Chemistry
General methods
All reagents and solvents were obtained from commercially available sources and were used without further purification. Reaction progress was monitored using analytical thin layer chromatography (TLC) on precoated silica gel GF254 (Qingdao Haiyang Chemical Plant, Qing-Dao, China) plates and spots were detected under UV light (254 nm). Melting points were determined on a WRS-2B digital melting point apparatus and uncorrected. IR spectra were recorded using a Nicolet 380 Fourier-transform infrared (FTIR) spectrophotometer (Thermo, USA) from KBr pellets. 1H NMR and 13C NMR spectra were recorded on a Bruker AVANCE III-600 NMR spectrometer (Bruker Biospin Co., Switzerland) with tetramethylsilane (TMS) as the internal standard and CDCl3 or DMSO-d6 as solvent and known chemical shifts of residual proton signals of deuterated solvents (1H NMR: δ: 2.50 for DMSO-d6 and δ: 3.33 for H2O) or carbon signals of deuterated solvents (13C NMR: δ: 39.52 for DMSO-d6) as internal standard. MS (ESI) measurement was conducted on an Agilent 1100 LC-MS spectrometer (Agilent, Palo Alto, USA).
Dimethyl (3-oxo-1, 3-dihydro-isobenzofuran-1-yl)-phosphonate (2)
Compounds 2, 3 and 4 were prepared according to the literature procedure [32]. A mixture of 2-formylbenzoic acid 1 (10.0 g, 66.7 mmol) and dimethyl phosphate (16.8 g, 152.7 mmol) was heated to 100 °C in oil bath and stirred for 8 h. Subsequently, the mixture was cooled to room temperature and then poured into ice-cold water (50 mL), which was followed by extraction with dichloromethane (3×60 mL). The combined organic extracts were dried over MgSO4, and were evaporated in vacuum to produce a white solid which was crystallized in ethanol to yield 10.1g compound 2. Yield: 62.5%, mp: 96.1-98.2℃. 1H-NMR (600 MHz, CDCl3), δ: 7.93 (d, J=7.68Hz, 1H, ArH), 7.76-7.70 (m, 2H, ArH), 7.58 (t, J=7.56Hz, 1H, ArH), 5.70 (d, J=10.98Hz, 1H, CH), 3.91 (d, J=10.92Hz, 3H, OCH3), 3.58 (d, J=10.62Hz, 3H, OCH3).
2-fluoro-5-[(3-oxo-2-benzofuran-1-ylidene) methyl] benzonitrile (3)
To a mixture of 2 (4.3 g, 17.8 mmol) and 2-fluoro-5-formylbenzonitrile (2.6 g, 17.5 mmol) in anhydrous THF (40 mL) was added triethylamine (1.8 mL, 13mmol) dropwise in 30 min, and the temperature was maintained below 15℃. The reaction mixture was slowly warmed to room temperature. The progress of the reaction was monitored by TLC. After completion of the reactions, the reaction mixture was then concentrated in vacuo. The residue was slurried in water (50 mL) for 30 min, and the solid was collected by filtration, was washed with diethyl ether (2×10 mL), and was dried to afford a white solid which was crystallized in ethanol to yield 3.6g compound 3. Yield: 92.6%, mp: 217.2-220.4℃. 1H-NMR (600MHz, DMSO-d6) δ:8.13-8.10 (m, 1H, ArH), 8.03(dd, J=6.06, 2.28Hz, 1H, ArH), 7.97(d, J=7.68Hz, 1H, ArH), 7.76 (td, J=8.06, 5.94Hz, 2H, ArH), 7.61 (td, J=6.06, 2.16Hz, 1H, ArH), 7.25 (dd, J=13.05, 8.70Hz, 1H, ArH), 6.32 (s, 1H, =CH).
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl) methyl] benzoic Acid (4)
To a stirred suspension of 3 (1.0 g, 3.8 mmol) in water (10 mL) was added aqueous NaOH (10 mol/L, 1.8 mL) with subsequent heating to 90℃ for 1 h. The reaction mixture was cooled to 70℃ into which hydrazine hydrate (2.7 mL, 47.0 mmol) was added, and the mixture was stirred for 18 h at 70℃ before TLC indicated the reaction was completed. The mixture was cooled to ambient temperature and was acidified with HCl (4 mol/L) to pH 4, then the suspension was filtered and was washed with diethyl ether and dried to get 1.1 g of 4 as a light red powder. Yield: 93.7%,mp: 208.4-210.1℃。1H-NMR (600 MHz, DMSO-d6) δ: 13.05 (s, 1H, COOH), 12.56 (s, 1H, NH), 8.26-8.20 (m, 1H, ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH), 7.91-7.84 (m, 1H, ArH), 7.83-7.75 (m, 2H, ArH), 7.58-7.50 (m, 1H, ArH), 7.20 (m, 1H , ArH), 4.32 (s, 2H, CH2).
General procedure for the synthesis of compounds (7a-7o)
To a mixture of various substituted bromomethyl benzene 6 (4.8 mmol) and tert-butyl (piperidin-4-yl)methylcarbamate or tert-butyl piperidin-4-ylcarbamate 5 (4.8 mmol) in anhydrous DMF (10 mL) was added potassium carbonate (1.0 g, 7.2 mmol). The reaction mixture was stirred and warmed to 70℃. The progress of the reaction was monitored by TLC. After completion of the reactions, the reaction mixture was poured into ice-cold water (30 mL) and stirred for 30 min. The solid was collected by filtration, and then it was dried to afford a white solid which was crystallized in ethanol to yield 7(7a-7o).
tert-butyl 1-benzylpiperidin-4-ylcarbamate (7a)
A white solid, yield: 80.3%, mp: 118.2-119.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.32 -7.29 (m, 3H, ArH), 7.28 -7.23 (m, 2H, ArH), 4.44 (d, J = 6.66 Hz, 1H, NH), 3.49 (s, 2H, PhCH2N), 3.49-3.48(m, 1H, NCH), 2.81 (t, J = 9.36 Hz, 2H, NCH2), 2.09 (t, J = 10.56 Hz, 2H, NCH2), 1.90 (d, J = 11.6 Hz, 2H, CH2), 1.43 (s, 9H, C(CH3)3), 1.43-1.40(m, 2H, CH2).
tert-butyl 1-(2-fluorobenzyl)piperidin-4-ylcarbamate (7b)
A white solid, yield: 78.5%, mp: 121.7-122.9 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.35(td, J = 7.44, 1.14Hz, 1H, ArH), 7.25-7.21(m, 1H, ArH), 7.10(td, J = 7.50, 0.96Hz, 1H, ArH), 7.02(td, J = 8.34, 0.78Hz, 1H, ArH), 4.43 (d, J = 6.66 Hz, 1H, NH), 3.56 (s, 2H, PhCH2N), 3.48-3.46(m, 1H, NCH), 2.82 (d, J = 9.6 Hz, 2H, NCH2), 2.15 (t, J = 10.9 Hz, 2H, NCH2), 1.90 (d, J = 11.5 Hz, 2H, CH2), 1.46-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(2-nitrobenzyl)piperidin-4-ylcarbamate (7c)
A light yellow solid, yield: 79.8%, mp: 118.5-119.9 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.81 (d, J = 7.38 Hz, 1H, ArH), 7.63(t, J = 3.18 Hz, 1H, ArH), 7.55(t, J = 7.26 Hz, 1H, ArH), 7.41(t, J = 7.68 Hz, 1H, ArH), 4.44 (d, J = 6.18 Hz, 1H, NH), 3.83(s, 2H, PhCH2N), 3.51-3.47(t, m, 1H, NCH), 2.76 (t, J = 14.94 Hz, 2H, NCH2), 2.21 (t, J = 14.64 Hz, 2H, NCH2), 1.89(d, J = 11.94 Hz, 2H, CH2), 1.46-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(3-methoxybenzyl)piperidin-4-ylcarbamate (7d)
A white solid, yield: 80.4%, mp: 95.6-96.0 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.22 (t, J = 7.68 Hz, 1H, ArH), 6.89(d, J = 7.32 Hz, 2H, ArH), 6.80(d, J = 7.14 Hz, 1H, ArH), 4.44 (d, J = 6.48 Hz, 1H, NH), 3.80(s, 3H, OCH3), 3.48(s, 3H, PhCH2N & NCH), 2.82(t, J = 14.94 Hz, 2H, NCH2), 2.11(t, J = 9.72 Hz, 2H, NCH2), 1.91(d, J = 11.52 Hz, 2H, CH2), 1.46-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(4-methylbenzyl)piperidin-4-ylcarbamate (7e)
A white solid, yield: 74.7%, mp: 98.7-98.9 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.19 (d, J = 7.50 Hz, 2H, ArH), 7.12 (d, J = 7.74 Hz, 2H, ArH), 4.44 (d, J = 6.06 Hz, 1H, NH), 3.47 (s, 3H, PhCH2N & NCH), 2.83(t, J = 5.28 Hz, 2H, NCH2), 2.33(s, 3H, CH3), 2.08(t, J = 9.18 Hz, 2H, NCH2), 1.90 (dd, J = 11.4, 0.78 Hz, 2H, CH2), 1.47-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(4-fluorobenzyl)piperidin-4-ylcarbamate (7f)
A white solid, yield: 75.3%, mp: 130.0-130.5 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.28(t, J = 8.64 Hz, 2H, ArH), 6.99(t, J = 8.64 Hz, 2H, ArH), 4.47-4.43(m, 1H, NH), 3.48(s, 2H, PhCH2N), 3.48-3.45(m, 1H, NCH), 2.79(t, J = 10.96 Hz, 2H, NCH2), 2.08(t, J = 11.34 Hz, 2H, NCH2), 1.90(d, J = 11.46 Hz, 2H, CH2), 1.47-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(4-(trifluoromethyl)benzyl)piperidin-4-ylcarbamate (7g)
A white solid, yield: 89%, mp: 122.5-123.7 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.68(d, J = 7.84 Hz, 2H, ArH), 7.52(d, J = 7.88 Hz, 2H, ArH), 4.47-4.44(m, 1H, NH), 3.48(s, 2H, PhCH2N), 3.48-3.46(m, 1H, NCH), 2.71(t, J = 11.30 Hz, 2H, NCH2), 2.04(t, J = 10.78 Hz, 2H, NCH2), 1.89(d, J = 11.36 Hz, 2H, CH2), 1.47-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl 1-(4-(trifluoromethoxy)benzyl)piperidin-4-ylcarbamate (7h)
A white solid, yield: 88%, mp: 103.9-104.7 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.78 (d, J = 7.86 Hz, 2H, ArH), 7.37(d, J = 7.62 Hz, 2H, ArH), 4.46-4.43(m, 1H, NH), 3.47(s, 2H, PhCH2N), 3.47-3.45(m, 1H, NCH), 2.69(t, J = 11.36 Hz, 2H, NCH2), 2.05(t, J = 10.78 Hz, 2H, NCH2), 1.90(d, J = 11.36 Hz, 2H, CH2), 1.47-1.43(m, 2H, CH2), 1.43 (s, 9H, C(CH3)3).
tert-butyl (1-benzylpiperidin-4-yl)methylcarbamate (7i)
A white solid, yield: 85%, mp: 76.2-76.6 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.31-7.29 (m, 3H, ArH), 7.25 (d, J = 7.4 Hz, 2H, ArH), 4.59 (s, 1H, NH), 3.51(s, 2H, PhCH2N), 3.01(t, J = 5.82 Hz, 2H, NCH2), 2.91 (d, J = 11.1 Hz, 2H, NCH2), 1.97(t, J = 10.44 Hz, 2H, NCH2), 1.65 (d, J = 12.66 Hz, 2H, CH2), 1.43 (s, 9H, C(CH3)3), 1.32-1.29 (m, 2H).
tert-butyl (1-(2-fluorobenzyl)piperidin-4-yl)methylcarbamate (7j)
A white solid, yield: 79.3%, mp: 73.6-74.1 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.36 (t, J = 7.44 Hz, 1H, ArH), 7.23-7.20(m, 1H, ArH), 7.09 (t, J = 7.44 Hz, 1H, ArH), 7.01 (t, J = 9.00 Hz, 1H, ArH), 4.58 (s, 1H, NH), 3.57 (s, 2H, PhCH2N), 3.00 (t, J = 5.94 Hz, 2H, NCH2), 2.90 (d, J = 11.46 Hz, 2H, NCH2), 2.00 (t, J = 11.46 Hz, 2H, CH2), 1.77-1.74(m, 1H, CH), 1.65(d, J = 12.90 Hz, 2H, CH2), 1.42(s, 9H, C(CH3)3), 1.30-1.24(m, 2H, CH2).
tert-butyl (1-(3-methoxybenzyl)piperidin-4-yl)methylcarbamate (7k)
A white solid, yield: 89.3%, mp: 72.3-73.5 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.21(t, J = 7.74 Hz, 1H, ArH), 6.90-6.89(m, 2H, ArH), 6.80(d, J = 7.14 Hz, 1H, ArH), 4.56 (s, 1H, NH), 3.80(s, 3H, OCH3), 3.55 (s, 2H, PhCH2N), 3.16(t, J = 6.00 Hz, 2H, NCH2), 2.92(d, J = 10.50 Hz, 2H, NCH2), 1.99(t, J = 10.80 Hz, 2H, NCH2), 1.72 (d, J = 8.82 Hz, 2H, CH2), 1.77-1.74(m, 1H, CH), 1.42(s, 9H, C(CH3)3), 1.38-1.34(m, 2H, CH2).
tert-butyl (1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methylcarbamate (7l)
A white solid, yield: 75.6%, mp: 98.7-99.7 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.58 (d, J = 8.04 Hz, 2H, ArH), 7.49 (d, J = 7.14 Hz, 2H, ArH), 4.64 (s, 1H, NH), 3.64 (s, 2H, PhCH2N), 3.02(t, J = 6.12 Hz, 2H, NCH2), 2.95(t, J = 4.26 Hz, 2H, NCH2), 2.08-2.05(m, 2H, CH2), 1.69(d, J = 12.06 Hz, 2H, CH2), 1.53-1.50(m, 1H, CH), 1.42(s, 9H, C(CH3)3), 1.40-1.38 (m, 2H, CH2).
tert-butyl (1-(4-methylbenzyl)piperidin-4-yl)methylcarbamate (7m)
A white solid, yield: 74.6%, mp: 81.2-83.1 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.19 (d, J = 7.74 Hz, 2H, ArH), 7.12 (d, J = 7.74 Hz, 2H, ArH), 4.58 (s, 1H, NH), 3.48(s, 2H, PhCH2N), 3.01(t, J = 6.18 Hz, 2H, NCH2), 2.89(d, J = 10.8 Hz, 2H, NCH2), 2.33(s, 3H, CH3), 1.94(t, J = 11.94 Hz, 2H, CH2), 1.65(d, J = 12.30 Hz, 2H, CH2), 1.53-1.43(m, 1H, CH), 1.43(s, 9H, C(CH3)3), 1.30-1.23 (m, 2H, CH2).
tert-butyl (1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)methylcarbamate (7n)
A white solid, yield: 79.8%, mp: 88.4-88.9 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.34 (d, J = 8.04 Hz, 2H, ArH), 7.15 (d, J = 8.10 Hz, 2H, ArH), 4.59 (s, 1H, NH), 3.48(d, J = 5.52 Hz, 2H, PhCH2N), 3.01(t, J = 6.36 Hz, 2H, NCH2), 2.89(d, J = 10.86 Hz, 2H, NCH2), 1.93(t, J = 11.94 Hz, 2H, CH2), 1.66(d, J = 12.48 Hz, 2H, CH2), 1.43(s, 9H, C(CH3)3), 1.43-1.41(m, 1H, CH), 1.30-1.23 (m, 2H, CH2).
tert-butyl (1-(4-fluorobenzyl)piperidin-4-yl)methylcarbamate(7o)
A white solid, yield: 79.2%, mp: 86.4-87.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 7.26(t, J = 8.22 Hz, 2H, ArH), 6.98(t, J = 8.64 Hz, 2H, ArH), 4.59 (s, 1H, NH), 3.45 (s, 2H, PhCH2N), 3.01(t, J = 6.12 Hz, 2H, NCH2), 2.86(d, J = 11.22 Hz, 2H, NCH2), 1.93(t, J = 11.34 Hz, 2H, CH2), 1.66(d, J = 12.66 Hz, 2H, CH2), 1.53-1.43(m, 1H, CH), 1.43(s, 9H, C(CH3)3), 1.29-1.25(m, 2H, CH2)
General procedure for the synthesis of intermediates 8
Compound 7 (12.0 mmol) was dissolved and stirred in dichloromethane (DCM, 30 mL) which was cooled by ice-cold water, and then trifluoroacetic acid (8.90 g, 78.0 mmol) was added dropwise in 10 min. Subsequently, the temperature was slowly warmed to room temperature and maintained for 12 h. Methanol (20 mL) was added to the mixture, followed by basification with saturated sodium hydroxide solution to pH 10. The mixture was stirred for 30min, and then extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated and purified by silica gel column chromatography (hexanes/EtOAc (v/v)= (6-3): 1) to give 8 (8a-8o) as colorless or light yellow oil. The material 8 was carried forward without further purification
General procedure for the synthesis of compounds (11a-11d)
Compounds 11a-11d were synthesized by following a similar procedure for the synthesis of 7, while using tert-butyl piperidin-3-ylcarbamate to replace tert-butyl piperidin-4-yl-carbamate.
tert-butyl 1-benzylpiperidin-3-yl-carbamate (11a)
A white solid, yield: 75.2%, mp: 83.8-84.2 ℃, 1H NMR (600 MHz, DMSO-d6) δ: 7.30-7.25(m, 4H, ArH), 7.22(t, J = 7.02 Hz, 1H, ArH), 6.66 (d, J = 7.74 Hz, 1H, NH), 3.42 (s, 2H, PhCH2N), 3.39-3.36(m, 1H, NCH), 2.71 (d, J = 8.22 Hz, 1H, NCHH), 2.59 (d, J = 9.54 Hz, 1H, NCHH), 1.81(t, J = 9.48 Hz, 1H, NCHH), 1.72(t, J = 8.58 Hz, 1H, NCHH), 1.67-1.65(m, 1H, CHH), 1.59-1.57(m, 1H, CHH), 1.43-1.38(m, 1H, CHH), 1.33(s, 9H, C(CH3)3), 1.12-1.09(m, 1H, CHH).
tert-butyl 1-(2-fluorobenzyl)piperidin-3-yl-carbamate (11b)
A white solid, yield: 69.7%, mp: 59.5-61.7 ℃, 1H NMR (600 MHz, DMSO-d6) δ: 7.37(t, J = 6.96 Hz, 1H, ArH), 7.29(q, J = 7.26 Hz, 1H, ArH), 7.16-7.11(m, 2H, ArH), 6.66 (d, J = 7.98 Hz, 1H, NH), 3.39 (s, 2H, PhCH2N), 3.35-3.34(m, 1H, NCH), 2.73 (d, J = 8.76 Hz, 1H, NCHH), 2.69 (d, J = 9.48 Hz, 1H, NCHH), 1.85(t, J = 10.56 Hz, 1H, NCHH), 1.75(t, J = 8.94 Hz, 1H, NCHH), 1.65-1.64(m, 1H, CHH), 1.59-1.57(m, 1H, CHH), 1.44-1.38(m, 1H, CHH), 1.34(s, 9H, C(CH3)3), 1.11-1.06(m, 1H, CHH).
tert-butyl 1-(4-fluorobenzyl)piperidin-3-yl-carbamate (11c)
A white solid, yield: 74.7%, mp: 75.2-76.3 ℃, 1H NMR (600 MHz, DMSO-d6) δ: 7.35 (dd, J = 31.24, 7.6 Hz, 4H, ArH), 6.65 (d, J = 7.84 Hz, 1H, NH), 3.38 (s, 2H, PhCH2N), 3.35-3.34(m, 1H, NCH), 2.74 (d, J = 8.84 Hz, 1H, NCHH), 2.69 (d, J = 9.56 Hz, 1H, NCHH), 1.84(t, J = 10.84 Hz, 1H, NCHH), 1.74(t, J = 8.94 Hz, 1H, NCHH), 1.65-1.64(m, 1H, CHH), 1.59-1.57(m, 1H, CHH), 1.44-1.39(m, 1H, CHH), 1.34(s, 9H, C(CH3)3), 1.12-1.07(m, 1H, CHH).
tert-butyl 1-(4-methylbenzyl)piperidin-3-yl-carbamate (11d)
A white solid, yield: 79.6%, mp: 90.6-91.3 ℃, 1H NMR (600 MHz, DMSO-d6) δ: 7.11(dd, J = 25.80, 7.8 Hz, 4H, ArH), 6.65 (d, J = 7.98 Hz, 1H, NH), 3.49 (s, 2H, PhCH2N), 3.34-3.33(m, 1H, NCH), 2.69 (d, J = 8.64 Hz, 1H, NCHH), 2.58 (d, J = 10.44 Hz, 1H, NCHH), 2.25(s, 3H, CH3), 1.79(t, J = 10.68 Hz, 1H, NCHH), 1.67(t, J = 10.62 Hz, 2H, CH2), 1.58-1.55(m, 1H, CHH), 1.33(s, 9H, C(CH3)3), 1.31-1.25(m, 1H, CHH), 1.09-1.08(m, 1H, CHH).
General procedure for the synthesis of intermediates 12a-12d
Compounds 12a-12d were synthesized by following a similar procedure for the synthesis of 8. The intermediates 12a-12d were got by silica gel column chromatography (hexanes/EtOAc(v/v) = 3: 1) as colorless oil, which were carried forward without further purification.
General procedure for the synthesis of intermediates 15a-15b
The piperidin-4-ol 13 (1.0g, 9.8mmol) and the substituted bromomethyl benzene 14 (9.8mmol) were dissolved and stirred in anhydrous DMF (10mL), and then anhydrous K2CO3 (2.07g, 14.7mmol) was added. The mixture was stirred at 70℃ for 1 h, and then cooled to room temperature, followed by pouring into ice-water (30 mL). The solution was stirred for 10 min, and then extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated and purified by silica gel column chromatography (hexanes/EtOAc(v/v) = 3: 1) to give 15a-15b as colorless oil. The material 15 was carried forward without further purification.
General procedure for the synthesis of target compounds 16-36
Compound 4 (1.00g, 3.35mmol), DIPEA (0.65g, 5.03mmol) and HATU (1.90g, 5.03mmol) were dissolved and stirred in DCM (10mL) at 0℃ for 10 min, and then 8, 12 or 15 (5.03mmol) were added. The mixture was warmed to room temperature and stirred for 2 h, followed by pouring into ice-water (30 mL). The solution was stirred for 10 min, and then extracted with DCM (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated and purified by silica gel column chromatography (hexanes/EtOAc(v/v) =(2-1): 1) to give 16-36.
N-(1-benzylpiperidin-4-yl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide (16)
A white solid, yield: 60%, mp: 196.6-197.4 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.24(s, 1H, CONH-N=), 8.46(d, J = 6.78 Hz, 1H, ArH), 8.07(d, J = 6.0 Hz, 1H, ArH), 7.73-7.72(m, 3H, ArH), 7.31-7.26(m, 6H, CONH & ArH), 7.01(t, J = 10.20 Hz, 1H, ArH), 6.66(t, J =10.68 Hz, 1H, ArH), 4.31(s, 2H, PhCH2C=N), 4.05-4.04(m, 1H, CH), 3.52(s, 2H, PhCH2), 2.83(t, J = 7.80 Hz, 2H, NCH2), 2.22 (d, J = 8.52 Hz, 2H, NCH2), 2.02-2.00(m, 2H, CH2), 1.62-1.57(m, 2H, CH2); 13C NMR (150 MHz, CDCl3) δ:162.27, 160.62, 162.25, 160.63, 160.31, 158.68, 145.66, 138.19, 133.60, 131.94, 131.47, 129.13, 128.26, 127.11, 127.07, 125.06, 121.24, 121.16, 116.51, 116.35, 63.06, 52.09, 46.96, 37.83, 32.01; IR (KBr, cm-1): 3455, 3262, 3071, 2939, 1653, 1559, 1489; ESI-MS:471.22 [M+H]+.
N-(1-(2-fluorobenzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide (17)
A white solid, yield: 55%, mp: 182.3-183.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.15(s, 1H, CONH-N=), 8.45(d, J = 6.96 Hz, 1H, ArH), 8.06(d, J = 5.94 Hz, 1H, ArH), 7.73(d, J = 6.42 Hz, 3H, ArH), 7.37(t, J = 6.90 Hz, 1H, ArH), 7.31(s, 1H, CONH), 7.24(d, J = 6.24 Hz, 1H, ArH), 7.10(t, J = 7.32 Hz, 1H, ArH), 7.01(dd, J = 18.96, 9.96 Hz, 2H, ArH), 6.67(t, J = 8.04 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.03-4.02(m, 1H, CH), 3.60(s, 2H, PhCH2), 2.86(t, J = 4.38 Hz, 2H, NCH2), 2.27(t, J = 10.38 Hz, 2H, NCH2), 2.02-2.00(m, 2H, CH2), 1.63-1.58(m, 2H, CH2); 13C NMR (150 MHz, CDCl3) δ:162.32, 162.19, 160.60, 160.30, 158.67, 145.70, 134.22, 133.63, 133.13, 131.91, 131.58, 131.49, 129.50, 128.86, 128.27, 127.10, 125.06, 123.88, 121.22, 116.52, 115.34, 55.25, 51.84, 46.80, 37.80, 31.91; IR (KBr, cm-1): 3453, 3054, 2946, 1667, 1548; ESI-MS:489.21[M+H]+.
N-(1-(2-nitrobenzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(18)
A light yellow solid, yield: 50%, mp: 192.0-193.1 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.40(s, 1H, CONH-N=), 8.45(d, J = 6.84 Hz, 1H, ArH), 8.05(d, J = 5.88 Hz, 1H, ArH), 7.82(d, J = 6.66 Hz, 1H, ArH), 7.77-7.71(m, 3H, ArH), 7.55(t, J = 6.30 Hz, 2H, ArH), 7.41(t, J = 9.36 Hz, 1H, ArH), 7.33(s, 1H, CONH), 7.03(td, J = 10.11, 2.82 Hz, 1H, ArH), 6.67-6.64(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.07-4.02(m, 1H, CH), 3.85(s, 2H, PhCH2), 2.78(t, J = 9.54 Hz, 2H, NCH2), 2.23(t, J = 13.62 Hz, 2H, NCH2), 2.03-1.98(m, 2H, CH2), 1.76-1.66(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 163.45, 159.81, 158.95, 157.31, 150.04, 145.38, 134.64, 133.95, 133.52, 132.99, 131.99, 130.28, 129.49, 128.91, 128.31, 126.49, 125.97, 125.06, 124.56, 116.42, 58.72, 52.46, 47.02, 36.87, 31.71; IR (KBr, cm-1): 3343, 3016, 2911, 2804, 1662, 1615, 1522; ESI-MS:516.20 [M+H]+.
N-(1-(3-methoxybenzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide (19)
A white solid, yield: 65%, mp: 193.0-194.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.15(s, 1H, CONH-N=), 8.45(d, J = 7.38 Hz, 1H, ArH), 8.08(d, J = 6.90 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.32(s, 1H, CONH), 7.22(t, J = 8.04 Hz, 1H, ArH), 7.01(td, J = 10.11, 2.58 Hz, 1H, ArH), 6.90(s, 2H, ArH), 6.79(d, J = 7.98 Hz, 1H, ArH), 6.66(dd, J = 12.36, 8.04 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.04-4.03(m, 1H, CH), 3.80(s, 3H, OCH3), 3.50(s, 2H, PhCH2), 2.83(t, J = 7.80 Hz, 2H, NCH2), 2.20(t, J = 9.84 Hz, 2H, NCH2), 2.02-2.00(m, 2H, CH2), 1.62-1.57(m, 2H, CH2); 13C NMR (150 MHz, CDCl3) δ:162.27, 160.62, 160.31, 159.60, 158.68, 145.67, 134.25, 133.61, 133.11, 131.94, 131.48, 129.51, 129.17, 128.29, 127.11, 125.06, 121.41, 121.23, 116.52, 114.56, 112.47, 62.95, 55.19, 52.10, 46.95, 37.83, 32.01; IR (KBr, cm-1): 3452, 3177, 3069, 2943, 2802, 1649, 1559; ESI-MS:501.23[M+H]+.
N-(1-(4-methylbenzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide (20)
A white solid, yield: 55%, mp: 201.4-202.2 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.01(s, 1H, CONH-N=), 8.45(dd, J = 6.06, 1.44 Hz, 1H, ArH), 8.07(dd, J = 7.26, 2.16 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.32(s, 1H, CONH), 7.20(d, J = 7.86 Hz, 2H, ArH), 7.12(d, J = 7.80 Hz, 2H, ArH), 7.01(td, J = 10.05, 3.06 Hz, 1H, ArH), 6.66(dd, J = 12.72, 7.92 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.04-4.03(m, 1H, CH), 3.49(s, 2H, PhCH2), 2.83(t, J = 5.34 Hz, 2H, NCH2), 2.33(s, 3H, CH3), 2.19(t, J = 10.68 Hz, 2H, NCH2), 2.02-2.00(m, 2H, CH2), 1.62-1.57(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:163.47, 159.82, 158.94, 157.30, 145.37, 134.69, 133.95, 132.60, 132.00, 130.26, 129.49, 129.23, 128.31, 126.50, 125.96, 125.06, 124.95, 116.58, 116.43, 61.93, 52.12, 46.89, 36.87, 31.35, 21.15; IR (KBr, cm-1): 3456, 3071, 2939, 1651, 1559; ESI-MS:485.23 [M+H]+.
N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide (21)
A white solid, yield: 54%, mp: 201.0-202.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.09(s, 1H, CONH-N=), 8.44(d, J = 7.08 Hz, 1H, ArH), 8.05(d, J = 6.24 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.37-7.33(m, 3H, CONH & ArH), 7.06-7.02(m, 3H, NH & ArH), 6.67(dd, J = 7.26, 4.02 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.09-4.02(m, 1H, CH), 3.58(s, 2H, PhCH2), 2.93(t, J = 7.56 Hz, 2H, NCH2), 2.30(t, J = 8.70 Hz, 2H, NCH2), 2.06-2.04(m, 2H, CH2), 1.66-1.60(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 163.43, 159.81, 158.93, 157.29, 145.37, 135.22, 134.69, 133.96, 132.56, 132.01, 130.97, 130.26, 129.49, 128.31, 126.50, 125.98, 125.10, 116.58, 115.37, 61.62, 52.29, 47.20, 36.86, 31.75; IR (KBr, cm-1): 3455, 3070, 2942, 1656, 1504; ESI-MS:489.21[M+H]+.
N-((1-(4-trifluoromethyl)benzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(22)
A white solid, yield: 56%, mp: 229.3-230.3 ℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.58(s, 1H, CONH-N=), 8.24(d, J = 7.98 Hz, 1H, ArH), 8.19(d, J = 6.30 Hz, 1H, ArH), 7.95(d, J = 7.92 Hz, 1H, ArH), 7.87(td, J = 7.26, 1.26 Hz, 1H, ArH), 7.81(td, J = 7.50, 0.96 Hz, 1H, ArH), 7.67(d, J = 7.80 Hz, 2H, ArH), 7.51(d, J = 7.80 Hz, 2H, ArH), 7.47(dd, J = 6.30, 1.80 Hz, 1H, ArH), 7.41(s, 1H, CONH), 7.17(td, J = 9.36, 1.08 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.72-3.68(m, 1H, CH), 3.53(s, 2H, PhCH2), 2.74(t, J = 10.80 Hz, 2H, NCH2), 2.04(t, J = 14.34 Hz, 2H, NCH2), 1.77-1.73(m, 2H, CH2), 1.52-1.47(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:163.46, 159.82, 158.93, 157.30, 145.38, 134.69, 133.95, 132.58, 132.00, 130.28, 129.72, 129.48, 128.30, 128.10, 127.88, 127.50, 126.50, 125.97, 125.48, 125.90, 123.90, 116.58, 61.78, 52.40, 47.08, 36.86, 31.70; IR (KBr, cm-1): 3266, 2944, 1651, 1563; ESI-MS:539.20 [M+H]+.
N-((1-(4-trifluoromethoxy)benzyl)piperidin-4-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(23)
A white solid, yield: 45%, mp: 227.1-228.0 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.68(s, 1H, CONH-N=), 8.45(dd, J = 7.17, 1.98 Hz, 1H, ArH), 8.07(dd, J = 7.20, 1.68 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.37(d, J = 7.62 Hz, 2H, ArH), 7.33(s, 1H, CONH), 7.16(d, J = 8.16 Hz, 2H, ArH), 7.17(td, J = 10.08, 3.00 Hz, 1H, ArH), 6.66(dd, J = 12.66, 9.36 Hz, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 4.06-4.05(m, 1H, CH), 3.53(s, 2H, PhCH2), 2.84(t, J = 4.62 Hz, 2H, NCH2), 2.23(t, J = 7.86 Hz, 2H, NCH2), 2.04-2.02(m, 2H, CH2), 1.66-1.60(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:163.49, 159.81, 158.93, 157.29, 145.38, 134.70, 133.95, 132.60, 132.00, 131.00, 130.25, 129.49, 128.31, 126.49, 125.97, 125.07, 124.97, 121.38, 119.68, 116.43, 54.02, 52.21, 42.27, 36.86, 31.62; IR (KBr, cm-1): 3457, 2945, 1650, 1566, 1495;ESI-MS:555.19 [M+H]+.
N-((1-benzylpiperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(24)
A white solid, yield: 65%, mp: 191.1-192.2 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.07(s, 1H, CONH-N=), 8.45(d, J = 7.44, Hz, 1H, ArH), 8.07(dd, J = 7.32, 1.98 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.34-7.32(m, 1H, CONH), 7.30-7.28(m, 4H, ArH), 7.25-7.22(m, 1H, ArH), 7.02(td, J = 10.02, 3.00 Hz, 1H, ArH), 6.84-6.80(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.50(s, 2H, PhCH2), 3.36(t, J = 6.06 Hz, 2H, NCH2), 2.91(d, J = 11.4 Hz, 2H, NCH2), 1.96(t, J = 11.4 Hz, 2H, NCH2), 1.72-1.70(m, 2H, CH2), 1.64-1.60(m, 1H, CH), 1.39-1.33(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 164.06, 160.85, 159.81, 158.99, 157.37, 145.77, 134.73, 133.97, 132.66, 131.98, 131.03, 130.38, 129.50, 128.31, 126.49, 125.96, 124.83, 116.59, 115.37, 61.77, 53.75, 45.07, 36.77, 35.93, 29.74; IR (KBr, cm-1): 3288, 2926, 1665, 1540, 1493; ESI-MS: 485.23 [M+H]+.
N-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(25)
A white solid, yield: 55%, mp: 178.9-180.4 ℃, 1H NMR (600 MHz, CDCl3) δ: 11.20(s, 1H, CONH-N=), 8.45(d, J = 7.74, Hz, 1H, ArH), 8.07(dd, J = 7.32, 2.10 Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.36(t, J = 6.66 Hz, 1H, ArH), 7.34-7.31(m, 1H, CONH), 7.23-7.20(m, 1H, ArH), 7.08(t, J = 7.32 Hz, 1H, ArH), 7.00(td, J = 8.82, 1.68 Hz, 2H, ArH), 6.85-6.81(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.59(s, 2H, PhCH2), 3.45(t, J = 6.06 Hz, 2H, NCH2), 2.93(d, J = 11.46 Hz, 2H, NCH2), 2.04(t, J = 10.08 Hz, 2H, NCH2), 1.72 (d, J = 12.54 Hz, 2H, CH2), 1.62-1.58(m, 1H, CH), 1.40-1.33(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:163.15, 162.18, 160.62, 160.31, 158.67, 145.64, 134.29, 133.60, 133.13, 131.98, 131.67, 131.46, 129.51, 128.74, 128.29, 127.10, 125.05, 123.80, 121.14, 116.49, 115.23, 55.35, 52.96, 45.52, 37.81, 35.82, 29.89; IR (KBr, cm-1): 3330, 2927, 1662, 1547, 1490; ESI-MS:503.22 [M+H]+.
N-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(26)
A white solid, yield:59%, mp: 169.4-170.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.33(s, 1H, CONH-N=), 8.45(dd, J = 6.36, 1.74 Hz, 1H, ArH), 8.08(dd, J = 7.32, 1.98 Hz, 1H, ArH), 7.78-7.72(m, 3H, ArH), 7.35-7.32(m, 1H, CONH), 7.21(t, J = 7.74 Hz, 1H, ArH), 7.03(td, J = 10.08, 3.12 Hz, 1H, ArH), 6.90-6.89(m, 2H, ArH), 6.82-6.79(m, 2H, ArH), 4.30(s, 2H, PhCH2C=N), 3.80(s, 3H, OCH3), 3.50(s, 2H, PhCH2), 3.37(t, J = 6.00 Hz, 2H, NCH2), 2.92(d, J = 10.50 Hz, 2H, NCH2), 1.99(t, J = 10.80 Hz, 2H, NCH2), 1.72 (d, J = 8.82 Hz, 2H, CH2), 1.66-1.60(m, 1H, CH), 1.41-1.36(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 163.13, 160.34, 159.56, 158.70, 145.66, 134.22, 133.65, 133.15, 132.02, 131.52, 129.50, 129.11, 128.31, 127.12, 125.06, 121.54, 121.12, 116.52, 116.35, 114.65, 112.49, 63.13, 55.20, 53.23, 45.53, 37.80, 35.89, 29.84; IR (KBr, cm-1): 3300, 2922, 1665, 1603, 1542;ESI-MS: 515.24 [M+H] +.
N-((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)
benzamide(27)
A white solid, yield: 56%, mp: 215.5-216.6 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.96(s, 1H, CONH-N=), 8.45(d, J = 7.62 Hz, 1H, ArH), 8.07(d, J = 7.02 Hz, 1H, ArH), 7.76-7.72(m, 3H, ArH), 7.55(d, J = 7.92 Hz, 2H, ArH), 7.43(d, J = 7.86 Hz, 2H, ArH), 7.34-7.33(m, 1H, CONH), 7.02(td, J = 10.05, 2.70 Hz, 1H, ArH), 6.85-6.82(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.54(s, 2H, PhCH2), 3.37(t, J = 6.12 Hz, 2H, NCH2), 2.88(d, J = 11.16 Hz, 2H, NCH2), 1.99(t, J = 11.34 Hz, 2H, NCH2), 1.72 (d, J = 12.42 Hz, 2H, CH2), 1.66-1.62(m, 1H, CH), 1.39-1.34(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 164.07, 159.81, 158.99, 157.35, 145.37, 134.74, 133.93, 132.66, 131.98, 130.38, 129.50, 128.32, 127.50, 126.49, 125.97, 125.45, 124.83, 124.72, 123.90, 116.60, 61.97, 53.31, 45.06, 36.87, 35.86, 30.02; IR (KBr, cm-1): 3287, 2928, 1664, 1541, 1495;ESI-MS: 553.22 [M+H] +.
N-((1-(4-methylbenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide
(28)
A white solid, yield: 55%, mp: 194.3-195.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.53(s, 1H, CONH-N=), 8.45(dd, J = 7.59, 1.62 Hz, 1H, ArH), 8.08(dd, J = 7.26, 1.92 Hz, 1H, ArH), 7.77-7.72(m, 3H, ArH), 7.34-7.33(m, 1H, CONH), 7.19(d, J = 7.80 Hz, 2H, ArH), 7.11(d, J = 7.74 Hz, 2H, ArH), 7.02(td, J = 10.08, 3.00 Hz, 1H, ArH), 6.82-6.79(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.48(s, 2H, PhCH2), 3.36(t, J = 5.94 Hz, 2H, NCH2), 2.91(d, J = 10.92 Hz, 2H, NCH2), 2.33(s, 3H, CH3), 1.96(t, J = 10.74 Hz, 2H, NCH2), 1.71 (d, J = 12.72 Hz, 2H, CH2), 1.64-1.60(m, 1H, CH), 1.39-1.33(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:164.06, 159.81, 158.98, 157.34, 145.38, 134.73, 133.95, 132.65, 131.99, 130.37, 129.49, 129.30, 129.15, 128.31, 126.49, 125.97, 124.83, 124.73, 116.60, 62.32, 53.17, 45.06, 36.86, 35.93, 29.98, 21.15; IR (KBr, cm-1): 3326, 2917, 1683, 1645, 1543, 1493;ESI-MS: 499.25[M+H] +.
N-((1-(4-trifluoromethoxybenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl) benzamide(29)
A white solid, yield: 56%, mp: 213.3-214.3 ℃, 1H NMR (600 MHz, CDCl3) δ: 10.65(s, 1H, CONH-N=), 8.45(d, J =7.68 Hz, 1H, ArH), 8.08(d, J =5.94 Hz, 1H, ArH), 7.77-7.72(m, 3H, ArH), 7.36-7.35(m, 3H, CONH & ArH), 7.15(d, J = 7.98 Hz, 2H, ArH), 7.03(td, J = 10.08, 2.76 Hz, 1H, ArH), 6.85-6.81(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.53(s, 2H, PhCH2), 3.37(t, J = 5.88 Hz, 2H, NCH2), 2.92(d, J = 9.60 Hz, 2H, NCH2), 2.02(t, J = 11.34 Hz, 2H, NCH2), 1.74 (d, J = 12.36 Hz, 2H, CH2), 1.67-1.65(m, 1H, CH), 1.42-1.39(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:164.06, 159.81, 159.04, 157.39, 147.60, 145.37, 138.77, 134.73, 133.94, 132.64, 131.98, 130.76, 130.37, 129.50, 128.32, 126.49, 125.97, 121.14, 116.59, 116.44, 61.79, 53.31, 45.11, 36.86, 35.99, 30.10; IR (KBr, cm-1): 3288, 2930, 1664, 1542, 1503;ESI-MS: 569.21 [M+H] +.
N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide
(30)
A white solid, yield: 55%, mp:153.4-155.4℃, 1H NMR (600 MHz, CDCl3) δ: 12.58(s, 1H, CONH-N=), 8.45(d, J =5.94 Hz, 1H, ArH), 8.08(d, J =4.86 Hz, 1H, ArH), 7.75-7.73(m, 3H, ArH), 7.34-7.29(m, 3H, CONH & ArH), 7.05-6.99(m, 3H, ArH), 6.83-6.81(m, 1H, ArH), 4.30(s, 2H, PhCH2C=N), 3.51(s, 2H, PhCH2), 3.37(t, J = 5.88 Hz, 2H, NCH2), 2.92(d, J = 9.60 Hz, 2H, NCH2), 2.02-2.00(m, 2H, NCH2), 1.74 (d, J = 10.80 Hz, 2H, CH2), 1.68-1.62(m, 1H, CH), 1.44-1.37(m, 2H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:164.06, 162.46, 160.85, 159.81, 158.99, 157.35, 145.37, 134.73, 133.93, 132.66, 131.98, 130.38, 129.50, 128.32, 126.49, 125.96, 124.83, 116.59, 115.34, 61.76, 53.15, 54.07, 36.87, 35.93, 29.99; IR (KBr, cm-1): 3287, 2932, 1663, 1542, 1504; ESI-MS: 503.22 [M+H]+.
N-(1-benzylpiperidin-3-yl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(31)
A white solid, yield: 60%, mp: 199.9-201.1℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.58(s, 1H, CONH-N=), 8.24(d, J =7.80 Hz, 1H, ArH), 8.06(d, J =6.30 Hz, 1H, ArH), 7.95(d, J =7.98 Hz, 1H, ArH), 7.87(t, J =7.38 Hz, 1H, ArH), 7.80(t, J =7.56 Hz, 1H, ArH), 7.52(d, J =5.58 Hz, 1H, ArH), 7.42(s, 1H, CONH), 7.30-7.28(m, 4H, ArH), 7.22-7.16(m, 2H, ArH), 4.30(s, 2H, PhCH2C=N), 3.92-3.87(m, 1H, CH), 3.45(s, 2H, PhCH2), 2.72-2.70(m, 1H, NCHH), 2.57-2.53(m, 1H, NCHH), 1.99(d, J =11.58 Hz, 2H, NCH2), 1.71-1.69(m, 1H, CHH), 1.65-1.62(m, 1H, CHH), 1.48-1.44(m, 1H, CHH), 1.34-1.29(m, 1H, CHH); 13C NMR (150MHz, DMSO-d6) δ: 163.11, 159.80, 159.12, 157.49, 145.36, 138.75, 134.76, 133.96, 132.84, 132.00, 130.50, 129.49, 129.11, 128.58, 128.31, 127.32, 126.50, 125.97, 116.63, 62.52, 58.16, 53.24, 46.65, 36.86, 29.89, 23.73; IR (KBr, cm-1): 3434, 2795, 1653, 1549, 1494; ESI-MS: 471.22 [M+H]+.
N-(1-(2-fluorobenzyl)piperidin-3-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(32)
A white solid, yield: 55%, mp: 163.9-165.7℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.59(s, 1H, CONH-N=), 8.24(d, J =7.74 Hz, 1H, ArH), 8.06(d, J =6.06 Hz, 1H, ArH), 7.95(d, J =8.04Hz, 1H, ArH), 7.86(t, J =7.20Hz, 1H, ArH), 7.80(t, J =7.56Hz, 1H, ArH), 7.53 (d, J =5.28Hz, 1H, ArH), 7.43-7.38(m, 2H, CONH & ArH), 7.30-7.27(m, 1H, ArH), 7.18(dd, J = 9.51, 1.14 Hz, 1H, ArH), 7.16-7.12(m, 2H, ArH), 4.30(s, 2H, PhCH2=N), 3.90-3.88(m, 1H, CH), 3.52(s, 2H, PhCH2), 2.75(d, J =8.94Hz, 1H, NCHH), 2.56(d, J =8.04Hz, 1H, NCHH), 2.02(t, J =10.50Hz, 2H, NCH2), 1.70-1.68(m, 1H, CHH), 1.64-1.62(m, 1H, CHH), 1.46(td, J = 13.68, 10.20 Hz, 1H, CHH), 1.32-1.27(m, 1H, CHH); 13C NMR (150MHz, DMSO-d6) δ:163.16, 162.00, 160.38, 159.81, 159.12, 157.48, 145.36, 134.77, 133.95, 132.85, 131.99, 130.51, 129.49, 128.32, 126.50, 125.96, 124.91, 124.56, 124.41, 116.48, 115.48, 57.99, 54.98, 52.98, 46.67, 36.87, 29.77, 23.74; IR (KBr, cm-1): 3436, 2940, 1668, 1541, 1493; ESI-MS: 489.21 [M+H]+.
N-(1-(4-fluorobenzyl)piperidin-3-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(33)
A white solid, yield: 56%, mp: 137.9-140.0℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.57(s, 1H, CONH-N=), 8.24(d, J =7.86 Hz, 1H, ArH), 8.07-8.05(m, 1H, ArH), 7.95(d, J =8.04Hz, 1H, ArH), 7.87(td, J =7.68, 0.96Hz, 1H, ArH), 7.80(t, J =7.50Hz, 1H, ArH), 7.52 (d, J =5.70Hz, 1H, ArH), 7.43(s, 1H, CONH), 7.32(dd, J =1.50, 0.66Hz, 2H, ArH), 7.18(t, J = 9.66Hz, 1H, ArH), 7.16-7.12(m, 2H, ArH), 4.30(s, 2H, PhCH2=N), 3.93-3.88(m, 1H, CH), 3.45(s, 2H, PhCH2), 2.72(d, J =8.88Hz, 1H, NCHH), 2.53(d, J =9.90Hz, 1H, NCHH), 1.99(t, J =7.74Hz, 2H, NCH2), 1.72-1.64 (m, 2H, CH2), 1.50-1.45(m, 1H, CHH), 1.35-1.29(m, 1H, CHH); 13C NMR (150MHz, DMSO-d6) δ:163.14, 162.45, 160.85, 159.81, 159.11, 157.48, 145.36, 134.75, 133.95, 132.84, 132.00, 130.90, 130.50, 129.49, 128.31, 126.50, 125.97, 116.63, 115.36, 61.56, 58.07, 53.07, 46.66, 36.87, 29.89, 23.74; IR (KBr, cm-1): 3430, 2940, 1658, 1520; ESI-MS: 489.21 [M+H]+.
N-(1-(4- methylbenzyl)piperidin-3-yl)-2-fluoro-5-((1,2-dihydro-1-oxophthalazin-4-yl)methyl)benzamide(34)
A white solid, yield: 51%, mp: 187.9-189.1℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.57(s, 1H, CONH-N=), 8.24(d, J =7.86 Hz, 1H, ArH), 8.04(d, J =6.12Hz, 1H, ArH), 7.95(d, J =8.04Hz, 1H, ArH), 7.87(td, J =7.68, 0.96Hz, 1H, ArH), 7.80(t, J =7.38Hz, 1H, ArH), 7.53 (d, J =6.54Hz, 1H, ArH), 7.43-7.41(m, 1H, CONH), 7.19(d, J = 10.08Hz, 1H, ArH), 7.16(d, J = 7.98Hz, 2H, ArH), 7.09(d, J = 7.74Hz, 2H, ArH), 4.30(s, 2H, PhCH2=N), 3.89-3.88(m, 1H, CH), 3.41(s, 2H, PhCH2), 2.68(d, J =7.38Hz, 1H, NCHH), 2.53(d, J =7.80Hz, 1H, NCHH), 2.25(s, 3H, PhCH3), 2.02-1.95 (m, 2H, NCH2), 1.70-1.69(m, 1H, CHH), 1.63-1.61(m, 1H, CHH), 1.49-1.43(m, 1H, CHH), 1.34-1.28 (m, 1H, CHH); 13C NMR (150MHz, DMSO-d6) δ: 163.09, 159.81, 159.13, 157.49, 145.36, 136.33, 135.59, 134.77, 133.95, 132.86, 131.99, 130.53, 129.49, 129.16, 128.31, 126.50, 125.96, 116.63, 116.48, 62.26, 58.05, 53.21, 46.63, 36.87, 29.91, 23.73, 21.13; IR (KBr, cm-1): 3439, 2931, 1660, 1531, 1492; ESI-MS: 485.23 [M+H]+.
1-benzylpiperidin-4-yl 2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-yl)methyl)benzoate (35)
A white solid, yield: 50%, mp: 182.1-183.4℃, 1H NMR (600 MHz, DMSO-d6) δ: 12.61(s, 1H, CONH-N=), 8.25(d, J =7.86 Hz, 1H, ArH), 7.96(d, J =8.04Hz, 1H, ArH), 7.88(td, J =7.68, 0.96Hz, 1H, ArH), 7.82(t, J =7.26Hz, 1H, ArH), 7.77 (dd, J =6.48, 1.44Hz, 1H, ArH), 7.60 (td, J =4.26, 1.44Hz, 1H, ArH), 7.31-7.25(m, 5H, ArH), 7.23-7.21(m, 1H, ArH), 4.94-4.93(m, 1H, OCH), 4.36(s, 2H, PhCH2=N), 3.43(s, 2H, PhCH2), 2.47(t, J = 8.82Hz, 2H, NCH2), 2.28(t, J = 9.30Hz, 2H, NCH2), 1.88-1.85(m, 2H, CH2), 1.66-1.64(m, 2H, CH2); 13C NMR (150MHz, DMSO-d6) δ: 163.24, 159.80, 159.32, 145.26, 138.94, 135.86, 134.92, 133.98, 132.02, 131.97, 129.51, 129.13, 128.58, 128.29, 127.28, 126.52, 125.88, 117.67, 117.52, 71.27, 62.45, 50.16, 36.67, 30.68; IR (KBr, cm-1): 3403, 2946, 1677, 1608, 1494; ESI-MS: 472.20 [M+H]+.
1-(4-fluorobenzyl)piperidin-4-yl 2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4-yl)methyl)benzoate (36)
A white solid, yield: 49%, mp: 156.7-157.1℃, 1H NMR (600 MHz, CDCl3) δ: 11.45(s, 1H, CONH-N=), 8.49(d, J =6.66 Hz, 1H, ArH), 7.87(d, J =4.92Hz, 1H, ArH), 7.76-7.71(m, 3H, ArH), 7.40-7.39(m, 1H, ArH), 7.28-7.26(m, 2H, ArH), 7.04(t, J =9.12Hz, 1H, ArH), 6.98(t, J =8.10Hz, 2H, ArH), 5.12-5.04(m, 1H, OCH), 4.31(s, 2H, PhCH2=N), 3.48(s, 2H, PhCH2), 2.64(t, J = 8.92Hz, 2H, NCH2), 2.36(t, J = 9.10Hz, 2H, NCH2), 2.03-1.92(m, 2H, CH2), 1.89-1.79(m, 2H, CH2); 13C NMR (150MHz, CDCl3) δ:163.75, 162.76, 161.68, 160.80, 159.96, 145.58, 134.37, 133.61, 133.33, 131.92, 131.52, 130.54, 128.29, 127.17, 124.96, 119.28, 117.31, 114.92, 109.99, 71.09, 62.15, 50.24, 37.71, 30.63; IR (KBr, cm-1): 3420, 2950, 1713, 1667, 1607, 1501; ESI-MS: 490.19 [M+H]+.