PIPERIDINE AND AZEPINE DERIVATIVES AS PROKINETICIN RECEPTOR MODULATORS

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof (Formula (I)) in which m, X, R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined in the specification, processes for their preparation, pharmaceutical compositions N containing them and their use in therapy.

##STR00001##

Claims

1.-15. (canceled)

16. A pharmaceutical composition comprising a compound selected from the group consisting of: racemic 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine; a mixture of R and S enantiomers of 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine; 5-{[(3R)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine; racemic 4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine; a mixture of R and S enantiomers of 4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine; 4-({(3R)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine; 4-({(3S)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidinin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine; and pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

17. The pharmaceutical composition according to claim 16, wherein the compound is racemic 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or pharmaceutically acceptable salts thereof.

18. The pharmaceutical composition according to claim 16, wherein the compound is a mixture of R and S enantiomers of 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or pharmaceutically acceptable salts thereof.

19. The pharmaceutical composition according to claim 16, wherein the compound is 5-{[(3R)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 16, wherein the compound is racemic 4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or pharmaceutically acceptable salts thereof.

21. The pharmaceutical composition according to claim 16, wherein the compound is a mixture of R and S enantiomers of 4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or pharmaceutically acceptable salts thereof.

22. The pharmaceutical composition according to claim 16, wherein the compound is 4-({(3R)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition according to claim 16, wherein the compound is 4-({(3S)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or a pharmaceutically acceptable salt thereof.

24. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 16.

25. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 17.

26. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 18.

27. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 19.

28. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 20.

29. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 21.

30. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 22.

31. A method for treatment of schizophrenia, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 23.

32. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 16.

33. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 17.

34. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 18.

35. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 19.

36. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 20.

37. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 21.

38. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 22.

39. A method for treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 23.

40. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 16.

41. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 17.

42. A method for treatment of pain, comprising administering to a patient in need thereof; a pharmaceutical composition according to claim 18.

43. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 19.

44. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 20.

45. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 21.

46. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 22.

47. A method for treatment of pain, comprising administering to a patient in need thereof, a pharmaceutical composition according to claim 23.

Description

1. INTERMEDIATES

Intermediate 1a1

3-(2-Fluorophenyl)piperidine hydrochloride

[0416] ##STR00011##

[0417] Step (i)

[0418] Tetrakis(triphenylphosphine) palladium (0) (50 mg, 0.04 mmol) was added to a degassed solution of 3-iodopyridine (300 mg, 1.46 mmol) and (2-fluorophenyl)boronic acid (225 mg, 1.61 mmol) in toluene (7 mL) and EtOH (2 mL) under nitrogen. Sodium carbonate (465 mg, 4.39 mmol) was added and the reaction was heated in the microwave at 100° C. for 60 minutes. The reaction mixture was passed through a Celite cartridge, washing with EtOAc (10 mL), the residue was purified by column chromatography eluting with petroleum ether/ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated in vacuo to afford 3-(2-fluorophenyl)pyridine (160 mg, 0.92 mmol, 63%).

[0419] MS ES.sup.+: 173

[0420] Step (ii)

[0421] 3-(2-fluorophenyl)pyridine (160 mg, 0.92 mmol) was dissolved in anhydrous EtOH (50 mL) and hydrogen chloride (0.29 mL, 3.51 mmol) was added. The reaction mixture was evacuated and filled with nitrogen three times before platinum (IV) oxide (14 mg, 0.06 mmol) was added. The reaction was evacuated and filled with hydrogen from a balloon, then stirred at room temperature for 18 hours. The reaction mixture was filtered over Celite, washing with EtOH (10 mL) and then concentrated in vacuo to give 3-(2-fluorophenyl)piperidine hydrochloride (120 mg, 0.67 mmol, 72%)

[0422] MS ES.sup.+: 180

Intermediate 1a2

3-(2,4-Dichlorophenyl)piperidine hydrochloride

[0423] ##STR00012##

[0424] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) using 3-iodopyridine and (2,4-dichlorophenyl)boronic acid.

[0425] MS ES.sup.+: 230

Intermediate 1a3

3-(4-Chlorophenyl)piperidine hydrochloride

[0426] ##STR00013##

[0427] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) using 3-iodopyridine and (4-chlorophenyl)boronic acid.

[0428] MS ES.sup.+: 196

Intermediate 1a3A

(3S)-3-(4-Chlorophenyl)piperidine

[0429] ##STR00014##

[0430] Chiral resolution of racemic 3-(4-chlorophenyl)piperidine (Chembridge 4004245; CAS 55989-13-4) using chiral SFC (Chiralpak OD-H column, isocratic EtOH, 0.2% DEA) yielded (3S)-3-(4-Chlorophenyl)piperidine as the first eluting peak. Solvents removed in vacuo to give (3S)-3-(4-Chlorophenyl)piperidine as a solid.

[0431] MS ES.sup.+: 196

[0432] Chiral HPLC (Chiralpak AD column, isocratic EtOH 0.2% DEA) Rt=2.31 mins

Intermediate 1a3B

(3R)-3-(4-Chlorophenyl)piperidine

[0433] ##STR00015##

[0434] Chiral resolution of racemic 3-(4-chlorophenyl)piperidine (Chembridge 4004245; CAS 55989-13-4) using chiral SFC (Chiralpak OD-H column, isocratic, EtOH, 0.2% DEA) yielded (3R)-3-(4-chlorophenyl)piperidine as the second eluting peak. Solvents removed in vacuo to give (3R)-3-(4-chlorophenyl)piperidine as a solid.

[0435] MS ES.sup.+: 196

[0436] Chiral HPLC (Chiralpak AD column, isocratic EtOH 0.2% DEA) Rt=5.75 mins

Intermediate 1a4

Lithium(1+) ion 2-cyclopropylpyridine-4-carboxylate

[0437] ##STR00016##

[0438] Step (i)

[0439] A solution of methyl 2-bromoisonicotinate (500 mg, 2,314 mmol), potassium cyclopropyltrifluoroborate (685 mg, 4.63 mmol) and Cs.sub.2CO.sub.3 (2262 mg, 6.94 mmol) in THF (0.15 mL) and water (1.5 mL) was degassed by evacuating and flushing with N.sub.2. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (189 mg, 0.231 mmol) was added and the reaction was stirred at 85° C. for 18 hours. The reaction was diluted with EtOAc and filtered through celite. The eluent was concentrated under vacuum. The crude product was purified by column chromatography on silica eluting with petroleum ether/ethyl acetate from 100/0 to 80/20 to yield methyl 2-cyclopropylpyridine-4-carboxylate as a colourless oil (170 mg, 0.959 mmol, 42% yield).

[0440] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 0.98-1.10 (m, 4H) 2.05-2.20 (m, 1H) 3.95 (s, 3H) 7.52-7.65 (m, 1H) 7.72 (s, 1H) 8.47-8.65 (m, 1H)

[0441] MS ES.sup.+: 178.

[0442] Step (ii)

[0443] Methyl 2-cyclopropylpyridine-4-carboxylate (170 mg, 0.959 mmol) was dissolved in a mixture of THF (9 mL) and water (3 mL) and LiOH (45.98 mg, 1.920 mmol) was added. The mixture was stirred at ambient temperature for 19 hours. The reaction mixture was concentrated under vacuum used crude in the next step.

[0444] MS ES.sup.+: 164.

Intermediate 1a5

3-(4-Chloro-2-methylphenyl)piperidine hydrochloride

[0445] ##STR00017##

[0446] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) from 3-iodopyridine and (4-chloro-2-methylphenyl)boronic acid.

[0447] MS ES.sup.+: 210

Intermediate 1a6

3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride

[0448] ##STR00018##

[0449] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) from 3-iodopyridine and (4-chloro-2-(trifluoromethyl)phenyl)boronic acid. The product was optionally free based by loading on to a cation exchange cartridge (SCX-2) and eluting with EtOAc/[2M NH.sub.3 in MeOH].

[0450] MS ES.sup.+: 264

Intermediates 1a6A and 1a6B

3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (enantiomers)

[0451] ##STR00019##

[0452] Chiral resolution of racemic 3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6) using chiral SFC (Chiralcel-OD, 250×20 mm, 5 um column, eluting with heptane/IPA in a 80/20 ratio. Diethylamine (0.2%) was used as a modifier. The first eluting peak was assigned Intermediate 1a6A and the second eluting peak was assigned Intermediate 1a6B. The solvents were removed in vacuo to give the enantiomers of 3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride as solids.

[0453] MS ES.sup.+: 264

Intermediate 1a7

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine

[0454] ##STR00020##

[0455] 3-(4-Chlorophenyl)piperidine (0.1 g, 0.511 mmol) was added to a suspension of EDC (0.122 g, 0.639 mmol), HOBt (0.088 g, 0.572 mmol). TEA (0.249 mL, 1.789 mmol) and 2-fluoroisonicotinic acid (0.079 g, 0.562 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 18 hours. The crude reaction mixture was purified by column chromatography on silica, eluting with 0-80% ethyl acetate/petrol, to afford 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (149 mg, 0.467 mmol, 91% yield) as a solid.

[0456] MS ES.sup.+: 319

Intermediate 1a8

2-Fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0457] ##STR00021##

[0458] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (Intermediate 1a7) from 2-fluoroisonicotinic acid and 3-(4-methylphenyl)piperidine hydrochloride.

[0459] MS ES.sup.+: 299

Intermediate 1a9

2-Fluoro-4-{([3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0460] ##STR00022##

[0461] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (Intermediate 1a7) from 2-fluoroisonicotinic acid and 3-(2-methylphenyl)piperidine hydrochloride.

[0462] MS ES.sup.+: 299

Intermediate 1a10

3-(4-Chloro-2-fluorophenyl)piperidine hydrochloride

[0463] ##STR00023##

[0464] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) from 3-iodopyridine and (4-chloro-2-fluorophenyl)boronic acid.

[0465] MS ES.sup.+: 214

Intermediate 1a1

3-(2-Chloro-4-fluorophenyl)piperidine hydrochloride

[0466] ##STR00024##

[0467] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) from 3-iodopyridine and (2-chloro-4-fluorophenyl)boronic acid.

[0468] MS ES.sup.+: 214

Intermediate 1a12

2-Chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine

[0469] ##STR00025##

[0470] A solution of propylphosphonic anhydride (50% in EtOAc) (1.5 mL, 2.56 mmol) was added to a solution of 3-(4-chlorophenyl)piperidine (250 mg, 1.27 mmol) (Intermediate 1a3), triethylamine (0.36 mL, 2.56 mmol) and 2-chloroisonicotinic acid (242 mg, 1.53 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 2 hours. The crude product was purified by column chromatography on basic silica eluting with ethyl acetate/petrol 0-100% to afford 2-chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine (413 mg, 1.23 mmol, 96%) as a solid.

[0471] MS ES.sup.+: 335

Intermediate 1a13

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine

[0472] ##STR00026##

[0473] Prepared as described for 2-chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a12) using 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-fluoroisonicotinic acid.

[0474] MS ES.sup.+: 333

Intermediate 1a14

3-[4-(Trifluoromethyl)phenyl]piperidine hydrochloride

[0475] ##STR00027##

[0476] Step (i)

[0477] To a solution of 3-iodopyridine (4.00 g, 19.50 mmol), 4-(trifluoromethyl)phenylboronic acid (4.07 g, 21.50 mmol) in toluene (100 mL) and EtOH (25 mL) under nitrogen, was added 2 M aqueous sodium carbonate (29 mL, 58.50 mmol). The solution was degassed, tetrakis(triphenylphosphine) palladium (0) (750 mg, 0.65 mmol) was added and the reaction was heated at 100° C. for 3 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), washed with water (2×50 mL), saturated brine (1×50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with DCM to afford 3-(4-(trifluoromethyl)phenyl)pyridine (3.78 g, 87%) as a solid.

[0478] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 7.42-7.47 (m, 1H) 7.72 (d, J=8.86, 4H) 7.91-7.95 (m, 1H) 8.67-8.66 (m, 1H) 8.87 (s, 1H)

[0479] MS ES.sup.+: 224

[0480] Step (ii)

[0481] Platinum (IV) oxide (0.38 g, 1.69 mmol) was added to a degassed solution of 3-(4-(trifluoromethyl)phenyl)pyridine (3.78 g, 16.90 mmol) and hydrochloric acid (5 mL) in EtOH (132 mL) under nitrogen. The reaction mixture was evacuated and the autoclave filled with hydrogen at 5 bar pressure for 72 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo. This yielded 3-[4-(trifluoromethyl)phenyl]piperidine hydrochloride (4.21 g, 94% yield) as a solid.

[0482] MS ES.sup.+: 230

Intermediate 1a15

3-[2-(Trifluoromethyl)phenyl]piperidine hydrochloride

[0483] ##STR00028##

[0484] Step (i)

[0485] To a solution of 3-iodopyridine (0.4.00 g, 19.50 mmol), 2-(trifluoromethyl)phenylboronic acid (4.07 g, 21.50 mmol) in toluene (100 mL) and EtOH (25 mL) under nitrogen was added 2 M aqueous sodium carbonate (29 mL, 58.50 mmol). The solution was degassed, tetrakis(triphenylphosphine) palladium (0) (750 mg, 0.65 mmol) was added and the reaction was heated at 100° C. for 8 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), washed with water (2×50 mL), saturated brine (1×50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with DCM to afford 3-[2-(trifluoromethyl)phenyl]pyridine (3.08 g, 71%) as an oil.

[0486] MS ES.sup.+: 224

[0487] Step (ii)

[0488] Platinum (IV) oxide (310 mg, 1.38 mmol) was added to a degassed solution of 3-[2-(trifluoromethyl)phenyl]pyridine (3.08 g, 13.80 mmol) in EtOH (108 mL) and hydrogen chloride (4 mL) under nitrogen. The reaction mixture was evacuated and the autoclave filled with hydrogen at 5 bar pressure for 72 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo. This yielded 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (3.16 g, 13.8 mmol, 100%) as a solid.

[0489] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.79-1.91 (m, 4H) 2.95-2.98 (m, 1H) 3.16-3.47 (m, 4H) 7.46-7.50 (m, 1H) 7.68-7.75 (m, 3H) 9.00 (s, 1H) 9.32 (s, 1H)

[0490] MS ES.sup.+: 230

Intermediate 1a16

3-(2-Chlorophenyl)piperidine hydrochloride

[0491] ##STR00029##

[0492] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) from 3-iodopyridine and (2-chlorophenyl)boronic acid.

[0493] MS ES.sup.+: 196

Intermediate 1a17

3-(4-Methoxyphenyl)piperidine hydrochloride

[0494] ##STR00030##

[0495] Step (i)

[0496] To a solution of 3-iodopyridine (4.00 g, 19.50 mmol), 4-methoxy benzeneboronic acid (3.26 g, 21.50 mmol) in toluene (100 mL) and EtOH (25 mL) under nitrogen, was added 2 M aqueous sodium carbonate (29 mL, 58.50 mmol). The solution was degassed, tetrakis(triphenylphosphine) palladium (0) (750 mg, 0.65 mmol) was added and the reaction was heated at 100° C. for 3 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), washed with water (2×50 mL), saturated brine (1×50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with DCM to afford 3-(4-methoxyphenyl)pyridine (2.43 g, 67%) as an oil.

[0497] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 3.84 (s, 3H) 6.98-7.02 (m, 2H) 7.32-7.35 (m, 1H) 7.49-7.53 (m, 2H) 7.81-7.84 (m, 1H) 8.54 (d, J=4.09, 1H) 8.81 (s, 1H)

[0498] MS ES.sup.+: 186

[0499] Step (ii)

[0500] Platinum (IV) oxide (0.21 g, 0.93 mmol) was added to a degassed solution of 3-(4-methoxyphenyl)pyridine (1.73 g, 9.34 mmol) in EtOH (74 mL) and hydrogen chloride (3 mL) under nitrogen. The reaction mixture was evacuated and the autoclave filled with hydrogen at 10 bar pressure for 96 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo. This yielded 3-(4-methoxyphenyl)piperidine hydrochloride, as an oil, used without further purification.

[0501] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.41-1.86 (m, 5H) 2.67-2.96 (m, 4H) 3.71 (s, 3H) 6.91 (d, J=8.45, 2H) 7.20 (d, J=8.45, 2H)

[0502] MS ES.sup.+: 192

Intermediate 1a18

3-(2-Methoxyphenyl)piperidine

[0503] ##STR00031##

[0504] Step (i)

[0505] To a solution of 3-iodopyridine (4.00 g, 19.5 mmol), 2-methoxy benzeneboronic acid (3.26 g, 21.5 mmol) in toluene (100 mL) and EtOH (25 mL), under nitrogen, was added 2 M aqueous sodium carbonate (29.3 mL, 58.5 mmol). The solution was degassed, tetrakis(triphenylphosphine) palladium (0) (0.75 g, 0.65 mmol) was added and the reaction was heated at 100° C. for 8 hours. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (50 mL), washed with water (2×50 mL), saturated brine (0.1×50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with DCM to afford 3-(2-methoxyphenyl)pyridine (1.65 g, 46%) as an oil.

[0506] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 3.82 (s, 3H) 7.00-7.09 (m, 2H) 7.31-7.41 (m, 3H) 7.89-7.91 (m, 1H) 8.57 (d, J=4.36, 1H) 8.79 (s, 1H)

[0507] MS ES.sup.+: 186

[0508] Step (ii)

[0509] Platinum (IV) oxide (0.20 g, 0.89 mmol) was added to a degassed solution of 3-(2-methoxyphenyl)pyridine (1.65 g, 8.91 mmol) in EtOH (70 mL) and hydrogen chloride (2.85 mL) under nitrogen. The reaction mixture was evacuated and the autoclave filled with hydrogen at 10 bar pressure for 120 hours. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo. Water (50 mL) was added and the solution was adjusted to pH 8 with 1M NaOH solution. This was then taken up in EtOH, filtered and concentrated in vacuo. This yielded 3-(2-methoxyphenyl)piperidine (quantitative yield) as a solid, which was used without further purification.

[0510] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.42-1.78 (m, 5H) 2.33-2.54 (m, 2H) 2.89-3.03 (m, 2H) 3.78 (s, 3H) 6.87-6.96 (m, 2H) 7.13-7.24 (m, 2H) 8.54 (s, 1H)

[0511] MS ES.sup.+: 192

Intermediate 1a19

3-[2-(Trifluoromethoxy)phenyl]piperidine hydrochloride

[0512] ##STR00032##

[0513] Step (i)

[0514] Prepared as described for 3-[2-(trifluoromethyl)phenyl]pyridine (Intermediate 1a15, step (i)) from (2-(trifluoromethoxy)phenyl)boronic acid and 3-iodopyridine.

[0515] MS ES.sup.+: 240

[0516] Step (ii)

[0517] Prepared as described for 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a15, step (ii)) from 3-[2-(trifluoromethoxy)phenyl]pyridine.

[0518] MS ES.sup.+: 246

Intermediate 1a20

3-(4-Chloro-2-ethoxyphenyl)piperidine hydrochloride

[0519] ##STR00033##

[0520] Step (i)

[0521] Prepared as described for 3-[2-(trifluoromethyl)phenyl]pyridine (Intermediate 1a15, step (i)) from (4-chloro-2-ethoxyphenyl)boronic acid and 3-iodopyridine.

[0522] MS ES.sup.+: 234

[0523] Step (ii)

[0524] Prepared as described for 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a15, step (ii)) from 3-(4-chloro-2-ethoxyphenyl)pyridine

[0525] MS ES.sup.+: 240

Intermediate 1a21

3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidine hydrochloride

[0526] ##STR00034##

[0527] Step (i)

[0528] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1, step (i)) except using 1,4-dioxane/water (5:1) as solvent, 120° C. microwave irradiation and 3-iodopyridine and (4-methoxy-2-(trifluoromethyl)phenyl)boronic acid.

[0529] MS ES.sup.+: 254

[0530] Step (ii)

[0531] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1, step (ii)) from 3-[4-methoxy-2-(trifluoromethyl)phenyl]pyridine.

[0532] MS ES.sup.+: 260

Intermediate 1a22

3-(4-Methoxy-2-methylphenyl)piperidine

[0533] ##STR00035##

[0534] Step (i)

[0535] A microwave vial was charged with 3-iodopyridine (561 mg, 2.74 mmol), (4-methoxy-2-methylphenyl)boronic acid (500 mg, 3.01 mmol), sodium carbonate (1135 mg, 10.71 mmol) and tetrakis(triphenylphosphine) palladium (0) (104 mg, 0.090 mmol). Dioxane (5 mL) and water (0.1 mL) were added and the vial was sealed, purged with nitrogen and irradiated in a microwave at 100° C. for 20 minutes and then at 120° C. for 60 minutes. The reaction mixture was diluted in EtOAc (30 mL) and washed with water (2×10 mL), dried over MgSO.sub.4, filtered, and reduced in vacuo. The crude product was purified by column chromatography on silica, eluting with 15-100% ethyl acetate/petrol, to afford 3-(4-methoxy-2-methylphenyl)pyridine (525 mg, 2.63 mmol, 96% yield) as an oil.

[0536] MS ES.sup.+: 200

[0537] Step (ii)

[0538] A solution of 3-(4-methoxy-2-methylphenyl)pyridine (0.415 g, 2.083 mmol) and HCl (0.234 mL, 7.71 mmol) in ethanol/acetic acid (9:1; 20 mL) was eluted through a hydrogen flow reactor (Thales H-cube) fitted with a PtO.sub.2 catalyst cartridge on continual cycling mode at 100 bar, 100° C. Reaction very slow so switched to 5% Rh/Al.sub.2O.sub.3 and initiated cycling flow at 2 mL/min, 70° C. and 70 bar. After 3 hours eluant was collected and the solvent removed in vacuo. The crude product was dissolved in ethanol (5 mL) and loaded onto a 20 g SCX-2 cation exchange cartridge, washed with EtOH (50 mL) and eluted off with 2M NH.sub.3 in MeOH solution (50 mL). Solvent removed in vacuo to give 3-(4-methoxy-2-methylphenyl)piperidine (0.364 g, 1.773 mmol, 85% yield) as an oil.

[0539] MS ES.sup.+: 206

Intermediate 1a23

3-[2-(Difluoromethoxy)phenyl]piperidine hydrochloride

[0540] ##STR00036##

[0541] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) using 3-iodopyridine and (2-(difluoromethoxy)phenyl)boronic acid.

[0542] MS ES.sup.+: 228

Intermediate 1a24

2-(Piperidin-3-yl)benzonitrile hydrochloride

[0543] ##STR00037##

[0544] Step (i)

[0545] To a sealed tube containing 3-bromopyridine (2.27 g, 14.4 mmol) dissolved in DMF (60 mL) was added (2-carbamoylphenyl)boronic acid (5.0 g, 30.3 mmol) and potassium carbonate (3.01 g, 27.6 mmol). The solution was degassed and 1,1-bis(diphenylphosphino)ferrocenepalladium (II) dichloride (0.902 g, 1.52 mmol) was added, the tube was sealed and heated to 125° C. overnight. The reaction mixture was cooled to ambient temperature and solvent removed in vacuo. The residue was re-dissolved in 1N aqueous hydrochloric acid (200 mL) and washed with EtOAc (100 mL). The pH was adjusted to pH8 with 1N NaOH and extracted with DCM (3×100 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) filtered and concentrated in vacuo. The solid was triturated with ether to give 2-(pyridin-3-yl)benzamide as a solid (2.07 g, 73%).

[0546] MS ES.sup.+: 199

[0547] Step (ii)

[0548] Platinum (IV) oxide (0.237 g, 1.04 mmol) was added to a degassed solution of 2-(pyridin-3-yl)benzamide (2000 mg, 10.100 mmol) in EtOH (85 mL) and hydrogen chloride (3.33 mL) under nitrogen. The reaction mixture was evacuated and the autoclave filled with hydrogen at 10 bar pressure for 48 hours at 55° C. The reaction mixture was filtered through a bed of Celite and concentrated in vacuo to give 2-(piperidin-3-yl)benzamide hydrochloride as a solid (2.50 g, 100%).

[0549] MS ES.sup.+: 205

[0550] Step (iii)

[0551] To a suspension of 2-(piperidin-3-yl)benzamide hydrochloride (2.50 g, 10.38 mmol) in THF (25 mL) was added triethylamine (2420 mg, 23.88 mmol) followed by the drop wise addition of trifluoroacetic acid anhydride (1.59 mL, 11.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo, DCM (100 mL) was added and washed with saturated aqueous sodium hydrogen carbonate solution (3×100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification was carried out via silica column chromatography solvent system: 0-100% DCM to give 2-[1-(trifluoroacetyl)piperidin-3-yl]benzonitrile (1.90 g, 65%) as an oil. The material was carried through to the next step without further characterisation.

[0552] Step (iv)

[0553] To a solution of 2-[1-(trifluoroacetyl)piperidin-3-yl]benzonitrile (1.9 g, 6.70 mmol) in EtOH (47 mL) was added a solution of potassium carbonate (5.56 g, 40.2 mmol) in water (0.16 mL) and the resulting mixture was heated at reflux overnight. The reaction was concentrated in vacuo, water (100 mL) was added and extracted with DCM (2×100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give 2-(piperidin-3-yl)benzoic acid (1.9 g) as a solid.

[0554] MS ES.sup.+: 206

[0555] Step (v)

[0556] To a solution of 2-(piperidin-3-yl)benzoic acid (1.9 g, 9.25 mmol), triethylamine (2.57 mL, 18.5 mmol) in DCM (50 mL) was added di-tert-butyl dicarbonate (2.12 g, 9.71 mmol). The mixture was stirred overnight at room temperature. Water (50 mL) was added and extracted with DCM (3×50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification was carried out via silica column chromatography solvent system: 0-5% MeOH/DCM to give 2-{l-[(tert-butoxy)carbonyl]piperidin-3-yl}benzoic acid (0.7 g, 25%) as a solid.

[0557] MS ES.sup.+: 306

[0558] Step (vi)

[0559] To a solution of 2-{1-[(tert-butoxy)carbonyl]piperidin-3-yl}benzoic acid (0.7 g, 2.29 mmol) in THF (15 mL) was added 1,1-carbonyl diimidazole (0.74 g, 4.58 mmol) and the reaction mixture was stirred at room temperature overnight. Ammonia (33% in water, 2.19 mL, 114.6 mmol) was added in THF (7 mL) and stirred for 3 hours. The reaction was concentrated in vacuo, water was added (25 mL) and extracted with EtOAc (3×25 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give tert-butyl 3-(2-carbamoylphenyl)piperidine-1-carboxylate (0.110 g, 100%) as a solid.

[0560] MS ES.sup.+: 305

[0561] Step (vii)

[0562] To a suspension of tert-butyl 3-(2-carbamoylphenyl)piperidine-1-carboxylate (0.100 g, 0.328 mmol) in THF (1 mL) was added triethylamine (0.0.076 g, 0.105 mL, 0.755 mmol) followed by the drop wise addition of trifluoroacetic acid anhydride (0.076 g, 0.050 mL, 0.361 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and DCM (20 mL) was added, washed with saturated sodium hydrogen carbonate (3×10 mL), dried Na.sub.2SO.sub.4 and concentrated in vacuo to give tert-butyl 3-(2-cyanophenyl)piperidine-1-carboxylate (0.08 g, 85%) as a solid.

[0563] MS ES.sup.+: 287

[0564] Step (viii)

[0565] tert-Butyl 3-(2-cyanophenyl)piperidine-1-carboxylate (0.08 g, 0.279 mmol) was dissolved in 1,4-dioxane (0.5 mL) and 4M hydrogen chloride in 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 2-(piperidin-3-yl)benzonitrile hydrochloride (0.062 g, 100%) as a solid.

[0566] MS ES.sup.+: 187

Intermediate 1a25

3-(4-Chloro-2,6-dimethylphenyl)piperidine hydrochloride

[0567] ##STR00038##

[0568] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) using 3-iodopyridine and (4-chloro-2,6-dimethylphenyl)boronic acid.

[0569] MS ES.sup.+: 224

Intermediate 1b1

6-(Dimethylamino)pyridazine-4-carboxylic acid

[0570] ##STR00039##

[0571] Step (i)

[0572] Methyl 6-chloropyridazine-4-carboxylate (406 mg, 2.35 mmol) was added to a solution of dimethylamine hydrochloride (188 mg, 2.3 mmol) and triethylamine (0.737 mL, 5.29 mmol) in THF (1.5 mL). The reaction was sealed and heated to 90° C. for 18 hours. The reaction was allowed to cool to room temperate. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organics were washed with saturated brine (1×10 mL), dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude product was purified by column chromatography on basic silica, eluting with 10-50% ethylacetate/petrol to afford methyl 6-(dimethylamino)pyridazine-4-carboxylate (182 mg, 1.004 mmol, 44% yield) as a solid.

[0573] MS ES.sup.+: 182

[0574] Step (ii)

[0575] A solution of 1M lithium hydroxide (1.142 mL, 1.142 mmol) was added to a solution of methyl 6-(dimethylamino)pyridazine-4-carboxylate (0.18 g, 0.993 mmol) in THF (2 mL) and MeOH (0.500 mL). The reaction was stirred at room temperature for 15 minutes. The reaction was concentrated in vacuo, diluted with water (1.25 mL) and THF (1 mL) and acidified to pH 2-3 with a 10% aqueous hydrogen chloride solution. The reaction mixture was reduced in vacuo to give the title compound which was carried through without further purification.

[0576] MS ES.sup.+: 166

Intermediate 1b2

6-Chloropyridazine-4-carboxylic acid

[0577] ##STR00040##

[0578] To a stirred solution of methyl 6-chloropyridazine-4-carboxylate (5.05 g, 29.3 mmol) in THF (10 mL)/Water (20 mL) was added lithium hydroxide (1.402 g, 58.5 mmol). After 90 minutes the reaction mixture was acidified to pH 1-2 with conc. HCl (11.8M, 5 mL) and concentrated in vacuo to remove the THF component. Resultant precipitate stirred in predominantly aqueous medium at ambient temperature/pressure for about 30 minutes and was then filtered through a sinter under vacuum. The solid was dried in a vacuum oven to give 6-chloropyridazine-4-carboxylic acid (3.685 g, 23.24 mmol, 79% yield) as a solid.

[0579] MS ES.sup.+: 159

Intermediate 1b3

3-[2-Methoxy-4-(trifluoromethyl)phenyl]piperidine hydrochloride

[0580] ##STR00041##

[0581] Prepared as described for 3-(2-fluorophenyl)piperidine hydrochloride (Intermediate 1a1) using 3-iodopyridine and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid.

[0582] MS ES.sup.+: 260

Intermediate 2a1

3-(4-Chloro-2-methylphenyl)-1-[(1-methyl-5-nitro-1H-pyrazol-4-yl)carbonyl]piperidine

[0583] ##STR00042##

[0584] Prepared as described for 3-chloro-5-{3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 1-methyl-5-nitro-1H-pyrazole-4-carboxylic acid.

[0585] MS ES.sup.+: 363

Intermediate 2a2

tert-Butyl N-[4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-yl]carbamate

[0586] ##STR00043##

[0587] Step (i)

[0588] Boc-anhydride (3.23 g, 14.78 mmol) was added to a solution of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (1 g, 5.91 mmol), triethylamine (2.472 mL, 17.73 mmol) and DMAP (0.01 g, 0.082 mmol) in THF (30 mL). The reaction was heated to reflux for 48 hours. Additional Boc-anhydride (3.23 g, 14.78 mmol) was added and the solution heated to reflux overnight. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine (100 mL), passed through a phase separator cartridge to remove the aqueous phase and concentrated in vacuo to give ethyl 3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate as an oil. It was used in the next step without further purification.

[0589] MS ES.sup.+: 370

[0590] Step (ii)

[0591] Sodium hydroxide (5.90 mL, 11.80 mmol) was added to a solution of ethyl 3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate in EtOH (30 mL) under nitrogen. The reaction was heated to reflux for 4 hours. Additional sodium hydroxide (5.90 mL, 11.80 mmol) was added and the suspension heated to reflux for 2 hours. The suspension was concentrated in vacuo. The solution was acidified with 2M hydrogen chloride then partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate (3×100 mL). The combined organics were dried (MgSO.sub.4) and concentrated in vacuo to give 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid (1.22 g, 5.06 mmol, 86% yield) as a solid.

[0592] MS ES.sup.−:240

[0593] Step (iii)

[0594] 3-{[(tert-Butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid (0.805 g, 3.34 mmol) was added to a suspension of 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine (Intermediate 1a6) (0.8 g, 3.03 mmol), triethylamine (1.269 mL, 9.10 mmol). EDC (0.872 g, 4.55 mmol) and HOAt (0.619 g, 4.55 mmol) in DCM (15 mL). The reaction was stirred at room temperature for 2.5 hours. The mixture was diluted with DCM, washed with saturated NaHCO.sub.3 (1×50 mL), 5% citric acid (1×50 mL), water (1×50 mL), the aqueous phase removed using a phase separator cartridge and the organics concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-100% ethyl acetate/petrol and then increasing to 10% methanol/ethyl acetate to afford tert-butyl N-[4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-yl]carbamate (0.988 g, 2.03 mmol, 66.9% yield) as a solid.

[0595] MS ES.sup.+: 487

Intermediate 3a1

1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-one

[0596] ##STR00044##

[0597] To a stirred suspension of 2-(dimethylamino)isonicotinic acid hydrochloride (1.5 g, 7.40 mmol) in DCM (25 mL) was added triethylamine (3.30 mL, 23.69 mmol). The reaction mixture became homogeneous. Propylphosphonic anhydride (50% solution in EtOAc) (8.72 mL, 14.80 mmol) was added. After 25 minutes piperidin-3-one hydrochloride (1,204 g, 8.88 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate (25 mL) and diluted further with water (25 mL). The phases were separated and the aqueous phase was extracted with DCM (25 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and reduced in vacuo. The crude product was purified by reverse phase column chromatography eluting with 0-60% acetonitrile/water containing 0.1% ammonia to afford 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-one (0.505 g, 1.981 mmol, 26.8% yield) as an amber gum.

[0598] MS ES.sup.+: 248.

Intermediate 3a2

1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}-1,4,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

[0599] ##STR00045##

[0600] To a stirred solution of lithium bis(trimethylsilyl)amide [1.0M in THF] (10.89 mL, 10.89 mmol) in THF (20 mL) at −78° C. was added a solution of 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-one (Intermediate 3a1) (1.92 g, 7.78 mmol) in THF (15 mL) drop wise over 5 minutes under a nitrogen atmosphere, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (2.52 mL, 14.00 mmol) was added. After 1 hour additional 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (2.52 mL, 14.00 mmol) was added. After 55 minutes additional 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (0.5 mL, 2.78 mmol) was added, then the reaction was removed from the cold bath and allowed to warm to ambient temperature. The solvent was removed in vacuo. The crude product was purified by silica column chromatography (solvent system: 20-80% ethyl acetate/petrol). The first eluting component was isolated and identified as 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}-1,4,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1,268 g, 2,395 mmol, 31%), anoil.

[0601] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.7-2.0 (m, 2H), 2.3-2.4 (m, 2H), 2.95 (s, 6H), 3.3-3.7 (m, 2H), 6.35 (m, 2H), 6.7/7.5 (split signal, m, 1H), 8.1 (m, 1H)

[0602] MS ES.sup.+: 530

[0603] The second eluting component was isolated and identified as 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (0.284 g, 0.536 mmol, 7% yield), anoil.

[0604] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 2.2-2.5 (m, 2H), 3.0 (s, 6H), 3.3-3.8 (m, 2H), 3.9-4.3 (m, 2H), 5.9 (m, 1H), 6.3-6.4 (m, 2H), 8.1 (m, 1H)

[0605] MS ES.sup.+: 530

Intermediate 4

3-Chloro-5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine

[0606] ##STR00046##

[0607] To a stirred suspension of 6-chloropyridazine-4-carboxylic acid (Intermediate 1 b2) (0.1 g, 0.631 mmol) in DCM (2 ml) was added propylphosphonic anhydride (50% solution in EtOAc, 0.446 ml, 0.757 mmol) and triethylamine (0.176 ml, 1,261 mmol). After 15 minutes 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) (0.155 g, 0.631 mmol) was added. The reaction was stirred at ambient temperature for 5 hours. The reaction mixture was diluted in EtOAc (20 ml), then washed with saturated aqueous NaHCO3 (2×10 ml), HCl (3%; 2×10 ml) then brine (10 ml). The crude product was purified by column chromatography on silica, eluted with 12-100% ethyl acetate/petrol to afford 3-chloro-5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (0.114 g, 0.319 mmol, 51% yield) as a colourless gum.

[0608] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.53-2.09 (m, 4H) 2.12-2.47 (m, 3H) 2.67-3.72 (m, 4H) 4.64-4.93 (m, 1H) 6.94-7.26 (m, 3H) 7.41-7.65 (m, 1H) 9.06-9.23 (m, 1H)

[0609] MS ES.sup.+: 350

Intermediate 5

3-Chloro-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine

[0610] ##STR00047##

[0611] Prepared as described for 3-chloro-5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (Intermediate 4) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2) and 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6).

[0612] MS ES.sup.+: 404

Intermediate 6

3-Chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine

[0613] ##STR00048##

[0614] 3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidine hydrochloride (280 mg, 0.947 mmol) (Intermediate 1b3) was dissolved in DCM (30 mL) and treated with 6-chloropyridazine-4-carboxylic acid (150 mg, 0.947 mmol) (Intermediate 1b2), propylphosphonic anhydride (50% in EtOAc) (1.2 g, 1.894 mmol) and triethylamine and stirred at room temperature for 3 hours. The reaction was then quenched with 2N NaHCO.sub.3 and stirred for 30 minutes. Reaction was then diluted with DCM (10 mL) and passed through a phase separation cartridge and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-100% ethyl acetate/petrol to afford 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.291 g, 0.729 mmol, 77% yield) as a colourless foam.

[0615] MS ES.sup.+: 400

Intermediate 7

3-Chloro-5-{[3-(4-methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine

[0616] ##STR00049##

[0617] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2) and 3-(4-methoxy-2-methylphenyl)piperidine (Intermediate 1a22).

[0618] MS ES.sup.+: 346

Intermediate 8

3-Chloro-5-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine

[0619] ##STR00050##

[0620] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a21) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2).

[0621] MS ES.sup.+: 400

Intermediate 9

3-Chloro-5-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}pyridazine

[0622] ##STR00051##

[0623] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2) and 3-(4-chloro-2-ethoxyphenyl)piperidine hydrochloride (Intermediate 1a20).

[0624] MS ES.sup.+: 381

Intermediate 10

3-Chloro-4-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-6-methylpyridazine

[0625] ##STR00052##

[0626] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 3-chloro-6-methylpyridazine-4-carboxylic acid.

[0627] MS ES.sup.+: 364

Intermediate 11

3-Chloro-5-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}pyridazine

[0628] ##STR00053##

[0629] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 3-(2-methoxyphenyl)piperidine (Intermediate 1a18) and 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2).

[0630] MS ES.sup.+: 332

Intermediate 12

1-[(6-Chloropyridazin-4-yl)carbonyl]-3-(4-methoxyphenyl)azepane

[0631] ##STR00054##

[0632] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2) and 3-(4-methoxyphenyl)azepane hydrochloride.

[0633] MS ES.sup.+: 346

Intermediate 13

3-(4-Chlorophenyl)-1-[(6-chloropyridazin-4-yl)carbonyl]azepane

[0634] ##STR00055##

[0635] Prepared as described for 3-chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (Intermediate 6) from 6-chloropyridazine-4-carboxylic acid (Intermediate 1b2) and 3-(4-chlorophenyl)azepane hydrochloride.

[0636] MS ES.sup.+: 350

2. EXAMPLES

Example 1

4-{[3-(2-Fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0637] ##STR00056##

[0638] 2-(Dimethylamino)isonicotinic acid (75 mg, 0.451 mmol) was dissolved in DCM (3 mL) at room temperature and 3-(2-fluorophenyl)piperidine hydrochloride (120 mg, 0.558 mmol) (Intermediate 1a1) was added, followed by HOBt (77 mg, 0.505 mmol), EDC (108 mg, 0.564 mmol) and Et.sub.3N (0.126 mL, 0.903 mmol). The mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture which was stirred vigorously for 30 minutes before the phases were separated using a phase separator cartridge. The organics were concentrated in vacuo. The residues were dissolved in DMSO (together with a few drops of methanol) and purified by preparative LCMS (basic conditions) to give 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (15 mg, 0.046 mmol, 10%)

[0639] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.54-2.15 (m, 4H) 2.70-2.94 (m, 1H) 2.98-3.21 (m, 8H) 3.68-3.87 (m, 1H) 4.76 (m, 1H) 6.44-6.60 (m, 2H) 6.94-7.38 (m, 4H) 8.18 (m, 1H)

[0640] MS ES.sup.+: 328.

Example 2

4-{[3-(2,4-Dichlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0641] ##STR00057##

[0642] Prepared as described for 4-{([3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) using 2-(dimethylamino)isonicotinic acid and 3-(2,4-dichlorophenyl)piperidine hydrochloride (Intermediate 1a2).

[0643] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.55-2.14 (m, 4H) 2.69-3.33 (m, 9H) 3.77 (m, 1H) 4.77 (m, 1H) 6.45-6.58 (m, 2H) 7.11-7.52 (m, 3H) 8.10-8.27 (m, 1H)

[0644] MS ES.sup.+: 378.

Example 3

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-cydopropylpyridine

[0645] ##STR00058##

[0646] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chlorophenyl)piperidine hydrochloride (Intermediate 1a3) and lithium(1+) ion 2-cyclopropylpyridine-4-carboxylate (Intermediate 1a4).

[0647] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.10-1.31 (m, 4H) 1.52-2.19 (m, 4H) 2.64-2.91 (m, 3H) 2.99-3.16 (m, 1H) 3.58 (m, 1H) 4.74 (m, 1H) 7.06-7.41 (m, 6H) 8.53 (m, 1H)

[0648] MS ES.sup.+: 341.

Example 4

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-ethylpyridine

[0649] ##STR00059##

[0650] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-ethylisonicotinic acid.

[0651] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.23-1.43 (m, 3H) 1.51-2.09 (m, 4H) 2.10-2.52 (m, 3H) 2.62-3.16 (m, 5H) 3.47-3.73 (m, 1H) 4.63-4.85 (m, 1H) 6.96-7.33 (m, 5H) 8.50-8.65 (m, 1H)

[0652] MS ES.sup.+: 343.

Example 5

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-methylpyridine

[0653] ##STR00060##

[0654] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-methylisonicotinic acid.

[0655] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.52-2.08 (m, 4H) 2.15 (s, 1H) 2.44 (s, 1H) 2.52-3.17 (m, 6H) 3.47-3.73 (m, 1H) 4.60-4.83 (m, 2H) 6.97-7.28 (m, 5H) 8.44-8.75 (m, 1H)

[0656] MS ES.sup.+: 329.

Example 6

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-ethylpyridine

[0657] ##STR00061##

[0658] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6) and 2-ethylisonicotinic acid.

[0659] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.27 (br. s., 3H) 1.52-2.30 (m, 4H) 2.70-3.28 (m, 5H) 3.43-3.81 (m, 1H) 4.67-4.89 (m, 1H) 6.99-7.79 (m, 5H) 8.47-8.67 (m, 1H)

[0660] MS ES.sup.+: 397.

Example 7

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine

[0661] ##STR00062##

[0662] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6) and 2-(dimethylamino)isonicotinic acid.

[0663] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.67-2.16 (m, 4H) 2.75-2.85 (m, 1H) 2.99-3.25 (m, 8H) 3.56-3.87 (m, 1H) 4.67-4.84 (m, 1H) 6.37-6.61 (m, 2H) 7.31-7.77 (m, 3H) 8.07-8.25 (m, 1H)

[0664] MS ES.sup.+: 412.

Example 8

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N-(propan-2-yl)pyridin-2-amine

[0665] ##STR00063##

[0666] A solution of 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (Intermediate 1a7) in IPA (4 mL) in a microwave vial was treated with propan-2-amine (0.015 mL, 0.188 mmol) and triethylamine (0.044 mL, 0.314 mmol). The vial was sealed and the reaction mixture was heated at 100° C. for 4 days. The reaction mixture was concentrated under vacuum and the crude product was purified by preparative LCMS (0.1% ammonia modifier) to give 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N-(propan-2-yl)pyridin-2-amine (35 mg, 0.097 mmol, yield 62%).

[0667] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.17-1.32 (m, 6H) 1.48-2.22 (m, 5H) 2.59-2.89 (m, 2H) 3.05 (m, 1H) 3.64-3.99 (m, 2H) 4.72 (m, 1H) 6.32-6.60 (m, 2H) 7.10 (m, 1H) 7.21-7.45 (m, 3H) 7.98-8.09 (m, 1H)

[0668] MS ES.sup.+: 358.

Example 9

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-methoxypyridine

[0669] ##STR00064##

[0670] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6) and using 2-methoxyisonicotinic acid.

[0671] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.55-2.14 (m, 4H) 2.82 (m, 1H) 2.95-3.23 (m, 2H) 3.54-3.80 (m, 1H) 3.88-4.09 (m, 3H) 4.66-4.85 (m, 1H) 6.61-7.01 (m, 2H) 7.29-7.78 (m, 3H) 8.13-8.36 (m, 1H)

[0672] MS ES.sup.+: 399.

Example 10

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-methylpyridine

[0673] ##STR00065##

[0674] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6) and 2-methylisonicotinic acid.

[0675] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.53-2.18 (m, 5H) 2.48-2.69 (m, 3H) 2.73-2.91 (m, 1H) 3.02-3.26 (m, 1H) 3.50-3.76 (m, 1H) 4.69-4.89 (m, 1H) 7.02-7.79 (m, 5H) 8.44-8.64 (m, 1H)

[0676] MS ES.sup.+: 383

Example 11

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine

[0677] ##STR00066##

[0678] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-methylphenyl)piperidine hydrochloride and 2-(methylamino)isonicotinic acid.

[0679] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.68-2.00 (m, 3H) 2.06-2.16 (m, 1H) 2.29-2.40 (m, 3H) 2.60-2.85 (m, 2H) 2.90-3.10 (m, 4H) 3.71-3.83 (m, 1H) 4.60-4.72 (m, 1H) 4.76-4.87 (m, 1H) 6.33-6.44 (m, 1H) 6.52-6.61 (m, 1H) 6.98-7.05 (m, 1H) 7.07-7.22 (m, 3H) 8.10-8.19 (m, 1H)

[0680] MS ES.sup.+: 310

Example 12

2-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0681] ##STR00067##

[0682] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-methylphenyl)piperidine hydrochloride and 2-methylisonicotinic acid.

[0683] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.68-2.00 (m, 2H) 2.07-2.19 (m, 1H) 2.25-2.41 (m, 3H) 2.55-2.71 (m, 4H) 2.73-2.87 (m, 2H) 2.99-3.12 (m, 1H) 3.61-3.73 (m, 1H) 4.75-4.89 (m, 1H) 6.97-7.04 (m, 1H) 7.05-7.24 (m, 5H) 8.52-8.63 (m, 1H)

[0684] MS ES.sup.+: 295

Example 13

N,N-Dimethyl-4-{[3-(3-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine

[0685] ##STR00068##

[0686] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(3-methylphenyl)piperidine hydrochloride and 2-(dimethylamino)isonicotinic acid.

[0687] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.70-1.99 (m, 2H) 2.06-2.17 (m, 1H) 2.27-2.41 (m, 3H) 2.60-2.86 (m, 2H) 2.97-3.17 (m, 8H) 3.73-3.84 (m, 1H) 4.75-4.89 (m, 1H) 6.45-6.57 (m, 2H) 6.89-6.96 (m, 1H) 7.01-7.27 (m, 3H) 8.15-8.26 (m, 1H)

[0688] MS ES.sup.+: 324

Example 14

N,N-Dimethyl-4-{[3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine

[0689] ##STR00069##

[0690] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(2-methylphenyl)piperidine hydrochloride and 2-(dimethylamino)isonicotinic acid.

[0691] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.69-2.11 (m, 3H) 2.19 (s, 2H) 2.46 (s, 1H) 2.67-3.05 (m, 3H) 3.05-3.18 (m, 7H) 3.64-3.86 (m, 1H) 4.75-4.89 (m, 1H) 6.42-6.59 (m, 2H) 7.05-7.26 (m, 4H) 8.14-8.26 (m, 1H)

[0692] MS ES.sup.+: 324

Example 15

N,N-Dimethyl-4-[(3-phenylpiperidin-1-yl)carbonyl]pyridin-2-amine

[0693] ##STR00070##

[0694] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-phenylpiperidine and 2-(dimethylamino)isonicotinic acid.

[0695] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.71-1.99 (m, 3H) 2.09-2.19 (m, 1H) 2.65-2.90 (m, 2H) 2.99-3.17 (m, 7H) 3.75-3.85 (m, 1H) 4.78-4.89 (m, 1H) 6.47-6.56 (m, 2H) 7.09-7.17 (m, 1H) 7.19-7.41 (m, 4H) 8.17-8.26 (m, 1H)

[0696] MS ES.sup.+: 310

Example 16

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0697] ##STR00071##

[0698] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chlorophenyl)piperidine hydrochloride (Intermediate 1a3) and 2-(dimethylamino)isonicotinic acid. The reaction product was purified via silica column chromatography eluted with 0-100% ethyl acetate/petrol. The residue was recrystallised from MTBE and petrol to give the title product.

[0699] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.61-2.01 (m, 3H) 2.05-2.19 (m, 1H) 2.63-2.89 (m, 2H) 2.92-3.19 (m, 7H) 3.71-3.85 (m, 1H) 4.73-4.88 (m, 1H) 6.44-6.55 (m, 2H) 7.00-7.10 (m, 1H) 7.18-7.38 (m, 3H) 8.16-8.26 (m, 1H)

[0700] MS ES.sup.+: 344

Example 17

4-{[(3S)-3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0701] ##STR00072##

[0702] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 16) from (3S)-3-(4-chlorophenyl)piperidine (Intermediate 1a3A) and 2-(dimethylamino)isonicotinic acid hydrochloride.

[0703] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.66-2.00 (m, 3H) 2.04-2.16 (m, 1H) 2.63-2.88 (m, 2H) 2.93-3.18 (m, 7H) 3.72-3.85 (m, 1H) 4.75-4.87 (m, 1H) 6.44-6.57 (m, 2H) 7.00-7.10 (m, 1H) 7.18-7.38 (m, 3H) 8.15-8.26 (m, 1H)

[0704] MS ES.sup.+: 344

[0705] Chiral SFC (Chiralpak OD-H column, isocratic MeOH with ammonium acetate [10 mM]) Rt=9.43 mins (98% e.e.)

Example 18

4-{[(3R)-3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0706] ##STR00073##

[0707] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 16) from (3R)-3-(4-chlorophenyl)piperidine (Intermediate 1a3B) and 2-(dimethylamino)isonicotinic acid hydrochloride.

[0708] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.66-2.00 (m, 3H) 2.04-2.16 (m, 1H) 2.63-2.88 (m, 2H) 2.93-3.18 (m, 7H) 3.72-3.85 (m, 1H) 4.75-4.87 (m, 1H) 6.44-6.57 (m, 2H) 7.00-7.10 (m, 1H) 7.18-7.38 (m, 3H) 8.15-8.26 (m, 1H)

[0709] MS ES.sup.+: 344

[0710] Chiral SFC (Chiralpak OD-H column, isocratic MeOH with Ammonium Acetate [10 mM]) Rt=8.07 mins (100% e.e.)

[0711] A sample of the material was recrystallised from MeOH/EtOAc. Single crystal x-ray structure determination assigns absolute stereochemistry as the R configuration by the Flack parameter (χ=0.01(1)).

Example 19

4-{[3-(4-Fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0712] ##STR00074##

[0713] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-(dimethylamino)isonicotinic acid hydrochloride and 3-(4-fluorophenyl)piperidine.

[0714] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.65-2.00 (m, 3H) 2.05-2.16 (m, 1H) 2.64-2.88 (m, 2H) 2.94-3.08 (m, 1H) 3.09-3.17 (m, 6H) 3.73-3.83 (m, 1H) 4.75-4.87 (m, 1H) 6.46-6.56 (m, 2H) 6.93-7.12 (m, 3H) 7.21-7.33 (m, 1H) 8.17-8.25 (m, 1H)

[0715] MS ES.sup.+: 328

Example 20

2-Ethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0716] ##STR00075##

[0717] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-methylphenyl)piperidine hydrochloride and 2-ethylisonicotinic acid. The product was purified via silica column chromatography (solvent system: 0-100% ethyl acetate/petrol).

[0718] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.27-1.41 (m, 3H) 1.68-1.84 (m, 2H) 1.92-2.01 (m, 1H) 2.09-2.17 (m, 1H) 2.28-2.40 (m, 3H) 2.62-2.94 (m, 4H) 2.98-3.13 (m, 1H) 3.61-3.73 (m, 1H) 4.74-4.90 (m, 1H) 6.96-7.05 (m, 1H) 7.07-7.24 (m, 5H) 8.54-8.66 (m, 1H)

[0719] MS ES.sup.+: 309

Example 21

2-(Azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0720] ##STR00076##

[0721] Azetidine (0.029 g, 0.503 mmol) was added to a solution of 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (0.05 g, 0.168 mmol) (Intermediate 1a8) in THF (1 mL) under nitrogen. The reaction was heated to 85° C. for 18 hours. The crude reaction mixture was purified by silica column chromatography eluting with 0-100% ethyl acetate/petrol to afford 2-(azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (49 mg, 0.146 mmol, 87% yield) as a solid.

[0722] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.65-1.98 (m, 3H) 2.04-2.17 (m, 1H) 2.28-2.49 (m, 5H) 2.60-2.83 (m, 2H) 2.94-3.09 (m, 1H) 3.71-3.81 (m, 1H) 4.01-4.13 (m, 4H) 4.74-4.86 (m, 1H) 6.20-6.31 (m, 1H) 6.51-6.59 (m, 1H) 6.98-7.06 (m, 1H) 7.07-7.22 (m, 3H) 8.13-8.23 (m, 1H)

[0723] MS ES.sup.+: 336

Example 22

2-(Azetidin-1-yl)-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine

[0724] ##STR00077##

[0725] Prepared as described for 2-(azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Example 21) from 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (Intermediate 1a7) and azetidine.

[0726] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.62-2.01 (m, 3H) 2.02-2.17 (m, 1H) 2.35-2.50 (m, 2H) 2.63-2.88 (m, 2H) 2.93-3.10 (m, 1H) 3.69-3.83 (m, 1H) 4.01-4.15 (m, 4H) 4.72-4.85 (m, 1H) 6.20-6.31 (m, 1H) 6.51-6.58 (m, 1H) 6.99-7.10 (m, 1H) 7.17-7.38 (m, 3H) 8.13-8.25 (m, 1H)

[0727] MS ES.sup.+: 356

Example 23

2-(Azetidin-1-yl)-4-{[3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0728] ##STR00078##

[0729] Prepared as described for 2-(azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Example 21) from 2-fluoro-4-{[3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a9) and azetidine.

[0730] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.69-1.88 (m, 2H) 1.91-2.12 (m, 2H) 2.20 (s, 2H) 2.33-2.52 (m, 3H) 2.64-3.14 (m, 3H) 3.61-3.85 (m, 1H) 3.99-4.16 (m, 4H) 4.73-4.90 (m, 1H) 6.16-6.34 (m, 1H) 6.50-6.61 (m, 1H) 7.09-7.26 (m, 4H) 8.11-8.25 (m, 1H)

[0731] MS ES.sup.+: 336

Example 24

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0732] ##STR00079##

[0733] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-(dimethylamino)isonicotinic acid hydrochloride.

[0734] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.59-2.08 (m, 4H) 2.16-2.43 (m, 3H) 2.63-3.00 (m, 3H) 3.06-3.11 (s, 3H) 3.14 (s, 3H) 3.50-3.90 (m, 1H) 4.68-4.88 (m, 1H) 6.48-6.54 (m, 2H) 7.08-7.21 (m, 3H) 8.17-8.24 (m, 1H)

[0735] MS ES.sup.+: 358

Example 25

4-{[3-(4-Chloro-2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0736] ##STR00080##

[0737] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chloro-2-fluorophenyl)piperidine hydrochloride (Intermediate 1a10) and 2-(dimethylamino)isonicotinic acid hydrochloride.

[0738] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.72-2.15 (m, 4H) 2.75-3.08 (m, 3H) 3.12 (s, 6H) 3.72-3.84 (m, 1H) 4.75-4.84 (m, 1H) 6.42-6.58 (m, 2H) 6.94-7.22 (m, 3H) 8.17-8.25 (m, 1H)

[0739] MS ES.sup.+: 362

Example 26

4-{[3-(2-Chloro-4-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0740] ##STR00081##

[0741] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(2-chloro-4-fluorophenyl)piperidine hydrochloride (Intermediate 1a11) and 2-(dimethylamino)isonicotinic acid hydrochloride.

[0742] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.49-2.17 (m, 4H) 2.71-2.96 (m, 1H) 2.98-3.32 (m, 6H) 3.80 (m, 2H) 4.83 (m, 2H) 6.52 (m, 2H) 6.89-7.22 (m, 2H) 8.12-8.31 (m, 2H)

[0743] MS ES.sup.+: 362

Example 27

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine

[0744] ##STR00082##

[0745] A solution of propylphosphonic anhydride (50% in EtOAc) (0.298 mL, 0.511 mmol) was added to a solution of 3-(4-chlorophenyl)piperidine (0.05 g, 0.256 mmol), triethylamine (0.071 mL, 0.511 mmol) and 2-(methylamino)isonicotinic acid (0.047 g, 0.307 mmol) in DCM (0.1 mL). The reaction was stirred at room temperature for 18 hours. Water was added to the reaction mixture which was stirred vigorously for 30 minutes before the phases were separated using a phase separation cartridge. The organic phase was concentrated in vacuo. The crude product was purified by preparative LCMS (basic conditions) to give the title compound 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine (28 mg, 0.085 mmol, 33% yield).

[0746] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.50-2.02 (m, 4H) 2.05-2.16 (m, 1H) 2.64-2.87 (m, 2H) 2.91-3.08 (m, 2H) 3.70-3.84 (m, 1H) 4.63-4.84 (m, 2H) 6.30-6.45 (m, 1H) 6.53-6.59 (m, 1H) 7.01-7.12 (m, 1H) 7.20-7.40 (m, 3H) 8.11-8.20 (m, 1H)

[0747] MS ES.sup.+: 330

Example 28

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2,6-dimethylpyridine

[0748] ##STR00083##

[0749] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine (Example 27) from 3-(4-chlorophenyl)piperidine and 2,6-dimethylisonicotinic acid.

[0750] .sup.1H NMR (CHCl.sub.3-d)) δ ppm 1.61 (m, 2H) 1.74-1.86 (m, 1H) 2.12-2.15 (m, 1H) 2.33 (br. s., 3H) 2.55 (br. s., 3H) 2.81 (m, 2H) 3.09 (m, 1H) 3.85 (m, 1H) 4.79-4.82 (m, 1H) 7.02-7.13 (m, 1H) 7.30-7.37 (m, 1H) 7.40-7.62 (m, 2H) 8.41 (s, 2H)

[0751] MS ES.sup.+: 329

Example 29

2-Chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine

[0752] ##STR00084##

[0753] A solution of propylphosphonic anhydride (50% in EtOAc) (1.5 mL, 2.56 mmol) was added to a solution of 3-(4-chlorophenyl)piperidine (250 mg, 1.27 mmol), triethylamine (0.36 mL, 2.56 mmol) and 2-chloroisonicotinic acid (242 mg, 1.53 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 2 hours. The crude product was purified by column chromatography on basic silica eluted with 0-100% ethyl acetate/petrol to afford 2-chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine (413 mg, 1.23 mmol, 96%) as a solid.

[0754] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.49-1.64 (m, 1H) 1.64-2.27 (m, 3H) 2.62-2.99 (m, 2H) 3.06-3.24 (m, 1H) 3.63 (m, 1H) 4.79-4.82 (m, 1H) 6.97-7.13 (m, 1H) 7.14-7.50 (m, 5H) 8.37-8.65 (m, 1H)

[0755] MS ES.sup.+: 335

Example 30

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-(propan-2-yl)pyridine

[0756] ##STR00085##

[0757] Isopropylmagnesium chloride (0.403 mL, 0.805 mmol) was added dropwise to a solution of 2-chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine (0.15 g, 0.447 mmol) (Intermediate 1a12) and tris(((Z)-4-oxopent-2-en-2-yl)oxy)iron (7.90 mg, 0.022 mmol) in THF (4.47 mL) under nitrogen. The reaction was stirred at room temperature for 10 minutes, diluted with EtOAc and carefully quenched with a few drops of 2M hydrogen chloride. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (1×5 mL), saturated brine (1×5 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to give an oil. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-(propan-2-yl)pyridine (8 mg, 0.022 mmol, 5% yield) as a colourless gum.

[0758] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.23-1.45 (m, 6H) 1.51-1.63 (m, 2H) 1.69-1.85 (m, 2H) 2.13-2.15 (m, 1H) 2.70-2.94 (m, 1H) 2.94-3.24 (m, 2H) 3.60-3.76 (m, 1H) 4.77-4.88 (m, 1H) 6.97-7.15 (m, 2H) 7.18-7.39 (m, 4H) 8.58-8.73 (m, 1H)

[0759] MS ES.sup.+: 343

Example 31

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine

[0760] ##STR00086##

[0761] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine (Example 27) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-(methylamino)isonicotinic acid. The reaction product was purified via column chromatography on basic silica (solvent system: 10-100% ethyl acetate/petrol).

[0762] .sup.1H NMR (DCM-d.sub.2) δ ppm 1.57-1.62 (m, 1H) 1.74-2.05 (m, 3H) 2.18-2.44 (m, 3H) 2.63-3.14 (m, 7H) 3.58-3.89 (m, 1H) 4.61-4.83 (m, 1H) 6.29-6.60 (m, 1H) 7.05-7.29 (m, 3H) 8.04-8.18 (m, 1H)

[0763] MS ES.sup.+: 344

Example 32

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-methoxypyridine

[0764] ##STR00087##

[0765] Prepared as described for 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine (Example 27) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 2-methoxyisonicotinic acid. The reaction product was purified via column chromatography on basic silica (solvent system: 10-100% ethyl acetate/petrol).

[0766] .sup.1H NMR (DCM-d.sub.2) δ ppm 1.59-1.65 (m, 1H) 1.71-2.04 (m, 3H) 2.17-2.44 (m, 3H) 2.66-3.18 (m, 3H) 3.57-3.79 (m, 1H) 3.96-4.00 (m, 3H) 4.64-4.82 (m, 1H) 6.69-6.95 (m, 2H) 7.08-7.25 (m, 3H) 8.16-8.29 (m, 1H)

[0767] MS ES.sup.+: 345

Example 33

2-(Azetidin-1-yl)-4-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0768] ##STR00088##

[0769] Prepared as described for 2-(azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Example 21) from 4-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-fluoropyridine (Intermediate 1a13).

[0770] .sup.1H NMR (MeOH-d.sub.4) δ ppm 1.59-2.07 (m, 4H) 2.35-2.56 (m, 3H) 2.78-3.27 (m, 3H) 3.43-3.61 (m, 1H) 3.72-3.79 (m, 2H) 4.07-4.15 (m, 4H) 4.56-4.74 (m, 1H) 6.30-6.42 (m, 1H) 6.58-6.65 (m, 1H) 7.10-7.35 (m, 3H) 8.01-8.12 (m, 1H)

[0771] MS ES.sup.+: 370

Example 34

2-Methoxy-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0772] ##STR00089##

[0773] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-methylphenyl)piperidine hydrochloride and 2-methoxyisonicotinic acid.

[0774] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.68-1.99 (m, 3H) 2.05-2.16 (m, 1H) 2.28-2.40 (m, 3H) 2.59-2.87 (m, 2H) 2.99-3.11 (m, 1H) 3.64-3.75 (m, 1H) 3.90-4.02 (m, 3H) 4.75-4.87 (m, 1H) 6.70-6.80 (m, 1H) 6.84-6.93 (m, 1H) 6.97-7.06 (m, 1H) 7.08-7.22 (m, 3H) 8.17-8.29 (m, 1H)

[0775] MS ES.sup.+: 311

Example 35

4-{[3-(4-Methylphenyl)piperidin-1-yl]carbonyl}-2-(pyrrolidin-1-yl)pyridine

[0776] ##STR00090##

[0777] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-methylphenyl)piperidine hydrochloride and 2-(pyrrolidin-1-yl)isonicotinic acid. The reaction product was purified via column chromatography on silica (solvent system: 0-80% ethyl acetate/petrol).

[0778] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.67-1.83 (m, 2H) 1.91-2.15 (m, 6H) 2.29-2.39 (m, 3H) 2.61-2.84 (m, 2H) 2.96-3.09 (m, 1H) 3.41-3.53 (m, 4H) 3.74-3.85 (m, 1H) 4.77-4.87 (m, 1H) 6.29-6.39 (m, 1H) 6.45-6.52 (m, 1H) 6.98-7.05 (m, 1H) 7.07-7.13 (m, 1H) 7.14-7.22 (m, 2H) 8.14-8.25 (m, 1H)

[0779] MS ES.sup.+: 350

Example 36

4-{[(3S)-3-(3-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0780] ##STR00091##

[0781] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-(dimethylamino)isonicotinic acid hydrochloride and (S)-3-(3-methoxyphenyl)piperidine. The reaction product was purified via column chromatography on silica (solvent system: 0-100% ethyl acetate/petrol).

[0782] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.69-2.00 (m, 3H) 2.09-2.19 (m, 1H) 2.63-2.87 (m, 2H) 2.99-3.17 (m, 7H) 3.74-3.88 (m, 4H) 4.76-4.88 (m, 1H) 6.46-6.56 (m, 2H) 6.63-6.93 (m, 3H) 7.17-7.26 (m, 1H) 8.16-8.26 (m, 1H)

[0783] MS ES.sup.+: 340

Example 37

N-Ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine

[0784] ##STR00092##

[0785] N-methylethanamine (0.030 g, 0.503 mmol) was added to a solution of 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (0.050 g, 0.168 mmol) (Intermediate 1a8) in THF (1 mL) and heated at 85° C. in a sealed tube for 48 hours. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl})pyridin-2-amine (39 mg, 0.168 mmol, 65%).

[0786] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.10-1.23 (m, 3H) 1.68-1.98 (m, 3H) 2.06-2.16 (m, 1H) 2.29-2.40 (m, 3H) 2.60-2.84 (m, 2H) 2.95-3.10 (m, 4H) 3.54-3.66 (m, 2H) 3.75-3.85 (m, 1H) 4.76-4.88 (m, 1H) 6.41-6.53 (m, 2H) 6.98-7.05 (m, 1H) 7.07-7.14 (m, 1H) 7.16-7.22 (m, 2H) 8.14-8.23 (m, 1H)

[0787] MS ES.sup.+: 338

Example 38

2-(3,3-Difluoroazetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine

[0788] ##STR00093##

[0789] Prepared as described for N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 37) from 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a8) and 3,3-difluoroazetidine.

[0790] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.68-2.01 (m, 3H) 2.07-2.17 (m, 1H) 2.30-2.40 (m, 3H) 2.59-2.86 (m, 2H) 2.97-3.13 (m, 1H) 3.66-3.78 (m, 1H) 4.30-4.47 (m, 4H) 4.74-4.86 (m, 1H) 6.35-6.45 (m, 1H) 6.67-6.74 (m, 1H) 6.97-7.05 (m, 1H) 7.08-7.22 (m, 3H) 8.18-8.30 (m, 1H)

[0791] MS ES.sup.+: 372

Example 39

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}-N-propylpyridin-2-amine

[0792] ##STR00094##

[0793] Prepared as described for N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 37) from 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a8) and N-methylpropan-1-amine.

[0794] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 0.88-1.02 (m, 3H) 1.58-1.84 (m, 4H) 1.89-2.00 (m, 1H) 2.05-2.17 (m, 1H) 2.27-2.40 (m, 3H) 2.60-2.87 (m, 2H) 2.95-3.13 (m, 4H) 3.42-3.55 (m, 2H) 3.72-3.84 (m, 1H) 4.75-4.88 (m, 1H) 6.40-6.52 (m, 2H) 6.97-7.06 (m, 1H) 7.07-7.23 (m, 3H) 8.12-8.23 (m, 1H)

[0795] MS ES.sup.+: 352

Example 40

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}-N-(propan-2-yl)pyridin-2-amine

[0796] ##STR00095##

[0797] Prepared as described for N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 37) from 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a8) and N-methylpropan-2-amine.

[0798] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.12-1.25 (m, 6H) 1.61-2.00 (m, 3H) 2.05-2.17 (m, 1H) 2.27-2.40 (m, 3H) 2.61-2.91 (m, 5H) 2.94-3.11 (m, 1H) 3.74-3.86 (m, 1H) 4.73-4.98 (m, 2H) 6.41-6.55 (m, 2H) 6.97-7.05 (m, 1H) 7.07-7.23 (m, 3H) 8.13-8.25 (m, 1H)

[0799] MS ES.sup.+: 352

Example 41

1-(4-{[3-(4-Methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-yl)azetidin-3-ol

[0800] ##STR00096##

[0801] Prepared as described for N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 37) from 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine (Intermediate 1a8) and azetidin-3-ol.

[0802] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.65-2.00 (m, 2H) 2.06-2.15 (m, 1H) 2.19-2.29 (m, 1H) 2.29-2.40 (m, 3H) 2.59-2.85 (m, 2H) 2.96-3.10 (m, 1H) 3.69-3.80 (m, 1H) 3.84-3.96 (m, 2H) 4.26-4.39 (m, 2H) 4.74-4.88 (m, 2H) 6.25-6.35 (m, 1H) 6.54-6.64 (m, 1H) 6.98-7.06 (m, 1H) 7.07-7.22 (m, 3H) 8.13-8.25 (m, 1H)

[0803] MS ES.sup.+: 352

Example 42

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-ethoxypyridine

[0804] ##STR00097##

[0805] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chlorophenyl)piperidine and 2-ethoxyisonicotinic acid. The crude reaction mixture was purified by column chromatography on silica, eluting with 0-100% ethyl acetate/petrol to afford 4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}-2-ethoxypyridine (66 mg, 0.172 mmol, 67% yield) as a colourless gum.

[0806] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.34-1.48 (m, 3H) 1.66-1.86 (m, 2H) 1.89-2.02 (m, 1H) 2.04-2.18 (m, 1H) 2.59-2.90 (m, 2H) 2.95-3.14 (m, 1H) 3.65-3.78 (m, 1H) 4.31-4.47 (m, 2H) 4.72-4.88 (m, 1H) 6.66-6.76 (m, 1H) 6.80-6.90 (m, 1H) 6.99-7.11 (m, 1H) 7.17-7.39 (m, 3H) 8.14-8.28 (m, 1H)

[0807] MS ES.sup.+: 345

Example 43

N-Cyclopropyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine

[0808] ##STR00098##

[0809] Prepared as described for N-ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 37) from 2-fluoro-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl)}pyridine (Intermediate 1a8) and N-methylcyclopropanamine.

[0810] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 0.62-0.74 (m, 2H) 0.85-0.95 (m, 2H) 1.58-1.98 (m, 3H) 2.07-2.17 (m, 1H) 2.30-2.40 (m, 3H) 2.48-2.60 (m, 1H) 2.63-2.87 (m, 2H) 2.95-3.10 (m, 1H) 3.12-3.24 (m, 3H) 3.74-3.84 (m, 1H) 4.77-4.88 (m, 1H) 6.54-6.63 (m, 1H) 6.91-7.05 (m, 2H) 7.06-7.23 (m, 3H) 8.17-8.29 (m, 1H)

[0811] MS ES.sup.+: 350

Example 44

N,N-Dimethyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine formate

[0812] ##STR00099##

[0813] A solution of propylphosphonic anhydride (50% in EtOAc, 0.96 g, 0.89 mL, 1.50 mmol) was added to a solution of 3-[4-(trifluoromethyl)phenyl]piperidine hydrochloride (0.19 g, 0.75 mmol) (Intermediate 1a14) triethylamine (0.23 g, 0.31 mL, 2.23 mmol) and 2-dimethyl aminoisonicotinic acid (0.15 g, 0.90 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature overnight. Aqueous sodium bicarbonate solution (5 mL) was added and extracted with DCM (3×10 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The resulting mixture was purified with reverse phase HPLC using acetonitrile/water and formic acid buffer. This yielded the title compound (98.0 mg, 31% yield) as a colourless oil.

[0814] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.45-2.01 (m, 4H) 2.67-2.9 (m, 1H) 3.00 (s, 3H) 3.04 (s, 3H) 3.05-3.55 (m, 3H) 4.49-4.55 (m, 1H) 6.51-6.56 (m, 2H) 7.41-7.72 (m, 4H) 8.09-8.15 (m, 2H)

[0815] MS ES.sup.+: 378

Example 45

N,N-Dimethyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine

[0816] ##STR00100##

[0817] A solution of propylphosphonic anhydride (50% in EtOAc, 0.96 g, 0.89 mL, 1.50 mmol) was added to a solution of 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (0.19 g, 0.75 mmol) (Intermediate 1a15), triethylamine (0.23 g, 0.31 mL, 2.23 mmol) and 2-(dimethylamino)isonicotinic acid (0.15 g, 0.90 mmol) in DCM (3 mL). The reaction mixture was stirred at ambient temperature overnight. Aqueous sodium bicarbonate solution (5 mL) was added and extracted with DCM (3×10 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The resulting mixture was purified with reverse phase HPLC using acetonitrile/water and formic acid buffer. This yielded the title compound (52.0 mg, 16% yield) as a colourless oil.

[0818] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.52-1.88 (m, 4H) 2.85-3.65 (m, 4H) 2.95 (s, 3H) 3.02 (s, 3H) 4.45-4.57 (m, 1H) 6.37-6.54 (m, 2H) 7.36-7.75 (m, 4H) 8.02-8.12 (m, 2H)

[0819] MS ES.sup.+: 378

Example 46

4-{[3-(2-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0820] ##STR00101##

[0821] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-(dimethylamino)isonicotinic acid and 3-(2-chlorophenyl)piperidine hydrochloride (Intermediate 1a16).

[0822] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.33-2.20 (m, 6H) 2.69-3.41 (m, 7H) 3.76-3.80 (m, 1H) 4.67-4.89 (m, 1H) 6.56 (s, 2H) 7.12-7.51 (m, 4H) 8.08-8.26 (m, 1H)

[0823] MS ES.sup.+: 344

Example 47

4-{[3-(4-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0824] ##STR00102##

[0825] To a stirred solution of 2-(dimethylamino)isonicotinic acid hydrochloride (106 mg, 0.523 mmol) in DCM (2 mL) was added 3-(4-methoxyphenyl)piperidine (Intermediate 1a17—as free base) (100 mg, 0.523 mmol), triethylamine (0.146 mL, 1.046 mmol) and propylphosphonic anhydride (0.616 mL, 1.046 mmol). After 2 hours the reaction was quenched by addition of saturated aqueous NaHCO.sub.3 (2 mL), diluted in ethyl acetate (15 mL) and washed with water (2×5 mL) then brine (5 mL). The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 4-{[3-(4-methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (90.2 mg, 0.252 mmol, 48% yield) as a solid.

[0826] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.44-1.95 (m, 4H) 2.63-2.82 (m, 2H) 2.97-3.08 (m, 7H) 3.38-3.58 (m, 1H) 3.65-3.77 (m, 3H) 4.42-4.57 (m, 1H) 6.46-6.58 (m, 2H) 6.77-6.97 (m, 2H) 7.01-7.12 (m, 1H) 7.19-7.26 (m, 1H) 8.07-8.17 (m, 1H)

[0827] MS ES.sup.+: 340

Example 48

4-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0828] ##STR00103##

[0829] To a stirred suspension of 2-(dimethylamino)isonicotinic acid hydrochloride (0.1 g, 0.493 mmol) and 3-(2-methoxyphenyl)piperidine hydrochloride (Intermediate 1a 18) (0.112 g, 0.493 mmol) in DCM (2 ml) was added triethylamine (0.206 ml, 1.480 mmol) then propylphosphonic anhydride (0.727 ml, 1,234 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was diluted with EtOAc (20 ml) and washed with saturated (aq.) NaHCO.sub.3 (2×10 ml) then brine (10 ml). The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia) and lyophilised to afford 4-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (10.6 mg, 0.031 mmol, 6% yield) as a solid.

[0830] .sup.1H NMR (400 MHz, MeCN-d.sub.3) δ ppm 1.51-1.91 (m, 4H) 2.69-2.93 (m, 2H) 3.02-3.09 (m, 7H) 3.56-3.87 (m, 4H) 4.55-4.65 (m, 1H) 6.44-6.54 (m, 2H) 6.80-7.02 (m, 2H) 7.11-7.30 (m, 2H) 8.08-8.16 (m, 1H)

[0831] MS ES.sup.+: 340

Example 49

N,N-Dimethyl-4-[3-(4-methylphenyl)piperidin-1-yl]carbonyl)pyridin-2-amine

[0832] ##STR00104##

[0833] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-(dimethylamino)isonicotinic acid and 3-(4-methylphenyl)piperidine hydrochloride. The crude product was purified by column chromatography on basic silica, eluting with 0-60% ethyl acetate/petrol to afford N,N-dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (9 mg, 59%) as a solid.

[0834] .sup.1H NMR (400 MHz. MeOH-d.sub.4) δ ppm 1.54-2.12 (m, 4H) 2.23-2.38 (m, 3H) 2.68-2.96 (m, 2H) 3.04-3.23 (m, 7H) 3.60-3.76 (m, 1H) 4.59-4.72 (m, 1H) 6.52-6.65 (m, 2H) 6.99-7.11 (m, 2H) 7.12-7.25 (m, 2H) 8.09-8.19 (m, 1H)

[0835] MS ES.sup.+: 324

Examples 50 and 51

N,N-Dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (enantiomers)

[0836] ##STR00105##

[0837] Racemic N,N-dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (Example 49, 20 mg, 0.062 mmol) was separated by chiral liquid chromatography using a Chiralpak AD column and 10% EtOH in heptane (Isocratic) as solvent to give Enantiomer 1 (Rt=15.8 mins) and Enantiomer 2 (Rt=18.1 mins).

Example 50 (Enantiomer 1)

[0838] MS ES.sup.+: 324

[0839] Chiral SFC (Jasco) Chiralpak AD-H (4.6×100 mm, 51 μm Daicel); 100 mbar CO.sub.2 with 16%

[0840] EtOH; 40° C.; Rt=6.27 mins.

Example 51 (Enantiomer 2)

[0841] MS ES.sup.+: 324

[0842] Chiral SFC (Jasco) Chiralpak AD-H (4.6×100 mm, 5 μm Daicel); 100 mbar CO.sub.2 with 16% EtOH; 40° C.; Rt=7.23 mins.

Example 52

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-ethylpyridine

[0843] ##STR00106##

[0844] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-ethylisonicotinic acid and 3-(4-chlorophenyl)piperidine.

[0845] .sup.1H NMR (DCM-d.sub.2) δ ppm 1.26-1.43 (m, 3H) 1.53-2.15 (m, 4H) 2.61-3.13 (m, 5H) 3.55-3.70 (m, 1H) 4.68-4.70 (m, 1H) 7.06-7.41 (m, 6H) 8.55-8.65 (m, 1H)

[0846] MS ES.sup.+: 329

Example 53

N-Methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine

[0847] ##STR00107##

[0848] A solution of propylphosphonic anhydride (50 wt % in EtOAc, 0.760 mL), 2-(methylamino)isonicotinic acid hydrochloride hemi hydrate (50 mg, 0.253 mmol) and triethylamine (0.106 mL, 0.759 mmol) in DCM (2 mL) was added to 3-[4-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a14) (0.067 g, 0.253 mmol). The reaction was stirred at ambient temperature for 23 hours, then quenched by addition of saturated (aq.) NaHCO.sub.3 (5 mL) with vigorous stirring for 15 mins. The reaction was diluted in DCM (5 mL) and the phases separated. The aqueous was extracted with DCM (5 mL). The combined organics were reduced in vacuo and purified by reverse phase preparative HPLC (ACN/Water+0.1% formic acid) to afford N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine(10 mg, 0.253 mmol, 11%) as a solid.

[0849] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.48-2.23 (m, 4H) 2.66-3.17 (m, 6H) 3.68-3.89 (m, 1H) 4.68-4.91 (m, 1H) 5.15 (br. s, 1H) 6.28-6.62 (m, 2H) 7.16-7.28 (m, 1H) 7.34-7.70 (m, 3H) 8.00-8.21 (m, 1H)

[0850] MS ES.sup.+: 364

Example 54

N-Methyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine

[0851] ##STR00108##

[0852] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-(methylamino)isonicotinic acid hydrochloride hemi hydrate and 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a15).

[0853] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.65-2.17 (m, 4H) 2.68-3.26 (m, 6H) 3.64-3.89 (m, 1H) 4.74-4.94 (m, 1H) 5.15 (br. s, 1H) 6.28-6.65 (m, 2H) 7.30-7.78 (m, 4H) 7.94-8.20 (m, 1H)

[0854] MS ES.sup.+: 364

Example 55

4-{[3-(4-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine hemi formate

[0855] ##STR00109##

[0856] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-(methylamino)isonicotinic acid hydrochloride hemi hydrate and 3-(4-methyoxyphenyl)piperidine hydrochloride (Intermediate 1a17) except purified by reverse phase prep HPLC (ACN/Water+0.1% formic acid) to give the hemi formate salt.

[0857] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.63-2.23 (m, 4H) 2.69-3.13 (m, 6H) 3.61-3.89 (m, 4H) 4.67-4.88 (m, 1H) 5.70 (br. s, 1H) 6.31-6.63 (m, 2H) 6.75-6.94 (m, 2H) 6.97-7.10 (m, 1H) 7.14-7.26 (m, 1H) 7.95-8.16 (m, 1H) 8.35 (s, 0.5H, hemi-formate)

[0858] MS ES.sup.+: 326

Example 56

4-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine

[0859] ##STR00110##

[0860] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-(methylamino)isonicotinic acid hydrochloride hemi hydrate and 3-(2-methoxyphenyl)piperidine hydrochloride (Intermediate 1a18).

[0861] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.51-2.16 (m, 4H) 2.68-3.33 (m, 6H) 3.58-3.98 (m, 4H) 4.66-4.89 (m, 1H) 5.30 (br. s, 1H) 6.34-6.49 (m, 1H) 6.53-6.67 (m, 1H) 6.72-7.02 (m, 2H) 7.07-7.27 (m, 2H) 7.96-8.18 (m, 1H)

[0862] MS ES.sup.+: 326

Example 57

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine

[0863] ##STR00111##

[0864] 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (50 mg, 0.167 mmol) (Intermediate 1a6) was dissolved in DCM (5 mL) at room temperature and 2-(methylamino)isonicotinic acid, hydrogen chloride (47.1 mg, 0.250 mmol) was added, followed by propylphosphonic anhydride (50% wt solution in ethyl acetate) (0.106 mL, 0.167 mmol) and triethylamine (0.023 mL, 0.167 mmol). The mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture which was stirred vigorously for 30 minutes before the phases were separated using a phase separator cartridge. The organics were concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine (35 mg, 0.09 mmol, 53% yield).

[0865] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.51 (br. s., 1H) 1.65-1.97 (m, 3H) 2.62-3.30 (m, 6H) 3.38-3.65 (m, 1H) 4.36-4.58 (m, 1H) 6.19-6.72 (m, 3H) 7.60-8.12 (m, 4H)

[0866] MS ES.sup.+: 398

Example 58

2-Ethyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridine

[0867] ##STR00112##

[0868] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-ethylisonicotinic acid and 3-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a15).

[0869] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.01-1.34 (m, 3H) 1.48-2.00 (m, 4H) 2.61-3.07 (m, 4H) 3.18-3.51 (m, 2H) 4.43-4.64 (m, 1H) 6.96-7.85 (m, 6H) 8.37-8.62 (m, 1H)

[0870] MS ES.sup.+: 363

Example 59

2-Ethyl-4-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}pyridine

[0871] ##STR00113##

[0872] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-ethylisonicotinic acid and 3-(2-methoxyphenyl)piperidine hydrochloride (the hydrochloride salt of Intermediate 1a18).

[0873] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.09-1.35 (m, 3H) 1.45-1.98 (m, 4H) 2.68-3.89 (m, 9H) 4.37-4.64 (m, 1H) 6.78-7.33 (m, 6H) 8.57 (d, J=5.05 Hz, 1H)

[0874] MS ES.sup.+: 325

Example 60

N,N-Dimethyl-4-({3-[2-(trifluoromethoxy)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine

[0875] ##STR00114##

[0876] A solution of 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 10.6 mL, 1.06 mmol) was added to a solution of 3-[2-(trifluoromethoxy)phenyl]piperidine hydrochloride (0.150 g, 0.532 mmol) (Intermediate 1a19), triethylamine (0.148 mL, 1.06 mmol) and 2-(dimethylamino)isonicotinic acid (0.106 g, 0.639 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 24 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The phases were separated and the aqueous extracted with DCM (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% formic acid) to afford N,N-dimethyl-4-({3-[2-(trifluoromethoxy)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (55 mg, 0.140 mmol, 26%) as a colourless oil.

[0877] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.10-2.00 (m, 4H) 2.6-3.2 (m, 9H) 3.5-3.7 (m, 1H) 4.6-4.8 (m, 1H) 6.44-6.59 (m, 2H) 7.2-7.4 (m, 4H) 8.08-8.13 (m, 1H)

[0878] MS ES.sup.+: 394

Example 61

4-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0879] ##STR00115##

[0880] A solution of 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 10.6 mL, 1.06 mmol) was added to a solution of 3-(4-chloro-2-ethoxyphenyl)piperidine hydrochloride (0.150 g, 0.626 mmol) (Intermediate 1a20), triethylamine (0.17 mL, 1.25 mmol) and 2-(dimethylamino)isonicotinic acid (0.125 g, 0.751 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 24 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The phases were separated and the aqueous phase was extracted with DCM (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC, eluting with acetonitrile/water (with 0.1% formic acid) to afford 4-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (0.069 g, 0.178 mmol, 29%).

[0881] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.15-1.97 (m, 6H) 2.89-3.13 (m, 12H) 3.58-3.67 (m, 1H) 4.68-4.75 (m, 1H) 6.19-6.51 (m, 2H) 6.93-7.19 (m, 3H) 8.09-8.17 (m, 1H)

[0882] MS ES.sup.+: 388

Example 62

4-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine

[0883] ##STR00116##

[0884] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine(Example 53) from 2-(dimethylamino)isonicotinic acid hydrochloride and 3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a21).

[0885] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.35-1.95 (m, 4H) 2.72-3.62 (m, 10H) 3.70-3.90 (m, 3H) 4.39-4.61 (m, 1H) 6.32-6.64 (m, 2H) 7.01-7.30 (m, 2H) 7.47-7.73 (m, 1H) 7.98-8.19 (m, 1H)

[0886] MS ES.sup.+: 408

Example 63

4-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine

[0887] ##STR00117##

[0888] Prepared as described N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 3-(4-methoxy-2-methylphenyl)piperidine (Intermediate 1a22) and 2-(methylamino)isonicotinic acid hydrochloride.

[0889] .sup.1H NMR (400 MHz, MeCN-d.sub.3) δ ppm 1.40-2.03 (m, 4H) 2.05-2.25 (m, 3H) 2.57-3.16 (m, 6H) 3.36-3.86 (m, 4H) 4.45-4.73 (m, 1H) 5.14-5.36 (m, 1H) 6.25-6.60 (m, 2H) 6.64-6.87 (m, 2H) 7.00-7.30 (m, 1H) 7.91-8.17 (m, 1H)

[0890] MS ES.sup.+: 340

Example 64

4-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine formate

[0891] ##STR00118##

[0892] Prepared as described for N-methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine (Example 53) from 2-(methylamino)isonicotinic acid hydrochloride and 3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a21). The reaction product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia). This was repeated a second time but using instead, as the eluant, acetonitrile/water (with 0.1% formic acid) to afford 4-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine formate (12.3 mg, 0.028 mmol, 9.63% yield) as a solid.

[0893] .sup.1H NMR (400 MHz. MeCN-d.sub.3) δ ppm 1.42-2.11 (m, 4H) 2.88 (br. s, 3H) 2.95-3.20 (m, 2H) 3.31 (s, 1H) 3.43-3.71 (m, 1H) 3.73-3.95 (m, 3H) 4.44-4.73 (m, 1H) 5.50 (br. s, 1H) 6.29-6.62 (m, 2H) 7.03-7.32 (m, 2H) 7.33-7.63 (m, 1H) 7.90-8.20 (m, 1H) 8.13 (s, 1H, formate)

[0894] MS ES.sup.+: 394

Example 65

4-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine

[0895] ##STR00119##

[0896] To a stirred solution of 2-(methylamino)isonicotinic acid hydrochloride (63.2 mg, 0.320 mmol), 3-(4-chloro-2-ethoxyphenyl)piperidine hydrochloride (80 mg, 0.291 mmol) (Intermediate 1a20) and triethylamine (0.081 mL, 0.582 mmol) in DCM (4 mL) was added propylphosphonic anhydride (0.257 mL, 0.436 mmol). In a separate flask additional 2-(methylamino)isonicotinic acid hydrochloride (57.5 mg, 0.291 mmol) in DCM (0.5 mL) was incubated with triethylamine (0.040 mL, 0.291 mmol, 1 eq.) and propylphosphonic anhydride (0.257 mL, 0.436 mmol, 1.5 eq). After 10 minutes the solution was added to the reaction mixture. Further 2-(methylamino)isonicotinic acid hydrochloride (57 mg. 0.29 mmol, 1 eq) and EDC (55.7 mg, 0.291 mmol) were added. After 17 hours the reaction was quenched with saturated (aq.) NaHCO.sub.3 (2 mL) then diluted with EtOAc (20 mL) and washed with saturated aqueous) NaHCO.sub.3 (2×5 mL). The reaction mixture was concentrated in vacuo and the crude product was purified twice by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to give 4-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine (10 mg, 0.025 mmol, 9% yield) as a solid.

[0897] .sup.1H NMR (400 MHz, MeCN-d.sub.3) δ ppm 1.13-2.02 (m, 7H) 2.65-3.35 (m, 6H) 3.56-3.78 (m, 1H) 3.84-4.17 (m, 2H) 4.43-4.70 (m, 1H) 5.16-5.40 (m, 1H) 6.26-6.58 (m, 2H) 6.79-7.07 (m, 2H) 7.10-7.33 (m, 1H) 8.01-8.12 (m, 1H)

[0898] MS ES.sup.+: 374

Example 66

4-({3-[2-(Difluoromethoxy)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine

[0899] ##STR00120##

[0900] A solution of 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.67 mL, 1.13 mmol) was added to a solution of 3-[2-(difluoromethoxy)phenyl]piperidine hydrochloride (0.150 g, 0.568 mmol) (Intermediate 1a23), triethylamine (0.159 mL, 1.13 mmol) and 2-(dimethylamino)isonicotinic acid (0.113 g, 0.683 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 24 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The phases were separated and the aqueous phase was extracted with DCM (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% formic acid) to afford 4-({3-[2-(difluoromethoxy)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine (58 mg, 0.140 mmol, 27%) as a colourless gum.

[0901] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.59-2.02 (m, 4H) 2.72-3.24 (m, 9H) 3.61-3.71 (m, 1H) 4.74-4.78 (m, 1H) 6.56-6.64 (m, 3H) 6.95-7.30 (m, 4H), 8.16 (m, 1H)

[0902] MS ES.sup.+: 376

Example 67

2-(1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-yl)benzonitrile

[0903] ##STR00121##

[0904] A solution of 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.32 mL, 0.556 mmol) was added to a solution of 2-(piperidin-3-yl)benzonitrile hydrochloride (0.062 g, 0.278 mmol) (Intermediate 1a24), triethylamine (0.078 mL, 0.556 mmol) and 2-(dimethylamino)isonicotinic acid (0.055 g, 0.330 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The phases were separated and the aqueous phase was extracted with DCM (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% formic acid) to afford 2-(1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-yl)benzonitrile(37 mg, 0.140 mmol, 40%) as a foam.

[0905] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.76-2.15 (m, 4H) 2.60-2.77 (m, 1H) 3.01-3.18 (m, 8H) 3.6-3.8 (m, 1H) 4.79-4.88 (m, 1H) 6.5-6.7 (m, 2H) 7.20-7.40 (m, 2H) 7.57-7.59 (m, 2H) 8.17-8.21 (m, 1H)

[0906] MS ES.sup.+: 335

Example 68

4-{[3-(4-Chloro-2,6-dimethylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[0907] ##STR00122##

[0908] A solution of 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.34 mL, 0.580 mmol) was added to a solution of 3-(4-chloro-2,6-dimethylphenyl)piperidine hydrochloride (0.065 g, 0.291 mmol) (Intermediate 1a25), triethylamine (0.058 mL, 0.580 mmol) and 2-(dimethylamino)isonicotinic acid (0.058 g, 0.349 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 24 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO.sub.3. The phases were separated and the aqueous phase was extracted with DCM (3×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% formic acid) to afford 4-{[3-(4-chloro-2,6-dimethylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (32 mg, 0.140 mmol, 28%) as a foam.

[0909] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.78-2.11 (m, 4H), 2.14 (s, 6H), 2.54-2.69 (m, 1H), 3.18 (s, 6H), 3.48-3.62 (m, 2H), 4.53-4.71 (m, 2H), 6.47-6.59 (m, 2H), 6.80-6.87 (m, 2H), 8.10-8.17 (m, 1H).

[0910] MS ES.sup.+: 372

Example 69

5-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[0911] ##STR00123##

[0912] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chlorophenyl)piperidine and 6-(dimethylamino)pyridazine-4-carboxylic acid (Intermediate 1b1) in suspension (DMF). Purification was carried out via silica column chromatography (solvent system: 0-100% ethyl acetate/petrol).

[0913] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.61-2.19 (m, 4H) 2.69-2.89 (m, 1H) 3.01-3.30 (m, 8H) 3.63-3.77 (m, 1H) 4.73-4.86 (m, 1H) 6.73-6.84 (m, 1H) 7.01-7.11 (m, 1H) 7.19-7.39 (m, 3H) 8.54 (s, 1H)

[0914] MS ES.sup.+: 345

Example 70

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[0915] ##STR00124##

[0916] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (Intermediate 1a5) and 6-(dimethylamino)pyridazine-4-carboxylic acid (Intermediate 1b1). The crude product was purified via column chromatography on basic silica (solvent system: 10-100% ethyl acetate/petrol).

[0917] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.53-2.45 (m, 7H) 2.63-3.14 (m, 2H) 3.15-3.27 (m, 6H) 3.31-3.77 (m, 1H) 4.68-4.84 (m, 1H) 6.68-6.86 (m, 1H) 7.01-7.22 (m, 4H) 8.48-8.57 (m, 1H)

[0918] MS ES.sup.+: 358

Example 71

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0919] ##STR00125##

[0920] To a stirred solution of 3-chloro-5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (0.055 g, 0.157 mmol) (Intermediate 4) in butan-1-ol (3 mL) and N-methyl-2-pyrrolidinone (0.3 mL) was added methylamine (2.0M in THF) (0.314 mL, 0.628 mmol). The reaction vial was purged with nitrogen, sealed and irradiated in a microwave reactor at 100° C. for 10 minutes. Additional methylamine (2.0M in THF) (0.5 mL, 1 mmol) was added and the reaction irradiated in a microwave reactor at 135° C. for 140 minutes. Additional methylamine (2.0M in THF) (0.5 mL, 1 mmol) was added and the reaction was irradiated in a microwave reactor at 135° C. for 60 another minutes. Solvent and excess amine was removed in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (35.4 mg, 0.103 mmol, 65% yield) as a solid.

[0921] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.47-1.97 (m, 4H) 2.03-2.44 (m, 3H) 2.62-2.98 (m, 5H) 3.01-3.25 (m, 1H) 3.25-3.54 (m, 1H) 4.28-4.62 (m, 1H) 6.66-6.83 (m, 1H) 6.90-7.06 (m, 1H) 7.10-7.39 (m, 3H) 8.45 (m, 1H)

[0922] MS ES.sup.+: 345

Examples 72 and 73

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (enantiomers)

[0923] ##STR00126##

[0924] Racemic 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (Example 71) was dissolved to 25 mg/mL and was resolved by chiral HPLC using a Lux Amylose-2 21.2×250 mm 5 um column. The eluant used was heptane/ethanol in a 50/50 ratio with 0.1% TFA added to the diluent. The flow rate was 21 mL/min. The first product component to elute was collected and assigned ‘enantiomer 1’ and the second product component to elute was collected and assigned ‘enantiomer 2’. The fractions were then evaporated using a rotary evaporator and dried in a vacuum oven at 40° C. and 25 mbar for 18 hours to give 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine enantiomers as trifluoroacetate salts. The samples were free-based and triturated from petroleum ether (40-60) and diethyl ether to give 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine enantiomer 1 and enantiomer 2 as solids.

Example 72—Enantiomer 1

5-{[(3R)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0925] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.47-1.97 (m, 4H) 2.03-2.44 (m, 3H) 2.62-2.98 (m, 5H) 3.01-3.25 (m, 1H) 3.25-3.54 (m, 1H) 4.28-4.62 (m, 1H) 6.66-6.83 (m, 1H) 6.90-7.06 (m, 1H) 7.10-7.39 (m, 3H) 8.45 (m, 1H)

[0926] MS ES.sup.+: 345

[0927] Chiral HPLC (Chiralpak AY column, 100×4.6 mm; isocratic 50% EtOH/50% IPA+0.2% TEA; 1.0 mL/min; 10° C.) Rt=2.8 mins.

Example 73—Enantiomer 2

5-{[(3S)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0928] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.47-1.97 (m, 4H) 2.03-2.44 (m, 3H) 2.62-2.98 (m, 5H) 3.01-3.25 (m, 1H) 3.25-3.54 (m, 1H) 4.28-4.62 (m, 1H) 6.66-6.83 (m, 1H) 6.90-7.06 (m, 1H) 7.10-7.39 (m, 3H) 8.45 (m, 1H)

[0929] MS ES.sup.+: 345

[0930] Chiral HPLC (Chiralpak AY column, 100×4.6 mm; isocratic 50% EtOH/50% IPA+0.2% TEA; 1.0 mL/min; 10° C.) Rt=4.2 mins.

Example 74

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methoxypyridazine

[0931] ##STR00127##

[0932] To a stirred solution of 3-chloro-5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (0.055 g, 0.157 mmol) (Intermediate 4) in MeOH (2 mL) was added sodium methoxide (25 wt % in MeOH) (0.144 mL, 0.628 mmol). The reaction vial was purged with nitrogen, sealed and irradiated in a microwave reactor at 100° C. for 10 minutes. The reaction was quenched by addition of saturated aqueous ammonium chloride (1 mL), diluted in ethyl acetate (20 mL) and extracted with dilute aqueous hydrogen chloride (3%, 3×10 mL). The organic phase was reduced in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to yield the title product 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methoxypyridazine (2.6 mg, 7.44 μmol, 5% yield) as a colourless solid.

[0933] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.47-2.10 (m, 4H) 2.12-2.50 (m, 3H) 2.61-3.27 (m, 3H) 3.42-3.76 (m, 1H) 4.07-4.27 (m, 3H) 4.66-4.90 (m, 1H) 6.84-7.26 (m, 4H) 8.73-9.04 (m, 1H)

[0934] MS ES.sup.+: 346

Example 75

5-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine

[0935] ##STR00128##

[0936] To a stirred solution of 3-chloro-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.060 g, 0.148 mmol) (Intermediate 5) in butan-1-ol (3 mL) was added dimethylamine (2.0M in THF) (0.742 mL, 1.484 mmol). The reaction vial was purged with nitrogen, sealed and irradiated in a microwave reactor at 135° C. for 45 minutes. Solvent and excess dimethylamine was removed in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine (34.1 mg, 0.083 mmol, 56% yield) as a solid.

[0937] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.52-1.96 (m, 4H) 2.74-3.60 (m, 10H) 4.40-4.65 (m, 1H) 6.92-7.14 (m, 1H) 7.55-7.88 (m, 3H) 8.30-8.56 (m, 1H)

[0938] MS ES.sup.+: 413

Example 76

5-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine

[0939] ##STR00129##

[0940] A solution of 3-chloro-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.18 g, 0.445 mmol) (Intermediate 5) and methanamine (2M in THF) (4 mL, 8.00 mmol) was heated by microwave irradiation at 120° C. for 5.5 hours. The suspension was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia). The product was freeze dried to afford 5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine (0.085 g, 0.213 mmol, 47.9% yield) as solid.

[0941] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.48-1.96 (m, 4H) 2.77-3.05 (m, 5H) 3.13-3.61 (m, 2H) 4.38-4.61 (m, 1H) 6.64-6.82 (m, 1H) 6.97 (br. s., 1H) 7.63-7.86 (m, 3H) 8.30-8.49 (m, 1H)

[0942] MS ES.sup.+: 399

Example 77

3-(Azetidin-1-yl)-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine

[0943] ##STR00130##

[0944] To a stirred solution of 3-chloro-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.060 g, 0.148 mmol) (Intermediate 5) in butan-1-ol (3 mL) was added azetidine (0.100 mL, 1.484 mmol). The reaction vial was purged with nitrogen, sealed and irradiated in a microwave reactor at 135° C. for 45 minutes. The crude product was concentrated in vacuo and then purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 3-(azetidin-1-yl)-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (40.2 mg, 0.095 mmol, 63.7% yield) as a solid.

[0945] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.49-1.99 (m, 4H) 2.27-2.46 (m, 2H) 2.76-3.05 (m, 2H) 3.10-3.56 (m, 2H) 3.87-4.17 (m, 4H) 4.37-4.64 (m, 1H) 6.64-6.84 (m, 1H) 7.61-7.88 (m, 3H) 8.35-8.59 (m, 1H)

[0946] MS ES.sup.+: 425

Example 78

5-({3-[2-Methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine

[0947] ##STR00131##

[0948] 3-Chloro-5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (79 mg, 0.198 mmol) (Intermediate 6) was dissolved in THF (30 mL) and treated with methanamine (2M solution in THF) (3 mL, 6.00 mmol). This was heated at 130° C. in the microwave for 24 hours in total. The crude product was purified by column chromatography on basic silica, eluting with 20-100% ethyl acetate/petrol to afford 5-({3-[2-methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine (35 mg, 0.089 mmol, 45%).

[0949] .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ ppm 1.62-1.88 (m, 2H) 1.98-2.02 (m, 2H) 2.85-3.00 (m, 1H) 3.20-3.41 (m, 2H) 3.40 (s, 3H) 3.66-3.82 (m, 2H) 3.80 (s, 3H) 4.80 (br, 1H) 6.81-6.83 (m, 1H) 7.10 (s, 1H) 7.20-7.31 (m, 1H) 7.35-7.40 (m, 1H) 8.40 (m, 1H)

[0950] MS ES.sup.+: 395

Example 79

5-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0951] ##STR00132##

[0952] To a stirred solution of 3-chloro-5-{[3-(4-methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (0.067 g, 0.194 mmol) (Intermediate 7) in butan-1-ol (2 mL) and NMP (1 mL) was added methylamine (2.0M in THF) (1.453 mL, 2.91 mmol). The vial was purged with nitrogen, sealed and irradiated in the microwave at 135° C. for 30 minutes. The crude reaction mixture was diluted with EtOAc (20 mL) and washed firstly with water (3×10 mL) and then with brine (10 mL), dried (with what) and then evapourated in vacuo?. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (43.1 mg, 0.127 mmol, 65% yield) as a solid.

[0953] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.44-1.92 (m, 4H) 1.98-2.38 (m, 3H) 2.62-3.58 (m, 7H) 3.62-3.81 (m, 3H) 4.29-4.63 (m, 1H) 6.56-7.27 (m, 5H) 8.44 (d, J=4.55 Hz, 1H)

[0954] MS ES.sup.+: 341

Example 80

5-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[0955] ##STR00133##

[0956] To a stirred solution of 3-chloro-5-{[3-(4-methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}pyridazine (0.067 g, 0.194 mmol) (Intermediate 7) in butan-1-ol (2 mL) was added dimethylamine (2M in THF) (1.453 mL, 2.91 mmol). The vial was purged with nitrogen, sealed and irradiated in the microwave at 135° C. for 30 minutes. The resulting mixture was concentrated in vacuo, diluted with EtOAc (20 mL) and washed with water (3×10 mL) and then with brine (10 mL). The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine (26.4 mg, 0.073 mmol, 38% yield) as a solid.

[0957] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.38-1.92 (m, 4H) 1.96-2.41 (m, 3H) 2.60-3.55 (m, 10H) 3.58-3.80 (m, 3H) 4.32-4.61 (m, 1H) 6.57-6.83 (m, 2H) 6.98-7.29 (m, 2H) 8.50 (d, J=8.34 Hz, 1H)

[0958] MS ES.sup.+: 355

Example 81

5-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine

[0959] ##STR00134##

[0960] A solution of 3-chloro-5-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.072 g, 0.180 mmol) (Intermediate 8) and methylamine (2.0M in THF) (1.351 mL, 2.70 mmol) in NMP (1 mL) and butan-1-ol (2 mL) was irradiated in a sealed tube in a microwave at 135° C. for 150 minutes. The crude product was concentrated in vacuo, re-dissolved in EtOAc (20 mL) and washed with water (3×5 mL) and then brine (5 mL). The organic phase was concentrated in vacuo and purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine (36.4 mg, 0.092 mmol, 51% yield) as a solid.

[0961] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.43-1.97 (m, 4H) 2.73-2.99 (m, 5H) 3.10-3.60 (m, 2H) 3.70-3.90 (m, 3H) 4.36-4.66 (m, 1H) 6.54-6.83 (m, 1H) 6.96 (br. s, 1H) 7.05-7.32 (m, 2H) 7.48-7.74 (m, 1H) 8.23-8.52 (m, 1H)

[0962] MS ES.sup.+: 395

Example 82

5-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine

[0963] ##STR00135##

[0964] A solution of 3-chloro-5-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine (0.072 g, 0.180 mmol) (Intermediate 8) and dimethylamine (2M in THF) (1.351 mL, 2.70 mmol) in NMP (1 mL) and butan-1-ol (2 mL) was irradiated in a sealed tube in a microwave at 135° C. for 30 minutes. The resulting mixture was concentrated in vacuo, re-dissolved in EtOAc (20 mL) and washed with water (3×5 mL) and brine (5 mL). The organic phase was concentrated in vacuo and purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-({3-[4-methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine (36.6 mg, 0.090 mmol, 50% yield) as a solid.

[0965] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.43-2.00 (m, 4H) 2.76-3.01 (m, 2H) 3.03-3.19 (m, 6H) 3.21-3.56 (m, 2H) 3.68-3.89 (m, 3H) 4.38-4.69 (m, 1H) 6.89-7.34 (m, 3H) 7.50-7.74 (m, 1H) 8.31-8.56 (m, 1H)

[0966] MS ES.sup.+: 409

Example 83

5-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0967] ##STR00136##

[0968] To a solution of 3-chloro-5-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}pyridazine (0.050 g, 0.131 mmol) (Intermediate 9) in butan-1-ol (2 mL) and NMP (1 mL) was added methylamine (2.0M in THF) (0.986 mL, 1.972 mmol). The vial was sealed and irradiated in the microwave at 135° C. for 60 minutes. The reaction was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (36 mg, 0.096 mmol, 73.0% yield) as a solid.

[0969] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.05-1.44 (m, 3H) 1.47-1.96 (m, 4H) 2.65-3.18 (m, 6H) 3.44-3.63 (m, 1H) 3.84-4.20 (m, 2H) 4.51 (br. s., 1H) 6.62-6.82 (m, 1H) 6.89-7.10 (m, 3H) 7.13-7.32 (m, 1H) 8.32-8.49 (m, 1H)

[0970] MS ES.sup.+: 375

Example 84

5-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[0971] ##STR00137##

[0972] To a solution of 3-chloro-5-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}pyridazine (0.050 g, 0.131 mmol) (Intermediate 9) in butan-1-ol (2 mL) and NMP (1 mL) was added dimethylamine (2M in THF) (0.986 mL, 1.972 mmol). The vial was sealed and irradiated in the microwave at 135° C. for 90 minutes. The resulting mixture was concentrated in vacuo and then purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine (40.5 mg, 0.104 mmol, 79% yield) as a solid.

[0973] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.04-1.46 (m, 3H) 1.51-1.96 (m, 4H) 2.70-2.86 (m, 1H) 2.92-3.20 (m, 8H) 3.40-3.58 (m, 1H) 3.80-4.23 (m, 2H) 4.52 (m, 1H) 6.76-7.11 (m, 3H) 7.15-7.36 (m, 1H) 8.38-8.58 (m, 1H)

[0974] MS ES.sup.+: 389

Example 85

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methylpyridazine

[0975] ##STR00138##

[0976] A solution of 3-chloro-4-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-6-methylpyridazine (0.1 g, 0.275 mmol) (Intermediate 10) in MeOH (10 mL) was eluted through a hydrogen flow reactor (Thales H-cube) fitted with 5% palladium on carbon catalyst cartridge at 20° C., 1.5 mL/min and atmospheric pressure. After 90 mins the solvent was removed in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methylpyridazine as a colourless solid.

[0977] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.44-2.53 (m, 7H) 2.58-3.28 (m, 6H) 3.33-3.78 (m, 1H) 4.68-4.93 (m, 1H) 6.94-7.45 (m, 4H) 8.98-9.15 (m, 1H)

[0978] MS ES.sup.+: 330

Example 86

5-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine

[0979] ##STR00139##

[0980] A sealed microwave tube containing 3-chloro-5-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}pyridazine (7.2 mg, 0.022 mmol) (Intermediate 11) and methylamine (2.0M in THF) (0.271 mL, 0.543 mmol) dissolved in butan-1-ol (1 mL) and NMP (0.2 mL), this was irradiated in the microwave at 135° C. for 150 minutes. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) and lyophilised to afford 5-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine (3.3 mg, 10.11 μmol, 47% yield) as a solid.

[0981] .sup.1H NMR (400 MHz, MeCN-d.sub.3) δ ppm 1.46-1.88 (m, 3H) 2.07-2.26 (m, 1H) 2.68-3.02 (m, 5H) 3.03-3.26 (m, 1H) 3.53-3.94 (m, 4H) 4.48-4.69 (m, 1H) 5.52 (br. s., 1H) 6.54-6.74 (m, 1H) 6.76-7.11 (m, 2H) 7.14-7.38 (m, 2H) 8.34-8.55 (m, 1H)

[0982] MS ES.sup.−: 325

Example 87

3-(4-Chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[0983] ##STR00140##

[0984] A solution of 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (50 mg, 0.203 mmol) (Intermediate 1a5) in DCM (10 mL) was treated with 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (31.3 mg, 0.223 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (48.7 mg, 0.254 mmol), 1-hydroxybenzotriazole hydrate (34.8 mg, 0.227 mmol) and triethylamine (0.057 mL, 0.406 mmol). The mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture which was stirred vigorously for 30 minutes before the phases were separated using a phase separation cartridge. The organic phase was concentrated in vacuo. The crude product was purified by preparative LCMS (basic conditions) to give the title compound 3-(4-chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine (42 mg, 62%).

[0985] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.57-2.07 (m, 4H) 2.32 (s, 6H) 2.78-3.07 (m, 3H) 3.87 (s, 3H) 4.12-4.52 (m, 2H) 7.14-7.22 (m, 3H) 7.45 (s, 1H)

[0986] MS ES.sup.+: 332

Example 88

3-(4-Chlorophenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[0987] ##STR00141##

[0988] Prepared as described for 3-(4-chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine (Example 87) from 3-(4-chlorophenyl)piperidine and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid.

[0989] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 1.53-1.93 (m, 3H) 2.09 (m, 1H) 2.24-2.39 (m, 3H) 2.75 (m, 1H) 2.92 (br. s., 2H) 3.88 (s, 3H) 4.34 (br. s., 2H) 7.22 (m, 2H) 7.33 (m, 2H) 7.45 (s, 1H)

[0990] MS ES.sup.+: 318

Example 89

3-(4-Chlorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine

[0991] ##STR00142##

[0992] Prepared as described for 3-(4-chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine (Example 87) from 3-(4-chlorophenyl)piperidine and 1-methyl-1H-pyrazole-4-carboxylic acid.

[0993] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.62-1.82 (m, 2H) 1.83-1.94 (m, 1H) 2.07-2.16 (m, 1H) 2.69-3.23 (m, 3H) 3.94 (s, 3H) 4.22-4.89 (m, 2H) 7.13-7.23 (m, 2H) 7.25-7.35 (m, 2H) 7.63 (s, 1H) 7.71 (s, 1H)

[0994] MS ES.sup.+: 304

Example 90

3-(4-Chlorophenyl)-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[0995] ##STR00143##

[0996] Prepared as described for 3-(4-chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine (Example 87) from 3-(4-chlorophenyl)piperidine and 1-ethyl-1H-pyrazole-4-carboxylic acid.

[0997] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.43-1.82 (m, 7H) 1.85-1.94 (m, 1H) 2.07-2.16 (m, 2H) 2.78-2.30 (m, 2H) 4.20-4.25 (m, 2H) 7.14-7.25 (m, 2H) 7.25-7.34 (m, 2H) 7.64 (s, 1H) 7.76 (s, 1H)

[0998] MS ES.sup.+: 318

Example 91

3-(4-Chlorophenyl)-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine

[0999] ##STR00144##

[1000] Prepared as described for 3-(4-chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine (Example 87) from 3-(4-chlorophenyl)piperidine and 1-isopropyl-1H-pyrazole-4-carboxylic acid.

[1001] .sup.1H NMR (CHCl.sub.3-d) δ ppm 1.47-1.83 (m, 10H) 1.83-1.94 (m, 1H) 2.07-2.16 (m, 2H) 2.71-2.85 (m, 2H) 4.45-4.56 (m, 1H) 7.13-7.22 (m, 2H) 7.27-7.38 (m, 2H) 7.64 (s, 1H) 7.80 (s, 1H)

[1002] MS ES.sup.+: 332

Example 92

3-(4-Chloro-2-methylphenyl)-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[1003] ##STR00145##

[1004] Propylphosphonic anhydride (50 wt % solution in EtOAc; 0.257 mL, 0.404 mmol) was added to a suspension of 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (0.065 g, 0.264 mmol) (Intermediate 1a5), 1-ethyl-1H-pyrazole-4-carboxylic acid and triethylamine (0.092 mL, 0.660 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 3-(4-chloro-2-methylphenyl)-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine (52 mg, 0.149 mmol, 68% yield) as a solid.

[1005] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.52 (t, J=7.33 Hz, 3H) 1.57-1.84 (m, 2H) 1.85-1.96 (m, 1H) 1.97-2.09 (m, 1H) 2.14-2.51 (m, 3H) 2.61-3.30 (m, 3H) 4.20 (q. J=7.30 Hz, 2H) 4.28-4.89 (m, 2H) 7.08-7.22 (m, 3H) 7.57-7.83 (m, 2H)

[1006] MS ES.sup.+: 332

Example 93

3-(4-Chloro-2-methylphenyl)-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine

[1007] ##STR00146##

[1008] Propylphosphonic anhydride (50 wt % solution in EtOAc; 0.257 mL, 0.404 mmol) was added to a suspension of 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (0.065 g, 0.264 mmol) (Intermediate 1a5), 1-isopropyl-1H-pyrazole-4-carboxylic acid (41 mg, 0.264) in DCM (1 mL). The reaction was stirred at room temperature for 18 hours was and then reduced in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 3-(4-chloro-2-methylphenyl)-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine (55 mg, 0.151 mmol, 69% yield) as a solid.

[1009] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.54 (d, J=6.82 Hz, 6H) 1.65-1.85 (m, 2H) 1.85-1.95 (m, 1H) 1.97-2.08 (m, 1H) 2.14-2.50 (m, 3H) 2.58-3.30 (m, 3H) 4.07-4.42 (m, 1H) 4.44-4.57 (m, 1H) 4.60-4.85 (m, 1H) 7.08-7.24 (m, 3H) 7.56-7.87 (m, 2H)

[1010] MS ES.sup.+: 346

Example 94

3-(4-Chloro-2-methylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine

[1011] ##STR00147##

[1012] Propylphosphonic anhydride (50 wt % solution in EtOAc; 0.257 mL, 0.440 mmol) was added to a suspension of 3-(4-chloro-2-methylphenyl)piperidine hydrochloride (0.065 g, 0.264 mmol) (Intermediate 1a5), 1-methyl-1H-pyrazole-4-carboxylic acid (33 mg, 0.264) in DCM (1 mL). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 3-(4-chloro-2-methylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine (58 mg, 0.173 mmol, 79% yield) as a solid.

[1013] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.63-1.83 (m, 2H) 1.84-1.96 (m, 1H) 1.97-2.08 (m, 1H) 2.12-2.48 (m, 3H) 2.60-3.33 (m, 3H) 3.94 (s, 3H) 4.08-4.88 (m, 2H) 7.06-7.23 (m, 3H) 7.56-7.80 (m, 2H)

[1014] MS ES.sup.+: 318

Example 95

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-amine

[1015] ##STR00148##

[1016] A solution of 3-(4-chloro-2-methylphenyl)-1-[(1-methyl-5-nitro-1H-pyrazol-4-yl)carbonyl]piperidine (205 mg, 0.565 mmol) (Intermediate 2a1) in MeOH (10 mL) was cycled through a hydrogen flow cell (Thales H-Cube) at 1.0 mL/min, 20° C., fitted with 10% Pt/C catalyst cartridge. After 1 hour the reactor was washed through with additional MeOH (3 mL). The solvent was removed in vacuo to give 4-{[(3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-amine (0.195 g, 0.557 mmol, 99% yield) as a gum that partially crystallised on standing to give a solid.

[1017] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.43-1.93 (m, 4H) 2.20-2.38 (m, 3H) 2.67-3.09 (m, 3H) 3.53 (s, 3H) 4.14-4.39 (m, 2H) 6.05 (s, 2H) 7.14-7.40 (m, 4H)

[1018] MS ES.sup.+: 333

Example 96

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine

[1019] ##STR00149##

[1020] Method 1:

[1021] Triethylamine (0.836 mL, 6.00 mmol) was added to a suspension of 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (0.6 g, 1.999 mmol) (Intermediate 1a6), 1H-pyrazole-4-carboxylic acid (0.246 g, 2.199 mmol), EDC (0.575 g, 3.00 mmol) and 1-hydroxybenzotriazole hydrate (0.408 g, 3.00 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 48 hours. The mixture was diluted with DCM, washed with saturated aqueous NaHCO.sub.3 (1×50 mL), 5% aqueous citric acid (1×50 mL), water (1×50 mL) and the organic phase was isolated using a phase separator cartridge and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-100% ethyl acetate/petrol to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine (0.473 g, 1.322 mmol, 66% yield) as a colourless glass.

[1022] Method 2:

[1023] Triethylamine (1.776 mL, 12.75 mmol) was added to a suspension of 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine (1.120 g, 4.25 mmol) (Intermediate 1a6), 1H-pyrazole-4-carboxylic acid (0.5 g, 4.46 mmol). EDC (1,222 g, 6.37 mmol) and HOAt (0.867 g, 6.37 mmol) in DCM (30 mL). The reaction was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with saturated aqueous NaHCO.sub.3 (1×100 mL), 5% aqueous citric acid (1×100 mL), water (1×100 mL) and the organic phase was isolated using a phase separator cartridge and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-100% ethyl acetate/petrol to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine (1.25 g, 3.49 mmol, 82% yield) as a foam.

[1024] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.44-1.59 (m, 1H) 1.70-1.94 (m, 3H) 2.54-3.23 (m, 3H) 4.15-4.74 (m, 2H) 7.69-7.81 (m, 5H) 13.15 (br. s., 1H)

[1025] MS ES.sup.+: 358

Example 97

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine

[1026] ##STR00150##

[1027] Sodium hydride (0.011 g, 0.280 mmol) was added to a solution of 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine (0.1 g, 0.280 mmol) (Example 96) in DMF (2 mL) under nitrogen. The reaction was stirred at room temperature for 10 minutes then methyl iodide (0.0.017 mL, 0.280 mmol) was added and the reaction stirred for 1 hour. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate (3×25 mL). The combined organics were concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine (0.048 g, 0.129 mmol, 46% yield) as a solid.

[1028] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.53 (br. s., 1H) 1.75-1.92 (m, 3H) 2.90 (br. s., 2H) 3.83 (s, 3H) 4.00-4.40 (m, 3H) 7.62 (br. s., 1H) 7.72-7.82 (m, 3H) 8.03 (br. s., 1H) MS ES.sup.+: 372

Example 98

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[1029] ##STR00151##

[1030] Sodium hydride (0.056 g, 1.398 mmol) was added to a solution of 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine (0.5 g, 1.398 mmol) (Example 96) in THF (10 mL) under nitrogen. The reaction mixture was stirred at room temperature for 10 minutes. Ethyl iodide (0.113 mL, 1.398 mmol) was added and the suspension stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated brine (1×75 mL) and concentrated in vacuo. The crude product was purified by reverse phase chromatography on C18 silica eluting with 40-70% acetonitrile/water (with 0.05% NH.sub.4OH) and freeze dried to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine (0.368 g, 0.954 mmol, 68% yield) as a glass.

[1031] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.36 (t, J=6.82 Hz, 3H) 1.52 (m, 1H) 1.70-1.97 (m, 3H) 2.6-3.6 (br. m, 3H), 3.9-4.6 (br. m, 2H) 4.13 (q. J=6.82 Hz, 2H) 7.48-7.86 (m, 4H) 8.06 (br. m., 1H)

[1032] MS ES.sup.+: 386

Example 99

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine

[1033] ##STR00152##

[1034] Sodium hydride (0.011 g, 0.280 mmol) was added to a solution of 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine (0.1 g, 0.280 mmol) (Example 96) in THF (2 mL) under nitrogen. The reaction mixture was stirred at room temperature for 10 minutes then 2-iodopropane (0.048 g, 0.280 mmol) was added and the reaction mixture was stirred overnight. Additional portions of sodium hydride (0.011 g, 0.280 mmol) and 2-iodopropane (0.288 g, 1.680 mmol) were added and the reaction mixture was stirred overnight and then heated to reflux for 24 hours. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organics were washed with saturated brine (25 mL) separated and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) and freeze dried to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl)piperidine (0.046 g, 0.115 mmol, 41% yield) as a solid.

[1035] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.31-1.46 (m, 6H) 1.54 (br. s., 1H) 1.73-1.96 (m, 3H) 2.65-3.12 (m, 3H) 4.22-4.91 (m, 3H) 7.62 (br. s., 1H) 7.70-7.82 (m, 3H) 8.08 (br. s., 1H)

[1036] MS ES.sup.+: 400

Example 100

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine

[1037] ##STR00153##

[1038] Hydrogen chloride (4M in dioxane) (0.770 mL, 3.08 mmol) was added to a solution of tert-butyl N-[4-((3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl carbonyl)-1-methyl-1H-pyrazol-3-yl]carbamate (0.5 g, 1.027 mmol) (Intermediate 2a2) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 48 hours. A further portion of hydrogen chloride (4M in dioxane) (0.770 mL, 3.08 mmol) was added and the reaction mixture stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and azeotroped with toluene. The crude product was purified by reverse phase chromatography on C18 silica eluting with 25-50% acetonitrile/water (with 0.05% ammonia) to afford 4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (0.269 g, 0.695 mmol, 67.7% yield) as a solid.

[1039] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.42-1.63 (m, 1H) 1.72-1.93 (m, 3H) 2.82-3.11 (m, 3H) 3.59 (s, 3H) 4.19-4.36 (m, 2H) 5.16 (s, 2H) 7.63-7.83 (m, 4H)

[1040] MS ES.sup.+: 387

Example 101

1-[(1,3-Dimethyl-1H-pyrazol-4-yl)carbonyl]-3-(4-methoxy-2-methylphenyl)piperidine

[1041] ##STR00154##

[1042] Propylphosphonic anhydride (50% solution in EtOAc) (0.448 mL, 0.511 mmol) was added to a solution of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (0.057 g, 0.409 mmol), 3-(4-methoxy-2-methylphenyl)piperidine (0.07 g, 0.341 mmol) (Intermediate 1a22), and triethylamine (0.143 mL, 1.023 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with saturated NaHCO.sub.3 (1×25 mL), and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]-3-(4-methoxy-2-methylphenyl)piperidine (0.029 g, 0.089 mmol, 26% yield) as a glass.

[1043] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.46-1.59 (m, 1H) 1.68-1.89 (m, 3H) 2.12-2.27 (m, 6H) 2.64-2.77 (m, 1H) 2.78-3.04 (m, 2H) 3.71 (s, 3H) 3.75 (s, 3H) 4.05-4.47 (m, 2H) 6.68-6.78 (m, 2H) 7.12-7.18 (m, 1H) 7.80 (s, 1H)

[1044] MS ES.sup.+: 328

Example 102

4-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-3-amine

[1045] ##STR00155##

[1046] Prepared as described for 4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (Example 100) from ethyl 3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate (Intermediate 2a2, step (ii)) and 3-(4-methoxy-2-methylphenyl)piperidine (Intermediate 1a22).

[1047] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.51-1.62 (m, 1H) 1.67-1.89 (m, 3H) 2.25 (s, 3H) 2.65-2.84 (m, 2H) 2.97 (br. s., 1H) 3.60 (s, 3H) 3.71 (s, 3H) 4.16-4.34 (m, 2H) 5.14 (s, 2H) 6.70-6.78 (m, 2H) 7.12-7.20 (m, 1H) 7.71 (s, 1H)

[1048] MS ES.sup.+: 329

Example 103

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine

[1049] ##STR00156##

[1050] Propylphosphonic anhydride (50% in ethyl acetate) (0.499 mL, 0.569 mmol) was added to a solution of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (0.058 g, 0.417 mmol), 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine (0.1 g, 0.379 mmol) (Intermediate 1a6) and triethylamine (0.159 mL, 1.138 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated aqueous NaHCO.sub.3 (1×25 mL) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) and then freeze-dried to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine as a solid.

[1051] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.42-1.59 (m, 1H) 1.72-1.91 (m, 3H) 2.15 (s, 3H) 2.89 (br. s., 1H) 3.02 (br. s., 2H) 3.74 (s, 3H) 4.00-4.42 (m, 2H) 7.69-7.80 (m, 4H)

[1052] MS ES.sup.+: 386

Example 104

4-{[5-(4-Chlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[1053] ##STR00157##

[1054] A microwave vial containing 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}-1,4,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (0.1 g, 0.189 mmol) (Intermediate 3a2), (4-chlorophenyl)boronic acid (0.032 g, 0.208 mmol), tetrakis(triphenylphosphine) palladium (0) (10.91 mg, 9.45 μmol) and cesium carbonate (0.129 g, 0.397 mmol) in dioxane (2 mL)/water (0.5 mL) was purged with nitrogen, sealed and irradiated at 100° C. for 10 mins in the microwave. The reaction was diluted in EtOAc (20 mL) and washed with water (5 mL) and brine (5 mL), dried over MgSO.sub.4, filtered and reduced in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 4-{[5-(4-chlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (30 mg, 0.088 mmol, 46.5% yield) as a solid.

[1055] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.81-2.07 (m, 2H) 2.48 (m, 2H) 3.05 (s, 6H) 3.51 (br. s., 1H) 3.76 (br. s., 1H) 6.52-6.73 (m, 2H) 7.14-7.53 (m, 4H) 7.60-7.79 (m, 1H) 8.18 (d, J=4.80 Hz, 1H)

[1056] MS ES.sup.+: 342

Example 105

4-{[5-(4-Chloro-2-methylphenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[1057] ##STR00158##

[1058] Prepared as described for 4-{[5-(4-chlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 104) from 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}-1,4,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 3a2) and (4-chloro-2-methylphenyl)boronic acid.

[1059] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.77-2.08 (m, 2H) 2.18 (br. s, 2H) 2.31 (br. s, 3H) 2.93-3.10 (m, 6H) 3.46-3.58 (m, 1H) 3.78 (br. s., 1H) 6.21 (s, 1H) 6.48-6.71 (m, 2H) 7.03-7.36 (m, 3H) 8.07-8.23 (m, 1H)

[1060] MS ES.sup.+: 356

Example 106

4-{[5-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[1061] ##STR00159##

[1062] Prepared as described for 4-{[5-(4-chlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 104) from 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}-1,4,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 3a2) and (2,4-dichlorophenyl)boronic acid.

[1063] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.00 (m, 2H) 2.29-2.44 (m, 2H) 2.92-3.10 (m, 6H) 3.43-3.86 (m, 2H) 6.38-6.74 (m, 3H) 7.19-7.69 (m, 3H) 8.06-8.25 (m, 1H)

[1064] MS ES.sup.+: 376

Example 107

N,N-Dimethyl-4-[(3-phenylazepan-1-yl)carbonyl]pyridin-2-amine

[1065] ##STR00160##

[1066] Prepared as described for 4-{[3-(2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 1) from 2-(dimethylamino)isonicotinic acid hydrochloride and 3-phenylazepane.

[1067] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.24-2.14 (m, 6H) 2.70-3.09 (m, 7H) 3.14-3.27 (m, 1H) 3.36-3.51 (m, 2H) 3.82-4.13 (m, 1H) 6.42-6.60 (m, 2H) 6.94-7.41 (m, 5H) 8.12 (m, 1H)

[1068] MS ES.sup.+: 324

Example 108

4-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[1069] ##STR00161##

[1070] To a stirred solution of 2-(dimethylamino)isonicotinic acid hydrochloride (62.8 mg, 0.31 mmol) and 3-(4-chlorophenyl)azepane hydrochloride (76 mg, 0.310 mmol) in DCM (2 mL) was added triethylamine (0.130 mL, 0.930 mmol) and propylphosphonic anhydride (50% solution in EtOAc) (0.219 mL, 0.372 mmol).

[1071] The reaction was quenched by addition of saturated aqueous NaHCO.sub.3 (2 mL). The mixture was diluted in EtOAc (15 mL) and washed with water (2×5 mL). The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% formic acid) and lyophilised to afford 4-{[3-(4-chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (29.5 mg, 0.082 mmol, 27% yield).

[1072] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.30-2.10 (m, 6H) 2.81-3.09 (m, 1H) 3.14-3.55 (m, 9H) 3.79-4.09 (m, 1H) 6.77-7.00 (m, 1H) 7.05-7.47 (m, 5H) 7.90-8.12 (m, 1H)

[1073] MS ES.sup.+: 358

Example 109

4-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine

[1074] ##STR00162##

[1075] Prepared as described for 4-{[3-(4-chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine (Example 108) from 2-(dimethylamino)isonicotinic acid hydrochloride and 3-(4-methoxyphenyl)azepane hydrochloride.

[1076] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.32-2.06 (m, 6H) 2.70-3.52 (m, 10H) 3.58-3.78 (m, 3H) 3.82-4.11 (m, 1H) 6.58-6.71 (m, 1H) 6.72-6.84 (m, 2H) 6.86-7.00 (m, 2H) 7.16-7.27 (m, 1H) 7.98-8.12 (m, 1H)

[1077] MS ES.sup.+: 354

Example 110

4-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine

[1078] ##STR00163##

[1079] To a stirred solution of 2-(methylamino)isonicotinic acid hydrochloride (70 mg, 0.354 mmol) and triethylamine (0.148 mL, 1.063 mmol) in DCM (2 mL) was added propylphosphonic anhydride (50% solution in EtOAc) (0.522 mL, 0.886 mmol), then 3-(4-methoxyphenyl)azepane hydrochloride (86 mg, 0.354 mmol). The reaction was quenched with saturated aqueous NaHCO.sub.3 (2 mL). The mixture was diluted with EtOAc (10 mL), washed with saturated aqueous NaHCO.sub.3 (3×5 mL) and brine (5 mL). The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 4-{[3-(4-methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine (73.3 mg, 0.216 mmol, 61% yield) as a solid.

[1080] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.29-2.05 (m, 6H) 2.67-2.97 (m, 4H) 3.09-3.23 (m, 1H) 3.35-3.45 (m, 2H) 3.55-3.78 (m, 3H) 3.80-4.09 (m, 1H) 6.24-6.50 (m, 2H) 6.55-6.68 (m, 1H) 6.70-7.01 (m, 3H) 7.12-7.26 (m, 1H) 7.92-8.09 (m, 1H)

[1081] MS ES.sup.+: 340

Example 111

4-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine

[1082] ##STR00164##

[1083] Prepared as for 4-{[3-(4-methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine (Example 110) from 2-(methylamino)isonicotinic acid hydrochloride and 3-(4-chlorophenyl)azepane hydrochloride.

[1084] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.31-2.06 (m, 6H) 2.72-3.02 (m, 4H) 3.16-3.29 (m, 1H) 3.34-3.46 (m, 2H) 3.78-4.09 (m, 1H) 6.24-6.51 (m, 2H) 6.55-6.72 (m, 1H) 6.97-7.16 (m, 1H) 7.20-7.45 (m, 3H) 7.91-8.08 (m, 1H)

[1085] MS ES.sup.+: 344

Example 112

5-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine

[1086] ##STR00165##

[1087] To a stirred solution of 1-[(6-chloropyridazin-4-yl)carbonyl]-3-(4-methoxyphenyl)azepane (108 mg, 0.311 mmol) (Intermediate 12) in butan-1-ol (4 mL) and NMP (2 mL) was added methylamine (2.0M in THF; 2.333 mL, 4.67 mmol). The vial was purged with nitrogen, sealed and irradiated in the microwave at 135° C. for 110 minutes. Additional methylamine (2.0M in THF; 0.77 mL, 1.56 mmol) was added and the reaction mixture was irradiated in the microwave at 135° C. for another 30 minutes, followed by irradiation in the microwave at 150° C. for 60 minutes. The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine (72.9 mg, 0.214 mmol, 69% yield) as a solid.

[1088] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.34-2.05 (m, 6H) 2.65-2.96 (m, 4H) 3.13-3.51 (m, 3H) 3.61-3.79 (m, 3H) 3.82-4.09 (m, 1H) 6.64-7.05 (m, 5H) 7.14-7.29 (m, 1H) 8.33-8.50 (m, 1H)

[1089] MS ES.sup.+: 341

Example 113

5-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine

[1090] ##STR00166##

[1091] To a stirred solution of 3-(4-chlorophenyl)-1-[(6-chloropyridazin-4-yl)carbonyl]azepane (109 mg, 0.311 mmol) (Intermediate 13) in butan-1-ol (4 mL) and NMP (2 mL) was added methylamine (2.0M in THF; 2.333 mL, 4.67 mmol). The vial was purged with nitrogen, sealed and irradiated in the microwave at 135° C. for 110 minutes. Additional methylamine (2.0M in THF; 0.77 mL, 1.56 mmol) was added and the reaction mixture was irradiated in the microwave at 135° C. for a further 30 minutes, followed by irradiation in the microwave at 150° C. for 60 minutes. The reaction was concentrated in vacuo and the crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford 5-{[3-(4-chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine (63.7 mg, 0.185 mmol, 59% yield) as a solid.

[1092] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.21-2.12 (m, 6H) 2.75-3.03 (m, 4H) 3.15-3.52 (m, 3H) 3.77-4.09 (m, 1H) 6.64-6.82 (m, 1H) 6.87-7.04 (m, 1H) 7.07-7.18 (m, 1H) 7.23-7.45 (m, 3H) 8.33-8.54 (m, 1H)

[1093] MS ES.sup.+: 345

Example 114

5-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[1094] ##STR00167##

[1095] Prepared as described for 5-{[3-(4-chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine (Example 113) from 1-[(6-chloropyridazin-4-yl)carbonyl]-3-(4-methoxyphenyl)azepane (Intermediate 12) and dimethylamine (2M in THF).

[1096] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.21-2.05 (m, 6H) 3.03-3.16 (m, 6H) 3.17-3.51 (m, 4H) 3.62-3.77 (m, 3H) 3.81-4.13 (m, 1H) 6.69-6.83 (m, 1H) 6.86-6.99 (m, 2H) 7.00-7.10 (m, 1H) 7.16-7.31 (m, 1H) 8.42-8.58 (m, 1H)

[1097] MS ES.sup.+: 355

Example 115

5-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine

[1098] ##STR00168##

[1099] Prepared as described for 5-{[3-(4-chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine (Example 113) from 3-(4-chlorophenyl)-1-[(6-chloropyridazin-4-yl)carbonyl]azepane (Intermediate 13) and dimethylamine (2M in THF).

[1100] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.34-2.10 (m, 6H) 2.80-3.55 (m, 10H) 3.79-4.14 (m, 1H) 6.90-7.15 (m, 2H) 7.21-7.45 (m, 3H) 8.40-8.58 (m, 1H) MS ES.sup.+: 359

Example 116

3-(4-Chloro-2-methylphenyl)-1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-ol

[1101] ##STR00169##

[1102] To a stirred solution of 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-one (250 mg, 1.011 mmol) (Intermediate 3a1) in anhydrous THF (1 mL), cooled in an ice bath, was added a solution of (4-chloro-2-methylphenyl)magnesium bromide (0.5M in THF) (3.03 mL, 1.516 mmol) drop wise over 5 minutes under a nitrogen gas atmosphere. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (10 mL), ethyl acetate was added (10 mL) and the mixture was stirred vigorously for 18 hours before being diluted with water (10 mL). The phases were separated, the aqueous phase was extracted with ethyl acetate (2×10 mL) and the combined organic phases were concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluting with acetonitrile/water (with 0.1% ammonia) to afford the title compound 3-(4-chloro-2-methylphenyl)-1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-ol (10.8 mg, 0.028 mmol, 2.77% yield) as a colourless gum.

[1103] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.41-2.36 (m, 7H) 2.54-2.90 (m, 2H) 2.98-3.17 (m, 6H) 3.18-3.42 (m, 1H) 3.68-4.00 (m, 1H) 4.63-4.90 (m, 1H) 6.47-6.61 (m, 2H) 7.04-7.38 (m, 3H) 8.07-8.34 (m, 1H)

[1104] MS ES.sup.+: 374

Example 117

1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}-3-(4-fluorophenyl)piperidin-3-ol

[1105] ##STR00170##

[1106] Prepared as described for 3-(4-chloro-2-methylphenyl)-1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-ol (Example 116) from 1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-one (Intermediate 3a1) and (4-fluorophenyl)magnesium bromide.

[1107] .sup.1H NMR (400 MHz, CHCl.sub.3-d) δ ppm 1.16-2.85 (m, 6H) 2.97-3.13 (m, 6H) 3.15-3.25 (m, 1H) 3.61-3.82 (m, 1H) 4.55-4.83 (m, 1H) 6.47-6.73 (m, 2H) 6.93-7.11 (m, 2H) 7.32-7.53 (m, 2H) 8.08-8.26 (m, 1H)

[1108] MS ES.sup.+: 344

Example 118

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (Enantiomer 1)

[1109] ##STR00171##

[1110] A solution of propylphosphonic anhydride (50 wt % in EtOAc, 0.219 ml, 0.250 mmol) was added to a solution of 3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-4-carboxylic acid (Intermediate 2a2 step ii)) (0.044 g, 0.183 mmol), 3-[4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6A, 0.05 g, 0.167 mmol) and triethylamine (0.070 ml, 0.500 mmol) in DCM (2 ml). The reaction was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with saturated NaHCO.sub.3 (1×15 ml), dried (phase separator) and concentrated. The residue was taken up in methanol (2 ml). HCl (4M in dioxane) (0.208 ml, 0.833 mmol) was added and the reaction was stirred for 3 hours. Additional HCl (4M in dioxane) (0.208 ml, 0.833 mmol) was added and the reaction was stirred overnight. The solution was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia) to afford (4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (Enantiomer 1; 0.033 g, 0.085 mmol, 51% yield) as a foam.

[1111] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.42-1.64 (m, 1H) 1.71-1.92 (m, 3H) 2.66-3.16 (m, 3H) 3.59 (s, 3H) 4.17-4.36 (m, 2H) 5.16 (s, 2H) 7.70 (s, 1H) 7.73-7.81 (m, 3H)

[1112] MS ES.sup.+: 387

Example 119

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (Enantiomer 2)

[1113] ##STR00172##

[1114] Prepared as described for Example 118 using 3-[(4-chloro-2-(trifluoromethyl)phenyl]piperidine hydrochloride (Intermediate 1a6B, 0.05 g, 0.167 mmol) to afford (4-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (Enantiomer 2; 0.036 g, 0.093 mmol, 56% yield) as a solid.

[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.45-1.61 (m, 1H) 1.75-1.91 (m, 3H) 2.83-3.13 (m, 3H) 3.59 (s, 3H) 4.22-4.34 (m, 2H) 5.16 (s, 2H) 7.70 (s, 1H) 7.74-7.81 (m, 3H)

[1116] MS ES.sup.+: 387

3. Biological Assay

[1117] 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.

[1118] 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.

[1119] 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.

[1120] Results

TABLE-US-00001 Compound of Mean IC.sub.50 Compound of Mean IC.sub.50 Example No. (μM) Example No. (μM) 1 1.82 2 0.19 3 1.74 4 0.07 5 0.45 6 0.28 7 0.1 8 3.27 9 1.37 10 1.17 11 0.29 12 2.8 13 1.92 14 0.19 15 1.14 16 0.27 17 0.84 18 0.18 19 1.22 20 1.21 21 1.2 22 1.04 23 0.96 24 0.03 25 0.53 26 0.47 27 0.13 28 1.33 29 3.29 30 0.83 31 0.03 32 0.49 33 0.09 34 5.27 35 8.82 36 5.51 37 5.53 38 6.5 39 8.22 40 7.03 41 8.46 42 8.35 43 7.05 44 4.4 45 0.22 46 7.79 47 0.46 48 0.41 49 0.42 50 0.99 51 0.31 52 0.51 53 2.92 54 0.23 55 0.35 56 0.44 57 0.05 58 0.82 59 1.6 60 1.6 61 0.1 62 0.1 63 0.04 64 0.05 65 0.07 66 0.7 67 2.26 68 1.54 69 0.81 70 0.12 71 0.07 72 0.03 73 1.18 74 0.35 75 0.11 76 0.08 77 0.73 78 3 79 0.13 80 0.16 81 0.13 82 0.21 83 0.17 84 0.09 85 1.14 86 1.26 87 0.2 88 1.82 89 1.28 90 0.66 91 0.96 92 0.11 93 0.18 94 0.17 95 0.15 96 2.44 97 0.10 98 0.17 99 0.33 100 0.54 101 1.03 102 1.54 103 0.49 104 0.42 105 0.27 106 1.23 107 2.97 108 3.23 109 0.96 110 0.45 111 0.43 112 1.27 113 0.93 114 1.43 115 1.44 116 1.36 117 3.94 118 >10 119 0.33

[1121] 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.