(E)-(4-氟苯乙烯基)硼酸

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

实验步骤: N-{3-[(E)-2-(4-Fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)-indazole-1-carboxylate, 575 mg trans-2-(4-fluorophenyl)vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 41 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of N-{3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of an off-white solid melting at 248° C. (analysis C22H18FN3O4S2 % calculated C, 56.04; H, 3.85; F, 4.03; N, 8.91; O, 13.57; S, 13.60. % found C, 56.21; H, 4.09; F, 3.95; N, 8.64; S, 13.31).

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

实验步骤: N-{3-[(E)-2-(4-Fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)-indazole-1-carboxylate, 575 mg trans-2-(4-fluorophenyl)vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 41 mg of tetrakis(triphenylphosphine)palladium[0]. 240 mg of N-{3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of an off-white solid melting at 248° C. (analysis C22H18FN3O4S2 % calculated C, 56.04; H, 3.85; F, 4.03; N, 8.91; O, 13.57; S, 13.60. % found C, 56.21; H, 4.09; F, 3.95; N, 8.64; S, 13.31).

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

实验步骤: The title compound was prepared from 2-[(4-bromo-3-methylphenyl)sulfonyl]benzamide (Step 1) and [(E)-2-(4-fluorophenyl)vinyl]boronic acid according to the method of Example 1 Step 4. m/z (ES+) 379 [(M-NH2)+].

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

实验步骤: The title compound was prepared from 2-[(4-bromo-3-methylphenyl)sulfonyl]benzamide (Step 1) and [(E)-2-(4-fluorophenyl)vinyl]boronic acid according to the method of Example 1 Step 4. m/z (ES+) 379 [(M-NH2)+].

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: An Emrys microwave vial containing (1S)-1-[2-({4-bromo-3-methylphenyl}sulfonyl)phenyl]ethanol (71 mg, 0.2 mmol), [(E)-2-(4-fluorophenyl)vinyl]boronic acid (43 mg, 0.26 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.020 mmol), THF (2 mL) and 2M aqueous sodium carbonate (1 mL) was heated in an Emrys microwave reactor at 150° C. for 10 minutes. On cooling, the mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant 30% EtOAc/isohexane) to afford the title compound as a white solid (45 mg). δH (500 MHz, d6 DMSO): 8.01 (1H, d, J 7.9), 7.88 (1H, d, J 8.2), 7.80 (1H, d, J 7.8), 7.73-7.63 (5H, m), 7.52 (1H, t, J 7.6), 7.37 (1H, d, J 16.3), 7.29 (1H, d, J 16.2), 7.22 (2H, t, J 8.7), 5.45 (1H, s), 5.30 (1H, s), 2.46 (3H, s), 1.11 (3H, d, J 5.9). m/z (ES+) 379 [(M-OH)+]. On cooling the mixture was partitioned between EtOAc (15 mL) and water (15 mL) the organic phase was washed with brine dried (MgSO4) filtered concentrated in vacuo The crude material was purified by flash chromatography on silica (eluant 30% EtOAc/isohexane)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: An Emrys microwave vial containing (1S)-1-[2-({4-bromo-3-methylphenyl}sulfonyl)phenyl]ethanol (71 mg, 0.2 mmol), [(E)-2-(4-fluorophenyl)vinyl]boronic acid (43 mg, 0.26 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.020 mmol), THF (2 mL) and 2M aqueous sodium carbonate (1 mL) was heated in an Emrys microwave reactor at 150° C. for 10 minutes. On cooling, the mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant 30% EtOAc/isohexane) to afford the title compound as a white solid (45 mg). δH (500 MHz, d6 DMSO): 8.01 (1H, d, J 7.9), 7.88 (1H, d, J 8.2), 7.80 (1H, d, J 7.8), 7.73-7.63 (5H, m), 7.52 (1H, t, J 7.6), 7.37 (1H, d, J 16.3), 7.29 (1H, d, J 16.2), 7.22 (2H, t, J 8.7), 5.45 (1H, s), 5.30 (1H, s), 2.46 (3H, s), 1.11 (3H, d, J 5.9). m/z (ES+) 379 [(M-OH)+]. On cooling the mixture was partitioned between EtOAc (15 mL) and water (15 mL) the organic phase was washed with brine dried (MgSO4) filtered concentrated in vacuo The crude material was purified by flash chromatography on silica (eluant 30% EtOAc/isohexane)

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

实验步骤: A solution of (E)-4-fluorostyrylboronic acid (5 g, 30.1 mmol) and 2,4-dibromopyridine (6.49 g, 27.4 mmol) in tetrahydrofuran (150 mL) was purged with nitrogen for 20 min. To this was added Pd(Ph3P)4 (2.37 g, 2.05 mmol) and a 10% w/w solution of thallium(I) hydroxide (137 g, 62 mmol) in water. The reaction was stirred under nitrogen at room temperature. After 3 h, the gray suspension was diluted with dichloromethane and filtered through celite. The organics were washed with water, dried over magnesium sulfate, and concentrated. The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%). 1H NMR (CDCl3) Shift: 8.43 (d, J=5.2 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.50-7.59 (m, 3H), 7.34 (dd, J=5.3, 1.7 Hz, 1H), 7.10 (t, J=8.7 Hz, 2H), 7.02 (d, J=16.2 Hz, 1H). 13C NMR (CDCl3) Shift: 163.1, 157.0, 150.4, 133.3, 133.2, 132.5, 129.0, 126.4, 125.3, 116.0. 19F NMR (CDCl3) Shift: −112.69 (bs, 1F). Mass spec.: 278.2 (MH)+. filtered through celite The organics were washed with water dried over magnesium sulfate concentrated The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%)

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

实验步骤: A solution of (E)-4-fluorostyrylboronic acid (5 g, 30.1 mmol) and 2,4-dibromopyridine (6.49 g, 27.4 mmol) in tetrahydrofuran (150 mL) was purged with nitrogen for 20 min. To this was added Pd(Ph3P)4 (2.37 g, 2.05 mmol) and a 10% w/w solution of thallium(I) hydroxide (137 g, 62 mmol) in water. The reaction was stirred under nitrogen at room temperature. After 3 h, the gray suspension was diluted with dichloromethane and filtered through celite. The organics were washed with water, dried over magnesium sulfate, and concentrated. The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%). 1H NMR (CDCl3) Shift: 8.43 (d, J=5.2 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.50-7.59 (m, 3H), 7.34 (dd, J=5.3, 1.7 Hz, 1H), 7.10 (t, J=8.7 Hz, 2H), 7.02 (d, J=16.2 Hz, 1H). 13C NMR (CDCl3) Shift: 163.1, 157.0, 150.4, 133.3, 133.2, 132.5, 129.0, 126.4, 125.3, 116.0. 19F NMR (CDCl3) Shift: −112.69 (bs, 1F). Mass spec.: 278.2 (MH)+. filtered through celite The organics were washed with water dried over magnesium sulfate concentrated The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%)

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-fluorostyrylboronic acid (49.7 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a light yellow solid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=16.17 Hz, 1H), 2.00-2.21 (m, 1H), 3.55-3.71 (m, 2H), 3.79-3.93 (m, 2H), 3.93-4.10 (m, 1H), 4.33-4.46 (m, 2H), 4.54 (d, J=8.84 Hz, 1H), 7.15 (d, J=5.05 Hz, 1 H), 7.28 (t, J=8.84 Hz, 1H), 7.58-7.74 (m, 3H), 7.93 (br s, 3H), 8.15 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20F2N4O2, 387. found, 387. In a 30 mL sealed The cap was sealed extracted with EtOAc (2×30 mL) The combined organic phase was dried over sodium sulfate evaporated

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-fluorostyrylboronic acid (49.9 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and was extracted into EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) for 1.5 hours to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a tan solid (58 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.92 (m, 8H), 3.74 (br s, 1H), 4.40 (d, J=2.53 Hz, 2H), 4.51 (br s, 1H), 6.86 (d, J=6.57 Hz, 1H), 7.27 (t, J=8.84 Hz, 1H), 7.56-7.73 (m, 3H), 7.82 (br s, 3H), 8.14 (d, J=15.92 Hz, 1H), 8.49 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22F2N4O, 385. found, 385. In a 30 mL sealed The cap was sealed was extracted into EtOAc (2×30 mL) The combined organic phase was dried over sodium sulfate evaporated

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl 2-chloroisonicotinate (5.5 g, 32.05 mmol), (E)-4-fluorostyrylboronic acid (7.98 g, 48.08 mmol), potassium phosphate (3.93 mL, 48.08 mmol) and PdCl2 (dppf) (0.464 g, 0.64 mmol) were split into 5 equal portions and each portion was placed in a microwave reaction vessel. The vessels were evacuated and backfilled with nitrogen. Methanol (15 mL) was added to each vessel, the vessels were sealed and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vessels was pooled and water and DCM were added, the phases separated and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 6:1 to 4:1 of EtOAc in heptane over 15 CV was used as mobile phase. (E)-Methyl 2-(4-fluorostyryl)isonicotinate (3.88 g, 47%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.04-7.18 (m, 3H), 7.52-7.62 (m, 2H), 7.63-7.71 (m, 2H), 7.93 (s, 1H), 8.74 (d, 1H). MS m/z 258 (M+H)+ each portion was placed in a microwave reaction vessel The vessels were evacuated Methanol (15 mL) was added to each vessel the vessels were sealed water and DCM were added the phases separated the aqueous layer was extracted with DCM The combined organic layers were filtered through a phase separator evaporated The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) in 1-propanol (0.1 M) was added [(E)-2-(4-fluorophenyl)vinyl]boronic acid (1.5 equiv), 2.0 M aqueous Na2CO3 solution (2.5 equiv), and a 3:1 mixture of Ph3P:Pd(OAc)2 (0.1 equiv). The mixture was degassed and then stirred at 100° C. for 2.5 h, and was then partitioned between EtOAc/THF and H2O. The organic layer was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. The crude material was purified by flash chromatography, eluting with 1:1 Et2O:hexanes. The product was stirred with 1:10 EtOAc:hexanes containing trace acetone to yield the title compound as a pale yellow solid after filtration. The mixture was degassed was then partitioned between EtOAc/THF and H2O The organic layer was washed with H2O and brine was then dried (MgSO4) filtered evaporated The crude material was purified by flash chromatography eluting with 1:1 Et2O The product was stirred with 1:10 EtOAc