CAB mixture was refluxed for 8 h, and the reaction mixture was 2.2 Hz, 1H, Ar-H), 3.27 (s, 3H, CH3), 2.91(s, 2H evaporated to dryness. The residue was dissolved in CH2CO), 2.70(t, J=7.5 Hz, 2H, CH2), 2.47-2.38(m EtOAC(100 mL), washed with H2O(50 mL), dried, and 10H, CH2), 1.91-1.80(m, 2H, CH2).C-NMR (100 MHz, evaporated to obtain the crude product, which was puri- CDCl3 )8 169.53, 158.81, 156.49, 143.55, 132.88, 129.70 afford tert-butyl 4-(2-cyclohexyl(phenyl)amino)-2 oxethyl) 111.58, 110.26, 109.99, 103.90, 103.67, 59.61, 58.16, piperazine-1-carboxylate 9 as a yellow liquid(4.58 g, yield 53.24, 53.02, 37.49, 27.13, 22.87. ESI-MS m/z 409.2 4%),To a solution of compound 93.0 g, M+H 8.68 mmol) in CH2Cl2 (15 mL was added trifluoroacetic acid(15 mL). The mixture was stirred at room temperature for 12 h, then concentrated, washed with PE and Et2O 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1 separately to yield N-cyclohexyl-N-phenyl-2-(piperazin-1-yl) yl)-N-isopropyl-N-phenylacetamide(11d) acetamide 10 as an off-white solid(2.68 g, yield 90%),(iv) White solid (81 mg, yield 40.5%).H NMR(400 MHZ, A solution of compound 10(0.467 g, 1.17 mmol), com- CDCl3)8 8.04(s, 1H), 7.41 (d, J=6.1 HZ, 3H), 7.26-7.20 pound30.3g,1.17mmo,andK2CO30.324g,(m,2H,7.15-7.06m,2H),7.02(s,1H,6.92td,d=9.1 2.34 mmol)in acetonitrile(20 mL was stirred at 80C for 2.4 Hz, 1H), 5. 10-4.89(m, 1H), 2.75(s, 2H),2.70(t, 12 h, then the reaction mixture was evaporated to dry- J=7.5 Hz, 2H), 2. 48-2.38(m, 10H), 1.93-1.80(m, 2H) ness, water added, and the mixture was extracted with 1.05(d, J=6.8 Hz, 6H).C-NMR(100 MHZ, CDCl3) 8 CH2 Cl2(3×30mlL, washed with brine, dried over anhy.168.72,15881,156.49,137.96,132.88,130.51,129.16 drous Na2SO4, and concentrated. The residue was puri- 128. 37, 128.01, 127.92, 123. 10, 116.44, 116.40, 111.68 fied with flash chromatography on silica gel (CH2Cl2/ 111.58, 110.25, 109.99, 103.90, 103.67, 60.45, 58.17, MeOH, 40/1)to afford compound 11a as an off-white solid 53. 24, 53.26, 53.04, 46.16, 27. 09, 22.86, 20.93 ESI-Ms (0.2 g, yield 35.7%)(17). H NMR(400 MHZ, CDCl3)8 m/z 437.2 [M+HI 8.11(s,1H,NH,7.40(d,J=5.1Hz,3H,Ar-H,7.24(d, J=13.6,8.6Hz,2H,Ar-H,7.11-7.09(m,2H,Ar-+H 7.02(s, 1H, Ar-H), 6.92(t, J=9.0 Hz, 1H, Ar-H), 4.59(t, N-cyclohexyl-2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl) J=12.0Hz,1H,NCH,2.75(s,2H,cH2CO,2.70 piperazin-1-yI)-N-(2-methoxyphenyl)acetamide J=7.5Hz,2H,CH2,2.44m,J=22.1,14.7Hz,10H,(11e) CH2), 1.91-1.81(m, 6H, CH2), 1.72(d, J=13.6 Hz, 3H), White solid(154 mg, yield 43.4%). White solid(160 mg 1.57(d,J=126Hz,1H),1.39(d,J=26.0,12.9Hz,yied433%HNMR(400MHz,cDOD)6741 2H,0.98(m,4H.CMR(100MHz,CDc)5170.38,J=7.8Hz,H,7.250d,J=9.3,4,7Hz,1H,717-7.07 159.94,15763,139.33,134.79,131.56,130.45,12986,(m,3H,7.07(s,1H,7.01(t,J=78H,1H,6.82(d 129.10,12901,124.99,11609,116.04,11296,11287,J=9.0,2.4Hz,1H,4.42(tJ=12.1,35Hz,1H),382 110.38,110.12,104.34,103.81,61.17,5927,56.03,(s,3H,2.81-267m,4H,2.48-2.01m,10H,1.92 3.73,5369,3262,27.99,26.92,26.52,2388.ES|-Ms1.1.74m,5H,1.67(d,J=11.4Hz,1H,1.57(d m/24772M+H J=129Hz,1H),1.42-1.30m,2H,0.960.80(m,3H CNMR(100MHz,CDC6170.86,159.84,157.54 157.47,134.70,132.28,131.46,129.01,128.91,127.89, 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1 124.94,121.86,115.97,115.92,113.13,112.90,11 yl)-N-phenylacetamide(11b) 110.31,110.04,103.98,103.75,60.64,59.26 White solid(150mg,yied40.5%).HNMR(400Mz,5590,5373,5361,3310,30.82,27.96,26.89 CDc)69.13(,1H,8.06(s,1H),7.58-7.56m,2H,26.60,23.84.ES|MSm/z5074M+H 7.34(t,J=7.Hz,2H,7.27-7.23m,2H),7.11( J=7.4H,1H,7.03(,J=1.8Hz,H,6.93td J=9.1, 2. 4 Hz, 1H),3.14(, 2H), 2.75(t, J=7.5 Hz, 2(4-(3-(5-chloro-1H-indol-3-ylpropyl)piperazin-1 3H), 2.68(s, 4H), 2.56(s, 4H), 2.47(t, =8.0 HZ, 2H), yl)-N-cyclohexyl-N-phenylacetamide(11f) 1.94-1.87(m,2H).C-NMR(100 MHZ, CDCl3 8 168.42, White solid(160 mg, yield 43.3%).H NMR(400 MHZ, 15886,156.53,137.64,13288,129.05,128.03,127.94,CDCd8.50(s,1H,7.41-7.40(m,3H,727-724m 124.22,123.06,11947,116.51,116.46,111.69,111.60,2H,7.12(d,J=7.9Hz,1H,7.06-7.03(m,3H,6.90(td 110.37,110.10,103.93,103.70,61.7,58.01,53.52,J=90,1.9H,1H,4.53(,J=12.1H,1H,295-259 5340,27.24,22.79.ES-Msm/z3952M+H m,14H),2082.0m,2H,1.79(d,J=10.7Hz,2H) 1.71(d,J=13.1H,2H,1.55d,J=12.6Hz,1H 141-1.31(m,2H,1.060.84(m,3H).1CNMR 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1 (100MHz,CDCa167.94,158.80,156.47,137.65 yl)-N-methyl-N-phenylacetamide(11c) 13283,130.07,129.49,128.78,127.47,127.37,123.55, White solid(150mg,yied39.5%).HNMR(400MHz,114.07,11200,11191,110.47,110.21,10342,103.19 717m,1H,A-HD,700(,1H,A+,.6.91t.J=9.0,2523,2429,213 ESI-MS m/2472M+6°8,2566 CDCa)806(s,1H,NH),7.45-7.30(m,3H,Ar-+H,7265938,56.91,54.47,51.87,50.61,31.34,29 328 Chem Biol Drug Des 2013: 82: 326-335mixture was refluxed for 8 h, and the reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc (100 mL), washed with H2O (50 mL), dried, and evaporated to obtain the crude product, which was puri- fied by flash chromatography (CH2Cl2/MeOH, 40:1) to afford tert-butyl 4-(2-(cyclohexyl(phenyl)amino)-2- oxoethyl) piperazine-1-carboxylate 9 as a yellow liquid (4.58 g, yield 95.4%), (iii) To a solution of compound 9 (3.0 g, 8.68 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (15 mL). The mixture was stirred at room temperature for 12 h, then concentrated, washed with PE and Et2O separately to yield N-cyclohexyl-N-phenyl-2-(piperazin-1-yl) acetamide10 as an off-white solid (2.68 g, yield 90%), (iv) A solution of compound 10 (0.467 g, 1.17 mmol), com￾pound 3 (0.3 g, 1.17 mmol), and K2CO3 (0.324 g, 2.34 mmol) in acetonitrile (20 mL) was stirred at 80 °C for 12 h, then the reaction mixture was evaporated to dry￾ness, water added, and the mixture was extracted with CH2Cl2 (3 9 30 mL), washed with brine, dried over anhy￾drous Na2SO4, and concentrated. The residue was puri- fied with flash chromatography on silica gel (CH2Cl2/ MeOH, 40/1) to afford compound 11a as an off-white solid (0.2 g, yield 35.7%) (17). 1 H NMR (400 MHz, CDCl3) d 8.11 (s, 1H, NH), 7.40 (d, J = 5.1 Hz, 3H, Ar-H), 7.24 (dd, J = 13.6, 8.6 Hz, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H), 7.02 (s, 1H, Ar-H), 6.92 (t, J = 9.0 Hz, 1H, Ar-H), 4.59 (t, J = 12.0 Hz, 1H, NCH), 2.75 (s, 2H, CH2CO), 2.70 (t, J = 7.5 Hz, 2H, CH2), 2.44 (m, J = 22.1, 14.7 Hz, 10H, CH2), 1.91–1.81 (m, 6H, CH2), 1.72 (d, J = 13.6 Hz, 3H), 1.57 (d, J = 12.6 Hz, 1H), 1.39 (dd, J = 26.0, 12.9 Hz, 2H), 0.98 (m, 4H).13C-NMR (100 MHz, CDCl3) d 170.38, 159.94, 157.63, 139.33, 134.79, 131.56, 130.45, 129.86, 129.10, 129.01, 124.99, 116.09, 116.04, 112.96, 112.87, 110.38, 110.12, 104.34, 103.81, 61.17, 59.27, 56.03, 53.73, 53.69, 32.62, 27.99, 26.92, 26.52, 23.88. ESI-MS m/z 477.2 [M + H]+ . 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1- yl)-N-phenylacetamide (11b) White solid (150 mg, yield 40.5%). 1 H NMR (400 MHz, CDCl3) d 9.13 (s, 1H), 8.06 (s, 1H), 7.58–7.56 (m, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.27–7.23 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.93 (td, J = 9.1, 2.4 Hz, 1H), 3.14 (s, 2H), 2.75 (t, J = 7.5 Hz, 3H), 2.68 (s, 4H), 2.56 (s, 4H), 2.47 (t, J = 8.0 Hz, 2H), 1.94–1.87 (m, 2H). 13C-NMR (100 MHz, CDCl3) d 168.42, 158.86, 156.53, 137.64, 132.88, 129.05, 128.03, 127.94, 124.22, 123.06, 119.47, 116.51, 116.46, 111.69, 111.60, 110.37, 110.10, 103.93, 103.70, 61.97, 58.01, 53.52, 53.40, 27.24, 22.79. ESI-MS m/z 395.2 [M + H]+ . 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1- yl)-N-methyl-N-phenylacetamide (11c) White solid (150 mg, yield 39.5%). 1 H NMR (400 MHz, CDCl3) d 8.06 (s, 1H, NH), 7.45–7.30 (m, 3H, Ar-H), 7.26– 7.17 (m, 1H, Ar-H), 7.00 (s, 1H, Ar-H), 6.91 (t, J = 9.0, 2.2 Hz, 1H, Ar-H), 3.27 (s, 3H, CH3), 2.91 (s, 2H, CH2CO), 2.70 (t, J = 7.5 Hz, 2H, CH2), 2.47–2.38 (m, 10H, CH2), 1.91–1.80 (m, 2H, CH2). 13C-NMR (100 MHz, CDCl3) d 169.53, 158.81, 156.49, 143.55, 132.88, 129.70, 128.02, 127.92, 127.33, 123.09, 116.48, 116.43, 111.68, 111.58, 110.26, 109.99, 103.90, 103.67, 59.61, 58.16, 53.24, 53.02, 37.49, 27.13, 22.87. ESI-MS m/z 409.2 [M + H]+ . 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1- yl)-N-isopropyl-N-phenylacetamide (11d) White solid (81 mg, yield 40.5%). 1 H NMR (400 MHz, CDCl3) d 8.04 (s, 1H), 7.41 (d, J = 6.1 Hz, 3H), 7.26–7.20 (m, 2H), 7.15–7.06 (m, 2H), 7.02 (s, 1H), 6.92 (td, J = 9.1, 2.4 Hz, 1H), 5.10–4.89 (m, 1H), 2.75 (s, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.48–2.38 (m, 10H), 1.93–1.80 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H). 13C-NMR (100 MHz, CDCl3) d 168.72, 158.81, 156.49, 137.96, 132.88, 130.51, 129.16, 128.37, 128.01, 127.92, 123.10, 116.44, 116.40, 111.68, 111.58, 110.25, 109.99, 103.90, 103.67, 60.45, 58.17, 53.24, 53.26, 53.04, 46.16, 27.09, 22.86, 20.93. ESI-MS m/z 437.2 [M + H]+ . N-cyclohexyl-2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl) piperazin-1-yl)-N-(2-methoxyphenyl)acetamide (11e) White solid (154 mg, yield 43.4%). White solid (160 mg, yield 43.3%). 1 H NMR (400 MHz, CD3OD) d7.41 (t, J = 7.8 Hz, 1H), 7.25 (dd, J = 9.3, 4.7 Hz, 1H), 7.17–7.07 (m, 3H), 7.07(s, 1H), 7.01(t, J = 7.8 Hz, 1H), 6.82(td, J = 9.0, 2.4 Hz, 1H), 4.42 (tt, J = 12.1, 3.5 Hz, 1H), 3.82 (s, 3H), 2.81–2.67 (m, 4H), 2.48–2.01 (m, 10H), 1.92– 1.1.74 (m, 5H), 1.67 (d, J = 11.4 Hz, 1H), 1.57 (d, J = 12.9 Hz, 1H), 1.42–1.30(m, 2H), 0.96–0.80 (m, 3H). 13C-NMR (100 MHz, CDCl3) d 170.86, 159.84, 157.54, 157.47, 134.70, 132.28, 131.46, 129.01, 128.91, 127.89, 124.94, 121.86, 115.97, 115.92, 113.13, 112.90, 112.80, 110.31, 110.04, 103.98, 103.75, 60.64, 59.26, 56.68, 55.90, 53.73, 53.61, 33.10, 30.82, 27.96, 26.89, 26.86, 26.60, 23.84. ESI-MS m/z 507.4 [M + H]+ . 2-(4-(3-(5-chloro-1H-indol-3-yl)propyl)piperazin-1- yl)-N-cyclohexyl-N-phenylacetamide (11f) White solid (160 mg, yield 43.3%). 1 H NMR (400 MHz, CDCl3) d 8.50 (s, 1H), 7.41–7.40 (m, 3H), 7.27–7.24 (m, 2H), 7.12 (d, J = 7.9 Hz, 1H), 7.06–7.03 (m, 3H), 6.90 (td, J = 9.0, 1.9 Hz, 1H), 4.53 (t, J = 12.1 Hz, 1H), 2.95–2.59 (m, 14H), 2.08–2.0 (m, 2H), 1.79 (d, J = 10.7 Hz, 2H), 1.71 (d, J = 13.1 Hz, 2H), 1.55 (d, J = 12.6 Hz, 1H), 1.41–1.31 (m, 2H), 1.06–0.84 (m, 3H). 13C-NMR (100 MHz, CDCl3) d 167.94, 158.80, 156.47, 137.65, 132.83, 130.07, 129.49, 128.78, 127.47, 127.37, 123.55, 114.07, 112.00, 111.91, 110.47, 110.21, 103.42, 103.19, 59.38, 56.91, 54.47, 51.87, 50.61, 31.34, 29.68, 25.66, 25.23, 24.29, 22.13. ESI-MS m/z 477.2 [M + H]+ . 328 Chem Biol Drug Des 2013; 82: 326–335 Du et al