"A PDE4 INHIBITOR PYRAZOLE COMPOUND ACCORDING TO FORMULAS II, III, V, OR VI"

4-Methoxy-3-(3 S)-tetrahydrofuryloxybenzaldehyde.

Example 1B : Synthesis of 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole Sodium hydride (60% in mineral oil, 1. 51g, 37.7 mmol) was suspended in THF (20 mL) and cooled to sec followed by addition of diethoxyphosphorylacetaldehyde tosylhydrazone (6.51 g, 18.7 mmol) in THF (20 mL) over 10 minutes. After stirring for 30 minutes at 5°C, the yellow suspension was treated with a solution of 4-methoxy-3- (3R)-tetrahydrofuryloxybenzaldehyde (2.84 g, 12.8 mmol) in THF (20 mL) and stirred for 1 hour at room temperature and 16 hours at 80°C in an oil bath. After cooling to room temperature, the reaction was poured into 5% aqueous NaH2PO4 and extracted with ethyl acetate. The extract was washed with water and brine, dried over Na2S04 and concentrated to afford a yellow solid. Recrystallization from ethyl acetate furnished 1.9 g (57%) of 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole in two crops as light yellow solids. (mp 149-151°C) ; 1H NMR (CDC13, 300, MHz) 6 2.23 (m, 2H), 3.85- 4.10 (m, 4H), 3.89 (s, 3H), 5.02 (m, lH), 6.54 (m, lH), 6.92 (m, lH), 7.25 (m, 2H), 7.60 - (m, lH) ;. MS [M+H] = 261.

The following compounds were prepared in a similar fashion with different starting materials: A. 3- (3, 4-Dimethoxyphenyl)-lH-pyrazole B. 3- (3-Cyclopentyloxy-4-methoxyphenyl)-lH-pyrazole C. 3- [3, 4-Bis (difluoromethoxy) phenyl]-1H-pyrazole D. 3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole E. 3- (3-Benzyloxy-4-methoxyphenyl) pyrazole F. 3- [3- (2, 3-Difluorobenzyloxy) -4-methoxyphenyl] pyrazole Example 2 Synthesis of 1- (2, 3-difluorobenzyl)-3- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1H-pyrazole Chiral u I N, N- 0 -y F XLn F F 3- [4-Methoxy-3- (3R) tetrahydrofuranyloxyphenyl]-lH-pyrazole (243 mg, 0.96 mmol) was dissolved in DMF (8 mL) at room temperature and treated with sodium hydride (75 mg, 1. 86mmol) with stirring for 3 hours. The reaction mixture was treated with a solution of 2,3-difluorobenzyl bromide (0.35 mL, 2.79 mmol) in DMF (1 mL) and stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water three times and brine once. The organic layer was dried over sodium sulfate and concentrated to an oil which was purified on a column of silica gel using a hexane/ethyl acetate gradient. Tubes containing the compound were pooled and evaporated under vacuum to afford 327mg (90%) of 1- (2, 3-difluorobenzyl)-3- [4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole as a colorless oil. MS [M+H] = 387 ; 1H NMR (CDC13,300 MHz) 8 2.23 (m, 2H), 3.8-4. 1 (m, 4H), 3.92 (s, 3H), 5.1 (m, 1H), 5.4 (s, 2H), 6.5 (s, 1H), 6.9 (m, 2H), 6.95-7. 11 (m, 2H), 7. 3 (m, 2H), 7.45 (s, lH). A minor product consisting of 1- (2, 3-difluorobenzyl)-5- [4-methoxy-3- (3R)- tetrahydrofuranyloxy-phenyl]-lH-pyrazole was also formed, which can be separated and- isolated by preparative HPLC (see, e. g. , Example 3).

The following compounds were prepared in a similar fashion with different starting materials (in some cases, the 5-regioisomer was also formed and could be separated by methods known in the art such as preparative HPLC) : A. 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2-methylbenzyl)-1H-pyrazole B. 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl)-1H-pyrazole C. 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (4-nitrobenzyl)-1H-pyrazole D. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methylbenzyl)-lH-pyrazole E. 1-(4-Aminobenzyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1H-pyrazole F. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-nitrobenzyl)-lH-pyrazole G. 1- (4-Aminobenzyl)-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole H. 3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-nitrobenzyl)-1H- pyrazole I. 3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methylbenzyl)-1H- pyrazole J. 1- (2, 3-Difluorobenzyl)-3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- 1H-pyrazole K. 1-(4-Aminobenzyl)-3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole L. 1- (2, 3-Difluorob enzyl)-3- [4-methoxy-3- (3 S)-tetrahydro furanyloxyphenyl]-1 H- pyrazole M. 1-Cyclohexylmethyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole N. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- (3-phenpropyl)-lH-pyrazole


O. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-pyridylmethyl)-lH-pyrazole P. 1-Ethylsulfonyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole Q. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (l-propyl)-lH-pyrazole R. 1-Benzylsulfonyl-3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole S. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-pyridylmethyl)-1H-pyrazole _ T. 3-(3-Benzyloxy-4-methoxyphenyl)-1-(2,3-difluorobenzyl)-1H-pyrazole U. 3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-[N-(1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl]-1 H-pyrazole V. 1- [N- (7-Azaindolyl) carbonylmethyl]-3- [4-Methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole W. 1- (2, 3-Difluorobenzyl)-3- [3- (2, 3-difluorobenzyloxy)-4-methoxyphenyl]-lH-pyrazole X. 1- (2, 3-Difluorobenzyl)-3- (3-hydroxy-4-methoxyphenyl)-1 H-pyrazole Y. 3- [4-Methoxy-3- (3R)-tetrahydrofitranyloxyphenyl]-1- (2-phenethyl)-lH-pyrazole Z. 2- {3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-1-phenyl-1- ethanone] AA. 1-Benzyl-3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole AB. 1-Cyclopentyl-3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole AC. 3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-[2-(6-methylpyridyl]-1H- pyrazole AD. 1-Cyclohexylmethyl-3-(4-methoxy-3-(3S)-tetrahydrofuranyloxyphenyl)-1H- pyrazole AE. 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (methylsulfonylbenzyl)-1H- pyrazole AF. 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (2, 3-difluorobenzyl)-lH-pyrazole AGF. 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(4-methylsulfonylbenzyl)-1H-pyrazole AH. 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (2-methylbenzyl)-lH-pyrazole AI. 1- (2-Methoxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H-pyrazole AJ. 1- (2-Cyclopropylmethoxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofiranyloxyphenyl]- IH-pyrazole Example 3 l-Cyclohexylmethyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole Chiral ou ^ N-N 0-6 and 1-Cyclohexylmethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole Chiral u I 'N ( A solution of3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole (78 mg, 0.3 mmol) in DMF (2. mL) was treated with sodium hydride (60% in oil, 24 mg, 0.6 mmol) and stirred at room temperature for three hours. The reaction mixture was then treated with a solution of (bromomethyl) cyclohexane (0.13 mL, 0.9 mmol) in DMF (0.8 mL) and stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (60 mL) and washed with water (2x20 mL) and brine (1x15 mL), dried (Na2S04) and concentrated to 250 mg of an oil, which was chromatographed over silica gel using a 10-30% ethyl acetate/hexane gradient. Concentration of fractions afforded 92 mg of an oil consisting of a mixture of regioisomers in a ratio of. 3 : 5: 1 as deteremined by LCMS.

The mixture of regioisomers was taken in 1 mL of acetonitrile/water (3: 2 with 0.1 % formic acid) and resolved by preparative hplc using a Waters C18,5 um, 30x100 mm column with a flow rate of 45 mL/min. A gradient of 35-80% acetonitrile/water containing 0.1 % formic acid over 6 minutes was employed and a Waters 2996 PDA detector was utilized to trigger collection at 248 nm. Baseline resolution was achieved with peak A eluting at 7.61 min and peak B eluting at 8.15 min. Tubes containing each regioisomer were concentrated on a Genevac HT4 Series II Evaporator supplying 14mg of (peak A; retention time = 7.61 minutes) 1-cyclohexylmethyl-5- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole and 54 mg of (peak B; retention time = 8.15 minutes). l-cyclohexylmethyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole, each as colorless oils. Both peaks exhibit [M+H] =357. lH NMR for peak A (CDC13, 300 MHz) 8 0.80 (m, 2H), 1.1-1. 3 (m, 3H), 1.4-1. 7 (m, 5H), 1.9 (m, 1H), 2.2 (m, 2H), 3.8-4. 2 (m, 9H), 4.97 (s, 1H), 6.22 (s, 1H), 6.82 (s, 1H), 6.96 (s, 2H), 7.55 (s, 1H).

'H NMR of peak B (CDC13, 300 MHz) 6 0.80 (m, 2H), 1. 1-1. 3 (m, 3H), 1.4-1. 7 (m, 5H), 1. 9 (m, 1H), 2.2 (m, 2H), 3.8-4. 2 (m, 9H), 5. 08 (s, 1H), 6.44 (s, 1H), 6.9 (d, 1H), 7. 35 (m, 3H).

The following compounds were prepared in a similar fashion with different starting materials: A. 1-Cyclohexylmethyl-5- [4-methoxy-3- (3S)-tetrahydrofuranyloxyphenyl]-lH-pyrazole B. Isopropyl2- {5- [4-methoxy-3- (3R)-tetrahydrofuranylphenyl]-pyrazol-l-yl} acetate C. 1- (2, 3-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranylphenyl]-lH-pyrazole Example 4 Intermediate B: Synthesis of 2-Acetyl-4-bromo-7-methoxybenzofuran 2-Acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) was dissolved in glacial acetic acid (29 mL) followed by addition of sodium acetate (1.3 g, 15.8 mmol). The reaction was treated dropwise with a solution of bromine (0.26 mL, 5. 26. mmol) in glacial acetic acid (10 mL) at room temperature followed by stirring for one hour. The solvent was removed under vacuum. The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were washed with 2% aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel using a 50-100% dichloromethane/hexane gradient affording the product as a white solid. (1.00 g, 75%). 1H NMR (CDC13,300 MHz) 8 7. 44 (s, 1H), 7.32 (d, 1H), 6.80 (d, 1H), 4.0 (s, 3H), 2.62 (s, 3H).

Intermediate-C : Synthesis of 4-bromo-7-methoxy-2- [2-methyl- (1, 3-dioxolan) -2- yl] benzofuran A solution of 2-acetyl-4-bromo-7-methoxybenzofuran (0.50 g, 1. 86 mmol), 5 mL of ethylene glycol, and PPTS-(46 mg, 0.186mmol) was refluxed overnight in benzene (37 mL) using a Dean Stark apparatus. The reaction was cooled to room temperature, washed with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum to afford 293 mg (50%) of 4-bromo-7-methoxy-2- [2-methyl- (1, 3--

dioxolan) -2-yl] benzofuran as an oil. 1H NMR (CDC13, 300 MHz) 8 7.28 (d, 1H), 6.74 (s, 1H), 6.69 (d, 1H), 4. 04 (m, 4H), 1.84 (s, 3H).

Intermediate D: Synthesis of 7-methoxy-2- [2-methyl- (1, 3-dioxolan)-2-yl]-


. benzofuran-4-carboxaldehyde


4-Bromo-7-methoxy-2- [2-methyl- (1, 3-dioxolan) -2-yl] benzofuran (666 mg, 2.1 mmol) was dissolved in THF (21 mL), cooled to-60 °C under an argon atmosphere, and t-butyl lithium (2.6 mL, 1.7 M) was added with stirring at-60 °C. The mixture was stirred at-60 °C for one hour, DMF (0.82 mL, 10.6 mmol) in THF (20 mL) was added, and the reaction was stirred at ambient temperature overnight. The reaction was poured into aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extracts were washed once with water, once with brine, and dried over sodium sulfate. Evaporation of the solvent under reduced pressure followed by purification on silica gel using a 10-50% ethyl acetate/hexane gradient afforded 7-methoxy-2- [2-methyl- (1, 3-dioxolan)-2-yl]-benzofuran-4-carboxaldehyde (399 mg ;'72%) as an oil. 1H NMR (CDC13,300 MHz) 8 10.01 (s, 1H), 7.66 (d, 1H), 7.45 (s, 1H), 6. 88 (d, 1H), 4.08 (m, 7H), 1.84 (s, 3H).

Example 5 Synthesis of 3- (2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole A suspension of sodium hydride (60% in oil, 174 mg, 4.36 mmol) in THF (5 mL) was cooled to 0°C under argon, and then treated with a solution of diethoxyphosphorylacetaldehyde tosylhydrazone (759 mg, 2.2 mmol) in THF (7mL).

After stirring at 0°C for 30 minutes a solution of 7-methoxy-2- (2-methyl- [1, 3] dioxolan-2- yl) benzofuran-4-carboxaldehyde (381 mg, 1.45 mmol) in THF (5mL)-was added and the reaction stirred at room temperature overnight followed by stirring at 65°C for 5 hours.

After cooling to room temperature, the reaction was poured into 5% aqueous NaH2PO4 and extracted with ethyl acetate. The extract was washed with water, washed with brine, dried over Na2S04, and concentrated. The residue was chromatographed on silica gel using a 25-50% ethyl acetate/hexane gradient to afford the dioxolane protected pyrazole (306 mg, 70%). The masked ketone (306 mg) was taken in 3M HC1 in THF (10 mL) and stirred at room temperature for 2 hours. The solution was neutralized with sodium bicarbonate and extracted with ethyl acetate three times. The combined extracts were washed with water, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel using hexane/ethyl acetate (1: 1; v/v) to isolate 3-(2-Acetyl-7-methoxybenzofuran-4-yl) pyråzole (192 mg, 74%) as a yellow solid.

'H NMR (CDC13,300 MHz) 6 8. 09 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 6.98 (d, 1H), 6.70 (d, 1H), 4.07 (s, 3H), 2.65 (s, 3H).

Example 6 Intermediate E: Synthesis of 4-difluoromethoxy-3-hydroxybenzaldehyde 3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55°C under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10 % aqueous HC1 followed by extraction with ethyl acetate (3x 500 mL).

The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20% ethyl acetate/hexane gradient. 4-difluoromethoxy-3- hydroxybenzaldehyde was isolated in 24% yield (6.62 g). IH NMR (CDC13,400 MHz) 8 6.1 (br s, 1H), 6.48-6. 85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).

Intermediate F: Synthesis of tert-Butyl 2- {3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl] pyrazol-1-yl} acetate 3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole (199 mg, 0.67 mmol) was dissolved in DMF (9mL). Sodium hydride (60% in oil, 54 mg, 1.34 mmol) was added at room temperature and stirred for 1 hour followed by addition of tert- butyl bromoacetate (0.30 mL, 2.01 mmol) in DMF (lmL). The reaction was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water twice and brine once. The solvent was dried over sodium sulfate and concentrated to 500 mg of a pale yellow oil, which was purified on silica gel using a 20-50% ethyl acetate/hexane gradient to afford tert-butyl 2- {3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl] pyrazol-1-yl} acetate as a colorless oil (145 mg, 53%). MS [M+H] =411. 1H NMR (DMSO 300 MHz) 8 1.42 (s, 9H), 2. 05 (m, 1H), 2.23 (m, 1H), 3.8-4. 0 (m, 4H), 4.98 (s, 2H), 5. 18 (br s, 1H), 6.78-7. 28 (t, 1H OCHF2), 6. 80 (s, 1H), 7.21 (d, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 7.77 (s, 1H).

Synthesis of 2-f 3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl] pyrazole- 1-yl} acetic acid FYF Chiral 0 11 If o O O tert-Butyl 2- 3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl] pyrazol- 1-yl} acetate (762 mg, 1.85 mmol) was stirred in dichloromethane (llmL) and treated with trifluoroacetic acid (llmL) with stirring for 90 minutes. The solvent was removed under reduced pressure and partitioned between ethyl acetate/water. The organic layer was washed with water three times and brine once. After drying over sodium sulfate, the solvent was stripped to furnish 2-3- [4-difluoromethoxy-3- (tetrahydrofuryloxy) phenyl] pyrazole-1-yl} acetic acid as a semisolid (657 mg, 100%) MS [M+H] =355. in NMR (CDC13 300 MHz) 8 2.25 (m, 2H), 4.02 (m, 4H), 5.07 (m, 2H), 5.2 (br s, 1H), 6.31-6. 81 (t, 1H OCHF2), 6.61 (s, 1H), 7.19-7. 28 (m, 3H), 7.29 (s, 1H), 7.52 (s, 1H).

2- {3-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)pyrazole-1-yl} acetic acid was synthesized in a similar manner with different starting materials.

Example 7 Synthesis of 2- {3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol- 1-yl}-N-(2, 3-difluorophenyl) acetamide 2- 3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl] pyrazol-1-yl} acetic acid (84 mg, 0.23 mmol) was dissolved in dichloromethane (2mL), cooled to 5°C and treated the oxalyl chloride (2M in dichloromethane, 0. 13mL, 0.26 mmol) and stirred for 90 minutes. In a separate flask, 2,3-difluoroaniline (0.35mL, 0. 35mmol) in THF (2mL) was treated with sodium hydride (60% in oil, 22 mg, 0.56 mmol) and stirred for 90 minutes. The solvent from the initial flask was removed under reduced pressure. The residue was taken in THF (2mL), cooled to 5°C and treated with the difluoroaniline/hydride suspension followed by stirring at ambient temperature for 16 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate/water. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated to afford 57 mg of a brown oil. This was adsorbed onto a preparative. thin layer chromatography silica gel plate (20x20 cm, 2000 micron) using ethyl acetate/hexane (1 : 1 v/v) to elute.. The product was isolated from the plate by scraping and suspending the silica gel in ethyl acetate following by filtering through a bed of Celite. Evaporation of the solvent afforded 2- {3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- (2, 3-difluorophenyl) acetamide as a white foam (15 mg, 14%) MS [M+H] =446 ; 1H NMR (CDC13, 300 MHz) 8 2.28 (m, 2H), 4.05 (m, 4H), 4.98 (s, 2H). 5.1 (s, 1H), 6.3-6. 7 (t, 1H OCHF2) 6.65 (s, 1H), 6.8 (m, 1H), 6.9 (m, 1H), 7.25 (m, 2H), 7.56 (s, 2H) 8.3 (t, 1H), 9.8 (s, 1H).

The following compounds were prepared in a similar fashion with different starting materials: A. 2- {3- [3, 4-Bis (difluoromethoxy)-phenyl]-pyrazol-1-yl}-N-(2- methylphenyl) acetamide] B. 2-f3- [3, 4-Bis (difluoromethoxy)-phenyl]-pyrazol-1-yl}-N-(2, 3- difluorophenyl) acetamide] C. 1-N- (2-cyanophenyl)-2-f 3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- pyrazol-1-yl} acetamide D. 2- {3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- [2- (6-methylpyridyl) ] acetamide] Example 8 Intermediate G: Methyl 3-ethyl-lH-indazol-6-yl-carboxylate To a solution of 1.35 g (7. 1 mmol) of 3-ethyl-lH-indazol-6-yl-carboxylic acid, [Marfat, A. , et al.,"Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U. S.

Patent No. 6,262, 040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2C12 was added 1.5 g (7.8 mmol) of EDCI-HC1. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of IN HC1, 40 mL of water and 40 mL of brine, dried (Na2S04), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-lH-indazol-6-yl- , carboxylate. 1H-NMR (CDC13) 8 11. 7 (s, 1H), 8. 18 (s, 1H), 7.73 (apparent q, 9. 0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).

Intermediate H: Methyl 1-Cyclopentyl-3-ethyl-lH-indazol-6-yl-carboxylate To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-lH-indazol-6-yl-carboxylate. This mixture was stirred at room temperature for 3 hours and then 1.35 mL (12.6 mmol) of cyclopentyl bromide was added and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mL of brine, dried- (Na2S04), and concentrated. The residue was purified by column chromatography over Si02 using a step gradient of 10% ethyl acetate in hexanes until the first compound eluted and then 50% ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 1- cyclopentyl-3-ethyl-lH-indazol-6-yl-carboxylate as a clear oil along with 144 mg (0.53 mmol) methyl 2- (cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellowoil.'H- NMR (CDC13) 8 8.17 (s, 1H), 7.71 (dd, J1= 8.4 Hz, J2 = 6.7 Hz, 2H), 5.0 (p, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J = 7.5 Hz, 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J = 7. 6 Hz, 3H).

Intermediate I : l-Cyclopentyl-3-ethyl-6-hydroxymethyl-lH-indazole DIBAL (10 mL, 1M in toluene) was slowly added with stirring at-50 °C to a solution of 886 mg (3.25 mmol) of methyl 1-cyclopentyl-3-ethyl-lH-indazol-6-yl- carboxylate in 32 mL of CH2C12. The reaction stirred at-50 °C for 1 hour and was quenched by the slow addition of 4 mL of MeOH and then, with stirring, poured into a saturated Rochelle's salt and ethyl acetate mixture (60 ml each). Stirring continued at room temperature until both layers were clear. The organic layer was separated and the aqueous layer was extracted with 3 x 40 mL of ethyl acetate. The organic fractions were combined, dried (Na2SO4), and concentrated. The compound was purified via column chromatography over Si02 using a 1: 4 solution of EtOAc in hexanes as eluant to yield 427 mg (1.75 mmol) of 1-cyclopentyl-3-ethyl-6-hydroxymethanol-lH-indazole as a clear oil. lH-NMR (CDC13) 6 7.66 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J = 8.2 Hz), 4.92 (p, J = 7.7 Hz, 1H), 4.84 (d, J = 5.5 Hz, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.15 (m, 4H), 2.04 (m, 2H), 1.73 (m, 2H), 1.38 (t, J = 7.6 Hz, 3H).

Intermediate J: 1-Cyclopentyl-3-ethyl-lH-indazol-6-yl-carboxaldehyde To a solution of 427 mg (1.75 mmol) 1-cyclopentyl-3-ethyl-6-hydroxymethanol- 1H-indazole in 58 mL of CHC13 was added 2.1 g (24.1 mmol) of Mn02. The reaction was stirred at room temperature for 6 hours, the solids were removed by filtration and the filtrate was concentrated. The residue was purified via column chromatography over Si02 using 3% ethyl acetate in hexanes as eluant to give 332 mg (1.37 mmol) of 1- cyclopentyl-3-ethyl-lH-indazol-6-yl-carboxaldehyde as a clear oil. IH-NMR (CDCl3) 6 10.13 (s, 1H), 7.94 (s. 1H), 7.78 (d, J = 8. 2 Hz, 1H), 7.61 (d, J = 8. 2 Hz, 1H), 5.02 (p, J= 7.4 Hz, 1H), 3.02 (q, J = 7.5 Hz, 2H), 2.19 (m, 4H), 2.02 (m, 2H), 1.76 (m, 2H), 1.40 (t, J = 7.5 Hz, 3H).

3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl]-lH-pyrazole A flask containing 165 mg (4.12 mmol) of NaH (60% in mineral oil) and 4 mL of THF was placed under Ar and cooled to 0 °C. A solution of 716 mg (2.06 mmol) of diethoxyphosphorylacetaldehyde tosylhydrazone in 7 mL of THF was added over 5 minutes. The reaction stirred at 0 °C for 30 minutes followed by the addition of a solution of 332 mg (1.37 mmol) of 1-cyclopentyl-3-ethyl-lH-indazol-6-yl- carboxaldehyde in 4.5 mL THF. The ice bath was removed and the solution was stirred at room temperature for 4 hours, and then heated to 65 °C overnight. The reaction mixture was cooled to room temperature, poured into 50 mL of 5% NaH2PO4 and extracted with 3 x 25 mL of ethyl acetate. The organic layers were combined, dried over Na2S04, concentrated, and purified by column chromatography over Si02 using a gradient from 10% to 50% ethyl acetate in hexanes over 20 minutes to yield 185 mg (0.66 mmol) of 1-cyclopentyl-3-ethyl-6-(lH-pyrazol-3-yl)-lH-indazole as a white foam.

1H-NMR (CDC13) 8 7.80 (s, 1H), 7.69 (d, J = 8. 3 Hz, 1H), 7.65 (s, 1H), 7.5 (d, J = 8.3 Hz ; 1H), 6.7 (s, 1H) 4.90 (p, J = 7.5 Hz, 1H), 3.00 (q, J = 7. 5 Hz, 2H), 2.13 (m, 4H), 2.00 (m, 2H), 1.71 (m, 2H), 1.40 (t, J = 7.5, 3H).

Example 9 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl]-1- (2, 3-difluorobenzyl)-lH-pyrazole A solution of 31.8 mg (0.11 mmol) of 3- [ (1-cyclopentyl-3-ethylindazol)-6-yl]-lH-- pyrazole in 1 mL of DMF was added to a flask containing 12.9 mg (0.32 mmol) of NaH (60% in mineral oil) and 1 mL of DMF. This was stirred at room temperature for 3 hours. Then, a solution of 43 I1L (0.33 mmol) of 2,3-difluorobenzyl bromide in 1 mL of DMF was added and the reaction was stirred at room temperature overnight. The mixture was poured into a mixture of 10 mL of water and 10 mL of ethyl acetate. The organic layer was washed with 2 x 10 mL of water and 1 x 10 mL of brine. The organic layer was then dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification via column chromatography over 4 g of silica using 5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes gradient over 10 minutes to give 24 mg (0.06 mmol, 52% yield) of 3- [ (l-cyclopentyl-3-ethylindazol)-6-yl]-1- (2, 3- difluorobenzyl)-lH-pyrazole as a clear oil.. 1H-NMR (CDC13) 8 7.84 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.15-7. 04 (m, 3H), 6.68 (s, 1H), 5. 48 (s, 2H), 4.99 (p, J = 7.6 Hz, 1H), 3.01 (q, J = 7.4 Hz, 2H), 2.12 (s, 4H), 1.98 (s, 2H), 1.75- 1.72 (m, 2H), 1.40 (t, 7 : 4 Hz, 3H).

The following compounds were synthesized in a similar manner with different starting materials: A. 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(2, 3-difluorophenyl)-lH-pyrazole B. 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-methylbenzyl)-lH-pyrazole C. 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl])-1- (4-methylsulfonylbenzyl)-lH-pyrazole D. 3- [ (l-Cyclopentyl-3-ethylindazol)-6-yl])-1- (2-pyridylmethyl)-lH-pyrazole Example 10 Synthesis of 2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithiane 4-Methoxy-3- (3R)-tetrahydrofuranyloxybenzaldehyde (8.37 g; 37.6 mmol) was dissolved in dichloromethane (120 mL) followed by addition of 1, 3-propanedithiol (11. 3 mL; 113 mmol) and boron trifluoride etherate (0.6 mL). The reaction mixture became mildly exothermic and turbid. Reaction monitoring by LC-MS showed complete conversion taking place in 90 minutes. The reaction was washed with 30 mL of water and 30 mL of brine, dried over anhydrous sodium sulfate and concentrated. Trituration of the residue with ether produced a white solid that was collected by filtration and dried yielding 9.09 g (77%) of 2- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithiane.

'H NMR (CDC13 ; 300 MHz) 6 1.85-2. 25 (m, 4H); 2.85-2. 95 (m, 2H); 3.0-3. 1 (m, 2H); 3.85 (s, 3H); 3.9-4. 1 (m, 4H); 4.95-5. 00 (m, 1H); 5.1 (s, 1H); 6.85 (d, 1H); 7.00 (d, 1H) ; 7.05 (d, 1H). ES-MS [M+H] +=313. 2 Example 11 Synthesis of 2- {2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithian-2- yl} propanol Solid 2- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithiane (2.5 g; 8 mmol) was added to an oven-dried flask equipped with a stir bar, septum and an inert gas line. Dry tetrahydrofuran (40 mL) was added and stirred at-40 °C using an acetonitrile/dry ice bath. To the resulting solution was added n-butyl lithium (2. 5M in hexanes ; 4.2 mL; 10.4 mmol) via syringe over 15 minutes. After stirring at-40 °C for thirty minutes, HMPA (1.4 mL; 8 mmol) was injected over two minutes and stirred for 10 minutes followed by rapid addition of propylene oxide (0.62 mL; 8.8 mmol). After stirring at-40 °C for 1 hour, the reaction was quenched with aqueous ammonium chloride (5 mL), diluted with water (30 mL) and extracted with ethyl acetate (70 mL).

The organic layer was washed with 25 mL of water and 25 mL of brine, dried over anhydrous sodium sulfate and evaporated to yield 3.5 g of a viscous yellow oil. The crude alcohol was purified by flash chromatography on silica gel using a 20-60% ethyl acetate/hexane gradient affording the product as a colorless, viscous oil (2.7 g; 91%). IH NMR (CDC13; 300 MHz) 8 1. l (d, 3H); 2.0-2. 5 (m, 7H); 2.75 (m, 4H); 3.8 (s. 3H) ; 3.9-4. 1 (m, 5H) ; 5.0 (m, 1H) 6. 9. (d, 1H) ; 7.5 (m, 2H). ES-MS [M+H] += 371. 2 The following compounds were synthesized in a similar manner with different starting materials: 1- {2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithian-2-yl} butan-2-ol.

Example 12 Synthesis of 1-f 2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithian-2- yl} propan-2-one 1- {2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithian-2-yl} propan-2- ol (158 mg; 0.42 mmol) was stirred in dichloromethane (5mL) and treated with Dess Martin periodinane (15% solution in dichloromethane; 356 mg; 0.84 mmol) and stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure and the residue was loaded onto a column of silica gel and eluted with a 20-60% ethyl acetate/hexane gradient. The product was isolated as an oil (23 mg; 15%). 1H NMR (CDC13 ; 300 MHz) 5 2.0 (s, 3H); 2.1-2. 5 (m, 4H); 2. 8 (m, 4H); 3.2 (s, 2H); 3.8-4. 2 (m, 7H); 5.0 (m, 1H) ; 6.9 (m, 1H) ; 7.5 (m, 2H). ES-MS [M+H] += 369.1 The following compounds were synthesized in a similar manner with different starting materials: 1- {2- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dithian-2-yl} butan-2-one.

Alternative Method for Example 12.

1- {2- [4-Methoxy-3- (3R)-tetrahydroiuranyloxyphenyl]-l, 3-dithian-2-yl} propan-2- ol (119 mg; 0.32 mmol) was stirred in dichloromethane (5 mL) and treated with Dess- Martin periodinane (15% solution in dichloromethane; 173 mg; 0.41 mmol) and stirred at room temperature for 10 minutes. Upon formation of a precipitate, thin layer chromatography analysis using hexane/ethyl acetate (1: 1 v/v) determined the reaction to be complete. The reaction was diluted with dichloromethane (40 mL) and washed with 20 mL portions of aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to a crude solid, which was used as such in Example 7.

Example 13 Synthesis of 1- (2-Methoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxy- phenyl]-3-methyl-lH-pyrazole 1- {2- [4-Mcthoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l, 3-dithian-2-yl} propan-2- one (115 mg, 0.32 mmol) was reconstituted in toluene (5 mL) and treated with 2- methoxybenzyl hydrazine dihydrochloride (144 mg; 0.64 mmol) and molecular sieves (4A; 500 mg). The reaction was heated at 100 °C for two hours and cooled to room temperature. Molecular sieves were removed via filtration and the filtrate was diluted with ethyl acetate (50mL), washed with 20 mL portions of water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to an oil. The product was isolated by flash chromatography on silica gel using a 20-50% ethyl acetate/hexane gradient to afford 57 mg (45%) of 1- (2-methoxybenzyl)-5- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole as a yellow foam. IH NMR (CDC13; 300 MHz) § 1.7-2. 0 (m, 2H); 2.3 (s, 3H); 3.6-4. 0 (m, 10H) ; 4.5 (m, 1H) ; 5.3 (s, 2H); 6.2 (s, 1H); 6.6 (m, 1H); 6.7 (d, 1H): 6.8-7. 0 (m, 4H); 7.2 (d, 1H). ES-MS [M+H] += 395.3 The following compounds were synthesized in a similar manner with different starting materials: 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-phenyl-lH-pyrazole ; 1-Cyclohexyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1- (l-Butyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1- (2-Fluorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH- pyrazole; 1- (4-Chlorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole;


3-Ethyl-1- (2-methoxyb enzyl)-5- [4-methoxy-3- (3 R)-tetrahydrofuranyloxyphenyl]-1 H- pyrazole; 1-Cyclohexyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-Benzyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; Ethyl 3-ethyl- [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-lH-pyrazol-1- yl] acetate; 1- (2, 3-Dimethylphenyl)-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole;


1- (3, 4-Dimethylphenyl)-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 3-Ethyl-5- [4-methoxy-3- (3R)-tetrahydro furanyloxyphenyl]-1- (2-methylphenyl)-1H- pyrazole;


1- (2-Benzothiazolyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole; 1- (3, 4-Dimethylphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl- IH-pyrazole ;


1- (2, 3-Dimethylphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxypheriyl]-3-methyl- 1H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (3-nitrophenyl)-lH- pyrazole ;


5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-methylphenyl)-lH- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofiranyloxyphenyl]-3-methyl-1- (2-phenylethyl)-lH- pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(4- trifluoromethoxyphenyl)-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofaranyloxyphenyl]-3-methyl- 1- (2-quinoxalinyl)-lH- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-methoxyphenyl) 3-methyl-lH- pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methoxycarbonyl-3-thienyl)-3- methyl-lH-pyrazole ; 1- [2- (6-Fluoropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1 H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-pyridyl)- IH-pyrazole ; 1- [2- (6-Chloropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl- 1H-pyrazole.

Example 14 Synthesis of 1- (3, 4-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxy- phenyl]-lH-pyrazole 2-{4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl}-5, 5-dimethyl- [1, 3,2] dioxaborinane (87 mg, 0.28 mmol), 5-bromo-1- (3, 4-difluorobenzyl)-lH-pyrazole (65 mg, 0.23 mmol), Pd (PPh3) 2CI2 (37 mg. 0.004 mmol), 2 M Na2C03 aqueous solution (0.2 mL) and 3 mL of a solvent mixture which consisted of 7: 3: 2: : DME: H20 : EtOH was placed into a 2.0-5. 0 mL Smith Process vial. This was sealed and placed into a Personal Chemistry Emrys Optimizer, stirred for 30 seconds, and then heated to 140 °C for 120 seconds. The solution was then diluted with 10 mL water and 10 mL ethyl acetate. The organic layer was separated, dried over Na2S04, filtered and the solvent was removed.

Purification by silica gel column chromatography using a gradient elution from 10% to 50% ethyl acetate in hexanes provided 72 mg (79%) of 1- (3, 4-difluorobenzyl)-5- [4- methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole as a clear oil. 1H-NMR (CDC13, 300 MHz) 5 7.6 (d, lH), 7.1-6. 8 (m, 5H), 6.7 (d, 1H), 6.3 (d, 1H), 5. 3 (s, 2H), 4.8 (m, 1H), 4. 0-3.8 (m, 7H), 2.1-2. 0 (m, 2H). (M+1) = 387.2 The following compounds were synthesized in a similar manner with different starting materials: 1-(2,3-Difluorobenzyl)-5-(3,4-dimethoxyphenyl)-1H-pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methybenzyl)-1H-pyrazole ; 1- (4-tert-Butylbenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethylbenzyl)-1H- pyrazole; 1- (3, 4-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofaranyloxyphenyl]-IH-pyrazole ; 1- (2-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (3-nitrobenzyl)-lH-pyrazole ; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methoxycarbonylbenzyl)-1H- pyrazole; 1- (3-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3, 5-Dimethoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3-Methoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3, 4-Difluorobenzyl)-5- (3-fluoro-4-methoxyphenyl)-1H-pyrazole ; 5- (3-Fluoro-4-methoxyphenyl) 1- (4-methoxycarbonylbenzyl)-1 H-pyrazole ; 1-(2,6-Difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; 1-(4-Fluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole, Example 15 Synthesis of 2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-5,5-dimethyl- [1, 3,2] dioxaborinane 1-Bromo-4-methoxy-3-(3R)-tetrahydrofuranyloxybenzene (500 rng, 1.83 mmol) was added to a flask containing 10 mL of THF. This was cooled to-78 °C under argon and butyllithium (1.5 mL, 2. 5 M) was slowly added. After stirring at-78 °C for 1.5 hours, trimethyl borate (0.41 mL, 3.7 mmol) in 10 mL of THF was added and the mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of 20 mL of an aqueous saturated solution of NH4C1 and 2Q mL of diethyl ether.

The organic layer was washed with 10 mL of water, 10 mL of brine, dried over Na2SO4, and concentrated. The residue was dissolved in 18 mL of toluene and 270 mg of (2.6 mmol) 2, 2-dimethylpropane-1, 3-diol was added. This was heated to reflux for 4 hours, concentrated, and diluted with hexanes. The insoluble material was washed three times with hexanes. The combined organic layer was removed and the product was purified using column chromatography using a gradient elution from 10% to 100% ethyl acetate in hexanes to give 198 mg (35%) of 2-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]- 5, 5-dimethyl- [1, 3,2] dioxaborinane as a clear oil.'H-NMR (CDC13, 300 MHz) 5 7. 4. (d, 1H), 7.3 (d, 1H), 6.9 (d, 1H), 5.0 (m, 1H), 4.0 (m, 3H), 3.9-3. 8 (m, 4H), 3.7, (s, 4H), 2.1 (m, 2H), 1.0 (s, 6H).

Example 16 Synthesis of 1- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] ethanol A flask containing 1.7 g (7.5 mmol) of 4-methoxy-3- (3R)- tetrahydrofuranyloxybenzaldehyde and 75 mL of THF was cooled to-78 °C under argon and 5.0 mL (3 M) of MeMgCl was slowly added. The reaction was stirred at room temperature for 12 hours and was quenched by the addition of 100 mL of saturated aqueous NH4C1. The aqueous layer was extracted with 3 X 50 mL of ethyl acetate and the combined organic extracts were dried over Na2S04, filtered and concentrated.

Purification by silica gel column chromatography using a gradient elution from 50% to 100% ethyl acetate in hexanes yielded 1.46 g (80%) of l- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl] -ethanol as a white solid. 1H-NMR (CDC13, 300 MHz) 6 6.9 (m, 3H), 5.0 (m, 1H), 4.8 (m, 1H), 4.0-3. 8 (m, 4H), 3.8 (s, 3H), 2.1 (m, 2H), 1.4 (d, 3H). (M-H2O+1) = 221.2 Example 17 Synthesis of 1- [4-Methoxy-3-(3 R)-tetrahydrofuranyloxyphenyl] ethanone Pyridium chlorochromate (2.8 g; 12.3 mmol) was added to a flask containing 1.46 g (6,. 1 mmol) of 1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl] ethanol and 65 mL of CH2Cl2. The mixture was stirred at room temperature for one hour and the solids were filtered through silica gel, rinsing with 200 mL ethyl acetate. The solvent was removed and the residue was purified by column chromatography using a gradient elution from 20% to 50% ethyl acetate in hexanes to give 1.2 g (83%) of 1- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl] ethanone as a white solid. IH-NMR (CDC13, 300 MHz) 6 7.5 (d, 1H), 7.4 (d, 1H), 6.8 (d, 1H), 4.9 (m, 1H), 4.0-3. 9 (m, 3H), 3.8 (m, 4H), 2.5 (s, 3H), 2.1 (m, 2H). (M+1) = 237. 2 Example 18 Synthesis of 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3- oxopropionaldehyde A suspension of sodium hydride (60% suspension in mineral oil, 210 mg, 5.25 mmol) in 4 mL of THF under argon was treated sequentially with 0.4 mL (4.77 mmol) of ethyl formate and a solution of 939 mg (3.98 mmol) of 1- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl] ethanone in 2 mL of THF. The resulting mixture was stirred at room temperature for 4 hours, and then acidified with 0.5 N HCl to PH 2 and extracted with 3 X 10 mL of ethyl acetate. The organic layer was dried over Na2S04, filtered and the solvent removed. Purification by column chromatography on silica gel using a gradient elution from 20% to 50% ethyl acetate in hexanes furnished 218 mg (21%) of 3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-oxopropionaldehyde as a yellow solid. 1H-NMR (CDC13, 300 MHz) 8 8.0 (s, 1H), 7.6-7. 5 (m, 2H), 7.4 (d, 1H), 6.1 (d, 1H), 5.0 (m, 1H), 4.0 (m, 4H), 3.9 (s, 3H), 2.2 (m, 2H). (M+1) = 265. 2 The following compounds were synthesized in a similar manner with different starting materials: 4,4, 4-trifluoro-1- {4-methoxy-3- [ (3R)-tetrahydrofuran-3-yloxy] phenyl} butane-1, 3-dione; Ethyl 1- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1, 3-dionebutanoate.

Example 19 Synthesis of 3-Dimethylamino-l- [4-methoxy-3- (3R)-tetrahydrofuranyloxy- phenyl] propenone To a solution of 440 mg (1.86 mmol) of 1- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-ethanone in 15 mL of DMF was added 0.30 mL (2.24 mmol) of N, N-dimethylformamide dimethyl acetal. The resulting mixture was heated to 140 °C for 16 hours, then cooled to room temperature and quenched by the addition of 25 mL of water. The mixture was extracted with 4 X 25 mL of ethyl acetate and the combined organic fractions were dried over Na2SO4, filtered and concentrated.

Purification by column chromatography over silica gel using a gradient elution from 100% CH2Cl2 to 90: 10: 5: : CH2C12 : MeOH: NH4OH provided 257 mg (56%) of 3-' dimethylamino-1- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] propenone as a yellow oil and 115 mg of the starting ketone. 1H-NMR (CDCl3, 300 MHz) 6 8. 0 (s, 1H), 7.7 (d, 1H), 7.5 (m, 2H), 6.9 (d, 1H), 5.7 (d, 1H), 5.1 (m, 1H), 4.0 (m, 3H), 3,9 (s, 4H), 2.9 (s, 3H), 2.8 (s, 3H), 2.2 (m, 2H). (M+1) =292.1 Example 20 Synthesis ofl- (4-Methoxypheny !)-5- [4-methoxy-3- (3R)-tetrahydrofuranyioxy- phenyl]-lH-pyrazole 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-oxopropionaldehyde (45 mg, 0.17 mmol), 4-methoxyphenyl hydrazine hydrochloride (36 mg, 0.20 mmol) and 1.7 mL of ethanol were combined in a 0.5-2. 0 mL Smith Process Vial. The vial was sealed and heated to 140. °C for 300 seconds using a Personal Chemistry Emrys Optimizer. The solvent was removed and purification by silica gel column chromatography using a gradient elution from 20% to 100% ethyl acetate in hexanes provided 40 mg (65%) of 1- (4-methoxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazoleas a brown solid. 1H-NMR (CDCl3, 300 MHz) 5 7.6 (d, 1H), 7.2 (m, 2H), 6.9 (m, 4H), 6.5 (d, 1H),. 6.4 (d, 1H), 4.6 (m, 1H), 3.9-3. 7 (m, 10H), 1.9 (m, 2H). (M+1) =367. 2 The following compounds were synthesized in a similar manner with different starting materials: Ethyl 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3- carboxylate ; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-3-trifluoromethyl-1 H- pyrazole; Ethyl [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-lH-pyrazol- 1-yl] acetate; [5- (4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-lH-pyrazol-1- yl] acetic acid ; Isopropyl [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-lH- pyrazol-1-yl] acetate ;



1- (3-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl- 1H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-lH-pyrazole ; 1-Cyclohexyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; Ethyl 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3- carboxylate ; 1- (4-Methoxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydro furanyloxyphenyl]-1 H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-phenylethyl)-lH-pyrazole ; 1- (4-Fluorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-(4-Bromophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethoxyphenyl)-1H- pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-pyridyl)-1H-pyrazole ; 1- (2-Benzothiazolyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- (3-Fluoro-4-methoxyphenyl)-1- (4-methoxyphenyl)-1 H-pyrazole ; 1-(2-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole; 1- [2- (6-Fluoropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole.

Example 21 Synthesis of 1- (4-Methoxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxy- phenyl]-lH-pyrazole 3-Dimethylamino-1- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] propenone, (461 mg, 1.6 mmol), 4-methoxyphenyl hydrazine hydrochloride (304 mg, 1.74 mmol), and 5 mL of ethanol were combined in a 2.0-5. 0 mL Smith Process Vial. The vial was sealed and heated to 140 °C for 300 seconds, quenched with 10 mL of water, and the aqueous layer was extracted with 3 X 10 mL of ethyl acetate. The combined organic fractions were dried over Na2S04, filtered and concentrated. Purification by silica gel column chromatography using a gradient elution from 20% to 100% ethyl acetate in r hexanes provided 436 mg (75%) of 1- (4-methoxyphenyl)-5- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole as a brown solid. 1H-NMR (CDC13, 300 MHz) 8 7.6 (d, 1H), 7.2 (m, 2H), 6.9 (m, 4H), 6.5 (d, 1H), 6.4 (d, 1H), 4.6 (m, 1H), 3.9-3. 7 (m, 10H), 1.9 (m, 2H). (M+1) =367.2 The following compounds were synthesized in a similar manner with different starting materials: 1-Benzyl-5-(3-fluoro-4-methoxyphenyl)-lH-pyrazole ; Ethyl 2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] pyrazol-1-yl} acetate; 5- (3, 4-Dimethoxyphenyl)-1- (4-fluorobenzyl)-lH-pyrazole ; 5- (3, 4-Dimethoxyphenyl)-1- (4-methoxyphenyl)-1 H-pyrazole ; 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-carboxyphenyl)-lH-pyrazole ; 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-methoxyphenyl)-1H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofaranyloxyphenyl]-l- [4- (4-morpholinyl) phenyl]-IH- pyrazole; l- (4-Carboxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole.

Example 22 Synthesis of 5-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-lH- pyrazole.

A solution of 5-chloro-3-methyl-1-phenyl-lH-pyrazole (61.8 mg, 0.32 mmol) in 5 mL of THF was cooled to-78 °C and t-butyllithium (0.47 mL, 1.7 M in heptane) was slowly added. The mixture was stirred at-78 °C for 1.5 hours and then zinc chloride (1.56 mL, 0.5 M) was added and after stirring at-78 °C for 15 minutes was warmed to room temperature. A solution containing 4-bromo-2-cyclopentyloxy-1-methoxybenzene (148 mg, 0.54 mmol) and Pd (PPh3) 4 (35 mg, 0.03 mmol) in 1 mL of THF was added and the reaction was heated to 60 °C for 12 hours. The mixture was diluted with 20 mL of ethyl acetate and the organic layer was washed with 10 mL of a saturated ammonium chloride solution, 20 mL of water and 20 mL of brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using a gradient elution from 20% to 50% ethyl acetate in hexanes yielded 31 mg of 5- (3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-lH- pyrazole. 1H-NMR (CDC13, 300 MHz) 5 7. 3 (m, 5H), 6.8 (m, 2H), 6.6 (d, 1H), 6.3 (s, 1H), 4.4 (m, 1H), 3.8 (s, 3H). 2.4 (s, 3H), 1.7-1. 5 (m, 8H). (M+1) =349.1 The following compounds were synthesized in a similar manner with different starting materials :' 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethoxybenzyl)-1H- pyrazole.

Example 23 Synthesis of {5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl- 1H-pyrazol-1-yl} acetic acid { 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-pyrazol-1- yl}-acetic acid ethyl ester (239 mg, 0.58 mmol) was dissolved in 5 mL of a solution made of 35 g KOH in 25 mL water. The reaction mixture was diluted with 100 mL of methanol, heated to 100 °C for 1 hour, and cooled to room temperature. Acidification with IN HCl resulted in the formation of a white solid, which was isolated-by filtration to give 100 mg of {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl- 1H-pyrazol-1-yl} acetic acid. 1H-NMR (CDCl3, 300 MHz) # 6. 9 (s, 2H), 6.8 (s, 1H), 6.5 (s, 1H), 4. 9 (m, 4H), 4.0 (s, 4H), 3.9 (s, 3H), 2.2 (s, 2H). (M+1) The following compounds were synthesized in a similar manner with different starting materials:



1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3-carboxylic acid; 1- (4-Carboxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Carboxybenzyl)-5- (3-fluoro-4-methoxyphenyl)-lH-pyrazole.

Example 24 Synthesis of N- (3-Fluorophenyl)-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxy- phenyl]-3-trifluoromethylpyrazol-1-yl} acetamide A solution of {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3- trifluoromethyl-lH-pyrazol-1-yl} acetic acid (50 mg, 0.13 mmol) in 2 mL of DMF was treated with HOBt (33 mg, 0.22 mmol), diisopropylethylamine (38 uL, 0.22 mmol), 3- fluoroaniline (21 uL, 0.22 mmol), and EDCI (38 uL, 0.22 mmol) and was then stirred at room temperature for 16 h. The reaction was diluted with 10 mL of ethyl acetate; the organic layer was separated and sequentially washed with 10 mL of water, 10 mL of 1N HCl, 10 mL of saturated NaHC03, and 10 mL of brine, dried (Na2S04) and concentrated.

Purification by silica gel column chromatography using 10% ethyl acetate in hexanes provided 21 mgofN- (3-fluorophenyl)-2- {5- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-pyrazol-1-yl} acetamide as a white solid. tH-NMR (CDC13,300 MHz) 8 8. 6 (s, 1H), 7. 5 (d, 1H), 7.3 (m, 1H), 7.1-7. 0 (m, 3H), 7.0- 6.8 (m, 2H), 6.6 (s, 1H), 5.0 (m, 1H), 4.9 (s, 2H), 4. 0-3. 9 (m, 7H), 2.2 (m, 2H).

The following compounds were synthesized in a similar manner with different starting materials: N-Cyclopropyl-2- {5- [4-methoxy-3- (3R)-tetrahydroiuranyloxyphenyl]-pyrazol-l- yl} acetamide; N-Isopropyl-2- 5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide ; N-Phenyl-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl} acetamide; N, N-Diethyl-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide.

Example 25 Synthesis of 2- 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazol-3-yl} propan-2-ol and 1- {l-Benzyl-5- [4-methoxy-3- (3R)-tetrahydro- furanyloxyphenyl]-lH-pyrazol-3-yl} ethanone A solution of 1-benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole-3-carboxylic acid ethyl ester (144 mg, 0.34 mmol) in 3 mL of THF was cooled to-78 °C under argon and MeMgCl (0.34 mL, 3.0 M) was added slowly. The solution was warmed to room temperature over 2 hours and then 10 mL of saturated aqueous NH4Cl was added. The mixture was extracted with 3 x 10 mL of ethyl acetate and the combined organic fractions were dried over Na2S04, filtered and concentrated.

Purification by silica gel column chromatography using a gradient elution from 20% to 50% ethyl acetate in hexanes yielded 55 mg of 2-{1-benzyl-5-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazol-3-yl} propan-2-ol A as a clear oil and 20 mg of 1- {1-benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H-pyrazol-3- yl} ethanone B as a clear oil. 1H-NMR (CDCl3, 300 MHz) A S 7.3 (m, 3H), 7.0 (d, 2H), 6.9 (m, 2H), 6. 6 (d, 1H), 6.2 (s, 1H), 5.3 (s, 2H), 4.6 (m, 1H), 4.0-3. 7 (m, 7H), 2.0 (m, 2H), 1.6 (s, 6H). 1H-NMR (CDCl3, 300 MHz) B 8 7.3 (m, 3H), 7.0 (d, 2H), 6. 9 (s, 2H), 6. 8 (s, 1H), 6.6 (s, 1H), 5.3 (s, 2H), 4.6 (m, 1H), 4.0-3. 7 (m, 7H), 2.6 (s, 3H), 1.9 (m, 2H), (M+1) A 409. 2 B 393.2 Example 26 Synthesis of {1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazol-3-yl} methanol A solution of 1-benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole-3-carboxylic acid ethyl ester (62 mg, 0.15 mmol) in 3 mL THF was cooled to 0 °C under argon. LAH (0.25 mL, 1M) was added and after stirring for 1 hour the reaction was quenched by the slow addition of 5 mL of methanol and 5 mL of 0.1 N HC1. The aqueous layer was extracted with 2 x 10 mL of ethyl acetate and the combined organic fractions were concentrated. Purification by silica gel column chromatography using a gradient elution from 50% to 100% ethyl acetate in hexanes yielded 20 mg of {1-Benzyl- 5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazol-3-yl} methanol as a clear oil. IH-NMR (CDCl3, 300 MHz) 8 7. 3 (m, 3H), 7. 0 (d, 2H), 6.9 (m, 2H), 6.6 (d, 1H), 6.3 (s, 1H), 5.3 (s, 2H), 4.7 (s, 2H), 4.6 (m, 1H), 3.9-3. 7 (m, 7H), 2.5 (s, 1H), 2.0-1. 4 (m, 2H). (M+1) = 381.2 The following compounds were synthesized in a similar manner with different starting materials: 1- (2-Hydroxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole.

Example 27 Synthesis of 5-Bromo-1- (2, 6-difluorobenzyl)-1H-pyrazole Step 1: 2- (2, 6-Difluorobenzyl)-l-hydroxy-IH-pyrazole 1-Hydroxypyrazole (49.3 mg, 0.59 mmol, 1.0 eq) was mixed with 165.8 mg (0.80 mmol, 1.36 eq) of 2, 6-difluorobenzyl bromide in-1-2 mL of anhydrous CHC13 under argon. The mixture was heated at 80 °C for 18 h under inert atmosphere in a sealed flask without condenser. The residue was partitioned between 37 weight percent aqueous HCl and toluene. The aqueous layer was collected and the toluene fraction extracted, again with 37 weight percent aqueous HC1. The combined aqueous HCL fractions were neutralized with 5N aqueous NaOH to pH#11-12 and then back-extracted with 3 x 30 mL of CHCl3. The organic layers were combined, washed with brine, dried over Na2S04 and concentrated under reduced pressure to yield 86.3 mg (70. 1% yield) of 2- (2, 6- difluorobenzyl)-l-hydroxy-lH-pyrazole as a tan brown solid. 1H NMR (CDC13 300 MHz) # 7.37 (m, 1H), 7.18 (d, 1H), 6.95 (t, 2H), 6.85 (d, 1H), 6.11 (t, 1H), 5.43 (s, 2.00 H). LC/MS (ES) M+1=211 ; 2 Step 2. 5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole 2-(2, 6-Difluorobenzyl)-l-hydroxy-lH-pyrazole (81.2 mg, 0.386 mmol, l. Oeq) and 5ml of anhydrous CHCl3 were combined in a flame-dried 25 mL round-bottom flask under argon and cooled in an ice/water bath. A solution of POBr3 (398.1 mg, 1.39 mmol, 3.60 eq) in 3 mL of CHC13 was added using a syringe in aliquots over an hour period with stirring.

The reaction solution was-warmed to room temperature and stirred for 16 hours. The CHCl3 was removed in vacuo and the resulting orange mixture was neutralized with saturated aqueous NaHC03 and extracted with 3 x 30 mL of diethyl ether. The combined ether fractions were washed with brine, dried over Na2SO4 and concentrated in vacuo to . yield 101.5 mg (96.7% yield) of 5-bromo-1-(2, 6-difluorobenzyl)-lH-pyrazole as a hygroscopic orange-tan colored solid. IH NMR (CDC13 300 MHz) 6 7.51 (d, 1H), 7. 34 (m, 1H), 6.94 (t, 2H), 6.29 (d, 1H), 5.50 (s, 2H). LC/MS (ES) M+1= 273.1, 275.1 The following compounds were synthesized in a similar manner with different starting materials : 5-Bromo-1- (4-trifluoromethoxybenzyl)-1 H-pyrazole ; 5-Bromo-1-(2, 3-difluorobenzyl)-lH-pyrazole ; 5-Bromo-l- (4-methylbenzyl)-lH-pyrazole ; 5-Bromo-1- (4-tert-butylbenzyl)- IH-pyrazole ; 5-Bromo-1- (4-trifluoromethylbenzyl)-1 H-pyrazole ; 5-Bromo-1-(3,4-difluorobenzyl)-1H-pyrazole ; 5-Bromo-1- (2-fluorobenzyl)-1 H-pyrazole ; 5-Bromo-1- (3-nitrobenzyl)- IH-pyrazole ; 5-Bromo-1-(4-methoxycarbonylbenzyl)-1H-pyrazole ; 5-Bromo-l- (3-fluorobenzyl)-lH-pyrazole ; 5-Bromo-1-(3,5-dimethoxybenzyl)-1H-pyrazole ; 1-Benzyl-5-bromo-IH-pyrazole ; 5-Bromo-1-(3-methoxybenzyl)-lH-pyrazole ; 5-Bromo-1-(4-fluorobenzyl)-1H-pyrazole ; 5-Bromo-1-(2, 6-difluorobenzyl)-lH-pyrazole.

Example 28 In Vitro Measurement of Type 4 Phosphodiesterase Enzyme Preparation: Human PDE4 was obtained from baculovirus-infected Sf9 cells that expressed the recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector. Insect cells (Sf9) were infected with the baculovirus and cells were cultured until protein was expressed. The baculovirus-infected cells were lysed and the lysate was used as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAE ion exchange chromatography. This procedure can be repeated using cDNA encoding other PDE-4 enzymes.

Assay : Type 4phosphodiesterases convert cyclic'adenosine monophosphate (cAMP) to. 5'- adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine.

Therefore the combined activity of PDE4 and nucleotidase converts cAMP to adenosine.

Adenosine is readily separated from cAMP by neutral alumina columns.

Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine.

Cell lysates (40 Ill) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0.4 llg enzyme, lOmM Tris-Cl (pH 7. 5), 10mM MgC12, 3 uM cAMP, 0.002 U 5'-nucleotidase, and 3 x 104 cpm of [3H] cAMP.

The reaction was stopped by adding 100 ul of boiling 5mM HC1. An aliquot of 75 gel of reaction mixture was transferred from each well to alumina columns (Multiplate ; Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000 rpm for 2 min; 150 tl per well-of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [3H] adenosine was determined using a Packard Topcount 96 counter.

All test compounds were dissolved in 100% DMSO and diluted into the assay such that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration. A decrease in adenosine concentration is indicative of inhibition of PDE activity. This procedure may be used to screen compounds of the present invention for their ability to inhibit PDE4. pIC50 values may be determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then plotting drug concentration versus 3H-adenosine concentration. Prism@ may be used to estimate pIC50 values.

Compounds of the invention show activity in the range of 10 nM-5000 nM IC50 in the assay.

Example 29 Passive Avoidance in Rats, an in vivo Test for Learning and Memory The test may be performed as previously described [Zhang, H. -T., Crissman, A. M, Dorairaj, N. R. , Chandler, L. J. , and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198-204]. The apparatus (Model E10-16SC, Coulbourn Instruments, Allentown,'PA) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by a guillotine door. The floor of the darkened compartment consisted of stainless steel rods through which an electric foot- shock may be delivered from a constant current source. All experimental groups may be first habituated to the apparatus the day before the start of the experiment. During the training, the rat (Male Spraque-Dawley (Harlan) weighing 250 to 350 g) may be placed in the illuminated compartment facing away from the closed guillotine door for 1 minute before the door was raised. The latency for entering the darkened compartment may be recorded. After the rat enters the darkened compartment, the door may be closed and a 0.5 mA electric shock was administered for 3 seconds. Twenty-four hours later, the rat may be administered 0.1 mg/kg of the test compound or saline, 30 minutes prior to the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i. p. ), which was 30 minutes before the retention test starts. The rat may be again placed in the illuminated compartment with the guillotine door open. The latency for entering the darkened compartment may be recorded for up to 180 seconds, at which time the trial was terminated.

All data may be analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Naive rats required less than 30 seconds, on average, to cross from the illuminated compartment to the darkened compartment.

Example 30 Radial arm maze task in Rats, an in vivo Test for Learning and Memory The test may be performed as previously described [Zhang, H. -T., Crissman, A. M. , Dorairaj, N. R. , Chandler, L. J. , and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198-204. ]. Five days after initial housing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) may be placed in the eight-arm radial maze (each arm was 60x10x12 cm high; the maze was elevated 70 cm above the floor) for acclimation for two days. Rats may be then placed individually in the center of the maze for 5 minutes with food pellets placed close to the food wells, and then, the next day, in the wells at the end of the arms; 2 sessions a day may be conducted. Next, four randomly selected arms may be then baited with one pellet of food each. The rat may be restricted to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely throughout the maze until it collected all pellets of food or 10 minutes passed, whichever came first.

Four parameters may be recorded: 1) working memory errors, i. e. , entries into baited arms that had already been visited during the same trial; 2) reference memory errors, i. e., entries into unbaited arms; 3) total arm entries; and 4) the test duration (seconds), i. e. , the time spent in the collection of all the pellets in the maze. If the working memory error is zero and the average reference memory error is less than one in five successive trials, the rats may begin the drug tests. The test compound or saline may be injected 15. minutes prior to vehicle or test agent, which-may be given 45 minutes before the test.

Experiments are performed in a lighted room, which contained several extra-maze visual cues.

All data may be analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention. Upon further study of the specification, further aspects, objects and advantages of this invention will become apparent to those skilled in the art.
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We Claim:
1. A compound according to Formulas II, III, V, or VI:
(Formula Removed)
wherein
XisCHorN;
L is a single bond; C1-C6 straight chain or branched alkylene, wherein a CH2 group is
optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or
more times by oxo, halogen, hydroxy, cyano or combinations thereof; (CH2)nCONH;
(CH2)nCON(C1-6-alkyl); (CH2)nNHCO; (CH2)nCONHS02; (CH2)nS02NH; (CH2)nS02
or (CH2)nC02;
nis0to3;
R1 is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or
more times by halogen;
R3 is in formula II and VH,
in formula II and V alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -C=C- groups,
in formula II and V cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof,
in formula II. Ill, V and VI aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, acylamido, imidazolyl, pyridinyl, morpholinyl, piperadinyl, piperazinyl, tetrazolyl, alkylsulphonimide, arylsulphonimide or combinations thereof,
in formula II. III. V and VI heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido, or combinations thereof,
in formula II. Ill, V and VI arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, acylamido, tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof,
in formula II, III, V and VI a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the
heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof,
in formula II and V cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or
in formula II and V alkoxyalkvl having 3 to 8 carbon atoms;
R4 is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -C=C- groups;
R5 is H,
alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -OC- groups;
R6 is H,
alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -OC- groups;
cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido, and acyloxy, or combinations thereof,
arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido, and acyloxy, or combinations thereof,
a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or
a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof;
R7 is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; and
R8 is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -C=C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or
hydroxyl, carboxy, alkoxycarbonyl having 2 to 6 carbon atoms, -CO-alkyl having 2 to
6 carbon atoms, or phenyl;
or a pharmaceutically acceptable salt thereof,
wherein said compound can be in the form of a mixture of enantiomers such as the
racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer
or a single diastereomer.
2. A compound as claimed in claim 1, wherein said compound is selected from Formula II.
3. A compound as claimed in claim 1, wherein said compound is selected from Formula III.
4. A compound as claimed in claim 1, wherein said compound is selected from Formula V.
5. A compound as claimed in claim 1, wherein said compound is selected from Formula VI.
6. A compound as claimed in claim 1, wherein R is CH3 or CF2H.
7. A compound as claimed in claim 1, wherein R is phenyl, bromophenyl, nitrophenyl, fluorophenyl, trifluoromethoxyphenyl, methoxyphenyl, carboxyphenyl, dimethylphenyl, or methylpyridyl.
8. A compound as claimed in claim 1, wherein R is 4-carboxyphenyl, 2,3-difluorophenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, or 4-fluorophenyl.
9. A compound as claimed in claim 1, wherein said compound is of Formula II or V and R is cyclohexyl or cyclopentyl.
10. A compound as claimed in claim 1, wherein said compound is of Formula II or V and R3 is ethyl, CH(CH3)2, n-propyl, n-butyl, or t-butyl.
11. A compound as claimed in claim 1, wherein R3 is thiazolyl or benzothiazolyl.
12. A compound as claimed in claim 1, wherein R3 is benzyl or phenethyl, which in each case is substituted or unsubstituted.
13. A compound as claimed in claim 1, wherein R3 is benzyl, methylbenzyl, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, carboxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, nitrobenzyl, methoxycarbonylbenzyl, or phenethyl.
14. A compound as claimed in claim 1, wherein R4 is CH3.
15. A compound as claimed in claim 1, wherein R5 is CH3 or CH2CH3.
16. A compound as claimed in claim 1, wherein R6 is cyclopentyl.
17. A compound as claimed in claim 1, wherein X is CH.
18. A compound as claimed in claim 1, wherein X is N.
19. A compound as claimed in claim 1, wherein L is a bond, CH2, CH2CH2, CH2CO, CH2C02,or CH2CONH.
20. A compound as claimed in claim 1, wherein subscript n is 0 or 1.
21. A compound as claimed in claim 1, wherein R7 is H, and R8 is H, CH3, C2H5, CF3, hydroxymethyl, 2-(2-hydroxy)propyl), carboxy, ethoxycarbonyl, CH3CO, or phenyl.
22. A compound as claimed in claim 1, wherein said compound is of Formula II or V, and R1 is CH3 or CF2H.
23. A compound as claimed in claim 1, wherein said compound is of Formula II or V, R1 is CH3 or CF2H, and R is aryl, heterocyclic, alkyl, or cycloalkyl.
24. A compound as claimed in claim 1, wherein said compound is of Formula II or V, R1 is CH3 or CF2H, and R is 2-(6-methyl.-pyridyl), 2-cyanophenyl, 2,3-difluorophenyl, 2-methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl, cyclohexyl, cyclopentyl, ethyl, t-butyl. tetrahydroisoquinolyl, 7-azaindolyl, or 4-methylsulfonylphenyl.
25. A compound as claimed in claim 1, wherein said compound is of Formula II or V, R1 is CH3 or CF2H, and R4 is CH3.
26. A compound as claimed in claim 1, wherein said compound is of Formula II or V, R1 is CH3 or CF2H, R is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6-difluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, or 4-carboxybenzyl, and L is a bond, CH2, CH2CH2, or CH2CONH.
27. A compound as claimed in claim 1, wherein said compound is of Formula II or V, R1 is CH3 or CF2H, R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6-difluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, or 4-carboxybenzyl, L is a bond, CH2, CH2CH2, or CH2CONH, and R4 is CH3.
28. A compound as claimed in claim 1, wherein said compound is of Formula III or VI, and R is aryl or heterocyclic.
29. A compound as claimed in claim 1, wherein said compound is of Formula III or VI, and R is alkyl having 1 to 3 carbon atoms.
30. A compound as claimed in claim 1, wherein said compound is of Formula III or VI, and R is cycloalkyl having 4 to 7 carbon atoms.
31. A compound as claimed in claim 1, wherein said compound is of Formula III or VI, R aryl or heterocyclic, R is CH2CH3 and R is cyclopentyl.
32. A compound as claimed in claim 1, wherein said compound is of Formula III or VI, and R3 is aryl or heterocyclic, R5 is CH2CH3, R6 is cyclopentyl, Y is CH, and L is CH2, CH2CH2, CH2CH2CH2, CH2CO, CH2CO2, S02, or CH2CONH.
33. A compound as claimed in claim 1, wherein R and R are each H.
34. A compound as claimed in claim 1, wherein said compound is selected from: 3 -(2-Acetyl-7-methoxybenzofuran-4-yl)-1 H-pyrazole;
3 -(2-Acetyl-7-methoxybenzofuran-4-yl)-1 -(2,3 -difluorobenzyl)-1 H-pyrazole;
3-(2-Acetyl-7-methoxybenzofuran-4-yl)-l-(4-methylsulfonylbenzyl)-lH-pyrazole;
3-(2-Acetyl-7-methoxybenzofuran-4-yl)-l-(2-methylbenzyl)-lH-pyrazole;
3 - [(1 -Cyclopentyl-3 ethylindazol)-6-yl] -l-(2,3 -difluorobenzyl)-1 H-pyrazole;
3-[(l-Cycolopentyl-3-ethylindazol-6-yl]-l-(4-carboxyphenyl)-lH-pyrazole;
3 - [(1 -Cyclopentyl-3 -ethylindazol)-6-yl] -l-(4-methoxyphenyl)-1 H-pyrazole;
3-[(l -Cyclopentyl-3-ethylindazol)-6-yl])-l-(2-methylbenzyl)-lH-pyrazole;
3 - [(1 -Cyclopentyl-3 -ethylindazol)-6-yl])-1 -(4-methylsulfonylbenzyl)-1 H-pyrazole;
3-[(l-Cyclopentyl-3-ethylindazol)-6-yl])-l-(2-pyridylmethyl)-lH-pyrazole;
5-[(l -Cyclopentyl-3-ethylindazol)-6-yl])-l -(2-pyridylmethyl)-lH-pyrazole;
and pharmaceutically acceptable salts thereof, wherein in each case the compound can
be in the form of a mixture of enantiomers such as the racemate, or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
35. A compound as claimed in claim 1, wherein said compound is selected from:
3-(2-Acetyl-7-methoxybenzofuran-4-yl)pyrazole
3 -(2-Acetyl-7-methoxybenzofuran-4-yl)-1 -(2,3 -difluorobenzyl)pyrazole,
3 - {2- Acetyl-7-methoxybenzofuran-4-yl)-1 -(4-methylsulfonylbenzyl)pyrazole,
3-(2-Acetyl-7-methoxybenzofuran-4-yl} -1 -(2-methylbenzyl)pyrazole,
3 -[(1 -Cyclopentyl-3 -ethylindazole)-6-yl]-1 -(2,3 -difluorophenyl )pyrazole,
3 - [(1 -Cyclopentyl-3 -ethylindazole)-6-yl] -1 -(2-methylbenzyl)pyrazole,
3-[(l-Cyclopentyl-3-ethylindazole)-6-yl])-l-(4-methylsulfonylbenzyl)pyrazole,
3 -[(1 -Cyclopentyl-3 -ethylindazole)-6-yl])-1 -(2-pyridylmethyl)pyrazole, and pharmaceutically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
36. A compound as claimed in claim 1, wherein said compound is selected from:
3-(2-Acetyl-7-methoxybenzofuran-4-yl)pyrazole,
3-(2-Aceyl-7-methoxybenzofuran-4-yl)-l-(4-methylsulfonylbenzyl)pyrazole, 3 -[(1 -Cyclopentyl-3 -ethylindazole)-6-yl] -1 -(2,3 -difluorophenyl)pyrazole,
3 -[(1 -Cyclopentyl-3 -ethylindazole)-6-yl])-1 -(4-methylsulfonylbenzyl)pyrazole, 3 - [(1 -Cyclopentyl-3 -ethylindazole)-6-yl])-1 -(2-pyridylmethyl)pyrazole, and pharmaceutically acceptable salts thereof wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
37. A pharmaceutical composition comprising a compound as claimed in anyone of claims 1 to 36 and a pharmaceutically acceptable carrier.
38. A compound as claimed in claim 1, wherein said compound is selected from: 3-[(l-Cyclopentyl-3-ethylindazol)-6-yl]-l-(2,3-difluorobenzyl)-lH-pyrazole; 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl] -1-(4-carboxyphenyl)-1 H-pyrazole;
3 - [(1 -Cyclopentyl-3 -ethy lindazol)-6-yl] -1 -(4-methoxyphenyl)-1 H-pyrazole;
3-[(l -Cyclopentyl-3 -ethylindazol)-6-yl])-1 -(2-methylbenzyl)-1 H-pyrazole;
3 - [(1 -Cyclopentyl-3 -ethylindazol)-6-yl])-1 -(4-methylsulfonylbenzyl)-1 H-pyrazole;
3-[(l-Cyclopentyl-3-ethylindazol)-6-yl])-l-(2-pyridylmethyl)-lH-pyrazole;
5-[(l-Cyclopentyl-3-ethylindazol)-6-yl])-l-(2-pyridylmethyl)-lH-pyrazole;
and pharmaceutically acceptable salts thereof, wherein in each case the compound can
be in the form of a mixture of enantiomers such as the racemate, or a mixture of
diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
39. A compound as claimed in claim 1, wherein said compound is selected from:
3-[(l-Cyclopentyl-3-ethylindazole)-6-yl])-l-(2,3-difluorophenyl)pyrazole,
3 - [(1 -Cyclopentyl-3 -ethylindazole)-6-yl])-1 -(2-methylbenzyl)pyrazole,
3 - [(1 -Cyclopentyl-3 -ethylindazole)-6-yl])-1 -(4-methylsulfonylbenzyl)pyrazole,
3-[(l-Cyclopentyl-3-ethylindazole)-6-yl])-l-(2-pyridylmethyl)pyrazole, and pharmaceutically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
40. A compound as claimed in claim 1, wherein said compound is selected from: 3-[(l -Cyclopentyl-3-ethylindazole)-6-yl)]-l-(2,3-difluorophenyl)pyrazole, 3 - [(1-Cyclopentyl-3-ethylindazole)-6-yl])-l-(4-methylsulfonylbenzyl)pyrazole, 3 - [(1 -Cyclopentyl-3 -ethy lindazole)-6-yl] )-l-(2-pyridylmethyl)pyrazole, and pharmaceutically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.