Tetrahydroimidazopyridine derivatives as modulators of TNF activity

Abstract

A series of substituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders. ##STR00001##

Claims

1. A compound represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00018## wherein E represents —CH.sub.2—; Q represents —CH.sub.2—, —CH.sub.2O— or —CH.sub.2OCH.sub.2—; Z represents hydrogen or methyl; R.sup.1 represents —SO.sub.2R.sup.a, —COR.sup.d or —CO.sub.2R.sup.d; or R.sup.1 represents C.sub.1-6 alkyl, which group may be optionally substituted by one or more substituents independently selected from halogen and C.sub.2-6 alkoxycarbonyl; R.sup.a represents C.sub.1-6 alkyl; R.sup.d represents trifluoromethyl or C.sub.1-6 alkyl; R.sup.12 represents hydrogen or halogen; R.sup.15 represents halogen or difluoromethoxy; and R.sup.16 represents hydrogen or halogen.

2. A compound that is 1-{3-[(2,5-Dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl}ethanone, Methyl 3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]-pyridine-5-carboxylate, Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}propanoate, 3-[(2,5-Dichlorophenyl)methyl]-2-methyl-5-(2,2,2-trifluoroethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine, 1-{3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}ethanone, 3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-5-(methylsulfonyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine, Methyl 3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate, 1-{3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}-2,2,2-trifluoroethanone, or Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo-[4, 5-c]pyridin-5-yl}propanoate.

3. A pharmaceutical composition comprising a compound of formula (IIA) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

4. The pharmaceutical composition as claimed in claim 3 further comprising an additional pharmaceutically active ingredient.

5. A method for the treatment of disorders for which the administration of a modulator of TNFα function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IIA) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the disorder is an inflammatory or autoimmune disorder.

Description

EXAMPLES

(1) Abbreviations

(2) DCM: dichloromethane

(3) DMSO: dimethylsulfoxide

(4) IPA: isopropanol

(5) SiO.sub.2: silica

(6) h: hour

(7) HPLC: High Performance Liquid Chromatography

(8) LCMS: Liquid Chromatography Mass Spectrometry

(9) ES+: Electrospray Positive Ionisation

(10) MeOH: methanol

(11) DMF: N,N-dimethylformamide

(12) THF: tetrahydrofuran

(13) M: mass

(14) RT: retention time

(15) Nomenclature

(16) Compounds were named with the aid of ACD/Name Batch (Network) version 11.01, and/or Accelrys Draw 4.0.

(17) Analytical Conditions

(18) Analytical HPLC

(19) Column: Waters, X Bridge, 20×2.1 mm, 2.5 μm Mobile Phase A: 10 mM ammonium formate in water+0.1% ammonia Mobile Phase B: acetonitrile+5% solvent A+0.1% ammonia Injection Volume: 5.0 μL Flow Rate: 1.00 mL/minute Gradient program: 5% B to 95% Bin 4 minutes; hold till 5.00 minutes; at 5.10 minutes B conc. is 5% up to 6.5 minutes

Intermediate 1

N-[(2,5-Dichlorophenyl)methyl]-4-nitropyridin-3-amine

(20) To a solution of 3-chloro-4-nitropyridine (3.20 g, 20 mmol) in ethanol (40 mL) were added triethylamine (8.35 mL, 60 mmol) and (2,5-dichlorophenyl)methanamine hydrochloride (8.5 g, 40 mmol) at 0° C. The reaction mixture was heated at 80° C. for 1 h, then concentrated in vacuo and diluted with ethyl acetate (40 mL). The organic layer was washed with brine (2×20 mL) and dried over anhydrous sodium sulphate, then filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 1% MeOH in DCM) to give the title compound (1.7 g, 80%). δ.sub.H (400 MHz, CDCl.sub.3) 9.27 (s, 2H), 8.57 (br s, 1H), 8.32 (d, 1H, J 6.0 Hz), 7.38 (d, 1H, J 8.4 Hz), 7.30-7.26 (m, 1H), 6.60 (d, 1H, J 6.0 Hz), 4.64 (d, 2H, J 6.0 Hz).

Intermediate 2

N3-[(2,5-Dichlorophenyl)methyl]pyridine-3,4-diamine

(21) To a stirred solution of Intermediate 1 (5.0 g, 16 mmol) in methanol (50 mL) was added Zn powder (5.49 g, 84 mol) at 0° C. The reaction mixture was stirred for 5 minutes, then ammonium formate (4.24 g, 64 mmol) was added at 0° C. The reaction mixture was stirred for 3 h, then filtered through celite, and the filtrate was concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 8% MeOH in DCM+0.1% NH.sub.3) to give the title compound (4.5 g, 50%). δ.sub.H (400 MHz, CDCl.sub.3) 7.59 (d, 1H, J 5.2 Hz), 7.40-7.38 (m, 2H), 7.34 (br s, 1H), 7.24 (dd, 1H, J 6.0, 2.4 Hz), 6.60 (d, 1H, J 5.2 Hz), 4.43 (s, 2H). LCMS (ES+) 267.9 (M+H).sup.+, RT 2.18 minutes.

Intermediate 3

N-(4-Aminopyridin-3-yl)-N-[(2,5-dichlorophenyl)methyl]acetamide

(22) To a solution of Intermediate 2 (4.5 g, 16.7 mmol) in DCM (10 mL) was added triethylamine (2.31 mL, 16.7 mmol) at 0° C. The reaction mixture was stirred for 5 minutes, then acetic anhydride (1.88 g, 18.4 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 h, then quenched by ice and extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 4% MeOH in DCM) to give the title compound (3.8 g, 73%). δ.sub.H (400 MHz, DMSO-d.sub.6) 9.47 (br s, 1H), 7.81 (d, 1H, J 4.8 Hz), 7.67 (s, 1H), 7.53 (d, 1H, J 8.4 Hz), 7.48 (br s, 1H), 7.45 (d, 1H, J 4.8 Hz), 7.38 (dd, 1H, J 6.0, 2.4 Hz), 5.93 (br s, 1H), 4.45 (d, 2H, J 6.0 Hz), 2.12 (s, 3H). LCMS (ES+) 309.9 (M+H).sup.+, RT 1.82 minutes.

Intermediate 4

3-[(2,5-Dichlorophenyl)methyl]-2-methylimidazo[4,5-c]pyridine

(23) To a solution of Intermediate 3 (3.8 g, 12.2 mmol) in IPA (30 mL) was added potassium tert-butoxide (1.51 g). The reaction mixture was heated at 90° C. for 3 h, then concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was then purified by column chromatography (SiO.sub.2, 5% MeOH in DCM) to give the title compound (2.6 g, 73%) as a yellow solid. δ.sub.H (400 MHz, CD.sub.3OD) 8.61 (s, 1H), 8.35 (d, 1H, J 5.6 Hz), 7.66 (d, 1H, J 5.6 Hz), 7.51 (d, 1H, J 8.8 Hz), 7.38 (dd, 1H, J 6.4, 2.0 Hz), 6.80 (d, 1H, J 1.6 Hz), 5.67 (s, 2H), 3.31 (s, 3H). LCMS (ES+) 292 (M+H).sup.+, RT 1.90 minutes.

Intermediate 5

3-[(2,5-Dichlorophenyl)methyl]-5-[(4-methoxyphenyl)methyl]-2-methylimidazo[4,5-c]-pyridin-5-ium chloride

(24) To a stirred solution of Intermediate 4 (2.6 g, 8.93 mmol) in acetone (20 mL) was added 4-methoxybenzyl chloride (2.09 g, 13.4 mmol). The mixture was heated in a sealed tube at 80° C. for 18 h, then the reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to give the title compound (3.0 g, 83%) as a brown solid. δ.sub.H (400 MHz, CD.sub.3OD) 9.20 (s, 1H), 8.71 (dd, 1H, J 5.6, 0.8 Hz), 8.12 (d, 1H, J 6.8 Hz), 7.49 (d, 1H, J 8.4 Hz), 7.41 (dd, 1H, J 6.4, 2.0 Hz), 7.37 (d, 2H, J 8.8 Hz), 7.03 (d, 1H, J 2.4 Hz), 6.96 (d, 2H, J 9.2 Hz), 5.77 (s, 2H), 5.73 (s, 2H), 3.80 (s, 3H), 2.76 (s, 3H). LCMS (ES+) 412 (M+H).sup.+, RT 3.00 minutes.

Intermediate 6

3-[(2,5-Dichlorophenyl)methyl]-5-[(4-methoxyphenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine

(25) To a stirred solution of Intermediate 5 (3 g, 7.28 mmol) in methanol (20 mL) at 0° C. was added NaBH.sub.4 (0.54 g, 14.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h, then quenched with dilute HCl (˜20 mL). The methanol was removed in vacuo. The residue was basified with 1N aqueous NaOH solution, then extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, then filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, 10% methanol and 0.1% NH.sub.3 in DCM) to give the title compound (2.3 g, 76%) as a brown solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.32 (d, 1H, J 8.8 Hz), 7.22 (d, 2H, J 8.0 Hz), 6.83 (d, 2H, J 8.4 Hz), 6.53 (d, 1H, J 2.0 Hz), 4.89 (s, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 3.29 (s, 3H), 2.84 (t, 2H, J 6.0 Hz), 2.70 (t, 2H, J 5.6 Hz), 2.29 (s, 3H). LCMS (ES+) 416 (M+H).sup.+, RT 2.72 minutes.

Intermediate 7

3-[(2,5-Dichlorophenyl)methyl]-2-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine

(26) A solution of Intermediate 6 (0.76 g, 1.8 mmol) in trifluoroacetic acid (3 mL) was heated under microwave irradiation at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo, then the residue was neutralized with saturated aqueous NaHCO.sub.3 solution and extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 8% methanol and 0.1% NH.sub.3 in DCM) to give the title compound (1.20 g, 75%) as a brown gum. δ.sub.H (400 MHz, CDCl.sub.3) 7.34 (d, 1H, J 8.4 Hz), 7.22 (dd, 1H, J 6.0, 2.4 Hz), 6.51 (d, 1H, J 2.0 Hz), 4.95 (s, 2H), 3.65 (s, 2H), 3.11 (t, 2H, J 6.0 Hz), 2.65 (t, 2H, J 5.6 Hz), 2.31 (s, 3H). LCMS (ES+) 296 (M+H).sup.+, RT 1.74 minutes.

Intermediate 8

N-(4-Aminopyridin-3-yl)-N-[(2,5-dichlorophenyl)methyl]-2-methoxyacetamide

(27) To a solution of Intermediate 2 (2.5 g, 9.3 mmol) in DCM (10 mL) was added triethylamine (3.86 mL, 27.9 mmol) at 0° C. The reaction mixture was stirred for 5 minutes, then methoxyacetyl chloride (1.21 g, 11.2 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, then quenched with ice and extracted with DCM (3×25 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 4% methanol in DCM) to give the title compound (2.30 g, 73%). δ.sub.H (400 MHz, CDCl.sub.3) 8.65 (s, 1H), 8.15 (d, 1H, J 5.2 Hz), 8.07 (s, 1H), 7.62 (d, 1H, J 5.2 Hz), 7.41 (d, 1H, J 2.0 Hz), 7.33 (d, 1H, J 8.4 Hz), 7.21 (dd, 1H, J 6.0, 2.4 Hz), 4.40 (d, 2H, J 6.4 Hz), 4.19 (br s, 1H), 4.08 (s, 2H), 3.53 (s, 3H). LCMS (ES+) 340 (M+H).sup.+, RT 2.15 minutes.

Intermediate 9

3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)imidazo[4,5-c]pyridine

(28) To a solution of Intermediate 8 (2.3 g, 6.78 mmol) in isopropyl alcohol (20 mL) was added potassium tert-butoxide (0.88 g, 7.88 mmol). The reaction mixture was heated at 90° C. for 2 h, then concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 4% methanol in DCM) to give the title compound (1.56 g, 73%). δ.sub.H (400 MHz, CDCl.sub.3) 8.63 (s, 1H), 8.49 (d, 1H, J 5.6 Hz), 7.71 (d, 1H, J 5.6 Hz), 7.39 (d, 1H, J 8.8 Hz), 7.23 (d, 1H, J 2.4 Hz), 6.65 (d, 1H, J 2.0 Hz), 5.60 (s, 2H), 4.56 (s, 2H), 3.41 (s, 3H). LCMS (ES+) 322 (M+H).sup.+, RT 1.98 minutes.

Intermediate 10

3-[2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-5-[(4-methoxyphenyl)methyl]-imidazo[4,5-c]pyridin-5-ium chloride

(29) To a stirred solution of Intermediate 9 (1.56 g, 4.86 mmol) in acetone (8 mL) was added 4-methoxybenzyl chloride (1.14 g, 7.28 mmol). The mixture was heated in a sealed tube at 80° C. for 18 h, then concentrated in vacuo. The residue was washed with hexane to give the title compound (1.60 g, 74%). δ.sub.H (400 MHz, DMSO-d.sub.6) 9.81 (s, 1H), 8.90 (d, 1H, J 6.8 Hz), 8.38 (d, 1H, J 6.8 Hz), 7.61 (d, 1H, J 8.4 Hz), 7.47 (d, 3H, J 8.8 Hz), 6.95 (d, 3H, J 9.2 Hz), 5.82 (s, 2H), 5.78 (s, 2H), 4.80 (s, 2H), 3.74 (s, 3H), 3.24 (s, 3H). LCMS (ES+) 442 (M)′, RT 3.52 minutes.

Intermediate 11

3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-5-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridine

(30) To a stirred solution of Intermediate 10 (1.30 g, 2.94 mmol) in methanol (15 mL) at 0° C. was added NaBH.sub.4 (0.23 g, 5.87 mmol). The reaction was allowed to warm to room temperature and stirred for 2 h, then quenched with dilute HCl (˜10 mL). The methanol was removed in vacuo. The residue was basified with 1N aqueous NaHCO.sub.3 solution, then extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, then filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 5% methanol in DCM) to give the title compound (0.98 g, 75%). δ.sub.H (400 MHz, CDCl.sub.3) 7.30 (d, 1H, J 8.4 Hz), 7.22-7.20 (m, 3H), 6.83 (d, 2H, J 8.4 Hz), 6.61 (d, 1H, J 2.4 Hz), 5.07 (s, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.61 (s, 2H), 3.29 (s, 3H), 3.26 (s, 2H), 2.83 (t, 2H, J 5.6 Hz), 2.72 (t, 2H, J 5.2 Hz). LCMS (ES+) 446 (M+H).sup.+, RT 2.75 minutes.

Intermediate 12

3-[2,5-Dichlorophenyl)methyl]-2-methoxymethyl)-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine

(31) A solution of Intermediate 11 (0.98 g, 3.0 mmol) in trifluoroacetic acid (5 mL) was heated under microwave irradiation at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo, then the residue was neutralized with saturated aqueous NaHCO.sub.3 solution and extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous sodium sulphate, then filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 8-10% methanol and 0.1% NH.sub.3 in DCM) to give the title compound (0.50 g, 51%) as a brown gum. δ.sub.H (400 MHz, CDCl.sub.3) 7.33 (d, 1H, J 8.4 Hz), 7.21 (dd, 1H, J 6.8, 1.6 Hz), 6.61 (br s, 1H), 5.13 (s, 2H), 4.46 (s, 2H), 3.63 (s, 2H), 3.31 (s, 3H), 3.10 (t, 2H, J 5.6 Hz), 2.67 (t, 2H, J 5.6 Hz). LCMS (ES+) 326 (M+H).sup.+, RT 1.66 minutes.

Intermediate 13

1-{3-[(2,5-Dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl}-2,2,2-trifluoroethanone

(32) To a stirred solution of Intermediate 7 (300 mg, 1.02 mmol) in DCM (3 mL) was added triethylamine (0.14 mL, 1.02 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic anhydride (214 mg, 1.02 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with ice and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, then filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, 3% methanol in DCM) to give the title compound (280 mg, 70%).

Example 1

1-{3-[(2,5-Dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl}ethanone

(33) To a stirred solution of Intermediate 7 (50 mg, 0.17 mmol) in DCM (2 mL) at 0° C. were added triethylamine (0.07 mL, 0.51 mmol) and acetyl chloride (16 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the title compound (34 mg, 59%) as a yellow gum. δ.sub.H (400 MHz, CDCl.sub.3) 7.35 (d, 1H, J 8.5 Hz), 7.23 (dd, 1H, J 8.5, 2.5 Hz), 6.50 (d, 1H, J 2.4 Hz), 5.01 (s, 2H), 4.40 (q, 2H, J 7.1 Hz), 3.72 (d, 2H, J 1.9 Hz), 2.81 (m, 2H), 2.38 (s, 3H), 2.19 (s, 3H). LCMS (ES+) 338 (M+H).sup.+, RT 1.80 minutes.

Example 2

Methyl 3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidazo[4,5-c]-pyridine-5-carboxylate

(34) To a stirred solution of Intermediate 7 (100 mg, 0.34 mmol) in DCM (2 mL) at 0° C. were added triethylamine (0.05 mL, 0.34 mmol) and methyl chloroformate (38 mg, 0.41 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (60 mg, 50%) as a yellow gum. δ.sub.H (400 MHz, DMSO-d.sub.6) 7.58 (d, 1H, J 8.5 Hz), 7.45 (dd, 1H, J 8.6, 2.6 Hz), 6.56 (d, 1H, J 8.9 Hz), 5.16 (s, 2H), 4.22 (s, 3H), 3.72-3.48 (m, 4H), 3.32 (m, 2H), 2.19 (s, 3H). LCMS (ES+) 354 (M+H).sup.+, RT 2.24 minutes.

Example 3

Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-methyl-6,7-dihydro-4H-imidiazo[4,5-c]-pyridin-5-yl}propanoate

(35) To a stirred solution of Intermediate 7 (200 mg, 0.68 mmol) in DMF (5 mL) at 0° C. was added NaH (32 mg, 1.36 mmol), followed by ethyl-3-bromopropionate (147 mg, 0.81 mmol). The reaction mixture was stirred at room temperature for 18 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (100 mg, 37%) as a white solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.35 (d, 1H, J 8.5 Hz), 7.23 (dd, 1H, J 8.5, 2.5 Hz), 6.50 (d, 1H, J 2.4 Hz), 4.95 (s, 2H), 4.12 (q, 2H, J 7.1 Hz), 3.35 (d, 2H, J 1.9 Hz), 2.98-2.78 (m, 4H), 2.78-2.62 (m, 2H), 2.52 (t, 2H, J 7.3 Hz), 2.30 (s, 3H), 1.23 (t 3H, J 7.2 Hz). LCMS (ES+) 396 (M+H).sup.+, RT 2.23 minutes.

Example 4

3-[(2,5-Dichlorophenyl)methyl]-2-methyl-5-(2,2,2-trifluoroethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine

(36) To a stirred solution of Intermediate 13 (200 mg, 0.51 mmol) in THF (10 mL) at 0° C. was added borane dimethyl sulphide complex (0.51 mL, 1.02 mmol). The reaction mixture was heated at 60° C. for 2 h, then quenched with a saturated aqueous solution of NH.sub.4Cl and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (12 mg, 6%) as a colourless gum. δ.sub.H (400 MHz, CDCl.sub.3) 7.35 (d, 1H, J 8.5 Hz), 7.23 (dd, 1H, J 8.5, 2.5 Hz), 6.50 (d, 1H, J 2.4 Hz), 4.98 (s, 2H), 3.59 (s, 2H), 3.19 (m, 2H), 3.08 (m, 2H), 2.78 (m, 2H), 2.35 (s, 3H). LCMS (ES+) 378 (M+H).sup.+, RT 2.38 minutes.

Example 5

1-{3-[2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}ethanone

(37) To a stirred solution of Intermediate 12 (70 mg, 0.22 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.03 mL, 0.22 mmol), followed by acetic anhydride (26 mg, 0.26 mmol). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (45 mg, 56%) as a colourless gum. δ.sub.H (400 MHz, CDCl.sub.3) 7.36 (dd, 1H, J 13.7, 8.6 Hz), 7.26-7.17 (m, 1H), 6.53 (d, 1H, J 2.6 Hz), 5.19 (d, 2H, J 6.9 Hz), 4.49 (m, 2H), 4.37 (m, 2H), 3.72 (t, 2H, J 5.8 Hz), 3.24 (s, 3H), 2.87-2.74 (m, 2H), 2.19 (s, 3H). LCMS (ES+) 368 (M+H).sup.+, RT 1.80 minutes.

Example 6

3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-5-(methylsulfonyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine

(38) To a stirred solution of Intermediate 12 (70 mg, 0.22 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.03 mL, 0.22 mmol), followed by methanesulfonyl chloride (29 mg, 0.26 mmol). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (50 mg, 56%) as a white solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.37 (d, 1H, J 8.5 Hz), 7.24 (d, 1H, J 2.4 Hz), 6.52 (d, 1H, J 2.6 Hz), 5.17 (s, 2H), 4.46 (s, 2H), 4.29-3.95 (m, 2H), 3.65 (t, 2H, J 5.8 Hz), 3.32 (s, 3H), 2.85 (td, 2H, J 5.7, 2.2 Hz), 2.81 (s, 3H). LCMS (ES+) 404 (M+H).sup.+, RT 2.00 minutes.

Example 7

Methyl 3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate

(39) To a stirred solution of Intermediate 12 (70 mg, 0.22 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.03 mL, 0.22 mmol), followed by methyl chloroformate (25 mg, 0.26 mmol). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (55 mg, 65%) as a colourless gum. δ.sub.H (400 MHz, CD.sub.3OD) 7.48 (d, 1H, J 8.6 Hz), 7.35 (dd, 1H, J 8.6, 2.5 Hz), 6.76-6.56 (m, 1H), 5.31 (s, 2H), 4.45 (s, 3H), 4.36-4.24 (m, 2H), 3.84-3.56 (m, 4H), 3.27 (s, 3H), 2.68 (t, 2H, J 5.8 Hz). LCMS (ES+) 384 (M+H).sup.+, RT 2.09 minutes.

Example 8

1-{3-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo[4,5-c]-pyridin-5-yl}-2,2,2-trifluoroethanone

(40) To a stirred solution of Intermediate 12 (300 mg, 0.92 mmol) in DCM (3 mL) was added triethylamine (0.13 mL, 0.92 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic anhydride (193 mg, 0.92 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with ice and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 3% methanol in DCM) to give the title compound (170 mg, 44%). δ.sub.H (400 MHz, CDCl.sub.3) 7.38-7.36 (m, 1H), 7.26-7.23 (m, 1H), 6.61 (br s, 1H), 5.20 (s, 2H), 4.50-4.34 (m, 4H), 3.87 (t, 2H, J 5.6 Hz), 3.32 (s, 3H), 2.86 (t, 2H, J 5.6 Hz). LCMS (ES+) 422 (M+H).sup.+, RT 2.42 minutes.

Example 9

Ethyl 3-{3-[(2,5-dichlorophenyl)methyl]-2-(methoxymethyl)-6,7-dihydro-4H-imidazo-[4,5-c]pyridin-5-yl}propanoate

(41) To a stirred solution of Intermediate 12 (250 mg, 0.77 mmol) in DMF (5 mL) at 0° C. was added NaH (37 mg, 1.54 mmol), followed by ethyl 3-bromopropionate (167 mg, 0.92 mmol). The reaction mixture was stirred at room temperature for 18 h, then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (50 mg, 15%) as a yellow gum. δ.sub.H (400 MHz, CD.sub.3OD) 7.47 (d, 1H, J 8.8 Hz), 7.34 (dd, 1H, J 6.0, 2.4 Hz), 6.66 (d, 1H, J 2.0 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 4.10 (q, 2H, J 6.8 Hz), 3.40 (s, 2H), 3.25 (s, 3H), 2.87 (t, 4H, J 7.2 Hz), 2.69 (t, 2H, J 5.2 Hz), 2.53 (t, 2H, J 6.8 Hz), 1.21 (t, 3H, J 6.8 Hz). LCMS (ES+) 426 (M+H).sup.+, RT 2.20 minutes.