* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 14, p. 4740 - 4749
8
[ 26120-43-4 ]
[ 77894-69-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen In ethanol for 2 h;
To a solution of Description 21 (0.97 g, 5.5 mmol) in ethanol (50 ml) was added catalytic 10 percent palladium on carbon. The resulting slurry was stirred under a balloon of hydrogen for 2 hours. The catalyst was removed by filtration and the solvent evaporated and the product azeotroped with toluene to give the title compound as a pale brown solid (0.78 g, 96 percent). m/z (ES+) 148 (M + H+).
96%
With hydrogen In ethanol for 2 h;
To a solution of 1-METHYL-4-NITRO-LH-INDAZOLE (Description 26,0. 97 g, 5.5 mmol) in ethanol (50 ml) was added catalytic 10 percent palladium on carbon. The resulting slurry was stirred under a balloon of hydrogen for 2 hours. The catalyst was removed by filtration, the solvent evaporated and traces of ethanol removed azeotropically by addition, then evaporation of toluene to give the title compound as a pale brown solid (0.78 g, 96 percent).'H NMR (400 MHz, CDCL3) 8 4.01 (3H, s), 4.11 (2H, br s), 6.33 (1H, d, J 7. 4), 6.77 (1H, d, J 8. 4), 7.17 (1H, dd, J 8. 4 and 7.4), 7.91 (1H, s); 77LEZ (ES+) 148 (M + H+).
80%
With palladium on activated charcoal; hydrogen In methanol; dichloromethane at 20℃; for 24 h;
1-Methyl-4-nitro-1H-indazole (849 mg,3.85 mmol) was dissolved in methanol/dichloromethane (30 mL, v:v = 1:1)and Pd/C (500 mg) was added. The resulting mixture was treated with H2(approx. 1bar) at rt for 24 h. Subsequently, the catalyst was filtered and thesolvent was removed to yield 4-amino-1-methyl-1H-indazole (567 mg,80percent) as colorless solid. Rf= 0.24 (Toluene/EtOAc 3:2); dH (400MHz, CDCl3) 4.02 (s, 3H, CH3), 6.34 (d, 3J5,6 = 7.4 Hz, 1H, H-5), 6.78(d, 3J6,7 = 8.4Hz, 1H, H-7), 7.18 (dd, 3J6,5= 7.4 Hz, 3J6,7= 8.4 Hz, 1H, H-6), 7.91 (s, 1H, H-3)
Reference:
[1] Patent: WO2004/46133, 2004, A1, . Location in patent: Page 28
[2] Patent: WO2005/28445, 2005, A2, . Location in patent: Page/Page column 36
[3] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 14, p. 4740 - 4749
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6025 - 6035
[6] Journal of Medicinal Chemistry, 2002, vol. 45, # 3, p. 740 - 743
[7] Tetrahedron, 1980, vol. 36, p. 3523 - 3534
[8] Patent: WO2007/42906, 2007, A1, . Location in patent: Page/Page column 35
With hydrogen;palladium 10% on activated carbon; In ethanol; for 2h;
To a solution of Description 21 (0.97 g, 5.5 mmol) in ethanol (50 ml) was added catalytic 10 % palladium on carbon. The resulting slurry was stirred under a balloon of hydrogen for 2 hours. The catalyst was removed by filtration and the solvent evaporated and the product azeotroped with toluene to give the title compound as a pale brown solid (0.78 g, 96 %). m/z (ES+) 148 (M + H+).
96%
With hydrogen;palladium 10% on activated carbon; In ethanol; for 2h;
To a solution of 1-METHYL-4-NITRO-LH-INDAZOLE (Description 26,0. 97 g, 5.5 mmol) in ethanol (50 ml) was added catalytic 10 % palladium on carbon. The resulting slurry was stirred under a balloon of hydrogen for 2 hours. The catalyst was removed by filtration, the solvent evaporated and traces of ethanol removed azeotropically by addition, then evaporation of toluene to give the title compound as a pale brown solid (0.78 g, 96 %).'H NMR (400 MHz, CDCL3) 8 4.01 (3H, s), 4.11 (2H, br s), 6.33 (1H, d, J 7. 4), 6.77 (1H, d, J 8. 4), 7.17 (1H, dd, J 8. 4 and 7.4), 7.91 (1H, s); 77LEZ (ES+) 148 (M + H+).
80%
With palladium on activated charcoal; hydrogen; In methanol; dichloromethane; at 20℃; under 750.075 Torr; for 24h;
1-Methyl-4-nitro-1H-indazole (849 mg,3.85 mmol) was dissolved in methanol/dichloromethane (30 mL, v:v = 1:1)and Pd/C (500 mg) was added. The resulting mixture was treated with H2(approx. 1bar) at rt for 24 h. Subsequently, the catalyst was filtered and thesolvent was removed to yield 4-amino-1-methyl-1H-indazole (567 mg,80%) as colorless solid. Rf= 0.24 (Toluene/EtOAc 3:2); dH (400MHz, CDCl3) 4.02 (s, 3H, CH3), 6.34 (d, 3J5,6 = 7.4 Hz, 1H, H-5), 6.78(d, 3J6,7 = 8.4Hz, 1H, H-7), 7.18 (dd, 3J6,5= 7.4 Hz, 3J6,7= 8.4 Hz, 1H, H-6), 7.91 (s, 1H, H-3)
With hydrogen;palladium 10% on activated carbon; In ethanol; under 3102.97 Torr; for 20h;
Step 3: 1 -methyl- 1 H-indazol-4-amineA solution of l-methyl-4-nitro-lH-indazole in ethanol was hydrogenated in the presence of 10% Pd/C at 60 psi for 20 hours. Reaction mixture was filtered through celite. Filtrate was concentrated under vacuum and the residue was column purified.eta NMR (DMSO- d6): delta 3.90 (3eta, s); 5.76 (2H, s); 6.13 (IH, d, J= 7.5 Hz); 6.63 (IH, d, J=8.4Hz); 7.02 (IH, t, J= 7.6Hz) ; 8.03 (IH, s).
N-(3,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene;
EXAMPLE 355 N-(3,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (390 mg, 2.65 mmol) and 3,4-dichlorobenzyl isocyanate (0.39 mL, 2.65 mmol) were combined in toluene (20 mL) and heated overnight at 80 C. The mixture was allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.86 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.59-7.64 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.91 (t, J=6.0 Hz), 4.35 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37Cl)+.
In toluene;
EXAMPLE 355 N-(3,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (390 mg, 2.65 mmol) and 3,4-dichlorobenzyl isocyanate (0.39 mL, 2.65 mmol) were combined in toluene (20 mL) and heated overnight at 80 C. The mixture was allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.86 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.59-7.64 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.91 (t, J=6.0 Hz), 4.35 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37Cl)+.
With pyridine; In tetrahydrofuran; chloroform; at 0 - 20℃; for 15.5h;
Step 4: Phenyl 1 -methyl- lH-indazol-4ylcarbamateA solution of phenyl chloroformate (1.1 mmol) in chloroform was cooled to O0C. 1 -methyl- IH- indazole-4- amine in dry THF was added to the reaction mixture dropwise at O0C. Pyridine (1 mmol) was added to the reaction mixture .Reaction mixture was stirred at O0C for 30 minutes and was then stirred at room temperature for 15 hours.Reaction mixture was concentrated under vacuum to remove the excess solvent .Residue was column purified to obtain the pure carbamate. EPO <DP n="37"/>1H NMR (DMSO- d6): delta 4.02 (3H, s); 6.75 (IH, d), 7.14 (IH, t), 7.25-7.55 (6H, m); 8.39 (IH, s); 10.48 (lH,s).
N-(4-chlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; triethylamine; In diethyl ether; ethanol; toluene;
EXAMPLE 344C N-(4-chlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (1.00 g, 6.8 mmol) in toluene (225 mL) was treated with phosgene (20% in toluene, 7 ml, 13.2 mmol). The mixture was heated at reflux for 3 hours, cooled, and the solvent removed under reduced pressure. The residue was taken in diethyl ether (100 ml) and triethyl amine (6 ml), and filtered. The filtrate was treated with 4-chlorobenzylamine (963 mg, 6.8 mmol). After stirring at ambient temperature for 16 hours, the solvent was reduced to half volume under reduced pressure, filtered, and the filter cake washed with diethyl ether:hexanes (1:1) to provide the title compound. The title compound was treated with HCl/ethanol and evaporated to dryness to provide the hydrochloride. 1H NMR (DMSO-d6) delta 9.25 (s, 1H), 8.25 (s, 1H), 7.68 (d, 1H), 7.39 (m, 5H), 7.24 (t, 1H), 7.13 (d, 1H), 4.34 (s, 2H), 3.99 (s, 3H); MS (ESI) m/z 315 (M+H)+.
With hydrogenchloride; triethylamine; In diethyl ether; ethanol; toluene;
Example 344C N-(4-chlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (1.00 g, 6.8 mmol) in toluene (225 mL) was treated with phosgene (20% in toluene, 7 ml, 13.2 mmol). The mixture was heated at reflux for 3 hours, cooled, and the solvent removed under reduced pressure. The residue was taken in diethyl ether (100 ml) and triethyl amine (6 ml), and filtered. The filtrate was treated with 4-chlorobenzylamine (963 mg, 6.8 mmol). After stirring at ambient temperature for 16 hours, the solvent was reduced to half volume under reduced pressure, filtered, and the filter cake washed with diethyl ether:hexanes (1:1) to provide the title compound. The title compound was treated with HCl/ethanol and evaporated to dryness to provide the hydrochloride. 1H NMR (DMSO-d6) delta 9.25 (s, 1H), 8.25 (s, 1H), 7.68 (d, 1H), 7.39 (m, 5H), 7.24 (t, 1H), 7.13 (d, 1H), 4.34 (s, 2H), 3.99 (s, 3H); MS (ESI) m/z 315 (M+H)+.
EXAMPLE 344B 1-methyl-1H-indazol-4-amine 1-Methyl-4-nitro-1H-indazole (6.1 g; 35.4 mmol) and 10% Pd/carbon (500 mg) were combined in ethanol and hydrogenated in a Parr apparatus at 60 PSI hydrogen at 50 C. for 1 hour. The mixture was allowed to cool to ambient temperature, filtered through Celite, and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) delta 8.02 (s, 1H), 7.02 (t, 1H), 6.62 (d, 1H), 6.14 (d, 1H), 5.75 (s, 2H), 3.90 (s, 2H).
In ethanol; hydrogen;
Example 344B 1-methyl-1H-indazol-4-amine 1-Methyl-4-nitro-1H-indazole (6.1 g; 35.4 mmol) and 10% Pd/carbon (500 mg) were combined in ethanol and hydrogenated in a Parr apparatus at 60 PSI hydrogen at 50 C. for 1 hour. The mixture was allowed to cool to ambient temperature, filtered through Celite, and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) delta 8.02 (s, 1H), 7.02 (t, 1H), 6.62 (d, 1H), 6.14 (d, 1H), 5.75 (s, 2H), 3.90 (s, 2H).
With diisopropylamine; In tetrahydrofuran; toluene;
EXAMPLE 354 N-(1-methyl-1H-indazol-4-yl)-4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinecarboxamide 1-Methyl-1H-indazol-4-amine (560 mg, 3.81 mmol) in toluene (20 mL) was treated with 20% phosgene solution (2.5 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in THF (20 mL) and treated with diisopropylamine (5 mL) and 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine (450 mg, 1.95 mmol). The mixture was refluxed overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.78 (s, 1H), 8.44 (m, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.83 (m, 1H), 7.19-7.31 (m, 3H), 7.02 (d, 9.2 Hz, 1H), 4.00 (s, 3H), 3.74 (m, 4H), 3.63 (m, 4H); MS (ESI+) m/z 405 (M+H)+.
With diisopropylamine; In tetrahydrofuran; toluene;
EXAMPLE 354 N-(1-methyl-1H-indazol-4-yl)-4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinecarboxamide 1-Methyl-1H-indazol-4-amine (560 mg, 3.81 mmol) in toluene (20 mL) was treated with 20% phosgene solution (2.5 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in THF (20 mL) and treated with diisopropylamine (5 mL) and 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine (450 mg, 1.95 mmol). The mixture was refluxed overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.78 (s, 1H), 8.44 (m, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.83 (m, 1H), 7.19-7.31 (m, 3H), 7.02 (d, 9.2 Hz, 1H), 4.00 (s, 3H), 3.74 (m, 4H), 3.63 (m, 4H); MS (ESI+) m/z 405 (M+H)+.
EXAMPLE 351 N-(4-tert-butylbenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 4-tert-Butylbenzylamine (0.46 mL, 2.62 mmol) in toluene (8 mL) was treated with 20% phosgene solution (1.4 mL) and refluxed for 3 hours. The mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was then taken up in toluene (10 mL) and treated with diisopropylamine (3 mL) and <strong>[77894-69-0]1-methyl-1H-indazol-4-amine</strong> (prepared as described in J. Med. Chem. 45:742 (2002); 200 mg, 1.36 mmol). The reaction mixture was heated at 80 C. for 3 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (98:2 CH2C12:CH3OH to 95:5 CH2Cl2:CH3OH, eluant gradient) to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.72 (s, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, 0.6 Hz, 1H), 7.37 (m, 2H), 7.27 (m, 2H), 7.24 (m, 1H), 7.13 (m, 1H), 6.74 (m, 1H), 4.30 (d, J=5.8 Hz, 2H), 3.99 (s, 3H), 1.27 (s, 9H); MS (ESI+) m/z 337 (M+H)+.
With diisopropylamine; In toluene;
EXAMPLE 351 N-(4-tert-butylbenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 4-tert-Butylbenzylamine (0.46 mL, 2.62 mmol) in toluene (8 mL) was treated with 20% phosgene solution (1.4 mL) and refluxed for 3 hours. The mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was then taken up in toluene (10 mL) and treated with diisopropylamine (3 mL) and <strong>[77894-69-0]1-methyl-1H-indazol-4-amine</strong> (prepared as described in J. Med. Chem. 45:742 (2002); 200 mg, 1.36 mmol). The reaction mixture was heated at 80 C. for 3 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (98:2 CH2C12:CH3OH to 95:5 CH2Cl2:CH3OH, eluant gradient) to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 8.72 (s, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, 0.6 Hz, 1H), 7.37 (m, 2H), 7.27 (m, 2H), 7.24 (m, 1H), 7.13 (m, 1H), 6.74 (m, 1H), 4.30 (d, J=5.8 Hz, 2H), 3.99 (s, 3H), 1.27 (s, 9H); MS (ESI+) m/z 337 (M+H)+.
EXAMPLE 356 N-(2,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80 C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 9.22 (s, 1H), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (m, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37CI)+.
In toluene;
EXAMPLE 356 N-(2,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea 1-Methyl-1H-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80 C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) delta 9.22 (s, 1H), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (m, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37CI)+.
EXAMPLE 120 N-(1-methyl-1H-indazol-4-yl)-N'-[4-(1-piperidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)+364.
EXAMPLE 120 N-(1-methyl-1H-indazol-4-yl)-N'-[4-(1-piperidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)+364.
EXAMPLE 121 N-[3-fluoro-4-(1-piperidinyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+ 382.
EXAMPLE 121 N-[3-fluoro-4-(1-piperidinyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+ 382.
EXAMPLE 122 N-(1-methyl-1H-indazol-4-yl)-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H), 7.12 (d, 1H), 6.94 (m, 1H), 6.73 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.24 (m, 4H), 1.98 (m, 4H); MS (ESI) (M+H)+350.
EXAMPLE 122 N-(1-methyl-1H-indazol-4-yl)-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H), 7.12 (d, 1H), 6.94 (m, 1H), 6.73 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.24 (m, 4H), 1.98 (m, 4H); MS (ESI) (M+H)+350.
N-[3-fluoro-4-(1-pyrrolidinyl)benzyl -N'-(1-methyl-1H-indazol-4-yl)urea[ No CAS ]
[ 41748-71-4 ]
Yield
Reaction Conditions
Operation in experiment
764300 Example 123 N-[3-fluoro-4-(1-pyrrolidinyl)benzyl -N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.12 (t, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H), 3.30 (m, 4H), 1.89 (m, 4H); MS (ESI) (M+H)+368.
764300 Example 123 N-[3-fluoro-4-(1-pyrrolidinyl)benzyl -N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.12 (t, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H), 3.30 (m, 4H), 1.89 (m, 4H); MS (ESI) (M+H)+368.
EXAMPLE 124 N-[4-(1-azepanyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.97 (s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H), 7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H), 1.90 (m, 4H), 1.53 (m, 4H); MS (ESI) (M+H)+ 378.
EXAMPLE 124 N-[4-(1-azepanyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 8.97(s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H), 7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H), 1.90 (m, 4H), 1.53 (m, 4H); MS (ESI) (M+H)+ 378.
EXAMPLE 125 N-[4-(1-azepanyl)-3-fluorobenzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.03 (s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H), 7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m, 4H), 1.55 (m, 4H); MS (ESI) (M+H)+ 396.
EXAMPLE 125 N-[4-(1-azepanyl)-3-fluorobenzyl]-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) delta 9.03(s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H), 7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m, 4H), 1.55 (m, 4H); MS (ESI) (M+H)+ 396.
With pyridine; In acetonitrile; at 20℃; for 0.5h;Product distribution / selectivity;
To a 100 mL round-bottomed flask was added N,N'-disuccinyl carbonate (1.38 g, 5.38 mmol), pyridine (0.435 mL, 5.38 mmol) and Example IG (0.754 g, 5.12 mmol) in acetonitrile (15 mL). The brown solution was stirred at room temperature for 30 min and treated with a solution of Example ID (1.00 g, 5.12 mmol) in acetonitrile (10 mL) followed by JV,jV-diisopropylethylamine (2.66 mL, 15.4 mmol). The reaction was stirred for 1 h, then poured into EtOAc (200 mL) and washed with saturated NaHCO3 (50 mL) and IN HCl (50 mL). The solution was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient elution, 0-50% EtOAc/hexanes) to provide the title compound (1.54 g, 4.18 mmol, 82%) as an off-white solid. 1H NMR (300 MHz, DMSO-J6) delta 8.76 (s, IH), 8.05 (d, J= 0.9 Hz, IH), 7.70 (dd, J= 7.5, 0.7 Hz, IH), 7.27 (d, J = 7.7 Hz, IH), 7.18 (dt, J= 8.3, 0.8 Hz, IH), 7.09 (ddd, J= 9.4, 3.1, 0.9 Hz, IH), 7.05-6.97 (m, IH), 6.78 (dd, J= 8.8, 4.8 Hz, 2H), 5.03-4.94 (m, IH), 4.01 (s, 3H), 2.29-2.16 (m, IH), 1.77 (dd, J= 13.2, 10.9 Hz, IH), 1.40 (s, 3H), 1.29 (s, 3H); MS (DCIZNH3) m/z 369 (M+H)+.
With pyridine; In acetonitrile; at 20℃; for 0.5h;Product distribution / selectivity;
To a 100 mL round-bottomed flask was added N,N'-disuccinyl carbonate (1.38 g, 5.38 mmol), pyridine (0.435 mL, 5.38 mmol) and Example IG (0.754 g, 5.12 mmol) in acetonitrile (15 mL). The brown solution was stirred at room temperature for 30 min and treated with a solution of Example ID (1.00 g, 5.12 mmol) in acetonitrile (10 mL) followed by JV,jV-diisopropylethylamine (2.66 mL, 15.4 mmol). The reaction was stirred for 1 h, then poured into EtOAc (200 mL) and washed with saturated NaHCO3 (50 mL) and IN HCl (50 mL). The solution was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient elution, 0-50% EtOAc/hexanes) to provide the title compound (1.54 g, 4.18 mmol, 82%) as an off-white solid. 1H NMR (300 MHz, DMSO-J6) delta 8.76 (s, IH), 8.05 (d, J= 0.9 Hz, IH), 7.70 (dd, J= 7.5, 0.7 Hz, IH), 7.27 (d, J = 7.7 Hz, IH), 7.18 (dt, J= 8.3, 0.8 Hz, IH), 7.09 (ddd, J= 9.4, 3.1, 0.9 Hz, IH), 7.05-6.97 (m, IH), 6.78 (dd, J= 8.8, 4.8 Hz, 2H), 5.03-4.94 (m, IH), 4.01 (s, 3H), 2.29-2.16 (m, IH), 1.77 (dd, J= 13.2, 10.9 Hz, IH), 1.40 (s, 3H), 1.29 (s, 3H); MS (DCIZNH3) m/z 369 (M+H)+.
A mixture of palladium(II) acetate (82 mg, 2 mol%) and Xantphos (287 mg, 3 mol%) in toluene (10 mL) was stirred for 5 min at ambient temperature. To the solution was added a solution of Example IF (3.68 g, 17.4 mmol) and benzophenone imine (3.00 g, 17.4 mmol) in toluene (30 mL). The mixture was evacuated and purged with nitrogen two times, then stirred at ambient temperature for 15 min. Sodium tert-butoxidc (1.90 g, 24.4 mmol) was added and the mixture was evacuated and purged with nitrogen. The mixture was heated to between 80 and 85 0C for 2 h, cooled to ambient temperature, and diluted with water (30 mL). The layers were partitioned and the aqueous layer was extracted with additional toluene (20 mL). The combined organic layers were stirred with 6 N HCl (10 mL) for 1 h, then 40 mL of water was added to dissolve the solids. The toluene layer was discarded and aqueous layer filtered to remove insoluble material. The aqueous layer was adjusted to pEta 14 with the addition of 50 % NaOH and the resulting solid was filtered and dried to provide the title compound. MS (DCI/NEta3) m/z 202 (M+H)+.
A mixture of palladium(II) acetate (82 mg, 2 mol%) and Xantphos (287 mg, 3 mol%) in toluene (10 mL) was stirred for 5 min at ambient temperature. To the solution was added a solution of Example IF (3.68 g, 17.4 mmol) and benzophenone imine (3.00 g, 17.4 mmol) in toluene (30 mL). The mixture was evacuated and purged with nitrogen two times, then stirred at ambient temperature for 15 min. Sodium tert-butoxidc (1.90 g, 24.4 mmol) was added and the mixture was evacuated and purged with nitrogen. The mixture was heated to between 80 and 85 0C for 2 h, cooled to ambient temperature, and diluted with water (30 mL). The layers were partitioned and the aqueous layer was extracted with additional toluene (20 mL). The combined organic layers were stirred with 6 N HCl (10 mL) for 1 h, then 40 mL of water was added to dissolve the solids. The toluene layer was discarded and aqueous layer filtered to remove insoluble material. The aqueous layer was adjusted to pEta 14 with the addition of 50 % NaOH and the resulting solid was filtered and dried to provide the title compound. MS (DCI/NEta3) m/z 202 (M+H)+.
In dimethyl sulfoxide; at 20℃; for 20h;Inert atmosphere;
To <strong>[77894-69-0]1-methyl-1H-indazol-4-ylamine</strong> (0.2 g, 1.36 mmol) under N2 was added Intermediate 110 (0.33 g, 1.36 mmol) and the mixture was dissolved in DMSO (1 mL). The reaction was stirred at room temperature for 20 hours. The title compound was precipitated with ice water, collected, and dried under nitrogen/vacuum.
In 1-methyl-pyrrolidin-2-one; at 0 - 25℃; for 0.916667h;
At 0 C. compound 8 (283 mg) was added to a solution of 1 (300 mg) in NMP (2 mL) and the mixture was stirred for 10 min. Stirring was continued for 45 min at 25 C. Methanol (3 mL) was added, the precipitate collected and dried to give compound 9 (389 mg) as a yellow solid. UPLC/MS found for C15H16N6O2S as (M+H)+ 345.1; UPLC retention time 0.99 min.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 90℃; for 48h;
4.2.6 4-Amino-N-(2-chloropyrimidin-4-yl)-1-methyl-1H-indazole (7c) 2,4-Dichloropyrimidine (1.34 g, 9.02 mmol) and DIPEA (1.22 g, 9.45 mmol) were added to 6c (1.26 g, 8.59 mmol) dissolved in absolute ethanol (25 mL). This mixture was allowed to stir under reflux for 2 d. After cooling to rt, water (20 mL) was added, the aqueous layer was extracted with EtOAc (3 * 25 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification was done by column chromatography (PE-EtOAc = 2:1 ? 1:1) to yield compound 7c (1.054 g, 47%) as light red solid.
at 25 - 60℃;
General procedure: Procedure for synthesizing compounds of general formula I [0058] The appropriate amine (II) was dissolved in methanol, isopropanol or ethylene glycol (0.2 g/mL). 1.2 eq of pyrimidine (III) and base were added [1.5 eq of N,N diisopropylethylamine (DIPEA) or 3 eq of NaHCO3] and the mixture was stirred at temperatures between 25 C and 60 C for 1 h to 48 h. The reaction mixture was dissolved in EtOAc/MeOH 9:1 and washed with saturated aqueous NaHCO3, water, and brine. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with heptane/EtOAc as eluent to give the intermediate (IV). In some cases the intermediate (IV) was precipitated out of the reaction mixture by the addition of water. No further purification was done in those cases. Intermediate 8 N-(2-chloropyrimidin-4-yl)-1-methyl-indazol-4-amine [0068] 1H NMR (400 MHz, DMSO-d6, 75 C) delta 8.16 (br d, 1H), 8.13 (s, 1H), 7.51 (br d, 1H), 7.42-7.33 (m, 2H), 6.86 (br m, 1H), 4.04 (s, 3H). MS (ESI+) m/z 260.1 [M + H]+
N-(1-methyl-1H-indazol-4-yl)ethanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.8%
With pyridine; In dichloromethane; at 20℃; for 5h;
A solution of i-methyl-1H-indazol-4-amine (0.300 g, 2.038 mmol), pyridine (0.197mL, 2.446 mmol) and ethanesulfonyl chloride (0.231 mL, 2.446 mmol) in dichloromethane (20 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous iN-hydrochloric acid solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The title compound was used without further purification (N-( 1-methyl-i H-indazol-4-yl)ethanesulfonamide, 0.350 g, 71.8 %, yellow oil).
methyl 3-fluoro-4-(((1-methyl-1H-indazol-4-yl)amino)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.7%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;
[3723] A solution of 1 -methyl- l H-indazol-4-amine (0.442 g, 3.000 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate (0.741 g, 3.000 mmol) and N,N-diisopropylethylamine ( 1.045 mL, 6.001 mmol) in acetonitrile ( 12 mL) was stirred at the room temperature for 18 hr, and then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS0 ), filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methy i 3-fluoro-4-((( l-methyl- l H-indazol-4-yl)amino)methyl)benzoate as pale brown oil (0.768 g, 81.7 %)
6-bromo-N-(1-methyl-1H-indazol-4-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).