N-甲基-3-吗啉丙-1-胺

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+(400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H). The resulting solution was extracted with 2×5 mL of dichloromethane The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3) mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+(400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H). The resulting solution was extracted with 2×5 mL of dichloromethane The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3) mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min)

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

实验步骤: By using N-(3-aminopropyl)morpholine (1.0 g) as a starting material, the title compound (57 mg) was obtained in the same manners as those of Reference Example 51, (1), Reference Example 8, (2) and Reference Example 19, (3).

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

实验步骤: To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added methyl-(3-morpholin-4-yl-propyl)amine (74 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 590 (M+H). concentrated in vacuo The residue is dissolved in EtOAc precipitated with hexane The precipitate is washed two times with hexane

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+ (400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H). The resulting solution was extracted with 2×5 mL of dichloromethane The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3) mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+(400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H). The resulting solution was extracted with 2×5 mL of dichloromethane The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3) mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min)