B-(6-Cyclopropyl-3-pyridinyl)boronic acid

A thick wall glass vessel was charged with compound 229 (200 mg, 0 459 mmol), To a solution of Compound 2a (130 mg, 0.20 mmol) in dioxane (4.0 mL) and H2O (1 mL) was added Pd(dppf)Ch (14.5 mg, 0.02 mmol), CS2CO3 (l94mg, 0.59 mmol) and (6- cyclopropylpyridin-3-yl)boronic acid (48.4 mg, 0.30 mmol). The mixture was stirred at 80C for 16 h under N2 atmosphere. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with dichloromethane/methanol (9/1, v/v) to afford the title compound (88.0 mg, 67%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 695.3.[00319] To a mixture of Example 23e (100 mg, 0.24 mmol), Example 23f (47 mg, 0.29 mmol), and K3P04 (153 mg, 0.72 mmol) in DMF (3 mL) was added Pd(dppf)Cl2 (18 mg, 0.024 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100C for 1 h by mircowave. The mixture was directly purified by Prep-HPLC, followed by prep-TLC (DCM/MeOH=10/l) to give the desired product Example 23 (1.1 mg, yield 1%) as a white solid. LCMS [M+l]+ = 453.0. NMR (400 MHz, Chloroform-) delta 11.46 (s, 1H), 8.68 (d, J= 2.0 Hz, 1H), 8.48 (d, J= 2.4 Hz, 1H), 8.23 (s, 1H), 8.05 (dd, J= 13.4, 7.8 Hz, 2H), 7.92 (t, J= 7.9 Hz, 1H), 7.78 (dd, J = 8.1, 2.3 Hz, 1H), 7.71 (dd, J= 8.5, 2.4 Hz, 1H), 7.20 (d, J= 8.1Hz, 1H), 7.13 (d, J= 8.6 Hz, 1H), 4.36 (t, J= 4.8 Hz, 2H), 4.33-4.26 (m, 2H), 2.09 (q, J= 7.8, 7.3 Hz, 3H), 2.04-1.96 (m, 2H), 1.07-1.01 (m, 4H)[00308] To a mixture of Example 21e (20 mg, 0.05 mmol), Example 21f (12 mg, 0.075 mmol), and Cs2C03 (49 mg, 0.15 mmol) in dioxane/H20 (3 mL, v/v = 10/1) was added Pd(dppf)Cl2 (10 mg, 0.014 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100C for 1 h under mircowave. The mixture was directly purified by Prep-HPLC to give the desired product Example 21 (7.4 mg, yield 34%) as a white solid. LCMS [M+l]+ = 438.0. As the 1HNMR of desired product in CDC13 or OMSO-d6 cannot reflect all hydrogen, respectively, the two sets of spectral graphs were complementary relationship. 'HNMR (400 MHz, DMSO- 6) delta 10.11 (s, 1H), 8.64 (s, 1H), 8.55 (d, J= 1.8 Hz, 1H), 7.78 (dd, J= 8.1, 2.3 Hz, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 7.1Hz, 1H), 7.43 (s, 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.27 (d, J= 8.1Hz, 2H), 7.20 (d, J= 8.8 Hz, 1H), 2.07 (s, 1H), 1.02-0.79 (m, 4H). NMR (400 MHz, Chloroform-) delta 8.49 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.64 (s, 2H), 7.40 (dd, J= 14.2, 6.5 Hz, 3H), 7.14 (s, 1H), 6.95 (d, J= 8.6 Hz, 1H), 4.47 (s, 2H), 4.13 (s, 2H).[00414] To a solution of Example 68a (25 mg, 0.05 mmol), Example 68b (11 mg, 0.06 mmol) in 1, 4- dioxane/H20 (4 mL/1 mL) were added Pd(dppf)Cl2 (4 mg, 0.005 mmol) and Na2C03 (11 mg, 0.1 mmol). The mixture was degassed by nitrogen for three times and heated at 90C for 2 hs. The reaction mixture was filtered, washed with EtOAc and concentrated. The residue was purified by prep-TLC (DCM/MeOH = 15/1) to afford the crude product which was triturated in MeOH (2 mL), filtered and dried to give the desired product Example 68 (8 mg, yield 33 %) as a gray solid.LCMS [M+l]+ =471.0. NMR (400 MHz, DMSO- 6) delta 11.06 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.05 (t, J= 8.5 Hz, 2H), 7.86 (t, J= 7.3 Hz, 2H), 7.81 (d, J= 8.3 Hz, 1H), 7.39 (dd, J= 10.2, 7.3 Hz, 2H), 4.37 (m, 2H), 4.26 (t, J= 8.5 Hz, 2H), 2.44 (m, 2H), 2.14 (m, 1H), 1.95 (m, 2H), 0.99-0.93 (m, 4H).[00256] A mixture of Example 9a (0.14g, 0.31 mmol), Example 9b (52 mg, 0.31 mmol), Pd(dppf)Cl2(24 mg, 0.03 mmol) and Cs2CO3(0.3g, 0.9 mmol) in Dioxane/H2O(3mL/0.3 mL), was exchange N2 for 3 times. After stirred at 85C for 16 h at N2, the mixture was concentrated under reduced pressure, the residue was purified by Pre-TLC (DCM/MeOH = 10/1) to give desired product (Example 9c, 63 mg, yield 41.2%) as a yellow solid. LCMS [M+l] + = 479.0[00266] A mixture of Example 14f (120 mg, 0.3mmol), Example 14g (46 mg, 0.3 mmol), Pd(dppf)Cl2(22 mg, 0.03 mmol) and Cs2CO3(0.3 g, 0.9 mmol) in Dioxane/H20(12 mL/1 mL), was exchange N2 for 3 times. After stirred at 85C for 16 h at N2, the mixture was concentrated under reduced pressure, the residue was purified by Pre-TLC (DCM/MeOH = 10/1) to give desired product ( , 12 mg, yield 9%) as a white solid. LCMS [M+l] + = 465.0. NMR (400 MHz, Chloroform-) delta 10.81 (s, 0.55H), 10.50 (s), 8.68 (s, 1H), 8.55 (s, 1H), 8.51 (d, J= 8.0 Hz), 8.43 (d, J= 8.0 Hz, 0.55), 8.22 - 8.07 (m, 2H), 7.93 - 7.82 (m, 1H), 7.78 (d, J= 7.6 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.23 - 7.04 (m, 2H), 6.03 - 5.70 (m, 1H), 5.64-5.54(m, lH), 4.36 (dt, J= 27.0, 5.4 Hz, 2H), 3.48 (s, 2H), 2.95 - 2.64 (m, 2H), 2.08 (m, 1H), 1.25 (m, 2H), 1.04 (m, 2H).[00255] A mixture of Example 8c (60 mg, 0.12 mmol), Example 8d (39.12 mg, 0.18 mmol), K3P04 (76.32 mg, 0.36 mmol) in DMF (2 mL), was added Pd(dppf)Cl2 (10 mg). The mixture was degassed with N2 for 3 times. Then the mixture was heated at 100C for 1.5 h under mircowave. After then, the mixture was purified by Prep-HPLC to give product ( Example 8 , 1.3 mg, yield 2.3%) as a white solid. LCMS [M+l] + = 451.0. 'HNMR (400 MHz, CDC13) delta 8.69 (d, J= 2.0 Hz, 1H), 8.28 (d, J= 7.7 Hz, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.96 (t, J = 7.9 Hz, 1H), 7.90 (d, J= 1.8 Hz, 1H), 7.78 (dd, J= 8.1, 2.4 Hz, 1H), 7.66 (dd, J= 8.0, 2.0 Hz, 1H), 7.44 (d, J= 8.1Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 4.63 - 4.53 (m, 2H), 2.96 - 2.84 (m, 2H), 2.14 - 1.92 (m, 5H), 1.85 - 1.75 (m, 2H), 1.09-1.03 (m, 4H).[00589] To a solution of Example 120a (50 mg, 0.105 mmol), Example 120b (21 mg, 0.126 mmol) and Na2C03 (33 mg, 0.316 mmol) in dioxane/H20 (2.5 mL, v/v = 4/1) was added Pd(dppf)Cl2 (7.7 mg, 0.01 1 mmol) at room temperature under N2. The reaction mixture was heated to 90C and stirred for 3 h under N2. The reaction mixture was purified by prep-HPLC and prep-TLC (DCM/MeOH = 10/1) to afford the desired product Example 120 (15.0 mg, yield 10%) as a white solid. LCMS [M+l]+ = 467.0. NMR (400 MHz, DMSO- 6) delta 11.21 (s, IH), 8.73-8.70 (d, J= 8.0 Hz, 2H), 8.20-8.19 (d, J= 8.0 Hz, IH), 8.08- 8.04 (t, 1H), 7.95-7.84 (m, 4H), 7.42-7.36 (dd, J= 8.0 Hz, 2H), 4.40-4.38 (dd, J= 8.0 Hz, 2H), 4.26-4.25 (d, J= 4.0 Hz, 1H), 3.99-3.97 (t, 1H), 3.16 (t, 1H), 2.15-2.12 (m, 2H), 1.58 (s, 1H), 1.14-1.13 (d, J= 4.0 Hz, 3H), 0.98-0.93 (m, 4H).

Molecular Weight:162.98
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:163.0804587
Monoisotopic Mass:163.0804587
Topological Polar Surface Area:53.4
Heavy Atom Count:12
Complexity:161
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes