6-Fluoropyridine-2-boronic acid

Under a nitrogen atmosphere, 2-bromo-6-fluoropyridine (L) (2.5 g, 14.6 mmol, 1 equiv.) and B(Step 5. Preparation of tert-butyl (2-(N-(6-fluoropyridin-2-yl)sulfamoyl)-4-(trifluoromethyl)thiazol-5-yl)carbamate To a mixture of tert-butyl (2-sulfamoyl-4-(trifluoromethyl)thiazol-5-yl)carbamate (3.41 g, 9.82 mmol) and triethylamine (4.11 mL, 29.46 mmol) in acetonitrile (55 mL) was added Step 5. Preparation of 4-((1-benzylpiperidin-4-yl)amino)-5-chloro-N-(6-fluoropyridin-2-yl)thiophene-2-sulfonamide To a mixture of 4-((1-benzylpiperidin-4-yl)amino)-5-chlorothiophene-2-sulfonamide (0.45 g, 1.16 mmol) and General procedure: Phenylboronic acid (61 mg, 0.50 mmol) and 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate I, 100 mg, 0.33 mmol) were mixed in DME (4 mL) in a sealable tube. A 2 M solution of sodium carbonate in water (0.45 mL, 0.90 mmol) and palladium(0)tetrakis (triphenylphosphine) (27 mg, 0.023 mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2 h at 90 C. The cooled reaction mixture was poured into ethyl acetate and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine (84 mg, 0.25 mmol, 74%) as a white solid. (0.670g, 4.76mmol) was mixed with DME (20mL) in a sealable tube. A 2M solution of sodium carbonate in water (5.49mL, l0.98mmol) was added followed by a solution of di-tert-butyl [3-(3-(chloromethyl)-l, 2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 1.500 g, 3.66mmol) in DME (2mL). Palladium tetrakis triphenylphosphine (0.296 g, 0.256 mmol) was added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 4h at 90 C. The cooled reaction mixture was poured into ethyl acetate (200mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate (0.900g, l.9lmmol), to which was added formic acid (5.5mL). The resulting mixture was stirred for 18h at 21-25 C to complete the di-Boc de -protection. Ice-water (50mL) and ethyl acetate (l50mL) were added and the pH was adjusted to 8-9 by the addition of 5N aqueous NaOH. The layers were separated and the aqueous phase was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the product was precipitated through the addition of hexane. The product was filtered and dried under vacuum to yield 3-(3-((6-fluoropyridin-2-yl)methyl)isoxazol-5-yl)pyridin-2 -amine (0.440g, l.63mmol, 44%) as a white solid. MS: 271.2 [M+H]+. (6.26 mmol), Compound 5 (2.14 g, 6.05 mmol), Na2CO3 (2.00 g, 18.78 mmol), DME (10.14mL) and H2O (2.50mL)Add to a 50 mL microwave vial.The vial was degassed with N2 for 35 minutes.PdCl 2 (dppf) CH 2 Cl 2 (0.55 g, 0.75 mmol) adduct was then added.The reaction mixture was heated at 120 C for 1 hour by microwave irradiation.The resulting mixture was diluted with ethyl acetate and filtered over EtOAc.It was then concentrated in vacuo.Purified by flash chromatography, Using 0-100% ethyl acetate / heptane as eluent, Obtaining an off-white solid 4-cyclopentyl-5-(6-fluoropyridin-2-yl)-1H-pyrrole-2-carboxylic acid-(4-methylcyclohexyl) ester, 2.06 g, yield 92%.(6-Fluoropyridin-2-yl)boronic acid (6.26 mmol), Compound 5 (1.79 g, 6.26 mmol), Na2CO3 (2.00 g, 18.78 mmol), DME (10.14 mL) and H2O (2.50 mL) were added to a 50 mL microwave vial.The vial was degassed with N2 for 35 minutes.PdCl 2 (dppf) CH 2 Cl 2 (0.55 g, 0.75 mmol) adduct was then added.The reaction mixture was heated at 120 C for 1 hour by microwave irradiation.The resulting mixture was diluted with ethyl acetate and filtered over EtOAc.It was then concentrated in vacuo.Fast colorPurification by chromatography, using 0-100% ethyl acetate / heptane as eluent, There was obtained an off-white solid ethyl 4-cyclopentyl-5-(6-fluoropyridin-2-yl)-1H-pyrrole-2-carboxylate, 1.68 g, yield 89%.Add 6-fluoro-pyridine-2-boronic acid (0.375 mmol), compound 4 (137.97 mg, 0.375 mmol), Na2CO3 (119.8 mg, 1.13 mmol), DME (0.61 mL) and H2O (0.15 mL) to a 5 mL microwave vial. The vial was degassed with N2 for 11 minutes. Then PdCl2(dppf)CH2Cl2 (33.1 mg, 0.045 mmol) adduct was added. The reaction mixture was heated at 120 C for 50 minutes by microwave irradiation. The resulting mixture was diluted with ethyl acetate and filtered over EtOAc. It was then concentrated in vacuo. Purified by flash chromatography, Using 0-100% ethyl acetate / heptane as eluent, Get a bright yellow powder 2-(6-fluoro-pyridin-2-yl)-5-(3-methyl-4-(((1R, 3R, 5R, 7R)-2-methyladamantan-2-yl)oxy)phenyl)pyridine, 138.03 mg, yield 86%.To a vial containing General procedure: Example 261 N-(4-(3-(6-Fluoropyridin-3-yl)-7-(1-hydroxyethyl)-1H-pyrrolo[3, 2-b]pyridin-2-yl)pyridin-2-yl)acetamide The solution of N-(4-(7-(1-hydroxyethyl)-3-iodo-1H-pyrrolo[3, 2-b]pyridin-2-yl)pyridin-2-yl)acetamide (30 mg, 0.071 mmol) and 2-fluoropyridine-5-boronic acid (12.0 mg, 0.085 mmol) in dioxane (2 mL) in a sealed tube. 1.0 M Na2CO3 solution (0.18 mL, 0.18 mmol) was added and the mixture was purged with nitrogen stream for 3 min, followed by addition of PdCl2(dppf) (5.2 mg, 7.11 mumol). The resulting mixture was heated at 90 C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH+2 drop of TFA and filtered through a syringe filter, purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the desired product 2 TFA salt as a yellow solid (5.3 mg, 12%); HPLC: RT=0.69 min (H2O/ACN with 0.1% TFA, Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-mum particles, gradient=3 min, wavelength=220 nm); MS (ES): m/z=392.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6) delta ppm 10.65 (s, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.04 (td, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=5.0 Hz, 1H), 7.27 (br. s., 1H), 7.20 (d, J=5.0 Hz, 1H), 5.49 (q, J=6.2 Hz, 1H), 2.07 (s, 3H), 1.50 (d, J=6.4 Hz, 3H). Example 262 N-(4-(3-(6-Fluoropyridin-2-yl)-7-(1-hydroxyethyl)-1H-pyrrolo[3, 2-b]pyridin-2-yl)pyridin-2-yl)acetamide Example 262 was prepared from 2-bromo-6-fluoropyridine by the general methods shown for Example 261. HPLC: RT=0.79 min (H2O/ACN with 0.1% TFA, Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-mum particles, gradient=3 min, wavelength=220 nm); MS (ES): m/z=392.1 [M+H]; 1H NMR (500 MHz, DMSO-d6) delta ppm 11.88 (s, 1H), 10.57 (s, 1H), 8.46 (d, J=4.7 Hz, 1H), 8.34 (d, J=5.0 Hz, 1H), 8.28-8.17 (m, 2H), 8.02 (q, J=8.2 Hz, 1H), 7.33 (d, J=4.7 Hz, 1H), 7.22 (d, J=4.1 Hz, 1H), 6.96 (dd, J=8.0, 2.3 Hz, 1H), 5.55 (d, J=4.4 Hz, 1H), 5.43-5.26 (m, 1H), 2.08 (s, 3H), 1.45 (d, J=6.4 Hz, 3H).

Molecular Weight:140.91
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:141.0397367
Monoisotopic Mass:141.0397367
Topological Polar Surface Area:53.4
Heavy Atom Count:10
Complexity:114
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes