Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof ##STR00001##
in which q, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are as defined in the specification, for use in therapy.

Claims

1. A process for the preparation of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof wherein ##STR00186## W.sup.1, X.sup.1, Y.sup.1, and Z.sup.1 each independently represent N, NH or CH, with the proviso that W.sup.1, X.sup.1, Y.sup.1 and Z.sup.1 do not each simultaneously represent a moiety CH; p is 0, 1, 2 or 3; each R.sup.11 independently represents halogen, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylcarbonyl, or C.sub.1-C.sub.6 alkyl optionally substituted by carboxyl or C.sub.1-C.sub.6 alkoxycarbonyl; q is 0, 1, 2, 3 or 4; each R.sup.12 independently represents halogen, cyano, carboxyl, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkoxyC.sub.1-C.sub.6 alkyl or a 5- to 9-membered heterocyclic ring system; R.sup.13 represents a group NR.sup.15 or CR.sup.16R.sup.17, with the provisos that (i) when R.sup.13 represents NH and ring A represents pyrazol-4-yl or imidazol-4-yl, then p must be 3 and R.sup.14 represents a substituted 6- to 10-membered aromatic or heteroaromatic ring system, and (ii) when R.sup.13 represents CH.sub.2 and ring A represents pyrazol-4-yl or imidazol-4-yl, then either p is 3, or, p is 2 and q is at least 1; R.sup.15 represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl group; R.sup.16 and R.sup.17 each independently represent a hydrogen or halogen atom or cyano, carboxyl, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkoxyC.sub.1-C.sub.6 alkyl or a 5- to 9-membered heterocyclic ring system; R.sup.14 represents a 6- to 10-membered aromatic or heteroaromatic ring system, the ring system itself being optionally substituted by at least one substituent selected from halogen, hydroxyl, cyano, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylsulphinyl, C.sub.1-C.sub.6 alkylsulphonyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonyloxy, C.sub.1-C.sub.6 alkoxycarbonyl, amino, —CON(R.sup.18).sub.2, C.sub.1-C.sub.6 alkylamino, di-(C.sub.1-C.sub.6 alkyl)amino, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyloxy or C.sub.3-C.sub.6 cycloalkylmethyl; and each R.sup.18 independently represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl group; but excluding the following compounds: 1) 1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[[2-(trifluoromethyl)phenyl]methyl]-4-piperidinemethanol, 2) 1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinecarboxylic acid, ethyl ester, 3) N-(2-methylphenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidineamine, 4) 1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine, 5) 1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(phenylmethyl)piperidine, 6) 1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine, 7) (4-(4-Methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol, 8) (4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol, 9) 1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinemethanol, and 10) 4-(phenylmethyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine, wherein the process comprises (i) reacting a compound of formula ##STR00187## wherein L.sup.1 represents a leaving group and p, W.sup.1, X.sup.1, Y.sup.1, Z.sup.1 and R.sup.11 are as defined in formula (Ia), with a compound of formula ##STR00188## or a suitable salt thereof, wherein q, R.sup.12, R.sup.13 and R.sup.14 are as defined in formula (Ia); and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (Ia) into another compound of formula (Ia) removing any protecting groups forming a pharmaceutically acceptable salt.

Description

1. INTERMEDIATES

Intermediate 1: 3,5-Diethyl-1-methyl-1H-pyrazole

(1) ##STR00015##

(2) Methylhydrazine (5.0 mL, 95.3 mmol) in ethanol (10 mL) was added drop-wise to a stirred solution of 3,5-heptanedione (1 g, 85.2 mmol) at 5° C. then allowed to stir at room temperature for 2 hours. Acetic acid (2 mL) was added and the mixture refluxed for 1 hour then allowed to cool to room temperature. The solution was concentrated in vacuo to give the title compound (12 g, 94%).

(3) MS ES.sup.+: 139

Intermediate 2: 1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazole

(4) ##STR00016##

(5) Prepared as described for 3,5-diethyl-1-methyl-1H-pyrazole (Intermediate 1) from methylhydrazine and 1,1,1-trifluoropentane-2,4-dione.

(6) MS ES.sup.+: 165

Intermediate 3: 3,5-Dimethyl-1H-pyrazole-4-sulfonyl chloride

(7) ##STR00017##

(8) 3,5-Dimethyl-1H-pyrazole (3.0 g, 1.0 eq) dissolved in chloroform (5 mL) was added drop-wise to a solution of chlorosulfonic acid (19.95 g, 5.5 eq.) in chloroform (20 mL) under a nitrogen atmosphere at 0° C. with continuous stirring. The reaction was heated at 60° C. for 15 hours under continuous stirring. The reaction was cooled to room temperature and thionyl chloride (4.0 g, 1.1 eq) was gradually added. The reaction was heated at 60° C. for a further 2 hours. The reaction was cooled to room temperature and added to a stirred mixture of dichloromethane (50 mL) and ice cold water (70 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×70 mL). The combined organic layer was dried over sodium sulfate and evaporated under vacuum to obtain the title compound, 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (2.0 g, 42%), as a white solid.

(9) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.40 (s, 6H)

(10) MS ES.sup.+: 195

Intermediate 4: 3,5-Diethyl-1-methyl-1H-pyrazole-4-sulfonyl chloride

(11) ##STR00018##

(12) Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) from 3,5-diethyl-1-methyl-1H-pyrazole (Intermediate 1).

(13) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.21-1.40 (m, 6H), 2.85 (m, 2H), 2.95 (m, 2H), 3.80 (s, 3H).

Intermediate 5: 1,3-Dimethyl-1H-pyrazole-4-sulfonyl chloride

(14) ##STR00019##

(15) Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) from 1,3-dimethylpyrazole.

(16) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.48 (s, 3H), 3.91 (s, 3H), 7.92 (s, 1H).

(17) MS ES.sup.+: 195

Intermediate 6: 3-(Trifluoromethyl)-1,5-dimethyl-1H-pyrazole

(18) ##STR00020##

(19) Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) from 1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole (Intermediate 2).

(20) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.63 (s, 3H), 3.91 (s, 3H)

Intermediate 7: 1,4-Dimethyl-1H-pyrazole-5-sulfonyl chloride

(21) ##STR00021##
Step (i):

(22) ##STR00022##

(23) A solution of 23% n-butyl lithium in hexane (17.3 mL, 1.2 eq) was added drop-wise to a solution of 1,4-dimethyl-1H-pyrazole (5 g, 1 eq.) in dry ether (50 mL) at −65° C. under a nitrogen atmosphere. The temperature of the resulting suspension was raised to 0° C. temperature over 1 hour and then cooled to −70° C. Excess sulfur dioxide was bubbled to the mixture for 30 minutes, while maintaining the temperature below −65° C. The solution was stirred at −65° C. for 1 hour and was then allowed to warm to room temperature. The resulting to precipitate was filtered, washed with ether and dried to yield the lithium sulfinate salt of 1,4-dimethyl-1H-pyrazole.

(24) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.03 (s, 3H) 3.87 (s, 3H) 6.94 (s, 1H)

(25) Step (ii):

(26) ##STR00023##

(27) The lithium sulfinate salt of 1,4-dimethyl-1H-pyrazole from step (i) was added to a biphasic mixture of dichloromethane (50 mL) and ice cold water (70 mL). N-chlorosuccinimide (6.23 g, 0.9 eq.) was added portion-wise with vigorous stirring. The reaction mixture was stirred further for 30 minutes at 5° C. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layer was dried over sodium sulfate and evaporated under vacuum to obtain the title compound, 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride (5.5 g, 55%). The regio-selectivity was confirmed by HMBC-HMQC analysis.

Intermediate 8: 1-(1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one

(28) ##STR00024##

(29) To a solution of 4-piperidine hydrochloride (3.67 g, 23.9 mmol) in dichloromethane (250 mL) was added magnesium sulfate (5 g) and the reaction was stirred at room temperature. After 15 minutes, 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride ((1.0 g, 4.79 mmol) and triethylamine (2.42 g, 23.9 mmol) were added successively and stirred overnight at room temperature. The reaction was filtered, treated with water (25 mL) and extracted into dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product, 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (1.24 g, 95%).

(30) MS ES.sup.+: 272

Intermediate 9: 1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

(31) ##STR00025##

(32) Prepared as described for 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate 8) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and piperidine-4-carbonitrile.

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.65-1.88 (m, 2H) 1.89-2.05 (m, 2H) 2.20-2.37 (m, 6H) 2.65-2.86 (m, 2H) 2.94 (tt, J=8.56, 4.07 Hz, 1H) 3.06-3.23 (m, 2H) 13.10 (br. s., 1H)

(34) MS ES.sup.+: 269

Intermediate 10: 4-(4-Chloro-3-fluorophenoxy)piperidine hydrochloride

(35) ##STR00026##
Step (i):

(36) ##STR00027##

(37) A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.484 mmol) and 4-chloro-3-fluorophenol in THF at 0° C. was treated with diisopropyl azodicarboxylate (483 μl, 2.484 mmol). The reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was treated with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The layers were separated. The aqueous phase was extracted with ethyl acetate and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to yield an oil. The crude product was purified by silica chromatography (solvent system: 20-100% ethyl acetate/petrol). The relevant fractions were combined and concentrated and the resulting product carried through to the next step.

(38) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.41 (s, 9H) 1.44-1.57 (m, 2H) 1.85-1.96 (m, 2H) 3.10-3.22 (m, 2H) 3.60-3.70 (m, 2H) 4.55-4.64 (m, 1H) 6.83-6.90 (m, 1H) 7.10-7.17 (m, 1H) 7.42-7.49 (m, 1H)

(39) Step (ii):

(40) ##STR00028##

(41) A solution of the tert-butyl 4-(4-chloro-3-fluorophenoxy)piperidine-1-carboxylate from step (i) in 1,4-dioxane (10 mL) was treated with 4M hydrogen chloride in dioxane (2 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The product was filtered and dried under vacuum to give the title compound which was used without further purification.

(42) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.76-1.91 (m, 2H) 2.05-2.15 (m, 2H) 2.98-3.11 (m, 2H) 3.15-3.27 (m, 2H) 4.63-4.72 (m, 1H) 6.86-6.94 (m, 1H) 7.13-7.24 (m, 1H) 7.44-7.53 (m, 1H) 8.93 (br. s., 2H)

(43) MS ES.sup.+: 230

Intermediate 11: 4-(4-Chloro-2-fluorophenoxy)piperidine hydrochloride

(44) ##STR00029##

(45) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 4-chloro-2-fluorophenol.

Intermediate 12: 5-Chloro-2-(piperidin-4-yloxy)benzonitrile hydrochloride

(46) ##STR00030##

(47) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 5-chloro-2-hydroxybenzonitrile.

Intermediate 13: 4-(3-Fluoro-4-methoxyphenoxy)piperidine hydrochloride

(48) ##STR00031##

(49) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 3-fluoro-4-methoxyphenol.

Intermediate 14: 4-(4-Chloro-2-(trifluoromethyl)phenoxy)piperidine hydrochloride

(50) ##STR00032##

(51) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 4-chloro-2-(trifluoromethyl)phenol.

Intermediate 15: 4-(3,5-Difluoro-4-methoxyphenoxy)piperidine hydrochloride

(52) ##STR00033##

(53) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 3,5-difluoro-4-methoxyphenol.

Intermediate 16: 4-(4-Chloro-2,6-difluorophenoxy)piperidine hydrochloride

(54) ##STR00034##

(55) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 4-chloro-2,6-difluorophenol.

Intermediate 17: 4-(4-(Trifluoromethyl)phenoxy)piperidine hydrochloride

(56) ##STR00035##

(57) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 4-(trifluoromethyl)phenol.

Intermediate 18: 5-Chloro-2-(piperidin-4-yloxy)pyridine hydrochloride

(58) ##STR00036##
Step (i):

(59) ##STR00037##

(60) Mesyl chloride (0.542 ml, 6.96 mmol) was added dropwise to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) and triethylamine (0.970 ml, 6.96 mmol) in dichloromethane (25 ml) under nitrogen in an ice bath. The resulting solution was stirred at room temperature for 1 hour. The solution was washed with water, dried (phase separator) and concentrated to give tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.80 g, 6.44 mmol, 130% yield), as a white solid.

(61) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (s, 9H) 1.52-1.72 (m, 2H) 1.80-2.04 (m, 2H) 3.11-3.20 (m, 2H) 3.20 (s, 3H) 3.51-3.67 (m, 2H) 4.76-4.89 (m, 1H)

(62) Step (ii):

(63) ##STR00038##

(64) Potassium carbonate (0.352 g, 2.55 mmol) was added to a solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate from step (i) (0.453 g, 1.621 mmol) and 5-chloropyridin-2-ol (0.15 g, 1.158 mmol) in N,N-dimethylformamide (10 ml) in a sealed tube. The reaction was stirred at 75° C. overnight. The reaction was quenched with water and extracted with DCM three times. The combined organics were washed with water, dried (phase separator) and concentrated. The crude product was freeze-dried to remove the remaining DMF. The crude product was purified by 10 g KP-silica Biotage SNAP cartridge eluted with 0-50% ethyl acetate/petrol to give tert-butyl 4-(5-chloropyridin-2-yloxy)piperidine-1-carboxylate (0.116 g, 0.371 mmol, 32.0% yield).

(65) .sup.1H NMR (400 MHz, Dichloromethane-d.sub.2) 6 ppm 1.48 (s, 9H) 1.64-1.81 (m, 2H) 1.90-2.03 (m, 2H) 3.19-3.35 (m, 2H) 3.70-3.85 (m, 2H) 5.13-5.25 (m, 1H) 6.73 (s, 1H) 7.52-7.62 (m, 1H) 8.05-8.14 (m, 1H)

(66) MS ES.sup.+: 257

(67) Step (iii):

(68) ##STR00039##

(69) A solution of the tert-butyl 4-(5-chloropyridin-2-yloxy)piperidine-1-carboxylate from step (ii) in 1,4-dioxane (10 mL) was treated with 4M HCl in dioxane (2 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The product was filtered and dried under vacuum to give the title compound which was used without further purification.

(70) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.80-1.95 (m, 2H) 2.07-2.23 (m, 2H) 3.00-3.15 (m, 2H) 3.17-3.27 (m, 2H) 5.10-5.26 (m, 1H) 6.85-6.96 (m, 1H) 7.78-7.90 (m, 1H) 8.15-8.27 (m, 1H) 8.77 (br. s., 2H)

Intermediate 19: 4-(4-Chlorophenoxy)-2-methylpiperidine hydrochloride

(71) ##STR00040##

(i) tert-Butyl 4-hydroxy-2-methylpiperidine-1-carboxylate

(72) ##STR00041##

(73) To a solution of 1-Boc-2-methyl-4-piperidinone (1.0 g, 4.68 mmol) in methanol (10 mL) at 0° C. was added sodium borohydride (265 mg, 7.03 mmol) portionwise. The reaction was stirred under an atmosphere of nitrogen at 0° C. for 1 hour. It was then allowed to reach room temperature and stirred for a further 2.5 hours. The reaction was deemed complete by its LC-MS analysis and quenched using saturated ammonium chloride aqueous solution and the methanol removed under reduced pressure. The remaining aqueous layer was extracted using dichloromethane (25 ml×3), the combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product, tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (1.0 g, 100%).

(74) MS ES.sup.+: 216.4

(ii) tert-Butyl 4-(4-chlorophenoxy)-2-methylpiperidine-1-carboxylate

(75) ##STR00042##

(76) Prepared as described for tert-Butyl 4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate (Intermediate 20 step (ii) from tert-Butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (Intermediate 19 step (i)).

(77) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.15 (d, 3H), 1.40 (s, 9H), 1.41-1.49 (m, 1H), 1.59-1.68 (m, 1H), 1.88-1.94 (m, 1H), 1.98-2.08 (m, 1H), 2.82-2.94 (m, 1H), 3.98-4.08 (m, 1H), 4.34-4.48 (m, 1H), 4.46-4.54 (m, 1H), 6.73-6.78 (m, 2H), 7.13-7.18 (m, 2H).

(78) MS: ES.sup.+326

(iii) 4-(4-Chlorophenoxy)-2-methylpiperidine hydrochloride

(79) ##STR00043##

(80) A solution of the tert-butyl 4-(4-chlorophenoxy)-2-methylpiperidine-1-carboxylate from step (ii) in 1,4-dioxane (10 mL) was treated with 4M hydrogen chloride in dioxane. The reaction mixture was stirred at room temperature for 16 hours. The product was filtered and dried under vacuum to give the title compound which was used without further purification.

(81) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.48 (d, 3H), 1.80-2.28 (m, 4H), 3.12-3.78 (m, 3H), 4.59-4.62 (m, 1H), 6.73-6.78 (m, 2H), 7.18-7.22 (m, 2H), 9.42 (br.s, 1H), 9.71 (br.s, 1H).

(82) MS: ES.sup.+226

Intermediate 20: 4-(4-Chlorophenoxy)-3-methylpiperidine hydrochloride

(83) ##STR00044##

(i) tert-Butyl 4-hydroxy-3-methylpiperidine-1-carboxylate

(84) ##STR00045##

(85) Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions to a solution of (R,S)-tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.68 mmol) in methanol (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour, then warmed to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and concentrated under reduced pressure in order to remove the methanol. This was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product as a colourless oil (quantitative yield).

(86) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.87-0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38 (s, 9H), 2.23-4.08 (m, 5H).

(87) MS: ES.sup.+216

(ii) tert-Butyl 4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate

(88) ##STR00046##

(89) Diethyl azodicarboxylate (0.46 mL, 2.90 mmol) was added to a solution of tert-butyl-4-hydroxy-3-methylpiperidine-1-carboxylate from step (i) (0.50 g, 2.32 mmol), 4-chlorophenol (0.25 g, 2.32 mmol) and triphenylphosphine (0.76 g, 2.90 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature overnight. LCMS analysis showed no reaction, so heated to 50° C. overnight then cooled to room temperature. Diethyl ether was added and washed with water, 0.4 M sodium hydroxide solution, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified via silica gel flash column chromatography using petroleum ether:ethyl acetate (97:3) as solvent system in order to afford the desired product as a colourless oil (138 mg, 18% yield).

(90) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.95 (d, 3H), 1.40 (s, 9H), 1.36-1.50 (m, 1H), 1.76-1.86 (m, 1H), 1.90-2.0 (m, 1H), 2.59-2.81 (m, 1H), 2.89-3.06 (m, 1H), 3.70-3.99 (m, 3H), 6.74-6.79 (m, 2H), 7.13-7.18 (m, 2H).

(91) MS: ES.sup.+326

(iii) 4-(4-Chlorophenoxy)-3-methylpiperidine hydrochloride

(92) ##STR00047##

(93) A solution of hydrochloric acid (4M in 1,4-dioxane) (0.53 mL, 2.11 mmol) was added to a solution of tert-butyl-4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate from step (ii) (138 mg, 0.42 mmol) in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature overnight. A further portion of hydrochloric acid (4M in 1,4-dioxane) (5 mL, 20.02 mmol) was added to the mixture and stirred for three hours. The reaction mixture was concentrated and was azeotroped with dichloromethane twice in order to give the desired product as a cream solid (quantitative yield).

(94) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.19 (d, 3H), 1.90-2.37 (m, 3H), 2.71-2.71 (m, 1H), 2.98-3.10 (m, 1H), 3.35-3.50 (m, 2H), 3.93-4.02 (m, 1H), 6.73-6.77 (m, 2H), 7.10-7.22 (m, 2H), 9.50 (br.s, 1H), 9.69 (br.s, 1H).

(95) MS: ES.sup.+: 226

Intermediate 21: Ethyl 4-(4-chlorobenzyl)piperidine-4-carboxylate hydrochloride

(96) ##STR00048##

(97) 1-tert-Butyl 4-ethyl 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (1 g, 2.62 mmol) was treated with 4 M HCl in dioxane (4 ml, 16.00 mmol) and stirred at room temperature for 18 hours. The reaction was evaporated to dryness to leave a white solid (0.708 g) that was used without purification.

(98) MS ES.sup.+: 282

Intermediate 22: tert-Butyl 4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate

(99) ##STR00049##

(100) Magnesium turnings (0.98 g, 0.04 mol) was added to anhydrous diethyl ether (25 mL) followed by addition of catalytic amount of iodine (0.05 g). The reaction was stirred at reflux under nitrogen atmosphere. A solution of 3,4-dichlorobenzyl chloride (4.0 g, 0.02 mol) in diethyl ether (10 mL) was added drop wise to the reaction mass at refluxed temperature and the resulting mixture was refluxed for 1.5 hrs. In a separate flask, N-Boc-4-piperidone (2.46 g, 0.012 mol) was dissolved in anhydrous diethyl ether (50 mL) and cooled to 0° C. under nitrogen. The prepared Grignard reagent was added to the solution at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-15% ethyl acetate/n-hexane to afford tert-Butyl 4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (3.0 g, 41% yield).

Intermediate 23: 4-(3,4-Dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate

(101) ##STR00050##

(102) Trifluoroacetic acid (15 mL) was added to a solution of tert-butyl 4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 22, 3.0 g, 8.3 mmol) in DCM (30 mL) at 0° C. The reaction was stirred at room temperature for 45 minutes then concentrated and azeotroped with DCM to afford 4-(3,4-Dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate (2.0 g, 65% yield).

Intermediate 24: tert-Butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate

(103) ##STR00051##

(104) A suspension of triphenylphosphine (2.347 g, 8.95 mmol) and 4-(bromomethyl)-1-chloro-2-fluorobenzene (2 g, 8.95 mmol) in ether (25 mL) was stirred at room temperature overnight. The suspension was concentrated to give (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide (quantitative) as a white solid that was used crude. Butyl lithium (1.6 M in hexanes) (6.03 mL, 9.65 mmol) was added slowly to a suspension of (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide (4.26 g, 8.77 mmol) in THF (40 mL) under inert atmosphere at 0° C. The resulting suspension was stirred at 0° C. for 15 minutes, then warmed to room temperature for 2 hours. tert-Butyl 4-oxopiperidine-1-carboxylate (1.922 g, 9.65 mmol) as a solution in THF (5 mL) was added and the suspension was stirred at room temperature overnight. Petroleum ether was added, the precipitate (O=PPh3) was filtered and the filtrate concentrated. The crude product was purified by silica chromatography eluted with 0-100% DCM/petroleum ether to give tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (2.03 g, 6.23 mmol, 71% yield) as a colourless oil that solidified on standing.

(105) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.42 (s, 9H) 2.28-2.30 (m, 2H) 2.39-2.40 (m, 2H) 3.27-3.34 (m, 2H) 3.36-3.47 (m, 2H) 6.35 (s, 1H) 7.06-7.13 (m, 1H) 7.25-7.28 (m, 1H) 7.51-7.55 (m, 1H)

Intermediate 25: 4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride

(106) ##STR00052##

(107) A flask charged with tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (2.03 g, 6.23 mmol, Intermediate 24) and platinum(IV)oxide (0.141 g, 0.623 mmol) was evacuated and flushed with argon three times. The flask was evacuated again and ethanol (20 mL) and ethyl acetate (20 mL) were added then the suspension stirred under an atmosphere of hydrogen for 2 hours. The suspension was filtered through diatomaceous earth and the filtrate concentrated to give tert-butyl 4-(4-chloro-3-fluorobenzyl)piperidine-1-carboxylate (2.01 g, 6.13 mmol, 98% yield) as a yellow oil that was used without further purification. Hydrogen chloride (4M in dioxane) (3.05 mL, 12.20 mmol) was added to a solution of tert-butyl 4-(4-chloro-3-fluorobenzyl)piperidine-1-carboxylate (2 g, 6.10 mmol) in Methanol (20 mL) and stirred overnight. The solution was concentrated and azeotroped with toluene to give 4-(4-chloro-3-fluorobenzyl)piperidine hydrochloride (1.56 g, 5.91 mmol, 97% yield) as a white solid.

(108) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.28-1.44 (m, 2H) 1.60-1.73 (m, 2H) 1.74-1.88 (m, 1H) 2.54-2.60 (m, 2H) 2.69-2.86 (m, 2H) 3.15-3.25 (m, 2H) 7.05-7.12 (m, 1H) 7.24-7.32 (m, 1H) 7.46-7.54 (m, 1H) 8.80 (br. s., 1H) 9.06 (br. s., 1H)

Intermediate 26: 4-(4-Chloro-2-methoxyphenoxy)piperidine hydrochloride

(109) ##STR00053##

(110) Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) from 4-chloro-2-methoxyphenol.

(111) MS: ES.sup.+242

Intermediate 27: tert-Butyl 4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

(112) ##STR00054##

(113) Prepared as described for tert-Butyl 4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 22) from 4-chloro-2-fluoro benzyl bromide.

(114) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.30-1.42 (m, 13H) 2.69 (s, 2H) 2.99 (br, s., 2H) 3.59-3.67 (m, 2H) 4.52 (s, 1H) 7.20-7.23 (m, 1H) 7.31-7.36 (m, 2H)

Intermediate 28: 4-(4-Chloro-2-fluorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate

(115) ##STR00055##

(116) Prepared as described for 4-(3,4-Dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 23) using tert-Butyl 4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 27).

(117) MS: ES.sup.+244

Intermediate 29: 5-Chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride

(118) ##STR00056##

(119) A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.5 g, 2.4 mmol) in DMF (5 mL) was added to a suspension of sodium hydride (0.065 g, 2.7 mmol) in DMF (3 mL) at room temperature and stirred for 30 minutes. 5-Chloro-2,3-difluoropyridine (0.4 g, 2.7 mmol) was added at 0° C. and then heated at 60° C. for 4 hours. The reaction was poured into cold water and extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-20% ethyl acetate in hexane to yield tert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy) piperidine-1-carboxylate (0.5 g, 60% yield). 12% HCl in dioxane (5 mL) was added to tert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy)piperidine-1-carboxylate (0.5 g, 1.5 mmol) in dioxane (2 mL) and stirred at room temperature for 2 hours. The reaction was concentrated. The crude compound was purified by trituration with diethyl ether (10×2 mL) to afford 5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride (0.3 g, 34% yield).

(120) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.88-1.97 (m, 2H) 2.13-2.19 (m, 2H) 3.09-3.14 (m, 2H) 3.21-3.24 (m, 2H) 5.27-5.31 (m, 1H) 8.06-8.09 (m, 2H) 8.91-8.92 (m, 2H)

Intermediate 30: 4-(4-Chloro-2-methoxybenzyl)piperidine hydrochloride

(121) ##STR00057##

(122) Prepared as described for 4-(4-chloro-3-fluorobenzyl)piperidine hydrochloride (Intermediate 25) using 4-chloro-1-(chloromethyl)-2-methoxybenzene.

(123) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.27-1.41 (m, 2H) 1.60-1.70 (m, 2H) 1.70-1.84 (m, 1H) 2.48 (br. s., 1H) 2.72-2.83 (m, 2H) 3.16-3.24 (m, 2H) 3.80 (s, 3H) 6.92-6.97 (m, 1H) 7.03-7.06 (m, 1H) 7.11-7.16 (m, 1H) 8.51 (br. s, 1H) 8.79 (br. s, 1H)

Intermediate 31: 4-(4-Chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride

(124) ##STR00058##

(125) A solution of tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 27, 5 g, 0.014 mol) in dry DCM (50 mL) was added dropwise at −70° C. to a stirred solution of diethylaminosulfurtrifluoride (2.81 g, 0.017 mol) in dry dichloromethane (50 mL) under nitrogen. After stirring at −50° C. for 45 min the reaction was warmed to room temperature. The reaction was poured into a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-5% ethyl acetate/n-hexane to yield tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1.7 g, 34% yield). HCl-dioxane (30 mL) was added dropwise to tert-butyl 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1.7 g, 0.005 mol) in dioxane (10 mL) at 0° C. The resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated. The crude compound was purified by triturating in diethyl ether (20 mL×3) to yield 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride (1.2 g, 87% yield).

(126) MS: ES.sup.+246

Intermediate 32: tert-Butyl 4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate

(127) ##STR00059##

(128) (4-chloro-2-methoxyphenyl) methanol (10 g, 0.058 mol) was dissolved in DCM (100 mL) and thionyl chloride (20.75 g, 0.174 mol) was added dropwise under nitrogen at room temperature. The reaction was refluxed for 30 minutes. The reaction was poured into ice water (100 mL) and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-10% ethyl acetate/n-hexane to yield 4-chloro-2-methoxy benzyl chloride (9.1 g, 82.42% yield). Magnesium turnings (1.26 g, 0.052 mol) were added to anhydrous diethyl ether (20 mL) followed by addition of catalytic iodine (0.005 g). The reaction was stirred at reflux under nitrogen. A solution of 4-chloro-2-methoxy benzyl chloride (5.0 g, 0.026 mol) in diethyl ether (15 mL) was added drop wise to the reaction at refluxed temperature and resulting mixture was refluxed for 1.5 hours. In another flask, tert-butyl 4-oxopiperidine-1-carboxylate (3.14 g, 0.015 mol) was dissolved in anhydrous diethyl ether (50 mL) and cooled to 0° C. under nitrogen. The prepared Grignard reagent was added to the solution at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-15% ethyl acetate/n-hexane to yield tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate (3.4 g, 37% yield).

(129) MS: ES.sup.+256 (M-100 (boc group))

Intermediate 33: 4-(4-Chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride

(130) ##STR00060##

(131) Sodium hydride (60% in paraffin; 0.56 g, 0.014 mol) was suspended in THF (50 mL) and tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 32, 2.5 g, 0.007 mol,) was added in THF (20 mL) slowly at room temperature. The reaction mixture was heated to 50° C. for 2 hours and then cooled to room temperature. Hexamethylphosphoramide (6.3 g, 0.035 mol) and methyl iodide (10 g, 0.07 mol) were added and the reaction was stirred at 50° C. overnight. The reaction was poured into saturated aqueous sodium bisulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude compound was purified by silica column chromatography eluted with 0-15% ethyl acetate/n-hexane to yield tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine-1-carboxylate (1.7 g, 66% yield). HCl-dioxane (30 mL) was added dropwise to tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine-1-carboxylate (1.7 g, 0.0046 mol) in dioxane (10 mL) at 0° C. and the resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated under vacuum. The crude compound was purified by triturating in diethyl ether (20 mL×3) to yield 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride (1.3 g, 93% yield).

(132) MS: ES.sup.+270

Intermediate 34: 4-(4-Chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride

(133) ##STR00061##

(134) HCl-dioxane (30 mL) was added dropwise to tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 32, 3.0 g, 0.008 mol) in dioxane (10 mL) at 0° C. and the resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated. The crude compound was purified by triturating in diethyl ether (20 mL×3) to yield 4-(4-chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride (2.1 g, 86% yield).

(135) MS: ES.sup.+256

Intermediate 35: 4-(4-Chloro-2-methoxybenzyl)-4-fluoropiperidine hydrochloride

(136) ##STR00062##

(137) Prepared as described for 4-(4-Chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride (Intermediate 31) using tert-butyl 4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 32).

(138) MS: ES.sup.+258

Intermediate 36: tert-Butyl 4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate

(139) ##STR00063##

(140) A solution of 2-(4-chloro-2-fluorophenyl)acetonitrile (0.353 g, 2.082 mmol) in DMF (5 mL) was cooled to 0-5° C., to this was added sodium hydride (0.050 g, 2.082 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (0.5 g, 1.893 mmol). The reaction was stirred at room temperature for 3 hours. The mixture was quenched with ice/water and partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with water, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-50% ethyl acetate/petroleum ether to afford tert-butyl 4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate (0.5 g, 75%).

Intermediate 37: 2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride

(141) ##STR00064##

(142) tert-Butyl 4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate (Intermediate 36, 0.5 g, 1.417 mmol) was dissolved in Dioxane (1 mL) and HCl 12% in dioxane (5.02 mL, 19.84 mmol) added. The reaction was stirred at room temperature for 4 hours then concentrated under reduced pressure and triturated with diethyl ether to give 2-(4-chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride (0.3 g, 85%).

Intermediate 38: tert-Butyl 4-((4-chlorophenyl)(cyano)methyl)piperidine-1-carboxylate

(143) ##STR00065##

(144) Prepared as described for tert-butyl 4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate (Intermediate 36) from 2-(4-chlorophenyl)acetonitrile.

(145) MS: ES− 333

Intermediate 39: 2-(4-Chlorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride

(146) ##STR00066##

(147) Prepared as described for 2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride (Intermediate 37) using tert-butyl 4-((4-chlorophenyl) (cyano)methyl)piperidine-1-carboxylate (Intermediate 38).

Intermediate 40: tert-Butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate

(148) ##STR00067##

(149) Di-tert-butyl dicarbonate (0.923 g, 4.23 mmol) was added to a solution of (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (1 g, 3.84 mmol) and triethylamine (1.179 mL, 8.46 mmol) in Methanol (20 mL) under nitrogen. The reaction was stirred at room temperature overnight. The suspension was concentrated in vacuo. The residue was taken up in ethyl acetate and water and the phases separated. The organic was washed with brine, dried (phase separator) and concentrated to give tert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (1.22 g, 3.77 mmol, 98% yield) as a white solid.

(150) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.33-1.46 (m, 11H) 1.72-1.81 (m, 2H) 2.83-3.00 (m, 2H) 3.62 (s, 1H) 3.92-4.02 (m, 2H) 7.58-7.65 (m, 2H) 7.98-8.04 (m, 2H)

Intermediate 41: tert-Butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

(151) ##STR00068##

(152) Sodium borohydride (0.140 g, 3.71 mmol) was added to a suspension of tert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (Intermediate 40, 1 g, 3.09 mmol) in Methanol (15 mL) under nitrogen at 0° C. The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with water and the methanol evaporated. The aqueous was extracted with ethyl acetate and the combined organics washed with brine, dried (phase separator) and concentrated to give tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.01 g, 3.10 mmol, 100% yield) as a colourless oil.

(153) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.00-1.12 (m, 2H) 1.20 (s, 1H) 1.37 (s, 9H) 1.51-1.64 (m, 1H) 1.66-1.74 (m, 1H) 2.53-2.69 (m, 2H) 3.83-4.00 (m, 2H) 4.27-4.33 (m, 1H) 5.29-5.33 (m, 1H) 7.28-7.33 (m, 2H) 7.34-7.39 (m, 2H)

Intermediate 42: (4-Chlorophenyl)(piperidin-4-yl)methanol hydrochloride

(154) ##STR00069##

(155) Hydrogen chloride (4M in dioxane, 0.614 mL, 2.455 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (Intermediate 41, 0.4 g, 1.228 mmol) in Methanol (10 mL). The reaction was stirred at room temperature overnight. The solution was concentrated and azeotroped with toluene to give (4-chlorophenyl)(piperidin-4-yl)methanol hydrochloride (0.305 g, 1.163 mmol, 95% yield) as a cream solid.

(156) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.33-1.47 (m, 3H) 1.67-1.84 (m, 2H) 2.74 (br. s., 2H) 3.15-3.27 (m, 2H) 4.33-4.38 (m, 1H) 5.49-5.53 (m, 1H) 7.30-7.35 (m, 2H) 7.37-7.43 (m, 2H) 8.48 (br. s., 1H) 8.93 (br. s., 1H)

Intermediate 43: 4-((4-Chlorophenyl)(methoxy)methyl)piperidine hydrochloride

(157) ##STR00070##

(158) Sodium hydride (60% in mineral oil, 0.221 g, 5.52 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (Intermediate 41, 0.6 g, 1.841 mmol) in THF (15 mL) under nitrogen at 0° C. The reaction was stirred at room temperature for 45 minutes. The suspension was cooled and methyl iodide (0.345 mL, 5.52 mmol) was added and then stirred at room temperature overnight. The reaction was quenched with methanol and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-20% ethyl acetate/petroleum ether to afford tert-butyl 4-((4-chlorophenyl)(methoxy)methyl)piperidine-1-carboxylate (0.545 g, 1.604 mmol, 87% yield) as a colourless oil. Hydrogen chloride (4M in dioxane) (0.802 mL, 3.21 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(methoxy)methyl)piperidine-1-carboxylate (0.545 g, 1.604 mmol) in methanol (10 mL). The reaction was stirred at room temperature overnight. The solution was concentrated in vacuo and azeotroped with toluene to give 4-((4-chlorophenyl)(methoxy)methyl)piperidine hydrochloride (0.480 g, 1.738 mmol, 108% yield) as a white solid.

(159) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.25-1.49 (m, 3H) 1.77-1.96 (m, 2H) 2.66-2.83 (m, 2H) 3.12 (s, 3H) 3.14-3.29 (m, 2H) 3.98-4.03 (m, 1H) 7.27-7.32 (m, 2H) 7.43-7.49 (m, 2H) 8.33-8.60 (m, 2H)

Intermediate 44: tert-Butyl 4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate

(160) ##STR00071##

(161) tert-Butyl 4-((4-chlorophenyl)(cyano)methyl)piperidine-1-carboxylate (Intermediate 38, 4 g, 11.95 mmol) was dissolved in toluene (15 mL) and cooled to −28° C., to this was added Diisobutylaluminium hydride (3.40 g, 23.89 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with ammonium chloride solution then acidified with 6N HCl to pH 2. Organic layer extracted and dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica, eluted with 0-50% ethyl acetate/petroleum ether to afford tert-butyl 4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate (2 g, 50% yield).

Intermediate 45: tert-Butyl 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate

(162) ##STR00072##

(163) tert-Butyl 4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate (Intermediate 44, 0.7 g, 2.072 mmol) was dissolved in MeOH (20 mL) and cooled to 0-5° C., to this was added sodium borohydride (0.157 g, 4.14 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and DCM added, followed by water. The aqueous layer was extracted with DCM. Organic layer dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica, eluted with 0-50% ethyl acetate/petroleum ether to afford tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (0.7 g, 35%).

Intermediate 46: 4-((4-Chlorophenyl)(ethoxy)methyl)piperidine hydrochloride

(164) ##STR00073##

(165) Sodium hydride (60% in mineral oil, 0.074 g, 1.841 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (Intermediate 41, 0.5 g, 1.535 mmol) in THF (15 mL) under nitrogen at 0° C. The reaction was stirred at room temperature for 1.5 hours. Iodoethane (0.370 mL, 4.60 mmol) was added and the suspension stirred at room temperature overnight. An additional portion of iodoethane (0.370 mL, 4.60 mmol) was added and stirred over the weekend. The reaction was quenched with methanol and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-20% ethyl acetate/petroleum ether to afford tert-butyl 4-((4-chlorophenyl)(ethoxy)methyl)piperidine-1-carboxylate (0.445 g, 1.257 mmol, 82% yield) as a colourless oil. Hydrogen chloride (4M in dioxane) (0.629 ml, 2.51 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(ethoxy)methyl)piperidine-1-carboxylate (0.445 g, 1.257 mmol) in Methanol (5 mL). The reaction was stirred at room temperature overnight. The solution was concentrated and azeotroped with toluene to give 4-((4-chlorophenyl)(ethoxy)methyl)piperidine hydrochloride (0.394 g, 1.358 mmol, 108% yield) as a colourless gum.

(166) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.04-1.13 (m, 3H) 1.30-1.47 (m, 3H) 1.73-1.97 (m, 2H) 2.30 (s, 1H) 2.65-2.83 (m, 2H) 3.12-3.28 (m, 3H) 4.04-4.14 (m, 1H) 7.26-7.35 (m, 2H) 7.40-7.49 (m, 2H) 8.74 (br. s., 2H)

Intermediate 47: 4-((4-Chlorophenyl)fluoromethyl)piperidine hydrochloride

(167) ##STR00074##

(168) Diethylaminosulfurtrifluoride (0.405 mL, 3.07 mmol) was added to a solution of tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (Intermediate 41, 0.5 g, 1.535 mmol) in DCM (15 mL) under nitrogen at −78° C. The reaction was stirred at −78° C. for 10 minutes, then at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium hydrogen carbonate. The aqueous was extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-20% ethyl acetate/petroleum ether to afford tert-butyl 4-((4-chlorophenyl)fluoromethyl)piperidine-1-carboxylate (0.425 g, 1.296 mmol, 84% yield) as a white solid.

(169) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.41-1.59 (m, 3H) 1.77-1.90 (m, 1H) 2.04-2.20 (m, 1H) 2.71-2.89 (m, 2H) 3.18-3.30 (m, 2H) 5.33-5.52 (m, 1H) 7.34-7.43 (m, 2H) 7.45-7.56 (m, 2H) 8.68 (br. s., 1H) 9.03 (br. s., 1H)

2. EXAMPLES

Example 1 4-(3,4-Dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(170) ##STR00075##

(171) 4-(3,4-Dichlorophenoxy)piperidine hydrochloride (143 mg, 0.508 mmol) (prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) using 3,4-dichlorophenol) and triethylamine (1424L, 1.16 mmol) in dichloromethane (10 mL) was treated with 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (106 mg, 0.508 mmol). The reaction was stirred for 2 hours at room temperature. The crude reaction was washed with 1N hydrochloric acid, filtered through a phase separation cartridge and concentrated in vacuo.

(172) The crude product was purified by silica column chromatography eluting with petrol/ethyl acetate to give the title compound. (160 mg, 76%)

(173) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.62-1.75 (m, 2H) 2.00-2.15 (m, 2H) 2.30 (s, 3H) 2.45 (s, 3H) 2.78-2.86 (m, 2H) 3.34-3.42 (m, 2H) 3.75 (s, 3H) 4.45-4.54 (m, 1H) 6.95-6.98 (m, 1H) 7.28 (s, 1H) 7.24 (m, 1H)

(174) MS ES.sup.+: 419.

Example 2 4-(3,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(175) ##STR00076##

(176) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(3,4-dichlorophenoxy)piperidine hydrochloride.

(177) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.75 (m, 2H) 1.98-2.05 (m, 2H) 2.30 (s, 3H) 2.40 (s, 3H) 2.75-2.89 (m, 2H) 3.30-3.40 (m, 2H) 4.48-4.54 (m, 1H) 6.98 (m, 1H) 7.28 (m 1H) 7.48 (m, 1H) 13.0 (s, 1H)

(178) MS ES.sup.+: 404.

Example 3 4-[4-(Trifluoromethoxy)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(179) ##STR00077##

(180) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-(trifluoromethoxy)phenoxy)piperidine hydrochloride (prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) using 4-(trifluoromethoxy)phenol).

(181) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.65-1.75 (m, 2H) 2.00-2.12 (m, 2H) 2.30 (s, 3H) 2.44 (s, 3H) 2.80-2.92 (m, 2H) 3.24-3.33 (m, 2H) 3.76 (s, 3H) 4.45-4.52 (m, 1H) 6.98 (m, 1H) 7.05 (d, J=7.7 Hz 2H) 7.28 (d, J=7.7 Hz 1H)

(182) MS ES.sup.+: 434.

Example 4 4-(4-Methylphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(183) ##STR00078##

(184) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(p-tolyloxy)piperidine hydrochloride.

(185) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.57-1.72 (m, 2H) 1.91-2.04 (m, 2H) 2.21 (s, 3H) 2.26 (s, 3H) 2.41 (s, 3H) 2.77-2.88 (m, 2H) 3.18-3.30 (m, 2H) 3.73 (s, 3H) 4.31-4.42 (m, 1H) 6.77-6.86 (m, 2H) 6.99-7.11 (m, 2H)

(186) MS ES.sup.+: 364.

Example 5 4-(4-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(187) ##STR00079##

(188) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorophenoxy)piperidine hydrochloride.

(189) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.73 (m, 2H) 1.94-2.05 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.77-2.86 (m, 2H) 3.23-3.31 (m, 2H) 3.73 (s, 3H) 4.39-4.47 (m, 1H) 6.92-6.99 (m, 2H) 7.26-7.32 (m, 2H)

(190) MS ES.sup.+: 384.

Example 6 4-(3-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(191) ##STR00080##

(192) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3-chlorophenoxy)piperidine hydrochloride.

(193) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.72 (m, 2H) 2.02-2.18 (m, 2H) 2.28 (s, 3H) 2.42 (s, 3H) 2.80-2.92 (m, 2H) 3.06-3.15 (m, 2H) 3.72 (s, 3H) 4.40-4.54 (m, 1H) 6.92 (d, 1H) 7.02 (d, 1H) 7.10 (s, 1H) 7.28 (m, 1H)

(194) MS ES.sup.+: 384.

Example 7 4-({1-[(1,3,5-Trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}oxy)benzonitrile

(195) ##STR00081##

(196) Prepared as described for 4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(piperidin-4-yloxy)benzonitrile hydrochloride.

(197) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.68-1.78 (m, 2H) 2.04-2.12 (m, 2H) 2.30 (s, 3H) 2.45 (s, 3H) 2.80-2.89 (m, 2H) 3.30-3.42 (m, 2H) 3.75 (s 3H) 4.58-4.60 (m, 1H) 7.12 (d, J=7.8 Hz 2H) 7.75 (d, J=7.8 Hz 2H)

(198) MS ES.sup.+: 375.

Example 8 4-(4-Chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(199) ##STR00082##

(200) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chlorophenoxy)piperidine hydrochloride (prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) using 4-chlorophenol).

(201) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.73 (m, 2H) 1.98-2.06 (m, 2H) 2.35 (s, 3H) 2.54 (s, 3H) 2.80-2.88 (m, 2H) 3.28-3.35 (m, 2H) 4.42-4.50 (m, 1H) 6.98 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

(202) MS ES.sup.+: 370.

Example 9 1-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxy)piperidine

(203) ##STR00083##

(204) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1-ethyl-3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(p-tolyloxy)piperidine hydrochloride.

(205) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.30 (t 3H) 1.60-1.71 (m, 2H) 1.95-2.05 (m, 2H) 2.21 (s, 3H) 2.30 (s, 3H) 2.45 (s, 3H) 2.80-2.88 (m, 2H) 3.25-3.30 (m, 2H) 4.05-4.10 (q, 1H) 4.36-4.40 (m, 2H) 6.80 (d, J=7.8 Hz 2H) 7.07 (d, J=7.8 Hz 2H)

(206) MS ES.sup.+: 378.

Example 10 1-{[1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-(4-methylphenoxy)piperidine

(207) ##STR00084##

(208) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole (Intermediate 6) and 4-(p-tolyloxy)piperidine hydrochloride.

(209) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.71 (m, 2H) 1.95-2.05 (m, 2H) 2.25 (s, 3H) 2.52 (s, 3H) 2.95-3.04 (m, 2H) 3.33-3.40 (m, 2H) 3.90 (s, 3H) 4.38-4.45 (m, 1H) 6.83 (d, J=7.8 Hz 2H) 7.07 (d, J=7.8 Hz 2H)

(210) MS ES.sup.+: 418.

Example 11 1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxy)piperidine

(211) ##STR00085##

(212) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(p-tolyloxy)piperidine hydrochloride.

(213) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.62-1.74 (m, 2H) 2.00-2.08 (m, 2H) 2.28 (s, 3H) 2.42 (s, 3H) 2.80-2.88 (m, 2H) 3.28-3.35 (m, 2H) 3.74 (s, 3H) 4.40-4.48 (m, 1H) 6.95 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

(214) MS ES.sup.+: 384.

Example 12 4-[4-(Trifluoromethyl)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(215) ##STR00086##

(216) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-trifluoromethyl)phenoxypiperidine hydrochloride (Intermediate 17).

(217) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.66-1.76 (m, 2H) 2.05-2.12 (m, 2H) 2.30 (s, 3H) 2.45 (s, 3H) 2.81-2.90 (m, 2H) 3.25-3.35 (m, 2H) 3.72 (s, 3H) 4.58-4.62 (m, 1H) 7.15 (d, J=7.8 Hz 2H) 7.64 (d, J=7.8 Hz 2H)

(218) MS ES.sup.+: 418.

Example 13 4-(2,4-Dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(219) ##STR00087##

(220) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(221) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.81 (m, 2H) 1.96-2.01 (m, 2H) 2.28 (s, 3H) 2.42 (s, 3H) 2.95-3.01 (m, 2H) 3.09-3.18 (m, 2H) 3.72 (s, 3H) 4.60-4.68 (m, 1H) 7.26 (d, 1H) 7.34 (m, 1H) 7.55 (s, 1H)

(222) MS ES.sup.+: 418.

Example 14 4-(4-Bromo-2-fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(223) ##STR00088##

(224) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-bromo-2-fluorophenoxy)piperidine hydrochloride.

(225) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.68-1.78 (m, 2H) 1.95-2.08 (m, 2H) 2.28 (s, 3H) 2.43 (s, 3H) 2.80-2.90 (m, 2H) 3.24-3.30 (m, 2H) 3.75 (s, 3H) 4.45-4.50 (m, 1H) 7.20 (m, 1H) 7.30 (m, 1H) 7.85 (m, 1H)

(226) MS ES.sup.+: 448.

Example 15 1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-chlorophenoxy)piperidine

(227) ##STR00089##

(228) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorophenoxy)piperidine hydrochloride.

(229) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.62-1.70 (m, 2H) 1.95-2.06 (m, 2H) 2.35 (s, 3H) 2.90-3.00 (m, 2H) 3.30-3.40 (m, 2H) 3.84 (s, 3H) 4.45-4.50 (m, 1H) 6.95 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

(230) MS ES.sup.+: 404.

Example 16 4-(4-Chlorophenoxy)-1-{[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine

(231) ##STR00090##

(232) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole (Intermediate 6) and 4-(4-chlorophenoxy)piperidine hydrochloride.

(233) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.75 (m, 2H) 1.97-2.06 (m, 2H) 2.50 (s, 3H) 2.95-3.04 (m, 2H) 3.30-3.40 (m, 2H) 3.90 (s, 3H) 4.45-4.50 (m, 1H) 6.95 (d, J=7.8 Hz 2H) 7.32 (d, J=7.8 Hz 2H)

(234) MS ES.sup.+: 438.

Example 17 4-(3-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(235) ##STR00091##

(236) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3-methoxyphenoxy)piperidine hydrochloride

(237) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.72 (m, 2H) 1.95-2.05 (m, 2H) 2.28 (s, 3H) 2.42 (s, 3H) 2.78-2.86 (m, 2H) 3.28-3.35 (m, 5H) 3.78 (s, 3H) 4.40-4.50 (m, 1H) 6.46-6.53 (m, 3H) 7.15 (t, 1H)

(238) MS ES.sup.+: 380.

Example 18 4-(4-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(239) ##STR00092##

(240) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-methoxyphenoxy)piperidine hydrochloride.

(241) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.60-1.70 (m, 2H) 1.95-2.00 (m, 2H) 2.28 (s, 3H) 2.43 (s, 3H) 2.80-2.90 (m, 2H) 3.22-3.28 (m, 2H) 3.70-3.80 (m, 6H) 4.28-4.32 (m, 1H) 6.85 (m, 4H)

(242) MS ES.sup.+: 380.

Example 19 4-Phenoxy-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(243) ##STR00093##

(244) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-phenoxypiperidine hydrochloride.

(245) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.59-1.74 (m, 2H) 1.96-2.07 (m, 2H) 2.27 (s, 3H) 2.42 (s, 3H) 2.76-2.89 (m, 2H) 3.22-3.30 (m, 2H) 3.73 (s, 3H) 4.39-4.50 (m, 1H) 6.85-6.97 (m, 3H) 7.21-7.31 (m, 2H)

(246) MS ES.sup.+: 350.

Example 20 4-(4-Fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(247) ##STR00094##

(248) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-fluorophenoxy)piperidine hydrochloride.

(249) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.59-1.72 (m, 2H) 1.94-2.04 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.76-2.88 (m, 2H) 3.22-3.29 (m, 2H) 3.73 (s, 3H) 4.32-4.43 (m, 1H) 6.90-6.98 (m, 2H) 7.03-7.14 (m, 2H)

(250) MS ES.sup.+: 368.

Example 21 4-(4-Chlorophenoxy)-3-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(251) ##STR00095##

(252) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorophenoxy)-3-methylpiperidine hydrochloride (Intermediate 20).

(253) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.07 (d, J=6.78, 3H) 1.68-1.77 (m, 1H) 2.03-2.15 (m, 2H) 2.39 (s, 3H) 2.47 (s, 3H) 2.55-2.59 (m, 1H) 2.80-2.86 (m, 1H) 3.42-3.49 (m, 2H), 3.77 (s, 3H) 3.81-3.86 (m, 1H) 6.78 (d, J=9.03, 2H) 7.21 (d, J=9.03, 2H)

(254) MS ES.sup.+: 398.

Example 22 4-(2,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(255) ##STR00096##

(256) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(257) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.84 (m, 2H) 1.90-2.02 (m, 2H) 2.32 (s, 6H) 2.96-3.04 (m, 2H) 3.08-3.18 (m, 2H) 4.59-4.66 (m, 1H) 7.25 (m, 1H) 7.33 (m, 1H) 7.55 (s, 1H) 9.45 (br.s, 1H)

(258) MS ES.sup.+: 404.

Example 23 4-(Naphthalen-2-yloxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(259) ##STR00097##

(260) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(naphthalen-2-yloxy)piperidine hydrochloride.

(261) .sup.1H NMR (400 MHz, Dichloromethane-d.sub.2) δ ppm 1.94-2.19 (m, 4H) 2.34-2.41 (s, 3H) 2.46-2.52 (s, 3H) 3.12-3.35 (m, 4H) 3.71-3.81 (s, 3H) 4.60 (m, 1H) 7.09-7.21 (m, 2H) 7.32-7.43 (m, 1H) 7.47 (t, J=7.07 Hz, 1H) 7.68-7.85 (m, 3H)

(262) MS ES.sup.+: 400.

Example 24 4-(4-Chlorophenoxy)-2-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(263) ##STR00098##

(264) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorophenoxy)-2-methylpiperidine hydrochloride (Intermediate 19).

(265) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.31 (d, J=7.12 3 H) 1.76-1.85 (m, 1H) 1.91-2.02 (m, 3H) 2.45 (s, 3H) 2.36 (m, 3H) 3.39-3.56 (m, 2H) 3.74 (s, 3H) 4.10-4.17 (m, 1H) 4.61-4.64 (m, 1H) 6.78 (d, J=9.00 2 H) 7.23 (d, J=9.00 2 H)

(266) MS ES.sup.+: 398.

Example 25 1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2,4-dichlorophenoxy)piperidine

(267) ##STR00099##

(268) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(269) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.84 (m, 2H) 1.95-2.05 (m, 2H) 2.38 (s, 3H) 3.06-3.15 (m, 2H) 3.18-3.24 (m, 2H) 3.84 (s, 3H) 4.64-4.70 (m, 1H) 7.26 (d, 1H) 7.36 (m, 1H) 7.58 (s, 1H)

(270) MS ES.sup.+: 440.

Example 26 4-(2,4-Dichlorophenoxy)-1-{[1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine

(271) ##STR00100##

(272) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole (Intermediate 6) and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(273) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.80 (m, 2H) 1.96-2.04 (m, 2H) 2.50 (s, 3H) 3.07-3.13 (m, 2H) 3.20-3.28 (m, 2H) 3.90 (s, 3H) 4.60-4.68 (m, 1H) 7.25 (d, J=7.8 Hz 1H) 7.46 (m, 1H) 7.58 (s, 1H)

(274) MS ES.sup.+: 472.

Example 27 4-(2,4-Dichlorophenoxy)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(275) ##STR00101##

(276) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 5) and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(277) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.84 (m, 2H) 1.94-2.02 (m, 2H) 2.30 (s, 3H) 2.95-3.12 (m, 4H) 3.80 (s, 3H) 4.64-4.70 (m, 1H) 7.26 (d, J=7.8 Hz 1H) 7.34 (m, 1H) 7.58 (s, 1H) 8.24 (s, 1H)

(278) MS ES.sup.+: 404.

Example 28 4-(2,4-Dichlorophenoxy)-1-[(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidine

(279) ##STR00102##

(280) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-diethyl-1-methyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 4) and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(281) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.08-1.20 (m, 6H) 1.70-1.80 (m, 2H) 1.90-2.00 (m, 2H) 2.70 (q, 2H) 2.86 (q, 2H) 2.96-3.02 (m, 2H) 3.10-3.18 (m, 2H) 3.80 (s, 3H) 4.60-4.70 (m, 1H) 7.28 (d, J=7.8 Hz 1H) 7.34 (m, 1H) 7.57 (s, 1H)

(282) MS ES.sup.+: 446.

Example 29 4-(2,4-Dichlorophenoxy)-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}piperidine

(283) ##STR00103##

(284) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(285) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.67-1.86 (m, 2H) 1.87-2.09 (m, 2H) 2.34 (s, 3H) 2.61 (s, 3H) 3.10 (m, 4H) 4.59-4.78 (m, 1H) 7.19-7.29 (m, 1H) 7.31-7.39 (m, 1H) 7.55 (m, 1H) 7.69-8.10 (m, 1H)

(286) MS ES.sup.+: 454.

Example 30 4-(4-Chloro-2-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(287) ##STR00104##

(288) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-fluorophenoxy)piperidine hydrochloride (Intermediate 11).

(289) .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 1.88-2.10 (m, 4H) 2.40 (s, 3H) 2.48 (s, 3H) 3.09-3.32 (m, 4H) 3.72-3.84 (m, 3H) 4.28-4.42 (m, 1H) 6.82-6.96 (m, 1H) 7.03 (dd, J=8.66, 1.63 Hz, 1H) 7.10 (dd, J=10.79, 2.51 Hz, 1H)

(290) MS ES.sup.+: 402.

Example 31 5-Chloro-2-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile

(291) ##STR00105##

(292) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 5-chloro-2-(piperidin-4-yloxy)benzonitrile hydrochloride (Intermediate 12).

(293) .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 2.02 (d, J=3.76 Hz, 4H) 2.38 (s, 3H) 2.48 (s, 3H) 2.95-3.18 (m, 2H) 3.30-3.49 (m, 2H) 3.76 (s, 3H) 4.62 (br. s., 1H) 6.90 (d, J=8.78 Hz, 1H) 7.36-7.61 (m, 2H)

(294) MS ES.sup.+: 409.

Example 32 1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine

(295) ##STR00106##

(296) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-(trifluoromethoxy)phenoxy)piperidine hydrochloride.

(297) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.72 (m, 2H) 1.98-2.08 (m, 2H) 2.28-2.40 (m, 6H) 2.80-2.88 (m, 2H) 3.24-3.33 (m, 2H) 4.44-4.52 (m, 1H) 7.05 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H) 13.01 (s, 1H)

(298) MS ES.sup.+: 420.

Example 33 1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(naphthalen-2-yloxy)piperidine

(299) ##STR00107##

(300) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(naphthalen-2-yloxy)piperidine hydrochloride.

(301) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.70-1.80 (m, 2H) 2.10-2.18 (m, 2H) 2.30 (m, 3H) 2.40 (s, 3H) 2.85-2.92 (m, 4H) 4.58-4.68 (m, 1H) 7.12 (m, 1H) 7.30-7.58 (m, 3H) 7.74-7.82 (m, 3H) 13.01 (s, 1H)

(302) MS ES.sup.+: 386

Example 34 5-Chloro-2-{[1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile

(303) ##STR00108##

(304) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 5-chloro-2-(piperidin-4-yloxy)benzonitrile hydrochloride (Intermediate 12).

(305) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.86 (m, 2H) 1.91-2.10 (m, 2H) 2.27 (s, 3H) 2.37 (s, 3H) 2.84-3.03 (m, 2H) 3.12-3.27 (m, 2H) 4.61-4.81 (m, 1H) 7.29-7.43 (m, 1H) 7.64-7.76 (m, 1H) 7.90 (s, 1H) 13.09 (br.s, 1H)

(306) MS ES.sup.+: 395

Example 35 4-(4-Chloro-2-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

(307) ##STR00109##

(308) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-fluorophenoxy)piperidine hydrochloride (Intermediate 11).

(309) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.80 (m, 2H) 1.93-2.10 (m, 2H) 2.28 (s, 3H) 2.37 (s, 3H) 2.77-2.92 (m, 2H) 3.16-3.27 (m, 2H) 4.40-4.56 (m, 1H) 7.15-7.32 (m, 2H) 7.43 (s, 1H) 13.11 (br. s., 1H)

(310) MS ES.sup.+: 388.

Example 36 4-(2,4-Dichlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine

(311) ##STR00110##

(312) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride (Intermediate 7) and 4-(2,4-dichlorophenoxy)piperidine hydrochloride.

(313) .sup.1H NMR (400 MHz, chloroform-d) δ ppm 2.00 (s, 4H) 2.28 (s, 3H) 3.20-3.35 (m, 2H) 3.37-3.50 (m, 2H) 4.08 (s, 3H) 4.49-4.59 (m, 1H) 6.80-6.90 (m, 1H) 7.14-7.21 (m, 1H) 7.36 (s, 2H)

(314) MS ES.sup.+: 404

Example 37 4-(4-Chlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine

(315) ##STR00111##

(316) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride (Intermediate 7) and 4-(4-chlorophenoxy)piperidine hydrochloride.

(317) .sup.1H NMR (400 MHz, chloroform-d) δ ppm 1.90-2.03 (m, 4H) 2.27 (s, 3H) 3.25-3.38 (m, 4H) 4.08 (s, 3H) 4.41-4.48 (m, 1H) 6.78-6.82 (m, 2H) 7.20-7.25 (m, 2H) 7.37 (s, 1H)

(318) MS ES.sup.+: 370.

Example 38 1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(2,6-dimethylphenoxy)piperidine

(319) ##STR00112##

(320) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(2,6-dimethylphenoxy)piperidine hydrochloride.

(321) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.61-1.77 (m, 2H) 1.88-2.02 (m, 2H) 2.17 (s, 6H) 2.23-2.39 (m, 6H) 2.54-2.66 (m, 2H) 3.41-3.53 (m, 2H) 3.81-3.93 (m, 1H) 6.83-6.94 (m, 1H) 6.96-7.04 (m, 2H)

(322) MS ES.sup.+: 364.

Example 39 4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(323) ##STR00113##

(324) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-(trifluoromethyl)phenoxy)piperidine hydrochloride (Intermediate 14).

(325) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.83 (m, 2H) 1.90-2.03 (m, 2H) 2.25 (s, 3H) 2.40 (s, 3H) 2.91-3.09 (m, 4H) 3.72 (s, 3H) 4.71-4.81 (m, 1H) 7.31-7.40 (m, 1H) 7.60-7.71 (m, 2H)

(326) MS ES.sup.+: 452.

Example 40 4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

(327) ##STR00114##

(328) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-(trifluoromethyl)phenoxy)piperidine hydrochloride (Intermediate 14).

(329) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.85 (m, 2H) 1.88-2.05 (m, 2H) 2.30 (s, 6H) 2.91-3.13 (m, 4H) 4.68-4.85 (m, 1H) 7.32-7.40 (m, 1H) 7.59-7.70 (m, 2H) 13.09 (br. s., 1H)

(330) MS ES.sup.+: 438.

Example 41 1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(3-fluoro-4-methoxyphenoxy)piperidine

(331) ##STR00115##

(332) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(3-fluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate 13).

(333) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.54-1.76 (m, 2H) 1.88-2.05 (m, 2H) 2.32 (s, 6H) 2.70-2.90 (m, 2H) 3.17-3.31 (m, 2H) 3.76 (s, 3H) 4.35 (tt, J=7.91, 3.71 Hz, 1H) 6.62-6.77 (m, 1H) 6.90 (dd, J=13.26, 2.91 Hz, 1H) 6.97-7.15 (m, 1H) 13.05 (br. s., 1H)

(334) MS ES.sup.+: 384.

Example 42 4-(3,5-Difluoro-4-methoxyphenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

(335) ##STR00116##

(336) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(3,5-difluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate 15).

(337) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.54-1.72 (m, 2H) 1.91-2.08 (m, 2H) 2.32 (br. s., 6H) 2.71-2.86 (m, 2H) 3.24-3.31 (m, 2H) 3.80 (s, 3H) 4.28-4.53 (m, 1H) 6.81 (d, J=10.74 Hz, 2H) 13.08 (br. s., 1H)

(338) MS ES.sup.+: 402.

Example 43 4-(3-Fluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(339) ##STR00117##

(340) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3-fluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate 13).

(341) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.55-1.73 (m, 2H) 1.88-2.04 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.73-2.88 (m, 2H) 3.14-3.30 (m, 2H) 3.75 (d, J=12.51 Hz, 6H) 4.34 (tt, J=7.99, 3.76 Hz, 1H) 6.65-6.76 (m, 1H) 6.90 (dd, J=13.26, 2.91 Hz, 1H) 7.04 (t, J=9.47 Hz, 1H)

(342) MS ES.sup.+: 398.

Example 44 4-(3,5-Difluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(343) ##STR00118##

(344) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3,5-difluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate 15).

(345) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.55-1.74 (m, 2H) 1.90-2.05 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.70-2.85 (m, 2H) 3.29 (d, J=6.06 Hz, 2H) 3.73 (s, 3H) 3.80 (s, 3H) 4.41 (tt, J=8.21, 3.85 Hz, 1H) 6.68-6.97 (m, 2H)

(346) MS ES.sup.+: 416.

Example 45 4-(4-Chloro-3-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(347) ##STR00119##

(348) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10).

(349) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.59-1.73 (m, 2H) 1.95-2.07 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.71-2.90 (m, 2H) 3.29 (br. s., 2H) 3.63-3.81 (m, 3H) 4.36-4.56 (m, 1H) 6.82 (ddd, J=8.97, 2.84, 1.07 Hz, 1H) 7.10 (dd, J=11.62, 2.78 Hz, 1H) 7.43 (t, J=8.91 Hz, 1H)

(350) MS ES.sup.+: 402.

Example 46 4-(4-Chloro-2,6-difluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

(351) ##STR00120##

(352) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2,6-difluorophenoxy)piperidine hydrochloride (Intermediate 16).

(353) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.66-1.82 (m, 2H) 1.88-2.03 (m, 2H) 2.25 (s, 3H) 2.40 (s, 3H) 2.89 (ddd, J=11.53, 7.99, 3.47 Hz, 2H) 3.09-3.25 (m, 2H) 3.72 (s, 3H) 4.23 (dt, J=7.26, 3.69 Hz, 1H) 7.31-7.53 (m, 2H)

(354) MS ES.sup.+: 420.

Example 47 4-(4-Chloro-3-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

(355) ##STR00121##

(356) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10).

(357) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.55-1.77 (m, 2H) 1.91-2.06 (m, 2H) 2.33 (br. s., 6H) 2.70-2.93 (m, 2H) 3.22-3.31 (m, 2H) 4.47 (tt, J=8.16, 3.84 Hz, 1H) 6.82 (ddd, J=8.97, 2.78, 1.01 Hz, 1H) 7.10 (dd, J=11.68, 2.84 Hz, 1H) 7.43 (t, J=8.91 Hz, 1H) 13.08 (br. s., 1H)

(358) MS ES.sup.+: 388

Example 48 5-Chloro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

(359) ##STR00122##

(360) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 5-chloro-2-(piperidin-4-yloxy)pyridine hydrochloride (Intermediate 18).

(361) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.80 (m, 2H) 1.99-2.12 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.75-2.92 (m, 2H) 3.19-3.29 (m, 2H) 3.72 (s, 3H) 4.92-5.05 (m, 1H) 6.80-6.87 (m, 1H) 7.73-7.86 (m, 1H) 8.14-8.20 (m, 1H)

(362) MS ES.sup.+: 385

Example 49 (4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone

(363) ##STR00123##

(364) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and (4-chlorophenyl)(piperidin-4-yl)methanone.

(365) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.50-1.65 (m, 2H) 1.76-1.80 (m, 2H) 2.28 (s, 3H) 2.43 (s, 3H) 2.48-2.54 (m, 2H) 3.45-3.52 (m, 1H) 3.58-3.62 (m, 2H) 3.78 (s, 3H) 7.60 (d, J=7.8 Hz 2H) 7.98 (d, J=7.8 Hz 2H)

(366) MS ES.sup.+: 396

Example 50 (3,4-Dichlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone

(367) ##STR00124##

(368) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and (3,4-dichlorophenyl)(piperidin-4-yl)methanone.

(369) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.5-1.62 (m, 2H) 1.85-1.92 (m, 2H) 2.28 (s, 3H) 2.45 (s, 3H) 2.45-2.58 (m, 2H) 3.48-3.55 (m, 1H) 3.60-3.65 (m, 2H) 3.74 (s, 3H) 7.8 (d, J=7.5 Hz 1H) 7.95 (d, J=7.5 Hz 1H) 8.20 (d, 1H)

(370) MS ES.sup.+: 430

Example 51 N-(4-Chlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

(371) ##STR00125##

(372) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and N-(4-chlorophenyl)piperidin-4-amine.

(373) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.46-1.58 (m, 2H) 1.92-2.00 (m, 2H) 2.30 (s, 3H) 2.40 (s, 3H) 2.45-2.55 (m, 2H) 3.28-3.35 (m, 1H) 3.52-3.60 (m, 2H) 3.72 (s, 3H) 6.30 (br, 1H) 7.90 (br, 2H) 7.25 (br, 2H)

(374) MS ES.sup.+: 383

Example 52 N-(3,4-Dichlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

(375) ##STR00126##

(376) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and N-(3,4-dichlorophenyl)piperidin-4-amine.

(377) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.46-1.58 (m, 2H) 1.92-2.00 (m, 2H) 2.30 (s, 3H) 2.40 (s, 3H) 2.45-2.55 (m, 2H) 3.28-3.35 (m, 1H) 3.52-3.60 (m, 2H) 3.72 (s, 3H) 6.30 (br, 1H) 7.90 (br, 1H) 7.25 (br, 1H)

(378) MS ES.sup.+: 417

Example 53 4-Chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline

(379) ##STR00127##

(380) A mixture of 4-chloroaniline (276 mg, 2.17 mmol), 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate 8, 590 mg, 2.17 mmol), acetic acid (303 mg, 5.05 mmol) and sodium triacetoxyborohydride (670 mg, 3.16 mmol) in 1,2-dichloroethane (21 mL) was stirred at room temperature overnight. Formaldehyde (37% in water, 350 mg, 4.33 mmol) and sodium triacetoxyborohydride (918 mg, 4.33 mmol) were added to the reaction mixture and this was then stirred overnight at room temperature. Dichloromethane (50 mL) was added. The reaction mixture was washed with water (3×25 mL) and the organic layer separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography to afford the desired product, 4-chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline (132 mg, 15%).

(381) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.76-1.94 (m, 4H) 2.39 (s, 3H) 2.42-2.49 (m, 2H) 2.47 (s, 3H) 2.74 (s, 3H) 3.45-3.53 (m, 2H) 3.77 (s, 3H) 3.86-3.89 (m, 1H) 6.66 (d, J=9.13 2 H) 7.15 (d, J=9.13 2 H)

(382) MS ES.sup.+: 397

Example 54 3,4-Dichloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline

(383) ##STR00128##

(384) Prepared as described for 4-chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline (Example 53) from 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate 8) and 3,4-dichloroaniline.

(385) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.76-1.93 (m, 4H) 2.39 (s, 3H) 2.44-2.50 (m, 2H) 2.48 (s, 3H) 2.74 (s, 3H) 3.45-3.51 (m, 2H) 3.77 (s, 3H) 3.86-3.91 (m, 1H) 6.56 (dd, J=3.00, 9.06 1 H) 6.77 (d, J=3.00, 1H) 7.21 (d, J=8.99, 1H)

(386) MS ES.sup.+: 431

Example 55 4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(387) ##STR00129##

(388) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorobenzyl)piperidine hydrochloride.

(389) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.24 (m, 2H) 1.43-1.55 (m, 1H) 1.56-1.66 (m, 2H) 2.20-2.26 (m, 5H) 2.37 (s, 3H) 2.48 (m, 2H) 3.49-3.59 (m, 2H) 3.70 (s, 3H) 7.14-7.20 (m, 2H) 7.28-7.35 (m, 2H)

(390) MS ES.sup.+: 382

Example 56 4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(391) ##STR00130##

(392) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3,4-dichlorobenzyl)piperidine hydrochloride.

(393) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.26 (m, 2H) 1.47-1.56 (m, 1H) 1.57-1.65 (m, 2H) 2.15-2.26 (m, 5H) 2.37 (s, 3H) 3.49-3.59 (m, 4H) 3.70 (s, 3H) 7.13-7.18 (m, 1H) 7.43-7.47 (m, 1H) 7.49-7.54 (m, 1H)

(394) MS ES.sup.+: 416

Example 57 4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(395) ##STR00131##

(396) To a flask charged with magnesium turnings (0.087 g, 3.6 mmol, 3.0 eq) was added anhydrous diethyl ether (15 mL) followed by addition of catalytic amount of iodine (0.005 g). The reaction was heated at reflux and then 4-chloro benzyl chloride (0.588 g, 3.6 mmol, 3.0 eq) was added dropwise. The resulting mixture was refluxed for 1 hour to produce Grignard reagent. 1-(1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (0.33 g, 1.2 mmol, 1.0 eq, Intermediate 8) was dissolved in THF (10 mL) and cooled to 0° C. The Grignard reagent was added to above solution at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using 60-120 mesh size neutral silica. The compound was eluted in 0-2% methanol in dichloromethane to yield 4-(4-chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyl)piperidin-4-ol. (0.18 g, 37.26% yield).

(397) .sup.1H NMR (400 MHz, Chloroform-d) δ ppm 1.51-1.69 (m, 2H) 1.80 (td, J=13.20, 4.43 Hz, 2H) 2.38 (s, 3H) 2.46 (s, 3H) 2.60-2.86 (m, 4H) 3.57 (d, J=11.60 Hz, 2H) 3.76 (s, 3H) 7.13 (d, J=7.32 Hz, 2H) 7.23-7.46 (m, 2H)

(398) MS ES.sup.+: 398

Example 58 4-(4-Chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(399) ##STR00132##

(400) Sodium hydride (60% in paraffin; 0.033 g, 0.85 mmol, 2.0 eq) was suspended in THF (5 mL) and 4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol (Example 57, 0.17 g, 0.42 mmol, 1.0 eq) was added in THF (10 mL) slowly at room temperature. The reaction mixture was heated to 50° C. for 2 hours and then cooled to room temperature. Hexamethylphosphoramide (0.383 g, 2.14 mmol, 5.0 eq) and methyl iodide (0.6 g, 4.28 mmol, 10.0 eq) were added and the reaction was stirred at 50° C. overnight. The reaction was poured into saturated aqueous sodium bisulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using 60-120 mesh size neutral silica. The compound was eluted in 0-2% methanol in dichloromethane to yield 4-(4-chlorobenzyl)-4-methoxy-1-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyl)piperidine (0.15 g, 85.71% yield).

(401) .sup.1H NMR (400 MHz, chloroform-d) δ ppm 1.62-1.69 (m, 2H) 1.70-1.85 (m, 2H) 2.39 (s, 3H) 2.44 (s, 3H) 2.55-2.69 (m, 2H) 2.74 (s, 2H) 3.27 (s, 3H) 3.43-3.60 (m, 2H) 3.77 (s, 3H) 7.02-7.14 (m, 2H) 7.23-7.28 (m, 2H)

(402) MS ES.sup.+: 412

Example 59 4-(2,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(403) ##STR00133##

(404) Prepared as described for 4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol (Example 57) from 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate 8) and 2,4-dichloro-1-(chloromethyl)benzene.

(405) .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) δ ppm 1.49-1.57 (m, 2H) 1.74 (s, 2H) 2.30 (s, 3H) 2.41 (s, 3H) 2.50-2.56 (m, 1H) 2.56-2.71 (m, 2H) 2.91 (s, 2H) 3.36-3.53 (m, 2H) 3.71 (s, 3H) 7.22-7.40 (m, 2H) 7.49 (s, 1H)

(406) MS ES.sup.+: 432

Example 60 4-(4-Chlorobenzyl)-4-(methoxymethyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(407) ##STR00134##

(408) Prepared as described for 4-(4-chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 58) from (4-(4-chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl) sulfonyl)piperidin-4-yl)methanol.

(409) .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) δ ppm 1.44-1.62 (m, 4H) 2.31 (s, 3H) 2.42 (s, 3H) 2.55-2.71 (m, 2H) 2.84-3.02 (m, 4H) 3.07-3.20 (m, 2H) 3.27 (s, 3H) 3.72 (s, 3H) 7.12 (s, 2H) 7.23-7.36 (m, 2H)

(410) MS ES.sup.+: 426

Example 61 Ethyl 4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

(411) ##STR00135##

(412) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and ethyl 4-(4-chlorobenzyl)piperidine-4-carboxylate hydrochloride (Intermediate 21).

(413) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.00 (t J=7 Hz 3H) 1.53-1.62 (m, 2H) 1.97-2.06 (m, 2H) 2.21 (s, 3H) 2.25-2.35 (m 2H) 2.38 (s 3H) 2.78 (s 2H) 3.33 (s 3H) 3.45-3.50 (m, 2H) 3.95-4.0.6 (ABq, J=8 Hz 2H) 7.08 (d, J=7.8 Hz 2H) 7.34 (d, J=7.8 Hz 2H)

(414) MS ES.sup.+: 454

Example 62 Ethyl 4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

(415) ##STR00136##

(416) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and ethyl 4-(4-bromobenzyl)piperidine-4-carboxylate hydrochloride (prepared as described for ethyl 4-(4-chlorobenzyl)piperidine-4-carboxylate hydrochloride (Intermediate 21) using 1-tert-butyl 4-ethyl 4-(4-bromobenzyl)piperidine-1,4-dicarboxylate).

(417) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.91-1.09 (m, 3H) 1.46-1.68 (m, 2H) 1.96-2.04 (m, 2H) 2.12-2.42 (m, 8H) 2.77 (s, 2H) 3.38-3.57 (m, 2H) 3.86-4.14 (m, 2H) 6.83-7.16 (m, 2H) 7.34-7.59 (m, 2H) 13.02 (br. s., 1H)

(418) MS ES.sup.+: 485

Example 63 Ethyl 4-(4-bromobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

(419) ##STR00137##

(420) Prepared as described for ethyl 4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate (Example 62) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride.

(421) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.05 (t, 3H) 1.55-1.63 (m, 2H) 1.99-2.05 (m, 2H) 2.22 (s, 3H) 2.28-2.34 (m, 2H) 2.38 (s, 3H) 2.76 (s, 2H) 3.46-3.52 (m, 2H) 3.72 (s, 3H) 4.00 (ABq, 2H) 6.95 (d, J=7.8 Hz 2H) 7.54 (d, J=7.8 Hz 2H)

(422) MS ES.sup.+: 499

Example 64 4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

(423) ##STR00138##

(424) A solution of 1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile (Intermediate 9) (100 mg, 0.373 mmol) at 0° C. in THF (5 ml) was treated with lithium bis(trimethylsilyl)amide (1M in THF) (0.783 ml, 0.783 mmol). The reaction mixture was stirred at 0° C. for 1 hour. 1-chloro-4-(chloromethyl)benzene (60 mg, 0.373 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was treated with 10% aqueous citric acid and DCM. The layers were separated. The aqueous phase was extracted with dichloromethane and the organic layers combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by preparative LCMS (basic conditions) to give the title compound, 4-(4-chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile (56 mg, 34%).

(425) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.73 (td, J=12.95, 3.79 Hz, 2H) 1.80-1.95 (m, 2H) 2.26 (s, 3H) 2.29-2.42 (m, 5H) 2.93 (s, 2H) 3.65 (d, J=12.13 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H) 7.42 (d, J=8.46 Hz, 2H) 13.09 (s, 1H)

(426) MS ES.sup.+: 393

Example 65 4-(2,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

(427) ##STR00139##

(428) Prepared as described for 4-(4-chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile (Example 64) from 1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile (Intermediate 9) and 2,4-dichloro-1-(chloromethyl)benzene.

(429) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.72-1.87 (m, 2H) 1.89-2.04 (m, 2H) 2.26 (s, 3H) 2.30-2.46 (m, 5H) 3.11 (s, 2H) 3.67 (d, J=12.38 Hz, 2H) 7.41-7.54 (m, 2H) 7.66 (d, J=1.77 Hz, 1H) 13.10 (s, 1H)

(430) MS ES.sup.+: 428

Example 66 4-(4-Chlorobenzyl)-1-((3,5-diethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(431) ##STR00140##

(432) A solution of 3,5-heptanedione (12.5 g, 97.5 mmol) in ethanol (50 mL) was treated dropwise with hydrazine hydrate (60%, 5.72 g, 107 mmol) whilst cooling in an ice bath. The reaction was stirred for 1.5 hours at room temperature. The reaction was concentrated under reduced pressure. The reaction mixture was partitioned between DCM and brine, the aqueous layer was extracted with DCM. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to afford 3,5-diethyl-1H-pyrazole that was used crude. 3,5-diethyl-1H-pyrazole (6.0 g, 0.048 mol) was added dropwise to chlorosulfonic acid (30.9 g, 17.7 mL, 0.265 mol) at 0° C. with stirring. The reaction was heated to 80° C. for 30 minutes. The reaction was cooled and thionyl chloride (6.32 g, 3.8 mL, 53.1 mol) was added dropwise. The reaction was heated to 65° C. for 4 hours. The reaction mixture was cooled to room temperature and carefully poured onto ice (100 g) with stirring. The resultant solid was filtered and dried under vacuum to afford 3,5-diethyl-1H-pyrazole-4-sulfonyl chloride as a brown solid (9.15 g, 85% yield). The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-diethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorobenzyl)piperidine hydrochloride.

(433) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.07-1.25 (m, 8H) 1.45-1.75 (m, 3H) 2.20-2.28 (m, 2H) 2.45-2.55 (m, 2H) 2.68-2.80 (m, 4H) 3.52-3.61 (m, 2H) 4.10 (br s, 1H) 7.15-7.25 (m, 2H) 7.28-7.32 (m, 2H)

(434) MS: ES.sup.+396

Example 67 4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(435) ##STR00141##

(436) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chlorobenzyl)piperidine hydrochloride.

(437) .sup.1H NMR (400 MHz, DMSO d.sub.6) δ ppm 1.34-1.59 (m, 4H) 1.88 (m, 1H) 2.54-2.61 (m, 2H) 2.77 (s, 6H) 2.91-3.01 (4H, m) 720-7.25 (m, 2H) 7.44-7.48 (m, 2H) 11.28 (br s, 1H)

(438) MS: ES.sup.+368

Example 68 1-((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(4chlorobenzyl)piperidine

(439) ##STR00142##

(440) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chlorobenzyl)piperidine hydrochloride.

(441) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.32-1.46 (m, 2H) 1.48-1.59 (m, 2H) 1.88 (m, 1H) 2.52-2.60 (m, 2H) 2.78 (s, 3H) 2.91-3.11 (4H, m) 3.95 (s, 3H) 7.21-7.27 (m, 2H) 7.42-7.46 (m, 2H)

(442) MS: ES.sup.+402

Example 69 4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(443) ##STR00143##

(444) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(3,4-dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 23).

(445) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.35-1.45 (m, 2H) 1.55-1.53 (m, 2H) 2.20 (s, 3H) 2.45 (s, 3H) 3.30-3.40 (4H, m) 3.70 (s, 3H) 7.20-7.22 (m, 1H) 7.45 (1H, s) 7.55-7.60 (m, 2H)

(446) MS: ES.sup.+432

Example 70 4-(3,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(447) ##STR00144##

(448) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(3,4-dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 23).

(449) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.34-1.44 (m, 2H) 1.53-1.56 (m, 2H) 2.27 (s, 3H) 2.45 (s, 3H) 3.30-3.40 (4H, m) 7.20-7.22 (m, 1H) 7.45 (1H, s) 7.55-7.60 (m, 2H) 11.05 (br s, 1H)

(450) MS: ES.sup.+418

Example 71 4-(4-Chloro-3-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(451) ##STR00145##

(452) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride (Intermediate 25).

(453) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.07-1.28 (m, 2H) 1.44-1.71 (m, 3H) 2.10-2.41 (m, 7H) 3.27-3.37 (m, 3H) 3.45-3.60 (m, 2H) 6.98-7.08 (m, 1H) 7.17-7.25 (m, 1H) 7.40-7.53 (m, 1H) 13.00 (br. s., 1H)

(454) MS: ES.sup.+386

Example 72 4-(4-Chloro-3-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(455) ##STR00146##

(456) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride (Intermediate 25).

(457) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12-1.25 (m, 2H) 1.47-1.66 (m, 3H) 2.16-2.26 (m, 5H) 2.37 (s, 3H) 3.28-3.31 (m, 2H) 3.49-3.58 (m, 2H) 3.68-3.72 (m, 3H) 6.99-7.06 (m, 1H) 7.20-7.26 (m, 1H) 7.43-7.50 (m, 1H)

(458) MS: ES.sup.+400

Example 73 4-(4-Chloro-2-methoxyphenoxy)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(459) ##STR00147##

(460) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-methoxyphenoxy)piperidine hydrochloride (Intermediate 26).

(461) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.62-1.74 (m, 2H) 1.87-1.99 (m, 2H) 2.22-2.41 (m, 6H) 2.83-2.94 (m, 2H) 3.15-3.25 (m, 2H) 3.71 (s, 3H) 4.30-4.39 (m, 1H) 6.85-6.90 (m, 1H) 6.98-7.04 (m, 2H) 13.08 (br. s., 1H)

(462) MS: ES.sup.+400

Example 74 4-(4-Chloro-2-methoxyphenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(463) ##STR00148##

(464) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-methoxyphenoxy)piperidine hydrochloride (Intermediate 26).

(465) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.63-1.75 (m, 2H) 1.89-2.00 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.81-2.90 (m, 2H) 3.15-3.25 (m, 2H) 3.71 (s, 3H) 3.74 (s, 3H) 4.30-4.38 (m, 1H) 6.85-6.92 (m, 1H) 6.99-7.04 (m, 2H)

(466) MS: ES.sup.+414

Example 75 4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(467) ##STR00149##

(468) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-Chloro-2-fluorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 28).

(469) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.34-1.44 (m, 2H) 1.53-1.56 (m, 2H) 2.27 (s, 2H) 2.75 (s, 6H) 3.30-3.40 (4H, m) 7.20-7.22 (m, 1H) 7.45 (1H, s) 7.55-7.60 (m, 2H) 11.05 (br s, 1H)

(470) MS: ES.sup.+402

Example 76 1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(2-fluorophenoxy)piperidine

(471) ##STR00150##

(472) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(2-fluorophenoxy)piperidine hydrochloride.

(473) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.77 (m, 2H) 1.95-2.06 (m, 2H) 2.28 (br. s., 3H) 2.37 (br. s., 3H) 2.81-2.91 (m, 2H) 3.21-3.29 (m, 2H) 4.42-4.50 (m, 1H) 6.91-6.98 (m, 1H) 7.06-7.12 (m, 1H) 7.15-7.24 (m, 2H) 13.07 (br. s., 1H)

(474) MS: ES.sup.+354

Example 77 5-Chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

(475) ##STR00151##

(476) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride (Intermediate 29).

(477) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.73-1.84 (m, 2H) 2.02-2.12 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.82-2.91 (m, 2H) 3.21-3.29 (m, 2H) 3.73 (s, 3H) 5.04-5.12 (m, 1H) 8.00-8.06 (m, 2H)

(478) MS: ES.sup.+403

Example 78 4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(479) ##STR00152##

(480) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)piperidine hydrochloride (Intermediate 30).

(481) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.26 (m, 2H) 1.43-1.54 (m, 1H) 1.54-1.64 (m, 2H) 2.16-2.28 (m, 5H) 2.33 (br. s., 3H) 2.41-2.47 (m, 2H) 3.49-3.56 (m, 2H) 3.77 (s, 3H) 6.86-6.93 (m, 1H) 6.97-7.01 (m, 1H) 7.05-7.11 (m, 1H) 13.00 (s, 1H)

(482) MS: ES.sup.+398

Example 79 4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(483) ##STR00153##

(484) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-methoxybenzyl)piperidine hydrochloride (Intermediate 30).

(485) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.25 (m, 2H) 1.42-1.53 (m, 1H) 1.54-1.63 (m, 2H) 2.14-2.25 (m, 5H) 2.37 (s, 3H) 2.42-2.47 (m, 2H) 3.47-3.56 (m, 2H) 3.69 (s, 3H) 3.77 (s, 3H) 6.86-6.94 (m, 1H) 6.98-7.02 (m, 1H) 7.06-7.11 (m, 1H)

(486) MS: ES.sup.+412

Example 80 4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine

(487) ##STR00154##

(488) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride (Intermediate 31).

(489) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.69-1.89 (m, 4H) 2.18-2.38 (m, 6H) 2.39-2.47 (m, 2H) 2.89-3.02 (m, 2H) 3.41-3.51 (m, 2H) 7.21-7.28 (m, 1H) 7.29-7.35 (m, 1H) 7.36-7.43 (m, 1H) 13.06 (br. s., 1H)

(490) MS: ES.sup.+404

Example 81 4-(4-Chloro-2-fluorobenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(491) ##STR00155##

(492) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride (Intermediate 31).

(493) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.70-1.88 (m, 4H) 2.23 (s, 3H) 2.38 (s, 3H) 2.39-2.47 (m, 2H) 2.91-3.01 (m, 2H) 3.41-3.50 (m, 2H) 3.70 (s, 3H) 7.22-7.28 (m, 1H) 7.28-7.35 (m, 1H) 7.37-7.43 (m, 1H)

(494) MS: ES.sup.+418

Example 82 4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(495) ##STR00156##

(496) tert-Butyl 4-(4-chloro-2-fluorobenzylidene)piperidine-1-carboxylate was prepared as described for tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (Intermediate 24) using 4-(bromomethyl)-1-chloro-3-fluorobenzene. Triethylsilane (2.157 mL 13.50 mmol) was added dropwise to a suspension of palladium on carbon (10% wt, 287 mg, 0.270 mmol) and tert-butyl 4-(4-chloro-2-fluorobenzylidene)piperidine-1-carboxylate (880 mg, 2.70 mmol) in methanol (50 mL) under nitrogen at 0° C. The reaction was stirred at room temperature for 15 minutes. The suspension was filtered through diatomaceous earth and the filtrate concentrated in vacuo to afford tert-butyl 4-(4-chloro-2-fluorobenzyl)piperidine-1-carboxylate as a colourless oil (quantitative). This was then taken up in methanol (25 mL) and HCl (4 M solution in dioxane, 1.35 mL) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and azeotroped with toluene to give 4-(4-chloro-2-fluorobenzyl)piperidine hydrochloride (0.715 g, 2.71 mmol, 100% yield) as a white solid.

(497) The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-fluorobenzyl)piperidine hydrochloride (described above).

(498) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.13-1.29 (m, 2H) 1.44-1.57 (m, 1H) 1.57-1.67 (m, 2H) 2.18-2.33 (m, 10H) 3.48-3.59 (m, 2H) 7.18-7.24 (m, 1H) 7.25-7.32 (m, 1H) 7.32-7.37 (m, 1H) 13.01 (br. s, 1H)

(499) MS: ES.sup.+386

Example 83 4-(4-Chloro-2-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(500) ##STR00157##

(501) Prepared as described for 4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 82) from 1,3,5-trimethyl-H-pyrazole-4-sulfonyl chloride.

(502) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.14-1.28 (m, 2H) 1.43-1.55 (m, 1H) 1.57-1.66 (m, 2H) 2.17-2.27 (m, 5H) 2.37 (s, 3H) 2.53-2.56 (m, 2H) 3.50-3.58 (m, 2H) 3.69 (s, 3H) 7.18-7.23 (m, 1H) 7.25-7.32 (m, 1H) 7.32-7.38 (m, 1H)

(503) MS: ES.sup.+400

Example 84 5-Chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

(504) ##STR00158##

(505) Sodium methoxide (0.053 g, 0.99 mmol) was added to a solution of 5-chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine (Example 77, 0.2 g, 0.49 mmol) in methanol (1 mL) under nitrogen, then heated to reflux for 5 hours. The reaction was concentrated and diluted with DCM and water. The phases were separated and the organic was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-70% ethyl acetate/hexane to afford 5-chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine (0.11 g, 55% yield).

(506) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.66-1.77 (m, 2H) 2.00-2.10 (m, 2H) 2.26 (s, 3H) 2.41 (s, 3H) 2.75-2.83 (m, 2H) 3.26-3.33 (m, 2H) 3.73 (s, 3H) 3.79 (s, 3H) 4.95-5.03 (m, 1H) 7.40-7.45 (m, 1H) 7.67-7.70 (m, 1H)

(507) MS: ES.sup.+415

Example 85 5-Chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-methoxypyridine

(508) ##STR00159##

(509) Prepared as described for 5-chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine (Example 84) from 5-chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-fluoropyridine (prepared as described for 5-chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl) sulfonyl)piperidin-4-yl)oxy)pyridine (Example 77) using 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3)).

(510) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.66-1.78 (m, 2H) 2.03 (br. s., 2H) 2.27 (br. s., 3H) 2.37 (br. s., 3H) 2.79-2.89 (m, 2H) 3.23-3.31 (m, 2H) 3.78 (s, 3H) 4.97-5.05 (m, 1H) 7.41-7.44 (m, 1H) 7.67-7.70 (m, 1H) 13.09 (br. s., 1H)

(511) MS: ES.sup.+401

Example 86 4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-methoxypiperidine

(512) ##STR00160##

(513) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride (Intermediate 33).

(514) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.38-1.48 (m, 2H) 1.67-1.75 (m, 2H) 2.29 (s, 6H) 2.39-2.48 (m, 2H) 2.72 (s, 2H) 3.14 (s, 3H) 3.26-3.31 (m, 2H) 3.78 (s, 3H) 6.91-6.95 (m, 1H) 7.01-7.03 (m, 1H) 7.07-7.12 (m, 1H) 13.01 (br. s, 1H)

(515) MS: ES.sup.+428

Example 87 4-(4-Chloro-2-methoxybenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(516) ##STR00161##

(517) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride (Intermediate 33).

(518) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.37-1.48 (m, 2H) 1.67-1.75 (m, 2H) 2.22 (s, 3H) 2.37 (s, 3H) 2.39-2.48 (m, 2H) 2.72 (s, 2H) 3.14 (s, 3H) 3.29 (br. s., 2H) 3.71 (s, 3H) 3.78 (s, 3H) 6.90-6.96 (m, 1H) 7.00-7.05 (m, 1H) 7.07-7.12 (m, 1H)

(519) MS: ES.sup.+442

Example 88 4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(520) ##STR00162##

(521) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride (Intermediate 34).

(522) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40-1.53 (m, 4H) 2.22 (s, 3H) 2.37 (s, 3H) 2.53-2.61 (m, 2H) 2.65 (s, 2H) 3.23-3.30 (m, 2H) 3.71 (s, 3H) 3.77 (s, 3H) 4.29 (s, 1H) 6.89-6.94 (m, 1H) 6.99-7.02 (m, 1H) 7.13-7.18 (m, 1H)

(523) MS: ES.sup.+428

Example 89 4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(524) ##STR00163##

(525) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride (Intermediate 34).

(526) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.38-1.53 (m, 4H) 2.29 (s, 6H) 2.53-2.62 (m, 2H) 2.65 (s, 2H) 3.21-3.30 (m, 2H) 3.77 (s, 3H) 4.29 (s, 1H) 6.89-6.94 (m, 1H) 6.98-7.03 (m, 1H) 7.14-7.19 (m, 1H) 13.02 (br. s, 1H)

(527) MS: ES.sup.+414

Example 90 4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine

(528) ##STR00164##

(529) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)-4-fluoropiperidine hydrochloride (Intermediate 35).

(530) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.61-1.71 (m, 1H) 1.71-1.80 (m, 3H) 2.30 (s, 6H) 2.53-2.58 (m, 2H) 2.86-2.95 (m, 2H) 3.37-3.46 (m, 2H) 3.80 (s, 3H) 6.92-6.97 (m, 1H) 7.03-7.07 (m, 1H) 7.11-7.16 (m, 1H) 12.92-13.02 (m, 1H)

(531) MS: ES.sup.+416

Example 91 4-(4-Chloro-2-methoxybenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(532) ##STR00165##

(533) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-(4-chloro-2-methoxybenzyl)-4-fluoropiperidine hydrochloride (Intermediate 35).

(534) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.61-1.70 (m, 1H) 1.70-1.79 (m, 3H) 2.23 (s, 3H) 2.38 (s, 3H) 2.39-2.48 (m, 2H) 2.85-2.94 (m, 2H) 3.38-3.46 (m, 2H) 3.71 (s, 3H) 3.79 (s, 3H) 6.93-6.98 (m, 1H) 7.04-7.09 (m, 1H) 7.10-7.15 (m, 1H)

(535) MS: ES.sup.+430

Example 92 2-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile

(536) ##STR00166##

(537) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride (Intermediate 37).

(538) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.37-1.44 (m, 1H) 1.46-1.55 (m, 1H) 1.83-1.91 (m, 1H) 2.20-2.28 (m, 5H) 2.33 (s, 5H) 3.53-3.60 (m, 1H) 3.61-3.68 (m, 1H) 4.34-4.41 (m, 1H) 7.37-7.41 (m, 1H) 7.42-7.49 (m, 1H) 7.54-7.59 (m, 1H) 13.05 (br. s., 1H)

(539) MS: ES.sup.+411

Example 93 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile

(540) ##STR00167##

(541) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 2-(4-chlorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride (Intermediate 39). 5 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.20-1.41 (m, 2H) 1.50-1.58 (m, 1H) 1.75-1.92 (m, 2H) 2.17-2.33 (m, 8H) 3.53-3.68 (m, 2H) 4.20-4.27 (m, 1H) 7.33-7.38 (m, 2H) 7.46-7.51 (m, 2H) 13.03 (br. s., 1H)

(542) MS: ES.sup.+393

Example 94 (4-Chlorophenyl)(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol

(543) ##STR00168##

(544) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and (4-chlorophenyl)(piperidin-4-yl)methanol hydrochloride (Intermediate 42).

(545) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.14-1.36 (m, 3H) 1.36-1.51 (m, 1H) 1.75-1.85 (m, 1H) 2.09-2.38 (m, 8H) 3.47-3.66 (m, 2H) 4.24-4.33 (m, 1H) 5.27-5.36 (m, 1H) 7.23-7.31 (m, 2H) 7.32-7.42 (m, 2H) 13.00 (br. s., 1H)

(546) MS: ES.sup.+384

Example 95 (4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol

(547) ##STR00169##

(548) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and (4-chlorophenyl)(piperidin-4-yl)methanol hydrochloride (Intermediate 42).

(549) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.16-1.35 (m, 3H) 1.37-1.49 (m, 1H) 1.74-1.84 (m, 1H) 2.09-2.19 (m, 2H) 2.21 (s, 3H) 2.36 (s, 3H) 3.48-3.63 (m, 2H) 3.69 (s, 3H) 4.25-4.32 (m, 1H) 5.27-5.33 (m, 1H) 7.25-7.31 (m, 2H) 7.33-7.39 (m, 2H)

(550) MS: ES.sup.+398

Example 96 4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(551) ##STR00170##

(552) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-((4-chlorophenyl)(methoxy)methyl)piperidine hydrochloride (Intermediate 43).

(553) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H) 1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H) 3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

(554) MS: ES.sup.+398

Example 97 4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, Enantiomer A

(555) ##STR00171##

(556) 4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine (Example 96) was separated into its enantiomers by supercritical fluid chromatography using a Daicel AD-H (250 mm×10 mm) column, eluting with 14% MeOH to give 4-((4-chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine, Enantiomer A, as the first eluting peak.

(557) e.e. 100%

(558) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H) 1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H) 3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

(559) MS: ES.sup.+398

Example 98 4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, Enantiomer B

(560) ##STR00172##

(561) 4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine (Example 96) was separated into its enantiomers by supercritical fluid chromatography using a Daicel AD-H (250 mm×10 mm) column, eluting with 14% MeOH to give 4-((4-chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine, Enantiomer B, as the second eluting peak.

(562) e.e. 100%

(563) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H) 1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H) 3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

(564) MS: ES.sup.+398

Example 99 4-((4-Chlorophenyl)(methoxy)methyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(565) ##STR00173##

(566) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and 4-((4-chlorophenyl)(methoxy)methyl)piperidine hydrochloride (Intermediate 43).

(567) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.10-1.30 (m, 3H) 1.45-1.57 (m, 1H) 1.86-1.98 (m, 1H) 2.07-2.18 (m, 1H) 2.19-2.23 (m, 4H) 2.36 (s, 3H) 3.07 (s, 3H) 3.46-3.62 (m, 2H) 3.69 (s, 3H) 3.90-3.94 (m, 1H) 7.22-7.28 (m, 2H) 7.38-7.44 (m, 2H)

(568) MS: ES.sup.+412

Example 100 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol

(569) ##STR00174##

(570) 2-(4-Chlorophenyl)-2-(piperidin-4-yl)ethanol hydrochloride (Intermediate 45, 0.7 g, 2.1 mmol) was dissolved in HCl (12% in dioxane, 3 mL) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo and the crude product was triturated with diethyl ether to give 2-(4-chlorophenyl)-2-(piperidin-4-yl)ethanol hydrochloride (0.4 g, 82%). The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 2-(4-chlorophenyl)-2-(piperidin-4-yl)ethanol hydrochloride.

(571) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.93-1.06 (m, 1H) 1.12-1.37 (m, 3H) 1.54-1.67 (m, 1H) 1.89-1.99 (m, 1H) 2.06-2.15 (m, 1H) 2.18-2.26 (m, 4H) 2.32 (s, 3H) 3.44-3.51 (m, 1H) 3.55-3.68 (m, 3H) 4.50-4.55 (m, 1H) 7.16-7.22 (m, 2H) 7.28-7.35 (m, 2H) 13.04 (s, 1H)

(572) MS: ES.sup.+398

Example 101 1-(4-Chlorophenyl)-1-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol

(573) ##STR00175##

(574) Methylmagnesium bromide (3M in ether) (3.09 mL, 9.26 mmol) was added slowly to a solution of tert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (Intermediate 40, 0.5 g, 1.544 mmol) in THF (10 mL) at 0° C. under nitrogen. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 2M HCl and partitioned between ethyl acetate and 2M HCl. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated brine, dried (phase separator) and concentrated in vacuo to afford tert-butyl 4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (0.481 g, 1.415 mmol, 92% yield) as a colourless oil.

(575) MS: ES− 338.

(576) Hydrogen chloride (4M in dioxane) (0.309 mL, 1.236 mmol) was added to a solution of tert-butyl 4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (0.21 g, 0.618 mmol) in methanol (10 mL). The reaction was stirred at room temperature overnight. The solution was concentrated and azeotroped with toluene to give 1-(4-chlorophenyl)-1-(piperidin-4-yl)ethanol hydrochloride as a white solid (quantitative, MS: ES.sup.+240).

(577) The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 1-(4-chlorophenyl)-1-(piperidin-4-yl)ethanol hydrochloride.

(578) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.15-1.33 (m, 3H) 1.37 (s, 3H) 1.43-1.54 (m, 1H) 1.66-1.77 (m, 1H) 2.01-2.20 (m, 2H) 2.27 (s, 6H) 3.48-3.66 (m, 2H) 4.95 (s, 1H) 7.31-7.35 (m, 2H) 7.36-7.41 (m, 2H) 13.00 (br. s., 1H)

(579) MS: ES.sup.+398

Example 102 4-(1-(4-Chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(580) ##STR00176##

(581) p-Toluenesulfonic acid monohydrate (0.963 g, 5.06 mmol) was added to a solution of tert-butyl 4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (described in the preparation of Example 101), (0.43 g, 1.265 mmol) in toluene (15 mL) under nitrogen. Magnesium sulfate was added and the reaction was heated to reflux for 5 hours then cooled overnight. The reaction was quenched with 2M NaOH and the mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate, the combined organics were washed with saturated brine, dried (phase separator) and concentrated in vacuo to give crude 4-(1-(4-chlorophenyl)ethylidene)piperidine 4-methylbenzenesulfonate. Triethylamine (0.386 mL, 2.77 mmol) was added to a suspension of crude 4-(1-(4-chlorophenyl)ethylidene)piperidine 4-methylbenzenesulfonate (0.364 g, 0.924 mmol) and 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3, 0.216 g, 1.109 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 4 hours. The mixture was diluted with DCM, washed with water, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-100% ethyl acetate/petroleum ether, then by reverse phase preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia) to afford 4-(1-(4-chlorophenyl)ethylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine. This was then taken in a flask with platinum(IV) oxide (3.47 mg, 0.015 mmol) and evacuated and purged with nitrogen three times. Ethanol (0.5 mL) and ethyl acetate (0.5 mL) were added under vacuum, then the suspension was stirred under an atmosphere of hydrogen for 1 hour. The suspension was filtered through diatomaceous earth and the filtrate concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia) to afford 4-(1-(4-chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (0.024 g, 0.063 mmol, 41.2% yield) as a white foam.

(582) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.97-1.09 (m, 1H) 1.11-1.22 (m, 4H) 1.27-1.43 (m, 2H) 1.84-1.92 (m, 1H) 2.06-2.15 (m, 1H) 2.16-2.25 (m, 1H) 2.26-2.31 (m, 7H) 3.45-3.66 (m, 2H) 7.16-7.21 (m, 2H) 7.30-7.34 (m, 2H) 12.99 (br. s, 1H)

(583) MS: ES.sup.+382

Example 103 N-(4-Chlorophenyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

(584) ##STR00177##

(585) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and N-(4-chlorophenyl)piperidin-4-amine hydrochloride.

(586) .sup.1H NMR (400 MHz, MeOD-d.sub.6) δ ppm 1.32-1.45 (m, 4H) 2.10-2.18 (m, 2H) 2.45 (s, 6H) 2.67-2.80 (m, 2H) 3.62-3.71 (m, 2H,) 4.10 (s, 1H) 6.54-6.61 (m, 2H) 7.08-7.12 (m, 2H)

(587) MS: ES.sup.+369

Example 104 4-((4-Chlorophenyl)(ethoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(588) ##STR00178##

(589) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-((4-chlorophenyl)(ethoxy)methyl)piperidine hydrochloride (Intermediate 46).

(590) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.01-1.10 (m, 3H) 1.16-1.30 (m, 3H) 1.49 (br. s., 1H) 1.90-1.97 (m, 1H) 2.10-2.24 (m, 2H) 2.24-2.31 (m, 6H) 3.18-3.26 (m, 2H) 3.48-3.63 (m, 2H) 3.99-4.04 (m, 1H) 7.23-7.28 (m, 2H) 7.37-7.43 (m, 2H) 13.00 (br. s., 1H)

(591) MS: ES.sup.+412

Example 105 4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(592) ##STR00179##

(593) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-((4-chlorophenyl)fluoromethyl)piperidine hydrochloride (Intermediate 47).

(594) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H) 2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H) 7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

(595) MS: ES.sup.+386

Example 106 4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine Enantiomer A

(596) ##STR00180##

(597) 4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 105) was separated into its enantiomers by supercritical fluid chromatography using a Chiralpak AD 20×250 mm 5 μm column eluting with 20% methanol to afford 4-((4-chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine, Enantiomer A, as the first eluting peak. e.e. 97.9%

(598) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H) 2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H) 7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

(599) MS: ES.sup.+386

Example 107 4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine Enantiomer B

(600) ##STR00181##

(601) 4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 105) was separated into its enantiomers by supercritical fluid chromatography using a Chiralpak AD 20×250 mm 5 m column eluting with 20% methanol to afford 4-((4-chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl) sulfonyl)piperidine, Enantiomer B, as the second eluting peak.

(602) e.e. 98.1%

(603) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H) 2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H) 7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

(604) MS: ES.sup.+386

Example 108 4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

(605) ##STR00182##

(606) tert-Butyl 4-(4-chlorobenzyl)-4-hydroxypiperidine-1-carboxylate was prepared as described for tert-butyl 4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 22). Hydrogen chloride (4M in dioxane) (0.609 mL, 2.437 mmol) was added to a solution of tert-butyl 4-(4-chlorobenzyl)-4-hydroxypiperidine-1-carboxylate (0.25 g, 0.767 mmol) in methanol (5 mL). The reaction was stirred at room temperature overnight, then concentrated and azeotroped with toluene to afford 4-(4-chlorobenzyl)piperidin-4-ol hydrochloride (quantitative). The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(4-chlorobenzyl)piperidin-4-ol hydrochloride.

(607) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.36-1.45 (m, 2H) 1.46-1.60 (m, 2H) 2.29 (br. s., 6H) 2.51-2.58 (m, 2H) 2.65 (s, 2H) 3.31-3.37 (m, 2H) 4.33 (s, 1H) 7.17-7.25 (m, 2H) 7.27-7.34 (m, 2H) 13.02 (br. s., 1H)

(608) MS: ES.sup.+384

Example 109 4-(1-(4-Chlorophenyl)-2-methoxyethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(609) ##STR00183##

(610) Sodium hydride (0.046 g, 1.94 mmol) was added to a solution of tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (Intermediate 45, 0.6 g, 1.76 mmol) in THF (15 mL). The reaction was heated to 60-65° C. for 2 hours then cooled to room temperature. Methyl iodide (0.276 g, 1.94 mmol) and HMPA (0.3 mL) were added and the reaction was refluxed for 15 hours. The reaction was quenched with ice/water and extracted with ethyl acetate. The combined organics were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-70% ethyl acetate/n-hexane to afford tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (0.35 g, 56%). This was taken up into dioxane (1 mL), treated with HCl/dioxane (7 mL) and stirred at room temperature overnight. The reaction was concentrated in vacuo and triturated with diethyl ether to afford 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine hydrochloride (0.2 g, 80%). The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine hydrochloride.

(611) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.95-1.10 (m, 1H) 1.15-1.36 (m, 3H) 1.51-1.64 (m, 1H) 1.85-1.94 (m, 1H) 2.06-2.15 (m, 1H) 2.23 (br. s., 3H) 2.32 (br. s., 3H) 2.58-2.70 (m, 1H) 3.15 (s, 3H) 3.44-3.51 (m, 1H) 3.51-3.56 (m, 2H) 3.57-3.64 (m, 1H) 7.17-7.23 (m, 2H) 7.30-7.35 (m, 2H) 13.03 (br. s., 1H)

(612) MS: ES.sup.+412

Example 110 1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(methoxy(phenyl)methyl)piperidine

(613) ##STR00184##

(614) Prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(methoxy(phenyl)methyl)piperidine hydrochloride (prepared as described for 4-((4-Chlorophenyl)(methoxy)methyl)piperidine hydrochloride (Intermediate 43) using phenyl(piperidin-4-yl)methanone hydrochloride).

(615) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.31 (m, 3H) 1.48-1.60 (m, 1H) 1.90 (m, 1H) 2.08-2.24 (m, 2H) 2.27 (s, 6H) 3.06 (s, 3H) 3.47-3.63 (m, 2H) 3.84-3.90 (m, 1H) 7.19-7.25 (m, 2H) 7.25-7.31 (m, 1H) 7.32-7.38 (m, 2H) 13.01 (br. s, 1H)

(616) MS: ES.sup.+364

Example 111 4-(1-(4-Chlorophenyl)-2,2-difluoroethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

(617) ##STR00185##

(618) Diethylaminosulfur trifluoride (0.242 mL, 1.835 mmol) was added to a solution of tert-butyl 4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate (Intermediate 44, 0.31 g, 0.918 mmol) in DCM (5 mL) under nitrogen at −78° C. The reaction was stirred at −78° C. for 2 hours, then warmed to room temperature overnight. A further portion of diethylaminosulfur trifluoride (0.242 mL, 1.835 mmol) was added and the reaction stirred at room temperature overnight. The reaction was quenched with saturated sodium hydrogen carbonate. The aqueous was extracted with DCM and combined organics were washed with water, dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-20% ethyl acetate/petroleum ether to afford tert-butyl 4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine-1-carboxylate (0.09 g, 0.250 mmol, 27.3% yield) as a colourless oil. Hydrogen chloride (4M in dioxane) (0.125 mL, 0.500 mmol) was added to a solution of tert-butyl 4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine-1-carboxylate (0.09 g, 0.250 mmol) in methanol (5 mL). The reaction was stirred at room temperature overnight. The solution was concentrated in vacuo and azeotroped with toluene to give 4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine hydrochloride (quantitative) as a colourless oil that was used without further purification. The title compound was prepared as described for 4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3) and 4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine hydrochloride.

(619) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.01-1.15 (m, 1H) 1.26-1.40 (m, 2H) 1.77-1.90 (m, 1H) 1.94-2.04 (m, 1H) 2.13-2.22 (m, 1H) 2.28 (s, 7H) 2.96-3.10 (m, 1H) 3.44-3.65 (m, 2H) 6.22-6.55 (m, 1H) 7.24-7.30 (m, 2H) 7.38-7.43 (m, 2H) 13.02 (br. s., 1H)

(620) MS: ES.sup.+418

3. BIOLOGICAL ASSAY

(621) Prokineticin receptor 1 (PKR1) antagonists may be functionally assessed by measurement of change in intracellular calcium levels induced by Gq mediated increase in inositol triphosphate (IP3) levels. The ability of a compound to block the intracellular release of calcium mediated by PK1 in RBL2H.sub.3 cells expressing human PKR1 receptors is determined as a measure of the compound's antagonist activity in vitro.

(622) Approximately 10,000 cells per assay well are seeded in normal culture medium in a 384 well plate (Corning). Twenty-four hours after seeding, the cells are loaded with a calcium sensitive fluorescent dye by replacing the culture medium with assay buffer (1× Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumin), pH 7.4) containing 1 mM probenecid and 1× Calcium 5 Reagent (Molecular Devices). Cells are incubated at 37° C. for 1 hour to allow for dye uptake.

(623) To test for antagonist activity, test compounds at a final concentration range between 0.32 nM-10 μM (diluted in assay buffer) are added to the assay wells and allowed to incubate for 10 minutes prior to stimulation with PK1. After incubation with test compounds the assay plate is placed in a FLIPR Tetra (Molecular Devices) and PK1 (diluted in assay buffer) is added at the determined EC80 concentration (final). Ligand-dependent changes in intracellular calcium levels are determined by measuring changes in fluorescence of the dye at 525 nM following to excitation at 485 nM. Readings from wells that do not contain antagonist enable percentage inhibition curves to be plotted using 4-parameter fit algorithm and IC50 values are calculated for each test compound.

(624) Results

(625) TABLE-US-00001 Compound of Compound of Example No. Mean IC.sub.50 (μM) Example No. Mean IC.sub.50 (μM)  1 1.4  2 1  3 1.4  4 0.82  5 0.53  6 2.2  7 7.3  8 1.45  9 2.3  10 1.7  11 0.86  12 4.7  13 0.79  14 0.47  15 2.9  16 4.6  17 3.6  18 7  19 5.6  20 3.6  21 2.1  22 1.18  23 0.22  24 1.5  25 1.3  26 1.7  27 5.6  28 0.32  29 1.1  30 0.51  31 0.31  32 3.4  33 0.44  34 0.24  35 1.1  36 1.1  37 7.4  38 3.2  39 0.21  40 0.21  41 5.9  42 5.9  43 6.3  44 5.1  45 1.4  46 1  47 1.9  48 3.8  49 1  50 2.1  51 1.5  52 2.7  53 0.9  54 5.2  55 0.52  56 0.95  57 1.6  58 2.4  59 2.4  60 0.9  61 1.08  62 0.68  63 0.64  64 0.89  65 0.94  66 1.01  67 0.52  68 2.02  69 6.47  70 8.62  71 0.78  72 0.44  73 0.20  74 0.17  75 6.98  76 3.73  77 3.19  78 0.07  79 0.05  80 0.81  81 0.67  82 1.02  83 0.73  84 0.72  85 1.23  86 4.60  87 5.88  88 0.20  89 0.41  90 0.17  91 0.14  92 1.85  93 0.61  94 1.74  95 0.71  96 0.08  97 4.62  98 0.16  99 0.06 100 9.42 101 2.38 102 0.47 103 1.76 104 0.72 105 0.41 106 4.00 107 0.31 108 1.64 109 1.86 110 3.01 111 0.34

(626) The compounds tested above exhibit IC.sub.50 values significantly less than 10 μM, with the most potent compounds showing antagonist activity at the prokineticin receptor with IC.sub.50 values <1 μM. Accordingly, the compounds of the invention are expected to be useful in the prevention or treatment of conditions in which prokineticin receptor modulation is implicated.

(627) In addition, the compounds of the present invention possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters. For example, the compounds of the invention exhibit one or more potentially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: hERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether-a-go-go-related gene, using for example the PatchXpress 7000A platform); CypP450 interactions (which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (September 2006), see www.fda.gov); phototoxicity (for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via multiple routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS/MS protocol); and in vivo receptor occupancy (determined, for example, using protocols based on Medhurst et al., Journal of Pharmacology and Experimental Therapeutics, 2007, 321, 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.