环丙基肼盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 92.1) (630 mg, 1.588 mmol) and cyclopropylhydrazine hydrochloride (517 mg, 4.76 mmol) in EtOH (8 mL) and toluene (8 mL) was stirred for 2 hr at reflux. The reaction mixture was concentrated, diluted with CH2Cl2/saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) to afford the title product (412 mg, 0.952 mmol, 59.9% yield) as a yellow foam. tR: 0.95 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.28 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.11 (m, 2H) 1.18-1.29 (m, 2H) 1.92 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 3.75-3.87 (m, 1H) 6.41 (s, 1H) 7.27-7.39 (m, 5H) 8.33-8.48 (m, 1H). at reflux The reaction mixture was concentrated diluted with CH2Cl2/saturated aq. NaHCO3 solution extracted with CH2Cl2 The combined organic layers were washed with water and brine dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 92.1) (630 mg, 1.588 mmol) and cyclopropylhydrazine hydrochloride (517 mg, 4.76 mmol) in EtOH (8 mL) and toluene (8 mL) was stirred for 2 hr at reflux. The reaction mixture was concentrated, diluted with CH2Cl2/saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) to afford the title product (412 mg, 0.952 mmol, 59.9% yield) as a yellow foam. tR: 0.95 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.28 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.11 (m, 2H) 1.18-1.29 (m, 2H) 1.92 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 3.75-3.87 (m, 1H) 6.41 (s, 1H) 7.27-7.39 (m, 5H) 8.33-8.48 (m, 1H). at reflux The reaction mixture was concentrated diluted with CH2Cl2/saturated aq. NaHCO3 solution extracted with CH2Cl2 The combined organic layers were washed with water and brine dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-acetyl-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(3-(trifluoromethoxy)-phenyl)pyrrolidine-2,3-dione (Step 91.1) (50 mg, 0.118 mmol) in Dioxane (1 mL) were added cyclopropylhydrazine hydrochloride (Step 17.2) (25.7 mg, 0.237 mmol) and TEA (0.082 mL, 0.592 mmol) and the resulting mixture was heated up and stirred at 120° C. for 2 hr. AcOH was added to acidify the reaction mixture and stirred at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%) to afford the title product (10 mg, 0.021 mmol, 18.1% yield) as yellow foam. tR: 1.03 min (LC-MS 2); ESI-MS: 459 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.3 Hz, 2H) 1.24 (br. s., 3H) 1.93 (s, 6H) 3.37-3.39 (m, 1H) 3.81 (br. s., 1H) 6.13 (s, 1H) 7.22-7.57 (m, 5H) 7.76 (br. s., 1H). the resulting mixture was heated up stirred at 100° C. for 30 min The reaction was cooled down to RT concentrated under reduced pressure The residue was dissolved in EtOAc washed with a saturated aq. NaHCO3 solution and brine dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-acetyl-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(3-(trifluoromethoxy)-phenyl)pyrrolidine-2,3-dione (Step 91.1) (50 mg, 0.118 mmol) in Dioxane (1 mL) were added cyclopropylhydrazine hydrochloride (Step 17.2) (25.7 mg, 0.237 mmol) and TEA (0.082 mL, 0.592 mmol) and the resulting mixture was heated up and stirred at 120° C. for 2 hr. AcOH was added to acidify the reaction mixture and stirred at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%) to afford the title product (10 mg, 0.021 mmol, 18.1% yield) as yellow foam. tR: 1.03 min (LC-MS 2); ESI-MS: 459 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.3 Hz, 2H) 1.24 (br. s., 3H) 1.93 (s, 6H) 3.37-3.39 (m, 1H) 3.81 (br. s., 1H) 6.13 (s, 1H) 7.22-7.57 (m, 5H) 7.76 (br. s., 1H). the resulting mixture was heated up stirred at 100° C. for 30 min The reaction was cooled down to RT concentrated under reduced pressure The residue was dissolved in EtOAc washed with a saturated aq. NaHCO3 solution and brine dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in analogy to the procedure described for Example 68 using 5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 70.1) and cyclopropylhydrazine hydrochloride. Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) to afford the title product as colorless foam. tR: 1.02 min (LC-MS 2); ESI-MS: 447 [M+H]+ (LC-MS 2); Rf=0.36 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.6 Hz, 3H) 1.03-1.11 (m, 2H) 1.21-1.32 (m, 2H) 2.29 (dt, J=15.0, 7.6 Hz, 1H) 2.38 (dt, J=15.1, 7.7 Hz, 1H) 2.45 (s, 3H) 2.64 (s, 3H) 3.85 (tt, J=7.4, 3.8 Hz, 1H) 6.48 (s, 1H) 7.28-7.42 (m, 5H) 8.45 (s, 1H). The title compound was prepared in analogy to the procedure Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in analogy to the procedure described for Example 68 using 5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 70.1) and cyclopropylhydrazine hydrochloride. Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) to afford the title product as colorless foam. tR: 1.02 min (LC-MS 2); ESI-MS: 447 [M+H]+ (LC-MS 2); Rf=0.36 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.6 Hz, 3H) 1.03-1.11 (m, 2H) 1.21-1.32 (m, 2H) 2.29 (dt, J=15.0, 7.6 Hz, 1H) 2.38 (dt, J=15.1, 7.7 Hz, 1H) 2.45 (s, 3H) 2.64 (s, 3H) 3.85 (tt, J=7.4, 3.8 Hz, 1H) 6.48 (s, 1H) 7.28-7.42 (m, 5H) 8.45 (s, 1H). The title compound was prepared in analogy to the procedure Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 4-methyl-3-oxopentanoate and cyclopropyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 100-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g.) and CH2Cl2 (25 mL). DCC (0.29 g, 1.0 eq.) was added and the mixture was cooled to 0° C. for the sequential addition of cyclopropylhydrazine hydrochloride (0.15 g, 1.0 eq.) and DIPEA (0.24 mL, 1.0 eq.). The reaction mixture was stirred for 1 h before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound. Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane) afforded 15 mg (yield: 2.6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-cyclopropylacrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 9.16 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.23-7.26 (d, J=10.4 Hz, 1H), 6.40-6.43 (d, J=10.4 Hz, 1H), 4.97 (s, 1H), 4.63 (s, 1H), 3.18-3.20 (m, 1H), 0.83-0.87 (m, 2H), 0.65-0.69 (m, 2H); LCMS for Chemical Formula: C16H14F6N5O [M+H]+ 406.31. found 406.19 (RT 2.74 min, purity: 98.85%). extracted with CH2Cl2 (2×50 mL) The combined organic extracts were washed with brine (50 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 100-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g.) and CH2Cl2 (25 mL). DCC (0.29 g, 1.0 eq.) was added and the mixture was cooled to 0° C. for the sequential addition of cyclopropylhydrazine hydrochloride (0.15 g, 1.0 eq.) and DIPEA (0.24 mL, 1.0 eq.). The reaction mixture was stirred for 1 h before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound. Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane) afforded 15 mg (yield: 2.6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-cyclopropylacrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 9.16 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.23-7.26 (d, J=10.4 Hz, 1H), 6.40-6.43 (d, J=10.4 Hz, 1H), 4.97 (s, 1H), 4.63 (s, 1H), 3.18-3.20 (m, 1H), 0.83-0.87 (m, 2H), 0.65-0.69 (m, 2H); LCMS for Chemical Formula: C16H14F6N5O [M+H]+ 406.31 found 406.19 (RT 2.74 min, purity: 98.85%). extracted with CH2Cl2 (2×50 mL) The combined organic extracts were washed with brine (50 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 100-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g) and CH2Cl2 (25 mL). DCC (0.29 g, 1.0 eq.) was added and the mixture was cooled to 0° C. for the sequential addition of cyclopropylhydrazine hydrochloride (0.15 g, 1.0 eq.) and DIPEA (0.24 mL, 1.0 eq.). The reaction mixture was stirred for 1 h before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound. Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane) afforded 15 mg (yield: 2.6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-cyclopropylacrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 9.16 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.23-7.26 (d, J=10.4 Hz, 1H), 6.40-6.43 (d, J=10.4 Hz, 1H), 4.97 (s, 1H), 4.63 (s, 1H), 3.18-3.20 (m, 1H), 0.83-0.87 (m, 2H), 0.65-0.69 (m, 2H); LCMS for Chemical Formula: C16H14F6N5O [M+H]+ 406.31. found 406.19 (RT 2.74 min, purity: 98.85%). extracted with CH2Cl2 (2×50 mL) The combined organic extracts were washed with brine (50 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Cyclopropyl-5-isopropyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 4-methyl-3-oxopentanoate and cyclopropyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 92.1) (630 mg, 1.588 mmol) and cyclopropylhydrazine hydrochloride (517 mg, 4.76 mmol) in EtOH (8 mL) and toluene (8 mL) was stirred for 2 hr at reflux. The reaction mixture was concentrated, diluted with CH2Cl2/saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) to afford the title product (412 mg, 0.952 mmol, 59.9% yield) as a yellow foam. tR: 0.95 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.28 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.11 (m, 2H) 1.18-1.29 (m, 2H) 1.92 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 3.75-3.87 (m, 1H) 6.41 (s, 1H) 7.27-7.39 (m, 5H) 8.33-8.48 (m, 1H). at reflux The reaction mixture was concentrated diluted with CH2Cl2/saturated aq. NaHCO3 solution extracted with CH2Cl2 The combined organic layers were washed with water and brine dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2)