SULFONYL PIPERIDINE DERIVATIVES AND THEIR USE FOR TREATING PROKINETICIN MEDIATED GASTROINTESTINAL DISORDERS

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof (Formula (I)) in which m, n, W, X, Y, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in the specification for use in treating irritable bowel syndrome or inflammatory bowel disease.

##STR00001##

Claims

1-15. (canceled)

16. A method of treating irritable bowel syndrome or inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula (I) ##STR00061## wherein W, X, Y and Z each independently represent N, NH or CH, with the proviso that W, X, Y and Z do not each simultaneously represent a moiety CH; m is 0, 1, 2 or 3; each R.sup.1 independently represents halogen, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, 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; n is 0, 1, 2, 3 or 4; each R.sup.2 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.3 represents ═CR.sup.6, or, when there is at least one R.sup.1 group present that represents a C.sub.3-C.sub.6 cycloalkyl group, then R.sup.3 may additionally represent a group —CR.sup.7R.sup.8—; R.sup.5 is absent or represents a hydrogen atom or a substituent as defined above for R.sup.2; R.sup.6 represents a hydrogen or halogen atom or a cyano, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxycarbonyl group; R.sup.7 and R.sup.8 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.4 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 (═O), 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 (—NH.sub.2), —CON(R.sup.9).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.9 independently represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl group; or a pharmaceutically acceptable salt thereof.

17. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, provided that the compound of formula (I) is not: 1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethylene)piperidine; 1-[[1-cyclopentyl-3-(1,1-dimethylethyl)-1H-pyrazol-4-yl]sulfonyl]-4-(phenylmethyl)piperidine; 1-[(1-cyclopentyl-3-methyl-1H-pyrazol-4-yl)sulfonyl-4-(phenylmethyl)piperidine; or 1-[(5-chloro-1-methyl-1H-imidazol-4-yl)sulfonyl]-4-[(3-fluorophenyl)methylene]piperidine.

18. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) at least two of W, X, Y and Z represent N or NH.

19. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) the ring A is selected from the group consisting of: ##STR00062##

20. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) m is 2 or 3.

21. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) each R.sup.1 independently represents C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.

22. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) n is 0 or 1.

23. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) R.sup.3 represents ═CR.sup.6.

24. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 23, wherein in the compound of formula (I) R.sup.6 represents a hydrogen or fluorine atom or a cyano, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkoxycarbonyl group.

25. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) R.sup.3 represents —CR.sup.7R.sup.8—.

26. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein in the compound of formula (I) R.sup.4 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, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 haloalkoxy.

27. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, wherein the compound of formula (I) is selected from: 4-(4-Chloro-3-fluorobenzyl)-1-((3-cyclopropyl-5-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine, Methyl 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate, 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(2,6-Difluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(4-Chlorophenyl)-2-(1-((3,5-diethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(4-Chlorophenyl)-2-(1-((1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(2,6-Difluorophenyl)-2-(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 2-(1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile, 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-ylidene)acetonitrile, 4-(4-Chloro-2-fluorobenzylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-(4-Chloro-2-fluorobenzylidene)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-(1-(4-Chlorophenyl)ethylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-(4-Chlorobenzylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 2-(4-Chlorophenyl)-2-(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile, 4-((4-Chlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((3-Chloro-4-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((2,4-Dichlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((3,4-Dichlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((4-Chloro-3-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((4-Chloro-2-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 4-((2,4-Difluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine, 3-((1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)fluoromethyl)quinoline, and pharmaceutically acceptable salts of any one thereof.

28. The method of treating irritable bowel syndrome or inflammatory bowel disease according to claim 16, further comprising administering to the patient in need thereof at least one additional therapeutic agent.

Description

1. INTERMEDIATES

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

[0156] ##STR00014##

[0157] 3,5-Dimethyl-1H-pyrazole (3.0 g, 1.0 eq) dissolved in chloroform (5 mL) was added dropwise 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.

[0158] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.40 (s, 6H)

[0159] MS ES.sup.+: 195

Intermediate 2 3-Cyclopropyl-5-methyl-1H-pyrazole-4-sulfonyl chloride

[0160] ##STR00015##

[0161] Hydrazine hydrate (7.93 g, 0.158 mol) was added to a solution of 1-cyclopropyl-1,3-butanedione (10 g, 0.079 mol) in ethanol (100 mL) and the reaction was heated to reflux for two hours then concentrated to afford 5-cyclopropyl-3-methyl-1H-pyrazole (9.59 g, 98% yield). This was reacted with chlorosulfonic acid as described in the preparation of 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1) to afford 5-cyclopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride.

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

[0162] ##STR00016##

[0163] 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 two 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.

[0164] .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 4: 4-(4-Chloro-3-fluorobenzyl)piperidine Hydrochloride

[0165] ##STR00017##

[0166] A flask charged with tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (2.03 g, 6.23 mmol, Intermediate 3) 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 two 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.

[0167] .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 5: Methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride

[0168] ##STR00018##

Step (i): tert-Butyl 4-(1-(4-chlorophenyl)-2-methoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate

[0169] ##STR00019##

[0170] A flask was charged with nitrogen and methyl 2-(4-chlorophenyl)acetate (2 g, 13.19 mmol) in tetrahydrofuran to give a colourless solution cooled to −78° C. n-Butyl lithium was added dropwise over 20 mins via a syringe pump and stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (2.63 g, 13.19 mmol) in THF was added dropwise via a syringe pump over 20 mins and stirred for a further 2.5 hours. While still cold the reaction was quenched with NH.sub.4Cl and allowed to warm to room temperature overnight. The organic phase was separated, dried and evaporated to leave an oil. The crude product was purified by column chromatography on silica, eluted with EtOAc/petroleum ether 0-30% to afford the product as an oil (2.77 g, 60%).

Step (ii): tert-Butyl 4-(1-(4-chlorophenyl)-2-methoxy-2-oxoethylidene)piperidine-1-carboxylate

[0171] ##STR00020##

[0172] A flask was charged with tert-butyl 4-(1-(4-chlorophenyl)-2-methoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (from step (i), 1.29 g, 3.68 mmol) in pyridine (2 mL) to give a colourless solution. Thionyl chloride (1.334 mL, 18.38 mmol) was added and the reaction stirred for 10 mins, then evaporated to dryness. The crude product was purified by column chromatography on silica, eluted with 10-50% Hexane/EtOAc to afford the product (0.78 g, 58%).

Step (iii): Methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride

[0173] ##STR00021##

[0174] tert-Butyl 4-(1-(4-chlorophenyl)-2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (from step (ii), 0.78 g, 2.14 mmol) was treated with 4N HCl in dioxane and stirred for one hour then evaporated to leave a white solid, (0.21 g, 33%).

[0175] MS: ES+ 266

Intermediate 6: 2-(4-Chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride

[0176] ##STR00022##

[0177] Prepared in a similar manner to methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5) using 2-(4-chlorophenyl) acetonitrile.

[0178] MS: ES+ 233

Intermediate 7: 2-(2,6-Difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride

[0179] ##STR00023##

[0180] Prepared in a similar manner to methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5) using 2-(2,6-difluorophenyl) acetonitrile.

[0181] MS: ES+ 235

Intermediate 8: 2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride

[0182] ##STR00024##

[0183] Prepared in a similar manner to methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5) using 2-(2-fluoro-4-chlorophenyl) acetonitrile.

[0184] MS: ES+ 251

Intermediate 9: 1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride

[0185] ##STR00025##

[0186] Prepared in a similar manner to 3-cyclopropyl-5-methyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 2) from 1,1,1-trifluoropentane-2,4-dione and methylhydrazine.

[0187] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.63 (s, 3H), 3.91 (s, 3H)

Intermediate 10: 2-(Piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)-acetonitrile hydrochloride

[0188] ##STR00026##

[0189] Prepared in a similar manner to methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5) using 2-(4-(trifluoromethoxy)phenyl)acetonitrile.

[0190] MS: ES+ 283

Intermediate 11: 2-(4-Chlorophenyl)-2-(3-methylpiperidin-4-ylidene)acetonitrile hydrochloride

[0191] ##STR00027##

[0192] Prepared in a similar manner to methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5) using 2-(4-chlorophenyl) acetonitrile and tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate.

[0193] MS: ES+ 247

Intermediate 12: tert-Butyl 4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate

[0194] ##STR00028##

[0195] 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.

[0196] .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).

[0197] 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 (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. MS: ES− 338.

Intermediate 13: 4-(4-Chlorobenzylidene)piperidine hydrochloride

[0198] ##STR00029##

[0199] (4-Chlorobenzyl)triphenylphosphonium bromide (prepared in an analogous manner to (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide described in the synthesis of Intermediate 3) (20 g, 42.8 mmol) was added to THF (200 mL) and n-BuLi (6.03 g, 94 mmol) added at 0° C. The reaction was stirred at room temperature for two hours. tert-Butyl 4-oxopiperidine-1-carboxylate (8.52 g, 42.8 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica, eluted with 0-10% ethyl acetate/petroleum ether to afford tert-butyl 4-(4-chlorobenzylidene)piperidine-1-carboxylate (7 g, 53%). Hydrogen chloride (4M in dioxane) (0.609 mL, 2.437 mmol) was added to a solution of tert-butyl 4-(4-chlorobenzylidene)piperidine-1-carboxylate (0.25 g, 0.812 mmol) in methanol (5 mL). The reaction was stirred at room temperature overnight. A further portion of hydrogen chloride (4M in dioxane) (0.609 mL, 2.437 mmol) was added and the solution stirred for three hours. The solution was concentrated and azeotroped with toluene to give 4-(4-chlorobenzylidene)piperidine hydrochloride (0.196 g, 0.803 mmol, 99% yield) as a white solid.

[0200] MS: ES+ 208

Intermediate 14: 4-((4-Chlorophenyl)fluoromethylene)piperidine hydrochloride

[0201] ##STR00030##

[0202] Diethyl ((4-chlorophenyl)fluoromethyl)phosphonate (prepared as described by Azizi et. al. Phosphorus, Sulfur and Silicon and the Related Elements, 178(6), 1255-1259; 2003 followed by Blackburn et. al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (6), 913-17; 1986) (0.61 g, 2.173 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.433 g, 2.173 mmol) in THF (20 mL) at 0° C. was treated with sodium hydride (60% in mineral oil, 0.229 g, 4.78 mmol). The reaction mixture was allowed to reach room temperature and stirred for 18 hours, then quenched with water and evaporated. To the reaction mixture was added DCM/H.sub.2O and the organic layer dried (phase separator) and concentrated in vacuo to yield an oil. The crude product was purified by column chromatography on silica, eluted with EtOAc/petroleum ether 0-50% to afford tert-butyl 4-((4-chlorophenyl)fluoromethylene)-piperidine-1-carboxylate (0.41 g, 58%).

[0203] .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) δ ppm 1.48 (s, 9H) 2.30-2.36 (m, 2H) 2.48-2.54 (m, 2H) 3.42-3.48 (m, 2H) 3.51-3.55 (m, 2H) 7.38-7.45 (m, 4H)

[0204] tert-Butyl 4-((4-chlorophenyl)fluoromethylene)piperidine-1-carboxylate (0.39 g, 1.19 mmol) was treated with 4N HCl in dioxane and stirred for one hour then evaporated to leave a white solid (quantitative) that was used without purification.

[0205] MS: ES+ 226

Intermediate 15: 4-((3-Chloro-4-fluorophenyl)fluoromethylene)piperidine hydrochloride

[0206] ##STR00031##

[0207] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 16: 4-((2,4-Dichlorophenyl)fluoromethylene)piperidine hydrochloride

[0208] ##STR00032##

[0209] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 17: 4-((3,4-Dichlorophenyl)fluoromethylene)piperidine hydrochloride

[0210] ##STR00033##

[0211] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 18: 4-((4-Chloro-3-fluorophenyl)fluoromethylene)piperidine hydrochloride

[0212] ##STR00034##

[0213] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 19: 4-((4-Chloro-2-fluorophenyl)fluoromethylene)piperidine hydrochloride

[0214] ##STR00035##

[0215] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 20: 4-((2,4-Difluorophenyl)fluoromethylene)piperidine hydrochloride

[0216] ##STR00036##

[0217] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

Intermediate 21: 3-(Fluoro(piperidin-4-ylidene)methyl)quinoline hydrochloride

[0218] ##STR00037##

[0219] Prepared in a similar manner to 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14).

2. EXAMPLES

Example 1 4-(4-Chloro-3-fluorobenzyl)-1-((3-cyclopropyl-5-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0220] ##STR00038##

[0221] The title compound was prepared from 5-cyclopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 2, 150 mg, 0.68 mmol) and 4-(4-chloro-3-fluorobenzyl)piperidine hydrochloride (Intermediate 4, 176 mg, 0.68 mmol). The reaction was stirred at room temperature for two hours. To the reaction mixture was added DCM/H.sub.2O and the organic layer dried (phase separator) and concentrated in vacuo to yield an oil. The crude product was purified by column chromatography on silica, eluted with EtOAc/petroleum ether 0-100% to afford the title compound, 0.14 g, 50% yield.

[0222] .sup.1H NMR (400 MHz, ACETONITRILE-d.sub.3) δ ppm 0.58-0.77 (m, 3H) 0.97-1.12 (m, 2H) 1.27-1.40 (m, 1H) 1.41-1.49 (m, 2H) 1.71-1.76 (m, 3H) 2.06-2.15 (m, 4H) 2.28-2.36 (m, 2H) 3.43-3.51 (m, 2H) 6.72-6.78 (m, 1H) 6.81-6.87 (m, 1H) 7.12-7.18 (m, 1H) 10.89-11.03 (m, 1H)

[0223] MS: ES+ 412

Example 2 Methyl 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate

[0224] ##STR00039##

[0225] A flask was charged with nitrogen and methyl 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetate hydrochloride (Intermediate 5, 210 mg, 0.790 mmol) in DCM (10 mL) to give a colourless solution. 3,5-Dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1; 114 mg, 0.586 mmol) and triethylamine (0.330 mL, 2.371 mmol) were added. The reaction was stirred at room temperature for two hours. To the reaction mixture was added DCM/H.sub.2O and the organic layer dried (phase separator) and concentrated in vacuo to yield an oil. The crude product was purified by column chromatography on silica, eluted with EtOAc/petroleum ether 0-100%, EtOAc/MeOH 0-20% to afford the title compound.

[0226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.28 (m, 2H) 2.34 (S, 6H) 2.75-2.78 (m, 2H) 2.96-2.96 (m, 2H) 3.01-3.03 (s, 2H) 3.60 (s, 3H) 7.16-7.29 (m, 2H) 7.38-7.41 (m, 2H)

[0227] MS: ES+ 424

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

[0228] ##STR00040##

[0229] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.32 g, 1.67 mmol) and 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 6, 0.39 g, 1.67 mmol) to give the title compound (0.49 g, 76%).

[0230] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.38 (m, 8H) 2.75-2.78 (m, 2H) 3.01-3.03 (s, 2H) 3.18-3.20 (m, 2H) 7.32-7.36 (m, 2H) 7.52-7.56 (m, 2H) 13.0 (s, 1H)

[0231] MS: ES+ 391

Example 4 2-(2,6-Difluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile

[0232] ##STR00041##

[0233] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.12 g, 0.58 mmol) and 2-(2,6-difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 7, 0.21 g, 0.89 mmol) to give the title compound (0.23 g, 67%).

[0234] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.38 (m, 8H) 2.82-2.90 (m, 2H) 2.93-3.03 (m, 2H) 3.18-3.20 (m, 2H) 7.25-7.33 (m, 2H) 7.58-7.63 (m, 1H) 13.0 (s, 1H)

[0235] MS: ES+ 393

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

[0236] ##STR00042##

[0237] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.3 g, 1.54 mmol) and 2-(4-chloro-2-fluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 8, 0.44 g, 1.54 mmol) to give the title compound (0.54 g, 86%).

[0238] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.38 (m, 8H) 2.80-2.88 (m, 2H) 2.96-3.03 (m, 2H) 3.18-3.20 (m, 2H) 7.41-7.48 (m, 2H) 7.60-7.63 (m, 1H) 13.0 (s, 1H)

[0239] MS: ES+ 409

Example 6 2-(4-Chlorophenyl)-2-(1-((3,5-diethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile

[0240] ##STR00043##

[0241] 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).

[0242] The title compound was prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-diethyl-1H-pyrazole-4-sulfonyl chloride (0.11 g, 0.47 mmol) and 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 6, 0.1 g, 0.47 mmol) in the following yield: 0.072 g (38%).

[0243] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.15-1.21 (m, 6H) 2.40-2.50 (m, 2H) 2.71-2.78 (m, 2H) 2.78-2.82 (m, 4H) 2.98-3.03 (m, 2H) 3.18-3.22 (m, 2H) 7.34-7.40 (m, 2H) 7.50-7.62 (m, 2H) 13.0 (s, 1H)

[0244] MS: ES+ 419

Example 7 2-(4-Chlorophenyl)-2-(1-((1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile

[0245] ##STR00044##

[0246] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (Intermediate 9, 0.1 g, 0.47 mmol) and 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 6, 0.12 g, 0.47 mmol) to give the title compound (0.11 g, 50%).

[0247] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.42-2.50 (m, 5H) 2.75-2.80 (m, 2H) 3.12-3.18 (m, 2H) 3.30-3.40 (m, 2H) 3.85 (s, 3H) 7.42-7.48 (m, 2H) 7.52-7.60 (m, 2H)

[0248] MS: ES+ 459

Example 8 2-(2,6-Difluorophenyl)-2-(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile

[0249] ##STR00045##

[0250] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (0.14 g, 0.58 mmol) and 2-(2,6-difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 7, 0.11 g, 0.89 mmol) to give the title compound (0.05 g, 26%).

[0251] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.20 (s, 3H) 2.20-2.34 (m, 2H) 2.40 (s, 3H) 2.82-2.90 (m, 2H) 2.98-3.00 (m, 2H) 3.18-3.24 (m, 2H) 3.70 (s, 3H) 7.24-7.30 (m, 2H) 7.58-7.63 (m, 1H)

[0252] MS: ES+ 407

Example 9 2-(1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile

[0253] ##STR00046##

[0254] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.12 g, 0.62 mmol) and 2-(piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile hydrochloride (Intermediate 10, 0.2 g, 0.62 mmol) to give the title compound (0.14 g, 50%).

[0255] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.32 (m, 6H) 2.45-2.30 (m, 2H) 2.80-2.85 (m, 2H) 2.98-3.05 (m, 2H) 3.18-3.22 (m, 2H) 7.42-7.52 (m, 4H) 13.0 (s, 1H)

[0256] MS: ES+ 441

Example 10 2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-ylidene)acetonitrile

[0257] ##STR00047##

[0258] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.085 g, 0.43 mmol) and 2-(4-chlorophenyl)-2-(3-methylpiperidin-4-ylidene)acetonitrile hydrochloride (Intermediate 11, 0.12 g, 0.43 mmol) to give the title compound (0.055 g, 31%).

[0259] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.20 (m, 3H) 2.20-2.25 (m, 2H) 2.42-2.60 (m, 3H) 2.60 (s, 6H) 3.18-3.22 (m, 2H) 7.25-7.60 (m, 4H) 13 (s, 1H)

[0260] MS: ES+ 405

Example 11 4-(4-Chloro-2-fluorobenzylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0261] ##STR00048##

[0262] 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 3) from 4-(bromomethyl)-1-chloro-3-fluorobenzene. Hydrogen chloride (4M in dioxane) (0.384 mL, 1.535 mmol) was added to a suspension of tert-butyl 4-(4-chloro-2-fluorobenzylidene)piperidine-1-carboxylate (0.25 g, 0.767 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-(4-chloro-2-fluorobenzylidene)piperidine hydrochloride (0.2 g, 0.763 mmol, 99% yield) as a white solid. The title compound was prepared as described for 4-(4-chloro-3-fluorobenzyl)-1-((3-cyclopropyl-5-methyl-1H-pyrazol-4-yl) sulfonyl)piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1) and 4-(4-chloro-2-fluorobenzylidene)piperidine hydrochloride.

[0263] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.39 (m, 8H) 2.41-2.47 (m, 2H) 2.89-2.99 (m, 2H) 3.00-3.09 (m, 2H) 6.22 (s, 1H) 7.19-7.32 (m, 2H) 7.37-7.45 (m, 1H) 13.05 (br. s., 1H)

[0264] MS: ES+ 384

Example 12 4-(4-Chloro-2-fluorobenzylidene)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0265] ##STR00049##

[0266] Prepared as described for 4-(4-chloro-2-fluorobenzylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine (Example 11) using 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride.

[0267] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.24 (s, 3H) 2.33-2.41 (m, 5H) 2.42-2.48 (m, 2H) 2.90-2.96 (m, 2H) 3.00-3.07 (m, 2H) 3.70 (s, 3H) 6.22 (s, 1H) 7.23-7.32 (m, 2H) 7.38-7.44 (m, 1H)

[0268] MS: ES+ 398

Example 13 4-(1-(4-Chlorophenyl)ethylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0269] ##STR00050##

[0270] 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 (Intermediate 12, 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 (2×200 ml). The combined organics were washed with saturated brine (2×100 ml), dried (phase separator) and concentrated in vacuo to afford 4-(1-(4-chlorophenyl)ethylidene)piperidine 4-methylbenzenesulfonate, which was taken on without further purification.

[0271] MS: ES+ 222

[0272] Triethylamine (0.386 ml, 2.77 mmol) was added to a suspension of 4-(1-(4-chlorophenyl)ethylidene)piperidine 4-methylbenzenesulfonate (0.364 g, 0.924 mmol) and 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 0.216 g, 1.109 mmol) in DCM (10 ml). The reaction was stirred at room temperature for 4 hours. The mixture was diluted with DCM, washed with water (1×25 ml), 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. LCMS/NMR shows mixture of products. The crude product was purified 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 (0.057 g, 0.150 mmol, 16.24% yield) as a white solid.

[0273] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.90 (s, 3H) 2.07-2.17 (m, 2H) 2.30 (br. s., 6H) 2.42-2.48 (m, 2H) 2.78-2.87 (m, 2H) 2.97-3.03 (m, 2H) 7.07-7.17 (m, 2H) 7.32-7.40 (m, 2H) 13.04 (br. s., 1H)

[0274] MS: ES+ 380

Example 14 4-(4-Chlorobenzylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0275] ##STR00051##

[0276] Prepared as described for 4-(4-chloro-3-fluorobenzyl)-1-((3-cyclopropyl-5-methyl-1H-pyrazol-4-yl) sulfonyl)piperidine (Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1) and 4-(4-Chlorobenzylidene)piperidine hydrochloride (Intermediate 13).

[0277] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.30 (br. s., 6H) 2.36-2.43 (m, 2H) 2.45-2.48 (m, 2H) 2.90-2.97 (m, 2H) 3.00-3.06 (m, 2H) 6.32 (s, 1H) 7.17-7.23 (m, 2H) 7.33-7.40 (m, 2H) 13.03 (br. s., 1H)

[0278] MS: ES− 364

Example 15 2-(4-Chlorophenyl)-2-(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile

[0279] ##STR00052##

[0280] Prepared as described for 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetonitrile (Example 3) using 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride.

[0281] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.08-2.20 (m, 4H) 2.48-2.50 (m, 4H) 2.78 (s, 3H) 3.70 (s, 3H) 7.32-7.38 (m, 2H) 7.48-7.52 (m, 2H)

[0282] MS: ES+ 405

Example 16 4-((4-Chlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0283] ##STR00053##

[0284] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 232 mg, 1.194 mmol) and 4-((4-chlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 14, 313 mg, 1.194 mmol) to afford the title compound (0.31 g, 67%).

[0285] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.42 (m, 10H) 2.96-3.08 (m, 4H) 7.40-7.46 (m, 2H) 7.48-7.52 (m, 2H) 13.0 (s, 1H)

[0286] MS: ES+ 384

Example 17 4-((3-Chloro-4-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0287] ##STR00054##

[0288] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 217 mg, 1.11 mmol) and 4-((3-chloro-4-fluorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 15, 312 mg, 1.11 mmol) to afford the title compound (0.19 g, 42%).

[0289] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.20-2.35 (m, 10H) 2.86-3.10 (m, 4H) 7.40-7.50 (m, 2H) 7.64-7.70 (m, 1H) 13.0 (s, 1H)

[0290] MS: ES+ 402

Example 18 4-((2,4-Dichlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0291] ##STR00055##

[0292] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 260 mg, 1.33 mmol) and 4-((2,4-dichlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 16, 480 mg, 1.33 mmol) to afford the title compound (0.26 g, 48%).

[0293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.00-2.15 (m, 2H) 2.20-2.40 (br s, 6H) 2.50-2.55 (m, 2H) 2.85-2.96 (m, 2H) 3.08-3.12 (m, 2H) 7.40-7.44 (m, 2H) 7.55 (s, 1H) 13.0 (s, 1H)

[0294] MS: ES+ 418

Example 19 4-((3,4-Dichlorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0295] ##STR00056##

[0296] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 385 mg, 1.97 mmol) and 4-((3,4-dichlorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 17; 712 mg, 1.97 mmol) to afford the title compound (0.57 g, 69%).

[0297] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.20-2.40 (m, 10H) 2.90-3.10 (m, 4H) 7.39-7.45 (m, 1H) 7.70-7.80 (m, 2H) 13.0 (s, 1H)

[0298] MS: ES+ 418

Example 20 4-((4-Chloro-3-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0299] ##STR00057##

[0300] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 178 mg, 0.91 mmol) and 4-((4-chloro-3-fluorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 18, 256 mg, 0.91 mmol) to afford the title compound (0.23 g, 61%).

[0301] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.20-2.50 (m, 10H) 2.95-3.12 (m, 4H) 7.25-7.31 (m, 1H) 7.42-7.48 (m, 1H) 7.58-7.67 (m, 1H) 13.0 (s, 1H)

[0302] MS: ES+ 402

Example 21 4-((4-Chloro-2-fluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0303] ##STR00058##

[0304] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 25 mg, 0.13 mmol) and 4-((4-chloro-2-fluorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 19, 45 mg, 0.13 mmol) to afford the title compound (0.036 g, 68%).

[0305] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.14-2.18 (m, 2H) 2.26 (s, 3H) 2.36 (s, 3H) 2.48-2.53 (m, 2H) 2.96-3.08 (m, 2H) 3.10-3.16 (m, 2H) 7.36-7.41 (m, 1H) 7.47-7.52 (m, 1H) 7.58-7.67 (m, 1H) 13.0 (s, 1H)

[0306] MS: ES+ 402

Example 22 4-((2,4-Difluorophenyl)fluoromethylene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

[0307] ##STR00059##

[0308] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 892 mg, 4.58 mmol) and 4-((2,4-difluorophenyl)fluoromethylene)piperidine hydrochloride (Intermediate 20, 1039 mg, 4.58 mmol) to afford the title compound (1.2 g, 68%).

[0309] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.16-2.22 (m, 2H) 2.34-2.45 (m, 6H) 2.55-2.60 (m, 2H) 2.91-3.08 (m, 2H) 3.10-3.22 (m, 2H) 7.14-7.22 (m, 1H) 7.31-7.38 (m, 1H) 7.38-7.55 n (m, 1H) 13.0 (s, 1H)

[0310] MS: ES+ 400

Example 23 3-((1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene) fluoromethyl) quinoline

[0311] ##STR00060##

[0312] Prepared as described for methyl 2-(4-chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ylidene)acetate (Example 2) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 1, 117 mg, 0.59 mmol) and 3-(fluoro(piperidin-4-ylidene)methyl)quinoline hydrochloride (Intermediate 21, 167 mg, 0.59 mmol) to afford the title compound (0.045 g, 18%).

[0313] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.25-2.41 (m, 6H) 2.45-3.50 (m, 2H) 2.62-2.65 (m, 2H) 2.99-3.05 (m, 2H) 3.08-3.12 (m, 2H) 7.67-7.71 (m, 1H) 7.80-7.90 (m, 1H) 8.05-8.10 (m, 2H) 8.45 (s, 1H) 8.90 (s, 1H) 13.0 (s, 1H)

[0314] MS: ES+ 401

3. BIOLOGICAL ASSAY

[0315] 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 RBL2H3 cells expressing human PKR1 receptors is determined as a measure of the compound's antagonist activity in vitro.

[0316] 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 (lx 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.

[0317] 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 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 IC.sub.50 values are calculated for each test compound.

[0318] Results

TABLE-US-00001 Compound of Compound of Example No. Mean IC.sub.50 (μM) Example No. Mean IC.sub.50 (μM) 1 1.37 2 3.10 3 0.04 4 3.68 5 0.18 6 0.05 7 0.21 8 5.43 9 0.15 10 0.47 11 0.60 12 0.55 13 0.76 14 0.76 15 0.04 16 0.16 17 1.88 18 0.26 19 0.52 20 0.19 21 0.40 22 1.63 23 0.06

[0319] 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.