5-Bromo-1-methyl-1H-pyrazol-3-amine

Step 3; To a solution of hydroxylamine hydrochloride (3.06 g) in ethanol (20 mL), a solution of potassium hydroxide (1.26 g) in water-ethanol (1:1, 40 mL), and 63 (2.3 g, 9 mmol) were added. The solution was then refluxed overnight. The reaction mixture was then concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1:5) to yield 64 as a white solid (1.45 g, y. 75percent). LC/MS (Method D): 0.58 min, [M+H]To a solution of 5-Bromo-3-(2, 5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (179 mg, 0.7 mmol) and hydroxylamine hydrochloride (502 mg, 7.0 mmol) in EtOH (2 ml) was added aq. KOH (2.3M, 3 ml).As shown in step 3-iii of Scheme 3, hydroxylamine hydrochloride (2.6 g, 31.7 mmol) was powdered and stirred in 12 mL of ethanol at ambient temperature for 30 minutes. KOH (1.1 g, 19.52 mmol) dissolved in 1.2 mL of water and 1.2 mL of ethanol was added to the reaction mixture to form a thick white paste.To a solution of 5-bromo-i-methyl-1H-pyrazol-3-amine (129 mg, 734.7 umol), 2- [3-(trifluoromethyl)phenyl]acetic acid (150 mg, 734.7 umo) in pyridine (2.0 mL) added EDCI (211 mg, 1.1 mmol). The mixture was stirred at 45C for 12 h. The reaction mixture was quenched by addition H20 (5.0 mL), extracted with dichloromethane 15.0 mL (5.0 mL x 3). The combined organic layers were washed with brine 15.0 mL (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si02, Petroleum ether / Ethyl acetate = i/i) to afford N-(5-bromo-i-methyl-1H- pyrazol-3 -yl)-2-(3 -(trifluoromethyl)phenyl)acetamide (150 mg, crude).To a solution of tert-butyl ((lr, 4r)-4-(bis(tert- butoxycarbonyl)amino)cyclohexyl)(6-(4, 4, 5, 5 -tetramethyl- 1, 3 , 2-dioxaborolan-2- yl)benzo[h]quinazolin-2-yl)carbamate (200 mg, 278.2 umol) and K2C03 (115 mg, 834.8 umol) in dioxane (10.0 mL) and H20 (1.0 mL) were added A mixture of tert-butyl ((1 r, 4r)-4-(bi s(tert-butoxycarbonyl)amino)cyclohexyl)(8 - ethyl-6-(4, 4, 5, 5-tetramethyl- 1, 3 , 2-dioxaborolan-2-yl)quinazolin-2-yl)carbamate (900 mg, 1.2 mmol), 5-bromo-i-methyl-1H-pyrazol-3-amine (227 mg, 1.2 mmol), K2C03 (536 mg, 3.9 mmol) and Pd(dppf)C12 (95 mg, 129.2 umol) in dioxane (4.0 mL) and H20 (400 uL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 10/i to 0/i) to afford tert-butyl (6-(3 -amino-i-methyl-i H-pyrazol-5 -yl)-8 -ethylquinazolin-2-yl)(( 1 r, 4r)-4-(bis(tert- butoxycarbonyl)amino)cyclohexyl)carbamate (590 mg, crude).To a solution of 2-[3, 5-bis(trifluoromethyl)phenyl]acetic acid (200 mg, 734.9 umol) and The solution of 4-(( 1 -methylpiperidin-4-yl)oxy)-3 -(trifluoromethyl)aniline (77 mg, 437.5 umol) and DIEA (106 mg, 820.3 umol, 143.2 uL) in DCM (3.0 mL) was cooled to - 30C for 0.5 h. Then triphosgene (53 mg, 180.4 umol) was added. The mixture was stirred at -30C for 1 h. Then a solution of A mixture of (2-(((lr, 4r)-4-(bis(tert-butoxycarbonyl)amino)cyclohexyl)(tert- butoxycarbonyl) amino)quinazolin-6-yl)boronic acid (330 mg, 562.6 umol), 5-bromo-l -methyl - lH-pyrazol-3-amine (119 mg, 675.2 umol), K2C03 (233 mg, 1.6 mmol) and Pd(dppf)Cl2 (41mg, 56.2 umol) in dioxane (15.0 mL) and H20 (1.5 mL) was degassed and purged with N2 three times, and the mixture was stirred at 90C for 12 h under N2. The reaction was concentrated and the residue was purified by column chromatography (Si02) to afford tert-butyl (6-(3 -amino- 1- methyl-lH-pyrazol-5-yl)quinazolin-2-yl)((lr, 4r)-4-(bis(tert- butoxycarbonyl)amino)cyclohexyl)carbamate (120 mg, crude).To a solution of compound 11-3 (2.0 g, 5.4 mmol) and K2C03 (2.2 g, 16.2 mmol) in dioxane (40 mL) and H20 (4 mL) were added 5-bromo-l-methyl-lH-pyrazol-3-amine (1.0 g, 5.9 mmol ) and Pd(dppf)Cl2 (395 mg, 540 umol). The mixture was stirred at 90C for 12 h under N2, cooled to rt and concentrated. The residue was purified by prep-TLC (Si02) followed by prep-HPLC. The eluent was adjusted to pH = 8 with sat.NaHC03 and extracted with ethyl acetate (20 mL chi 3). The combined organic layers was dried over Na2S04, filtered and concentrated under reduced pressure to afford 11-4 (114.9 mg, 337.0 umol, 6.2% yield). M+H+ = 340.2 (LCMS); 1H MR (DMSO-i, 400MHz): delta 9.89 (s, 1H), 9.12 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.92 (d, J= 8.6 Hz, 1H), 7.73 (dd, J= 1.5, 8.6 Hz, 1H), 5.67 (s, 1H), 4.63 (br s, 1H), 3.66 (s, 3H), 1.50 (s, 9H).To a solution of compound 3A-4 (400 mg, 1.4 mmol) in DCM (12 mL) was added DIEA (283 mg, 2.1 mmol, 382.4 uL) and triphosgene (143 mg, 481.8 umol) at -20C. The mixture was stirred at -20C for 0.5 h. A solution of 5-Brorno-l ~methyi- lH~pyrazol~3-amine (257 mg, 1.4 mmol) in DCM (4.0 mL) was added and the resulting mixture was stirred at 25C for 12 h. The reaction was quenched with MeOH (3.0 mL) and concentrated. The residue was purified by prep-TLC (Si02) to give compound 3A (500 mg, 799.3 umol, 54.7% yield). M+H+ = 475.1 (LCMS)To a solution of compound 2A-3 (150 mg, 270.5 umol) and K2C03 (112 mg, 811.5 umol) in dioxane (4 mL) and H20 (400 uL) were added 5-Bromo-l -methyl-lH-pyrazol-3-amine (47 mg, 270.5 umol) and Pd(dppf)Cl2 (19 mg, 27.0 umol). The mixture was stirred at 90C for 12 h under N2. The mixture was cooled to rt and concentrated to give a residue, which was purified by prep-TLC (Si02) to afford compound 2A (100 mg).To a solution of compound 46-8 (140 mg, 442.5 umol) in pyridine (2.0 mL) were added 5-bromo-l-methyl-lH-pyrazol-3-amine (77 mg, 442.5 umol) and EDCI (254 mg, 1.3 mmol). The mixture was stirred at 45C for 12 h, cooled to rt and concentrated to give a residue. The residue was purified by prep-TLC (Si02) to afford compound 46-9 (77 mg, 30% yield). M+H+ = 472.0 (LCMS).

Molecular Weight:176.01
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:174.97451
Monoisotopic Mass:174.97451
Topological Polar Surface Area:43.8
Heavy Atom Count:8
Complexity:87.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes