1-tert-butylpiperidine-4-thiol

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

实验步骤: A mixture of 9-bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (73 mg, 0.18 mmol), 1-tert-butylpiperidine-4-thiol (63 mg, 0.37 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol) and DIPEA (125 μL, 0.73 mmol) in dioxane (3 mL) was purged with argon and heated at 100° C. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 5-95%, 0.1% HCO2H in acetonitrile/water) affording 159 (56 mg, 31%). LCMS: RT 3.11 min [M+H]+ 492.1. 1H NMR (DMSO, 400 MHz): δ 8.51 (1H, d, J=2.40 Hz), 8.26-8.25 (1H, m), 8.21 (1H, s), 7.42 (1H, s), 7.31 (1H, dd, J=8.46, 2.42 Hz), 7.01 (1H, d, J=8.46 Hz), 4.47 (4H, s), 3.12-3.01 (1H, m), 3.05-2.93 (2H, m), 2.24 (2H, t, J=11.08 Hz), 1.92 (2H, d, J=12.67 Hz), 1.48-1.47 (2H, m), 1.02 (9H, s) was purged with argon was washed with MeOH the product eluted with 2M NH3/MeOH The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 3 (200 mg, 0.58 mmol), 1-tert-butylpiperidine-4-thiol (202 mg, 1.69 mmol), Pd2(dba)3 (160 mg, 10 mol %), XantPhos (68 mg, 20 mol %) and DIPEA (410 μL, 2.34 mmol) in dioxane (5 mL) was purged with argon and heated at 140° C. for 1 h using microwave irradiation. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 2-25% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 154 as a white solid (36 mg, 15%). LCMS: RT 2.40 min [M+H]+ 435.1. 1H NMR (CDC3, 400 MHz): δ 8.15-8.14 (1H, m), 7.76 (1H, td, J=8.52, 2.20 Hz), 7.67 (1H, s), 7.33 (1H, dd, J=8.45, 3.89 Hz), 7.15-7.15 (1H, m), 6.96 (1H, d, J=8.43 Hz), 4.46-4.45 (4H, m), 3.03-2.98 (4H, m), 2.20 (2H, t, J=11.00 Hz), 2.06-1.94 (3H, m), 1.66-1.62 (2H, m), 1.06 (9H, s) was purged with argon microwave irradiation The reaction mixture was filtered through Celite® the filtrate concentrated in vacuo was washed with MeOH the product eluted with 2M NH3/MeOH The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM was washed with MeOH the product eluted with 2M NH3/MeOH affording 154 as a white solid (36 mg, 15%)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 9-bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.10 mmol), 1-tert-butylpiperidine-4-thiol (53 mg, 0.30 mmol), Pd2(dba)3 (9 mg, 10 mol %), XantPhos (12 mg, 20 mol %) and DIPEA (72 μL, 0.41 mmol) in dioxane (2 mL) was purged with argon and heated at 120° C. for 40 min, then 130° C. for 1 h and 140° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc then C18, gradient 2-20% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%). LCMS: RT 2.42 min [M+H]+ 435.1. 1H NMR (CDCl3, 400 MHz): δ 9.03-9.02 (1H, m), 8.75-8.72 (1H, m), 8.51 (1H, dd, J=4.82, 1.67 Hz), 8.21 (1H, d, J=7.88 Hz), 7.35-7.33 (3H, m), 6.99 (1H, d, J=8.26 Hz), 4.52-4.50 (2H, m), 4.46-4.44 (2H, m), 3.03-2.98 (2H, br m), 2.20 (2H, br m), 2.06-1.94 (3H, br m), 1.66-1.62 (2H, br m), 1.06 (9H, br m) was purged with argon 140° C. for 1 h using microwave irradiation was washed with MeOH the product eluted with 2M NH3/MeOH The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc was washed with MeOH the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (100 mg, 0.27 mmol), 1-tert-butylpiperidine-4-thiol (120 mg, 0.69 mmol), Pd2(dba)3 (24 mg, 10 mol %), XantPhos (31 mg, 20 mol %) and DIPEA (186 μL, 1.07 mmol) in dioxane (3 mL) was purged with argon and heated at 120° C. for 40 min using microwave irradiation. The reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%). LCMS: RT 3.11 min [M+H]+ 467.4. 1H NMR (DMSO, 400 MHz): δ 8.54 (1H, d, J=2.35 Hz), 7.94 (1H, d, J=0.67 Hz), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.48 Hz), 5.92-5.91 (1H, m), 4.55-4.49 (4H, m), 3.06-3.04 (3H, m), 2.30 (2H, t, J=11.23 Hz), 2.08-1.96 (2H, m), 1.65-1.64 (2H, m), 1.58 (6H, d, J=6.65 Hz), 1.08 (9H, s) was purged with argon microwave irradiation The reaction mixture was diluted with DCM purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM was washed with MeOH the product eluted with 2M NH3/MeOH The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%)