7-Chloropyrido[3,4-b]pyrazine

Under Ar(g), to a mixture of pyrazin-2-amine (1) (158mg, 1.7mmol), 7- chloro-pyrido[3, 4-b]pyrazine (2) (250mg, 1.5mmol), Cs2C03 (0.99g, 3.0mmol) was added degassed dry 1 , 4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (69mg, 0.08mmol) and Xantphos (96mg, 0.17mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (61 mg, 18%).INTERMEDIATE 383-(Pyridor3, 4-&1pyrazin-7-ylN)benzaldehyde 7-Chloropyrido[3, 4-Z?]pyrazine (140 mg, 0.85 mmol), 3-formylbenzeneboronic acid (127 mg, 0.85 mmol), potassium phosphate (180 mg, 0.85 mmol), water (2 mL), DME (6 mL) and Pd(PPh3)4 (100 mg, 0.085 mmol) were combined in a sealed tube and heated under microwave irradiation to 1400C for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to dryness to give the title compound (155 mg, 77%) as an off-white solid. deltaH (DMSOd6) 10.21 (IH, s), 9.69 (IH, s), 9.26 (IH, d, J 1.82 Hz), 9.15 (IH, d, J 1.83 Hz), 8.93 (IH, s), 8.76 (IH, s), 8.70 (IH, d, J 7.80 Hz), 8.07 (IH, d, J 7.61 Hz), 7.84 (lH, t, J7.68 Hz).EXAMPLE 417- [3 -(Piperidin- 1 -ylmethv0phenyl1pyrido[3 , 4-61pyrazine4, 5-Diamino-2-chloropyridine (35 mg, 0.24 mmol) was dissolved in ethanol (1 mL) and glyoxal (0.5 niL, 40% in water) was added. After standing for 18 h the mixture was partitioned between water and EtOAc (20 mL each). The organic phase was washed with water, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DME (0.7 mL), and 3-(piperidin-l-ylmethyl)phenylboronic acid pinacol ester hydrochloride (81 mg, 0.24 mmol), 2M aqueous sodium carbonate solution (0.35 mL, 0.7 mmol) and Pd(PPh3)4 (8 mg, 0.007 mmol) were added. The mixture was heated to 12O0C in a sealed tube, under microwave irradiation, for 20 minutes. After cooling, the mixture was partitioned between water and EtOAc (2 mL each). The organic phase was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound (53 mg, 64%) as a pale yellow gum. deltaH (CDCl3) 9.63 (d, IH), 9.03 (d, IH), 8.92 (d, IH), 8.37 (d, IH), 8.17 (s, IH), 8.08-8.14 (m, IH), 7.44-7.57 (m, 2H), 3.74 (s, 2H), 2.50-2.65 (m, 4H), 1.59-1.73 (m, 4H), 1.40-1.54 (m, 2H). LCMS (ES+) 305 (M+H)+, RT 1.89 minutes.EXAMPLE 1117-[3-(Pyrrolidin-l-ylmethyl)phenyllpyrido[3, 4-Z>lpyrazineA mixture of 3-(bromomethyl)phenylboronic acid (150 mg, 0.69 mmol), pyrrolidine (70 muL, 0.84 mmol) and potassium phosphate (440 mg, 2.10 mmol) in DME (3 mL) was heated at 8O0C in a sealed reaction tube for 16 h. The reaction mixture was cooled to room temperature. 7-Chloropyrido[3, 4-d]pyrazine (110 mg, 0.69 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and water (0.5 mL) were then added. The resulting mixture was purged with nitrogen for 5 minutes, sealed and heated at 850C for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (5 mL) and filtered through Celite. The filtrate was concentrated to dryness and purified by preparative HPLC to give the title compound (12.0 mg, 6%) as a pale brown solid. 5H (CDCl3) 9.62 (IH, s), 9.02 (IH, d, J 1.78 Hz), 8.91 (IH, d, J 1.78 Hz), 8.37 (IH, s), 8.22 (IH, s), 8.13 (IH, dt, J 6.69, 2.04 Hz), 7.58-7.48 (2H, m), 3.96 (2H, s), 2.70-2.84 (4H, m), 2.03-1.79 (4H, m). LCMS (ES+) 291 (M+H)+, 9.83 minutes {Method 5).EXAMPLE 417- [3 -(Piperidin- 1 -ylmethv0phenyl1pyrido[3 , 4-61pyrazine4, 5-Diamino-2-chloropyridine (35 mg, 0.24 mmol) was dissolved in ethanol (1 mL) and glyoxal (0.5 niL, 40% in water) was added. After standing for 18 h the mixture was partitioned between water and EtOAc (20 mL each). The organic phase was washed with water, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DME (0.7 mL), and 3-(piperidin-l-ylmethyl)phenylboronic acid pinacol ester hydrochloride (81 mg, 0.24 mmol), 2M aqueous sodium carbonate solution (0.35 mL, 0.7 mmol) and Pd(PPh3)4 (8 mg, 0.007 mmol) were added. The mixture was heated to 12O0C in a sealed tube, under microwave irradiation, for 20 minutes. After cooling, the mixture was partitioned between water and EtOAc (2 mL each). The organic phase was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound (53 mg, 64%) as a pale yellow gum. deltaH (CDCl3) 9.63 (d, IH), 9.03 (d, IH), 8.92 (d, IH), 8.37 (d, IH), 8.17 (s, IH), 8.08-8.14 (m, IH), 7.44-7.57 (m, 2H), 3.74 (s, 2H), 2.50-2.65 (m, 4H), 1.59-1.73 (m, 4H), 1.40-1.54 (m, 2H). LCMS (ES+) 305 (M+H)+, RT 1.89 minutes.

Molecular Weight:165.58
XLogP3:1.1
Hydrogen Bond Acceptor Count:3
Exact Mass:165.0093748
Monoisotopic Mass:165.0093748
Topological Polar Surface Area:38.7
Heavy Atom Count:11
Complexity:142
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes