(3-BOC-AMINOPHENYL)BORONIC ACID

Compounds bearing the 3 -phenyl- 1 //-indazole template were prepared as described in Scheme 2 below. Suzuki-Miyaura cross coupling reaction between commercially available 3- acyl- l//-indazole or its derivative with 3 - (A- B o c - a m i n o ) p h c n y 1 b o ro n i c acid (which was prepared by bocylation of 3-aminophenylboronic acid) generated the required structural template, i.e., 3- phenyl-1//- indazole. Acidolysis of Boc provided the target amine for acrylation. In Scheme 2, the reaction conditions are: (a) B0C2O, NEt3, THF/H2O, 0 C to RT; (b) Pd(PPh3)4, phenylsilane, CH2CI2 (c) 50 % TFA in CH2CI2, triisopropylsilane, 0 C to RT.An appropriate indazole substituted with halide (bromide or iodide; 0.084 mmol, 1 eq.) was dissolved in dioxane (5 mL). To the reaction mixture were added 3-(N-Boc- amino)phenylboronic acid (0.12 mmol, 1.5 eq.), and K2CO3 (0.16 mmol, 2 eq.) dissolved in water (1 mL). The solution was degassed by bubbling argon through the solvent. After 20 minutes Pd(PPh3)4 catalyst (0.006 mmol, 0.07 eq.) was added, under a strong flow of argon. After the addition, the argon flow was stopped, and the reaction mixture was stirred for 5 hours at 100 C under inert atmosphere, then was left to stir at RT for 1-2 days, until HPLC showed consumption of the starting indazole. The reaction mixture was then cooled, diluted with EtOAc (50 mL), and extracted with saturated citric acid. The crude residue afforded was purified by silica gel chromatography (gradient: DCM to EtOAC).General procedure: Optionally substituted with R' at 6-position 3-bromo-lH-pyrazolo[3, 4-d]pyrimidin (0.3 mmol), boronic acid (1.2 eq), copper (II) acetate (0.3 eq), N, N-diisopropylethylamine (5 eq) and DMF (1.2 mL) were put in 2 dram vial and an 02 balloon was attached. The reaction was heated under oxygen atmosphere at 60 - 90 C for 1 - 15 hours and conversion was followed by LCMS and/or TLC. The crude reaction mixture was concentrated and purified by reverse-phase HPLC (5% to 100% MeCN/water with 0.1% TFA gradient over 30 minutes) to afford the desired product. If a pinacol ester was used instead of boronic acid, then loading of copper (II) acetate was increased to 1.5 equivalents, and no N, N-diisopropylethylamine was added. N-(3-(3-bromo-6-(((lR, 3R)-3-methyl-3-(methylcarbamoyl)cyclopentyl)amino)-lH- pyrazolo[3, 4-d]pyrimidin-l-yl)phenyl)pyrazine-2-carboxamide was prepared using general procedure A(a), followed by general procedure B with (3-((tert- butoxycarbonyl)amino)phenyl)boronic acid. Next, Boc group was removed under acidic conditions (TFA/DCM), and the product was acylated with pyrazine-2-carbonyl chloride in DCM in the presence of N, N-diisopropylethylamine. ' H NMR (400 MHz, Methanol-d4) d 9.32 - 9.22 (m, 3H), 8.80 (s, 1H), 8.61 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 4.64 - 4.39 (m, 1H), 2.89 - 2.50 (m, 4H), 2.33 - 2.19 (m, 1H), 2.18 - 2.07 (m, 1H), 1.86 - 1.59 (m, 2H), 1.53 - 1.37 (m, 1H), 1.31 (s, 3H), 1.29 - 1.23 (m, 1H). LCMS [M+H] 550.1.

Molecular Weight:237.06
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:237.1172382
Monoisotopic Mass:237.1172382
Topological Polar Surface Area:78.8
Heavy Atom Count:17
Complexity:265
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes