2,6 Bisheteroaryl-4-Aminopyrimidines as Adenosine Receptor Antagonists

EXAMPLE 1
2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

To a solution of Intermediate 4 (1.0 g, 5.1 mmol) in anhydrous DMF (20 mL) was added pyrazol (0.7 g, 10.2 mmol) and cesium carbonate (3.34 g, 10.2 mmol). The mixture was heated at 85° C. for 21 hours. The solution was poured into water (50 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL) and brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The resulting solid was purified by column chromatography with silica gel, eluting with methylene chloride/methanol (3%), to give (2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (0.64 g, 55%) as an off-white solid.

δ (250 MHz, CDCl₃): 5.12 (bs, 2H); 6.48-6.46 (m, 1H); 6.57-6.55 (m, 1H); 6.90 (s, 1H); 7.31 (d, J=3.6 Hz, 1H); 7.61 (s, 1H); 7.75 (d, J=1.2 Hz, 1H); 8.63 (d, J=3.0 Hz, 1H).

EXAMPLE 2
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

To a solution of the title compound of Example 1 (0.30 g, 1.32 mmol) in methylene chloride (7 mL) was added pyridine (0.21 g, 2.64 mmol) and acetyl chloride (0.21 g, 2.64 mmol). The mixture was stirred at room temperature for 5 hours and more pyridine (52 mg, 0.66 mmol) and acetyl chloride (52 mg, 0.66 mmol) was added. The reaction was allowed to stand for 1.5 further hours at room temperature. The solution was diluted with methylene chloride (20 mL), washed with 10% sodium hydroxide (2×10 mL), brine (10 mL), and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (1:3), gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (0.33 g, 92%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.25 (s, 3H); 6.51-6.49 (m, 1H); 6.61-6.58 (m, 1H); 7.36-7.34 (m, 1H); 7.62 (s, 1H); 7.81 (s, 1H); 8.21 (bs, 1H); 8.54 (s, 1H); 8.65-8.63 (m, 1H).

EXAMPLE 3
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 1 (0.34 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.35 g, 83%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.28 (t, J=7.3 Hz, 3H); 2.48 (q, J=7.3 Hz, 2H); 6.50-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (d, J=3.6 Hz, 1H); 7.62 (s, 1H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 4
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-methylpropanamide

Obtained from the title compound of Example 1 (0.10 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-methylpropanamide (90 mg, 72%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.28 (d, J=7.0 Hz, 6H); 2.58 (h, J=7.0 Hz, 1H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.60 (dd, J1=3.3 Hz, J2=1.5 Hz, 1H); 7.36 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.65-7.63 (m, 1H); 7.80-7.78 (m, 1H); 8.08 (bs, 1H); 8.64-8.61 (m, 2H).

EXAMPLE 5
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-yl]-2,2-dimethylpropanamide

Obtained from the title compound of Example 1 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 10:90 to 15:85) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2,2-dimethylpropanamide (25 mg, 6%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.35 (s, 9H); 6.49-6.47 (m, 1H); 6.59 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 7.36-7.35 (m, 1H); 7.64-7.63 (m, 1H); 7.78-7.77 (m, 1H); 8.19 (bs, 1H); 8.62 (d, J=2.7 Hz, 1H); 8.66 (s, 1H).

EXAMPLE 6
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclopropanecarboxamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclopropanecarboxamide (0.10 g, 39%) as an off-white solid.

δ (250 MHz, CDCl₃): 0.98-0.91 (m, 2H); 1.20-1.13 (m, 2H); 1.59-1.51 (m, 1H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.59 (dd, J1=3.6 Hz, J2=1.8 Hz, 1H); 7.35 (d, J=3.6 Hz, 1H); 7.64-7.63 (m, 1H); 7.77 (d, J=1.5 Hz, 1H); 8.42 (bs, 1H); 8.56 (s, 1H); 8.62 (d, J=2.7 Hz, 1H).

EXAMPLE 7
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclobutanecarboxamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclobutanecarboxamide (0.14 g, 67%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.50-1.93 (m, 6H); 3.22 (q, J=8.5 Hz, 1H); 6.49 (dd, J1=2.7 Hz, J2=1.8 Hz, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.35 (d, J=3.3 Hz, 1H); 7.63 (m, 1H); 7.79 (m, 1H); 7.97 (bs, 1H); 8.62 (s, 1H); 8.63 (s, 1H).

EXAMPLE 8
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclohexanecarboxamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclohexanecarboxamide (0.20 g, 91%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.00-1.26 (m, 10H); 2.35-2.23 (m, 1H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.34 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.63-7.62 (m, 1H); 7.78 (m, 1H); 8.14 (bs, 1H); 8.63-8.59 (m, 2H).

EXAMPLE 9
3-Cyclopentyl-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 1:9 to 2:8) as eluent gave 3-cyclopentyl-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.29 g, 94%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.18-1.07 (m, 2H); 1.86-1.51 (m, 9H); 2.43 (t, J=7.4 Hz, 2H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.5 Hz, 1H); 7.34 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 7.63-7.62 (m, 1H); 7.80-7.79 (m, 1H); 8.16 (bs, 1H); 8.58 (s, 1H); 8.63 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 10
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide (63 mg, 27%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.73 (s, 2H); 3.82 (s, 3H); 6.50-6.48 (m, 1H); 6.58-6.56 (m, 1H); 6.91 (s, 1H); 6.94 (s, 1H); 7.32-7.23 (m, 3H); 7.61-7.60 (m, 1H); 7.80-7.79 (m, 1H); 8.06 (bs, 1H); 8.59 (s, 1H); 8.62 (d, J=2.7 Hz, 1H).

EXAMPLE 11
2-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (80 mg) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave 2-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (87 mg, 61%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.73 (s, 2H); 3.90 (s, 6H); 6.51-6.48 (m, 1H); 6.59-6.56 (m, 1H); 6.84 (s, 1H); 6.88 (s, 2H); 7.33 (d, J=3.3 Hz, 1H); 7.61 (s, 1H); 7.80 (s, 1H); 8.10 (bs, 1H); 8.59 (s, 1H); 8.63 (d, J=2.7 Hz, 1H).

EXAMPLE 12
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]-3-phenylpropanamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-phenylpropanamide (0.27 g, 85%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.74 (t, J=7.8 Hz, 2H); 3.08 (t, J=7.8 Hz, 2H); 6.51-6.49 (m, 1H); 6.60-6.57 (m, 1H); 7.35-7.22 (m, 6H); 7.62 (s, 1H); 7.81 (s, 1H); 8.11 (bs, 1H); 8.58 (s, 1H); 8.64 (m, 1H).

EXAMPLE 13
(2S)—N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylcyclopropanecarboxamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave (2S)—N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylcyclopropanecarboxamide (0.23 g, 95%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.49-1.40 (m, 1H); 1.86-1.75 (m, 2H); 2.71-2.63 (m, 1H); 6.50-6.49 (m, 1H); 6.57 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.14-7.11 (m, 2H); 7.34-7.19 (m, 4H); 7.61 (m, 1H); 7.79 (m, 1H); 8.59-8.58 (m, 2H); 8.63 (d, J=2.7 Hz, 1H).

EXAMPLE 14
3,3,3-Trifluoro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

To a solution of 3,3,3-trifluoropropionic acid (0.21 g, 1.65 mmol) in methylene chloride (4 mL) was added oxalyl chloride (0.21 g, 1.65 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 1 hour. This solution was cooled at 0° C. and added at the same temperature to a solution of the title compound of Example 1 (125 mg, 0.55 mmol) and pyridine (123 mg, 1.65 mmol) in methylene chloride (4 mL). The mixture was stirred at room temperature for 22 hours and diluted with methylene chloride (8 mL). The organic layer was washed with water (2×8 mL) and brine (8 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (1:4), gave 3,3,3-trifluoro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.16 g, 87%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.33 (q, J=10.0 Hz, 2H); 6.52-6.50 (m, 1H); 6.61-6.59 (m, 1H); 7.36 (d, J=3.6 Hz, 1H); 7.64-7.63 (m, 1H); 7.82-7.81 (m, 1H); 8.40 (bs, 1H); 8.54 (s, 1H); 8.65-8.63 (m, 1H).

EXAMPLE 15
3-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 3:7 to 2:3) as eluent gave 3-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-61(H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.27 g, 72%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.71 (t, J=7.6 Hz, 2H); 3.02 (t, J=7.6 Hz, 2H); 3.85 (s, 3H); 3.86 (s, 3H); 6.50 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.80-6.76 (m, 3H); 7.34 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.62 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.81 (dd, J1=1.1 Hz, J2=0.6 Hz, 1H); 8.07 (bs, 1H); 8.58 (s, 1H); 8.64 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 16
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-methyl-3-phenylpropanamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-methyl-3-phenylpropanamide (0.14 g, 51%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.29 (d, J=6.4 Hz, 3H); 2.79-2.62 (m, 2H); 3.16-3.08 (m, 1H); 6.51-6.49 (m, 1H); 6.59-6.57 (m, 1H); 7.34-7.16 (m, 6H); 7.62 (m, 1H); 7.80 (m, 1H); 7.97 (bs, 1H); 8.63-8.61 (m, 2H)

EXAMPLE 17
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-phenoxypropanamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (30:70) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-phenoxypropanamide (0.23 g, 70%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.91 (t, 2H); 4.37 (t, 2H); 6.50-6.49 (m, 1H); 6.61-6.58 (m, 1H); 7.01-6.94 (m, 3H); 7.35-7.27 (m, 3H); 7.64 (m, 1H); 7.80 (m, 1H); 8.58 (s, 1H); 8.64 (d, J=2.4 Hz, 1H).

EXAMPLE 18
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-pyridin-3-ylpropanamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]-3-pyridin-3-ylpropanamide (0.19 g, 60%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.76 (t, J=7.3 Hz, 2H); 3.09 (t, J=7.3 Hz, 2H); 6.51-6.50 (m, 1H); 6.60-6.58 (m, 1H); 7.28-7.21 (m, 1H); 7.34 (d, J=3.6 Hz, 1H); 7.63-7.57 (m, 2H); 7.81 (s, 1H); 8.13 (s, 1H); 8.54-8.47 (m, 2H); 8.56 (s, 1H); 8.64 (d, J=2.4 Hz, 1H).

EXAMPLE 19
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide (0.70 g, 23%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 3.89 (s, 2H); 6.65 (dd, J1=2.6 Hz, J2=1.3 Hz, 1H); 6.75 (dd, J1=3.5 Hz, J2=1.7 Hz, 1H); 7.37 (dd, J1=7.9 Hz, J2=4.8 Hz, 1H); 7.49 (dd, J1=3.5 Hz, J2=0.9 Hz, 1H); 7.77 (dt, J1=7.9 Hz, J2=1.7 Hz, 1H); 7.91 (m, 1H); 7.97 (m, 1H); 8.40 (s, 1H); 8.48 (dd, J1=4.8 Hz, J2=1.7 Hz, 1H); 8.55 (d, J1=1.7 Hz, 1H); 8.77 (d, J1=2.6 Hz, 1H); 11.50 (s, 1H).

EXAMPLE 20
(2E)-3-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acrylamide

A solution of 3,4-dimethoxyphenylacrylic acid (0.55 g, 2.64 mmol) in thionyl chloride (4 mL) was stirred at 55° C. for 1 hour. The solvent was removed under reduced pressure. The resulting oil was dissolved in methylene chloride (2 mL) and the solution was cooled at 0° C. and added to a solution of the title compound of Example 1 (0.20 mg, 0.88 mmol) and pyridine (0.20 mg, 2.64 mmol) in methylene chloride (6 mL). The mixture was stirred at room temperature for 44 hours and diluted with methylene chloride (8 mL). The organic layer was washed with water (2×8 mL) and brine (8 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel, eluting with methylene chloride/ethanol (0.5%), gave (2E)-3-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acrylamide (0.70 g, 19%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.93 (s, 3H); 3.94 (s, 3H); 6.40 (d, J=15.5 Hz, 1H); 6.52-6.50 (m, 1H); 6.61-6.59 (m, 1H); 6.90 (d, J=8.2 Hz, 1H); 7.06 (d, J=1.8 Hz, 1H); 7.16 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H); 7.36 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 7.64-7.63 (m, 1H); 7.76 (d, J=15.5 Hz, 1H); 7.82 (m, 1H); 8.33 (bs, 1H); 8.66-8.65 (m, 1H); 8.69 (s, 1H).

EXAMPLE 21
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-amine

To a solution of Intermediate 4 (2.0 g, 10.2 mmol) in anhydrous DMSO (50 mL) was added 3,5-dimethylpyrazol (1.97 g, 20.5 mmol) and cesium carbonate (6.70 g, 20.6 mmol). The mixture was heated at 150° C. for 9 hours. The solution was poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (3×100 mL), brine (100 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The resulting solid was purified by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (from 3:7 to 1:1), to give 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-amine (1.86 g, 71%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.29 (s, 3H); 2.78 (s, 3H); 5.10 (bs, 2H); 6.00 (s, 1H); 6.55-6.52 (m, 1H); 6.84 (s, 1H); 7.19 (d, J=2.4 Hz, 1H); 7.58 (s, 1H).

EXAMPLE 22
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 21 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acetamide (0.25 g, 72%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.23 (s, 3H); 2.29 (s, 3H); 2.77 (s, 3H); 6.02 (s, 1H); 6.58-6.55 (m, 1H); 7.24 (d, J=3.3 Hz, 1H); 7.61-7.60 (m, 1H); 8.17 (bs, 1H); 8.48 (s, 1H).

EXAMPLE 23
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 21 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-yl]propanamide (0.26 g, 71%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.27 (t, J=7.6 Hz, 3H); 2.29 (s, 3H); 2.46 (q, J=7.6 Hz, 2H); 2.78 (s, 3H); 6.03 (s, 1H); 6.59-6.57 (m, 1H); 7.25 (d, J=2.7 Hz, 1H); 7.62-7.61 (m, 1H); 8.12 (bs, 1H); 8.55 (s, 1H).

EXAMPLE 24
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-methylpropanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-methylpropanamide (0.11 g, 60%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.28 (d, J=7.0 Hz, 6H); 2.27 (s, 3H); 2.56 (h, J=7.0 Hz, 1H); 2.77 (s, 3H); 6.02 (s, 1H); 6.58-6.56 (m, 1H); 7.26 (s, 1H); 7.62-7.61 (m, 1H); 8.03 (bs, 1H); 8.58 (s, 1H).

EXAMPLE 25
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2,2-dimethylpropanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (15:85) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)_2-2-furyl)pyrimidin-4-yl]-2,2-dimethylpropanamide (95 mg, 48%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.34 (s, 9H); 2.27 (s, 3H); 2.77 (s, 3H); 6.02 (s, 1H); 6.57 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.25 (d, J=0.9 Hz, 1H); 7.62 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.14 (bs, 1H); 8.62 (s, 1H).

EXAMPLE 26
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-cyclopropanecarboxamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]cyclopropanecarboxamide (70 mg, 37%) as an off-white solid.

δ (250 MHz, CDCl₃): 0.97-0.89 (m, 2H); 1.21-1.13 (m, 2H); 1.59-1.49 (m, 1H); 2.26 (s, 3H); 2.77 (s, 3H); 6.01 (s, 1H); 6.57 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.24 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.61 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.39 (bs, 1H); 8.52 (s, 1H).

EXAMPLE 27
3-Cyclopentyl-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/n-hexane (from 90% to pure methylene chloride) as eluent gave 3-cyclopentyl-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]propanamide (0.22 g, 99%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.16-1.07 (m, 2H); 1.83-1.51 (m, 9H); 2.28 (s, 3H); 2.42 (t, J=7.3 Hz, 2H); 2.77 (s, 3H); 6.02 (s, 1H); 6.57 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.24 (d, J=3.6 Hz, 1H); 7.61 (s, 1H); 8.16 (bs, 1H); 8.54 (s, 1H).

EXAMPLE 28
N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide (0.11 g, 46%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.28 (s, 3H); 2.76 (s, 3H); 3.71 (s, 2H); 3.82 (s, 3H); 6.01 (s, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.89 (s, 1H); 6.93 (s, 1H); 7.26-7.20 (m, 3H); 7.59-7.58 (m, 1H); 8.04 (s, 1H); 8.54 (s, 1H).

EXAMPLE 29
2-(3,4-Dimethoxyphenyl)-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave 2-(3,4-dimethoxyphenyl)-N-[6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acetamide (0.12%, 47%) as a n off-white solid.

δ (250 MHz, CDCl₃): 2.28 (s, 3H); 2.77 (s, 3H); 3.71 (s, 2H); 3.89 (s, 3H); 3.90 (s, 3H); 6.02 (s, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.82 (s, 1H); 6.87 (s, 1H); 6.88 (s, 1H); 7.22 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.59 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.02 (bs, 1H); 8.54 (s, 1H).

EXAMPLE 30
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3-phenylpropanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/n-hexane (from 90% to pure methylene chloride) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)_2-2-furyl)pyrimidinyl]-3-phenylpropanamide (0.23 g, 99%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.29 (s, 3H); 2.72 (t, J=7.6 Hz, 2H); 2.77 (5, 3H); 3.07 (t, J=7.6 Hz, 2H); 6.02 (s, 1H); 6.57-6.55 (m, 1H); 7.34-7.18 (m, 6H); 7.60 (m, 1H); 8.15 (bs, 1H); 8.54 (s, 1H).

EXAMPLE 31
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3,3,3-trifluoropropanamide

Obtained from the title compound of Example 21 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3,3,3-trifluoropropanamide (0.21 g, 49%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.29 (s, 3H); 2.78 (s, 3H); 3.30 (c, J=10.0 Hz, 2H); 6.04-6.02 (m, 1H); 6.59-6.57 (m, 1H); 7.28-7.24 (m, 1H); 7.62-7.61 (m, 1H); 8.30 (bs, 1H); 8.50 (s, 1H).

EXAMPLE 32
3-(3,4-Dimethoxyphenyl)-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-yl]propanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave 3-(3,4-dimethoxyphenyl)-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]propanamide (0.18 g, 67%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.70 (t, J=7.6 Hz, 2H); 2.77 (s, 6H); 3.02 (t, J=7.6 Hz, 2H); 3.85 (s, 3H); 3.87 (s, 3H); 6.03 (s, 1H); 6.58-6.55 (m, 1H); 6.82-6.75 (m, 3H); 7.23 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.60 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.09 (bs, 1H); 8.54 (s, 1H).

EXAMPLE 33
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3-phenoxypropanamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3-phenoxypropanamide (0.21 g, 88%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.28 (s, 3H); 2.78 (s, 3H); 2.89 (t, J=6.1 Hz, 2H); 4.36 (t, J=6.1 Hz, 2H); 6.02 (s, 1H); 6.58-6.56 (m, 1H); 7.00-6.93 (m, 3H); 7.33-7.24 (m, 3H); 7.62 (m, 1H); 8.47 (bs, 1H); 8.54 (s, 1H).

EXAMPLE 34
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide

Obtained from the title compound of Example 21 (0.15 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2.5%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide (55 mg, 25%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.19 (s, 3H); 2.74 (s, 3H); 3.87 (s, 2H); 6.20 (s, 1H); 6.73 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.30 (d, J=3.4 Hz, 1H); 7.37 (dd, J1=7.7 Hz, J2=4.7 Hz, 1H); 7.79-7.74 (m, 1H); 7.96 (s, 1H); 8.35 (s, 1H); 8.50-8.46 (m, 1H); 11.41 (s, 1H)

EXAMPLE 35
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-yl]-3-pyridin-3-ylpropanamide

Obtained from the title compound of Example 21 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]-3-pyridin-3-ylpropanamide (97 mg, 31%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.23 (s, 3H); 2.74 (s, 3H); 2.97-2.81 (m, 4H); 6.22 (s, 1H); 6.73-6.71 (m, 1H); 7.34-7.27 (m, 2H); 7.71-7.66 (m, 1H); 7.95 (m, 1H); 8.37 (s, 1H); 8.42-8.39 (m, 1H); 8.49 (m, 1H); 11.13 (s, 1H).

EXAMPLE 36
2-(2-Furyl)-6-(4-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 4 (0.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave 2-(2-furyl)-6-(4-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine (0.29 g, 47%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.16 (s, 3H); 5.10 (bs, 2H); 6.57-6.55 (m, 1H); 6.83 (s, 1H); 7.29 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 7.56 (s, 1H); 7.61 (m, 1H); 8.39 (s, 1H).

EXAMPLE 37
N-[2-(2-Furyl)-6-(4-methyl-1H-pyrazol-1-yl)pyrimidin 4-yl]-propanamide

Obtained from the title compound of Example 36 (0.19 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride as eluent gave N-[2-(2-furyl)-6-(4-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.20 g, 82%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.25 (t, J=7.3 Hz, 2H); 2.16 (s, 3H); 2.45 (q, J=7.3 Hz, 2H); 6.59-6.57 (m, 1H); 7.33 (d, J=3.3 Hz, 1H); 7.62-7.60 (m, 2H); 8.12 (bs, 1H); 8.37 (s, 1H); 8.51 (s, 1H).

EXAMPLE 38
2-(2-Furyl)-6-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 4 (0.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave 2-(2-furyl)-6-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine (0.47 g, 76%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.37 (s, 3H); 5.10 (bs, 2H); 6.26 (d, J=2.7 Hz, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.82 (s, 1H); 7.29 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.60 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.52-8.51 (m, 1H).

EXAMPLE 39
N-[2-(2-Furyl)-6-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 38 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(2-furyl)-6-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.17 g, 70%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.26 (t, J=7.6 Hz, 3H); 2.36 (s, 3H); 2.46 (q, J=7.6 Hz, 2H); 6.28 (d, J=2.4 Hz, 1H); 6.58 (dd, J1=3.6 Hz, J2=1.8 Hz, 1H); 7.33-7.31 (m, 1H); 7.61 (s, 1H); 8.11 (bs, 1H); 8.51-8.49 (m, 2H).

EXAMPLE 40
2-(2-Furyl)-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-amine

Obtained from Intermediate 4 (0.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave 2-(2-furyl)-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-amine (0.49 g, 65%) as an off-white solid.

δ (250 MHz, CDCl₃): 5.22 (bs, 2H); 6.58 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.72 (d, J=2.7 Hz, 1H); 6.95 (s, 1H); 7.32 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.62 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.70-8.69 (m, 1H).

EXAMPLE 41
N-{2-(2-Furyl)-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-yl}-propanamide

Obtained from the title compound of Example 40 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/n-hexane (from 90% to pure methylene chloride) as eluent gave N-{2-(2-furyl)-6-[3]-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-yl}propanamide (0.18 g, 99%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.27 (t, J1=7.6 Hz, 3H); 2.49 (q, J1=7.6 Hz, 2H); 6.60 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.73 (d, J1=2.7 Hz, 1H); 7.35 (d, J1=3.3 Hz, 1H); 7.64 (s, 1H); 8.18 (bs, 1H); 8.62 (s, 1H); 8.96 (m, 1H).

EXAMPLE 42
2-(2-Furyl)-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-amine

Obtained from Intermediate 4 (0.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 1:9 to 3:7) as eluent gave 2-(2-furyl)-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-amine (0.13 g, 16%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.84 (s, 3H); 5.26 (bs, 2H); 6.45 (s, 1H); 6.57-6.55 (m, 1H); 6.91 (s, 1H); 7.22 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.61-7.60 (m, 1H).

EXAMPLE 43
N-{2-(2-furyl)-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-pyrimidin-4-yl}propanamide

Obtained from the title compound of Example 42 (0.25 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-{2-(2-furyl)-6-[5-methyl-3-trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-4-yl}propanamide (0.23 g, 77%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.26 (t, J=7.6 Hz, 3H); 2.48 (q, J=7.6 Hz, 2H); 2.84 (s, 3H); 6.47 (s, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.28-7.26 (m, 1H); 7.63 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 8.16 (bs, 1H); 8.58 (s, 1H).

EXAMPLE 44
2-(2-Furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 4 (1.90 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/methanol (3%) as eluent gave 2-(2-furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1.64 g, 74%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.51-6.49 (m, 1H); 6.70 (s, 1H); 7.22 (d, J=3.0 Hz, 1H); 8.01 (s, 1H); 8.54 (s, 1H); 9.19 (s, 1H).

EXAMPLE 45
N-[2-(2-furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 44 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]acetamide (79 mg, 22%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.20 (s, 3H); 6.78-6.76 (m, 1H); 7.54 (d, J=3.8 Hz, 1H); 7.98 (bs, 1H); 8.36 (s, 1H); 8.40 (s, 1H); 9.60 (s, 1H); 11.35 (s, 1H).

EXAMPLE 46
N-[2-(2-Furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide

δ (250 MHz, DMSO-d₆): 1.09 (t, J=7.5 Hz, 3H); 2.51 (q, J=7.5 Hz, 3H); 6.79-6.77 (m, 1H); 7.57-7.54 (m, 1H); 7.99-7.98 (m, 1H); 8.41-8.39 (m, 2H); 9.61 (s, 1H); 11.30 (s, 1H).

EXAMPLE 47
3,3,3-Trifluoro-N-[2-(2-furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 44 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:3) as eluent gave 3,3,3-trifluoro-N-[2-(2-furyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide (0.18 g, 40%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 3.76 (q, J=10.9 Hz, 2H); 6.78-6.76 (m, 1H); 7.57-7.55 (m, 1H); 7.99-7.98 (m, 1H); 8.31 (s, 1H); 8.41 (s, 1H); 9.61 (s, 1H); 11.71 (s, 1H).

Intermediate 5. 4-Chloro-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidine

To a solution of Intermediate 3 (0.34 g, 1.57 mmol) in anhydrous DMF (8 mL) was added pyrazol (97 mg, 1.43 mmol) and cesium carbonate (0.51 g, 1.57 mmol). The mixture was heated at 65° C. for 7 hours. The solvent was removed under reduced pressure. The resulting solid was washed with water (2×25 mL) and ethyl ether to give 4-chloro-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidine (0.21 g, 54%) as an off-white solid.

δ (300 MHz, CDCl₃): 6.58 (dd, J1=2.7 Hz, J2=1.6 Hz, 1H); 6.65 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 7.45 (d, J=3.4 Hz, 1H); 7.60 (s, 1H); 7.86 (d, J=1.6 Hz, 1H); 7.90 (s, 1H); 8.67 (d, J=2.7 Hz, 1H).

Intermediate 6. 2-(5-Bromo-2-furyl)-4-chloro-6-(1H-pyrazol-1-yl)pyrimidine

To a solution of Intermediate 5 (1.0 g, 4.0 mmol) in anhydrous DMF (20 mL) was added N-bromosuccinimide (0.78 g, 4.4 mmol). The mixture was heated at 50° C. for 2 hours. The mixture was poured into water (75 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride as eluent gave the title compound (0.67 g, 51%) as an off-white solid.

δ (300 MHz, CDCl₃): 6.54-6.55 (m, 2H); 7.37-7.38 (m, 1H); 7.78 (s, 1H); 7.81-7.82 (m, 1H); 8.66-8.67 (m, 1H).

EXAMPLE 48
2-(5-Bromo-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

A suspension of Intermediate 6 (0.70 g, 2.13 mmol) in ethanol (22 mL) and 30% ammonium hydroxide (22 mL) was heated at 120° C. in a pressure reactor for 2.30 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The resulting solution was washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (1:1) as eluent gave the title compound (0.23 g, 36%) as an off-white solid.

m.p.: 221.0-221.7° C.

δ (300 MHz, DMSO-d₆): 6.58 (dd, J1=2.6 Hz, J2=1.8 Hz, 1H); 6.78 (s, 1H); 6.81 (d, J=3.3 Hz, 1H); 7.34 (d, J=3.3 Hz, 1H); 7.37 (bs, 2H); 7.85 (d, J=1.8 Hz, 1H); 8.66 (d, J=2.6 Hz, 1H).

EXAMPLE 49
N-[2-(5-bromo-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

A solution of the title compound of Example 48 (0.10 g, 0.33 mmol) in propanoic anhydride (1.5 mL) was heated at 140° C. for 2 hours. The mixture was poured into ice and extracted with methylene chloride (30 mL). The organic layer was washed with saturated solution of sodium bicarbonate (2×15 mL), water (15 mL), brine (15 mL), and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (1:1) as eluent gave the title compound (0.10 g, 84%) as an off-white solid.

m.p.: 199.5-200.3° C.

δ (300 MHz, DMSO-d₆): 1.08 (t, J=7.6 Hz, 3H); 2.50 (q, J=7.6 Hz, 2H); 6.67 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.90 (d, J=3.3 Hz, 1H); 7.53 (d, J=3.3 Hz, 1H); 7.94 (d, J=1.7 Hz, 1H); 8.48 (s, 1H) 8.81 (d, J=2.6 Hz, 1H); 11.19 (bs, 1H).

Intermediate 7. 4-Chloro-2-(5-chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidine

To a solution of Intermediate 5 (1.0 g, 4.0 mmol) in anhydrous DMF (20 mL) was added N-chlorosuccinimide (0.59 g, 4.4 mmol). The mixture was heated at 50° C. for 2 hours. The mixture was poured into water (75 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. 4-Chloro-2-(5-chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidine (1.12 g, 99%) was obtained as an off-white solid.

δ (300 MHz, CDCl₃): 6.41 (d, J=3.6 Hz, 1H), 6.55 (dd, J1=2.7 Hz, J2=1.6 Hz, 1H); 7.41 (d, J=3.6 Hz, 1H); 7.78 (s, 1H); 7.82 (d, J=1.6 Hz, 1H); 8.66 (d, J=2.7 Hz, 1H).

EXAMPLE 50
2-(5-Chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 7 (1.17 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (1:1) as eluent gave 2-(5-chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (0.48 g, 44%) as an off-white solid.

m.p.: 209.9-211.0° C.

δ (300 MHz, DMSO-d₆): 6.58 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.72 (d, J=3.6 Hz, 1H); 6.78 (s, 1H); 7.37-7.36 (m, 3H); 7.85 (s, 1H); 8.66 (d, J=2.6 Hz, 1H).

EXAMPLE 51
N-[2-(5-Chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 50 (0.28 g) by the procedure described in Example 49. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (3:1) as eluent gave N-[2-(5-chloro-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (0.23 g, 72%) as an off-white solid.

m.p.: 189.3-190.1° C.

δ (300 MHz, DMSO-d₆): 1.05 (t, J=7.6 Hz, 3H); 2.46 (q, J=7.6 Hz; 2H); 6.64 (dd, J1=2.8 Hz, J2=1.7 Hz, 1H); 6.78 (d, J=3.6 Hz, 1H); 7.54 (d, J=3.6 Hz, 1H); 7.92 (d, J1=1.7 Hz, J2=0.6 Hz, 1H); 8.45 (s, 1H); 8.78 (d, J1=2.8 Hz, J2=0.6 Hz, 1H); 11.16 (bs, 1H).

Intermediate 8. 5-Methyl-2-furancarboxamidine (HCl)

The title compound (3.71 g, 87%) was obtained as a pale yellow solid starting from 5-methyl-2-furonitrile (2.85 g) by the procedure described in Intermediate 1.

δ (300 MHz, DMSO-d₆): 2.27 (s, 3H); 6.36 (d, J=3.6 Hz, 1H); 7.64 (d, J=3.6 Hz, 1H); 8.49 (bs, 4H).

Intermediate 9. 6-Amino-2-(5-methyl-2-furyl)pyrimidin-4 of

To a solution of Intermediate 8 (3.71 g, 23 mmol) and cyanoacetic acid ethyl ester (2.60 g, 23 mmol) in butanol (25 mL) was added potassium tertbutoxide (5.45 g, 46 mmol). The mixture was stirred at 135° C. for 18 hours. The solvent was removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/methanol (from 2% to 10%) as eluent gave 6-amino-2-(5-methyl-2-furyl)pyrimidin-4-ol (1.96 g, 44%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 2.19 (s, 3H) 4.82 (s, 1H) 6.16 (d, J=3.3 Hz, 1H) 6.41 (s, 2H) 7.23 (d, J=3.3 Hz, 1H).

Intermediate 10. 6-Chloro-2-(5-methyl-2-furyl)pyrimidin-4-amine

A suspension of Intermediate 9 (2.45 g, 10.2 mmol) and phosphorous pentachloride (2.12 g, 10.2 mmol) in phosphorous oxychloride (7 mL) was stirred at 90° C. for 2 hours. The reaction mixture was diluted with methylene chloride (50 mL) and ice was added slowly. The organic layer was decanted and washed with saturated solution of sodium bicarbonate (2×25 mL), water (2×25 mL), brine (25 mL), and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/ethanol (8%) as eluent gave 6-chloro-2-(5-methyl-2-furyl)pyrimidin-4-amine (0.28 g, 13%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 2.35 (s, 3H); 6.27 (s, 1H); 6.28 (d, J=3.3 Hz, 1H); 7.05 (d, J=3.3 Hz, 1H); 7.32 (bs, 2H).

EXAMPLE 52
2-(5-Methyl-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 10 (0.10 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (9:1) as eluent gave 2-(5-methyl-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (44 mg, 36%) as an off-white solid.

δ (300 MHz, DMSO-d): 2.23 (s, 3H); 6.15-6.16 (m, 1H); 6.42-6.43 (m, 1H); 6.58 (s, 1H); 7.05 (d, J=3.0 Hz, 1H); 7.11 (s, 2H); 7.69 (s, 1H); 8.50 (d, J=2.5 Hz, 1H).

EXAMPLE 53
N-[2-(5-methyl-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 52 (40 mg) by the procedure described in Example 49. Purification by column chromatography with silica gel and methylene chloride/ethyl acetate (4:1) as eluent gave N-[2-(5-methyl-2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (11 mg, 19%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 0.94 (t, J=7.6 Hz, 3H); 2.26 (s, 3H); 2.36 (q, J=7.6 Hz, 2H); 6.24 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 6.51 (dd, J1=2.8 Hz, J2=1.7 Hz, 1H); 7.25 (d, J=3.3 Hz, 1H); 7.80-7.78 (m, 1H); 8.28 (s, 1H); 8.63 (dd, J=2.8 Hz, J2=0.6 Hz, 1H); 11.00 (bs, 1H).

Intermediate 11. 6-Amino-2-(2-furyl)pyrimidin-4-ol

To a solution of sodium methoxide (44 mmol) in methanol (10 mL) was slowly added Intermediate 1 (1.60 g, 11 mmol). The mixture was stirred at room temperature for 30 minutes and then, cyanoacetic acid ethyl ester (1.00 g, 8.8 mmol) was added. The suspension was refluxed for 18 hours. The solvent was removed under reduced pressure. The residue was suspended in water (20 mL) and acidified to pH=6 with 5N hydrochloric acid. The resulting solid was filtered and washed with water (20 mL). 6-Amino-2-(2-furyl)pyrimidin-4-ol was obtained (0.79 g, 50%) as a pale yellow solid.

δ (200 MHz, DMSO-d₆): 5.01 (s, 1H); 6.57 (s, 2H); 6.69 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.43 (d, J=3.4 Hz, 1H); 7.91 (d, J=1.7 Hz, 1H).

Intermediate 12. N-[6-Chloro-2-(2-furyl)pyrimidin-4-yl]propanamide

A solution of Intermediate 11 (1.20 g, 6.78 mmol) and propionic anhydride (1.5 mL) in phosphorous oxychloride (12 mL) was stirred at 90° C. for 18 hours. The solvent was removed under reduced pressure. The resulting oil was solved in methylene chloride (50 mL), washed with water (2×25 mL), and brine (25 mL). The organic layer was dried (Na₂SO₄) and the solvent removed under reduced pressure. The resulting solid was filtered and washed with n-pentane (20 mL) to give the title compound (1.40 g, 80%) as a brown solid.

δ (200 MHz, CDCl₃): 1.26 (t, J=7.4 Hz, 3H); 2.49 (q, J=7.2 Hz, 2H); 6.59 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.39 (d, J=3.4 Hz, 1H); 7.64 (s, 1H); 8.10 (d, J=1.71 Hz, 1H); 8.38 (bs, 1H).

EXAMPLE 54
N-[2-(2-Furyl)-6-pyridin-3-ylpyrimidin-4-yl]propanamide

To a solution of Intermediate 12 (1.20 g, 4.77 mmol) in 1,2-dimethoxyethane (120 mL) were added pyridin-3-ylboronic acid (0.88 g, 7.15 mmol), potassium carbonate (1.31 g, 9.54 mmol), water (8 mL) and tetrakis(triphenylphosphine)palladium (0) (2.65 g, 2.38 mmol). The mixture was stirred at 80° C. overnight. The crude reaction was filtered through Celite® and the organic layer was washed with saturated solution of sodium bicarbonate (2×50 mL), water (2×50 mL), brine (50 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography, eluting with ethyl acetate/n-hexane (from 1:6 to pure ethyl acetate), followed by digestion in hot acetonitrile gave N-[2-(2-furyl)-6-pyridin-3-ylpyrimidin-4-yl]propanamide (0.30 g, 21%) as an off-white solid.

m.p.: 251.8-253.2° C.

δ (200 MHz, DMSO-d₆): 1.10 (t, J=7.5 Hz, 3H); 2.50 (q, J=7.5 Hz, 2H) 6.75 (dd, J1=3.0 Hz, J2=1.7 Hz, 1H); 7.43 (d, J=3.5 Hz, 1H); 7.97 (s, 1H); 8.06 (d, J=5.6 Hz, 2H); 8.54 (s, 1H); 8.81 (d, J=5.6 Hz, 2H); 11.21 (bs, 1H).

EXAMPLE 55
2-(2-Furyl)-6-pyridin-3-ylpyrimidin-4-amine

To a solution of the title compound of Example 54 (0.20 g, 0.687 mmol) in ethanol (2 mL) was added 2N hydrochloric acid (2 mL). The mixture was stirred at 80° C. for 1 hour. The solution was diluted with water (10 mL) and 2N sodium hydroxide was added until pH=10. The mixture was extracted with methylene chloride (2×10 mL). The combined organic extracts were washed with water (2×10 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether, to give 2-(2-furyl)-6-pyridin-3-ylpyrimidin-4-amine (80 mg, 49%) as an off-white solid.

m.p.: 232.7-233.1° C.

δ (200 MHz, CDCl₃) 5.13 (bs, 2H); 6.58 (dd, J1=3.5 Hz, J2=1.7 Hz, 1H); 6.75 (s, 1H); 7.37 (d, J=3.5 Hz, 1H); 7.64-7.63 (m, 1H); 7.93 (d, J=6.0 Hz, 2H); 8.77 (d, J=6.0 Hz, 2H).

Intermediate 13. Thiophene-2-carboxamidine (HCl)

The title compound (12.7 g, 85%) was obtained as a solid starting from thiophene-2-carbonitrile (10.0 g) by the procedure described in Intermediate 1.

δ (250 MHz, DMSO-d₆): 7.32 (m, 1H); 8.13 (m, 1H); 8.17 (m, 1H); 8.94-8.33 (bs, 3H).

Intermediate 14. 6-Amino-2-(2-thienyl)pyrimidin-4-ol

The title compound (6.13 g, 76%) was obtained as a brown solid starting from Intermediate 13 (7.00 g) by the procedure described in Intermediate 11 (reaction time: 4 days).

δ (250 MHz, DMSO-d₆): 5.04 (bs, 1H); 6.52 (bs, 2H); 7.18 (bs, 1H); 7.78 (bs, 1H); 8.09 (bs, 1H).

Intermediate 15. 6-Chloro-2-(2-thienyl)pyrimidin-4-amine

A suspension of Intermediate 14 (6.30 g, 32.6 mmol) in phosphorous oxychloride (20 mL) was refluxed for 24 hours. The solvent was removed under pressure and ice and water were slowly added. The resulting solid was filtered, washed with 2N sodium hydroxide, and dried. 6-Chloro-2-(2-thienyl)pyrimidin-4-amine was obtained (4.40 g, 64%) as a brown solid.

MS (M⁺): 211

EXAMPLE 56
6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 15 (3.00 g) by the procedure described in Example 21. Purification by trituration with ethyl ether gave 6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine (1.00 g, 27%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.59-6.57 (m, 1H); 6.77 (s, 1H); 7.20-7.17 (m, 1H); 7.24 (bs, 2H); 7.72-7.70 (m, 1H); 7.85-7.84 (m, 1H); 7.97-7.95 (m, 1H); 8.67 (d, J=2.5 Hz, 1H).

EXAMPLE 57
N-[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 56 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]acetamide (0.19 g, 55%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.20 (s, 3H); 6.44-6.43 (m, 1H); 7.08 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.43 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H); 7.74-7.73 (m, 1H); 7.91 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.39 (m, 1H); 8.59-8.57 (m, 1H).

EXAMPLE 58
N-[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide

δ (250 MHz, CDCl₃): 1.28 (t, J=7.6 Hz, 3H); 2.51 (q, J=7.6 Hz, 2H); 6.50-6.49 (m, 1H); 7.15 (dd, J1=5.2 Hz, J2=3.9 Hz, 1H); 7.49 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H); 7.80-7.79 (m, 1H); 8.00-7.98 (m, 2H); 8.54 (s, 1H); 8.66-8.65 (m, 1H).

EXAMPLE 59
3-Cyclopentyl-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:9) as eluent gave 3-cyclopentyl-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.17 g, 57%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.18-1.10 (m, 2H); 1.63-1.51 (m, H); 1.85-1.75 (m, 5H); 2.48 (t, J=7.3 Hz, 2H); 6.50-6.49 (m, 1H); 7.15 (dd, J1=4.9 Hz, J2=3.6 Hz, 1H); 7.50 (dd, J1=4.9 Hz, J2=1.2 Hz, 1H); 7.99 (dd, J1=3.9 Hz, J2=1.2 Hz, 2H); 8.00 (d, J=1.2 Hz, 1H); 8.54 (s, 1H); 8.65 (d, J=2.7 Hz, 1H).

EXAMPLE 60
3-Phenyl-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave 3-phenyl-N-[6-(H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.29 g, 94%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.78 (t, J=7.6 Hz, 2H); 3.09 (t, J=7.6 Hz, 2H); 6.50 (dd, J1=2.7 Hz, J2=1.8 Hz, 1H); 7.15 (dd, J1=5.2 Hz, J2=3.6 Hz, 1H); 7.35-7.22 (m, 5H); 7.49 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H); 7.81 (m, 1H); 7.94 (bs, 1H); 7.97 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.54 (s, 1H); 8.65 (d, J=2.6 Hz, 1H).

EXAMPLE 61
3,3,3-Trifluoro-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 56 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave 3,3,3-trifluoro-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.33 g, 76%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.37 (q, J=10.3 Hz, 2H); 6.52-6.50 (m, 1H); 7.15 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.51 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H); 7.81-7.80 (m, 1H); 7.99 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.23 (bs, 1H); 8.48 (bs, 1H); 8.65-8.64 (m, 1H).

EXAMPLE 62
3-(3,4-Dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel eluting with methylene chloride/methanol (0.2%), followed by a second purification by column chromatography using ethyl acetate/n-hexane (1:1) as eluent gave 3-(3,4-dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.18 g, 51%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.76 (t, J=7.6 Hz, 2H); 3.04 (t, J=7.6 Hz, 2H); 3.85 (s, 3H); 3.87 (s, 3H); 6.50 (dd, J1=2.7 Hz, J2=1.8 Hz, 1H); 6.80-6.77 (m, 3H); 7.15 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.49 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H); 7.81-7.80 (m, 1H); 7.92 (bs, 1H); 7.97 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.53 (s, 1H); 8.65 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 63
3-Phenoxy-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave 3-phenoxy-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.28 g, 85%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.95 (t, J=6.0 Hz, 2H); 4.38 (t, J=6.0 Hz, 2H); 6.50-6.49 (m, 1H); 7.03-6.98 (m, 3H); 7.16 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.37-7.29 (m, 2H); 7.50 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H); 7.80-7.79 (m, 1H); 8.00 (dd, J1=3.9 Hz, J2=1.2 Hz, 1H); 8.53 (s, 1H); 8.63 (bs, 1H); 8.66 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 64
N-[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2.5%) as eluent gave N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-2-pyridin-3-ylacetamide (0.17 g, 56%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.82 (s, 2H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 7.16-7.13 (m, 1H); 7.37-7.32 (m, 1H); 7.50 (dd, J1=4.9 Hz, J2=1.2 Hz, 1H); 7.77-7.73 (m, 1H); 7.78 (dd, J1=1.5 Hz, J2=0.6 Hz, 1H); 7.98 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.04 (bs, 1H); 8.51 (s, 1H); 8.62-8.59 (m, 2H); 8.64 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 65
N-[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-3-pyridin-3-ylpropanamide

Obtained from the title compound of Example 56 (0.20 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[6-(1H-pyrazol-1-yl)_2-2-thienyl)pyrimidin-4-yl]-3-pyridin-3-ylpropanamide (0.13 g, 43%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.81 (t, J=7.3 Hz, 2H); 3.10 (t, J=7.3 Hz, 2H); 6.51 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 7.15 (dd, J1=5.2 Hz, J2=3.6 Hz, 1H); 7.25-7.21 (m, 1H); 7.50-7.48 (m, 1H); 7.61 (dt, J1=7.9 Hz, J2=2.1 Hz, 1H); 7.82-7.81 (m, 1H); 7.97 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.15 (bs, 1H); 8.5 (dd, J1=4.8 Hz, J2=1.5 Hz, 1H); 8.54-8.52 (m, 2H); 8.65 (d, J=2.7 Hz, 1H).

EXAMPLE 66
(2E)-3-(3,4-Dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]acrylamide

Obtained from the title compound of Example 56 (0.30 g) by the procedure described in Example 20. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave (2E)-3-(3,4-dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidinyl]acrylamide (0.20 g, 36%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.82 (s, 3H); 3.84 (s, 3H); 6.68 (dd, J1=2.7 Hz, J2=1.7 Hz, 1H); 7.09-7.02 (m, 2H); 7.28-7.23 (m, 3H); 7.66 (d, J1=15.5 Hz, 1H); 7.84 (dd, J1=5.0 Hz, J2=1.3 Hz, 1H); 7.97 (d, J1=1.3 Hz, 1H); 8.12 (dd, J1=3.7 Hz, J2=1.0 Hz, 1H); 8.57 (s, 1H); 8.82 (d, J1=2.7 Hz, 1H); 11.08 (s, 1H).

EXAMPLE 67
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 15 (3.0 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (3:10) as eluent gave 6-(3,5-dimethyl-1H-pyrazol-1-yl)_2-2-thienyl)pyrimidin-4-amine (1.75 g, 45%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.19 (s, 3H); 2.72 (s, 3H); 6.13 (s, 1H); 6.73 (s, 1H); 7.08 (bs, 2H); 7.19-7.15 (m, 1H); 7.70-7.67 (m, 1H); 7.82-7.79 (m, 1H).

EXAMPLE 68
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-acetamide

Obtained from the title compound of Example 67 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (3:10) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]acetamide (80 mg, 23%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.20 (s, 3H); 2.23 (s, 3H); 2.74 (s, 3H); 5.96 (s, 1H); 7.07 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.40 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H); 7.84 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 7.94 (bs, 1H); 8.39 (s, 1H).

EXAMPLE 69
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 67 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]propanamide (0.17 g, 47%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 1.27 (t, J=7.3 Hz, 3H); 2.28 (s, 3H); 2.49 (q, J=7.3 Hz, 2H); 2.80 (s, 3H); 6.02 (s, 1H); 7.13 (dd, J1=4.9 Hz, J2=3.6 Hz, 1H); 7.46 (dd, J1=4.9 Hz, J2=1.2 Hz, 1H); 7.92-7.89 (m, 2H); 8.50 (s, 1H).

EXAMPLE 70
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]-3,3,3-trifluoropropanamide

Obtained from the title compound of Example 67 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (15:85) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)_2-2-thienyl)pyrimidin-4-yl]-3,3,3-trifluoropropanamide (55 mg, 13%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.32 (s, 3H); 2.84 (s, 3H); 3.38 (q, J=10.0 Hz, 2H); 6.06 (s, 1H); 7.18-7.16 (m, 1H); 7.52-7.50 (m, 1H); 7.96-7.94 (m, 1H); 8.12 (s, 1H); 8.48 (bs, 1H).

EXAMPLE 71
2-(2-Thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-amine

Obtained from Intermediate 15 (1.86 g) by the procedure described in Example 21. Purification by trituration with ethyl ether gave 2-(2-thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1.81 g, 84%) as an off-white solid.

δ (250 MHz, MeOD): 6.67 (s, 1H); 7.06 (dd, J1=5.0 Hz, J2=3.6 Hz, 1H); 7.40 (dd, J1=5.0 Hz, J2=1.3 Hz, 1H); 7.88-7.86 (m, 1H); 8.01 (s, 1H); 9.19 (s, 1H).

EXAMPLE 72
N-[2-(2-Thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 71 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 1:1 to 4:1) as eluent gave N-[2-(2-thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]acetamide (0.21 g, 63%) as an off-white solid.

δ (250 MHz, DMSO-d₈): 2.15 (s, 3H); 7.20 (dd, J1=4.9 Hz, J2=3.8 Hz, 1H); 7.79 (dd, J1=4.9 Hz, J2=1.4 Hz, 1H); 8.11 (dd, J1=3.8 Hz, J2=1.4 Hz, 1H); 8.29 (s, 1H); 8.34 (s, 1H); 9.57 (s, 1H); 11.00 (s, 1H).

EXAMPLE 73
N-[2-(2-Thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 71 (0.14 g) by the procedure described in Example 2. Purification by trituration with ethyl ether gave N-[2-(2-thienyl-6-(1H-1,2,4-triazol-1-yl)pyrimidinyl]propanamide (0.13 g, 75%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 1.05 (t, J=7.4 Hz, 3H); 2.49 (q, J=7.4 Hz, 2H); 7.25-7.20 (m, 1H); 7.83-7.80 (m, 1H); 8.14-8.12 (m, 1H); 8.34 (s, 1H); 8.36 (s, 1H); 9.58 (s, 1H); 11.09 (s, 1H).

EXAMPLE 74
3,3,3-Trifluoro-N-[2-(2-thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 71 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (10%) as eluent gave 3,3,3-trifluoro-N-[2-(2-thienyl)-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide (0.2 mg, 47%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 3.57 (q, J=11.0 Hz, 2H); 7.09-7.04 (m, 1H); 7.68-7.65 (m, 1H); 8.00-7.97 (m, 1H); 8.10 (s, 1H); 8.21 (s, 1H); 9.45 (s, 1H); 11.31 (s, 1H).

Intermediate 16. 3-Methylthiophene-2-carboxamidine (HCl)

The title compound (3.25 g, 43%) was obtained as an off-white solid starting from 3-methylthiophene-2-carbonitrile (5.26 g) by the procedure described in Intermediate 1.

δ (300 MHz, DMSO-d₆): 2.36 (s, 3H); 7.42 (bs, 4H); 8.24 (s, 1H).

Intermediate 17. 6-Amino-2-(3-methyl-2-thienyl)pyrimidin-4-ol

Obtained from Intermediate 16 (3.20 g) by the procedure described in Intermediate 11. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent, followed by a preparative HPLC-MS purification gave 6-amino-2-(3-methyl-2-thienyl)pyrimidin-4-ol (80 mg, 2%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 2.36 (s, 3H); 5.07 (s, 1H); 6.36 (bs, 2H); 6.82 (d, J=4.9 Hz, 1H); 7.40 (d, J=4.9 Hz, 1H).

Intermediate 18. N-[6-Chloro-2-(3-methyl-2-thienyl)pyrimidin-4-yl]propanamide

Obtained from Intermediate 17 (80 mg) by the procedure described in Intermediate 12. Purification by column chromatography with silica gel and methylene chloride as eluent gave N-[6-chloro-2-(3-methylthiophen-2-yl)pyrimidinyl]propionamide (40 mg, 37%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 0.93 (t, J=7.4 Hz, 3H); 2.36-2.37 (m, 5H); 6.92 (d, J=5.0 Hz, 1H); 7.54 (d, J=5.0 Hz, 1H); 7.78 (s, 1H).

EXAMPLE 75
N-[2-(3-Methyl-2-thienyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-propanamide

Obtained from Intermediate 18 (40 mg) by the procedure described in Example 21. Purification by column chromatography with silica gel and ethyl acetate/methylene chloride (1:5) as eluent gave N-[2-(3-methyl-2-thienyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (5 mg, 11%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.10 (t, J=7.6 Hz, 3H); 2.54 (q, J=7.6 Hz, 2H); 2.74 (s, 3H); 6.68-6.67 (m, 1H); 7.08 (d, J=5.1 Hz, 1H); 7.95-7.94 (m, 1H); 8.42 (s, 1H); 8.63 (d, J=5.1 Hz, 1H); 10.89 (bs, 1H).

Intermediate 19. 3-Amino-3-(2-furyl)acrylonitrile

To a solution of diisopropilamine (0.92 g, 9.13 mmol) in anhydrous tetrahydrofuran (17 mL), cooled at −78° C., was slowly added 1.6M solution of n-butyllithium in hexanes (5.85 mL). The mixture was stirred at −78° C. for 30 minutes and then, a solution of acetonitrile (0.33 g, 8.06 mmol) in anhydrous tetrahydrofuran (3.5 mL) was slowly added. After 30 minutes at the same temperature, a solution of 2-furonitrile (0.50 g, 5.37 mmol) was added. The mixture was allowed to stand at −78° C. for 20 minutes and at room temperature overnight. Water (6 mL) was added and the solvent removed under reduced pressure. The resulting solid was suspended in water (50 mL) and extracted with methylene chloride (3×25 mL). The organic layer was washed with brine (2×20 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The title compound was obtained (0.70 g, 97%) as a brown solid, which was used in the next step without further characterisation.

Intermediate 20. 4-Amino-6-(2-furyl)pyrimidin-2-thiol

To a solution of Intermediate 19 (1.38 g, 10.3 mmol) in ethanol (17 mL) were added sodium ethoxide (1.54 g, 22.6 mmol) and thiourea (1.56 g, 22.6 mmol). The mixture was refluxed for 45 hours. The resulting suspension was cooled and water was added (12 mL). The solution was acidified with 1N hydrochloric acid until pH=5. The resulting solid was filtered, washed with water (2×20 mL), ethyl ether (10 mL) and dried (Na₂SO₄). 4-Amino-6-(2-furyl)pyrimidin-2-thiol was obtained (1.20 g, 60%) as a solid.

δ (250 MHz, DMSO-d₆): 6.27 (s, 1H); 6.71 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.76-7.53 (m, 2H); 7.95 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H); 12.14 (bs, 1H).

Intermediate 21. 6-(2-Furyl)-2-methylsulfanylpyrimidin-4-amine

To a solution of Intermediate 20 (1.87 g, 9.68 mmol) in 10% sodium hydroxide (15 mL) was added methyl iodide (1.51 g, 10.6 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was partially removed under reduced pressure and 2N hydrochloric acid was added until pH=10. The resulting solid was filtered, washed with water (2×20 mL) and dried. 6-(2-furyl)-2-methylsulfanylpyrimidin-4-amine was obtained (1.90 g, 95%) as an off-white solid.

δ (400 MHz, MeOD): 3.46 (s, 3H); 7.48 (s, 1H); 7.52 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 8.08 (dd, J1=3.4 Hz, J2=0.8 Hz, 1H); 8.59 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H).

Intermediate 22. 6-(2-Furyl)-2-methanesulfonylpyrimidin-4-amine

To a suspension of Intermediate 21 (1.90 g, 9.20 mmol) in chloroform (70 mL), cooled at 0° C., was added 70% m-chloroperbenzoic acid (4.53 g, 18.4 mmol). The mixture was stirred at 0° C. for 45 minutes. The solvent was partially removed under reduced pressure and the resulting solid was filtered, washed with ethyl ether, and dried. 1.36 g of the title compound were obtained. The organic solution was washed with 2N sodium hydroxide (2×25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. 0.47 g of the title compound were obtained (overall yield: 83%).

δ (400 MHz, MeOD): 4.27 (s, 3H); 7.6 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.86 (s, 1H); 8.27 (dd, J1=3.4 Hz, J2=0.8 Hz, 1H); 8.68 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H).

EXAMPLE 76
6-(2-Furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-amine

To a solution of Intermediate 22 (1.16 g, 4.85 mmol) in anhydrous DMSO (20 mL) was added pyrazol (0.36 g, 5.33 mmol) and cesium carbonate (1.71 g, 5.33 mmol). The mixture was heated at 110° C. for 2.5 hours and at room temperature overnight. The solution was poured into water (60 mL) and extracted with ethyl acetate (3×40 mL). The organic layer was washed with water (2×50 mL), brine (50 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent, followed by trituration with ethyl ether gave 6-(2-furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-amine (0.56 g, 51%) as an off-white solid.

δ (250 MHz, CDCl₃): 5.33 (bs, 2H); 6.47-6.46 (m, 1H); 6.58-6.56 (m, 1H); 6.68 (s, 1H); 7.27 (s, 1H); 7.56 (s, 1H); 7.79 (s, 1H); 8.63 (d, J=2.4 Hz, 1H).

EXAMPLE 77
N-[6-(2-Furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 76 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[6-(2-furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (0.19 g, 80%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.21 (s, 3H); 6.46 (bs, 1H); 6.56-6.55 (m, 1H); 7.31 (d, J=3.6 Hz, 1H); 7.60 (s, 1H); 7.77 (s, 1H); 8.29 (s, 1H); 8.55 (bs, 1H); 8.60 (d, J=2.4 Hz, 1H).

EXAMPLE 78
N-[6-(2-Furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 76 (0.28 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[6-(2-furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (84 mg, 24%) as a pale yellow solid.

δ (250 MHz, CDCl₃): 1.27 (t, J=7.3 Hz, 3H); 2.47 (q, J=7.3 Hz, 2H); 6.49-6.48 (m, 1H); 6.58-6.57 (m, 1H); 7.33 (d, J=3.6 Hz, 1H); 7.61 (s, 1H); 7.79 (s, 1H); 8.34 (bs, 1H); 8.36 (d, J=1.2 Hz, 1H); 8.64 (d, J=2.4 Hz, 1H).

EXAMPLE 79
3,3,3-Trifluoro-N-[6-(2-furyl)-2-(1H-pyrazol-1-yl)pyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 76 (0.25 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (4%) as eluent gave 3,3,3-trifluoro-N-[2-(2-furyl)-2-(1H-pyrazol-1-yl)pyrimidin-yl]propanamide (0.19 mg, 49%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.32 (q, J=9.8 Hz, 2H); 6.51-6.49 (m, 1H); 6.61-6.59 (m, 1H); 7.37 (d, J=3.6 Hz, 1H); 7.63 (s, 1H); 7.80 (s, 1H); 8.32 (s, 1H); 8.63 (d, J=2.4 Hz, 1H); 8.68 (bs, 1H).

EXAMPLE 80
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-amine

Obtained from Intermediate 22 (3.00 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and chloroform/isopropanol (1:1) as eluent, followed by a second column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave 2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-amine (0.15 g, 5%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.33 (s, 3H); 2.72 (s, 3H); 5.18 (bs, 2H); 6.01 (s, 1H); 6.54 (dd, J1=6.3 Hz, J2=1.8 Hz, 1H); 6.63 (s, 1H); 7.15-7.13 (m, 1H); 7.55-7.54 (m, 1H).

EXAMPLE 81
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-yl]-propanamide

Obtained from the title compound of Example 80 (95 mg) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (10%) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-yl]propanamide (50 mg, 43%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.25 (t, J=7.6 Hz, 3H); 2.35 (s, 3H); 2.45 (q, J=7.6 Hz, 2H); 2.75 (s, 3H); 6.05 (s, 1H); 6.58-6.56 (m, 1H); 7.24-7.23 (m, 1H); 7.61 (s, 1H); 8.27 (bs, 1H); 8.33 (s, 1H).

EXAMPLE 82
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide

Obtained from the title compound of Example 80 (100 mg) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (10%) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(2-furyl)pyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide (50 mg, 30%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.32 (s, 3H); 2.71 (s, 3H); 3.69 (s, 2H); 3.81 (s, 3H); 6.03 (s, 1H); 6.57-6.55 (m, 1H); 6.90 (d, J=8.8 Hz, 2H); 7.24-7.20 (m, 3H); 7.60 (d, J=1.5 Hz, 1H); 8.35 (s, 2H).

EXAMPLE 83
6-(2-Furyl)-2-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine

To a solution of Intermediate 22 (0.21 g, 0.88 mmol) in anhydrous DMF (3 mL) was added [1,2,4]-triazol (60 mg, 0.88 mmol) and potassium carbonate (0.12 g, 0.88 mmol). The mixture was heated at 80° C. for 2 hours. The solution was poured into water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride as eluent gave 6-(2-furyl)-2-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (70 mg, 35%) as an off-white solid.

δ (200 MHz, DMSO-d₆): 6.70 (s, 1H); 6.73-6.72 (m, 1H); 7.30 (d, J=3.4 Hz, 1H); 7.57 (bs, 2H); 7.93-7.92 (m, 1H); 8.22 (s, 1H); 9.35 (s, 1H).

EXAMPLE 84
N-[6-(2-Furyl)-2-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 83 (45 mg) by the procedure described in Example 49. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[6-(2-furyl)-2-(1H-1,2,4-triazol-1-yl)pyrimidin-yl]propanamide (16 mg, 28%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.16 (t, J=7.4 Hz, 3H); 2.53 (q, J=7.4 Hz, 2H); 6.66 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 7.43 (dd, J1=3.4, J2=0.8 Hz, 1H); 7.79 (dd, J1=1.8 Hz, J2=0.8 Hz, 1H); 8.12 (s, 1H); 8.44 (s, 1H); 9.34 (s, 1H); 11.16 (bs, 1H).

Intermediate 23. 3-Amino-3-pyridin-2-ylacrylonitrile

To a solution of pyridine-2-carbonitrile (5.0 g, 48.0 mmol) in toluene (175 mL) was added potassium tertbutoxide (16.2 g, 0.144 mol) and acetonitrile (3.94 g, 96.0 mmol). The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added saturated solution of potassium bicarbonate (200 mL) and the mixture was extracted with ethyl ether (2×200 mL). The organic layer was dried (Na₂SO₄) and the solvent removed under reduced pressure. The title compound was obtained (5.44 g, 78%) as a light brown solid, which was used in the next step without further characterisation.

Intermediate 24. 4-Amino-6-pyridin-2-ylpyrimidin-2-thiol

Obtained from Intermediate 23 (1.14 g) by the procedure described in Intermediate 20. Purification by trituration with ethyl ether gave 4-amino-6-pyridin-2-ylpyrimidin-2-thiol (1.28 g, 80%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.70 (bs, 1H); 7.60 (m, 1H); 7.79 (bs, 1H); 8.15-7.98 (m, 2H); 8.74 (m, 1H); 11.21 (bs, 1H).

Intermediate 25. 2-Methylsulfanyl-6-pyridin-2-ylpyrimidin-4-amine

Obtained from Intermediate 24 (4.0 g) by the procedure described in Intermediate 21. Purification by trituration with ethyl ether gave the title compound (4.16 g, 97%) as an orange solid.

MS (M⁺): 218.

Intermediate 26. 2-Methanesulfonyl-6-pyridin-2-ylpyrimidin-4-amine

Obtained from Intermediate 25 (4.16 g) by the procedure described in Intermediate 22. Purification by trituration with ethyl ether gave 2-methanesulfonyl-6-pyridin-2-ylpyrimidin-4-amine (3.89 g, 82%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 3.38 (s, 3H); 7.59-7.53 (m, 2H); 7.86 (bs, 1H); 8.05-7.97 (m, 1H); 8.34 (m, 1H); 8.73 (m, 1H).

EXAMPLE 85
2-(1H-Pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-amine

Obtained from Intermediate 26 (0.43 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave 2-(1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-amine (0.25 g, 47%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.54 (t, J=1.7 Hz, 1H); 7.38 (s, 1H); 7.46 (bs, 2H); 7.56-7.50 (m, 1H); 7.78-7.77 (m, 1H); 7.99 (dt, J1=7.7 Hz, J2=1.7 Hz, 1H); 8.45 (d, J=7.7 Hz, 1H); 8.71 (d, J=2.7 Hz, 2H).

EXAMPLE 86
N-[2-(1H-Pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-yl]propanamide

Obtained from the title compound of Example 85 (0.19 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-yl]propanamide (0.15 g, 65%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.28 (t, J=7.6 Hz, 2H); 2.49 (q, J=7.6 Hz, 2H); 6.53-6.51 (m, 1H); 7.45-7.39 (m, 1H); 7.90-7.83 (m, 2H); 8.30 (bs, 1H), 8.47 (dd, J1=7.9 Hz, J2=0.9 Hz, 1H); 8.77-8.72 (m, 2H); 9.08 (s, 1H).

EXAMPLE 87
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-amine

Obtained from Intermediate 26 (3.90 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and methylene chloride/acetonitrile (from 4:1 to 1:4) as eluent, followed by a second column chromatography with silica gel and methylene chloride/acetonitrile/methanol (1:4:0.25) as eluent gave 2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-amine (0.42 g, 10%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.35 (s, 3H); 2.79 (s, 3H); 5.26 (bs, 2H); 6.05 (s, 1H); 7.41-7.36 (m, 2H); 7.85 (dt, J1=7.6 Hz, J2=1.8 Hz, 1H); 8.38-8.34 (m, 1H); 8.70-8.67 (m, 1H).

EXAMPLE 88
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-yl]propanamide

Obtained from the title compound of Example 87 (0.17 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 5% methanol) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-yl]propanamide (0.10 g, 64%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.26 (t, J=7.6 Hz, 3H); 2.36 (s, 3H); 2.46 (q, J=7.6 Hz, 2H); 2.81 (s, 3H); 6.08 (s, 1H); 7.40 (ddd, J1=7.6 Hz, J2=1.8 Hz, 1H); 7.85 (dt, J1=7.6 Hz, J2=1.8 Hz, 1H); 8.36-8.31 (m, 2H); 8.76-8.73 (m, 1H); 9.05 (s, 1H).

EXAMPLE 89
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide

Obtained from the title compound of Example 87 (0.17 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from 1% to 5%) as eluent, followed by a second column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 10% methanol) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-2-ylpyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide (94 mg, 31%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.34 (s, 3H); 2.78 (s, 3H); 3.71 (s, 2H); 3.81 (s, 3H); 6.07 (s, 1H); 6.89-6.87 (m, 1H); 6.93-6.91 (m, 1H); 7.26-7.21 (m, 2H); 7.40 (ddd, J1=7.6 Hz, J2=4.8 Hz, 1H); 7.84 (dt, J1=7.6 Hz, J2=1.8 Hz, 1H); 8.25 (bs, 1H); 8.33 (dt, J1=7.6 Hz, J2=1.2 Hz, 1H); 8.74 (dt, J1=4.8 Hz, J2=1.8 Hz, 1H); 9.06 (s, 1H).

Intermediate 27. 3-Amino-3-pyridin-3-ylacrylonitrile

Obtained from pyridine-3-carbonitrile (5.00 g) by the procedure described in Intermediate 23 (reaction time: 3 days). Purification by trituration with ethyl ether gave 3-amino-3-pyridin-3-ylacrylonitrile (2.81 g, 40%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 4.58 (s, 1H); 6.96 (s, 2H); 7.46 (dd, J1=7.9 Hz, J2=4.6 Hz, 1H); 7.98-7.93 (m, 1H); 8.64 (dd, J1=4.7 Hz, J2=1.6 Hz, 1H); 8.77 (dd, J1=2.5 Hz, J2=0.8 Hz, 1H).

Intermediate 28. 4-Amino-6-pyridin-3-ylpyrimidin-2-thiol

Obtained from Intermediate 27 (2.81 g) by the procedure described in Intermediate 20. Purification by trituration with ethyl ether gave 4-amino-6-pyridin-3-ylpyrimidin-2-thiol (3.28 g, 83%) as an off-white solid.

δ (200 MHz, DMSO-d₆): 7.53 (dd, J1=8.1 Hz, J2=4.7 Hz, 2H); 7.67 (s, 2H); 8.12-8.07 (m, 1H); 8.71 (d, J=4.7 Hz, 1H); 8.85 (s, 1H); 12.40 (bs, 1H).

Intermediate 29. 2-Methylsulfanyl-6-pyridin-3-ylpyrimidin-4-mine

Obtained from Intermediate 28 (3.00 g) by the procedure described in Intermediate 21. Purification by trituration with ethyl ether gave the title compound (2.96 g, 92%) as a solid, which was used in the next step without further characterisation.

Intermediate 30. 2-Methanesulfonyl-6-pyridin-3-ylpyrimidin-4-amine

Obtained from Intermediate 29 (2.00 g) by the procedure described in Intermediate 22. Purification by trituration with ethyl ether gave 2-methanesulfonyl-6-pyridin-3-ylpyrimidin-4-amine (1.90 g, 83%) as an off-white solid.

MS (M⁺): 250

EXAMPLE 90
2-(1H-Pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-amine

Obtained from Intermediate 30 (1.00 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and methylene chloride/methanol (from 2% to 3%) as eluent gave 2-(1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-amine (0.24 g, 25%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.55-6.53 (m, 1H); 6.91 (s, 1H); 7.45 (bs, 2H); 7.56 (dd, J1=7.9 Hz, J2=4.9 Hz, 1H); 7.78 (s, 1H); 8.46-8.41 (m, 1H); 8.72-8.69 (m, 2H); 9.26-9.24 (m, 1H).

EXAMPLE 91
N-[2-(1H-Pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-yl]propanamide

Obtained from the title compound of Example 90 (0.14 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent, followed by a second column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave N-[2-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-yl]propanamide (54 mg, 31%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 1.10 (t, J=7.4 Hz, 3H); 2.53 (q, J=7.4 Hz, 2H); 6.63 (m, J1=2.6 Hz, J2=1.4 Hz, 1H); 7.65-7.60 (m, 1H); 7.88-7.87 (m, 1H); 8.51 (t, J=1.4 Hz, 1H); 8.55 (s, 1H); 8.78 (dd, J1=4.6 Hz, J2=1.4 Hz, 1H); 8.84 (dd, J1=2.6 Hz, J2=0.5 Hz, 1H); 9.35 (d, J=1.9 Hz, 1H); 11.36 (s, 1H).

EXAMPLE 92
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-amine

Obtained from Intermediate 30 (1.77 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and methylene chloride/methanol (4%) as eluent gave 2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-amine (0.35 g, 8%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.18 (s, 3H); 2.63 (s, 3H); 6.09 (s, 1H); 6.86 (s, 1H); 7.37 (bs, 2H); 7.56 (dd, J1=8.0 Hz, J2=4.7 Hz, 1H); 8.34 (dt, J1=8.0 Hz, J2=1.6 Hz, 1H); 8.69 (dd, J1=4.7 Hz, J2=1.6 Hz, 1H); 9.17 (d, J=2.2 Hz, 1H).

EXAMPLE 93
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 92 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 2% methanol) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-yl]propanamide (74 mg, 41%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.27 (t, J=7.6 Hz, 3H); 2.48 (q, J=7.6 Hz, 2H); 2.80 (s, 3H); 6.09 (s, 1H); 7.46 (dd, J1=8.2 Hz, J2=5.2 Hz, 1H); 8.40-8.35 (m, 2H); 8.54 (s, 1H); 8.60 (d, J=2.4 Hz, 1H); 8.77-8.74 (m, 1H); 9.39-9.38 (m, 1H).

EXAMPLE 94
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-yl]-2-(4-methoxyphenyl)acetamide

Obtained from the title compound of Example 92 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 5% methanol) as eluent gave N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-pyridin-3-ylpyrimidin-4-yl]-2-(4-methoxyphenyl)acetamide (0.20 g, 86%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.34 (s, 3H); 2.77 (s, 3H); 3.72 (s, 2H); 3.81 (s, 3H); 6.07 (s, 1H); 6.91 (d, J=8.8 Hz, 2H); 7.23 (d, J=8.8 Hz, 2H); 7.47-7.42 (m, 1H); 8.40-8.33 (m, 2H); 8.56 (s, 1H); 8.76-8.73 (m, 1H); 9.38-9.36 (m, 1H).

Intermediate 31. 3-Amino-3-pyridin-ylacrylonitrile

Obtained from pyridine-4-carbonitrile (5.00 g) by the procedure described in Intermediate 23 (reaction time: 12 hours). Purification by trituration with ethyl ether gave 3-amino-3-pyridin-4-ylacrylonitrile, which was used in the next step without further purification.

Intermediate 32. 4-Amino-6-pyridin-4-ylpyrimidin-2-thiol

Obtained from Intermediate 31 by the procedure described in Intermediate 20. Purification by trituration with ethyl ether gave 4-amino-6-pyridin-4-ylpyrimidin-2-thiol (7.43 g, global yield: 76%) as a solid, which was used in the next step without further characterisation.

Intermediate 33. 2-Methylsulfanyl-6-pyridin-4-ylpyrimidin-4-amine

Obtained from Intermediate 32 (7.00 g) by the procedure described in Intermediate 21. Purification by trituration with ethyl ether gave the title compound (6.12 g, 82%) as a solid, which was used in the next step without further characterisation.

Intermediate 34. 2-Methanesulfonyl-6-pyridin-ylpyrimidin-4-amine

Obtained from Intermediate 33 (2.00 g) by the procedure described in Intermediate 22. Purification by trituration with ethyl ether gave 2-methanesulfonyl-6-pyridin-4-ylpyrimidin-4-amine (2.29 g, 99%) as a solid, which was used in the next step without further characterisation.

EXAMPLE 95
2-(1H-Pyrazol-1-yl)-6-pyridin-4-ylpyrimidin-4-amine

Obtained from Intermediate 34 (2.00 g) by the procedure described in Example 76. Purification by column chromatography with silica gel and methylene chloride/methanol (3%) as eluent gave 2-(1H-pyrazol-1-yl)-6-pyridin-4-ylpyrimidin-4-amine (0.32 g, 17%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.56-6.54 (m, 1H); 6.95 (s, 1H); 7.53 (bs, 2H); 7.79-7.78 (m, 1H); 8.02-8.00 (m, 2H); 8.70-8.68 (m, 1H); 8.76-8.74 (m, 2H).

EXAMPLE 96
N-[2-(1H-Pyrazol-1-yl)-6-pyridin-4-ylpyrimidin-4-amine

Obtained from the title compound of Example 95 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave N-[2-(1H-pyrazol-1-yl)-6-pyridin-4-ylpyrimidin-4-amine (64 mg, 22%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 1.10 (t, J=7.7 Hz, 3H); 2.53 (q, J=7.7 Hz, 2H); 6.65-6.63 (m, 1H); 7.89-7.88 (m, 1H); 8.12-8.10 (m, 2H); 8.59 (s, 1H); 8.83-8.80 (m, 3H); 11.4 (bs, 1H).

Intermediate 35. 3-(2-Furyl)-3-oxopropionic acid ethyl ester

To a solution of 60% sodium hydride (95.4 mmol) in diethyl carbonate (90 ml) was slowly added 2-acetylfurane (5.50 g, 45.4 mmol). The resulting solution was stirred at room temperature for 1 hour and at 90° C. for 2 hours. The reaction mixture was poured into ice/water and acetic acid (5 mL) was added. The mixture was extracted with ethyl acetate (2×75 mL). The organic layer was washed with water (2×50 mL), brine (50 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by flash chromatography with silica gel and ethyl acetate/n-hexane (4:1) as eluent gave the title compound (5.90 g, 71%) as a red oil.

δ (200 MHz, CDCl₃): 1.26 (t, J=7.2 Hz, 3H); 3.86 (s, 2H); 4.21 (q, J=7.2 Hz, 2H); 6.58 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.28 (d, J=3.4 Hz, 1H); 7.62 (d, J=1.7 Hz, 1H).

Intermediate 36. 6-(2-Furyl)-2-pyridin-2-ylpyrimidin-4-ol

To a solution of potassium tertbutoxide (0.87 g, 7.79 mmol) in butanol (3 ml) were added Intermediate 35 (1.00 g, 5.49 mmol) and pyridine-2-carboxamidine (HCl) (1.08 g, 6.86 mmol). The mixture was heated at 135° C. for 5 hours. The resulting solid was filtered and washed with n-pentane. Purification by flash chromatography with silica gel and methylene chloride/methanol (from 1% to 3%) as eluent gave 642-furyl)-2-pyridin-2-ylpyrimidin-4-ol (0.33 g, 25%) as an off-white solid.

δ (200 MHz, CDCl₃): 6.58 (s, 1H); 6.75 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.39 (d, J=3.4 Hz, 1H); 7.66-7.72 (m, 1H); 7.97 (s, 1H); 8.06-8.14 (m, 1H); 8.49 (d, J=7.7 Hz, 1H); 8.77 (d, J=4.7 Hz, 1H).

Intermediate 37. 4-Chloro-6-(2-furyl)-2-pyridin-2-ylpyrimidine

Obtained from Intermediate 36 (0.33 g) by the procedure described in Intermediate 10. 4-Chloro-6-(2-furyl)-2-(pyridin-2-yl)pyrimidine (0.36 g, 78%) was obtained as a brown solid.

MS (M⁺): 257.

EXAMPLE 97
6-(2-Furyl)-2-pyridin-2-ylpyrimidin-4-amine

Obtained from Intermediate 37 (0.28 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave 6-(2-furyl)-2-pyridin-2-ylpyrimidin-4-amine (0.16 mg, 62%) as an off-white solid.

δ (300 MHz, CDCl₃): 5.55 (bs, 2H); 6.51 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 6.78 (s, 1H); 7.26 (d, J=3.4 Hz, 1H); 7.34 (dd, J1=8.1 Hz, J2=5.3 Hz, 1H); 7.52-7.51 (m, 1H); 7.80 (dt, J1=7.6 Hz, J2=1.7 Hz, 1H); 8.50 (d, J=8.1 Hz, 1H); 8.77-8.74 (m, 1H).

EXAMPLE 98
N-[6-(2-Furyl)-2-pyridin-2-ylpyrimidin yl]propanamide

Obtained from the title compound of Example 97 (0.10 g) by the procedure described in Example 49. Purification by trituration with n-pentane gave N-[6-(2-furyl)-2-pyridin-2-ylpyrimidin-4-yl]propanamide (63 mg, 51%) as an off-white solid.

δ (300 MHz, CDCl₃): 1.24 (t, J=7-5 Hz, 3H); 2.45 (q, J=7.5 Hz, 2H); 6.56 (dd, J1=3.4, J2=1.8 Hz, 1H); 7.36 (d, J=3.4 Hz, 1H); 7.43-7.39 (m, 1H); 7.60-7.59 (m, 1H); 7.88 (dt, J1=7.6 Hz, J2=1.8 Hz, 1H); 8.48 (s, 2H); 8.60 (d, J=8.1 Hz, 1H); 8.82-8.81 (m, 1H).

Intermediate 38. 3-Methylpyridine-2-carboxamidine (HCl)

Obtained from 3-methylpyridine-2-carbonitrile (5.15 g) by the procedure described in Intermediate 1. Purification by trituration with ethyl ether gave the title compound (3.13 g, 42%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 2.41 (s, 3H), 7.56-7.67 (m, 5H); 8.40 (s, 1H); 8.56 (d, J=3.8 Hz, 1H).

Intermediate 39. 6-Amino-2-(3-methylpyridin-2-yl)pyrimidin-4-ol

Obtained from Intermediate 38 (2.91 g) by the procedure described in Intermediate 11. Purification by column chromatography with silica gel and methylene chloride/methanol (from 2% to 5%) as eluent gave 6-amino-2-(3-methylpyridin-2-yl)pyrimidin-4-ol (0.58 g, 17%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 2.52 (s, 3H); 5.05 (s, 1H); 6.57 (s, 2H); 7.47 (dd, J1=7.6 Hz, J2=4.7 Hz, 1H); 7.80 (d, J=7.6 Hz, 1H); 8.50 (d, J=4.7 Hz, 1H); 11.26 (bs, 1H).

Intermediate 40. N-[6-Chloro-2-(3-methylpyridin-2-yl)pyrimidin-4-yl]propanamide

Obtained from Intermediate 39 (0.60 g) by the procedure described in Intermediate 12. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave N-[6-chloro-2-(3-methylpyridin-2-yl)pyrimidin-4-yl]propanamide (0.14 g, 17%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.10 (t, J=7.4 Hz, 3H); 2.40-2.50 (m, 5H); 7.60 (dd, J1=7.6 Hz, J2=4.7 Hz, 1H); 8.00 (d, J=7.6 Hz, 1H); 8.20 (s, 1H); 8.60 (d, J=4.7 Hz, 1H); 11.40 (bs, 1H).

EXAMPLES 99 AND 100
2-(3-Methylpyridin-2-yl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine and N-[2-(3-methylpyridin-2-yl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from Intermediate 40 (0.14 g) by the procedure described in Example 21 (reaction temperature: 110° C.). Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent 2-(3-methylpyridin-2-yl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (12 mg, 8%) and N-[2-(3-methylpyridin-2-yl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (5 mg, 4%) as off-white solids.

EXAMPLE 99

δ (300 MHz, DMSO-d₆): 2.33 (s, 3H); 6.54 (dd, J1=2.7 Hz, J2=1.7 Hz, 1H); 6.91 (s, 1H); 7.31 (bs, 2H); 7.37 (dd, J1=7.8 Hz, J2=4.7 Hz, 1H); 7.74-7.71 (m, 1H); 7.85 (dd, J1=1.7 Hz, J2=0.6 Hz, 1H); 8.38 (bs, 1H) 8.44 (dd, J1=4.7 Hz, J2=1.1 Hz, 1H); 8.50 (dd, J1=2.75 Hz, J2=0.6 Hz, 1H).

EXAMPLE 100

δ (300 MHz, DMSO-d₆): 1.08 (t, J=7.6 Hz, 3H); 2.40 (s, 1H); 2.46 (q, J=7.6 Hz, 2H); 6.63 (dd, J1=2.8 Hz, J2=1.7 Hz, 1H); 7.81-7.78 (m, 1H); 7.96-7.94 (m, 1H); 8.51-8.49 (m, 1H); 8.62 (s, 1H); 8.64 (dd, J1=2.8 Hz, J2=0.6 Hz, 1H); 11.24 (bs, 1H).

Intermediate 41. Pyridine-3-carboxamidine (HCl)

Obtained from pyridin-3-carbonitrile (10.0 g) by the procedure described in Intermediate 1. Purification by trituration with ethyl ether gave the title compound (11.64 g, 99%) as an off-white solid.

δ (200 MHz, DMSO-d₆): 7.66-7.70 (m, 1H); 8.23 (d, J=6.4 Hz, 1H); 8.80-8.90 (m, 5H); 9.00 (s, 1H).

Intermediate 42. 2-(Pyridin-3-yl)pyrimidin-4,6-diol

Obtained from Intermediate 41 (11.64 g) by the procedure described in Intermediate 2. Purification by trituration with ethyl ether gave the title compound (13.68 g, 75%) as an off-white solid.

MS (M⁺): 189.

Intermediate 43. 4,6-Dichloro-2-(pyridin-3-yl)pyrimidine

Obtained from Intermediate 42 (12.80 g) by the procedure described in Intermediate 3 (reaction time: 40 hours). Purification by trituration with ethyl ether gave 4,6-dichloro-2-(pyridin-3-yl)pyrimidine (6.50 g, 42%) as a solid, which was used in the next step without further characterisation.

Intermediate 44. 6-Chloro-2-(pyridin-3-yl)pyrimidin-amine

Obtained from Intermediate 43 (2.00 g) by the procedure described in Intermediate 48 (reaction time: 21 hours). Purification by trituration with ethyl ether gave 6-chloro-2-(pyridin-3-yl)pyrimidin-4-amine (2.14 g, 78%) as a solid, which was used in the next step without further characterisation.

EXAMPLE 101
6-(1H-Pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-amine

Obtained from Intermediate 44 (1.80 g) by the procedure described in Example 21. Purification by trituration with ethyl ether gave 6-(1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-amine (1.40 g, 67%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.61-6.59 (m, 1H); 6.89 (s, 1H); 7.35 (bs, 2H); 7.57-7.51 (m, 1H); 7.87-7.86 (m, 1H); 8.71-8.66 (m, 2H); 8.86-8.83 (m, 1H); 9.55-9.53 (m, 1H).

EXAMPLE 102
N-[6-(1H-Pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-yl]acetamide

Obtained from the title compound of Example 101 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (4%) as eluent gave N-[6-(1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]acetamide (80 mg, 23%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.33 (s, 3H); 6.53-6.51 (m, 1H); 7.46-7.40 (m, 1H); 7.83-7.82 (m, 1H); 8.56 (bs, 1H); 8.70-8.64 (m, 3H); 8.75-8.72 (m, 1H); 9.65-9.64 (m, 1H).

EXAMPLE 103
N-[6-(1H-Pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]propanamide

δ (250 MHz, CDCl₃): 1.30 (t, J=7.6, 3H); 2.56 (q, J=7.6 Hz, 2H); 6.53-6.51 (m, 1H); 7.46-7.40 (m, 1H); 7.82-7.81 (m, 1H); 8.36 (bs, 1H); 8.75-8.64 (m, 4H); 9.64-9.63 (m, 1H).

EXAMPLE 104
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-amine

Obtained from Intermediate 44 (1.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-amine (1.25 g, 63%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.20 (s, 3H); 2.76 (s, 3H); 6.15 (s, 1H); 6.86 (s, 1H); 7.18 (bs, 2H); 7.56-7.51 (m, 1H); 8.53-8.52 (m, 1H); 8.69-8.66 (m, 1H); 9.42-9.41 (m, 1H).

EXAMPLE 105
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]-acetamide

Obtained from the title compound of Example 104 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (4%) as eluent, followed by a second column chromatography with silica gel and ethyl acetate/n-hexane/methanol (85:13:2) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]acetamide (92 mg, 26%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.30 (s, 3H); 2.31 (s, 3H); 2.81 (s, 3H); 6.04 (s, 1H); 7.41 (dd, J1=7.9 Hz, J2=4.8 Hz, 1H); 8.46 (bs, 1H); 8.60-8.55 (m, 2H); 8.71 (dd, J1=4.8 Hz, J2=1.5 Hz, 1H); 9.58-9.56 (m, 1H).

EXAMPLE 106
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]-propanamide

Obtained from the title compound of Example 104 (0.30 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from 4% to 10%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]propanamide (0.13 g, 34%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.29 (t, J=7.6 Hz, 3H); 2.30 (s, 3H); 2.53 (q, J=7.6 Hz, 2H); 2.83 (s, 3H); 6.05 (s, 1H); 7.42 (ddd, J1=8.1 Hz, J2=4.8 Hz, 1H); 8.08 (bs, 1H); 8.60 (dt, J1=8.1 Hz, J2=2.0 Hz, 1H); 8.65 (s, 1H); 8.72 (dd, J1=4.8 Hz, J2=1.5 Hz, 1H); 9.59-9.57 (m, 1H).

EXAMPLE 107
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]-3,3,3-trifluoropropanamide

Obtained from the title compound of Example 104 (0.30 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (from 4% to 10%) as eluent gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-3-ylpyrimidin-4-yl]-3,3,3-trifluoropropanamide (0.11 g, 28%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.24 (s, 3H); 2.81 (s, 3H); 3.77 (q, J=10.9 Hz, 2H); 6.25 (s, 1H); 7.61 (dd, J1=7.9 Hz, J2=4.7 Hz, 1H); 8.47 (s, 1H); 8.60 (dd, J1=7.9 Hz, J2=1.4 Hz, 1H); 8.75 (dd, J1=4.7 Hz, J2=1.4 Hz, 1H); 9.46 (s, 1H); 11.41 (s, 1H).

EXAMPLE 108
2-Pyridin-3-yl-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 44 (1.50 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/methanol (4%) as eluent gave 2-pyridin-3-yl-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (0.26 g, 15%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.83 (s, 1H); 7.57-7.52 (m, 3H); 8.34 (s, 1H); 8.74-8.69 (m, 2H); 9.58-9.57 (m, 1H); 9.67 (s, 1H).

EXAMPLE 109
3,3,3-Trifluoro-N-[2-pyridin-3-yl-6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 108 (0.15 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (from 4% to 10%) as eluent gave 3,3,3-trifluoro-N-[2-pyridin-3-yl-6-(1H-1,2,4-triazol-1-yl)pyrimidinyl]propanamide (73 mg, 33%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 3.83 (q, J=10.9 Hz, 2H); 7.95-7.90 (m, 1H); 8.45 (s, 1H); 8.46 (s, 1H); 8.97-8.93 (m, 1H); 9.10 (d, J=8.2 Hz, 1H); 9.74 (bs, 1H); 9.95 (s, 1H); 11.81 (s, 1H).

Intermediate 45. 6-(2-Furyl)-2-pyridin-3-ylpyrimidin-4-ol

Obtained from Intermediate 35 (1.00 g) and Intermediate 41 (1.08 g) by the procedure described in Intermediate 36. Purification by trituration with n-pentane gave the title compound (0.27 g, 20%) as a brown solid.

δ (200 MHz, DMSO-d₆): 6.26 (s, 1H); 6.64 (d, J=1.7 Hz, 1H); 7.12 (d, J=3.4 Hz, 1H); 7.44-7.50 (m, 1H); 7.81 (s, 1H); 8.54 (s, 1H); 8.62 (d, J=4.7 Hz, 1H); 9.41 (s, 1H).

Intermediate 46. 4-Chloro-6-(2-furyl)-2-pyridin-3-ylpyrimidine

Obtained from Intermediate 45 (0.69 g) by the procedure described in Intermediate 10. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 15% methanol) gave the title compound (0.32 g, 43%) as a brown solid, which was used in the next step without further characterisation.

EXAMPLE 110
6-(2-Furyl)-2-pyridin-3-ylpyrimidin-4-ylamine

Obtained from Intermediate 46 (0.32 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride gave 6-(2-furyl)-2-pyridin-3-ylpyrimidin-4-ylamine (80 mg, 27%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 6.69 (dd, J1=3.6 Hz, J2=1.9 Hz, 1H); 6.70 (s, 1H); 7.15 (bs, 2H); 7.28 (dd, J1=3.3 Hz, J2=0.8 Hz, 1H); 7.51 (dd, J1=8.0 Hz, J2=4.7 Hz, 1H); 7.89 (dd, J1=1.9 Hz, J2=0.8 Hz, 1H); 8.61 (dt, J1=8.0 Hz, J2=1.9 Hz, 1H); 8.66 (bs, 1H); 9.47 (bs, 1H).

EXAMPLE 111
N-[6-(2-Furyl)-2-pyridin-3-ylpyrimidin-4-yl]propanamide

Obtained from the title compound of Example 110 (55 mg) by the procedure described in Example 49. Purification by trituration with n-pentane gave N-[6-(2-furyl)-2-pyridin-3-ylpyrimidin-4-yl]propanamide (28 mg, 41%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.11 (t, J=7.6 Hz, 3H); 2.53 (q, J=7.6 Hz, 2H); 6.79-6.77 (m, 1H); 7.51 (d, J=3.6 Hz, 1H); 7.59 (dd, J1=8.5 Hz, J2=4.4 Hz, 1H); 8.03-8.02 (m, 1H); 8.37 (s, 1H); 8.75-8.68 (m, 2H); 9.57 (d, J=1.8 Hz, 1H); 11.01 (s, 1H).

Intermediate 47. 6-Amino-2-pyridin-ylpyrimidin-4-ol

Obtained from pyridine-4-carboxamidine, hydrochloride (2.13 g) by the procedure described in Intermediate 9. Purification by trituration with ethyl ether gave the title compound (1.22 g, 48%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 5.27 (s, 1H); 6.70 (s, 2H); 8.00 (d, J=6.1 Hz, 2H); 8.71 (d, J=6.1 Hz, 2H); 11.74 (bs, 1H).

Intermediate 48. N-[6-Chloro-2-pyridin-4-ylpyrimidin-4-yl]propanamide

Obtained from Intermediate 47 (1.22 g) by the procedure described in Intermediate 12. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 2:1 to 4:1) as eluent gave impure N-[6-chloro-2-pyridin-4-ylpyrimidin-4-yl]propanamide (0.90 g). Purification (0.49 g) by column chromatography with silica gel and chloroform/methanol (3%) as eluent gave the title compound (0.35 g, 38%) as an off-white solid.

δ (200 MHz, ClCD₃): 1.29 (t, J=7.5 Hz, 3H); 2.57 (q, J=7.5 Hz, 2H); 8.20 (d, J=6.1 Hz, 2H); 8.26 (s, 1H); 8.40 (bs, 1H); 8.80 (d, J=6.1 Hz, 2H).

EXAMPLES 112 AND 113
N-[6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-pyridin-4-ylpyrimidin-4-yl]propanamide and 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-4-ylpyrimidin-4-amine

Obtained from Intermediate 48 (0.17 g) by the procedure described in Example 21 (reaction temperature: 85° C., reaction time: 20 hours). Purification by preparative HPLC-MS gave N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-4-ylpyrimidin-4-yl]propanamide (19 mg, 9%) and 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-pyridin-4-ylpyrimidin-4-amine (5 mg, 3%) as off-white solids.

EXAMPLE 112

δ (300 MHz, CDCl₃): 1.30 (t, J=7.4 Hz, 3H); 2.30 (s, 3H); 2.53 (q, J=7.4 Hz, 2H); 2.85 (s, 3H); 6.05 (s, 1H); 8.12 (bs, 1H); 8.17 (d, J=6.1 Hz, 2H); 8.70 (s, 1H); 8.77 (d, J=6.1 Hz, 2H).

EXAMPLE 113

δ (300 MHz, CDCl₃): 2.33 (s, 3H); 2.84 (s, 3H); 5.02 (bs, 2H); 6.06 (s, 1H); 7.00 (s, 1H); 8.21-8.19 (m, 2H); 8.76 (bs, 2H).

Intermediate 49. 6-(2-Furyl)-2-pyridin-4-ylpyrimidin-4-ol

Obtained from Intermediate 35 (1.00 g) and pyridine-4-carboxamidine, hydrochloride by the procedure described in Intermediate 36. Purification by trituration with n-pentane gave the title compound (0.38 g, 29%) as a brown solid.

δ (200 MHz, DMSO-d₆): 6.74 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.37 (d, J=3.4 Hz, 1H); 7.96 (d, J=1.7 Hz, 1H); 8.16 (d, J=6.4 Hz, 2H); 8.79 (d, J=6.4 Hz, 2H).

Intermediate 50. 4-Chloro-6-(2-furyl)-2-pyridin-4-ylpyrimidine

Obtained from Intermediate 49 (0.63 g) by the procedure described in Intermediate 15 (reaction time: 2 hours). 4-Chloro-6-(2-furyl)-2-pyridin-4-ylpyrimidine (0.51 g, 76%) was obtained as a brown solid.

δ (200 MHz, CDCl₃): 6.66-6.68 (m, 1H); 7.49 (d, J=3.4 Hz, 1H); 7.65 (d, J=1.7 Hz, 1H); 7.68 (s, 1H); 8.44 (d, J=4.9 Hz, 2H); 8.83 (d, J=4.9 Hz, 2H).

EXAMPLE 114
6-(2-Furyl)-2-pyridin-4-ylpyrimidin-4-ylamine

Obtained from Intermediate 50 (0.51 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 2% methanol) as eluent gave 6-(2-furyl)-2-pyridin-4-ylpyrimidin-4-amine (0.24 g, 51%) as an off-white solid.

δ (300 MHz, CDCl₃): 4.99 (bs, 2H); 6.57-6.55 (m, 1H); 6.75 (s, 1H); 7.28 (d, J=3.6 Hz, 1H); 7.55-7.54 (m, 1H); 8.25 (d, J=6.1 Hz, 2H); 8.72 (d, J=6.1 Hz, 2H).

EXAMPLE 115
N-[6-(2-Furyl)-2-pyridin-ylpyrimidin-4-yl]propanamide

Obtained from the title compound of Example 114 (0.14 g) by the procedure described in Example 49. Purification by trituration with ethyl ether gave N-[6-(2-furyl)-2-pyridin-4-ylpyrimidin-4-yl]propanamide (0.13 g, 75%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.10 (t, J=7.6 Hz, 3H); 2.53 (q, J=7.6 Hz, 2H); 6.78 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 7.51 (d, J=3.4 Hz, 1H); 8.03 (d, J=2.4 Hz, 1H); 8.29 (d, J=6.1 Hz, 2H); 8.41 (s, 1H); 8.80 (d, J=6.1 Hz, 2H); 11.07 (s, 1H).

Intermediate 51. 6-(2-Furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-ol

Obtained from thiazole-2-carboxamidine, hydrochloride (prepared by the procedure described in Intermediate 1) and Intermediate 35 (1.00 g) by the procedure described in Intermediate 36. Purification by column chromatography with silica gel and chloroform/methanol (5%) as eluent gave the title compound (0.40 g, 29%) as an off-white solid.

δ (300 MHz, CDCl₃): 6.60 (s, 1H); 6.74-6.72 (m, 1H); 7.27-7.24 (m, 1H); 7.97 (s, 1H); 8.15-8.12 (m, 2H).

Intermediate 52. 4-Chloro-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidine

Obtained from Intermediate 51 (0.39 g) by the procedure described in Intermediate 10. Purification by column chromatography with silica gel and methylene chloride as eluent gave 4-chloro-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidine (0.20 g, 48%) as a pale yellow solid.

δ (300 MHz, CDCl₃): 6.64-6.62 (m, 1H); 7.53-7.51 (m, 1H); 7.59-7.57 (m, 1H); 7.64 (s, 1H); 7.67 (s, 1H); 8.09 (s, 1H).

EXAMPLE 116
6-(2-Furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 52 (0.20 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride/ethyl ether (7:3) as eluent gave 6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (95 mg, 51%) as an off-white solid.

δ (300 MHz, CDCl₃): 5.22 (bs, 2H); 6.56 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 6.76 (s, 1H); 7.32 (dd, J1=3.6 Hz, J2=0.8 Hz, 1H); 7.48 (d, J=3.0 Hz, 1H); 7.55 (dd, J1=1.8 Hz, J2=0.8 Hz, 1H); 7.99 (d, J=3.0 Hz, 1H).

EXAMPLE 117
N-[6-(2-Furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 116 (95 mg) by the procedure described in Example 49. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 1:1 to pure ethyl acetate) as eluent gave N-[6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide (68 mg, 58%) as an off-white solid.

δ (300 MHz, CDCl₃): 1.27 (t, J=7.4 Hz, 3H); 2.48 (q, J=7.4 Hz, 2H); 6.59 (dd, J1=3.6 Hz, J2=1.7 Hz, 1H); 7.40 (dd, J1=3.6 Hz, J2=0.8 Hz, 1H); 7.53 (d, J=3.3 Hz, 1H); 7.63 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H); 8.02 (d, J=3.3 Hz, 1H); 8.24 (bs, 1H); 8.47 (s, 1H).

EXAMPLE 118
2-(4-Fluorophenyl)-N-[6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]acetamide

A solution of the title compound of Example 116 (98 mg, 0.4 mmol) and 4-fluorophenylacetyl chloride (164 μL, 1.20 mmol) in pyridine (6 mL) was heated at 120° C. overnight. The solvent was removed under reduced pressure. Methylene chloride was added (20 mL) and the solution was washed with water (2×10 mL), brine (10 mL), and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (from pure to 50% of n-hexane), gave 2-(4-fluorophenyl)-N-[6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidinyl]acetamide (62 mg, 59%) as an off-white solid.

δ (300 MHz, CDCl₃): 3.74 (s, 2H); 6.58 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 7.07 (t, J=8.6 Hz, 2H); 7.32-7.27 (m, 2H); 7.38 (dd, J1=3.4 Hz, J2=0.8 Hz, 1H); 7.52 (d, J=3.0 Hz, 1H); 7.61 (d, J=2.8 Hz, 1H); 8.00 (d, J=3.0 Hz, 1H); 8.22 (bs, 1H); 8.46 (s, 1H).

EXAMPLE 119
N-(Cyclopropylmethyl)-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

A solution of Intermediate 5 (0.50 g, 2.03 mmol) and cyclopropylmethylamine (0.43 g, 6.08 mmol) in pentanol (12.5 mL) was heated at 100° C. overnight. The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with chloroform, gave N-(cyclopropylmethyl)-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (0.55 g, 70%) as a solid.

m.p.: 100.9-101.7° C.

δ (300 MHz, CDCl₃): 0.27-0.32 (m, 2H); 0.57-0.63 (m, 2H); 1.06-1.18 (m, 1H); 3.24 (bs, 2H); 5.48 (bs, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.6 Hz, 1H); 6.56 (dd, J1=3.3 Hz, J2=1.6 Hz, 1H); 6.78 (s, 1H); 7.29 (dd, J1=3.3 Hz, J2=0.8 Hz, 1H); 7.61 (dd, J1=1.9 Hz, J2=0.8 Hz, 1H); 7.76 (d, J=0.8 Hz, 1H); 8.66 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

EXAMPLE 120
(2R)-2-{[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]amino}propan-1-ol

Obtained from Intermediate 5 (100 mg) and (R)-2-aminopropanol (189 μL, 2.43 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 95:5) as eluent gave (2R)-2-{[2-(2-furyl)-6)-(1H-pyrazol-1-yl)pyrimidin-4-yl]amino}propan-1-ol (88 mg, 76%) as an off-white solid.

m.p.: 163.0-163.8° C.

δ (300 MHz, CDCl₃): 1.32 (d, J=6.7 Hz, 3H); 3.65-3.83 (m, 3H); 4.11 (bs, 1H); 5.27 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.84 (s, 1H); 7.29 (dd, J1=3.3 Hz, J2=0.8 Hz, 1H); 7.61 (dd, J1=1.6 Hz, J2=0.8 Hz, 1H); 7.75 (dd, J1=1.6 Hz, J2=0.7 Hz, 1H); 8.64 (dd, J1=2.5 Hz, J2=0.7 Hz, 1H).

EXAMPLE 121
3-{[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]amino}propan-1-ol

Obtained from Intermediate 5 (100 mg) and 3-amino-1-propanol (93 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 95:5) as eluent gave 3-{[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]amino}propan-1-ol (104 mg, 90%) as an off-white solid.

δ (300 MHz, CDCl₃): 1.80-1.86 (m, 2H); 3.70 (bs, 4H); 5.31 (bs, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.6 Hz, 1H); 6.55 (dd, J1=3.5 Hz, J2=1.6 Hz, 1H); 6.82 (s, 1H); 7.29 (dd, J1=3.5 Hz, J2=0.8 Hz, 1H); 7.61 (dd, J1=1.6 Hz, J2=0.8 Hz, 1H); 7.75 (dd, J1=1.6 Hz, J2=0.8 Hz, 1H) 8.64 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

EXAMPLE 122
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]ethane-1,2-diamine

The precursor intermediate tert-butyl 2-{[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]amino}ethylcarbamate was obtained from Intermediate 5 (145 mg) and N—BOC-ethylenediamine (279 μL, 1.76 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 95:5) as eluent gave 351 mg, (80%) of the intermediate.

To a solution of the intermediate tert-butyl 2-{[2-(2-furyl)-6-(pyrazol-1-yl)pyrimidin-4-yl]amino}ethylcarbamate (0.28 g, 0.76 mmol) in chloroform (1.7 mL) was added trifluoroacetic acid (0.58 mL, 7.56 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was remove under reduced pressure. To the residue was added water (25 mL), potassium carbonate until basic pH, and methylene chloride (2×20 mL). The organic layer was dried (Na₂SO₄) and the solvent removed under reduced pressure. Purification of the obtained residue by trituration with ethyl ether/isopropyl ether (1:1) gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]ethane-1,2-diamine (77 mg, 38%) as an off white solid.

m.p.: 104.1-105.1° C.

δ (300 MHz, CDCl₃): 2.99-3.03 (t, J=5.9 Hz, 2H); 3.46-3.50 (m, 2H); 5.69 (bs, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.6 Hz, 1H); 6.55 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 6.83 (s, 1H); 7.29 (d, J=3.3 Hz, 1H) 7.60-7.61 (m, 1H); 7.75-7.76 (m, 1H); 8.65 (d, J=2.6 Hz, 1H).

EXAMPLE 123
2-(2-Furyl)-N-[2-(4-methoxyphenyl)ethyl]-6-(1H-pyrazol-1-yl)-pyrimidin-amine

Obtained from Intermediate 5 (100 mg) and (4-methoxyphenyl)ethylamine (177 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 10:1 to 2:1) as eluent gave 2-(2-furyl)-N-[2-(4-methoxyphenyl)ethyl]-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (111 mg, 76%) as an oil.

δ (300 MHz, CDCl₃): 2.92 (t, J=7.0 Hz, 2H); 3.65 (bs, 2H); 3.80 (s, 3H); 5.28 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.80 (s, 1H); 6.85-6.88 (m, 2H); 7.15-7.18 (m, 2H); 7.29 (dd, J=3.3 Hz, J2=0.7 Hz, 1H); 7.59-7.60 (m, 1H); 7.76 (d, J=1.1 Hz, 1H); 8.65 (dd, J1=2.6 Hz, J2=0.7 Hz, 1H).

EXAMPLE 124
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and (3,4-dimethoxyphenyl)ethylamine (177 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 99:1) as eluent gave N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (77 mg, 49%) as an oil.

δ (300 MHz, CDCl₃): 2.92 (t, J=7.0 Hz, 2H); 3.67 (bs, 2H); 3.87 (s, 3H); 3.88 (s, 3H); 5.30 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.75-6.76 (m, 1H); 6.80-6.82 (m, 3H); 7.29 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.60 (dd, J1=1.7 Hz, J2=0.9 Hz, 1H); 7.75-7.77 (m, 1H); 8.65 (dd, J=2.6 Hz, J2=0.7 Hz, 1H).

EXAMPLE 125
2-(2-Furyl)-6-(1H-pyrazol-1-yl)-N-[2-(pyridin-2-yl)ethyl]pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and 2-(2-aminoethyl)pyridine (145 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 8:2) as eluent gave 2-(2-furyl)-6-(1H-pyrazol-1-yl)-N-[2-(pyridin-2-yl)ethyl]pyrimidin-4-amine (86 mg, 64%) as an off-white solid.

m.p.: 110.2-110.9° C.

δ (300 MHz, CDCl₃): 3.14 (t, J=6.5 Hz, 2H); 3.88 (bs, 2H); 5.95 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.84 (s, 1H); 7.14-7.20 (m, 2H); 7.29 (dd, J1=3.3 Hz, J2=0.8 Hz, 1H); 7.59-7.65 (m, 2H); 7.75-7.76 (m, 1H); 8.56-8.59 (m, 1H); 8.65 (dd, J1=2.5 Hz, J2=0.8 Hz, 1H).

EXAMPLE 126
2-(2-Furyl)-6-(1H-pyrazol-1-yl)-N-[2-(pyridin-3-yl)ethyl]pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and 3<2-aminoethyl)pyridine (149 mg, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and chloroform/methanol (from pure chloroform to 1% methanol) as eluent gave 2-(2-furyl)-6-(1H-pyrazol-1-yl)/[2-(pyridin-3-yl)ethyl]pyrimidin-4-amine (94 mg, 70%) as an off-white solid.

m.p.: 164.0-164.9° C.

δ (300 MHz, CDCl₃): 3.00 (t, J=6.9 Hz, 2H); 3.71-3.75 (m, 2H); 5.30 (s, 1H); 6.48 (s, 1H); 6.55-6.56 (m, 1H); 6.82 (s, 1H); 7.24-7.30 (m, 3H); 7.57-7.60 (m, 2H); 7.76 (s, 1H); 8.50-8.53 (m, 2H); 8.65-8.66 (m, 1H).

EXAMPLE 127
2-(2-Furyl)-N-(3-phenylpropyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and 3-phenylpropylamine (173 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 10:1 to 2:1) as eluent gave 2-(2-furyl)-N-(3-phenylpropyl)-6-(1H-pyrazol-1-yl)pyrimidin-amine (124 mg, 89%) as an off-white solid.

δ (300 MHz, CDCl₃): 2.01 (q, J=7.5 Hz, 2H); 2.76 (t, J=7.5 Hz, 2H); 3.41 (bs, 2H); 5.34 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.56 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.77 (s, 1H); 7.19-7.31 (m, 6H); 7.61 (s, 1H); 7.76 (s, 1H); 8.65-8.66 (m, 1H)

EXAMPLE 128
2-(2-Furyl)-N-[3-(1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and 3-(imidazol-1-yl)propylamine (145 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (from pure methylene chloride to 97:3) as eluent gave 2-(2-furyl)-N-[3-1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)pyrimidin-4-amine (122 mg, 90%) as an off-white solid.

δ (300 MHz, CDCl₃): 2.18 (q, J=6.7 Hz, 2H); 3.43-3.50 (m, 2H); 4.11 (t, J=6.7 Hz, 2H); 5.26 (bs, 1H); 6.49 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.58 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 6.79 (s, 1H); 6.97-6.98 (m, 1H); 7.10-7.11 (m, 1H); 7.30 (dd, J1=3.3 Hz, J2=0.8 Hz, 1H); 7.54 (bs, 1H); 7.63 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H) 7.76-7.77 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H); 8.66 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

Intermediate 53. 2-(2-Thienyl)pyrimidine-4,6-diol

Obtained from Intermediate 13 (1.35 g) by the procedure described in Intermediate 2. Purification by trituration with diisopropyl ether gave 2-(2-thienyl)pyrimidine-4,6-diol (0.44 g, 34%) as a pale yellow solid.

δ (300 MHz, DMSO-d₆): 5.15 (s, 1H); 7.07-7.19 (m; 1H); 7.72-7.78 (m, 1H); 8.00-8.02 (m, 1H).

Intermediate 54. 4,6-Dichloro-2-(2-thienyl)pyrimidine

Obtained from Intermediate 53 (0.44 g) by the procedure described in Intermediate 3. Purification by trituration with diisopropyl ether gave 4,6-dichloro-2-(2-thienyl)pyrimidine (0.41 g, 78%) as a brown solid.

δ (300 MHz, CDCl₃): 7.12-7.20 (m, 2H); 7.54-7.60 (m, 1H); 8.05-8.08 (m, 1H).

Intermediate 55. 4-Chloro-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidine

Obtained from Intermediate 54 (0.69 g) by the procedure described in Intermediate 5. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 3:1) as eluent gave 4-chloro-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidine (0.49 g, 68%) as an off-white solid.

δ (300 MHz, CDCl₃): 6.56 (s, 1H); 7.16-7.20 (m, 1H); 7.54-7.58 (m, 1H); 7.75 (s, 1H); 7.84 (s, 1H); 8.08-8.11 (m, 1H); 8.68 (s 1H).

EXAMPLE 129
N-(Cyclopropylmethyl)-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and cyclopropylmethylamine (99 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 95:5 to 90:10) as eluent gave N-cyclopropylmethyl)-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine (98 mg, 87%) as an off-white solid.

m.p.: 134.6-135.3° C.

δ (300 MHz, CDCl₃): 0.31 (m, 2H); 0.60 (m, 2H); 1.08-1.18 (m, 1H); 3.27 (bs, 2H); 5.32 (bs, 1H); 6.47 (dd, J1=2.5 Hz, J2=1.7 Hz, 1H); 6.76 (s, 1H); 7.13 (dd, J1=4.9 Hz, J2=3.6 Hz, 1H); 7.44 (dd, J1=4.9 Hz, J2=1.2 Hz, 1H); 7.75 (bs, 1H); 7.97 (d, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.67 (d, J=2.2 Hz, 1H).

EXAMPLE 130
(2R)-2-{[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amino}-propan-1-ol

Obtained from Intermediate 55 (100 mg) and (R)-2-aminopropanol (177 μL, 2.28 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 3:2) as eluent gave (2R)-2-{[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amino}propan-1-ol (87 mg, 76%) as an off-white solid.

m.p.: 135.7-136.9° C.

δ (300 MHz, CDCl₃): 1.33 (d, J=6.9 Hz, 3H); 3.66-3.72 (m, 1H); 3.81-3.87 (m, 1H); 4.23 (bs, 1H); 5.15 (bs, 1H); 6.48-6.49 (m, 1H); 6.82 (s, 1H); 7.14 (dd, J1=5.1 Hz, J2=3.7 Hz, 1H); 7.46 (dd, J1=5.1 Hz, J2=1.2 Hz, 1H); 7.76 (m, 1H); 7.97 (dd, J1=3.7 Hz, J2=1.2 Hz, 1H); 8.66 (dd, J1=2.7 Hz, J2=1.9 Hz, 1H).

EXAMPLE 131
3-{[6-(1H-Pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amino}propan-1-ol

Obtained from Intermediate 55 (100 mg) and 3-amino-1-propanol (87 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 3:2) as eluent gave 3-{[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amino}propan-1-ol (94 mg, 82%) as an off-white solid.

m.p.: 129.9-130.8° C.

δ (300 MHz, CDCl₃): 1.87 (q, J=6.0 Hz, 2H); 3.73 (bs, 5H); 5.30 (s, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.79 (s, 1H); 7.13 (dd, J1=4.9 Hz, J2=3.6 Hz, 1H); 7.45 (dd, J1=4.9 Hz, J2=1.2 Hz, 1H); 7.75 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H); 7.96 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H); 8.65 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

EXAMPLE 132
N-(2-Aminoethyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amine

The intermediate tert-butyl 2-{[2-(2-thienyl)-6-(pyrazol-1-yl)pyrimidin-4-yl]amino}-ethylcarbamate was obtained from Intermediate 55 (100 mg) and N—BOC-ethylenediamine (180 μL, 1.14 mmol) by the synthetic procedure described in Example 122. Purification of the final product by column chromatography with silica gel and methylene chloride/methanol/NH₄OH (95:2.5:2.5) as eluent gave N-(2-aminoethyl)-N-[6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]amine (86 mg, (47%) as a solid.

m.p.: 146.6-147.1° C.

δ (300 MHz, CDCl₃): 0.01 (t, J=5.8 Hz, 2H); 3.50 (bs, 2H); 5.59 (bs, 1H); 6.46-6.48 (m, 1H); 6.80 (s, 1H); 7.11-7.15 (m, 1H); 7.45 (dt, J1=4.9 Hz, J2=1.1 Hz, 1H); 7.75-7.76 (m, 1H); 7.97 (dd, J1=3.7 Hz, J2=1.1 Hz, 1H); 8.66 (d, J=2.7 Hz, 1H).

EXAMPLE 133
N-[2-(4-Methoxyphenyl)ethyl]-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and (4-methoxyphenyl)ethylamine (166 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 4:1) as eluent gave N-[2-(4-methoxyphenyl)ethyl]-6-(pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine (121 mg, 84%) as an off-white solid.

m.p.: 99.6-100.4° C.

δ (300 MHz, CDCl₃): 2.92 (t, J=7.0 Hz, 2H); 3.67 (bs, 2H); 3.81 (m, 3H); 5.12 (bs, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.87 (dt, J1=4.4 Hz, J2=2.6 Hz, 2H); 7.11-7.26 (m, 3H); 7.45 (dd, J1=4.9 Hz, J2=1.4 Hz, 1H); 7.75 (d, J=0.8 Hz, 1H); 7.98 (dd, J1=3.6 Hz, J2=1.1 Hz, 1H); 8.66 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

EXAMPLE 134
N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and (3,4-dimethoxyphenyl)ethylamine (192 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 85:15 to 70:30) as eluent gave N-[2-(3,4-dimethoxyphenyl)ethyl]-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine (117 mg, 76%) as an oil.

m.p.: 116.2-117.3° C.

δ (300 MHz, CDCl₃): 2.93 (t, J=7.0 Hz, 2H); 3.70 (bs, 2H); 3.88 (s, 3H); 3.89 (m, 3H); 5.16 (bs, 1H); 6.47 (dd, J1=2.6 Hz, J2=1.7 Hz, 1H); 6.77-6.85 (m, 4H); 7.13 (dd, J1=4.9 Hz, J2=3.6 Hz, 1H); 7.45 (dd, J1=4.9 Hz, J2=1.4 Hz, 1H); 7.75 (d, J=0.8 Hz, 1H); 7.98 (dd, J1=3.6 Hz, J2=1.1 Hz, 1H); 8.66 (dd, J1=2.6 Hz, J2=0.8 Hz, 1H).

EXAMPLE 135
6-(1H-Pyrazol-1-yl)-N-(2-pyridin-3-ylethyl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and 2-(2-aminoethyl)pyridine (137 μL, 1.22 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 2:3) as eluent gave 6 (1H-pyrazol-1-yl)-N-(2-pyridin-3-ylethyl)-2-(2-thienyl)pyrimidin-4-amine (58 mg, 44%) as an off-white solid.

m.p.: 132.9-133.6° C.

δ (300 MHz, CDCl₃): 3.16 (t, J=6.5 Hz, 2H); 3.90 (bs, 2H); 5.88 (t, J=5.2 Hz, 1H); 6.46 (dd, J1=2.6 Hz, J2=1.6 Hz, 1H); 6.79 (s, 1H); 7.11-7.21 (m, 3H); 7.44 (dd, J1=5.1 Hz, J2=1.2 Hz, 1H); 7.63 (dt, J1=7.7 Hz, J2=1.9 Hz, 1H); 7.74-7.75 (m, 1H); 7.98 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H) 8.58 (m, 1H) 8.65 (dd, J1=2.6 Hz, J2=0.7 Hz, 1H).

EXAMPLE 136
6-(1H-Pyrazol-1-yl)-N-(2-pyridin-2-ylethyl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and 3-(2-aminoethyl)pyridine (139 mg, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 1:1 to pure ethyl acetate) as eluent gave 6-(1H-pyrazol-1-yl)-N-(2-pyridin-2-ylethyl)-2-(2-thienyl)pyrimidin-4-amine (106 mg, 80%) as an off-white solid.

m.p.: 159.0-160.5° C.

δ (300 MHz, CDCl₃): 3.02 (t, J=7.14 Hz, 2H) 3.75 (m, 2H) 5.16 (s, 1H) 6.48 (m, J=2.75, 1.65 Hz, 1H) 6.78 (s, 1H) 7.14 (dd, J=5.08, 3.71 Hz, 1H) 7.25 (dd, J=4.53, 0.69 Hz, 1H) 7.28 (dd, J=4.81, 0.69 Hz, 1H) 7.47 (dd, J=4.94, 1.37 Hz, 1H) 7.59 (m, J=7.69, 1.65, 0.55 Hz, 1H) 7.75 (dd, J=1.51, 0.69 Hz, 1H) 7.99 (dd, J=3.71, 1.24 Hz, 1H) 8.51 (dd, J=4.67, 1.65 Hz, 1H) 8.55 (d, J=1.65 Hz, 1H) 8.67 (dd, J=2.75, 0.82 Hz, 1H).

EXAMPLE 137
N-(3-Phenylpropyl)-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 55 (100 mg) and 3-phenylpropylamine (162 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 95:5 to 90:10) as eluent gave N-(3-phenylpropyl)-6-(1H-pyrazol-1-yl)_2-2-thienyl)pyrimidin-4-amine (98 mg, 72%) as an off-white solid.

m.p.: 83.6-84.5° C.

δ (300 MHz, CDCl₃): 2.02 (q, J=7.4 Hz, 2H); 2.76 (t, J=7.4 Hz, 2H); 3.44 (bs, 2H); 5.17 (bs, 1H); 6.47 (dd, J1=2.7 Hz, J2=1.7 Hz, 1H); 6.74 (s, 1H); 7.22-7.31 (m, 6H); 7.45 (dd, J1=5.1 Hz, J2=1.2 Hz, 1H); 7.75 (dd, J1=1.7 Hz, J2=0.6 Hz, 1H); 7.95 (dd, J1=3.7 Hz, J2=1.2 Hz, 1H); 8.66 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 138
N-[3-(1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 5 (100 mg) and 3-(1H-imidazol-1-yl)propylamine (136 μL, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography with silica gel and methylene chloride/methanol (97:3) as eluent gave N-[3-(1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)_2-2-thienyl)pyrimidin-4-amine (130 mg, 98%) as an off-white solid.

δ (300 MHz, CDCl₃): 2.20 (q, J=7.0 Hz, 2H); 3.46-3.54 (m, 2H); 4.11 (t, J=7.0 Hz, 2H); 5.14 (bs, 1H); 6.48 (dd, J1=2.7 Hz, J2=1.7 Hz, 1H); 6.77 (s, 1H); 6.97 (t, J=1.2 Hz, 1H); 7.10 (t, J=1.2 Hz, 1H); 7.14 (dd, J1=5.1 Hz, J2=3.7 Hz, 1H); 7.47 (dd, J1=5.1 Hz, J2=1.2 Hz, 1H); 7.54 (s, 1H); 7.75 (dd, J1=1.5 Hz, J2=0.7 Hz, 1H) 7.97 (dd, J1=3.7 Hz, J2=1.2 Hz, 1H); 8.66 (dd, J1=2.7 Hz, J2=0.7 Hz, 1H).

EXAMPLE 139
Ethyl 6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-yl]carbamate

A solution of the title compound of Example 56 (0.37 g, 1.52 mmol), diethyl pyrocarbonate (246 μL, 1.67 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) in tetrahydrofuran (4 mL) was heated at 45° C. overnight. The reaction was poured into water (40 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with n-hexane/ethyl acetate (9:1) as eluent gave ethyl 6-(1H-pyrazol-1-yl)-2-(2-thienyl)pyrimidin-4-ylcarbamate (34 mg, 7%) as an off-white solid.

δ (300 MHz, CDCl₃): 1.35 (t, J1=7.0 Hz, 3H); 4.31 (d, J=7.0 Hz, 2H); 6.50 (dd, J1=2.6 Hz, J2=1.2 Hz, 1H); 7.15 (dd, J1=5.1 Hz, J2=3.7 Hz, 1H); 7.49 (dd, J1=5.1 Hz, J2=1.6 Hz, 1H); 7.52 (bs, 1H); 7.80 (dd, J1=1.6 Hz, J2=0.7 Hz, 1H); 7.99 (dd, J1=3.7 Hz, J2=1.2 Hz, 1H); 8.33 (s, 1H); 8.66 (dd, J1=2.6 Hz, J2=0.7 Hz, 1H).

EXAMPLE 140
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-[(1S*,2R)-2-phenylcyclopropyl]urea (*relative trans configuration)

To a solution of the title compound of Example 1 (0.22 g, 0.97 mmol) in anhydrous tetrahydrofuran (14 mL), cooled at −78° C., was slowly added 2.5M solution of n-butyllithium in hexanes (0.78 mL). The mixture was stirred at −78° C. for 1 hour and then, a solution of (1S*,2R*)-2-phenylcyclopropylisocyanate (0.22 mg, 1.40 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added. The mixture was allowed to stand at room temperature for 2 hours. Water (15 mL) was added and the organic phase was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (2×20 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel, eluting with methylene chloride/methanol (99:1) as eluent, followed by a preparative HPLC-MS purification gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-[(1S*,2R*)-2-phenylcyclopropyl]urea (*relative trans configuration) (150 mg, 40%) as an off-white solid.

δ (400 MHz, DMSO-d₆): 1.18-1.32 (m, 1H); 2.05-2.12 (m, 1H): 2.81-2.88 (m, 1H): 6.64 (s, 1H); 6.76 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.14-7.22 (m, 3H); 7.26-7.31 (m, 2H); 7.44 (d, J=3.1 Hz, 1H); 7.89 (s, 1H); 7.91 (s, 1H); 7.98 (s, 1H); 8.10 (bs, 1H); 8.75 (d, J=2.3 Hz, 1H); 9.96 (bs, 1H).

EXAMPLE 141
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]-N-propylurea

Obtained from the title compound of Example 1 (0.22 g) and propylisocyanate (0.12 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (99:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-propylurea (68 mg, 20%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 0.94 (t, J=7.4 Hz, 3H); 1.53 (h, J=7.4 Hz, 2H); 3.18 (q, J=7.4 Hz, 2H); 6.65 (dd, J1=2.7 Hz, J2=1.7 Hz, 1H); 6.75 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.44 (dd, J1=3.4 Hz, J2=0.8 Hz, 1H); 7.86 (bs, 1H); 7.92 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H); 7.96 (dd, J1=1.7 Hz, J2=0.8 Hz, 1H); 8.75 (dd, J1=2.7 Hz, J2=0.7 Hz, 1H); 9.97 (bs, 1H).

EXAMPLE 142
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-isopropylurea

Obtained from the title compound of Example 1 (0.22 g) and isopropylisocyanate (0.12 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (99:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-isopropylurea (147 mg, 48%) as an off-white solid.

δ (400 MHz, DMSO-d₆): 1.19 (d, J=6.7 Hz, 6H); 3.84 (h, J=6.7 Hz, 1H); 6.64 (s, 1H); 6.75 (s, 1H); 7.42 (d, J=3.1 Hz, 1H); 7.80 (s, 1H); 7.92 (s, 1H); 7.97 (s, 1H); 8.75 (d, J=2.3 Hz, 1H); 9.87 (s, 1H).

EXAMPLE 143
N-Cyclopentyl-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]urea

Obtained from the title compound of Example 1 (0.22 g) and cyclopentylisocyanate (0.16 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (99:1) as eluent gave N-cyclopentyl-N′-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]urea (125 mg, 38%) as an off-white solid.

δ (300 MHz, DMSO-d₆): 1.42-1.54 (m, 2H); 1.55-1.66 (m, 2H); 1.67-1.75 (m, 2H); 1.84-1.96 (m, 2H); 3.99-4.09 (m, 1H); 6.65 (dd, J1=2.7 Hz, J2=1.6 Hz, 1H); 6.76 (dd, J1=3.4 Hz, J2=1.6 Hz, 1H); 7.43 (d, J=2.7 Hz, 1H); 7.76 (s, 1H); 7.92 (d, J=1.1 Hz, 1H); 7.97 (s, 1H); 8.10 (bs, 1H); 8.75 (d, J=2.7 Hz, 1H); 9.89 (s, 1H).

EXAMPLE 144
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-(4-methoxyphenyl)urea

Obtained from the title compound of Example 1 (0.22 g) and 4-methoxybenzeneisocyanate (0.21 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (98:2) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-1-(4-methoxyphenyl)urea (82 mg, 22%) as an off-white solid.

δ (400 MHz, DMSO-d₆): 3.75 (s, 3H); 6.66 (dd, J1=2.7 Hz, J2-=1.8 Hz, 1H); 6.78 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.93-7.0 (m, 2H); 7.46-7.52 (m, 3H); 7.89 (s, 1H); 7.94 (s, 1H); 8.03 (s, 1H); 8.78 (d, J=2.7 Hz, 1H); 10.13 (s, 1H); 10.17 (bs, 1H).

EXAMPLE 145
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-N′-(2-phenylethyl)urea

Obtained from the title compound of Example 1 (0.22 g) and phenethylisocyanate (0.21 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (99:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]-N′-(2-phenylethyl)urea (35 mg, 10%) as an off-white solid.

δ (400 MHz, DMSO-d₆): 2.83 (t, J=7.0 Hz, 2H); 3.47 (q, J=7.0 Hz, 2H); 6.64 (dd, J1=2.7 Hz, J2=1.6 Hz, 1H); 6.72 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.18-7.24 (m, 1H); 7.26-7.34 (m, 5H); 7.64 (bs, 1H); 7.90-7.92 (m, 2H); 7.93-7.95 (m, 1H); 8.73 (d, J=2.7 Hz, 1H); 9.98 (bs, 1H).

EXAMPLE 146
N-Benzyl-N′-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]urea

Obtained from the title compound of Example 1 (0.22 g) and benzylisocyanate (0.19 g, 1.40 mmol) by the procedure described in Example 140. Purification by column chromatography with silica gel and methylene chloride/methanol (from 99:1 to 85:5) as eluent, followed by a preparative HPLC-MS purification gave N-benzyl-N′-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]urea (10 mg, 3%) as an off-white solid.

MS (M⁺): 360.

EXAMPLE 147
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-methylbutanamide

Obtained from the title compound of Example 1 (0.24 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3-methylbutanamide (0.38 g, 85%) as an off-white solid.

δ (400 MHz, CDCl₃): 1.21 (s, 9H); 2.38 (s, 2H); 6.51-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (d, J=3.6 Hz, 1H); 7.62 (s, 1H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 148
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3,3-dimethyl-butanamide

Obtained from the title compound of Example 1 (0.24 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3,3-dimethylbutanamide (0.41 g, 91%) as an off-white solid.

δ (400 MHz, CDCl₃): 1.28 (d, J=7.0 Hz, 6H); 2.36 (d, J=7.0 Hz, 2H); 2.58 (h, J=7.0 Hz, 1H); 6.51-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (d, J=3.6 Hz, 1H); 7.62 (s, 1H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 149
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclopentanecarboxamide

Obtained from the title compound of Example 1 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride as eluent followed by trituration with diethyl ether gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]cyclopentanecarboxamide (0.12 g, 55%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.98-1.60 (m, 8H); 2.76 (q, J=7.8 Hz, 1H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.34 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.63 (m, 1H); 7.78 (m, 1H); 8.16 (bs, 1H); 8.61 (s, 1H); 8.62 (d, J=2.7 Hz, 1H).

EXAMPLE 150
2-Chloro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylacetamide

To a solution of the title compound of Example 1 (0.10 g, 0.44 mmol) and a catalytic amount of 4-dimethylaminopyridine in methylene chloride (2.3 mL) was added pyridine (71 μL, 0.88 mmol) and a solution of chloro(phenyl)acetyl chloride (139 μL, 0.88 mmol) in methylene chloride (1 mL). The mixture was stirred at room temperature for 3 hours and more pyridine (36 μL, 0.44 mmol) and chloro(phenyl)acetyl chloride (70 μL, 0.44 mmol) were added. The reaction was allowed to stand for 12 further hours at room temperature. The solution was diluted with methylene chloride (20 mL), washed with 1N citric acid (2×10 mL), saturated solution of sodium bicarbonate (2×10 mL), brine (10 mL) and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (3:7), gave 2-chloro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylacetamide (0.108 g, 65%) as an off-white solid.

δ (400 MHz, CDCl₃): 5.53 (s, 1H); 6.49-6.50 (m, 1H); 6.61 (dd, J1=2.4 Hz, J2=1.6 Hz, 1H); 7.30-7.42 (m, 4H); 7.50-7.60 (m, 2H); 7.66 (s, 1H); 7.78 (s, 1H); 8.57 (s, 1H); 8.64 (d, J=2.8 Hz, 1H); 8.97 (s, 1H).

EXAMPLE 151
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylacetamide

Obtained from the title compound of Example 1 (0.1 g) and phenylacetyl chloride (0.136 g, 0.88 mmol) by the procedure described in Example 150. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:8) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-phenylacetamide (58 mg, 38%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.79 (s, 2H); 6.49 (dd, J1=2.8 Hz, J2=1.6 Hz, 1H); 6.57 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 7.25-7.45 (m, 6H); 7.64 (s, 1H); 7.79 (s, 1H); 8.07 (bs, 1H); 8.59 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

EXAMPLE 152
2-(4-Fluorophenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (0.1 g) and (4-fluorophenyl)acetyl chloride (121 μL, 0.88 mmol) by the procedure described in Example 150. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (3:7) as eluent gave 2-(4-fluorophenyl-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (82 mg, 51%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.78 (s, 2H); 6.51 (dd, J1=2.4 Hz, J2=1.6 Hz, 1H); 6.60 (dd, J1=2.8 Hz, J2=1.6 Hz, 1H); 7.10 (t, J=8.6 Hz, 2H); 7.25-7.35 (m, 3H); 7.64 (s, 1H); 7.81 (s, 1H); 8.08 (s, 1H); 8.61 (s, 1H); 8.64 (d, J=2.4 Hz, 1H).

EXAMPLE 153
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(3-methoxyphenyl)acetamide

To a solution of the title compound of Example 1 (0.10 g, 0.44 mmol) and a catalytic amount of 4-dimethylaminopyridine in pyridine (2.3 mL) was added a solution of (3-methoxyphenyl)acetyl chloride (0.162 g, 0.88 mmol) in pyridine (1.3 mL). The mixture was stirred overnight at 80° C. The solution was diluted with ethyl acetate (30 mL), washed with 1N citric acid (3×20 mL), saturated solution of sodium bicarbonate (2×15 mL), brine (10 mL) and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (1:2) gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(3-methoxyphenyl)acetamide (0.06 g, 36%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.76 (s, 2H); 3.83 (s, 3H); 6.47-6.51 (m, 1H); 6.5-6.59 (m, 1H); 6.80-7.00 (m, 3H); 7.20-7.40 (m, 2H); 7.61 (s, 1H); 7.80 (s, 1H); 8.07 (s, 1H); 8.55-8.65 (m, 2H).

EXAMPLE 154
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(2-methoxyphenyl)acetamide

Obtained from the title compound of Example 1 (0.1 g) and (2-methoxyphenyl)acetyl chloride (0.162 g, 0.88 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:2) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(2-methoxyphenyl)acetamide (78 mg, 47%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.78 (s, 2H); 3.96 (s, 3H); 6.46-6.49 (m, 1H); 6.56-6.59 (m, 1H); 6.93-7.03 (m, 2H); 7.27-7.35 (m, 3H); 7.62 (s, 1H); 7.78 (s, 1H); 8.54 (bs, 1H); 8.56 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

EXAMPLE 155
2-(3,4-Dichlorophenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (0.1 g) and (3,4-dichlorophenyl)acetyl chloride (0.197 g, 0.88 mmol) by the procedure described in Example 150. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (3:7) as eluent gave 2-(3,4-dichlorophenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (58 mg, 32%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.72 (s, 2H); 6.49 (dd, J1=2.8 Hz, J2=2.0 Hz, 1H); 6.59 (dd, J1=3.6 Hz, J2=2.0 Hz, 1H); 7.16-7.20 (m, 1H); 7.32-7.35 (m, 1H); 7.42-7.47 (m, 2H); 7.62 (s, 1H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.55 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

EXAMPLE 156
2-(1,3-Dibenzodioxol-5-yl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (0.1 g) and benzo[1,3]dioxol-5-yl-acetyl chloride (0.175 g, 0.88 mmol) by the procedure described in Example 150. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:2) as eluent gave 2-(1,3-benzodioxol-5-yl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]acetamide (92 mg, 54%) as a yellow solid.

δ (400 MHz, CDCl₃): 3.70 (s, 2H); 5.99 (s, 2H); 6.49 (dd, J1=2.8 Hz, J2=1.6 Hz, 1H); 6.57 (dd, J1=3.6 Hz, J2=2.0 Hz, 1H); 6.75-6.84 (m, 3H); 7.33 (d, J=3.6 Hz, 1H); 7.61 (d, J=0.8 Hz, 1H); 7.79 (d, J=1.6 Hz, 1H); 8.04 (s, 1H); 8.59 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

EXAMPLE 157
2-(3,4-Dihydroxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

To a solution of the title compound of Example 11 (0.10 g, 0.247 mmol) in methylene chloride (2.5 mL) was added a 1M solution of boron tribromide in methylene chloride (2 mL, 2 mmol) at −40° C. under nitrogen. The solution was stirred at −40° C. for 30 min before warming to room temperature. The reaction was quenched by slow addition of ethanol (3.5 mL) at 0° C. and the reaction mixture was added to a solution of saturated solution of sodium bicarbonate (50 mL), diluted with ethyl acetate (30 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2×30 mL), the organic layer was dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with methylene chloride/methanol (98:2) gave 2-(3,4-dihydroxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (39 mg, 42%) as an off-white solid.

δ (400 MHz, DMSO-d₆): 3.61 (s, 2H); 6.58-6.70 (m, 3H); 6.75 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 6.77 (d, J=2.0 Hz, 1H); 7.48 (d, J=3.2 Hz, 1H); 7.92 (s, 1H); 7.97 (s, 1H); 8.42 (s, 1H); 8.74 (s, 1H); 8.77 (d, J=2.2 Hz, 1H); 8.86 (s, 1H); 11.29 (s, 1H).

EXAMPLE 158
2-(2,5-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (0.1 g) and (2,5-dimethoxyphenyl)acetyl chloride (0.19 g, 0.88 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:8) as eluent gave 2-(2,5-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]acetamide (165 mg, 93%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.75 (s, 2H); 3.78 (s, 3H); 3.92 (s, 3H); 6.48 (dd, J1=2.8 Hz, J2=1.6 Hz, 1H); 6.57 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 6.80-6.92 (m, 3H); 7.30 (d, J=3.6 Hz, 1H); 7.62 (s, 1H); 7.78 (s, 1H); 8.55 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

Intermediate 56. (4-Chloro-3-methylphenyl)acetic acid

A suspension of 4-chloro-3-methylacetophenone (25 g, 0.148 mol) and sulfur (4.70 g, 0.146 mol) in morpholine (14.1 mL, 0.161 mol) was stirred at 140° C. overnight. The mixture was cooled and diluted with ethyl ether (50 mL). The resulting solid was filtered, washed with ethyl ether (2×25 mL) and solved in ethanol (540 mL). To this solution was added water (100 mL) and potassium hydroxide (84 g, 1.5 mol). The mixture was stirred at 90° C. overnight. The solvent was removed under reduced pressure and the reaction crude was diluted with water. The aqueous layer was washed with ethyl ether (2×50 mL), acidified with 1N hydrochloric acid and extracted with ethyl ether (3×50 mL). The organic layer was washed with 1N hydrochloric acid (2×25 mL), water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The resulting solid was filtered and washed with n-hexane (50 mL) to yield the title compound (11.15 g, 41%) as a yellow solid.

δ (300 MHz, CDCl₃): 2.34 (s, 3H); 3.60 (s, 2H); 7.02-7.11 (m, 1H); 7.16-7.22 (m, 1H); 7.27-7.34 (m, 1H).

EXAMPLE 159
2-(4-Chloro-3-methylphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

To a solution of (4-chloro-3-methylphenyl)acetic acid (0.162 g, 0.88 mmol) and a catalytic amount of DMF in methylene chloride (2 mL) was added oxalyl chloride (84 μL, 0.97 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give (4-chloro-3-methylphenyl)acetyl chloride that was used in the next step without further purification. 2-(4-Chloro-3-methylphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide was obtained from the title compound of Example 1 (0.1 g) and (4-chloro-3-methylphenyl)acetyl chloride (0.179 g, 0.88 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:9) as eluent gave the title compound (55 mg, 32%) as an off-white solid.

δ (400 MHz, CDCl₃): 2.39 (s, 3H); 3.71 (s, 2H); 6.49 (dd, J1=2.4 Hz, J2=1.6 Hz, 1H); 6.58 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 7.08-7.13 (m, 1H); 7.19-7.26 (m, 1H); 7.32-7.37 (m, 2H); 7.62 (s, 1H); 7.79 (s, 1H); 8.06 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.8 Hz, 1H).

EXAMPLE 160
2-(3,5-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 1 (0.3 g) and (3,5-dimethoxyphenyl)acetyl chloride (0.567 g, 2.64 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:8) as eluent gave 2-(3,5-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (188 mg, 35%) as an off-white solid.

δ (400 MHz, CDCl₃): 3.71 (s, 2H); 3.79 (s, 6H); 6.41-6.44 (m, 1H); 6.45-6.48 (m, 2H); 6.49 (dd, J1=2.8 Hz, J2=2.0 Hz, 1H); 6.57 (dd, J1=3.6 Hz, J2=2.0 Hz, 1H); 7.32 (d, J=3.6 Hz, 1H); 7.61 (d, J=1.6 Hz, 1H); 7.80 (d, J=1.6 Hz, 1H); 8.08 (bs, 1H); 8.59 (s, 1H); 8.63 (d, J=2.8 Hz, 1H).

EXAMPLE 161
2-[3-(Benzyloxy)-4-methoxyphenyl]-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

To solution of (3-benzyloxy-methoxyphenyl)acetic acid (0.299 g, 1.10 mmol) and a catalytic amount of DMF in methylene chloride (2.2 mL) was added oxalyl chloride (105 μL, 1.21 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give (3-benzyloxy-4-methoxyphenyl)acetyl chloride that was used in the next reaction without further purification. 2-[3-Benzyloxy)-4-methoxyphenyl]-N-[2-(2-furyl)-6-(H-pyrazol-1-yl)pyrimidin-4-yl]acetamide was obtained from the title compound of Example 1 (0.1 g) and (3-benzyloxy-4-methoxyphenyl)acetyl chloride (0.320 g, 1.10 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:2) as eluent gave the title compound (86 mg, 41%) as a yellow solid.

δ (400 MHz, CDCl₃): 3.67 (s, 2H); 3.90 (s, 3H); 5.16 (s, 2H); 6.49-6.51 (m, 1H); 6.58 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 6.82-6.94 (m, 3H); 7.20-7.26 (m, 1H); 7.30-7.36 (m, 3H); 7.42-7.45 (m, 2H); 7.62 (s, 1H); 7.81 (s, 1H); 7.99 (bs, 1H); 8.57 (s, 1H); 8.63 (d, J=2.8 Hz, 1H).

Intermediate 57. Methyl [4-(benzyloxy)-3-methoxyphenyl]acetate

To a solution of (4-benzyloxy-3-methoxyphenyl)acetic acid (5.0 g, 18 mmol) in methanol (25 mL) was added concentrated sulphuric acid (1 mL). The reaction was heated at reflux overnight. The solvent was removed under reduced pressure and the crude was diluted with ethyl acetate (100 mL), washed with saturated solution of sodium bicarbonate (2×50 mL), brine (50 mL) and dried (Na₂SO₄). The solvent was removed under reduced pressure and methyl [4-(benzyloxy)-3-methoxyphenyl]acetate was obtained as an off-white solid.

MS (M⁺): 286.

Intermediate 58. Methyl (4-hydroxy-3-methoxyphenyl)acetate

To a solution of Intermediate 57 (5.22 g, 18 mmol) in ethyl acetate (40 mL) was added palladium on charcoal (0.52 g, 1.83 mmol). The mixture was stirred under hydrogen and at room temperature for 7 hours. The palladium on charcoal was filtered over Celite® and the solvent removed under reduced pressure, to give methyl (4-hydroxy-3-methoxyphenyl)acetate (3.40 g, 64%) as an oil.

δ (250 MHz, CDCl₃): 3.57 (s, 2H); 3.71 (s, 3H); 3.86 (s, 2H); 6.79-6.89 (m, 3H)

Intermediate 59. Methyl [4-(cyclobutyloxy)-3-methoxyphenyl]acetate

To a solution of Intermediate 58 (0.33 g, 1.7 mmol) in DMF (2 mL) was added cyclobutyl bromide (0.165 mL, 1.75 mmol) and cesium carbonate (0.56 g, 1.75 mmol). The reaction was heated at 60° C. overnight. The mixture was cooled, acidified with 10% hydrochloric acid (25 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (2×10 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave the title compound (100 mg, 23%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.59-1.72 (m, 1H); 1.77-1.89 (m, 1H); 2.20-2.28 (m, 2H); 2.39-2.51 (m, 2H); 3.55 (s, 2H); 3.69 (s, 3H); 3.86 (s, 3H); 4.62 (qt, J=7.0 Hz, 1H); 6.70 (d, J=8.0 Hz, 1H); 6.76 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H); 6.79 (s, 1H).

Intermediate 60. [4-(Cyclobutyloxy)-3-methoxyphenyl]acetic acid

A solution of Intermediate 59 (0.17 g, 0.67 mmol) and lithium hydroxide (72 mg, 1.72 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was stirred at room temperature for 3 h. The organic solvent was removed under reduced pressure and the resulting aqueous solution was acidified with acetic acid until pH=5 and extracted with methylene chloride (3×50 mL). The organic layer was dried (MgSO₄) and the solvent removed under reduced pressure to give [4-(cyclobutyloxy)-3-methoxyphenyl]acetic acid as an oil (0.16 g, 99%).

δ (250 MHz, CDCl₃): 1.64-1.71 (m, 1H); 1.72-1.86 (m, 1H); 2.17-2.39 (m, 2H); 2.40-2.50 (m, 2H); 3.57 (s, 2H); 3.85 (s, 3H); 4.63 (qt, J=7.0 Hz, 1H); 6.68 (d, J=8.0 Hz, 1H); 6.75 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H); 6.79 (s, 1H).

EXAMPLE 162
2-[4-(Cyclobutyloxy)-3-methoxyphenyl]-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide

To a solution of Intermediate 60 (0.21 g, 0.89 mmol) in methylene chloride (2 mL) was added oxalyl chloride (0.11 g, 0.89 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 2 hours. This solution was added to a solution of the title compound of Example 1 (135 mg, 0.59 mmol) and pyridine (71 mg, 0.89 mmol) in methylene chloride (6 mL). The mixture was stirred at room temperature for 3 hours and diluted with methylene chloride (8 mL). The organic layer was washed with water (2×8 mL) and brine (8 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (1:4), followed by a second column chromatography with silica gel and methylene chloride/acetonitrile (10%) as eluent gave 2-[4-(cyclobutyloxy)-3-methoxyphenyl]-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]acetamide (29 mg, 11%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.71 (s, 2H); 3.88 (s, 3H); 4.67 (q, J=7.0 Hz, 1H); 6.49 (m, 1H); 6.57 (m, 1H); 6.74 (m, 1H); 6.83 (m, 2H); 7.35-7.26 (m, 1H); 7.62 (m, 1H); 7.81 (m, 1H); 8.08 (bs, 1H); 8.61 (m, 2H).

Intermediate 61. 4-(Difluoromethoxy)-3-methoxybenzaldehyde

A solution of 4-hydroxy-3-methoxybenzaldehyde (2.0 g, 0.013 mol), sodium 2-chloro-2,2-difluoroacetate (4.8 g, 0.031 mol) and cesium carbonate (72 mg, 0.018 mol) in DMF (14 mL) and water (14 mL) was heated at 100° C. for 3.5 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL), dried (MgSO₄) and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave 4-(difluoromethoxy)-3-methoxybenzaldehyde (2.41 g, 91%) as an oil.

δ (250 MHz, CDCl₃): 3.76 (s, 3H); 6.49 (t, J_F-H=74.0 Hz, 1H); 7.11 (d, J=8.0 Hz, 1H); 7.27 (dd, J1=1.7 Hz, J2=8.0 Hz, 1H); 7.31 (d, J=1.7 Hz, 1H); 9.74 (s, 1H).

Intermediate 62. [4-(Difluoromethoxy)-3-methoxyphenyl]methanol

To a solution of Intermediate 61 (2.7 g, 0.013 mol) in tetrahydrofuran (25 mL) and methanol (5 mL) was cooled at 0° C. and sodium borohydride (0.62 g, 0.016 mol) was added in small portions. The mixture was stirred at room temperature for 30 minutes, cooled at 0° C., and a solution of ammonium chloride (25 mL) was added. The crude was extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The title compound was obtained (2.7 g, 99%) as an oil.

δ (250 MHz, CDCl₃): 3.85 (s, 3H); 4.63 (s, 2H); 6.52 (t, J_F-H=75.0 Hz, 1H); 6.86 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 6.98 (d, J=2.0 Hz, 1H); 7.10 (d, J=8.0 Hz, 1H).

Intermediate 63. 4-(Chloromethyl)-1-(difluoromethoxy)-2-methoxybenzene

To a cooled solution of Intermediate 62 (1.46 g, 7.1 mmol) in methylene chloride (20 mL) was added pyridine (1.43 g, 18 mmol) and methane sulfonyl chloride (1.57 g, 13.7 mmol). The reaction was stirred at room temperature for 11 hours. The mixture was poured into a saturated solution of sodium bicarbonate (40 mL) and extracted with methylene chloride (2×20 mL). The combined organic extracts were washed with a saturated solution of sodium bicarbonate (2×15 mL), 1N hydrochloric acid (2×15 mL), brine (1×15 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. 4-(Chloromethyl)-1-(difluoromethoxy)-2-methoxybenzene was obtained (1.2 g, 60%) as an oil.

δ (250 MHz, CDCl₃): 3.60 (s, 3H); 4.56 (s, 2H); 6.55 (t, J_F-H=75.0 Hz, 1H); 6.94 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 7.01 (d, J=2.0 Hz, 1H); 7.13 (d, J=8.0 Hz, 1H).

Intermediate 64. [4-(Difluoromethoxy)-3-methoxyphenyl]acetonitrile

To a solution of Intermediate 63 (0.15 g, 0.69 mmol) in dimethylsulfoxide (1.6 mL) was added sodium cyanide (40 mg, 0.82 mmol). The mixture was stirred at room temperature for 7 hours. The reaction was poured into water (10 mL) and extracted with ethyl acetate (2×5 mL). The organic layer was washed with brine (2×5 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The title compound was obtained (144 mg, 98%).

δ (250 MHz, CDCl₃): 3.71 (s, 2H); 3.84 (s, 3H); 6.53 (t, J_F-H=75.0 Hz, 1H); 6.83 (s, 1H); 6.88 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 7.10 (d, J=8.0 Hz, 1H).

Intermediate 65. [4-(Difluoromethoxy)-3-methoxyphenyl]acetic acid

A suspension of Intermediate 64 (0.60 g, 2.8 mmol) in 1N sodium hydroxide (20 mL) was heated at 110° C. for 3.5 hours. The resulting solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×15 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent gave [4-(difluoromethoxy)-3-methoxyphenyl]acetic acid (0.31 g, 48%).

δ (250 MHz, CDCl₃): 3.63 (s, 2H); 3.87 (s, 3H); 6.53 (t, J_F-H=75.0 Hz, 1H); 6.83 (s, 1H); 6.87 (dd, J1=2.0 Hz, J2=8.0 Hz, 1H); 7.11 (d, J=8.0 Hz, 1H).

EXAMPLE 163
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(4 difluoromethoxy-3-methoxyphenyl)acetamide

Obtained from the title compound of Example 1 (0.11 g) and Intermediate 65 (0.16 g, 0.70 mmol) by the procedure described in Example 162. Purification by column chromatography with silica gel and methylene chloride/acetonitrile (5%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(4-difluoromethoxy-3-methoxyphenyl)acetamide (31 mg, 15%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.75 (s, 2H); 3.89 (s, 3H); 6.49 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.55 (t, J=75.2 Hz, 1H); 6.58 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.95-6.86 (m, 2H); 7.16 (d, J=7.9 Hz, 1H); 7.33 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 7.62 (dd, J1=1.5 Hz, J2=0.9 Hz, 1H); 7.79 (dd, J1=1.5 Hz, J2=0.6 Hz, 1H); 8.15 (bs, 1H); 8.58 (bs, 1H); 8.62 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H).

EXAMPLE 164
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(3,4,5-trimethoxyphenyl)acetamide

To a solution of (3,4,5-trimethoxyphenyl)acetic acid (0.199 g, 0.88 mmol) and a catalytic amount of DMF in methylene chloride (2 mL) was added oxalyl chloride (84 μL, 0.968 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give (3,4,5-trimethoxyphenyl)acetyl chloride that was used in the next reaction without further purification. N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-(3,4,5-trimethoxyphenyl)acetamide was obtained from the title compound of Example 1 (0.1 g) and (3,4,5-trimethoxyphenyl)acetyl chloride (0.215 g, 0.88 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:8) as eluent gave the title compound (27 mg, 14%) as a red solid.

δ (400 MHz, CDCl₃): 3.72 (s, 2H); 3.86 (s, 3H); 3.88 (s, 6H); 6.50 (dd, J1=2.8 Hz, J2=1.6 Hz, 1H); 6.53 (s, 2H); 6.58 (dd, J1=3.6 Hz, J2=1.6 Hz, 1H); 7.33 (dd, J1=3.6 Hz, J2=0.8 Hz, 1H); 7.61 (dd, J1=2.0 Hz, J2=0.8 Hz, 1H); 7.80 (d, J=0.8 Hz, 1H); 8.11 (bs, 1H); 8.60 (s, 1H); 8.63 (dd, J1=2.0 Hz, J2=0.8 Hz, 1H).

Intermediate 66. Methyl (3,4-dimethoxyphenyl)acetate

Obtained from (3,4-dimethoxyphenyl)acetic acid (5.0 g, 26 mmol) by the procedure described in Intermediate 57. Methyl (3,4-dimethoxyphenyl)acetate was obtained as an off-white solid (4.74 g, 88%).

δ (300 MHz, CDCl₃): 3.52 (s, 2H); 3.69 (s, 3H); 3.92 (s, 6H); 6.81 (s, 3H).

Intermediate 67. Methyl 2-(3,4-dimethoxyphenyl)propanoate

A 1.6M solution of n-butyllithium in hexanes (4.83 mL, 7.74 mmol) was added to a stirred solution of diisopropylamine (1.18 mL, 8.40 mmol) in tetrahydrofuran (7 mL) at −78° C. under nitrogen. After 15 min, a solution of Intermediate 66 (1.0 g, 4.75 mmol) in tetrahydrofuran (14 mL) was slowly added at −78° C. and the solution was stirred at the same temperature for one hour. A solution of methyl iodide (0.59 mL, 9.5 mmol) in tetrahydrofuran (5 mL) was then added and the resulting mixture was stirred 30 min at −78° C. before warming to room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine (50 mL), dried (Na₂SO₄) and the solvent removed under reduced pressure to give methyl 2-(3,4-dimethoxyphenyl)propanoate as a brown oil (1.03 g, 97%).

δ (300 MHz, CDCl₃): 1.46 (d, J=7.0 Hz, 3H); 3.64 (s, 3H); 3.65 (q, J=7.0 Hz, 1H); 3.88 (s, 3H); 3.89 (s, 3H); 6.82 (s, 3H).

Intermediate 68. 2-(3,4-Dimethoxyphenyl)propanoic acid

Obtained from Intermediate 67 (1 g, 4.45 mmol) by the procedure described in Intermediate 60. 2-(3,4-Dimethoxyphenyl)propanoic acid was obtained as an off-white solid (4.74 g, 88%).

δ (300 MHz, CDCl₃): 1.51 (d, J=7.0 Hz, 3H); 3.66 (q, J=7.0 Hz, 1H); 3.88 (s, 3H); 3.89 (s, 3H); 6.80-6.97 (m, 3H).

EXAMPLE 165
2-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide

To a solution of 2-(3,4-dimethoxyphenyl)propanoic acid (0.185 g, 0.88 mmol) and a catalytic amount of DMF in methylene chloride (2 mL) was added oxalyl chloride (84 mL, 0.968 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give 2-(3,4-dimethoxyphenyl)propanoyl chloride that was used in the next reaction without further purification. 2-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide was obtained from the title compound of Example 1 (0.1 g) and 2-(3,4-dimethoxy phenyl)propanoyl chloride (0.201 g, 0.88 mmol) by the procedure described in Example 153. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (2:8) as eluent gave 2-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]propanamide (178 mg, 96%) as an off-white solid.

δ (400 MHz, CDCl₃): 1.58 (d, J=7.0 Hz, 3H); 3.68 (q, J=7.0 Hz, 1H); 3.88 (s, 3H); 3.89 (s, 3H); 6.49 (dd, J1=2.4 Hz, J2=1.6 Hz, 1H); 6.57 (dd, J1=3.2 Hz, J2=1.6 Hz, 1H); 6.82-6.91 (m, 3H); 7.31 (d, J=2.4 Hz, 1H); 7.60 (d, J=0.8 Hz, 1H); 7.79 (d, J=0.8 Hz, 1H); 8.00 (bs, 1H); 8.61 (d, J=2.4 Hz, 1H); 8.63 (s, 1H).

EXAMPLE 166
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzamide

To a solution of the title compound of Example 1 (0.20 g, 0.88 mmol) in methylene chloride (10 mL) was added pyridine (89 mg, 1.06 mmol) and benzoyl chloride (0.15 g, 1.06 mmol). The mixture was stirred at room temperature for 18 hours and more pyridine (0.13 g, 1.6 mmol) and benzoyl chloride (0.22 g, 1.5 mmol) were added. The reaction was allowed to stand for 96 further hours at room temperature. The solution was diluted with methylene chloride (50 mL), washed with water (20 mL), with 1% sodium hydroxide (2×20 mL), and dried (Na₂SO₄). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with methylene chloride, followed by a second column chromatography with silica gel and ethyl acetate/n-hexane (1:4) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzamide (0.16 g, 49%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.52 (dd, J1=2.7 Hz, J2=1.8 Hz, 1H); 6.61 (dd, J1=3.6 Hz, J2=1.8 Hz, 1H); 7.38 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.63-7.5 (m, 3H); 7.66 (dd, J1=1.5 Hz, J2=0.9 Hz, 1H); 7.83 (dd, J1=1.5 Hz, J2=0.6 Hz, 1H); 7.98 (m, 2H); 8.67 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H); 8.78 (s, 1H); 8.81 (bs, 1H).

EXAMPLE 167
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3,4-dimethoxybenzamide

To a solution of the title compound of Example 1 (0.14 g, 0.62 mmol) in DMF (5 mL) was added sodium hydride (30 mg, 1.23 mmol). The mixture was stirred at room temperature for 1 hour. Then, a solution of 3,4-dimethoxybenzoyl chloride (0.49 g, 2.47 mmol) in DMF (4 mL) was added. The reaction was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The crude was solved with methylene chloride (25 mL), washed with 10% sodium hydroxide (2×25 mL), water (2×25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent, followed by trituration with ethyl ether gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-3,4-dimethoxybenzamide (48 mg, 13%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.97 (s, 3H); 3.99 (s, 3H); 6.51 (m, 1H); 6.61 (m, 1H); 6.95 (m, 1H); 7.39 (m, 1H); 7.55 (m, 2H); 7.66 (m, 1H); 7.82 (bs, 1H); 8.66 (m, 1H); 8.77 (m, 1H); 8.80 (bs, 1H).

EXAMPLE 168
2,6-Difluoro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-benzamide

Obtained from the title compound of Example 1 (0.25 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave 2,6-difluoro-N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-benzamide (0.38 g, 82%) as a white solid.

δ (400 MHz, CDCl₃): 6.51-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (m, 2H); 7.62 (m, 2H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 169
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-2-furamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 166. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]-2-furamide (210 mg, 65%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.51 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.61 (m, 2H); 7.36 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.38 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.57 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.66 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.82 (m, 1H); 8.66 (dd, J1-=2.7 Hz, J2=0.6 Hz, 1H); 8.70 (s, 1H); 8.96 (bs, 1H).

EXAMPLE 170
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]thiophene-2-carboxamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 166. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]thiophene-2-carboxamide (195 mg, 58%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.51 (dd, J1=2.7 Hz, J2=1.5 Hz, 1H); 6.61 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.18 (dd, J1=5.2 Hz, J2=3.9 Hz, 1H); 7.38 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.67-7.64 (m, 2H); 7.76 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.81 (dd, J1=1.5 Hz, J2=0.6 Hz, 1H); 8.65 (dd, J1=2.7 Hz, J2=0.6 Hz, 1H); 8.68 (bs, 1H); 8.71 (s, 1H).

EXAMPLE 171
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]nicotinamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 166. Purification by trituration with ethyl ether gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]nicotinamide (43 mg, 13%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.69 (m, 1H); 6.77 (m, 1H); 7.56 (m, 2H); 7.98 (m, 2H); 8.37 (m, 1H); 8.60 (bs, 1H); 8.80 (m, 2H); 9.15 (bs, 1H); 11.75 (s, 1H).

EXAMPLE 172
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]isonicotinamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 166. Purification by trituration with methylene chloride/diethyl ether gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]isonicotinamide (43 mg, 36%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.53 (dd, J1=2.7 Hz, J2=1.8 Hz, 1H); 6.61 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.38 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.65 (dd, J1=1.5 Hz, J2=0.6 Hz, 1H); 7.85-7.78 (m, 3H); 8.66 (m, 1H); 8.74 (s, 1H); 8.86 (m, 2H); 8.91 (bs, 1H).

EXAMPLE 173
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-1-naphthamide

Obtained from the title compound of Example 1 (0.22 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-1-naphthamide (0.44 g, 87%) as a white solid.

δ (400 MHz, CDCl₃): 6.51-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (m, 4H); 7.62 (m, 5H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 174
N-[2-(2-Furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]quinoline-2-carboxamide

Obtained from the title compound of Example 1 (0.20 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent gave N-[2-(2-furyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-quinoline-2-carboxamide (0.32 g, 67%) as a white solid.

δ (400 MHz, CDCl₃): 6.51-6.48 (m, 1H); 6.60-6.58 (m, 1H); 7.34 (m, 4H); 7.62 (m, 4H); 7.79 (s, 1H); 8.13 (bs, 1H); 8.58 (s, 1H); 8.62 (d, J=2.4 Hz, 1H).

EXAMPLE 175
(2E)-3-(3,4-Dimethoxyphenyl)-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acrylamide

Obtained from the title compound of Example 21 (0.30 g), (2E)-(3,4-dimethoxyphenyl)acrylic acid (2.24 g, 10.8 mmol) and pyridine (6 mL, 74 mmol) by the procedure described in Example 20. Purification by column chromatography with silica gel and methylene chloride/methanol (0.3%) as eluent, followed by trituration with ethyl ether gave (2E)-3-(3,4-dimethoxyphenyl)-N-[6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(2-furyl)pyrimidin-4-yl]acrylamide (0.15 g, 27%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.26 (s, 3H); 2.76 (s, 3H); 3.81 (s, 3H); 3.83 (s, 3H); 6.24 (s, 1H); 6.75 (s, 1H); 7.32-6.99 (m, 6H); 7.64 (d, J=15.5 Hz, 1H); 7.98 (s, 1H); 8.51 (s, 1H).

EXAMPLE 176 AND EXAMPLE 177
2-(2-Furyl)-6-(2H-1,2,3-triazol-2-yl)pyrimidin-4-amine and 2-(2-furyl)-6-(1H-1,2,3-triazol-1-yl)pyrimidin-4-amine

Obtained from Intermediate 4 (0.51 g) by the procedure described in Example 21. Purification by column chromatography with silica gel and methylene chloride/methanol (from 0.5% to 2%) as eluent gave 2-(2-furyl)-(2H-1,2,3-triazol-2-yl)pyrimidin-4-amine (0.16 g, 27%) and 2-(2-furyl)-6-(1H-1,2,3-triazol-1-yl)pyrimidin-4-amine (0.30 g, 51%) as off-white solids.

EXAMPLE 176

δ (250 MHz, CDCl₃): 5.25 (bs, 2H); 6.55-6.57 (m, 1H); 6.99 (s, 1H); 7.25 (s, 1H); 7.60 (s, 1H); 7.92 (s, 1H).

EXAMPLE 177

δ (250 MHz, CDCl₃): 6.67-6.68 (m, 1H); 6.70 (s, 1H); 7.32 (s, 1H); 7.52 (bs, 2H); 7.89 (s, 1H); 7.99 (s, 1H); 8.86 (s, 1H).

EXAMPLE 178
N-[2-(2-Furyl)-6-(2H-1,2,3-triazol-2-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 176 (0.11 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from 0.5% to 1%) as eluent gave N-[2-(2-furyl)-6-(2H-1,2,3-triazol-2-yl)pyrimidinyl]propanamide (95 mg, 70%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.27 (t, J=7.6 Hz, 3H); 2.50 (c, J=7.6 Hz, 2H); 6.59 (dd, J1=3.3 Hz, J2=1.5 Hz, 1H); 7.46 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.64 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.96 (s, 2H); 8.26 (bs, 1H); 8.72 (s, 1H).

EXAMPLE 179
2-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(2H-1,2,3-triazol-2-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 176 (0.10 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent, followed by trituration with ethyl ether/n-hexane gave 2-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-6-(2H-1,2,3-triazol-2-yl)-pyrimidin-yl]acetamide (74 mg, 42%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.75 (s, 2H); 3.90 (s, 6H); 6.57 (dd, J1=3.6 Hz, J2=1.8 Hz, 1H); 6.84 (s, 1H); 6.89 (bs, 2H); 7.42 (dd, J1=3.6 Hz, J2=0.9 Hz, 1H); 7.62 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.96 (s, 2H); 8.20 (bs, 1H); 8.72 (s, 1H).

EXAMPLE 180
N-[2-(2-Furyl)-6-(1H-1,2,3-triazol-1-yl)pyrimidin-yl]propanamide

Obtained from the title compound of Example 177 (0.15 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (0.5%) as eluent, followed by trituration with ethyl ether gave N-[2-(2-furyl)-6-(1H-1,2,3-triazol-2-yl)pyrimidin-4-yl]propanamide (95 mg, 56%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 1.09 (t, J=7.4 Hz, 3H); 6.76 (dd, J1=3.4 Hz, J2=1.7 Hz, 1H); 7.51 (d, J=3.7 Hz, 1H); 7.98 (bs, 1H); 8.07 (d, J=1.0 Hz, 1H); 8.64 (s, 1H); 9.02 (d, J=1.0 Hz, 1H); 11.36 (s, 1H).

Intermediate 69. Ethyl 3-oxo-3-(1,3-thiazol-2-yl)propanoate

Obtained from 2-acetylthiazole (5.0 g) by the procedure described in Intermediate 35. The title compound was obtained (4.4 g, 56%) as an oil by distillation under reduced pressure.

δ (250 MHz, CDCl₃): 1.23 (t, 3H); 4.15 (m, 4H); 7.71 (d, J=5.3 Hz, 1H); 7.99 (d, J=5.3 Hz, 1H).

Intermediate 70. 2-(2-Furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-ol

Obtained from Intermediate 69 (2.30 g) and Intermediate 1 (2.0 g) by the procedure described in Intermediate 36. Purification by trituration with ethyl ether gave 2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-ol (1.3 g, 46%) as an off-white solid.

δ (250 MHz, CDCl₃): 6.76-6.78 (m, 1H); 6.87 (m, 1H); 7.62 (s, 1H); 8.05 (m, 1H); 8.09 (m, 2H); 12.92 (bs, 1H).

Intermediate 71. 4-Chloro-2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidine

Obtained from Intermediate 70 (2.80 g) by the procedure described in Intermediate 15. Purification by column chromatography with silica gel and methylene chloride/methanol (3%) as eluent gave 4-chloro-2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidine (1.87 g, 62%) as an off-white solid.

MS (M⁺): 263.

EXAMPLE 181
2-(2-Furyl)-6-(1,3-thiazol-2-yl)pyrimidin-amine

Obtained from Intermediate 71 (1.87 g) by the procedure described in Example 48. Purification by column chromatography with silica gel and methylene chloride/methanol (from 2% to 5%) as eluent gave 2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine (1.30 g, 74%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.66 (dd, J1=3.3 Hz, J2=1.6 Hz, 1H); 7.04 (s, 1H); 7.17 (dd, J1=3.3 Hz, J2=0.6 Hz, 1H); 7.30 (bs, 2H); 7.88-7.87 (m, 1H); 7.93 (d, J=3.0 Hz, 1H); 8.03 (d, J=3.0 Hz, 1H).

EXAMPLE 182
N-[2-(2-Furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 181 (0.22 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave N-[2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide (0.22 g, 90%) as an off-white solid.

δ (250 MHz, CDCl₃): 1.27 (t, J=7.6 Hz, 3H); 2.48 (c, J=7.6 Hz, 2H); 6.59 (dd, J1=3.6 Hz, J2=1.8 Hz, 1H); 7.40 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.55 (d, J=3.3 Hz, 1H); 7.64 (m, 1H); 8.02 (d, J=3.3 Hz, 1H); 8.13 (bs, 1H); 8.78 (s, 1H).

EXAMPLE 183
3-(3,4-Dimethoxyphenyl)-N-[2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide

Obtained from the title compound of Example 181 (0.2 g) by the procedure described in Example 14. Purification by column chromatography with silica gel and methylene chloride/methanol (1%) as eluent gave 3-(3,4-dimethoxyphenyl)-N-[2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-yl]propanamide (86 mg, 24%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.72 (t, J=7.6 Hz, 2H); 3.02 (t, J=7.6 Hz, 2H); 3.85 (s, 3H); 3.86 (s, 3H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.79-6.76 (m, 3H); 7.39 (d, J=3.3 Hz, 1H); 7.56 (d, J1=3.3 Hz, 1H); 7.63 (m, 1H); 8.03 (d, J=3.3 Hz, 1H); 8.05 (bs, 1H); 8.77 (s, 1H).

EXAMPLE 184
2,6-Di-2-furylpyrimidin-4-amine

Obtained from Intermediate 4 (0.2 g) by the procedure described in Example 54. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (7:3) as eluent gave 2,6-di-2-furylpyrimidin-4-amine (0.27 g, 89%) as an off-white solid.

δ (250 MHz, CDCl₃): 5.09 (bs, 2H); 6.62-6.46 (m, 3H); 7.28-7.17 (m, 2H); 7.57-7.47 (m, 2H).

EXAMPLE 185
N-(2,6-Di-2-furylpyrimidin-4-yl)-2-(3,4-dimethoxyphenyl)acetamide

Obtained from the title compound of Example 184 (0.2 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (7:3) as eluent gave N-(2,6-di-2-furylpyrimidin-4-yl)-2-(3,4-dimethoxyphenyl)acetamide (0.22 g, 60%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.72 (s, 2H); 3.90 (2s,6H); 6.55 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.57 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.83 (m, 1H); 6.88 (m, 2H); 7.32 (m, 2H); 7.60 (m, 2H); 8.12 (bs, 1H); 8.34 (s, 1H).

Intermediate 72. N-[6-Chloro-2-(2-furyl)pyrimidin-4-yl]acetamide

Obtained from Intermediate 4 (0.89 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and methylene chloride/methanol (from 0.5% to 1%) as eluent gave N-[6-chloro-2-(2-furyl)pyrimidinyl]acetamide (1.03 g, 95%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.21 (s, 3H); 6.56-6.57 (m, 1H); 7.29 (d, J=3.8 Hz, 1H); 7.60 (m, 1H); 8.03 (s, 1H); 8.29 (bs, 1H).

EXAMPLE 186
6-(1,3-Benzothiazol-2-yl)-21(2-furyl)pyrimidin-4-amine

To a solution of Intermediate 72 (0.15 g, 0.63 mmol) in anhydrous DMF (2 mL) were added 2-tributylstannanylbenzothiazole (0.32 g, 0.76 mmol) and bis(triphenylphosphine) palladium (II) chloride (90 mg, 0.13 mmol). The mixture was stirred at 80° C. overnight and more tributylstannanylbenzothiazole (0.30 g, 0.70 mmol) and bis(triphenylphosphine) palladium (II) chloride (70 mg, 0.10 mmol) were added. The mixture was stirred at 80° C. for 6 hours. The crude reaction was filtered through Celite® and the solvent was removed under reduced pressure. The residue was solved in chloroform (25 mL) and the resulting solution was washed with saturated solution of sodium bicarbonate (2×25 mL), water (2×25 mL), brine (25 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 3:7 to 2:3) as eluent gave N-[6-(1,3-benzothiazol-2-yl)-2-(2-furyl)pyrimidin-4-yl]acetamide (0.15 g, 71%). Hydrolisis of the resulting solid in methanol (5 mL) and 15% hydrochloric acid (10 mL) at 70° C. for 3 hours, followed by purification by column chromatography with silica gel and methylene chloride/methanol (2%) as eluent, gave the title compound (93 mg, 71%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 6.69 (dd, J1=3.3 Hz, J2=1.7 Hz, 1H); 7.22 (m, 2H); 7.41 (bs, 2H); 7.56 (m, 2H); 7.90 (dd, J1=1.7 Hz, J2=1.0 Hz, 1H); 8.12 (dd, J1=7.7 Hz, J2=1.0 Hz, 1H); 8.20 (dd, J1=7.7 Hz, J2=1.0 Hz, 1H).

Intermediate 73. 2-(5-Methyl-2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-ol

To a solution of potassium tertbutoxide (0.57 g, 6.03 mmol) in butanol (2 mL) were added Intermediate 69 (0.85 g, 4.26 mmol) and Intermediate 8 (0.75 g, 4.69 mmol). The mixture was heated at 135° C. for 3 hours. The crude reaction was poured into water (20 mL) and acidified with 10% hydrochloric acid (25 mL). The resulting solid was filtered, washed with water (2×25 mL) and dried. The title compound was obtained (0.64 g, 50%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.45 (s, 3H); 6.38 (d, J=2.8 Hz, 1H); 6.77 (s, 1H); 7.44 (d, J=2.8 Hz, 1H); 7.98 (d, J=2.8 Hz, 1H); 8.03 (d, J=2.8 Hz, 1H).

Intermediate 74. 4-Chloro-2-(5-methyl-2-furyl)-6-(1,3-thiazol-2-yl)pyrimidine

Obtained from Intermediate 73 (0.63 g) by the procedure described in Intermediate 15. Purification by column chromatography with silica gel and methylene chloride as eluent gave 4-chloro-2-(5-methyl-2-furyl)-6-(1,3-thiazol-2-yl)pyrimidine (0.44 g, 66%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.41 (s, 3H); 6.15 (d, J=4.8 Hz, 1H); 7.31 (d, J=3.2 Hz, 1H); 7.53 (d, J=3.2 Hz, 1H); 7.81 (s, 1H); 8.03 (d, J=4.8 Hz, 1H).

EXAMPLE 187
2-(5-Methyl-2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 74 (0.25 g) by the procedure described in Example 48. Purification by trituration with ethyl ether gave 2-(5-methyl-2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine (0.12 g, 53%) as an off-white solid.

δ (250 MHz, DMSO-d₆): 2.38 (s, 3H); 6.29 (dd, J1=3.0 Hz, J2=1.0 Hz, 1H); 6.99 (m, 1H); 7.08 (d, J=3.4 Hz, 1H); 7.28 (bs, 2H); 7.93 (dd, J1=3.0 Hz, J2=1.0 Hz, 1H); 8.03 (dd, J1=3.0 Hz, J2=1.0 Hz, 1H).

Intermediate 75. 6-(1,3-Thiazol-2-yl)-2-(2-thienyl)pyrimidin-ol

Obtained from Intermediate 69 (1.00 g) and Intermediate 13 (0.98 g) by the procedure described in Intermediate 73. Purification by trituration iwtyh ethyl ether gave the title compound (0.44 g, 66%) as an off-white solid.

MS (M⁺): 261.

Intermediate 76. 4-Chloro-6-(1,3-thiazol-2-yl)-2-(2-thienyl)pyrimidine

Obtained from Intermediate 75 (0.45 g) by the procedure described in Intermediate 15. Purification by column chromatography with silica gel and methylene chloride/methanol (5%) as eluent gave 4-chloro-6-(1,3-thiazol-2-yl)-2-(2-thienyl)pyrimidine (0.48 g, 99%) as an off-white solid.

MS (M⁺): 279.

EXAMPLE 188
6-(1,3-Thiazol-2-yl)-2-(2-thienyl)pyrimidin-4-amine

Obtained from Intermediate 76 (0.25 g) by the procedure described in Example 48. Purification by trituration with ethyl ether gave 6-(1,3-thiazol-2-yl)-2-(2-thienyl)pyrimidin-4-amine (94 mg, 40%) as an off-white solid.

δ (250 MHz, CDCl₃): 5.08 (bs, 2H); 7.10 (s, 1H), 7.14 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H); 7.46 (dd, J1=4.8 Hz, J2=1.2 Hz, 1H); 7.52 (d, J=3.3 Hz, 1H); 7.96 (d, J=3.3 Hz, 1H); 8.01 (dd, J1=3.6 Hz, J2=1.2 Hz, 1H).

EXAMPLE 189
2-(3,4-Dimethoxyphenyl)-N-[6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 116 (0.14 g) by the procedure described in Example 2. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 1:1 to pure ethyl acetate) as eluent gave 2-(3,4-dimethoxyphenyl)-N-[6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]acetamide (0.17 g, 75%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.73 (s, 2H); 3.89 (s, 3H); 3.90 (s, 3H); 6.59 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 6.82 (m, 1H); 6.87 (m, 2H); 7.39 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.52 (d, J=3.3 Hz, 1H); 7.63 (m, 1H); 8.00 (d, J=3.3 Hz, 1H); 8.26 (bs, 1H); 8.50 (s, 1H).

Intermediate 77. 6-Amino-2-(1,3-thiazol-2-yl)pyrimidin-4-ol

To a solution of potassium tertbutoxide (2.5 g, 22.24 mmol) in butanol (12.7 mL), ethyl cyanoacetate (2.37 mL, 22.24 mmol) and thiazole-2-carboxamidine (HCl) (1.82 g, 11.12 mmol) were added. The mixture was heated at 135° C. for 3 hours. The solvent was evaporated and the residue was diluted with water (50 mL). The aqueous solution was neutralized by addition of acetic acid, washed with ethyl ether (2×25 mL) and purified using a Bond-Elut C18 column. The final product was eluted using methanol as eluent. Final purification by flash chromatography with silica gel and chloroform/methanol (9:1) as eluent gave 6-amino-2-(1,3-thiazol-2-yl)pyrimidin-4-ol (350 mg, 16%) as a yellow solid.

δ (300 MHz, DMSO-d₆): 5.21 (s, 1H), 6.72 (s, 2H), 8.00-8.10 (m, 2H), 11.60 (s, 1H).

Intermediate 78. 6-Chloro-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

A solution of Intermediate 77 (687 mg, 3.54 mmol) in phosphorus oxychloride (2.14 mL, 23.0 mmol) was heated at 100° C. for 2 hours. The solvent was removed under reduced pressure and the resulting residue was treated with ice-water. The solution was neutralized with solid sodium bicarbonate and extracted with chloroform (3×50 mL). The combined organic extracts were washed with water (2×50 mL), dried (MgSO₄), and the solvent removed under reduced pressure, to yield 6-chloro-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (122.4 mg, 16%) as a brown solid.

δ (300 MHz, CDCl₃): 5.37 (bs, 2H); 6.47 (s, 1H); 7.54 (d, J=3.1 Hz, 1H); 8.01 (d, J=3.1 Hz, 1H).

EXAMPLE 190
6-(1H-Pyrazol-1-yl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

A suspension of Intermediate 78 (122.4 mg, 0.58 mmol), pyrazole (58.5 mg, 0.86 mmol) and potassium carbonate (118.9 mg, 0.86 mmol) in DMSO (4 mL) was stirred at 150° C. during 6 hours. After this reaction time, more pyrazole (58.5 mg, 0.86 mmol) and potassium carbonate (118.9 mg, 0.86 mmol) were added and the mixture was stirred at 150° C. overnight. The reaction mixture was diluted with water (25 mL) and extracted with chloroform (2×25 mL). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel and methylene chloride/methanol (9:1) as eluent, followed by a trituration with ethyl ether gave of 6-(1H-pyrazol-1-yl)-2-(1,3-thiazol-2-yl)pyrimidin-amine (50 mg, 35%) as an off-white solid.

δ (300 MHz, CDCl₃): 5.30 (bs, 2H); 6.50 (dd, J1=2.7 Hz, J2=1.6 Hz, 1H); 7.04 (s, 1H); 7.54 (d, J=3.0 Hz, 1H); 7.78 (s, 1H); 8.04 (d, J=3.3 Hz, 1H); 8.69 (d, J=1.9 Hz, 1H).

EXAMPLE 191
2-(3,4-Dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]acetamide

Obtained from the title compound of Example 190 (50 mg) and 3,4-dimethoxyphenylacetyl chloride (106 μL, 0.615 mmol) by the procedure described in Example 150. Purification by column chromatography with silica gel using chloroform/methanol (75:1) as eluent gave 2-(3,4-dimethoxyphenyl)-N-[6-(1H-pyrazol-1-yl)-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]acetamide (35 mg, 40%) as a solid foam.

δ (300 MHz, CDCl₃): 3.74 (s, 2H); 3.89 (s, 6H); 6.53 (dd, J1=2.7 Hz, J2=1.4 Hz, 1H); 6.83 (s, 1H); 6.85-6.89 (m, 2H); 7.56 (d, J=3.0 Hz, 1H); 7.83 (m, 1H); 8.03 (d, J=3.3 Hz, 1H), 8.26 (s, 1H); 8.66 (m, 1H); 8.77 (s, 1H).

EXAMPLE 192
2-(2-Furyl)-N-methyl-6-(1,3-thiazol-2-yl)pyrimidin-4-amine

A suspension of Intermediate 71 (0.2 g, 0.76 mmol) in a solution of 33% methylamine in ethanol (5 mL) was heated at 40° C. in a pressure reactor for 2 hours. The solvent was partially removed under reduced pressure. The resulting solid was filtered, washed with ethyl ether (25 mL), and dried. 2-(2-Furyl)-N-methyl-6-(1,3-thiazol-2-yl)pyrimidin-4-amine was obtained (90 mg, 46%) as an off-white solid.

δ (250 MHz, CDCl₃): 3.06 (d, J=5.2 Hz, 3H); 5.40 (bs, 1H); 6.55 (dd, J1=3.3 Hz, J2=1.8 Hz, 1H); 7.05 (s, 1H); 7.34 (dd, J1=3.3 Hz, J2=0.9 Hz, 1H); 7.52 (d, J=3.3 Hz, 1H); 7.61 (dd, J1=1.8 Hz, J2=0.9 Hz, 1H); 7.96 (d, J=3.3 Hz, 1H).

EXAMPLE 193
N-(Cyclopropylmethyl)-2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine

To a solution of Intermediate 71 (0.2 g, 0.76 mmol) in anhydrous DMF (5 mL) was added aminomethylcyclopropane (60 mg, 0.84 mmol) and cesium carbonate (0.27 g, 0.84 mmol). The mixture was heated at 80° C. for 8 hours. The solution was poured into water (25 mL) and extracted with ethyl acetate (2×15 mL). The organic layer was washed with water (2×10 mL) and brine (10 mL), dried (Na₂SO₄), and the solvent removed under reduced pressure. The resulting solid was purified by column chromatography with silica gel and ethyl acetate/n-hexane (from 10% to 20%) as eluent to give N-(cyclopropylmethyl)-2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine (0.11 g, 81%) as an off-white solid.

δ (250 MHz, CDCl₃): 0.32-0.26 (m, 2H); 0.63-0.55 (m, 2H); 1.25-1.05 (m, 1H); 3.26 (bs, 2H); 5.48 (bs, 1H); 6.56-6.54 (m, 1H); 7.02 (s, 1H); 7.33 (d, J=3.3 Hz, 1H); 7.51 (d, J=3.0 Hz, 1H); 7.51 (d, J=3.0 Hz, 1H); 7.95 (d, J=3.3 Hz, 1H).

EXAMPLE 194
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(2-furyl)-6-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 71 (0.20 g) by the procedure described in Example 193. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (from 20% to 35%) as eluent gave N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(2-furyl)-6-(1,3-thiazol-2-yl)-pyrimidin-4-amine (0.13 g, 66%) as an off-white solid.

δ (250 MHz, CDCl₃): 2.92 (t, J=6.9 Hz, 2H); 3.69 (bs, 2H); 3.86 (s, 3H); 3.87 (s, 3H); 5.24 (bs, 1H); 6.56-6.54 (m, 1H); 6.84-6.75 (m, 3H); 7.04 (bs, 1H); 7.33 (d, J=3.3 Hz, 1H); 7.51 (d, J=3.0 Hz, 1H); 7.61 (bs, 1H); 7.95 (d, J=3.3 Hz, 1H).

EXAMPLE 195
N-(Cyclopropylmethyl)-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 52 (100 mg) and cyclopropylmethylamine (81 mg, 98 μl) by the procedure described in Example 119. Purification by column chromatography using a 10 g silica Bond-Elut cartridge eluting with n-hexane/ethyl acetate (from 1:0 to 3:7), followed by a second column chromatography using a 10 g silica Bond-Elut cartridge and n-hexane/ethyl acetate (from 4:1 to 3:2) as eluent gave N-cyclopropylmethyl)-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (85 mg, 75%) as an off-white solid.

m.p.: 135.9-136.4° C.

δ (400 MHz, CDCl₃): 0.33 (m, 2H); 0.60 (m, 2H); 1.14 (m, 1H); 3.27 (bs, 2H); 5.48 (bs, 1H); 6.56-6.58 (m, 1H); 6.67 (s, 1H); 7.33 (d, J=3.1 Hz, 1H); 7.47 (m, 1H); 7.56 (s, 1H); 8.00 (m, 1H).

EXAMPLE 196
N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 52 (100 mg) and 2-(3,4-dimethoxyphenyl)ethylamine (207 mg, 192 μl) by the procedure described in Example 119. Purification by column chromatography using a 10 g silica Bond-Elut cartridge eluting with chloroform/methanol (99:1), followed by a second column chromatography using a 10 g silica Bond-Elut cartridge and n-hexane/ethyl acetate (from 1:0 to 3:2) as eluent gave N-[2-(3,4-dimethoxyphenyl)ethyl]-6-(2-furyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (110 mg, 71%) as solid foam.

m.p.: 83.0-83.8° C.

δ (400 MHz, CDCl₃): 2.94 (t, J=6.8 Hz, 2H); 3.70 (bs, 2H); 3.87 (s, 3H); 3.88 (s, 3H); 5.30 (bs, 1H); 6.55-6.58 (m, 1H); 6.64 (s, 1H); 6.76-6.85 (m, 3H); 7.33 (d, J=3.2 Hz, 1H); 7.47 (d, J=2.7 Hz, 1H); 7.55 (s, 1H); 7.99 (d, J=3.1 Hz; 1H).

EXAMPLE 197
6-(2-Furyl)-N-(2-pyridin-3-ylethyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

Obtained from Intermediate 52 (100 mg) and 2-pyridin-3-yl-ethylamine (139 mg, 1.14 mmol) by the procedure described in Example 119. Purification by column chromatography using a 10 g silica Bond-Elut cartridge eluting with chloroform/methanol (from pure chloroform to 98:2), followed by a second column chromatography using a 10 g silica Bond-Elut cartridge and methylene chloride/ethyl ether/methanol (from 1:1:0 to 1:1:0.1) as eluent gave 6-(2-furyl)-N-(2-pyridin-3-ylethyl)-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (103 mg, 77%) an oil.

δ (400 MHz, CDCl₃): 3.02 (t, J=7.2 Hz, 2H); 3.75 (bs, 2H); 5.30 (bs, 1H); 6.58 (dd, J1=3.5 Hz, J2=2.0 Hz, 1H); 6.66 (s, 1H); 7.25-7.28 (m, 1H); 7.35 (d, J=3.5 Hz, 1H); 7.48 (d, J=3.1 Hz, 1H); 7.56 (s, 1H); 7.60 (m, 1H); 8.01 (d, J=13.1 Hz, 1H); 8.51 (m, 1H); 8.56 (d, J=2.4 Hz, 1H).

EXAMPLE 198
6-(2-Furyl)-N-[(1S*,2R*)-2-phenylcyclopropyl]-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (*relative trans configuration)

Obtained from Intermediate 52 (100 mg) and trans-2-phenylcyclopropylamine (187 mg, 1.40 mmol) by the procedure described in Example 119. Purification by column chromatography using a 10 g silica Bond-Elut cartridge eluting with n-hexane/ethyl acetate (from 1:0 to 6:4) gave 6-(2-furyl)-N-[(1S*,2R*)-2-phenylcyclopropyl]-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (*relative trans configuration) (115 mg, 84%) as a solid foam.

m.p.: 90.0-91.9° C.

δ (400 MHz, CDCl₃): 1.32-1.37 (m, 1H); 1.46-1.51 (m, 1H); 2.15-2.20 (m, 1H); 2.81 (bs; 1H); 5.82 (bs, 1H); 6.56 (m, 1H); 6.93 (s, 1H); 7.19-7.38 (m, 6H); 7.47 (m, 1H); 7.54 (s, 1H); 7.99 (m, 1H).

EXAMPLE 199
Ethyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate

Obtained from the title compound of Example 1 (0.79 g) by the procedure described in Example 139. Purification by column chromatography with silica gel and chloroform as eluent, followed by a preparative HPLC/MS purification gave ethyl [2-(2-furyl)_6-1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate (45 mg, 2%) as an off-white solid.

m.p.: 121.3-121.8° C.

δ (400 MHz, CDCl₃): 1.34 (t, J=7.2 Hz, 3H); 4.30 (q, J=7.2 Hz, 2H); 6.49 (m, 1H); 6.58 (m, 1H); 7.34 (d, J=3.1 Hz, 1H); 7.62 (s, 1H); 7.64 (s, 1H), 7.79 (s, 1H), 8.37 (s, 1H), 8.65 (d, J=2.7 Hz, 1H).

Intermediate 79. Cyclopentylmethyl 4-nitrophenyl carbonate

To a solution of cyclopentylmethanol (0.54 mL, 4.99 mmol) and pyridine (0.60 mL, 7.43 mmol) in ethanol free chloroform (5 mL), cooled at 0-5° C. and under nitrogen, was added a solution of 4-nitrophenylchloroformate (1.26 g, 6.24 mmol) in ethanol free chloroform (5 mL). The reaction mixture was stirred at 0-5° C. for 1 hour and diluted with chloroform (150 mL). The organic layer was washed with water (50 mL), 2N hydrochloric acid (40 mL), water (2×50 mL), 4% sodium bicarbonate (2×40 mL) and water (50 mL), dried (MgSO₄), and the solvent removed under reduced pressure. The resulting oil was stirred in a mixture of ethyl ether/isopropyl ether at 0-5° C. for 1 hour to give a solid that was filtered, washed with isopropyl ether, and discarded. The mother liquors of filtration were combined, diluted with an equal volume of n-hexane, stirred at room temperature for 15 minutes. The resulting solid was filtered and the mother liquors were concentrated under reduced pressure to give cyclopentylmethyl 4-nitrophenyl carbonate (1.04 g, 78%) as an oil.

δ (300 MHz, CDCl₃): 1.23-1.40 (m, 2H); 1.56-1.74 (m, 4H); 1.77-1.89 (m, 2H); 2.32 (h, J=9.0 Hz, 1H); 4.19 (d, J=9.0 Hz, 1H); 7.39 (d, J=9.0 Hz, 2H); 8.29 (d, J=9.0 Hz, 2H).

EXAMPLE 200
Cyclopentylmethyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-carbamate

To a solution of the title compound of Example 1 (0.34 g, 1.51 mmol) in anhydrous tetrahydrofuran (15 mL), cooled at −78° C. and under nitrogen, was added a solution of 1.6M solution of n-butyllithium in hexanes (1.18 ml, 1.89 mmol). After 30 min at −78° C. a solution of Intermediate 79 (0.5 g, 1.89 mmol) in anhydrous tetrahydrofuran (8 mL) was added. The reaction mixture was maintained 30 minutes at −78° C., allowed to warm to room temperature and stirred at this temperature for 68 hours. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (MgSO₄), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (4:1) as eluent gave cyclopentylmethyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate (180 mg, 34%) of as a solid foam.

m.p.: 60.0-61.3° C.

δ (400 MHz, CDCl₃): 1.24-1.34 (m, 2H); 1.54-1.68 (m, 4H); 1.74-1.82 (m, 2H); 2.22-2.32 (m, 1H); 4.13 (m, 2H); 6.50 (m, 1H); 6.59 (m, 1H); 7.34 (d, J=3.1 Hz, 1H); 7.63 (m, 1H); 7.64 (s, 1H); 7.79 (s, 1H); 8.36 (s, 1H); 8.65 (d, J=2.7 Hz, 1H).

EXAMPLE 201
Benzyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-yl]carbamate

Obtained from the title compound of Example 1 (0.79 g) and benzyl chloroformate (0.2 mL, 1.40 mmol) by the procedure described in Example 200. Purification by column chromatography using silica gel and n-hexane/ethyl acetate (3:1) as eluent, followed by a HPLC/MS purification, gave benzyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate (38 mg, 10%) as an off-white solid.

δ (400 MHz, CDCl₃): 5.27 (s, 2H); 6.49 (m, 1H); 6.57 (dd, J1=3.5 Hz, J2=1.6 Hz, 1H); 7.30-7.44 (m, 6H); 7.62 (s, 1H); 7.73 (s, 1H); 7.80 (s, 1H); 8.38 (s, 1H); 8.64 (d, J=2.7 Hz, 1H).

Intermediate 80. 3,4-Dimethoxybenzyl 4-nitrophenyl carbonate

Obtained from 3,4-dimethoxybenzylalcohol (0.50 g, 2.97 mmol) by the procedure described in Intermediate 79. Purification by trituration with a mixture of ethyl ether/isopropyl ether (1:2), followed by a second trituration with ethyl ether gave the title compound (0.71 g, 71%).

δ (300 MHz, CDCl₃): 3.91 (s, 3H); 3.92 (s, 3H); 5.24 (s, 2H); 6.89 (d, J=8.4 Hz, 1H); 6.99 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H); 7.04 (d, J=2.1 Hz, 1H); 7.38 (d, J=9.3 Hz, 2H); 9.28 (d, J=9.3 Hz, 2H).

EXAMPLE 202
3,4-Dimethoxybenzyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate

Obtained from the title compound of Example 1 (0.20 g) and Intermediate 80 (0.37 g, 1.10 mmol) by the procedure described in Example 200. Purification by column chromatography using silica gel and n-hexane/ethyl acetate (from 2:1 to 0:1) as eluent gave 3,4-dimethoxybenzyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate (90 mg, 24%) as an off-white solid.

m.p.: 147.8-148.5° C.

δ (400 MHz, CDCl₃): 3.88 (s, 3H); 3.91 (s, 3H); 5.21 (s, 2H); 6.50 (m, 1H); 6.58 (m, 1H); 6.85-7.01 (m, 3H); 7.33 (m, 1H); 7.62 (s, 1H); 7.68 (s, 1H); 7.80 (s, 1H); 8.38 (s, 1H); 8.65 (m, 1H).

Intermediate 81. 4-Nitrophenyl pyridin-3-ylmethyl carbonate

Obtained from pyridin-3-ylmethanol (0.51 g, 4.63 mmol) by the procedure described in Intermediate 79. Purification by trituration with a mixture of ethyl ether/diisopropyl ether (1:2), followed by a second trituration with ethyl ether gave the title compound (0.57 g, 45%).

δ (300 MHz, CDCl₃): 5.35 (s, 2H); 7.36 (s, 1H); 7.39 (d, J=9.0 Hz, 2H); 7.75-7.83 (m, 1H); 8.29 (d, J=9.0 Hz, 2H); 8.64-8.65 (m, 1H); 8.71 (s, 1H).

EXAMPLE 203
Pyridin-3-ylmethyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-carbamate

Obtained from the title compound of Example 1 (0.375 g) and Intermediate 81 (0.57 g, 2.06 mmol) by the procedure described in Example 200. Purification by trituration with ethyl ether gave pyridin-3-ylmethyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidinyl]carbamate (0.26 g, 43%) as an off-white solid.

m.p.: 253.6-255.8° C.

δ (400 MHz, DMSO-d₆): 5.29 (s, 2H); 6.66 (s, 1H); 6.74 (s, 1H); 7.45 (m, 2H); 7.88-7.96 (m, 3H); 8.23 (s, 1H); 8.57 (s, 1H); 8.69 (s, 1H); 8.77 (s, 1H); 11.17 (s, 1H).

Intermediate 82. 4-Methoxyphenyl 4-nitrophenyl carbonate

Obtained from 4-methoxyphenol (0.50 g, 4.03 mmol) by the procedure described in Intermediate 79. Purification by trituration with isopropyl ether, followed by a second trituration with ethyl ether gave 4-methoxyphenyl 4-nitrophenyl carbonate (0.79 g, 68%).

δ (300 MHz, CDCl₃): 3.84 (s, 3H); 6.94 (d, J=9.0 Hz, 2H); 7.20 (d, J=9.0 Hz, 2H); 7.51 (d, J=9.0 Hz, 2H); 8.35 (d, J=9.0 Hz, 2H).

EXAMPLE 204
4-Methoxyphenyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]-carbamate

Obtained from the title compound of Example 1 (0.49 g) and Intermediate 82 (0.78 g, 2.70 mmol)) by the procedure described in Example 200. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 5:2 to 2:1) as eluent, followed by a trituration with a mixture of diethyl ether/diisopropyl ether (1:1) gave 4-methoxyphenyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate (0.11 g, 13%) as an off-white solid.

m.p.: 171.9-173.0° C.

δ (400 MHz, CDCl₃): 3.82 (s, 3H); 6.49 (m, 1H); 6.61 (m, 1H); 6.92 (m, 2H); 7.13 (m, 2H); 7.37 (d, J=3.1 Hz, 1H); 7.65 (m, 1H); 7.77 (s, 1H); 7.94 (s, 1H); 8.40 (s, 1H); 8.65 (d, J=2.7 Hz, 1H).

Intermediate 83. 3,4-Dimethoxyphenyl 4-nitrophenyl carbonate

Obtained from 3,4-dimethoxyphenol (0.50 g, 3.24 mmol) by the procedure described in Intermediate 79. Purification by trituration with isopropyl ether gave 3,4-dimethoxyphenyl 4-nitrophenyl carbonate (0.96 g, 92%).

δ (300 MHz, CDCl₃): 3.90 (s, 6H); 6.82 (s, 1H); 6.85-6.91 (m, 2H); 7.51 (d, J=9.0 Hz, 2H); 8.32 (d, J=9.0 Hz, 2H).

EXAMPLE 205
3,4-Dimethoxyphenyl [2-(2-furyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl]carbamate

Obtained from the title compound of Example 1 (0.54 g) and Intermediate 83 (0.95 g, 2.98 mmol)) by the procedure described in Example 200. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 2:1 to 1:2) as eluent, followed by preparative HPLC/MS purification gave 3,4-dimethoxyphenyl [2-(2-furyl-6-(1H-pyrazol-1-yl)pyrimidin-yl]carbamate (46 mg, 5%) as an off-white solid.

δ (300 MHz, CDCl₃): 3.89 (s, 3H); 3.90 (s, 3H); 6.49 (dd, J1=2.7 Hz; J2=1.6 Hz, 1H); 6.61 (dd, J1=3.4 Hz, J2=1.8 Hz, 1H); 6.72-6.90 (m, 3H); 7.38 (d, J=3.3 Hz; 1H); 7.66 (m, 1H); 7.78 (m, 1H); 8.05 (s, 1H); 8.40 (s, 1H); 8.65 (d, J=2.7 Hz, 1H).

EXAMPLE 206
(N-(2-Furan-2-yl-6-pyrazol-1-yl-pyrimidinyl)-2-methylamino acetamide

To 5 mL dichloromethane were added 0.3 g (1.3 mmol) of the compound of Example 1 (i.e., Compound 1), 0.22 g chloroacetyl chloride (0.20 mmol, 1.5 eq) and 0.16 g pyridine. The reaction mixture was stirred at r/t for 2 hours. The reaction was quenched with 5 mL saturated sodium bicarbonate and extracted; the aqueous solution was washed with an additional 5 mL dichloromethane. The organic layers combined and dried under sodium sulfate, concentrated to a yellow solid (0.4 g, 100% crude yield).

To 1 mL DMF were added 100 mg the product obtained above, 50 mg methylamine HCl salt, and 100 mg potassium carbonate. The reaction mixture was heated at 80 C for 6 hours. Purified by Prep LC-MS, clean separation. The fractions were concentrated, redissolved in dichloromethane and extracted with diluted ammonia solution to remove the TFA. The organic layer was dried under sodium sulfate, concentrated to a slight yellow solid (25 mg, 25.4% yield). LCMS (APCI) m/z 299.0 (MH⁺). δ (300 MHz, CDCl₃): 2.52 (s, 3H), 3.43 (s, 2H), 6.48-6.50 (m, 1H), 6.57-5.59 (m, 1H); 7.36 (d, J=3.3 Hz, 1H), 7.64-7.65 (m, 1H), 7.80 (s, 1H), 8.62-8.67 (m, 2H), 9.97 (s, 1H).

EXAMPLE 207
2-Dimethylamino-N-(2-furan-2-yl-6-pyrazol-1-yl-pyrimidin-4-yl)-acetamide

To 5 mL dichloromethane were added 0.3 g (1.3 mmol) of the compound of Example 1 (i.e., Compound 1), 6.22 g chloroacetyl chloride (0.20 mmol, 1.5 eq) and 0.16 g pyridine. The reaction mixture was stirred at r/t for 2 hours. The reaction was quenched with 5 mL saturated sodium bicarbonate and extracted; the aqueous solution was washed with an additional 5 mL dichloromethane. The organic layers combined and dried under sodium sulfate, concentrated to a yellow solid (0.4, 100% crude yield).

To 1 mL DMF were added 100 mg the product obtained above, 1.0 mL dimethylamine in THF (2.0 M). The reaction mixture was stirred at r/t for 2 hours. Purified by Prep LC-MS, clean separation. The fractions were concentrated, redissolved in dichloromethane and extracted with diluted ammonia solution to remove the TFA. The organic layer was dried under sodium sulfate, concentrated to a slight yellow solid (50 mg, 48.6% yield). LCMS (APCI) m/z 313.0 (MH⁺). δ (300 MHz, CDCl₃): 2.48 (s, 6H), 3.32 (s, 2H), 6.46-6.48 (m, 1H), 6.54-6.56 (m, 1H), 7.32 (s, 1H), 7.61 (s, 1H), 7.77 (s, 1H), 8.55-8.60 (m, 2H), 10.0 (s, 1H).

EXAMPLE 208
2-Methylamino-N-[2-(5-methyl-furan-2-yl)-6-thiazol-2-yl-pyrimidin-4-yl]-acetamide

The compound was obtained by starting with the product of Example 187 (i.e., Compound 187) and following the procedure of Example 206. The mixture was purified by RPHPLC-MS to give 19.5 mg product as the TFA salt. LCMS (APCI) m/z 330.0 (MH⁺).

EXAMPLE 209
2-Dimethylamino-N-[2-(5-methyl-furan-2-yl)-6-thiazol-2-yl-pyrimidin-4-yl]-acetamide

The compound was obtained by starting with the product of Example 187 (i.e., Compound 187) and following the procedure of Example 207. The mixture was purified by RPHPLC-MS to give 28.0 mg product as the TFA salt. LCMS (APCI) m/z 330.0 (MH⁺). δ (300 MHz, CDCl₃): 2.45 (s, 3H), 2.99 (s, 3H), 3.40 (m, 3H), 4.05 (s, 2H), 6.21 (d, J=3.3 Hz, 1H), 7.30 (d, J=3.3 Hz, 1H), 7.32 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H).

EXAMPLE 210
N-[2-(5-Methylfuran-2-yl)-6-thiazol-2-yl-pyrimidin-4-yl]-2-pyridin-3-yl-propionamide

To 3 mL THF were added 200 mg (1.5 mmol, 1 eq) 3-pyridylacetic acid, 200 mg (1.1 eq) oxalyl chloride, followed by a drop of DMF. The reaction mixture was stirred at r/t for 1 hour. Solvents was removed by nitrogen flow and the residue was resuspended in 3 mL dichloromethane followed by the aniline and 0.2 mL pyridine. The reaction mixture was stirred at r/t for 6 hours. The reaction mixture was extracted with 3 mL saturated sodium bicarbonate, dried under sodium sulfate and concentrated, purified by prep TLC plates using 95% chloroform, 4.9% methanol and 0.1% ammonia. Obtained a white solid. LCMS (APCI) m/z 377.9 (MH⁺). δ (300 MHz, CDCl₃): 2.45 (s, 3H), 3.78 (s, 2H), 6.18-6.20 (m, 1H), 7.30-7.34 (m, 2H), 7.53 (d, J=3.3 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.99 (d, J=3.3 Hz, 1H), 8.32 (s, 1H), 8.58 (s, 2H), 8.69 (s, 1H).

EXAMPLE 211
N-[2-(5-Methylfuran-2-yl)-6-thiazol-2-yl-pyrimidin-4-yl]-3-pyridin-3-yl-propionamide

Compound 211 was prepared as shown in Scheme 9 according to the procedure described in Example 210. LCMS (APCI) m/z 392.0 (MH⁺). δ (300 MHz, CDCl₃): 2.45 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H), 6.18-6.20 (m, 1H), 7.19-7.23 (m, 1H), 7.31 (d, J=3.3 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.57-7.60 (m, 1H), 8.02 (d, J=3.3 Hz, 1H), 8.19 (s, 1H), 8.49 (d, J=3.3 Hz, 1H), 8.52 (s, 1H), 8.70 (s, 1H).

Number	Date	Country	Kind
P2000302951	Dec 2003	ES	national
PCT/EP04/11086	Oct 2004	EP	regional

2,6 Bisheteroaryl-4-Aminopyrimidines as Adenosine Receptor Antagonists

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