Preparation of tert-butyl 4-butyryl-1,4-diazepane-1-carboxylate (2)

Tert-butyl 1,4-diazepane-1-carboxylate (1) (1.0 g, 4.99 mmol), TEA (1.04 mL, 7.48 mmol), and DCM (10 mL) were dissolved at 0 °C in a reaction jar. After then, the solution received a dropwise addition of butyryl chloride (798.0 mg, 7.48 mmol). The mixture was then mixed at room temperature for 30 min. The reaction mixture was then split equally between 100 mL of H2O and 100 mL of EtOAc. EtOAc (2 × 50 mL) was used to extract the aqueous layer further. Na2SO4 was used to mix and dry the organic layers. Tert-butyl 4-Butyryl-1,4-diazepane-1-carboxylate (2) (1.2 g, 88.88%) was obtained as the crude product after the solvent was removed under vacuum. The next stage didn't require any purification because the crude product was used immediately.

Preparation of 1-(1,4-diazepan-1-yl)butan-1-one hydrochloride salt (3)

The reaction mixture was agitated at room temperature for 16 h with tert-butyl 4-butyryl-1,4-diazepane-1-carboxylate (2) (1.0 g, 3.70 mmol) in 6N HCl-dioxane (10.0 mL). To produce the crude product, 1-(1,4-diazepan-1-yl)butan-1-one hydrochloride salt (3) (550 mg), the reaction mixture was then concentrated under vacuum. The crude product was utilized right away in the subsequent step of the reaction without going through any purifying procedures.

Preparation of ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (4)

Tert-butyl 4-oxopiperidine-1-carboxylate (578 mg, 2.90 mmol), 1-(1,4-diazepan-1-yl)butan-1-one hydrochloride salt (3) (500 mg, 2.90 mmol), TEA (1.2 mL, 8.70 mmol), ZnCl2 (8.0 mg, 0.1 mmol), and MeOH (7 mL) were mixed in an RBF. The mixture for the reaction was heated to 60 °C and given 4 h to react. The reaction mixture was then cooled to zero degrees Celsius. NaCNBH3 (540 mg, 8.70 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred for 16 h as it warmed to room temperature. A residue was produced after the reaction mixture was concentrated under a vacuum. The aqueous layer was extracted with EtOAc (250 mL) after the residue was divided between 500 mL of H2O and 500 mL of EtOAc. Na2SO4 was used to mix and dry the organic layers. A crude product was produced after the solvent was subsequently extracted under a vacuum. Column chromatography was used to purify the crude product. Ethyl 4-(1-(tert-butoxy carbonyl)piperidin-4-yl)-1,4-diazepane was the pure product that was produced.400 mg of − 1-carboxylate (4), 38.76% yield.

Ethyl 4-(piperidin-4-yl)-1,4-diazepane-1-carboxylate hydrochloride salt (5)

The reaction mixture was agitated at room temperature for 16 h with ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (4) (400 mg, 3.70 mmol) in 6N HCl-dioxane (4 mL). A crude product of ethyl 4-(piperidin-4-yl)-1,4-diazepane-1-carboxylate hydrochloride salt (5) (250 mg, 76.13% yield) was produced when the mixture was concentrated under vacuum. The crude product was utilized right away in the subsequent step of the reaction without going through any purifying procedures.

General procedure of compound (6a–o)

The carboxylic acid (1 equivalent) was mixed in DMF (10 volumes) in a reaction vessel. Next, the resulting mixture was cooled to absolute zero. After adding HATU (1.5 equivalents), the reaction mixture was stirred at 0 °C for 10 min. Ethyl 4-(piperidin-4-yl)-1,4-diazepane-1-carboxylate hydrochloride salt (5) (1.1 equivalents) and DIPEA (3 equivalents) were then added to the reaction mixture. The end product was stirred at room temperature for six hours. The reaction mixture was then dumped into ice-cold water after it had finished. The resultant residue was divided between 500 mL of H2O and 500 mL of EtOAc. EtOAc (250 mL) was used to extract the aqueous layer further. Na2SO4 was used to mix and dry the organic layers. The crude product was then produced after the solvent was removed under vacuum. To produce the final chemicals 6a-o, column chromatography was used to purify the crude product. (Supplementary File).

Ethyl 4-(1-(2-nitrobenzoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6a)

1H NMR (400 MHz, DMSO) δ 1.25–1.29 (3H, t), 1.81 (4H, m), 2.77 (6H, m), 3.06 (2H, m), 3.49 (5H, m), 4.12–4.18 (2H, q), 4.77–4.88 (2H, m), 7.3 (1H, m), 7.57–7.61 (1H, m), 7.72 (1H, m), 8.21–8.23 (2H, d, J = 8 Hz). LCMS m/z Cal. [M + H]+ 404.21 found [M + H]+405.21.

Ethyl 4-(1-(1-((benzyloxy)carbonyl)azetidine-3-carbonyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6b)

1H NMR (400 MHz, DMSO) δ 0.85–0.96 (4H, m), 1.27–1.30 (4H, m), 2.00 (2H, m), 2.57–2.63 (1H, t, J = 24 Hz), 2.78–2.90 (3H, m), 3.00 (2H, s), 3.49–3.55 (6H, m), 4.16–4.17 (6H, d, J = 4 Hz), 4.77 (1H, s), 5.11 (2H, s), 7.28–7.37 (5H, m). LCMS m/z Cal. [M + H]+ 472.27 found [M + H]+473.2.

Ethyl 4-(1-(6-bromo-5-fluoropicolinoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6c)

1H NMR (400 MHz, DMSO) δ 1.29–1.32 (4H, m), 1.49–1.55 (2H, s), 1.67–1.72 (2H, m), 2.00 (4H, s), 2.81–2.97 (3H, m), 3.11–3.22 (2H, m), 3.53–3.61 (1H, m), 3.67 (3H, s), 4.18–4.20 (2H, d, J = 8 Hz), 4.79–4.83 (1H, d, J = 16 Hz), 7.55–7.58 (1H, t, J = 12 Hz), 7.72–7.75 (1H, m). LCMS m/z Cal. [M-H]− 458.12 found [M-H]−457.6.

Ethyl 4-(1-(3-methyl-4-nitrobenzoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6d)

1H NMR (400 MHz, DMSO) δ 1.23–1.34 (3H, m), 1.42–1.58 (4H, m), 2.01–2.31 (4H, m), 2.64 (3H, s), 2.82–2.90 (1H, d), 3.15–3.23 (4H, m), 3.43–3.46 (1H, m), 3.51–3.57 (2H, s), 3.72–3.79 (2H, m), 4.13–4.18 (2H, m), 4.83 (1H, s), 7.28 (1H, s), 7.34–7.40 (1H, m), 8.00–8.02 (1H, d, J = 8 Hz). LCMS m/z Cal. [M + H]+ 418.22 found [M + H]+419.2.

Ethyl 4-(1-(3-bromobenzoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6e)

1H NMR (400 MHz, DMSO) δ 1.26–1.29 (3H, t, J = 12 Hz), 1.48–1.53 (4H, m), 1.88 (4H, s), 2.80 (4H, d), 3.03 (1H, s), 3.16–3.22 (1H, m), 3.50–3.59 (2H, m), 3.70–3.77 (2H, m), 4.13–4.18 (2H, m), 4.76 (1H, s), 7.23–7.33 (2H, m), 7.55–7.58 (2H, d, J = 12 Hz). LCMS m/z Cal. [M-2 + H]− 438.13 found [M + H]−405.21.

Ethyl 4-(1-(4-bromo-3-methylbenzoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6f)

1H NMR (400 MHz, DMSO) δ 1.26–1.30 (3H, t, J = 16 Hz), 1.47–1.52 (4H, m), 1.87–1.99 (2H, m), 2.10 (3H, m), 2.44 (3H, s), 2.93–2.98 (4H, m), 3.51–3.54 (4H, m), 3.65 (1H, m), 4.15–4.17 (2H, m), 4.80–4.90 (1H, s), 7.08 (1H, s), 7.20–7.28 (1H, s), 7.57–7.59 (1H, d, J = 8 Hz). LCMS m/z Cal. [M-H]− 453.15 found [M-H]−452.0.

Ethyl 4-(1-(2-amino-5-bromobenzoyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6 g)

1H NMR (400 MHz, DMSO) δ 1.29–1.32 (4H, m), 1.60–1.63 (4H, m), 2.01 (4H, s), 2.88–2.94 (6H, d, J = 24 Hz), 3.16–3.17 (1H, d, J = 4 Hz), 3.53–3.76 (2H, m), 4.16–4.21 (2H, m), 4.33 (2H, s), 6.64–6.66 (1H, d, J = 8 Hz), 7.20 (1H, s), 7.30 (1H, s). LCMS m/z Cal. [M + H]+ 452.14 found [M + H]+453.2.

Ethyl 4-(1-(3-(3-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6h)

1H NMR (400 MHz, DMSO) δ 0.88–0.92 (4H, m), 1.30 (8H, s), 2.32–2.75 (6H, m), 3.48 (4H, s), 3.69 (1H, s), 3.87–3.90 (2H, d, J = 12 Hz), 4.17–4.18 (2H, d, J = 4 Hz), 4.82 (1H, s), 7.04 (1H, s), 7.24–7.42 (3H, m). LCMS m/z Cal. [M + H]+ 470.25found [M + H]+471.2.

Ethyl 4-(1-(1-phenylpiperidine-4-carbonyl)piperidin-4-yl)-1,4-diazepane-1-carboxylate (6i)

1H NMR (400 MHz, DMSO) δ 1.28–1.32 (3H, m), 1.53 (4H, m), 1.81–1.84 (3H, m), 1.91–1.98 (7H, m), 2.52–2.60 (1H, m), 2.73–2.79 (1H, m), 2.84–2.98 (3H, m), 3.04–3.11 (1H, t, J = 28 Hz), 3.16–3.22 (1H, m,), 3.51–3.52 (2H, m), 3.55 (1H, m), 3.70–3.77 (2H, m), 4.02–4.05 (1H, m), 4.13–4.18 (2H, m), 4.73–4.76 (1H, d, J = 12 Hz), 6.87 (1H, s), 6.95–6.97 (2H, m), 7.26–7.28 (2H, m). LCMS m/z Cal. [M + H]+ 442.29 found [M + H]+442.60.

Ethyl 4-(1-benzoylpiperidin-4-yl)-1,4-diazepane-1-carboxylate (6j)

1H NMR (400 MHz, DMSO) δ 1.29–1.33 (3H, t, J = 12 Hz), 1.47–1.72 (2H, m), 2.23–2.26 (3H, d, J = 12 Hz), 2.43 (3H, s), 3.15–3.25 (3H, m), 3.62 (4H, s), 3.93 (3H, s), 4.19–4.22 (2H, t, J = 12 Hz), 7.31–7.45 (6H, m). LCMS m/z Cal. [M + H]+ 359.22 found [M + H]+359.47.