1-AMinoMethyl-1-(Boc-aMino)cyclopropane, 97%

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4-dichloro-6-methylquinazoline, tert-butyl 3-aminopyrrolidine-1-carboxylate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid instead of 2,4-dichloro-6-methylquinazoline, tert-butyl [1-(aminomethyl)cyclopropyl]carbamate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69-7.56 (m, 2 H), 7.48 (t, J=7.53 Hz, 1 H), 7.34 (dd, J=8.53, 1.25 Hz, 1 H), 7.22 (d, J=6.78 Hz, 1 H), 5.08 (br. s., 2 H), 4.47 (br. s., 2 H), 3.48-2.54 (m, 7 H), 2.33 (s, 3 H), 2.25-2.00 (m, 1 H), 1.81-1.68 (m, 1 H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro-6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room temperature. After being stirred at room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the product as a white powder. the resultant mixture was concentrated in vacuo to remove 20 mL of solvent stirred vigorously with water (200 mL) The formed solid was collected by filtration washed with water and ether dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro-6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room temperature. After being stirred at room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the product as a white powder. the resultant mixture was concentrated in vacuo to remove 20 mL of solvent stirred vigorously with water (200 mL) The formed solid was collected by filtration washed with water and ether dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 1.053 mmol) and N,N-diisopropyethyllamine (0.734 mL, 4.21 mmol) in THF (6 mL) was added tert-butyl 1-(aminomethyl)cyclopropylcarbamate (294 mg, 1.579 mmol). The resulting mixture was stirred at rt. After 16 h, the solvent was concentrated. The crude material was dissolved in THF (1 mL) and MeOH (2 mL), filtered and purified by reverse phase preparative HPLC (method 1) to give the title compound (499.5 mg, 58% yield) as a white solid. LCMS: m/e 756.7 (M+H)+, 2.75 min (method 7). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.5 Hz), 5.3-5.3 (1H, m), 5.1 (1H, br. s.), 4.8 (1H, s), 4.7 (1H, s), 3.9 (3H, s), 3.5-3.5 (1H, m), 3.4 (1H, d, J=14.3 Hz), 2.8 (1H, br. s.), 2.6 (1H, d, J=12.8 Hz), 2.4 (1H, dd, J=12.2, 8.2 Hz), 2.1 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.8 (1H, d, J=13.4 Hz), 1.7-1.8 (1H, m), 1.7 (3H, s), 1.7-1.7 (2H, m), 1.5-1.7 (3H, m), 1.5 (9H, s), 1.4-1.5 (5H, m), 1.2-1.3 (1H, m), 1.1-1.2 (2H, m), 1.1 (3H, s), 1.0 (3H, s), 1.0 (3H, s), 0.9 (6H, s), 0.8-0.9 (3H, m). 13C NMR (CHLOROFORM-d) δ ppm 14.1, 15.4, 16.1, 19.0, 19.5, 20.7, 20.8, 24.8, 27.0, 28.1, 29.1, 29.2, 29.4, 31.4, 33.2, 35.1, 36.0, 36.6, 37.2, 40.4, 41.4, 41.6, 46.0, 49.1, 49.6, 51.7, 52.5, 77.3, 80.1, 109.9, 123.7, 127.6, 128.2, 129.8, 146.0, 148.4, 149.2, 167.0. the solvent was concentrated The crude material was dissolved in THF (1 mL) MeOH (2 mL), filtered purified by reverse phase preparative HPLC (method 1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 20.5 mg (0.11 mmol) of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate were initially charged in a 96-well deep well multititre plate. A solution of 33.2 mg (0.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 0.4 ml of DMF/dichloromethane (1:1, v/v) and a solution of 49.4 mg (0.13 mol) of HATU in 0.4 ml of DMF/dichloromethane (1:1, v/v) were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Subsequently, the mixture was heated to 60° C. and shaken at this temperature for 7 h. Then the solvent was evaporated off completely. The residue was admixed with 0.6 ml of TFA and shaken at room temperature overnight. Then the mixture was concentrated fully, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.5 mg (1.3% of theory) of the title compound were obtained. Subsequently, the mixture was heated to 60° C. shaken at this temperature for 7 h Then the solvent was evaporated off completely shaken at room temperature overnight Then the mixture was concentrated fully the residue was dissolved in 0.8 ml of DMF filtered the target compound was isolated from the filtrate by preparative LC-MS (Method 9) The product-containing fractions were concentrated under reduced pressure The residue of each product fraction was dissolved in 0.6 ml of DMSO

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4-dichloro-6-methylquinazoline, tert-butyl 3-aminopyrrolidine-1-carboxylate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid instead of 2,4-dichloro-6-methylquinazoline, tert-butyl [1-(aminomethyl)cyclopropyl]carbamate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69-7.56 (m, 2 H), 7.48 (t, J=7.53 Hz, 1 H), 7.34 (dd, J=8.53, 1.25 Hz, 1 H), 7.22 (d, J=6.78 Hz, 1 H), 5.08 (br. s., 2 H), 4.47 (br. s., 2 H), 3.48-2.54 (m, 7 H), 2.33 (s, 3 H), 2.25-2.00 (m, 1 H), 1.81-1.68 (m, 1 H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro-6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room temperature. After being stirred at room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the product as a white powder. the resultant mixture was concentrated in vacuo to remove 20 mL of solvent stirred vigorously with water (200 mL) The formed solid was collected by filtration washed with water and ether dried in vacuo