrogen or methyl; R.sub.4 is hydrogen, methyl, ethyl, or trifluormethyl; R.sub.5 is hydrogen or fluoro, R.sub.6 is a group of the formula a), c), or c), ##STR00274## wherein *** marks the bond to the adjacent piperidine ring, wherein R.sub.7 and R.sub.7 are each independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluormethyl, difluormethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutyl-methoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropyl-methoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, or fluoro; n is 0 or 1; m is 1 the ring Q is a piperazine or a diazaheterobicyclic system of the formula ##STR00275## W.sup.2 is CH, W.sup.1 and W.sup.3 are each independently CH or N, R.sup.1 is fluorine, chlorine, bromine, methyl, tert-butyl, isopropyl, cyclopropyl, or cyclobutyl, R.sup.2 is cyclobutyl, cyclopentyl, or cyclohexyl, or R.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b), or an azole group of the formula (d) or formula (g) ##STR00276## R.sup.3 is hydrogen, fluorine, or chlorine; R.sup.4 is fluorine, chlorine, methyl, isopropyl, methoxy, or ethoxy; R.sup.5 is hydrogen, fluorine, chlorine, bromine, or methyl; R.sup.6 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy, or methylsulfanyl; R.sup.8A and R.sup.8B are each independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl, or cyclopropyl; R.sup.9 represents methyl or amino; and Y is O, S, or N(CH.sub.3), or a salt, solvate, or solvate of a salt thereof.

3. The combination of claim 1, wherein X, Y, and Z are selected from the group consisting of of S, N, O, and C to form 1,3-thiazolyl, 1,3-oxazolyl, or 1,2,4-oxadiazolyl; R.sub.1 is pyridinyl, 2-ethylpyridinyl, 4,6-dimethylpyridinyl, 3,5-difluoropyridinyl, 3-fluoropyridinyl, 4-trifluoromethylpyridinyl, 6-trifluoromethylpyridinyl, 5-chloro-3-fluoropyridinyl, 3-chloro-5-fluoropyridinyl, 3-methylpyridinyl, 4-methylpyridinyl, 6-methylpyridinyl 3-chloropyridinyl, 5-chloropyridinyl, 6-trifluoromethoxypyridinyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 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, or 5-fluoro-2-thienyl; R.sub.2 is hydrogen or methyl; R.sub.3 is hydrogen or methyl; R.sub.4 is hydrogen, methyl, ethyl, or trifluormethyl, wherein phenyl may be substituted by chloro; R.sub.5 is hydrogen or fluoro; R.sub.6 is a group of the formula a), c), or c), ##STR00277## wherein R.sub.7 and R.sub.7 are each independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, methoxy, ethoxy, methoxymethyl, monofluoromethyl, difluoromethyl, trifluormethyl, difluormethoxy, 3,3-difluorocyclobutylmethoxy, cyclobutylmethoxy, cyclopropylmethoxy, cyclopropyl-methoxymethyl, cyclobutyloxymethyl, 3-fluorobutyloxymethyl, 3,3-difluorocyclobutyl-methoxymethyl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluorocyclopropyl-methoxy, cyclobutyloxy, 3,3-difluorocyclobutyloxy, fluoromethylcyclopropylmethoxy, difluoromethylcyclopropylmethoxy, trifluoromethylcyclopropylmethoxy, or fluoro; n is 0 or 1; m is 1; the ring Q is a diazaheterobicyclic system of the formula ##STR00278## W.sup.1 is CH; W.sup.2 is CH; W.sup.3 is N; R.sup.1 is chlorine, bromine, isopropyl, or cyclobutyl; R.sup.2 is cyclopentyl or cyclohexyl, or R.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b), or an azole group of the formula (d), (e), or (f) ##STR00279## R.sup.4 is hydrogen, fluorine or chlorine; R.sup.5 is fluorine, chlorine, methyl, isopropyl, methoxy, or ethoxy; R.sup.6 is hydrogen, fluorine, chlorine, bromine, or methyl; R.sup.7 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy, or methylsulfanyl; R.sup.9A and R.sup.9B are and each independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl, or cyclopropyl; and Y is O or S, or a salt, solvate, or solvate of a salt thereof.

4. The combination of claim 1, wherein the compound of formula (I) is selected from the group consisting of: N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, 2-[4-(5-azaspiro[2.5]octan-5-yl)piperidin-1-yl]-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide, N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R*)-3-(methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, 4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, and N-[1-(3,5-difluoropyridin-2-yl)cyclopropyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, and the compound of formula (II) is selected from the group consisting of: (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, and (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone.

5. The combination of claim 1, wherein the compound of formula (I) is: N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, and the compound of formula (II) is selected from the group consisting of: (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(2-fluorophenyl)methanone, (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-isopropoxypyridin-2-yl)methanone, (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)[6-(trifluoromethoxy)pyridin-2-yl]methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, [5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxypyridin-2-yl)methanone, [5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxypyridin-2-yl)methanone, (3-Fluoro-6-methoxypyridin-2-yl)[5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]methanone, [5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxy-3-methylpyridin-2-yl)methanone, ()-[(1S,4S)-5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl](6-methoxypyridin-2-yl)methanone, ()-(3-Chloro-6-methoxypyridin-2-yl)[(1S,4S)-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl]methanone, ()-[(1S,4S)-5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone, ()-(5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(6-methoxypyridin-2-yl)methanone, (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)[6-(difluoromethoxy)pyridin-2-yl]methanone, (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone, (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, [3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone.

6. The combination of claim 1, wherein the compound of formula (I) is: N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide, and the compound of formula (II) is-(4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone.

7-8. (canceled)

9. A pharmaceutical composition comprising the combination of claim 1 and one or more inert, nontoxic, pharmaceutically suitable excipients.

10. A pharmaceutical composition comprising the combination of claim 1 and one or more further active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, and corticosteroids.

11. (canceled)

12. A method of treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders, or neuroimmunological disorders in humans and animals comprising administering an effective amount of at least one combination of claim 1.

13. The method of claim 12, wherein the method treats and/or prevents obstructive sleep apnoea, central sleep apnoea, or snoring.

14. A method of treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders, or neuroimmunological disorders comprising administering the medicament of claim 9 to a subject in need thereof.

15. The method of claim 14, wherein the method treats and/or prevents obstructive sleep apnoea, central sleep apnoea, or snoring.

16. A method of treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders, or neuroimmunological disorders comprising administering the medicament of claim 10 to a subject in need thereof.

17. The method of claim 16, wherein the method treats and/or prevents obstructive sleep apnoea, central sleep apnoea, or snoring.

Description

EXAMPLES

[0511] The synthesis of compounds of formula (I) are described in this section.

[0512] Abbreviations and Acronyms: [0513] abs. absolute [0514] Ac acetyl [0515] aq. aqueous, aqueous solution [0516] Boc tert-butoxycarbonyl [0517] br. broad (in NMR signal) [0518] Ex. Example [0519] Bu butyl [0520] c concentration [0521] cat. catalytic [0522] CI chemical ionization (in MS) [0523] d doublet (in NMR) [0524] d day(s) [0525] DCI direct chemical ionization (in MS) [0526] dd doublet of doublets (in NMR) [0527] diamix diastereomer mixture [0528] DMF N,N-dimethylformamide [0529] DMSO dimethyl sulfoxide [0530] dq doublet of quartets (in NMR) [0531] dt doublet of triplet (in NMR) [0532] o. t. of theory (in chemical yield) [0533] EI electron impact ionization (in MS) [0534] eq. equivalent(s) [0535] ESI electrospray ionization (in MS) [0536] Et ethyl [0537] h hour(s) [0538] HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate [0539] HOBt 1-hydroxy-1H-benzotriazole hydrate [0540] HPLC high-pressure, high-performance liquid chromatography [0541] iPr isopropyl [0542] conc. concentrated (in the case of a solution) [0543] LC liquid chromatography [0544] LC-MS liquid chromatography-coupled mass spectrometry [0545] lit. literature (reference) [0546] m multiplet (in NMR) [0547] Me methyl [0548] min minute(s) [0549] MS mass spectrometry [0550] NMR nuclear magnetic resonance spectrometry [0551] Ph phenyl [0552] Pr propyl [0553] q quartet (in NMR) [0554] quant. quantitative (in chemical yield) [0555] RP reverse phase (in HPLC) [0556] RT room temperature [0557] R.sub.t retention time (in HPLC, LC-MS) [0558] s singlet (in NMR) [0559] t triplet (in NMR) [0560] tBu tert-butyl [0561] TFA trifluoroacetic acid [0562] THF tetrahydrofuran [0563] UV ultraviolet spectrometry [0564] v/v volume to volume ratio (of a solution) [0565] tog. together

[0566] LC-MS, GC-MS and HPLC Methods

[0567] Method 1 (LC-MS):

[0568] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.175 mm, C18 1.8 m; mobile phase A: 1 1 of water+0.01% formic acid; mobile phase B: 1 1 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.

[0569] Method 2 (LC-MS):

[0570] MS instrument type: Waters TOF instrument; UPLC instrument type: Waters Acquity I-CLASS; column: Waters Acquity UPLC HSS T3 1.8 m 501 mm; mobile phase A: 1 1 of water+0.100 ml of 99% strength formic acid; mobile phase B: 1 1 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.

[0571] Method 3 (GC-MS):

[0572] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m200 m0.33 m; 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).

[0573] Method 4 (LC-MS):

[0574] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 m 501 mm; mobile phase A: 1 1 of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 1 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.

[0575] Method 5 (LC-MS):

[0576] Instrument: Waters Single Quad MS System; instrument Waters UPLC Acquity; column: Waters BEH C18 1.7 502.1 mm; mobile phase A: 1 1 of water+1.0 ml of (25% strength ammonia)/1, mobile phase B: 1 1 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.

[0577] Method 6 (LC-MS):

[0578] MS instrument: Waters SQD2 HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm2.1 mm, 1.8 m; 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.fwdarw.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.

[0579] Method 7 (Preparative HPLC):

[0580] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm.

[0581] 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).

[0582] 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.

[0583] Method 8 (Preparative HPLC):

[0584] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm.

[0585] 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).

[0586] 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.

[0587] Method 9 (Preparative HPLC):

[0588] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm.

[0589] 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).

[0590] 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.

[0591] Method 10 (Preparative HPLC):

[0592] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm.

[0593] 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).

[0594] 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.

[0595] Method 11 (Preparative HPLC):

[0596] Instrument: Abimed Gilson 305; column: Reprosil C18 10 m, 250 mm30 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.

[0597] Method 12 (LC-MS):

[0598] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 m 501 mm; mobile phase A: 1 1 of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 1 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.

[0599] Further Details:

[0600] 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.

[0601] Melting points and melting ranges, if stated, are uncorrected.

[0602] 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.

[0603] 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.

[0604] Starting Materials and Intermediates:

Example 1A

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

[0605] ##STR00033##

[0606] 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 , 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.

[0607] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /ppm): 4.59 (d, 2H), 7.90-7.95 (m, 1H), 8.27 (s, 1H), 8.48 (d, 1H), 9.32 (br. t, 1H).

[0608] LC-MS (Methode 1): R.sub.t=1.38 min; m/z=333/335 (M+H).sup.+.

[0609] 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 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4- methyl-1,3-thiazole-5-carboxamide [00034] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.55 min; m/z = 349/347 (M + H).sup.+. from 2-bromo-4-methyl-1,3-thiazole-5- carboxylic acid and 1-(3,5-difluoropyridin-2- yl)methanamine dihydrochloride 3A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-5- methyl-1,3-thiazole-4-carboxamide [00035] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.51 min; m/z = 349/347 (M + H).sup.+. from 2-bromo-5-methyl-1,3-thiazole-4- carboxylic acid and 1-(3,5-difluoropyridin-2- yl)methanamine dihydrochloride 4A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]- 1,3-thiazole-4-carboxamide [00036] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.56 min; m/z = 333/335 (M + H).sup.+. from 2-bromo-1,3-thiazole-4-carboxylic acid and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride 5A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4- (trifluoromethyl)-1,3-thiazole-5-carboxamide [00037] LC-MS (Methode 1): R.sub.t = 1.71 min; m/z = 401/403 (M + H).sup.+ from 2-bromo-4-(trifluoromethyl)-1,3-thiazole-5- carboxylic acid and 1-(3,5-difluoropyridin-2- yl)methanamine dihydrochloride 6A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-5- ethyl-1,3-thiazole-4-carboxamide [00038] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 2.06 min; m/z = 361/363 (M + H).sup.+. from 2-bromo-5-ethyl-1,3-thiazole-4-carboxylic acid and 1-(3,5-difluoropyridin-2- yl)methanamine dihydrochloride 7A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]- 1,3-oxazole-4-carboxamide [00039] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.37 min; m/z = 317/319 (M + H).sup.+. from 2-bromo-1,3-oxazole-4-carboxylic acid and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride 8A 2-bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-5- methyl-1,3-oxazole-4-carboxamide [00040] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.64 min; m/z = 331/333 (M + H).sup.+. from 2-bromo-5-methyl-1,3-oxazole-4- carboxylic acid and 1-(3,5-difluoropyridin-2- yl)methanamine dihydrochloride

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

[0610] ##STR00041##

[0611] 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.

[0612] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0613] LC-MS (Methode 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

[0614] ##STR00042##

[0615] 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.

[0616] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0617] LC-MS (Methode 1): R.sub.t=1.09 min; m/z=353 (M+H).sup.+.

Example 11A

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

[0618] ##STR00043##

[0619] 2 g (21.03 mmol) of pyridin-3-ol were dissoved in 40 ml of THF, and 7.17 g (27.34 mmol) of triphenylphoshine 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.

[0620] 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 , 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.

[0621] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0622] LC-MS (Methode 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)

[0623] ##STR00044##

[0624] 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).

[0625] Reaction Conditions:

[0626] catalyst: Pd/C 10%; solvent: glacial acetic acid; cartridge pressure: 80 bar of hydrogen; flow rate: 1 ml/min; temperature: 80 C.

[0627] 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.

[0628] GC-MS (Methode 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)

[0629] ##STR00045##

[0630] 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 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 , 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.

[0631] LC-MS (Methode 1): R.sub.t=1.04 min; m/z=353 (M+H).sup.+.

[0632] 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) [00046] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 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) [00047] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.02 min; m/z = 335 (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) [00048] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 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) [00049] LC-MS (Methode 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

[0633] ##STR00050##

[0634] 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.

[0635] LC-MS (Methode 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

[0636] ##STR00051##

[0637] 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.

[0638] LC-MS (Methode 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

[0639] ##STR00052##

[0640] Sodium methoxide solution (840 l, 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.

[0641] LC-MS (Methode 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

[0642] ##STR00053##

[0643] 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.

[0644] LC-MS (Methode 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

[0645] ##STR00054##

[0646] (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.

[0647] 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 m 10030 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.

[0648] LC-MS (Methode 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

[0649] ##STR00055##

[0650] Under argon, 2,2,2-trifluoroethanol (66 l, 910 mol) 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 mol) was added and the mixture was stirred at room temperature for 30 min.

[0651] Subsequently, rac-benzyl 3-{[(methylsulfonyl)oxy]methyl}[1,4-bipiperidine]-1-carboxylate (250 mg, 609 mol) 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.

[0652] LC-MS (Methode 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

[0653] ##STR00056##

[0654] Under argon, [1-(fluoromethyl)cyclopropyl]methanol (95.1 mg, 913 mol) 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 mol) 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 mol) 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.

[0655] LC-MS (Methode 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

[0656] ##STR00057##

[0657] Under argon, [1-(difluoromethyl)cyclopropyl]methanol (112 mg, 913 mol) 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 mol) 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 mol) 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.

[0658] LC-MS (Methode 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

[0659] ##STR00058##

[0660] Under argon, [1-(trifluoromethyl)cyclopropyl]methanol (128 mg, 913 mol) 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 mol) 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 mol) 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.

[0661] LC-MS (Methode 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

[0662] ##STR00059##

[0663] Acetic acid (74 l, 1.3 mmol) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (200 mg, purity 58%, 857 mol) and 3,3-dimethylpiperidine (240 l, 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.

[0664] LC-MS (Methode 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

[0665] ##STR00060##

[0666] Acetic acid (110 l, 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.

[0667] LC-MS (Methode 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

[0668] ##STR00061##

[0669] Acetic acid (110 l, 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.

[0670] LC-MS (Methode 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

[0671] ##STR00062##

[0672] Triethylamine (1.8 ml, 13 mmol) and acetic acid (740 l, 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.

[0673] LC-MS (Methode 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

[0674] ##STR00063##

[0675] Under argon, rac-benzyl 3-hydroxy[1,4-bipiperidine]-1-carboxylate (250 mg, 785 mol) 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 l, 1.2 mmol) was added and the reaction mixture was stirred at 60 C. overnight. (Bromomethyl)cyclopropane (110 l, 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 m, 25030 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.

[0676] LC-MS (Methode 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

[0677] ##STR00064##

[0678] Under argon, cyclobutanol (72 l, 910 mol) 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 mol) 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 mol) 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.

[0679] LC-MS (Methode 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

[0680] ##STR00065##

[0681] 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 l, 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 l, 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 m 10030 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.

[0682] LC-MS (Methode 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

[0683] ##STR00066##

[0684] Acetic acid (72 l, 1.3 mmol) was added to a solution of tert-butyl 4-oxoazepane-1-carboxylate (179 mg, 840 mol) 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

[0685] ##STR00067##

[0686] Under argon, rac-(2,2-difluorocyclopropyl)methanol (98.7 mg, 913 mol) 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 mol) 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 mol) 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.

[0687] LC-MS (Methode 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

[0688] ##STR00068##

[0689] Under argon,(3,3-difluorocyclobutyl)methanol (112 mg, 913 mol) 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 mol) 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 mol) 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.

[0690] LC-MS (Methode 1): R.sub.t=1.44 min; MS (ESIpos): m/z=437 [M+H].sup.+.

Example 37A

3-(Difluoromethyl)-1,4-bipiperidine dihydrochloride (racemate)

[0691] ##STR00069##

[0692] 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).

[0693] Reaction Conditions:

[0694] catalyst: Pd/C 10%; solvent: ethanol; cartridge pressure: 1 bar of hydrogen; flow rate: 1 ml/min; temperature: 50 C.

[0695] 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.

[0696] GC-MS (Methode 3): R.sub.t=4.87 min; m/z=218 (M2HCl).sup.+.

Example 38A

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

[0697] ##STR00070##

[0698] 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).

[0699] Reaction Conditions:

[0700] catalyst: Pd/C 10%; solvent: ethanol; cartridge pressure: 50 bar of hydrogen; flow rate: 1 ml/min; temperature: 50 C.

[0701] 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.

[0702] GC-MS (Methode 3): R.sub.t=6.42 min; m/z=288 (M).sup.+.

[0703] 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) [00071] GC-MS (Methode 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-(fluoromethyl)-1,4-bipiperidine dihydrochloride (racemate) [00072] GC-MS (Methode 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) [00073] GC-MS (Methode 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

[0704] ##STR00074##

[0705] rac-Benzyl 3-(methoxymethyl)[1,4-bipiperidine]-1-carboxylate (145 mg, 419 mol) 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 l, 2.0 M, 630 mol) 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.

[0706] GC-MS (Methode 3): R.sub.t=5.45 min; MS (ESIpos): m/z=212 [MHCl].sup.+.

Example 43A

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

[0707] ##STR00075##

[0708] Synthesis Method 1:

[0709] 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.

[0710] LC-MS (Methode 4): MS (ESIpos): m/z=200 [M2HCl].sup.+.

[0711] Synthesis Method 2:

[0712] 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.

[0713] GC-MS (Methode 3): MS (ESIpos): m/z=200 [M2HCl].

Example 44A

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

[0714] ##STR00076##

[0715] rac-Benzyl 3-[(2,2,2-trifluoroethoxy)methyl][1,4-bipiperidine]-1-carboxylate (218 mg, purity 81%, 526 mol) 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 l, 2.0 M, 790 mol) 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.

[0716] GC-MS (Methode 3): R.sub.1=5.26 min; MS (full ms): m/z=280 [M2HCl].sup.+.

Example 45A

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

[0717] ##STR00077##

[0718] rac-Benzyl 3-({[1-(fluoromethyl)cyclopropyl]methoxy}methyl)[1,4-bipiperidine]-1-carboxylate (204 mg, purity 40%, 487 mol) 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 l, 2.0 M, 740 mol) 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

[0719] ##STR00078##

[0720] rac-Benzyl 3-({[1-(difluoromethyl)cyclopropyl]methoxy}methyl)[1,4-bipiperidine]-1-carboxylate (197 mg, purity 51%, 451 mol) 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 l, 2.0 M, 680 mol) 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

[0721] ##STR00079##

[0722] rac-Benzyl 3-({[1-(trifluoromethyl)cyclopropyl]methoxy}methyl)[1,4-bipiperidine]-1-carboxylate (212 mg, purity 58%, 466 mol) 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 l, 2.0 M, 700 mol) 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

[0723] ##STR00080##

[0724] Benzyl 3,3-dimethyl[1,4-bipiperidine]-1-carboxylate (260 mg, purity 81%, 637 mol) was initially charged in 18 ml of THF, and palladium (27 mg; 10% on activated carbon, 255 mol) 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 l, 2.0 M, 956 mol) 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

[0725] ##STR00081##

[0726] 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 l, 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

[0727] ##STR00082##

[0728] 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 l, 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

[0729] ##STR00083##

[0730] rac-Benzyl 3-(cyclopropylmethoxy)[1,4-bipiperidine]-1-carboxylate (68.0 mg, purity 68%, 124 mol) 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 l, 2.0 M, 186 mol) 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

[0731] ##STR00084##

[0732] rac-Benzyl 3-[(cyclobutyloxy)methyl][1,4-bipiperidine]-1-carboxylate (290 mg, purity 46%, 386 mol) 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 l, 2.0 M, 518 mol) 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

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

[0733] ##STR00085##

[0734] rac-Benzyl 3-[(cyclopropylmethoxy)methyl][1,4-bipiperidine]-1-carboxylate (241 mg, purity 78%, 486 mol) 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 l, 2.0 M, 730 mol) 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

[0735] ##STR00086##

[0736] 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

[0737] ##STR00087##

[0738] diamix-Benzyl 3-({[-2,2-difluorocyclopropyl]methoxy}methyl)[1,4-bipiperidine]-1-carboxylate (343 mg, purity 56%, 446 mol) 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 l, 2.0 M, 670 mol) 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

[0739] ##STR00088##

[0740] rac-Benzyl 3-{[(3,3-difluorocyclobutyl)methoxy]methyl}[1,4-bipiperidine]-1-carboxylate (287 mg, purity 33%, 217 mol) 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 l, 2.0 M, 325 mol) 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

[0741] ##STR00089##

[0742] 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.

[0743] LC-MS (Methode 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

[0744] ##STR00090##

[0745] 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.

[0746] Conditions: The separation was carried out using 1 g portions. RP column Chromatorex C18, 10 m; 12530 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.

[0747] 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.

[0748] LC-MS (Methode 1): R.sub.t=0.54 min; m/z=310 (M+H2HCl).sup.+.

Example 59A

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

[0749] ##STR00091##

[0750] Ethyl 3-bromo-1,2,4-oxadiazole-5-carboxylate (100 mg, 452 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (173 mg, 679 mol) 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 m, 25030 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.

[0751] LC-MS (Methode 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

[0752] ##STR00092##

[0753] 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 THE 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.

[0754] LC-MS (Methode 4): R.sub.t=0.40 min; MS (ESIpos): m/z=186 [MHCl].sup.+.

Example 61A

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

[0755] ##STR00093##

[0756] 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 l, 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.

[0757] LC-MS (Methode 5): MS (ESIpos): m/z=192 [MHClH.sub.2SO.sub.4].sup.+.

Example 62A

3-(Cyclobutyloxy)pyridine hydrochloride

[0758] ##STR00094##

[0759] 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.

[0760] LC-MS (Methode 5): R.sub.t=1.34 min; MS (ESIpos): m/z=150 [MHCl].sup.+.

Example 63A

rac-3-(Cyclobutyloxy)piperidine sulfate hydrochloride

[0761] ##STR00095##

[0762] Under argon, 3-(cyclobutyloxy)pyridine hydrochloride (2.0 g, purity 51%, 5.51 mmol) was dissolved in 95 ml of ethanol. Sulfuric acid (550 l, 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.

[0763] LC/MS (Methode 4): MS (ESIpos): m/z=156 [MHClH.sub.2SO.sub.4].sup.+.

Example 64A

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

[0764] ##STR00096##

[0765] 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.

[0766] LC-MS (Methode 4): R.sub.t=1.01 min; MS (ESIpos): m/z=186 [MHCl].sup.+.

Example 65A

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

[0767] ##STR00097##

[0768] Under argon, 3-[(3,3-difluorocyclobutyl)oxy]pyridine hydrochloride (298 mg, 1.34 mmol) was dissolved in 12 ml of ethanol. Sulfuric acid (72 l, 1.3 mmol) and platinum(IV) oxide (76.3 mg, 336 mol) 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.

[0769] LC/MS (Methode 4): MS (ESIpos): m/z=192 [MHClH.sub.2SO.sub.4].sup.+.

Example 66A

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

[0770] ##STR00098##

[0771] N,N-Diisopropylethylamine (680 l, 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.

[0772] LC-MS (Methode 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

[0773] ##STR00099##

[0774] N,N-Diisopropylethylamine (630 l, 3.6 mmol) and propylphosphonic anhydride (930 l, 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.

[0775] LC-MS (Methode 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

[0776] ##STR00100##

[0777] Triethylamine (3.0 ml, 21 mmol) and acetic acid (740 l, 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.

[0778] LC-MS (Methode 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

[0779] ##STR00101##

[0780] 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 l, 8.4 mmol) was added and the reaction mixture was stirred at 60 C. overnight. (Bromomethyl)cyclopropane (820 l, 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 m 10030 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.

[0781] LC-MS (Methode 1): R.sub.4=1.19 min; MS (ESIpos): m/z=373 [M+H].sup.+.

Example 70A

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

[0782] ##STR00102##

[0783] Benzyl (3R)-3-(cyclopropylmethoxy)[1,4-bipiperidine]-1-carboxylate (100 mg, 268 mol) 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 l, 2.0 M, 400 mol) 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

[0784] ##STR00103##

[0785] N,N-Diisopropylethylamine (630 l, 3.6 mmol) and propylphosphonic anhydride (930 l, 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.

[0786] LC-MS (Methode 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

[0787] ##STR00104##

[0788] Ethyl 2-bromo-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate (150 mg, 433 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (166 mg, 649 mol) were combined and stirred at 120 C. in sodium carbonate solution (870 l, 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.

[0789] LC-MS (Methode 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

[0790] ##STR00105##

[0791] 4 M hydrochloric acid in 1,4-dioxane (720 l, 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 mol) 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

[0792] ##STR00106##

[0793] Ethyl 4-(2-chlorophenyl)-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxylate (199 mg, 444 mol) 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.

[0794] LC-MS (Methode 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

[0795] ##STR00107##

[0796] 2,4-Dibromo-1,3-thiazole-5-carboxylic acid (150 mg, 523 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (133 mg, 523 mol) 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.

[0797] LC-MS (Methode 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

[0798] ##STR00108##

[0799] N,N-Diisopropylethylamine (720 l, 4.1 mmol) and propylphosphonic anhydride (800 l, 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.

[0800] LC-MS (Methode 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

[0801] ##STR00109##

[0802] N,N-Diisopropylethylamine (560 l, 3.2 mmol) and propylphosphonic anhydride (620 l, 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 mol) 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.

[0803] LC-MS (Methode 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

[0804] ##STR00110##

[0805] Methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate (150 mg, 600 mol) 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 Nhydrochloric 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.

[0806] LC-MS (Methode 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

[0807] ##STR00111##

[0808] N,N-Diisopropylethylamine (300 l, 1.7 mmol) and propylphosphonic anhydride (330 l, 50% in ethyl acetate, 550 mol) were added to a solution of 2-bromo-4-ethyl-1,3-thiazole-5-carboxylic acid (100 mg, 424 mol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (120 mg, 550 mol) 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.

[0809] LC-MS (Methode 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

[0810] ##STR00112##

[0811] N,N-Diisopropylethylamine (570 l, 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 l, 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 m 10030 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.

[0812] LC-MS (Methode 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

[0813] ##STR00113##

[0814] 4 M hydrochloric acid in 1,4-dioxane (950 l, 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 mol) 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

[0815] ##STR00114##

[0816] N,N-Diisopropylethylamine (410 l, 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 l, 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 m 10030 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.

[0817] LC-MS (Methode 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

[0818] ##STR00115##

[0819] 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 , 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.

[0820] .sup.1H NMR (600 MHz, DMSO-d6) [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).

[0821] LC-MS (Methode 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

[0822] ##STR00116##

[0823] 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.

[0824] Conditions: The separation was carried out using portions of about 1 g. RP column Chromatorex C18, 10 m; 12530 mm, acetonitrile/water 10/90.fwdarw.gradient over 38 min 4 acetonitrile/water 90/10, flow rate 75 ml/min.

[0825] 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.

[0826] LC-MS (Methode 1): R.sub.t=0.39 min; m/z=311 (M+H).sup.+.

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

[0827] ##STR00117##

[0828] 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) (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 , 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.

[0829] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, S/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).

[0830] LC-MS (Methode 4): R.sub.t=0.50 min; m/z=436 (M+H).sup.+.

[0831] [].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

[0832] ##STR00118##

[0833] 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 , 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.

[0834] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0835] LC-MS (Methode 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)

[0836] ##STR00119##

[0837] 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 , D=12.5 cm), dried and concentrated to dryness on a rotary evaporator. The residue obtained was purified using the following method.

[0838] Method 7: Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0839] 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)

[0840] 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.

[0841] This gave 40.8 mg (0.09 mmol, 88% of theory) of the target compound as a white lyophylisate.

[0842] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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).

[0843] LC-MS (Methode 1): R.sub.t=1.13 min; m/z=476 (M+H).sup.+.

[0844] 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) [00120] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 5): R.sub.t = 1.51 min; m/z = 472 (M + H).sup.+. yl)methyl]-1,3-thiazole-5-carboxamide and 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) [00121] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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 (Methode 5): R.sub.t = 1.63 min; m/z = 490 (M + H).sup.+. yl)methyl]-1,3-thiazole-5-carboxamide and 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) [00122] from 2-bromo-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-5-carboxamide and 3- (fluoromethyl)-1,4-bipiperidine dihydrochloride .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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). LC-MS (Methode 5): R.sub.t = 1.48 min; m/z = 454 (M + H).sup.+. (racemate) 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) [00123] .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.11 min; m/z = 542 (M + H).sup.+. from 2-bromo-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-5-carboxamide 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 [00124] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 0.98 min; m/z = 450 (M + H).sup.+. yl)methyl]-4-methyl-1,3-thiazole-5-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 [00125] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 0.92 min; m/z = 450 (M + H).sup.+. yl)methyl]-5-methyl-1,3-thiazole-4-carboxamide and (3R)-3-methyl-1,4-bipiperidine dihydrochloride 10 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-4- carboxamide [00126] from 2-bromo-N-[(3,5-difluoropyridin-2- yl)methyl]-1,3-thiazole-4-carboxamide and (3R)- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 4): R.sub.t = 0.56 min; m/z = 436 (M + H).sup.+. 3-methyl-1,4-bipiperidine dihydrochloride 11 N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-4- (trifluoromethyl)-1,3-thiazole-5-carboxamide [00127] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.24 min; m/z = 504 (M + H).sup.+ from 2-bromo-N-[(3,5-difluoropyridin-2- yl)methyl]-4-(trifluoromethyl)-1,3-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 [00128] from 2-bromo-N-[(3,5-difluoropyridin-2- 1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 4): R.sub.t = 0.68 min; m/z = 464 (M + H).sup.+. yl)methyl]-5-ethyl-1,3-thiazole-4-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 [00129] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 4): R.sub.t = 0.52 min; m/z = 420 (M + H).sup.+. yl)methyl]-1,3-oxazole-4-carboxamide and (3R)- 3-methyl-1,4-bipiperidine dihydrochloride 14 N-[(3,5-difluoropyridin-2-yl)methyl]-5-methyl-2- [(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3- oxazole-4-carboxamide [00130] from 2-bromo-N-[(3,5-difluoropyridin-2- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 4): R.sub.t = 0.57 min; m/z = 434 (M + H).sup.+. yl)methyl]-5-methyl-1,3-oxazole-4-carboxamide and (3R)-3-methyl-1,4-bipiperidine dihydrochloride

Example 15

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

[0845] ##STR00131##

[0846] 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 l (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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0847] Method 8:

[0848] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0849] 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)

[0850] 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.

[0851] This gave 62 mg (0.14 mmol, 48% of theory) of the target compound as a white lyophylisate.

[0852] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0853] LC-MS (Methode 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)

[0854] ##STR00132##

[0855] 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 l (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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0856] Method 9:

[0857] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0858] 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)

[0859] 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.

[0860] This gave 60 mg (0.12 mmol, 44% of theory) of the target compound as a white lyophylisate.

[0861] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0862] LC-MS (Methode 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)

[0863] ##STR00133##

[0864] 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 l (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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0865] Method 7:

[0866] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0867] 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)

[0868] 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.

[0869] This gave 46 mg (0.10 mmol, 36% of theory) of the target compound as a white lyophylisate.

[0870] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0871] LC-MS (Methode 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

[0872] ##STR00134##

[0873] 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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0874] Method 7:

[0875] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0876] 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)

[0877] 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.

[0878] This gave 55 mg (0.12 mmol, 23% of theory) of the target compound as a white lyophylisate.

[0879] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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).

[0880] LC-MS (Methode 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

[0881] ##STR00135##

[0882] 100 mg (0.26 mmol) of 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxylic acid dihydrochloride were dissolved in 10 ml of dichloromethane, 56 mg (0.42 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added and the mixture was stirred at room temperature for 30 min. Subsequently, 60 l 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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0883] Method 11:

[0884] Instrument: Abimed Gilson 305; column: Reprosil C18 10 m, 250 mm30 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.

[0885] This gave 45 mg (0.10 mmol, 37% of theory) of the target compound.

[0886] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0887] LC-MS (Methode 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

[0888] ##STR00136##

[0889] 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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0890] Method 9:

[0891] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0892] 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)

[0893] 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.

[0894] This gave 5.4 mg (0.01 mmol, 5% of theory) of the target compound as a white lyophylisate.

[0895] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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).

[0896] LC-MS (Methode 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

[0897] ##STR00137##

[0898] 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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0899] Method 7:

[0900] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0901] 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)

[0902] 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.

[0903] 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.

[0904] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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).

[0905] LC-MS (Methode 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

[0906] ##STR00138##

[0907] 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 , D=12.5 cm), dried and concentrated to dryness under reduced pressure. The residue obtained was purified using the following method.

[0908] Method 10:

[0909] Instrument: Waters Prep LC/MS System, column: XBridge C18 5 m 10030 mm

[0910] 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)

[0911] 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.

[0912] This gave 25 mg (0.05 mmol, 17% of theory) of the target compound as a white lyophylisate.

[0913] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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).

[0914] LC-MS (Methode 1): R.sub.t=1.27 min; m/z=467 (M+H).sup.+.

[0915] 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 [00139] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.04 min; m/z = 452/454 (M + H).sup.+. and 1-(5-chloro-3-fluoropyridin-2- yl)methanamine hydrochloride (1:1) 24 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-N-[(3- methylpyridin-2-yl)methyl]-1,3-thiazole-5- carboxamide [00140] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d6, /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 (Methode 1): R.sub.t = 0.66 min; m/z = 414 (M + H).sup.+. and 1-(3-methylpyridin-2-yl)methanamine 25 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-N-[(4- methylpyridin-2-yl)methyl]-1,3-thiazole-5- carboxamide [00141] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 0.63 min; m/z = 414 (M + H).sup.+. 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(4-methylpyridin-2-yl)methanamine 26 N-[(3-chloropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5- carboxamide [00142] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 0.93 min; m/z = 434/436 (M + H).sup.+. and 1-(3-chloropyridin-2-yl)methanamine hydrochloride (1:1) 27 N-[(3-fluoropyridin-2-yl)methyl]-N-methyl-2- [(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3- thiazole-5-carboxamide [00143] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 0.91 min; m/z = 432 (M + H).sup.+. and (3-fluoropyridin-2-yl)-N-methylmethanamine 28 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-N-{[6- (trifluoromethyl)pyridin-2-yl]methyl}-1,3- thiazole-5-carboxamide [00144] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 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- LC-MS (Methode 1): methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5- R.sub.t = 0.91 min; m/z = 434/436 carboxamide (M + H).sup.+. from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic 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) [00145] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.22 min; m/z = 449 (M + H).sup.+. from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(2,5-difluorophenyl)ethanamine (racemate) 31 N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-2- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, [(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3- /ppm): 0.75-0.88 (m, 4H, thiazole-5-carboxamide including at 0.82 (d, 3H)), 1.33- from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1.68 (m, 6H), 1.71-1.83 (m, 3H), 1,3-thiazole-5-carboxylic acid dihydrochloride 2.06 (br. t, 1H), 2.44-2.57 (m, 1H, and 1-(3-chloro-5-fluoropyridin-2- partially obscured by DMSO), yl)methanamine hydrochloride (1:1) 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 (Methode 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- .sup.1H-NMR (400 MHz, DMSO-d.sub.6, (trifluoromethoxy)pyridin-2-yl]methyl}-1,3- /ppm): 0.75-0.89 (m, 4H, thiazole-5-carboxamide including at 0.82 (d, 3H)), 1.33- from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1.68 (m, 6H), 1.71-1.83 (m, 3H), 1,3-thiazole-5-carboxylic acid dihydrochloride 2.05 (br. t, 1H), 2.43-2.57 (m, 1H, and 1-[6-(trifluoromethoxy)pyridin-2- partially obscured by DMSO), yl]methanamine 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 (Methode 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 [00146] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1,3-thiazole-5-carboxylic acid dihydrochloride .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.18 min; m/z = 433/435 (M + H).sup.+. and 1-(4-chlorophenyl)methanamine 34 N-(2-chloro-5-fluorobenzyl)-2-[(3R)-3- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5- /ppm): 0.76-0.87 (m, 4H, carboxamide including at 0.82 (d, 3H)), 1.35- from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- 1.67 (m, 6H), 1.72-1.83 (m, 3H), 1,3-thiazole-5-carboxylic acid dihydrochloride 2.05 (td, 1H), 2.46-2.57 (m, 1H, and 1-(2-chloro-5-fluorophenyl)methanamine 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 (Methode 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 [00147] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.19 min; m/z = 413 (M + H).sup.+. 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(4-methylphenyl)methanamine 36 N-(3-methylbenzyl)-2-[(3R)-3-methyl[1,4- bipiperidin]-1-yl]-1,3-thiazole-5- carboxamide [00148] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.19 min; m/z = 413 (M + H).sup.+. 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(3-methylphenyl)methanamine 37 N-(2-methylbenzyl)-2-[(3R)-3-methyl[1,4- bipiperidin]-1-yl]-1,3-thiazole-5- carboxamide [00149] from 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]- .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): R.sub.t = 1.16 min; m/z = 413 (M + H).sup.+. 1,3-thiazole-5-carboxylic acid dihydrochloride and 1-(2-methylphenyl)methanamine

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)

[0916] ##STR00150##

[0917] 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 m, 250 mm20 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

[0918] ##STR00151##

[0919] yield: 97 mg

[0920] R.sub.t=4.93 min; chemical purity>99%; >99% ee

[0921] [column: Chiraltek AY-3, 3 m, 100 mm4.6 mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0922] LC-MS (Methode 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

[0923] ##STR00152##

[0924] yield: 101 mg

[0925] R.sub.t=6.03 min; chemical purity>96%; >94% ee

[0926] [column: Chiraltek AY-3, 3 m, 100 mm4.6 mm; mobile phase: isohexane/2-propanol+0.2% diethylamine 20:80; flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0927] LC-MS (Methode 5): R.sub.t=1.52 min; m/z=472 (M+H).sup.+.

[0928] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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)

[0929] ##STR00153##

[0930] 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 m, 250 mm20 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

[0931] ##STR00154##

[0932] yield: 71 mg

[0933] R.sub.t=10.94 min; chemical purity 99%; 99% ee

[0934] [column: Daicel Chiralcel IG, 5 m, 250 mm4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 C.; UV detection: 235 nm].

[0935] LC-MS (Methode 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

[0936] ##STR00155##

[0937] yield: 70 mg

[0938] R.sub.t=12.21 min; chemical purity 99%; 99% ee

[0939] [column: Daicel Chiralcel IG, 5 m, 250 mm4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40 C.; UV detection: 235 nm].

[0940] LC-MS (Methode 1): R.sub.t=0.84 min; m/z=454 (M+H).sup.+.

[0941] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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)

[0942] ##STR00156##

[0943] 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 m, 250 mm20 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-[(3S)-3-(trifluoromethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide

[0944] ##STR00157##

[0945] yield: 67 mg

[0946] R.sub.t=11.22 min; chemical purity 99%; 99% ee

[0947] [column: Daicel Chiralcel IG, 5 m, 250 mm4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50 C.; UV detection: 235 nm].

[0948] LC-MS (Methode 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

[0949] ##STR00158##

[0950] yield: 67 mg

[0951] R.sub.t=11.87 min; chemical purity 99%; >96% ee

[0952] [column: Daicel Chiralcel IG, 5 m, 250 mm4.6 mm; mobile phase: ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 50 C.; UV detection: 235 nm].

[0953] LC-MS (Methode 1): R.sub.t=0.96 min; m/z=490 (M+H).sup.+.

[0954] .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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)

[0955] ##STR00159##

[0956] 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 m, 250 mm20 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

[0957] ##STR00160##

[0958] yield: 93 mg

[0959] R.sub.t=1.50 min; chemical purity>99%; 99% ee

[0960] [column: Phenomenex Cellulose-1, 3 m, 50 mm4.6 mm; mobile phase: n-heptane/2-propanol+0.2% diethylamine); flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0961] LC-MS (Methode 4): R.sub.t=0.63 min; m/z=542 (M+H).sup.+.

Example 45 (enantiomer 2)

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

[0962] ##STR00161##

[0963] yield: 86 mg

[0964] R.sub.t=2.21 min; chemical purity>99%; 99% ee

[0965] [column: Phenomenex Cellulose-1, 3 m, 50 mm4.6 mm; mobile phase: n-heptane/2-propanol+0.2% diethylamine); flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0966] LC-MS (Methode 4): R.sub.t=0.62 min; m/z=542 (M+H).sup.+.

[0967] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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-5-carboxamide (diastereomers 1 and 2)

[0968] ##STR00162##

[0969] 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 m, 250 mm20 mm; mobile phase: n-heptane/ethanol 50:50; flow rate: 20 ml/min; UV detection: 220 nm; temperature: 40 C.]:

Example 46 (diastereomer 1)

[0970] yield: 20 mg

[0971] R.sub.t=1.32 min; chemical purity>99%; 99% ee

[0972] [column: Daicel Chiralpak OX-3, 3 m, 50 mm4.6 mm; mobile phase: n-heptane/ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0973] LC-MS (Methode 1): R.sub.t=1.22 min; m/z=449 (M+H).sup.+.

[0974] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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)

[0975] yield: 19 mg

[0976] R.sub.t=1.78 min; chemical purity>99%; 99% ee

[0977] [column: Daicel Chiralpak OX-3, 3 m, 50 mm4.6 mm; mobile phase: n-heptane/ethanol+0.2% diethylamine; flow rate: 1 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0978] LC-MS (Methode 1): R.sub.t=1.19 min; m/z=449 (M+H).sup.+.

[0979] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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

[0980] ##STR00163##

[0981] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (124 mg, 370 mol) and rac-3-(methoxymethyl)-1,4-bipiperidine dihydrochloride (123 mg, purity 75%, 285 mol) 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 m 10030 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.

[0982] LC-MS (Methode 4): R.sub.t=0.51 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[0983] .sup.1H-NMR (600 MHz, DMSO-d6) [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-5-carboxamide

[0984] ##STR00164##

[0985] N,N-Diisopropylethylamine (44 l, 250 mmol) and propylphosphonic anhydride (66 l, 50% in ethyl acetate, 110 mol) 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 mol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (24.0 mg, 110 mol) 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 m 10030 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.

[0986] LC-MS (Methode 1): R.sub.t=0.96 min; MS (ESIpos): m/z=421 [M+H].sup.+.

[0987] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[0988] ##STR00165##

[0989] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 mol) and diamix-(3R)-3-fluoro-3-methyl-1,4-bipiperidine dihydrochloride (142 mg, 519 mol) 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 m 10030 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.

[0990] LC-MS (Methode 4): R.sub.t=0.54 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[0991] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[0992] ##STR00166##

[0993] 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 m, 25020 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 m, 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.

[0994] LC-MS (Methode 1): R.sub.t=0.93 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[0995] .sup.1H.NMR (500 MHz, DMSO-d6) [ppm]: S 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)

[0996] ##STR00167##

[0997] 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 m, 25020 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 m, 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.

[0998] LC-MS (Methode 1): R.sub.t=0.93 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[0999] .sup.1H.NMR (500 MHz, DMSO-d6) [ppm]: 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

[1000] ##STR00168##

[1001] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (9.7 l, 170 mol) 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 mol) and rac-4-methylazepane (32.1 mg, 284 mol) in 2.5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 mol) 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 m 10030 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.

[1002] LC-MS (Methode 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1003] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1004] ##STR00169##

[1005] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (9.7 l, 170 mol) 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 mol) and rac-3-methylazepane hydrochloride (42.5 mg, 284 mol) in 2.5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 mol) 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 m 10030 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.

[1006] LC-MS (Methode 1): R.sub.t=0.97 min; MS (ESIpos): m/z=450 [M+H].sup.+

[1007] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1008] ##STR00170##

[1009] N,N-Diisopropylethylamine (182 l, 105 mol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and rac-1-(3,5-difluoropyridin-2-yl)ethanamine (45.5 mg, 288 mol) 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 m 10030 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.

[1010] LC-MS (Methode 1): R.sub.t=1.02 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1011] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1012] ##STR00171##

[1013] N,N-Diisopropylethylamine (230 l, 1.3 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(5-chloro-1,3-thiazol-2-yl)methanamine hydrochloride (53.2 mg, 288 mol) 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 m 10030 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.

[1014] LC-MS (Methode 1): R.sub.t=1.00 min; MS (ESIpos): m/z=440 [M+H].sup.+.

[1015] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1016] ##STR00172##

[1017] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(5-fluoro-2-thienyl)methanamine (37.7 mg, 288 mol) 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 m 10030 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.

[1018] LC-MS (Methode 1): R.sub.t=1.09 min; MS (ESIpos): m/z=423 [M+H].sup.+.

[1019] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1020] ##STR00173##

[1021] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(pyridin-4-yl)methanamine (31.1 mg, 288 mol) 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 m 10030 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.

[1022] LC-MS (Methode 1): R.sub.t=0.48 min; MS (ESIneg): m/z=398 [MH].sup..

[1023] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1024] ##STR00174##

[1025] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (118 mg, 353 mol) and rac-3-[(2,2,2-trifluoroethoxy)methyl]-1,4-bipiperidine dihydrochloride (164 mg, purity 75%, 348 mol) 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 m 10030 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.

[1026] LC-MS (Methode 5): R.sub.t=1.64 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1027] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1028] ##STR00175##

[1029] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (75.5 mg, 226 mol) 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 m 10030 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.

[1030] LC-MS (Methode 5): R.sub.t=1.65 min; MS (ESIpos): m/z=538 [M+H].sup.+.

[1031] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1032] ##STR00176##

[1033] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 300 mol) 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 m 10030 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.

[1034] LC-MS (Methode 5): R.sub.t=1.71 min; MS (ESIpos): m/z=556 [M+H].sup.+.

[1035] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1036] ##STR00177##

[1037] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (110 mg, 329 mol) 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 m 10030 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.

[1038] LC-MS (Methode 5): R.sub.t=1.78 min; MS (ESIpos): m/z=574 [M+H].sup.+.

[1039] .sup.1H-NMR (600 MHz, DMSO-d6) [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-5-carboxamide

[1040] ##STR00178##

[1041] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (50.0 mg, 150 mol) 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 mol) 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 m 10030 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.

[1042] LC-MS (Methode 1): R.sub.t=0.95 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1043] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1044] ##STR00179##

[1045] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (200 mg, 599 mol) 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 m 10030 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.

[1046] LC-MS (Methode 1): R.sub.t=0.90 min; MS (ESIpos): m/z=448 [M+H].sup.+.

[1047] .sup.1H.NMR (500 MHz, DMSO-d6) [ppm]: 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

[1048] ##STR00180##

[1049] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) 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 m 10030 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.

[1050] LC-MS (Methode 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1051] .sup.1H.NMR (500 MHz, DMSO-d6) [ppm]: 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

[1052] ##STR00181##

[1053] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (12 l, 210 mol) 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 mol) and rac-3-(cyclobutylmethoxy)piperidine hydrochloride (58.4 mg, 284 mol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 mol) was added and stirring of the mixture at room temperature was continued. After 1.5 h, more sodium triacetoxyborohydride (36.1 mg, 170 mol) 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 m 10030 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.

[1054] LC-MS (Methode 1): R.sub.t=1.22 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1055] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1056] ##STR00182##

[1057] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (60.8 mg, 182 mol) 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 m 10030 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.

[1058] LC-MS (Methode 1): R.sub.t=1.06 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1059] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1060] ##STR00183##

[1061] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) 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 m 10030 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.

[1062] LC-MS (Methode 1): R.sub.t=1.11 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1063] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1064] ##STR00184##

[1065] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (50.9 mg, 152 mol) 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 m 10030 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.

[1066] LC-MS (Methode 1): R.sub.t=1.12 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1067] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1068] ##STR00185##

[1069] Acetic acid (12 l, 210 mol) 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 mol) and rac-3-ethoxypiperidine (36.7 mg, 284 mol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 mol) 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 m 10030 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.

[1070] LC-MS (Methode 1): R.sub.t=0.94 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1071] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1072] ##STR00186##

[1073] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (70.0 mg, 209 mol) 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 mol) 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 m 10030 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.

[1074] LC-MS (Methode 5): R.sub.t=1.80 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1075] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1076] ##STR00187##

[1077] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(6-methylpyridin-3-yl)methanamine (35.1 mg, 288 mol) 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 m 10030 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.

[1078] LC-MS (Methode 1): R.sub.t=0.55 min; MS (ESIneg): m/z=412 [MH].sup..

[1079] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1080] ##STR00188##

[1081] N,N-Diisopropylethylamine (100 l, 580 mol) and propylphosphonic anhydride (47 l, 50% in ethyl acetate, 160 mol) 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 mol) and 1-phenylmethanamine (17 l, 160 mol) 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 m 10030 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.

[1082] LC-MS (Methode 1): R.sub.t=1.04 min; MS (ESIpos): m/z=399 [M+H].sup.+.

[1083] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1084] ##STR00189##

[1085] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) 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 m 10030 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.

[1086] 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.

[1087] LC-MS (Methode 1): R.sub.t=1.10 min; MS (ESIpos): m/z=526 [M+H].sup.+.

[1088] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1089] ##STR00190##

[1090] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) 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 m 10030 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.

[1091] LC-MS (Methode 1): R.sub.t=1.20 min; MS (ESIpos): m/z=556 [M+H].sup.+.

[1092] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1093] ##STR00191##

[1094] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(3-fluoropyridin-4-yl)methanamine (36.3 mg, 288 mol) 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 m 10030 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.

[1095] LC-MS (Methode 1): R.sub.t=0.82 min; MS (ESIneg): m/z=416 [MH].

[1096] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1097] ##STR00192##

[1098] Acetic acid (12 l, 210 mol) 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 mol) and rac-3-(2,2,2-trifluoroethoxy)piperidine (52.0 mg, 284 mol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (36.1 mg, 170 mol) was added and stirring of the mixture at room temperature was continued. After 1.5 h, more sodium triacetoxyborohydride (36.1 mg, 170 mol) 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 m 10030 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.

[1099] LC-MS (Methode 1): R.sub.t=1.06 min; MS (ESIpos): m/z=520 [M+H].sup.+.

[1100] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1101] ##STR00193##

[1102] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (86 l, 50% in ethyl acetate, 290 mol) 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 mol) and 1-(4,6-dimethylpyridin-3-yl)methanamine (39.2 mg, 288 mol) 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 m 10030 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.

[1103] LC-MS (Methode 1): R.sub.t=0.53 min; MS (ESIneg): m/z=426 [MH].sup..

[1104] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1105] ##STR00194##

[1106] 30.9 mg (0.10 mmol) of 2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxylic acid, 53.2 mg (0.14 mmol) of HATU and 50 l 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:

[1107] Prep. Lc-Ms Methods: [1108] MS instrument: Waters, HPLC instrument: Waters (column Waters X-Bridge C18, 19 mm50 mm, 5 m, 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). [1109] or alternatively: [1110] MS instrument: Waters, HPLC instrument: Waters (column Phenomenex Luna 5 C18(2) 100A, AXIA Tech. 5021.2 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).

[1111] In this way, 27.7 mg (63% of theory, 96% purity) of the title compound were obtained.

[1112] LC-MS (Methode 6, ESIpos): R.sub.t=0.69 min; m/z=437 (M+H).sup.+.

[1113] .sup.1H-NMR (500 MHz, DMSO-d.sub.6, /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).

[1114] 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 appropiate amine or its salt:

TABLE-US-00006 Example IUPAC name/structure (yield; purity) LC-MS (Method 6) 80 [00195] R.sub.t = 0.73 min; m/z = 429 (M + H).sup.+ 81 [00196] R.sub.t = 0.75 min; m/z = 435 (M + H).sup.+ 82 [00197] R.sub.t = 0.66 min; m/z = 415 (M + H).sup.+ 83 [00198] R.sub.t = 0.76 min; m/z = 427 (M + H).sup.+ 84 [00199] R.sub.t = 0.73 min; m/z = 417 (M + H).sup.+ 85 [00200] R.sub.t = 0.63 min; m/z = 400 (M + H).sup.+ 86 [00201] R.sub.t = 0.72 min; m/z = 417 (M + H).sup.+ 87 [00202] R.sub.t = 0.73 min; m/z = 417 (M + H).sup.+ 88 [00203] R.sub.t = 0.76 min; m/z = 437 (M + H).sup.+ 89 [00204] R.sub.t = 0.77 min; m/z = 428 (M + H).sup.+ 90 [00205] R.sub.t = 0.60 min; m/z = 414 (M + H).sup.+ 91 [00206] R.sub.t = 0.57 min; m/z = 414 (M + H).sup.+ 92 [00207] R.sub.t = 0.75 min; m/z = 413 (M + H).sup.+ 93 [00208] R.sub.t = 0.87 min; m/z = 425 (M + H).sup.+ 94 [00209] R.sub.t = 0.85 min; m/z = 433 (M + H).sup.+ 95 [00210] R.sub.t = 0.87 min; m/z = 427 (M + H).sup.+ 96 [00211] R.sub.t = 0.85 min; m/z = 435 (M + H).sup.+ 97 [00212] R.sub.t = 0.87 min; m/z = 433 (M + H).sup.+ 98 [00213] R.sub.t = 0.65 min; m/z = 414 (M + H).sup.+

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)

[1115] ##STR00214##

[1116] 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 m, 25020 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 m, 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.

[1117] LC-MS (Methode 1): R.sub.t=0.89 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1118] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1119] ##STR00215##

[1120] 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 m, 25020 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 m, 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.

[1121] LC-MS (Methode 1): R.sub.t=0.87 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1122] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1123] ##STR00216##

[1124] 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 m, 25020 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 m, 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.

[1125] LC-MS (Methode 4): R.sub.t=0.61 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1126] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1127] ##STR00217##

[1128] 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 m, 25020 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 m, 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.

[1129] LC-MS (Methode 4): R.sub.t=0.61 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1130] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1131] ##STR00218##

[1132] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (9.7 l, 170 mol) 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 mol) and rac-3-isopropylpiperidine (36.1 mg, 284 mol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 mol) 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 m 10030 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.

[1133] LC-MS (Methode 5): R.sub.t=1.85 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1134] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1135] ##STR00219##

[1136] 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 m, 25020 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 m, flow rate 1 ml/min; mobile phase A: 70% n-Heptan, 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.

[1137] LC-MS (Methode 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1138] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1139] ##STR00220##

[1140] 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 m, 25020 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 m, 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.

[1141] LC-MS (Methode 1): R.sub.t=0.98 min; MS (ESIpos): m/z=450 [M+H].sup.+.

[1142] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1143] ##STR00221##

[1144] 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 Daicelo Chiralpak AY-H, 5 m, 25020 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 m, 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.

[1145] LC-MS (Methode 1): R.sub.t=1.09 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1146] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1147] ##STR00222##

[1148] 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 m, 25020 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 m, 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. LC-MS (Methode 1): R.sub.t=1.08 min; MS (ESIpos): m/z=534 [M+H].sup.+.

[1149] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1150] ##STR00223##

[1151] N,N-Diisopropylethylamine (200 l, 1.1 mmol) was added to a solution of diamix-3-[(2,2-difluorocyclopropyl)methoxy]piperidine sulfate hydrochloride (185 mg, 568 mol) in 5 ml of dichloromethane, and the mixture was stirred for 5 min, after which N-[(3,5-difluoropyridin-2-yl)methyl-2-(4-oxopiperidin-1-yl)-1,3-thiazole-5-carboxamide (100 mg, 284 mol) and acetic acid (19 l, 340 mol) were added to the mixture. The mixture was then stirred at room temperature. After 3 h, sodium triacetoxyborohydride (90.2 mg, 426 mol) 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 m 10030 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.

[1152] LC-MS (Methode 1): R.sub.t=1.05 min; MS (ESIpos): m/z=528 [M+H].sup.+.

[1153] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1154] ##STR00224##

[1155] N,N-Diisopropylethylamine (200 l, 1.1 mmol) and acetic acid (19 l, 340 mol) 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 mol) and rac-3-(cyclobutyloxy)piperidine sulfate hydrochloride (164 mg, 568 mol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 mol) 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 m 10030 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.

[1156] LC-MS (Methode 1): R.sub.t=1.04 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1157] .sup.1H-NMR (600 MHz, DMSO-d6) [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-2-yl)methyl]-1,3-thiazole-5-carboxamide

[1158] ##STR00225##

[1159] N,N-Diisopropylethylamine (200 l, 1.1 mmol) and acetic acid (19 l, 340 mol) 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 mol) and rac-3-[(3,3-difluorocyclobutyl)oxy]piperidine sulfate hydrochloride (185 mg, 568 mol) in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 5 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 mol) 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 m 10030 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.

[1160] LC-MS (Methode 1): R.sub.t=1.06 min; MS (ESIpos): m/z=528 [M+H].sup.+.

[1161] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1162] ##STR00226##

[1163] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) and diamix-(3R)-3-fluoro-3-methyl-1,4-bipiperidine dihydrochloride (70.9 mg, 259 mol) 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 m 10030 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.

[1164] LC-MS (Methode 1): R.sub.t=0.95 min; MS (ESIpos): m/z=454 [M+H].sup.+.

[1165] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1166] ##STR00227##

[1167] 2-Chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide (100 mg, 314 mol) and diamix-(3R)-3-fluoro-3-methyl-1,4-bipiperidine dihydrochloride (86.5 mg, 317 mol) 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 m 10030 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.

[1168] LC-MS (Methode 1): R.sub.t=0.88 min; MS (ESIpos): m/z=438 [M+H].sup.+.

[1169] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1170] ##STR00228##

[1171] 2-Bromo-N-(5-chloro-2-fluorobenzyl)-1,3-thiazole-5-carboxamide (100 mg, 286 mol) and diamix-(3R)-3-fluoro-3-methyl-1,4-bipiperidine dihydrochloride (67.7 mg, 248 mol) 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 m 10030 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.

[1172] LC-MS (Methode 1): R.sub.t=1.17 min; MS (ESIpos): m/z=469 [M+H].sup.+.

[1173] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1174] ##STR00229##

[1175] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (80.2 mg, 240 mol) and (3R)-3-(cyclopropylmethoxy)-1,4-bipiperidine dihydrochloride (66.0 mg, 212 mol) 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 m 10030 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.

[1176] LC-MS (Methode 1): R.sub.t=1.01 min; MS (ESIpos): m/z=492 [M+H].sup.+.

[1177] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1178] ##STR00230##

[1179] 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 m, 25020 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 m, 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.

[1180] LC-MS (Methode 1): R.sub.t=1.07 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1181] .sup.1H-NMR (600 MHz, DMSO-d6) [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-2-yl)methyl]-1,3-thiazole-5-carboxamide (enantiomer 2)

[1182] ##STR00231##

[1183] 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 m, 25020 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 m, 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.

[1184] LC-MS (Methode 1): R.sub.t=1.07 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1185] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1186] ##STR00232##

[1187] rac-2-Bromo-N-[1-(2,5-difluorophenyl)ethyl]-1,3-thiazole-5-carboxamide (145 mg, 418 mol) and diamix-(3R)-3-fluoro-3-methyl-1,4-bipiperidine dihydrochloride (98.9 mg, 362 mol) 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 m 10030 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.

[1188] LC-MS (Methode 1): R.sub.t=1.18 min; MS (ESIpos): m/z=467 [M+H].sup.+.

[1189] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1190] ##STR00233##

[1191] N,N-Diisopropylethylamine (250 l, 1.4 mmol) and propylphosphonic anhydride (280 l, 50% in ethyl acetate, 460 mol) 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 mol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (101 mg, 464 mol) 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 m 10030 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.

[1192] LC-MS (Methode 5): R.sub.t=2.13 min; MS (ESIpos): m/z=546 [M+H].sup.+.

[1193] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1194] ##STR00234##

[1195] N,N-Diisopropylethylamine (180 l, 1.0 mmol) and propylphosphonic anhydride (200 l, 50% in ethyl acetate, 330 mol) 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 mol) and 1-(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (72.7 mg, 335 mol) 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 m 10030 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.

[1196] LC-MS (Methode 5): R.sub.t=2.00 min; MS (ESIneg): m/z=513 [MH].sup..

[1197] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1198] ##STR00235##

[1199] 2-Bromo-4-chloro-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 271 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (69.2 mg, 271 mol) were combined and stirred at 120 C. in sodium carbonate solution (540 l, 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.

[1200] LC-MS (Methode 5): R.sub.t=1.96 min; MS (ESIpos): m/z=470 [M+H].sup.+.

[1201] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1202] ##STR00236##

[1203] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (9.7 l, 170 mol) 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 mol) and rac-3-propylpiperidine (36.1 mg, 284 mol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 mol) 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 m 10030 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.

[1204] LC-MS (Methode 5): R.sub.t=1.89 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1205] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1206] ##STR00237##

[1207] 2-Bromo-4-cyclopropyl-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 267 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (68.2 mg, 267 mol) were combined and stirred at 120 C. in sodium carbonate solution (530 l, 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 m 10030 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.

[1208] LC-MS (Methode 5): R.sub.t=2.11 min; MS (ESIpos): m/z=476 [M+H].sup.+.

[1209] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1210] ##STR00238##

[1211] 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 m, 25020 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 m, 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.

[1212] LC-MS (Methode 2): R.sub.t=0.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1213] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1214] ##STR00239##

[1215] 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 m, 25020 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 m, 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.

[1216] LC-MS (Methode 2): R.sub.t=0.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1217] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1218] ##STR00240##

[1219] 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 m, 25020 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 m, 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.

[1220] LC-MS (Methode 1): R.sub.t=1.17 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1221] .sup.1H-NMR (600 MHz, DMSO-d6) [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)

[1222] ##STR00241##

[1223] 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 m, 25020 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 m, 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.

[1224] LC-MS (Methode 1): R.sub.t=1.17 min; MS (ESIpos): m/z=506 [M+H].sup.+.

[1225] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1226] ##STR00242##

[1227] N,N-Diisopropylethylamine (49 l, 280 mol) and acetic acid (9.7 l, 170 mol) 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 mol) and rac-3-(2-fluoroethyl)piperidine (37.2 mg, 284 mol) in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 6 h. Subsequently, sodium triacetoxyborohydride (45.1 mg, 213 mol) 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 m 10030 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.

[1228] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1229] ##STR00243##

[1230] Acetic acid (9.7 l, 170 mol) 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 mol) and piperidine (56 l, 570 mol) in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 4 h. Subsequently, sodium triacetoxyborohydride (90.2 mg, 426 mol) 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 m 10030 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.

[1231] LC-MS (Methode 1): R.sub.t=0.80 min; MS (ESIpos): m/z=422 [M+H].sup.+.

[1232] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1233] ##STR00244##

[1234] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32.6 mg, 170 mol), 1-hydroxy-1H-benzotriazole hydrate (26.0 mg, 170 mol) and N,N-diisopropylethylamine (110 l, 650 mol) 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 mol) 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 mol) 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 m 10030 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.

[1235] LC-MS (Methode 2): R.sub.t=0.56 min; MS (ESIpos): m/z=462 [M+H].sup.+.

[1236] .sup.1H-NMR (600 MHz, DMSO-d6) [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 (5.56).

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

[1237] ##STR00245##

[1238] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-4-ethyl-1,3-thiazole-5-carboxamide (150 mg, 414 mol) and (3R)-3-methyl-1,4-bipiperidine dihydrochloride (106 mg, 414 mol) were combined and stirred at 120 C. in sodium carbonate solution (830 l, 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 m 10030 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.

[1239] LC-MS (Methode 2): R.sub.t=0.60 min; MS (ESIpos): m/z=464 [M+H].sup.+.

[1240] .sup.1H-NMR (500 MHz, DMSO-d6) [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-2-yl)methyl]-1,3-thiazole-5-carboxamide (enantiomer 1)

[1241] ##STR00246##

[1242] 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 m, 25020 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 m, 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.

[1243] LC-MS (Methode 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1244] .sup.1H-NMR (600 MHz, DMSO-d6) [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-2-yl)methyl]-1,3-thiazole-5-carboxamide (enantiomer 2)

[1245] ##STR00247##

[1246] 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 m, 25020 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 m, 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.

[1247] LC-MS (Method 5): R.sub.t=1.56 min; MS (ESIpos): m/z=484 [M+H].sup.+.

[1248] .sup.1H-NMR (600 MHz, DMSO-d6) [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

[1249] ##STR00248##

[1250] N,N-Diisopropylethylamine (69 l, 400 mol) and acetic acid (14 l, 240 mol) 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 mol) and rac-3-phenylpiperidine (64.1 mg, 397 mol) in 4.2 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Subsequently, sodium triacetoxyborohydride (63.2 mg, 298 mol) 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 m 10030 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.

[1251] LC-MS (Methode 5): R.sub.t=1.74 min; MS (ESIpos): m/z=498 [M+H].sup.+.

[1252] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1253] ##STR00249##

[1254] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) and diamix-1,1-difluoro-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (96.1 mg, 299 mol) 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 m 10030 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.

[1255] LC-MS (Methode 5): R.sub.t=1.52 min; MS (ESIpos): m/z=502 [M+H].sup.+.

[1256] .sup.1H-NMR (400 MHz, DMSO-d6) [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

[1257] ##STR00250##

[1258] 2-Bromo-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (100 mg, 299 mol) and diamix-5-(3-fluoropiperidin-4-yl)-5-azaspiro[2.5]octane dihydrochloride (85.4 mg, 299 mol) 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 m 10030 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.

[1259] LC-MS (Methode 5): R.sub.t=1.52 min; MS (ESIpos): m/z=466 [M+H].sup.+.

[1260] .sup.1H-NMR (400 MHz, DMSO-d6) [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).

[1261] 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 [00251] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 0.76 min; m/z = 464 (M + H).sup.+. 137 [00252] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.02 min; m/z = 462 (M + H).sup.+. 138 [00253] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.13 min; m/z = 476 (M + H).sup.+. 139 [00254] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.10 min; m/z = 504/506 (M + H).sup.+. 140 [00255] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.01 min; m/z = 500 (M + H).sup.+. 141 [00256] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.07 min; m/z = 504/506 (M + H).sup.+. 142 [00257] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /ppm): 1.52-1.66 (m, 2H), 1.90 (br. d, 2H), 2.67-2.77 (m, 3H), 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 (Methode 1): Rt = 1.07 min; m/z = 504/506 (M + H).sup.+. 143 [00258] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.06 min; m/z = 484 (M + H).sup.+. 144 [00259] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.00 min; m/z = 488 (M + H).sup.+. 145 [00260] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.00 min; m/z = 500 (M + H).sup.+. 146 [00261] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.06 min; m/z = 484 (M + H).sup.+. 147 [00262] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.00 min; m/z = 488 (M + H).sup.+. 148 [00263] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 0.90 min; m/z = 480 (M + H).sup.+. 149 [00264] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.14 min; m/z = 478 (M + H).sup.+.

[1262] 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 [00265] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 0.99 min; m/z = 450 (M + H).sup.+. 151 [00266] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 1.17 min; m/z = 433/435 (M + H).sup.+. 152 [00267] .sup.1H-NMR (600 MHz, DMSO-d.sub.6, /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 (Methode 1): Rt = 0.94 min; m/z = 437 (M + H).sup.+.

[1263] B. Assessment of Pharmacological Efficacy of Compounds of Formula (I)

[1264] The pharmacological activity of the compounds of formula (I) 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.

[1265] B-1 In Vitro Radioligand Binding Studies for Determination of the Dissociation Constants K.sub.1 at the Human Adrenoreceptor ADRA2C (Eurofins Panlabs Discovery Services, Taiwan, Ltd)

[1266] 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.

[1267] 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 M). The radioactivity was determined in a scintiation counter.

[1268] 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.

[1269] From the IC.sub.50 value measured in the competition experiment and the K.sub.a 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 WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 22 (23): 3099-108. doi:10.1016/0006-2952(73)90196-2. PMID 4202581 PMID: 4202581].

[00001]$\begin{array}{cc}Ki=\frac{IC50}{\left(1+\frac{L}{Kd}\right)}& \mathrm{Formula}1\end{array}$

[1270] 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

[1271] Table 1a below shows the binding affinity to the human ADRA2C receptor (K.sub.i [nM]) and the half-maximal inhibition of the human ADRA2C receptor (IC50 [nM]) of representative embodiments of the invention:

TABLE-US-00009 TABLE 1a Example hAR.sub.2C hAR.sub.2C No. IC.sub.50 [nM] K.sub.i [nM] 1 54 24 100 5 2

[1272] The data in Table 1a 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.

[1273] B-2. In Vitro Activity Assay to Determine the Inhibition of Recombinant ADRA2C

[1274] 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.

[1275] The investigations of the inhibition of the recombinant human ADRA2C receptors were carried out with stabily transfected CHO-K1 cells coexpressing the G.sub.aq 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]

[1276] 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):

[00002]$\mathrm{Hill}\mathrm{function}$$\begin{array}{cc}Y\left(x\right)=\mathrm{Bottom}+\frac{\mathrm{Top}-\mathrm{Bottom}}{1+10^{\left(\mathrm{iogIC}50+x\right)-\mathrm{HillSlope}}}& \mathrm{Formula}2\end{array}$

[1277] Top=upper threshold, Bottom=lower threshold, Slope=slope, IC.sub.50=turning point

[1278] 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-00010 TABLE 2a Example AR.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 26 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 97 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

[1279] The data in Table 2a 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.

[1280] B-3 Animal Model of Obstructive Sleep Apnoea in the Pig

[1281] 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)].

[1282] 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).

[1283] 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.

[1284] Administration of the test substance can be intranasal, intravenous, subcutaneous, intraperitoneal, intraduodenal or intragastral.

[1285] C. Experimental Methods-Combination of an 2-Adrenoceptor Subtype C (Alpha-2C) Antagonists with a TASK Channel Blocker

[1286] Advantageous pharmacological properties of the combination of an 2-Adrenoceptor subtype C (alpha-2C) antagonists with a TASK channel blocker can be determined by the following methods.

[1287] The therapeutic potential of the the combination of an 2-Adrenoceptor subtype C (alpha-2C) antagonists with a TASK channel blocker according to the present invention in sleep apnea can be assessed preclinically in a pig model of obstructive sleep apnea (OSA).

[1288] Using negative pressure, it is possible to induce collapse and thus obstruction of the upper respiratory tract in anaesthetized, spontaneously breathing pigs (Wirth K. J. et al., Sleep 36(5) (2013) pp. 699-708).

[1289] German Landrace pigs are used for the model. The pigs are anaesthetized and tracheotomized. Two tracheal cannulas are inserted into the trachea, one into the rostral part and the other into the caudal part of the trachea. Using a connection piece, the rostral cannula is connected to a tube to the negative pressure device and to the distal tracheal cannula. The distal tracheal cannula is additionally connected to a tube with an open end to atmosphere via a connection piece that served for free tracheal breathing, circumventing the upper airway. By appropriate opening and clamping of those tubes breathing can be switched from nasal breathing to breathing through the caudal tracheal cannula, circumventing the upper airway, and the (isolated) upper airway can be connected to the negative pressure device, causing airflow in the inspiratory direction.

[1290] 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 (cm H.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.

[1291] In this OSA pig model, systemic application of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I), such as N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with intraduodenal administration of 0.01 mg/kg inhibited upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) in all pigs only at time point 150 and 180 min after intraduodenal application. At time point 230 min after intraduodenal administration, upper airway collapsibility was induced at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) in all pigs. The combination of this non effective dose of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of the TASK1/TASK3 channel blocker of 0.3 g ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl) imidazo[1,2-a]pyrimidin-3-yl]methyl}J-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone inhibits upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) for more than three hours (see Table 1, 2 and 3 and FIG. 1).

[1292] FIG. 1: Effect of intraduodenal administration of 0.01 mg/kg of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide given at time point 0 min in combination with intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone given at time point 230 min after beginning of the experiment on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00011 TABLE 1 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2- a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone inhibits upper airway collapsibility at negative pressures of 50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 50 cm H.sub.2O, % 0 0 30 0 60 0 90 33 120 100 150 100 180 100 210 67 Nasal application TASK1/3 230 0 channel blocker 240 100 270 100 300 100 330 100 360 100 390 100 420 100

TABLE-US-00012 TABLE 2 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2- a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone inhibits upper airway collapsibility at negative pressures of 100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 100 cm H.sub.2O, % 0 0 30 0 60 0 90 33 120 100 150 100 180 100 210 33 Nasal application TASK1/3 230 0 channel blocker 240 100 270 100 300 100 330 100 360 100 390 100 420 100

TABLE-US-00013 TABLE 3 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2- a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone inhibits upper airway collapsibility at negative pressures of 150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 150 cm H.sub.2O, % 0 0 30 0 60 0 90 33 120 67 150 100 180 100 210 0 Nasal application TASK1/3 230 0 channel blocker 240 100 270 100 300 100 330 100 360 100 390 100 420 100

[1293] Table 4, 5 and 6 and FIG. 2: Effect of intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker ((3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone given at time point 0 min on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00014 TABLE 4 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker ((3-chloro-6- methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- 3,8-diazabicyclo[3.2.1]oct-8-yl)methanone at negative pressures of 50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 50 cm H.sub.2O, % 0 0 10 33 30 0 60 0 90 0

TABLE-US-00015 TABLE 5 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker ((3-chloro-6- methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- 3,8-diazabicyclo[3.2.1]oct-8-yl)methanone at negative pressures of 100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 100 cm H.sub.2O, % 0 0 10 33 30 0 60 0 90 0

TABLE-US-00016 TABLE 6 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker ((3-chloro-6- methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}- 3,8-diazabicyclo[3.2.1]oct-8-yl)methanone at negative pressures of 150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 150 cm H.sub.2O, % 0 0 10 0 30 0 60 0 90 0

[1294] In a second set of experiments in this OSA pig model, systemic application of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I), such as N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with intraduodenal administration of 0.01 mg/kg inhibited upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) in all pigs at no time point after intraduodenal application. At time point 90 min after intraduodenal administration, upper airway collapsibility was induced at negative pressures of 100 and 150 cm head (cm H.sub.2O), upper airway collapsibility was only inhibited at negative pressures of 50 cm head (cm H.sub.2O). At time point 120 min after intraduodenal administration, upper airway collapsibility was induced at negative pressures of 150 cm head (cm H.sub.2O), upper airway collapsibility was only inhibited at negative pressures of 50 and 100 cm head (cm H.sub.2O). At time point 180 min after intraduodenal administration, upper airway collapsibility was induced at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) in all pigs. The combination of this non effective dose of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of the TASK1/TASK3 channel blocker of 0.3 g (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) for 90 minutes (see Table 7, 8 and 9 and FIG. 3).

[1295] FIG. 3: Effect of intraduodenal administration of 0.01 mg/kg of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3-methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide given at time point 0 min in combination with intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone given at time point 180 min after beginning of the experiment on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00017 TABLE 7 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} piperazin-1- yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 50 cm H.sub.2O, % 0 0 30 0 60 50 90 100 120 100 150 50 Nasal application TASK1/3 180 0 channel blocker 190 100 210 100 240 100 270 100 300 100 330 100

TABLE-US-00018 TABLE 8 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} piperazin-1- yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 100 cm H.sub.2O, % 0 0 30 0 60 0 90 50 120 100 150 0 Nasal application TASK1/3 180 0 channel blocker 190 50 210 100 240 100 270 100 300 100 330 50

TABLE-US-00019 TABLE 9 Combination of non effective dose of N-[(3,5-difluoropyridin-2-yl)methyl]-2-[(3R)-3- methyl[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl} piperazin-1- yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 150 cm H.sub.2O, % 0 0 30 0 60 0 90 50 120 0 150 0 Nasal application TASK1/3 180 0 channel blocker 190 50 210 100 240 100 270 100 300 100 330 50

[1296] In a third set of experiments in this OSA pig model, systemic application of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I), such as ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with intravenous administration of 15 g/kg as a bolus followed by i.v. infusion of 5 g/kg/h for four hours inhibited upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) in all pigs at no time point after intravenous application. At time point 120 min after intravenous administration, the non effective dose of the TASK1/TASK3 channel blocker of 0.3 g (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone was administered intranasally. The combination of this non effective dose of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I), such as ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of the TASK1/TASK3 channel blocker of 0.3 g (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at all negative pressures of 50, 100 and 150 cm head (cm H.sub.2O) for more than 4 hours (see Table 10, 11 and 12 and FIG. 4).

[1297] FIG. 4: Effect of intravenous administration of 15 g/kg as a bolus followed by i.v. infusion of 5 g/kg/h for four hours of the 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I), such as ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3-(methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide given at time point 0 min in combination with intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone given at time point 120 min after beginning of the experiment on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00020 TABLE 10 Combination of non effective dose of ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3- (methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 50 cm H.sub.2O, % 0 0 30 0 60 0 90 50 Nasal application TASK1/3 120 0 channel blocker 130 100 150 100 180 100 240 100 300 100 360 100

TABLE-US-00021 TABLE 11 Combination of non effective dose of ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3- (methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl} piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 100 cm H.sub.2O, % 0 0 30 0 60 0 90 50 Nasal application TASK1/3 120 0 channel blocker 130 100 150 100 180 100 240 100 300 100 360 100

TABLE-US-00022 TABLE 12 Combination of non effective dose of ent-N-[(3,5-Difluoropyridin-2-yl)methyl]-2-[3- (methoxymethyl)[1,4-bipiperidin]-1-yl]-1,3-thiazole-5-carboxamide with the non effective dose of 0.3 g of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of 150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 150 cm H.sub.2O, % 0 0 30 0 60 0 90 50 Nasal application TASK1/3 120 0 channel blocker 130 100 150 100 180 100 240 100 300 100 360 100

[1298] Table 13, 14 and 15 and FIG. 5: Effect of intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone given at time point 0 min on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00023 TABLE 13 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin- 1-yl)(6-methoxypyridin-2-yl)methanone at negative pressures of 50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 50 cm H.sub.2O, % 0 0 10 0 30 0 60 0

TABLE-US-00024 TABLE 14 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin- 1-yl)(6-methoxypyridin-2-yl)methanone at negative pressures of 100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 100 cm H.sub.2O, % 0 0 10 0 30 0 60 0

TABLE-US-00025 TABLE 15 Intranasal administration of 0.3 g of the TASK1/TASK3 channel blocker (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin- 1-yl)(6-methoxypyridin-2-yl)methanone at negative pressures of 150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps 150 cm H.sub.2O, % 0 0 10 0 30 0 60 0

[1299] From the above mentioned data it can be deducted that the combination of an 2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) with a TASK channel blocker inhibits upper airway collapsibility with improved efficacy compared to each treatment alone and is thus suitable to treat sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.