P Zhang er al/ European Joumal of Medicinal Chemistry 61(2013)95-103 4.1.3.4. 2, 3-Dihydro-2-(2-thienyl)-5-cyclohexthylmethyl-1,5-4.1.3.12. 2, 3-Dihydro-2-phenyl-5-(2-nitrobenzyl)-1, 5-benzothiazepin- benzothiazepin-4(5H)-one(6d). Yield: 15%; mp 142.5-1432C H 4(5H)-one(6I). Yield: 75%: mp 186.7-1895C:H NMR(400 MHZ, NMR(100MHz,CDCl3)61706,158.8,1461,1439,136.5,130.1,145.8,1436,1368,133.7,1327,130.7,1296,1288,1280,1278,1274 1294,129.1,128.7,1276,127.5,127.1,1261,1242,552,529.511,1271,1261,1250.1234,529.50.9,49.5,421,29.7;ESl-Ms( positive) 508,421,29.7;ES|Ms( positive):3581(M+1)+ 3909(M+1) 4.1.3.5. 2, 3-Dihydro-2-(2-thienyl)-5-benzoyl-1.5-benzothiazepin- 4.1.3.13. 23-Dihydro-2-phenyl-5-(2-cyanobenzyl-1, 5-benzothiazepin 4(5H)-one(6e). Yield: 89%6: mp 234.8-2356C: H NMR (400 MH 4(5H)-one(6m) Yield: 88%; mp 148.6-1498: H NMR(400 MHZ. CDCh)b826-6.58(m,12H),5.12(dd,J=11.61Hz,1H.3.01(ddd.cDl)b802-696(m.13H)256(d,J=160H,1H),512(d, 1432,1376,1343,133.1.1309,129.6,1286,1285,1269.1266,9.1H2H;CNMR(100MHz,CDl3)61707,1454,1436,138.3 1250,1242,474,43.5:ESMS( positive):366.1(M+1)+ 1368.1326,1316,131.1,1305,1292,1288,1278,127.6,1260,1239 1187,1124.528,511,41.8,31.9,29.7;ESMs( positive)}3708 4.1.3.6. 2,3-Dihydro-2-(2-thienyl)-5-benzyl-1, 5-benzothiazepin-(M+1) 4(5H)-one(6f). Yield: 86% mp 143.7-1451C:H NMR(400 MHz CDCl3)8758-7.15(m, 10H). 6.90-6.88(m, 1H), 5.99(d, J=3.5 HZ, 4.1.3.14. 2,3-Dihydro-2-phenyl-5-(2-flurobenzyl)-1, 5-benzothiazepin H519(d,J=149Hz,1H.5.4(m,1H).501(d,J=149Hz1H).4(5H)-one(6m) Yield:87%;mp1432-1464C:HNMR(400MHz 300(m,1H),285-279(m,1H):1CNMR(100 MHZ. CDCI3)b1701.cDC3)796-657(m,13H,550-495(m,2H),485(d,J=126 1477.14613731370134,13081305,1293,1284,1280,127.3.55H,1H)312-262(m,2H):1CNMR(1o0MHz,CDCl3)d1708, 1271,1267,126.5,1246,123.9,1236.585,51.8,485,429;ESI-MS145.9,143.9,136.5,130.3,130.31,130.27,129.00.128.92,128.76, (positive ) 3521(M+1). 127.69,127.30.127.24,12608,124.13,124.09,12395,123.91,123.76, 11513.11491,5282,44.90.4486,4201.ESMS( positive):3641 4.1.3.7. 2,3-Dihydro-2-(2-furyl)-5-benzyl-1,5-benzothiazepin-4(5H)-(M+ 1). one(6g). Yield: 75% mp 1049-1057C: H NMR(400 MHz, CDCl3) 8 7.47-7.14(m, 10H), 6.26(, 1H), 5.99(d, J=2.4 Hz, 1H), 5.17(d, 4.1.3.15. 2, 3-Dihydro-2-phenyl-5-2-chlorobenzyl) -1,5-benzothiazepin 153H,H.501(dJ=153Hz1H),489(ddJ=59,126Hz,1H.4(5H)one(6o)Yeld:100%;mp1693-1725c;HNMR(400MHz 292-281(m,2H:1CNMR(100 MHz. CDCl3)617041549.1461.CD3)b799-666(m,13H.526(5,2H),489d,J=128,52Hz 1422.137.0,13601303,1284,128012731270,1267,1238,110.3.1H),318-2,74(m,2H;1CMMR(100MHz,CDl3)61709,1460 1053.585,518,459,388;ESl-Ms( positive):336.1(M+1)+ 1438.136.6,1343,1328,130.4,129.3,1290,1288,1284,127.8,1273, 1271,1261,124.5,1236,529.509,49.3,421,297;ESl-Ms( positive) 4.1.3.8. 2, 3-Dihydro-5-benzyl-1,5-benzothiazepin-4(5H)-one (6h). 380.0(M+ 1). Yield:787%;mp1047-1058c:HNMR(400 MHZ. CDC13)6757- 7.55(d, =1.6 Hz, 1H), 7.35-7.19(m, 7H), 7. 16-7.13(m, 1H), 5.18- 4.1.3.16. 2, 3-Dihydro-2-phenyl-5-2-bromobenzyl-1, 5-benzothiazepin- 498(m,2H),3.5-3.3(m,2H,27-25(m,2H:1CNMR(100MHz,4(5H)one(6p)Yeld:71%;mp1686-1704°c;HNMR(400MHz CDCl3)d1720,1464,1372,1359,1299,1283,1282,1279,127.2,CDCl)6791-666(m,13H)524(d,J=46Hz,2H.4.91(s1H,293 124.51.8.34.5,34.2;ES-Ms( positive):270.1(M+1) (dd, J=26.2, 8.9 Hz, 2H): C NMR(100 MHZ, CDC13)6170.8. 146.1 1438,1366.1359,1326,1304,129.0,1288,128.7,1278,127.6,127 4.1.3.9. 2, 3-Dihydro-2-methyl-5-benzyl-1, 5-benzothiazepin-4(5H)- 127.1, 126. 1, 123.6, 122.8, 52.9, 51.9, 42.1, 31.4, 29.7: ESI-MS(positive) one(6)Yeld:79.5%;mp115.6-1179°:HNMR(400MHz,4240.4264(M+1)+ CDCl)76-748(dJ=74Hz,1H),741-718(m,7H),718-7.07(m 1H). 5.16-5.06(d, J= 15.3 Hz, 1H), 5.06-4.88(d, J= 15.3 Hz, 1H). 4.1.3.17. 2,3-Dihydro-2-phenyl-5-(2-methylbenzyl-1, 5-benzothiazepin- 390-355(m,1H).270-2.55(m,1H,2.36-217(m,1H).132-1,264(5H)-one6q)Yeld:85%;mp1332-1346c:HNMR(400MHz (d,J=66Hz,3H);cNMR(100MHz,CDC2)1714,1463,1372 CDCl3)785-671(m,13H.510(dd,J=632.15.9Hz,2H.487(dd, 136.8,1354,130.4,129.8.128.3,128.0,127.6.1272,1268,123.8,51.7, 12.7.5.1Hz,1H),3.10-2.74(m.2H)2.33(5,3H); 451,42.5,24.3;ES-MS(〔 positive):284.2(M+1)+. 100MHz,CD3)6170.6.1464.1440.1365.135.7,1348,1303.1301, 1288.1277,127.3,127.2,1271,1261,1260,1239.585,529,49.7,422 4.1.3. 10. 2, 3-Dihydro-2-(3-pyridyl)-5-benzyl-1,5-benzothiaze 193,184:ESMs( positive3601(M+1)+ 4(5H)-one(6j). Yield: 60%: mp 178.9-1802C: H NMR(400 MH CDCI3)88.52(d, J=4.7 Hz, 1H), 8.43(5, 1H). 7.57(dd, J=2.0 Hz, 4.1.3.18. 2, 3-Dihydro-2-phenmy-5-4-methoxylbenzyl) -1,5-benzothiazepin 78Hz,1H.7.35-700(m,10H,5.32(d,J=160Hz,1H.5.16(d,4(5H)one(6r)Yed:60%;mp1108-1131°;HNMR(400MHz J=16.0Hz,H,3.71(dd,J=5,9.8Hz,1H,3.36(dd,J=5.1,dcb)6807-650(m.7H.5.12(d,J=126,54Hz1H)423(dd 141Hz,1H,2.86(dd,J=9.8,145HzH);1cNMR(100MHz.J=137,78H1H).375(s3H331(ddJ=137.58Hz1H307-246 CDCl3)6165,1504.1482,139.2.137.1366,1329,1291,1288.(m,2H):1CNMR(100MHCD)b1700,1479.1466,1372.1305 1275,127.3,126.2,1240.1234,121.2,1179,489,44.8,320;ES-MS127.0.1267,1266,1265,124.5,1239,123.5,546,509,489,485,431, (positive): 347.2(M+1)*. 37.0, 31.2: ESI-MS(positive): 3761(M+1)+. 4.1.3.11. 2, 3-Dihydro-2-phenyl-5-benzyl-1, 5-benzothiazepin-4(5H)-.1.3.19. 23-Dihydro-2-phenyl-5-3-carboxylbenzyl-1, 5-benzothiazepin ne(6k) Yield: 89%: mp 146.7-1506C: H NMR(400 MHz, -4(5H-one(6s). A solution of 6m(0. 2 g, 0.54 mmol)in conc. HCI(5 ml) CDCl3)8758-7. 14(m, 14H), 5.23(d,J=15.2 Hz), 1H, 5.01(d, was reflux in a sealed tube at 100Cfor 7 h, and then cooled to room J= 15.2 Hz, 1H), 4.88-4.83(m, 1H), 2.94-2.82(m, 2H): C NMR temperature. The pale-yellow precipitate was collected by filtration and (100MHz,CD3)61707.1462.,144.0,1371.1366,1302.128.8. washed with methanol, yield:.70%mp1864-1887c;HNMR 1284,1280.127.7,127.3,127.2,126.1,1241.529,51.8.421;ESMS(400MHz, DMSO-d6)61289(s,1H),788(s,1H).7.74(d.J=76Hz1H) (positive ): 346. 1(M +1). 762-7.16(m11H.544(d,=156H,1H.44(d,J=156Hz,1H,4984.1.3.4. 2,3-Dihydro-2-(2-thienyl)-5-cyclohexthylmethyl-1,5- benzothiazepin-4(5H)-one (6d). Yield: 15%; mp 142.5e143.2 C; 1 H NMR (400 MHz, CDCl3) d 7.84e6.52 (m, 7H), 5.23 (d, J ¼ 15.0 Hz, 1H), 5.08e4.70 (m, 2H), 3.10e2.60 (m, 2H), 1.98e1.08 (m, 11H). 13C NMR (100 MHz, CDCl3) d 170.6, 158.8, 146.1, 143.9, 136.5, 130.1, 129.4, 129.1, 128.7, 127.6, 127.5, 127.1, 126.1, 124.2, 55.2, 52.9, 51.1, 50.8, 42.1, 29.7; ESI-MS (positive): 358.1 (M þ 1)þ. 4.1.3.5. 2,3-Dihydro-2-(2-thienyl)-5-benzoyl-1,5-benzothiazepin- 4(5H)-one (6e). Yield: 89%; mp 234.8e235.6 C; 1 H NMR (400 MHz, CDCl3) d 8.26e6.58 (m, 12H), 5.12 (dd, J ¼ 11.1, 6.1 Hz, 1H), 3.01 (ddd, J ¼ 23.5, 12.3, 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 172.3, 170.3, 143.2, 137.6, 134.3, 133.1, 130.9, 129.6, 128.6, 128.5, 126.9, 126.6, 125.0, 124.2, 47.4, 43.5; ESI-MS (positive): 366.1 (M þ 1)þ. 4.1.3.6. 2,3-Dihydro-2-(2-thienyl)-5-benzyl-1,5-benzothiazepin- 4(5H)-one (6f). Yield: 86%; mp 143.7e145.1 C; 1 H NMR (400 MHz, CDCl3) d 7.58e7.15 (m, 10H), 6.90e6.88 (m, 1H), 5.99 (d, J ¼ 3.5 Hz, 1H), 5.19 (d, J ¼ 14.9 Hz, 1H), 5.14 (m, 1H), 5.01 (d, J ¼ 14.9 Hz, 1H), 3.00 (m, 1H), 2.85e2.79 (m, 1H); 13C NMR (100 MHz, CDCl3) d 170.1, 147.7, 146.1, 137.1, 137.0, 133.4, 130.8, 130.5, 129.3, 128.4, 128.0, 127.3, 127.1, 126.7, 126.5, 124.6, 123.9, 123.6, 58.5, 51.8, 48.5, 42.9; ESI-MS (positive): 352.1 (M þ 1)þ. 4.1.3.7. 2,3-Dihydro-2-(2-furyl)-5-benzyl-1,5-benzothiazepin-4(5H)- one (6g). Yield: 75%; mp 104.9e105.7 C; 1 H NMR (400 MHz, CDCl3) d 7.47e7.14 (m, 10H), 6.26 (s, 1H), 5.99 (d, J ¼ 2.4 Hz, 1H), 5.17 (d, J ¼ 15.3 Hz,1H), 5.01 (d, J ¼ 15.3 Hz,1H), 4.89 (dd, J ¼ 5.9,12.6 Hz,1H), 2.92e2.81 (m, 2H); 13C NMR (100 MHz, CDCl3) d 170.4, 154.9, 146.1, 142.2,137.0, 136.0, 130.3, 128.4,128.0, 127.3, 127.0, 126.7,123.8,110.3, 105.3, 58.5, 51.8, 45.9, 38.8; ESI-MS (positive): 336.1 (M þ 1)þ. 4.1.3.8. 2,3-Dihydro-5-benzyl-1,5-benzothiazepin-4(5H)-one (6h). Yield: 78.7%; mp 104.7e105.8 C; 1 H NMR (400 MHz, CDCl3) d 7.57e 7.55 (d, J ¼ 1.6 Hz, 1H), 7.35e7.19 (m, 7H), 7.16e7.13 (m, 1H), 5.18e 4.98 (m, 2H), 3.5e3.3 (m, 2H), 2.7e2.5 (m, 2H); 13C NMR (100 MHz, CDCl3) d 172.0, 146.4, 137.2, 135.9, 129.9, 128.3, 128.2, 127.9, 127.2, 124.1, 51.8, 34.5, 34.2; ESI-MS (positive): 270.1 (M þ 1)þ. 4.1.3.9. 2,3-Dihydro-2-methyl-5-benzyl-1,5-benzothiazepin-4(5H)- one (6i). Yield: 79.5%; mp 115.6e117.9 C; 1 H NMR (400 MHz, CDCl3) d 7.6e7.48 (d, J ¼ 7.4 Hz, 1H), 7.41e7.18 (m, 7H), 7.18e7.07 (m, 1H), 5.16e5.06 (d, J ¼ 15.3 Hz, 1H), 5.06e4.88 (d, J ¼ 15.3 Hz, 1H), 3.90e3.55 (m, 1H), 2.70e2.55 (m, 1H), 2.36e2.17 (m, 1H), 1.32e1.26 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 171.4, 146.3, 137.2, 136.8, 135.4, 130.4, 129.8, 128.3, 128.0, 127.6, 127.2, 126.8, 123.8, 51.7, 45.1, 42.5, 24.3; ESI-MS (positive): 284.2 (M þ 1)þ. 4.1.3.10. 2,3-Dihydro-2-(3-pyridyl)-5-benzyl-1,5-benzothiazepin- 4(5H)-one (6j). Yield: 60%; mp 178.9e180.2 C; 1 H NMR (400 MHz, CDCl3) d 8.52 (d, J ¼ 4.7 Hz, 1H), 8.43 (s, 1H), 7.57 (dd, J ¼ 2.0 Hz, 7.8 Hz, 1H), 7.35e7.00 (m, 10H), 5.32 (d, J ¼ 16.0 Hz, 1H), 5.16 (d, J ¼ 16.0 Hz, 1H), 3.71 (dd, J ¼ 5.1, 9.8 Hz, 1H), 3.36 (dd, J ¼ 5.1, 14.1 Hz, 1H), 2.86 (dd, J ¼ 9.8, 14.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 166.5, 150.4, 148.2, 139.2, 137.1, 136.6, 132.9, 129.1, 128.8, 127.5, 127.3, 126.2, 124.0, 123.4, 121.2, 117.9, 48.9, 44.8, 32.0; ESI-MS (positive): 347.2 (M þ 1)þ. 4.1.3.11. 2,3-Dihydro-2-phenyl-5-benzyl-1,5-benzothiazepin-4(5H)- one (6k). Yield: 89%; mp 146.7e150.6 C; 1 H NMR (400 MHz, CDCl3) d 7.58e7.14 (m, 14H), 5.23 (d, J ¼ 15.2 Hz), 1H, 5.01 (d, J ¼ 15.2 Hz, 1H), 4.88e4.83 (m, 1H), 2.94e2.82 (m, 2H); 13C NMR (100 MHz, CDCl3) d 170.7, 146.2, 144.0, 137.1, 136.6, 130.2, 128.8, 128.4, 128.0, 127.7, 127.3, 127.2, 126.1, 124.1, 52.9, 51.8, 42.1; ESI-MS (positive): 346.1 (M þ 1)þ. 4.1.3.12. 2,3-Dihydro-2-phenyl-5-(2-nitrobenzyl)-1,5-benzothiazepin- 4(5H)-one (6l). Yield: 75%; mp 186.7e189.5 C; 1 H NMR (400 MHz, CDCl3) d 8.24e6.88 (m, 13H), 5.54 (d, J ¼ 25.7 Hz, 2H), 5.06e4.73 (m, 1H), 3.15e2.74 (m, 2H); 13C NMR (100 MHz, CDCl3) d 171.0, 148.1, 145.8, 143.6, 136.8, 133.7, 132.7, 130.7, 129.6, 128.8, 128.0, 127.8, 127.4, 127.1, 126.1, 125.0, 123.4, 52.9, 50.9, 49.5, 42.1, 29.7; ESI-MS (positive): 390.9 (M þ 1)þ. 4.1.3.13. 2,3-Dihydro-2-phenyl-5-(2-cyanobenzyl)-1,5-benzothiazepin- 4(5H)-one (6m). Yield: 88%; mp 148.6e149.8; 1 H NMR (400 MHz, CDCl3) d 8.02e6.96 (m, 13H), 5.69 (d, J ¼ 16.0 Hz, 1H), 5.12 (d, J ¼ 16.0 Hz, 1H), 4.87 (dd, J ¼ 12.6, 5.6 Hz, 1H), 2.90 (dd, J ¼ 15.9, 9.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 170.7, 145.4, 143.6, 138.3, 136.8, 132.6, 131.6, 131.1, 130.5, 129.2, 128.8, 127.8, 127.6, 126.0, 123.9, 118.7, 112.4, 52.8, 51.1, 41.8, 31.9, 29.7; ESI-MS (positive): 370.8 (M þ 1)þ. 4.1.3.14. 2,3-Dihydro-2-phenyl-5-(2-flurobenzyl)-1,5-benzothiazepin- 4(5H)-one (6n). Yield: 87%; mp 143.2e146.4 C; 1 H NMR (400 MHz, CDCl3) d 7.96e6.57 (m, 13H), 5.50e4.95 (m, 2H), 4.85 (dd, J ¼ 12.6, 5.5 Hz, 1H), 3.12e2.62 (m, 2H); 13C NMR (100 MHz, CDCl3) d 170.8, 145.9, 143.9, 136.5, 130.3, 130.31, 130.27, 129.00, 128.92, 128.76, 127.69, 127.30, 127.24, 126.08, 124.13, 124.09, 123.95, 123.91, 123.76, 115.13, 114.91, 52.82, 44.90, 44.86, 42.01. ESI-MS (positive): 364.1 (M þ 1)þ. 4.1.3.15. 2,3-Dihydro-2-phenyl-5-(2-chlorobenzyl)-1,5-benzothiazepin- 4(5H)-one (6o). Yield: 100%; mp 169.3e172.5 C; 1 H NMR (400 MHz, CDCl3) d 7.99e6.66 (m, 13H), 5.26 (s, 2H), 4.89 (dd, J ¼ 12.8, 5.2 Hz, 1H), 3.18e2.74 (m, 2H); 13C NMR (100 MHz, CDCl3) d 170.9, 146.0, 143.8, 136.6, 134.3, 132.8, 130.4, 129.3, 129.0, 128.8, 128.4, 127.8, 127.3, 127.1, 126.1, 124.5, 123.6, 52.9, 50.9, 49.3, 42.1, 29.7; ESI-MS (positive): 380.0 (M þ 1)þ. 4.1.3.16. 2,3-Dihydro-2-phenyl-5-(2-bromobenzyl)-1,5-benzothiazepin- 4(5H)-one (6p). Yield: 71%; mp 168.6e170.4 C; 1 H NMR (400 MHz, CDCl3) d 7.91e6.66 (m, 13H), 5.24 (d, J ¼ 4.6 Hz, 2H), 4.91 (s, 1H), 2.93 (dd, J ¼ 26.2, 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 170.8, 146.1, 143.8, 136.6, 135.9, 132.6, 130.4, 129.0, 128.8, 128.7, 127.8, 127.6, 127.2, 127.1, 126.1, 123.6, 122.8, 52.9, 51.9, 42.1, 31.4, 29.7; ESI-MS (positive): 424.0, 426.4 (M þ 1)þ. 4.1.3.17. 2,3-Dihydro-2-phenyl-5-(2-methylbenzyl)-1,5-benzothiazepin- 4(5H)-one (6q). Yield: 85%; mp 133.2e134.6 C; 1 H NMR (400 MHz, CDCl3) d 7.85e6.71 (m, 13H), 5.10 (dd, J ¼ 63.2, 15.9 Hz, 2H), 4.87 (dd, J ¼ 12.7, 5.1 Hz, 1H), 3.10e2.74 (m, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) d 170.6, 146.4, 144.0, 136.5, 135.7, 134.8, 130.3, 130.1, 128.8, 127.7, 127.3, 127.2, 127.1, 126.1, 126.0, 123.9, 58.5, 52.9, 49.7, 42.2, 19.3, 18.4; ESI-MS (positive): 360.1 (M þ 1)þ. 4.1.3.18. 2,3-Dihydro-2-phenyl-5-(4-methoxylbenzyl)-1,5-benzothiazepin -4(5H)-one (6r). Yield: 60%; mp 110.8e113.1 C; 1 H NMR (400 MHz, CDCl3) d 8.07e6.50 (m, 7H), 5.12 (dd, J ¼ 12.6, 5.4 Hz, 1H), 4.23 (dd, J ¼ 13.7, 7.8 Hz,1H), 3.75 (s, 3H), 3.31 (dd, J ¼ 13.7, 5.8 Hz,1H), 3.07e2.46 (m, 2H); 13C NMR (100 MHz, CDCl3) d 170.0, 147.9, 146.6, 137.2, 130.5, 127.0, 126.7, 126.6, 126.5, 124.5, 123.9, 123.5, 54.6, 50.9, 48.9, 48.5, 43.1, 37.0, 31.2; ESI-MS (positive): 376.1 (M þ 1)þ. 4.1.3.19. 2,3-Dihydro-2-phenyl-5-(3-carboxylbenzyl)-1,5-benzothiazepin -4(5H)-one (6s). A solution of 6m (0.2 g, 0.54 mmol) in conc. HCl (5 ml) was reflux in a sealed tube at 100 C for 7 h, and then cooled to room temperature. The pale-yellow precipitatewas collected byfiltration and washed with methanol, yield: 70%, mp 186.4e188.7 C; 1 H NMR (400 MHz, DMSO-d6) d 12.89 (s, 1H), 7.88 (s, 1H), 7.74 (d, J ¼ 7.6 Hz, 1H), 7.62e7.16 (m,11H), 5.44 (d, J¼ 15.6 Hz,1H), 4.94 (d, J¼ 15.6 Hz,1H), 4.98 P. Zhang et al. / European Journal of Medicinal Chemistry 61 (2013) 95e103 101