3-OXO-3-(TETRAHYDRO-PYRAN-4-YL)-PROPIONIC ACID ETHYL ESTER

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g, 0.498 mmol) and 4-[(2,3-dichlorophenyl)methyl]-1H-pyrazole-3,5-diamine (0.128 g, 0.498 mmol) was added in Acetic Acid (2 mL). The reaction vessel was subjected to MW irradiation at 100° C. for 40 min then 70° C. for 180 min. The mixture was concentrated. The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) and then repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product. 1 M ether/HCl (3 mL) was added to the solution of the product in MeOH (10 mL). The mixture was stirred for 3 h. The solvent was removed to give the titled product as solid (55 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.84 (m, 4H) 2.63-2.83 (m, 1H) 3.22-3.46 (m, 2H) 3.93 (m, 2H) 4.01 (s, 2H) 5.63 (s, 1H) 6.90 (d, J=7.07 Hz, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.43-7.59 (m, 1H) 11.92 (br. s., 1H). LC/MS: MS (ES+) m/e 393.0 [M+H]+. The reaction vessel was subjected to MW irradiation at 100° C. for 40 min The mixture was concentrated The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product The solvent was removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g, 0.498 mmol) and 4-[(2,3-dichlorophenyl)methyl]-1H-pyrazole-3,5-diamine (0.128 g, 0.498 mmol) was added in Acetic Acid (2 mL). The reaction vessel was subjected to MW irradiation at 100° C. for 40 min then 70° C. for 180 min. The mixture was concentrated. The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) and then repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product. 1 M ether/HCl (3 mL) was added to the solution of the product in MeOH (10 mL). The mixture was stirred for 3 h. The solvent was removed to give the titled product as solid (55 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.84 (m, 4H) 2.63-2.83 (m, 1H) 3.22-3.46 (m, 2H) 3.93 (m, 2H) 4.01 (s, 2H) 5.63 (s, 1H) 6.90 (d, J=7.07 Hz, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.43-7.59 (m, 1H) 11.92 (br. s., 1H). LC/MS: MS (ES+) m/e 393.0 [M+H]+. The reaction vessel was subjected to MW irradiation at 100° C. for 40 min The mixture was concentrated The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product The solvent was removed

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.2 g, 0.999 mmol) and 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (0.270 g, 0.999 mmol) was added Methanol (4 mL) and hydrochloric acid (0.4 mL, 0.500 mmol) in methanol (1.25 N). The reaction vessel was sealed and heated at 65° C. for 6 days. The reaction mixture was concentrated to 1 mL. The solid was filtered and wash with methanol (2 ml×3) and dried (0.19 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.84 (m, 4H) 2.47 (s, 3H) 2.58-2.75 (m, 1H) 3.34-3.39 (m, 2H) 3.85 (s, 2H) 3.93 (dd, J=11.24, 3.16 Hz, 2H) 5.28 (s, 2H) 5.41 (d, J=1.52 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.28 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.18 (s, 1H); LC/MS: MS (ES+) m/e 407.2 [M+H]+. The reaction vessel was sealed The reaction mixture was concentrated to 1 mL The solid was filtered wash with methanol (2 ml×3) dried (0.19 g, 45%)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.2 g, 0.999 mmol) and 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (0.270 g, 0.999 mmol) was added Methanol (4 mL) and hydrochloric acid (0.4 mL, 0.500 mmol) in methanol (1.25 N). The reaction vessel was sealed and heated at 65° C. for 6 days. The reaction mixture was concentrated to 1 mL. The solid was filtered and wash with methanol (2 ml×3) and dried (0.19 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.84 (m, 4H) 2.47 (s, 3H) 2.58-2.75 (m, 1H) 3.34-3.39 (m, 2H) 3.85 (s, 2H) 3.93 (dd, J=11.24, 3.16 Hz, 2H) 5.28 (s, 2H) 5.41 (d, J=1.52 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.28 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.18 (s, 1H); LC/MS: MS (ES+) m/e 407.2 [M+H]+. The reaction vessel was sealed The reaction mixture was concentrated to 1 mL The solid was filtered wash with methanol (2 ml×3) dried (0.19 g, 45%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 5-amino-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (136 mg, 0.5 mmol) in ethanol (1 mL) were added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.5 mmol) and 4 M HCl solution in dioxane (25 uL, 0.1 mmol). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes. Reaction was cooled down. The precipitate was collected by filtration. It was washed with acetic acid (1 mL), then methanol (1 mL) and dried. The titled compound was obtained. (52 mg, 25%); LC/MS: MS (ES+) m/e 408 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (dd, J=12.51, 4.17 Hz, 1H) 1.73-1.80 (m, 3H) 2.46 (s, 3H) 2.72 (s, 1H) 3.34-3.45 (m, 2H) 3.83 (s, 2H) 3.93 (br. s., 2H) 5.51 (s, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.29 (t, J=7.71 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 11.46 (s, 1H). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes Reaction was cooled down The precipitate was collected by filtration It was washed with acetic acid (1 mL) methanol (1 mL) and dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 5-amino-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (136 mg, 0.5 mmol) in ethanol (1 mL) were added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.5 mmol) and 4 M HCl solution in dioxane (25 uL, 0.1 mmol). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes. Reaction was cooled down. The precipitate was collected by filtration. It was washed with acetic acid (1 mL), then methanol (1 mL) and dried. The titled compound was obtained. (52 mg, 25%); LC/MS: MS (ES+) m/e 408 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (dd, J=12.51, 4.17 Hz, 1H) 1.73-1.80 (m, 3H) 2.46 (s, 3H) 2.72 (s, 1H) 3.34-3.45 (m, 2H) 3.83 (s, 2H) 3.93 (br. s., 2H) 5.51 (s, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.29 (t, J=7.71 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 11.46 (s, 1H). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes Reaction was cooled down The precipitate was collected by filtration It was washed with acetic acid (1 mL) methanol (1 mL) and dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-[(2,3-dichlorophenyl)methyl]-3-ethyl-1H-pyrazol-5-amine (257 mg, 0.95 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (200, 1.0 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. Reaction mixture was cooled and diluted with acetic acid (2 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (1 mL), then with methanol (2 mL×2) and dried to afford expected compound. (288 mg, 71%); LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.45 Hz, 3H) 1.76 (br. s., 4H) 1.91 (s, 3H) 2.45 (q, J=7.41 Hz, 2H) 3.39 (br. s., 2H) 4.07 (s, 2H) 5.56 (s, 1H) 6.87 (s, 1H) 7.25 (s, 1H) 7.51 (s, 1H). The reaction vessel was sealed irradiated (microwave) at 140° C. for 40 minutes Reaction mixture was cooled The precipitate was collected washed with acetic acid (1 mL) with methanol (2 mL×2) and dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-[(2,3-dichlorophenyl)methyl]-3-ethyl-1H-pyrazol-5-amine (257 mg, 0.95 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (200, 1.0 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. Reaction mixture was cooled and diluted with acetic acid (2 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (1 mL), then with methanol (2 mL×2) and dried to afford expected compound. (288 mg, 71%); LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.45 Hz, 3H) 1.76 (br. s., 4H) 1.91 (s, 3H) 2.45 (q, J=7.41 Hz, 2H) 3.39 (br. s., 2H) 4.07 (s, 2H) 5.56 (s, 1H) 6.87 (s, 1H) 7.25 (s, 1H) 7.51 (s, 1H). The reaction vessel was sealed irradiated (microwave) at 140° C. for 40 minutes Reaction mixture was cooled The precipitate was collected washed with acetic acid (1 mL) with methanol (2 mL×2) and dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-[(2,3-dichlorophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine TFA salt (201 mg, 0.48 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.50 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. The reaction mixture was cooled and diluted with acetic acid (5 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (2 mL), then with cooled methanol (2 mL) and dried to give crude product. The crude material was purified by reverse-phase HPLC to provide titled compound. (16 mg, 7.5%); LC/MS: MS (ES+) m/e 446 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 4H) 2.82 (s, 1H) 3.38-3.41 (m, 2H) 3.96 (dd, J=10.99, 2.91 Hz, 2H) 4.21 (s, 2H) 5.84 (s, 1H) 6.77-6.83 (m, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.54 (dd, J=7.96, 1.39 Hz, 1H) 12.22 (s, 1H). The reaction vessel was sealed irradiated (microwave) at 140° C. for 40 minutes The reaction mixture was cooled The precipitate was collected washed with acetic acid (2 mL) with cooled methanol (2 mL) and dried to give crude product The crude material was purified by reverse-phase HPLC

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.78 mg, 3.90 mmol) in acetic acid was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (1.0 g, 3.71 mmol) in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (5 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with acetic acid (2 mL) and cooled methanol (2 mL). Solid was dried. The titled compound was obtained and used in next step. (1.02 g, 68%) LC/MS: MS (ES+) m/e 406 (MH+). in microwave reaction vessel It was sealed The reaction mixture was cooled filtered Solid was washed with acetic acid (2 mL) cooled methanol (2 mL) Solid was dried

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.78 mg, 3.90 mmol) in acetic acid was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (1.0 g, 3.71 mmol) in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (5 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with acetic acid (2 mL) and cooled methanol (2 mL). Solid was dried. The titled compound was obtained and used in next step. (1.02 g, 68%) LC/MS: MS (ES+) m/e 406 (MH+). in microwave reaction vessel It was sealed The reaction mixture was cooled filtered Solid was washed with acetic acid (2 mL) cooled methanol (2 mL) Solid was dried

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (98 mg, 0.49 mmol) in acetic acid (2 mL) was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (125 mg, 0.46 mmol), prepared as described in Example 1, step a, in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (2 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with cooled methanol. Solid was dried. The titled compound was obtained. (75 mg, 38%) LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.80 (m, 4H) 2.05 (s, 3H) 2.46 (s, 3H) 2.75 (s, 1H) 3.37 (td, J=11.68, 2.40 Hz, 2H) 3.95 (d, J=14.40 Hz, 2H) 3.99 (s, 2H) 5.57 (s, 1H) 7.00 (d, J=7.33 Hz, 1H) 7.28 (t, J=7.45 Hz, 1H) 7.55 (d, J=7.58 Hz, 1H) 11.59 (d, J=1.01 Hz, 1H). prepared in microwave reaction vessel It was sealed The reaction mixture was cooled filtered Solid was washed with cooled methanol Solid was dried